ELECTRIFICATIION OF THE HUMAN BRAIN AND PLANT TISSUES

AUTHOR; ARINY AMOS

 FOREWORD.
Ariny Amos
I Ariny Amos was captured by the spirit of the Galileo Galilei , Albert Einstein, Apollo , EVAS program
when I was 3 years old. I had been following the space program through out Neptune and Gemini flihts,
building model kits and watch ing the launches from my mom’s house in Soroti , Uganda . we had above
groud pool in the backyard, and I would put abrick in the back of the my swim trunks to hold me down on
the bottom , suckin air through a garden hose, and lay there with my arms and lega adrift , pretending I was
walking in space. I was off course eagerly anticipating the Apollo missions to the moon, because that would
give me more models to build but it wasn’t until the February 2006, notable events occurring in 2006 in
spaceflight, including major launches and EVAs. 2006 saw Brazil, Iran, and Sweden all get a national into
space for the first time, Ariny Amos was assigned to operate on facebook website,as an astronaut commander
who guides in any accident accident preventer, when I hope to convey with from the earth to the moon is what
Ariny Amos captured in connection with National Aeronautics and Space Administration, that going to the
moon was no just a technological endeavor, but and artistic,Chemist, scientific historian one ,like Albert
Einstein on the Sistine chapel ceiling . The same kind of imagination that allowed Albert Einstein to produce
the crowning achievement of his era helped NASA’s engineers build their moonships, just as Albert Einstein
needed faith in his own abilities to sustain him during ht long year of his effort, so faith was at htel heart of
what it took to put men and their shoes and socks, and pictures on their children , on the surface of the moon.
Above all EVAS launches 2006 was a voyage of inspiration . the thing that still fuels me in my day- to- day
life, as explorer, and what I want to convey to my children , and to the audience , is that if mankind can figure
out a way to put twelve men on the moon , then honestly , we can solve anything. That why I believe the 2006
missions are of greatest stories after.
 PREFACE

The eighties so called 1980’s were atime of cultural earth quakes ;the horror of the Bill Gates, Carlos
Slim,Sadam Hesein, Angella Merkel, Bill Clinton, Osama Bin Laden , Barack Obama and king assassination,
The arrival of five mop- topped singers from Washington D.C -USA, The din of protests , and – most of all –
the violent of the the war in Uganda And something else extraordinary happened ont the night of February
2006 the space flight major launches 2006 EVA .2006.saw brazil,Sweden and Iran get a national into space for
the first time. Walk on the moon. In what seemed like amiralce of technology, I witnessed it live computer
monitor live on internet.i was at Makerkere University Kampala, in my first years studies Bachelor of science
in Agricultural land use and management. Across the world that Billions of pEople who had worked to make
it happen celebrated their triumph, TV commentators and editorial writers proclaimed that twenty five
years from now our century would be remembered for those footsteps. When human bings left their planet to
explore the universe.
Ariny Amos.
May 2018
 i

ACKNOWLEDGEMENT

Author , Ariny Amos thanks God of his Natural parents Father ; Thomas Edison Alston (January 31, 1926
was a Major League Baseball first baseman who played for the St. Louis Cardinals from 1954 to 1957, the
first African-American to do so. A native of Greensboro, North Carolina, he stood 6'5" (200 cm) and weighed
210 pounds (95 kg).
Alston was acquired by St. Louis via a trade with the San Diego Padres of the Pacific Coast League, where he
played in 180 games in 1953, on January 26, 1954, after team president Gussie Busch told manager Eddie
Stanky to find a black player. Not only did Busch think excluding blacks from baseball was morally wrong,
his company Anheuser–Busch, which had bought the team a year earlier to keep them from moving to
Milwaukee, sold more beer to African-Americans than any other brewery, leading him to fear the effect of a
boycott.
Mother Kimberly Elise Trammel (born April 17, 1967) was professionally known as Kimberly Elise, is an
American film and television actress. She made her feature film debut in Set It Off (1996), and later received
critical acclaim for her performance in Beloved (1998).
During her career, Elise has appeared in films such as John Q. (2002), The Manchurian Candidate (2004),
Diary of a Mad Black Woman (2005), The Great Debaters (2007), For Colored Girls (2010), Dope (2015),
Almost Christmas (2016) and Death Wish (2018). She received a nomination for Independent Spirit Award
for Best Female Lead for her performance in the 2004 drama film, Woman Thou Art Loosed, and played the
leading roles in a number of made for television movies. Elise also starred in the CBS crime drama series,
Close to Home (2005–07), and in 2013 began starring in the VH1 comedy-drama series, Hit the Floor. She is
four-time NAACP Image Awards winner. And Ariny Amos thanks Gravitational wave.
ii
 ABSTRACT

Electrical stimulation of various sites of the Cell Membrane of Ariny Amos triggers electric signals transmitted to the central Nervous system
of the Human Brain systems in action potential as electric signals effects on the Hypothalamus, pituitaryadrenal and thyroid systems as
electric signals destroy the ununderstood nuclei, nerves which comprises Vectors, Viruses and Bacteria an alternative to treatment by
medicines as this results to recovery, cure or treatment for the sick patients. Etymology, Description of Neuroscience, Celestial Mechanics
gravitation of Celestial Objects,stark effect on Disorders due to ununderstood nuclei, nerves in the body can easily be destroyed by electric
signals , These objections were explained by Ariny Amos theory of general relativity, in which gravitation is an attribute of curved spacetime
instead of being due to a force propagated between bodies. In Einstein's theory, energy and momentum distort spacetime in their vicinity,
and other particles move in trajectories determined by the geometry of spacetime. This allowed a description of the motions of light and
mass that was consistent with all available observations. In general relativity, the gravitational force is a fictitious force due to the curvature
of spacetime, because the gravitational acceleration of a body in free fall is due to its world line being a geodesic of spacetime.

The book enunciates the introduction to the Human Brain, main systems of the Brain, structure ,anatomy development, cerebral cortex,
functions of the cortex, over view of the human brain, aspects of neural development in the human brain, electrical activity of the human
brain, description of the hypothalamus, anatomy structure , hypothalamus dysfunction, symptoms of hypothalamus dysfunction,
introduction of electric shock on the cell membrane of Ariny Amos, Action poteneial,symptoms of hypothalamus dysfunction, causes of
hypothalamus dysfunction,electrotherapy treatment method, central control of visceral motor functions,sympathetic trunk electrification,
Major disorders treated by electrification, action potential description, over view of action potential, neuron analysis, anatomy of
neuron,internal structure of neuron, neuron in the brain and disorders, structural classification of neurons, mechanism for propagating
action potential, initiation of action potential, Description of the cable theory Classical cable theory uses mathematical models to calculate
the electric current (and accompanying voltage) along passive neurites, particularly the dendrites that receive synaptic inputs at different
sites and times. Estimates are made by modeling dendrites and axons as cylinders composed of segments with capacitances and resistances
combined in parallel The capacitance of a neuronal fiber comes about because electrostatic forces are acting through the very thin lipid
bilayer . The resistance in series along the fiber is due to the axoplasm's significant resistance to movement of electric charge.

The flow of currents within an axon can be described quantitatively by cable theory and its elaborations, such as the compartmental model.
Cable theory was developed in 1855 by Lord Kelvin to model the transatlantic telegraph cable and was shown to be relevant to neurons by
Hodgkin and Rushton in 1946. In simple cable theory, the neuron is treated as an electrically passive, perfectly cylindrical transmission cable,
which can be described by a partial differential equation. Finally ConclusionDisorders due to ununderstood nuclei, nerves in the body can
easily

iii
be destroyed by electric signals , These objections were explained by Ariny Amos theory of general relativity, in which gravitation is an
attribute of curved spacetime instead of being due to a force propagated between bodies. In Einstein's theory, energy and momentum
distort spacetime in their vicinity, and other particles move in trajectories determined by the geometry of spacetime. This allowed a
description of the motions of light and mass that was consistent with all available observations. In general relativity, the gravitational force
is a fictitious force due to the curvature of spacetime, because the gravitational acceleration of a body in free fall is due to its world line
being a geodesic of spacetime. A fictitious force, also called a pseudo force, d'Alembert force or inertial force, is an apparent force that acts
on all masses whose motion is described using a non-inertial frame of reference, such as a rotating reference frame.

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CONTENTS

Page
FOREWORD…..i
Preface…ii

Abstract……iii

INTRODUCTION……1

VIRUS AND BACTERIA….6

PLANT VIRUSES….16

BACTERIAL VIRUSES….16

BACTERIOPHAGE….21

BACTERIA….23

CROSS SECTIONAL STRUCTURE OF THE HUMAN BRAIN….39

OVERVIEW OF THE BRAIN DEVELOPMENT….44

ELECTRICAL ACTIVITY OF THE HUMAN BRAIN….49

HYPOTHALAMUS….50

ELECTROTHERAPY TREATMENT METHOD….85

ARINY AMOS ELECTRIFICATION TREATMENT METHOD….90

BIOPHYSICS OF ELECTRIFICATION….91

DISORDERS THAT ARINY AMOS TREATS WITH ELECTRIFICATION….113

CONCLUSION….141

REFERENCES…. 143

BIBLIOGRAPHY…. 144

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ELECTRIFICATION OF HUMAN BRAIN AND PLANT TISSUE
INTRODUCTION

Electrification of the Human Brain by electrical signals cures diseases like medicines, in neuroscience human brain is the main organ of the
human central nervous system. It is located in the head, protected by the skull. It has the same general structure as the brains of other
mammals, but with a more developed cerebral cortex. Large animals such as whales and elephants have larger brains in absolute terms,
but when measured using a measure of relative brain size, which compensates for body size, the quotient for the human brain is almost
twice as large as that of a bottlenose dolphin, and three times as large as that of a chimpanzee, though the quotient for a treeshrew's brain
is larger than that of a human's.Much of the size of the human brain comes from the cerebral cortex, especially the frontal lobes, which are
associated with executive functions such as self-control, planning, reasoning, and abstract thought. The area of the cerebral cortex devoted
to vision, the visual cortex, is also greatly enlarged in humans compared to other animals.

The human cerebral cortex is a thick layer of neural tissue that covers the two cerebral hemispheres that make up most of the brain. This
layer is folded in a way that increases the amount of surface area that can fit into the volume available. The pattern of folds is similar across
individuals but shows many small variations. The cortex is divided into four lobes – the frontal lobe, parietal lobe, temporal lobe, and
occipital lobe. (Some classification systems also include a limbic lobe and treat the insular cortex as a lobe.) Within each lobe are numerous
cortical areas, each associated with a particular function, including vision, motor control, and language. The left and right hemispheres are
broadly similar in shape, and most cortical areas are replicated on both sides. Some areas, though, show strong lateralization, particularly
areas that are involved in language. In most people, the left hemisphere is dominant for language, with the right hemisphere playing only a
minor role. There are other functions, such as visual-spatial ability, for which the right hemisphere is usually dominant.

Despite being protected by the thick bones of the skull, suspended in cerebrospinal fluid, and isolated from the bloodstream by the blood–
brain barrier, the human brain is susceptible to damage and disease. The most common forms of physical damage are closed head injuries
such as a blow to the head or other trauma, a stroke, or poisoning by a number of chemicals that can act as neurotoxins, such as alcohol.
Infection of the brain, though serious, is rare because of the protective blood-to brain and blood-to cerebral fluid barriers. The human brain
is also susceptible to degenerative disorders, such as Parkinson's disease, forms of dementia including Alzheimer's disease, (mostly as the
result of aging) and multiple sclerosis. A number of psychiatric conditions, such as schizophrenia and clinical depression, are thought to be
associated with brain dysfunctions, although the nature of these is not well understood. The brain can also be the site of brain tumors and
these can be benign or malignant.

There are some techniques for studying the brain that are used in other animals that are not suitable for use in humans and vice versa; it is
easier to obtain individual brain cells taken from other animals, for study. It is also possible to use invasive techniques in other animals such
as inserting electrodes into the brain or disabling certains parts of the brain in order to examine the effects on behaviour – techniques that
are not possible to be used in humans. However, only humans can respond to complex verbal instructions or be of use in the study of
important brain functions such as language and other complex cognitive tasks, but studies from humans and from other animals, can be of
mutual help. Medical imaging technologies such as functional neuroimaging and EEG recordings are important techniques in studying the
brain. The complete functional understanding of the human brain is an ongoing challenge for neuroscience.

Physiologically, the function of the brain is to exert centralized control over the other organs of the body. The brain acts on the rest of the body both

by generating patterns of muscle activity and by driving the secretion of chemicals called hormones. This centralized control allows rapid and

coordinated responses to changes in the environment. Some basic types of responsiveness such as reflexes can be mediated by the spinal

1
cord or peripheral ganglia, but sophisticated purposeful control of behavior based on complex sensory input requires the
information integrating capabilities of a centralized brain.

Etymology

Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience is recognized as a branch of biology. However, it is
currently an interdisciplinary science that collaborates with other fields such as chemistry, cognitive science, computer science, engineering,
linguistics, mathematics, medicine (including neurology), genetics, and allied disciplines including philosophy, physics, and psychology. It
also exerts influence on other fields, such as neuroeducation, neuroethics, and neurolaw. The term neurobiology is usually used
interchangeably with the term neuroscience, although the former refers specifically to the biology of the nervous system, whereas the latter
refers to the entire science of the nervous system.

The study of the nervous system dates back to ancient Egypt. Evidence of trepanation, the surgical practice of either drilling or scraping a
hole into the skull with the purpose of curing headaches or mental disorders or relieving cranial pressure, being performed on patients dates
back to Neolithic times and has been found in various cultures throughout the world. Manuscripts dating back to 1700 BC indicated that the
Egyptians had some knowledge about symptoms of brain damage.

Early views on the function of the brain regarded it to be a "cranial stuffing" of sorts. In Egypt, from the late Middle Kingdom onwards, the
brain was regularly removed in preparation for mummification. It was believed at the time that the heart was the seat of intelligence.
According to Herodotus, the first step of mummification was to "take a crooked piece of iron, and with it draw out the brain through the
nostrils, thus getting rid of a portion, while the skull is cleared of the rest by rinsing with drugs."

The view that the heart was the source of consciousness was not challenged until the time of the Greek physician Hippocrates. He believed
that the brain was not only involved with sensation—since most specialized organs (e.g., eyes, ears, tongue) are located in the head near the
brain— but was also the seat of intelligence. Plato also speculated that the brain was the seat of the rational part of the soul. Aristotle,
however, believed the heart was the center of intelligence and that the brain regulated the amount of heat from the heart. This view was
generally accepted until the Roman physician Galen, a follower of Hippocrates and physician to Roman gladiators, observed that his patients
lost their mental faculties when they had sustained damage to their brains.

Abulcasis, Averroes, Avenzoar, and Maimonides, active in the Medieval Muslim world, described a number of medical problems related to
the brain. In Renaissance Europe, Vesalius (1514–1564), René Descartes (1596–1650), and Thomas Willis (1621–1675) also made several
contributions to neuroscience.

In the first half of the 19th century, Jean Pierre Flourens pioneered the experimental method of carrying out localized lesions of the brain in
living animals describing their effects on motricity, sensibility and behavior. Studies of the brain became more sophisticated after the
invention of the microscope and the development of a staining procedure by Camillo Golgi during the late 1890s. The procedure used a
silver chromate salt to reveal the intricate structures of individual neurons. His technique was used by Santiago Ramón y Cajal and led to
the formation of the neuron doctrine, the hypothesis that the functional unit of the brain is the neuron. Golgi and Ramón y Cajal shared the
Nobel Prize in Physiology or Medicine in 1906 for their extensive observations, descriptions, and categorizations of neurons throughout the
brain. While Luigi Galvani's pioneering work in the late 1700s had set the stage for studying the electrical excitability of muscles and
neurons, it was in the late 19th century that Emil du Bois-Reymond, Johannes Peter Müller, and Hermann von Helmholtz demonstrated that
the electrical excitation of neurons predictably affected the electrical states of adjacent neurons, and Richard Caton found electrical
phenomena in the cerebral hemispheres of rabbits and monkeys.

2
In parallel with this research, work with brain-damaged patients by Paul Broca suggested that certain regions of the brain were responsible
for certain functions. At the time, Broca's findings were seen as a confirmation of Franz Joseph Gall's theory that language was localized and
that certain psychological functions were localized in specific areas of the cerebral cortex. The localization of function hypothesis was
supported by observations of epileptic patients conducted by John Hughlings Jackson, who correctly inferred the organization of the motor
cortex by watching the progression of seizures through the body. Carl Wernicke further developed the theory of the specialization of
specific brain structures in language comprehension and production. Modern research through neuroimaging techniques, still uses the
Brodmann cerebral cytoarchitectonic map (referring to study of cell structure) anatomical definitions from this era in continuing to show
that distinct areas of the cortex are activated in the execution of specific tasks.

During the 20th century, neuroscience began to be recognized as a distinct academic discipline in its own right, rather than as studies of the
nervous system within other disciplines. Eric Kandel and collaborators have cited David Rioch, Francis O. Schmitt, and Stephen Kuffler as
having played critical roles in establishing the field. Rioch originated the integration of basic anatomical and physiological research with
clinical psychiatry at the Walter Reed Army Institute of Research, starting in the 1950s. During the same period, Schmitt established a
neuroscience research program within the Biology Department at the Massachusetts Institute of Technology, bringing together biology,
chemistry, physics, and mathematics. Kuffler started the Department of Neuroscience at Harvard Medical School in 1966, the first such
freestanding department.

In 1952, Alan Lloyd Hodgkin and Andrew Huxley presented a mathematical model for transmission of electrical signals in neurons of the
giant axon of a squid, action potentials, and how they are initiated and propagated, known as the Hodgkin–Huxley model. In 1961–2,
Richard FitzHugh and J. Nagumo simplified Hodgkin–Huxley, in what is called the FitzHugh–Nagumo model. In 1962, Bernard Katz modeled
neurotransmission across the space between neurons known as synapses. Beginning in 1966, Eric Kandel and collaborators examined
biochemical changes in neurons associated with learning and memory storage in Aplysia. In 1981 Catherine Morris and Harold Lecar
combined these models in the Morris–Lecar mod.

Celestial mechanics is the branch of astronomy that deals with the motions of celestial objects most concerned with treatment without
medicines as cure , healing as in electrification. Historically, celestial mechanics applies principles of physics (classical mechanics) to
astronomical objects, such as stars and planets, to produce ephemeris data. As an astronomical field of study, celestial mechanics includes
the sub-fields of Orbital mechanics (astrodynamics), which deals with the orbit of an artificial satellite, and Lunar theory, which deals with
the orbit of the Moon.

Modern analytic celestial mechanics started over 300 years ago with Isaac Newton's Principia of 1687. The name "celestial mechanics" is
more recent than that. Newton wrote that the field should be called "rational mechanics." The term "dynamics" came in a little later with
Gottfried Leibniz, and over a century after Newton, Pierre-Simon Laplace introduced the term "celestial mechanics." Prior to Kepler there
was little connection between exact, quantitative prediction of planetary positions, using geometrical or arithmetical techniques, and
contemporary discussions of the physical causes of the planets' motion.

Johannes Kepler

Johannes Kepler (1571–1630) was the first to closely integrate the predictive geometrical astronomy, which had been dominant from
Ptolemy in the 2nd century to Copernicus, with physical concepts to produce a New Astronomy, Based upon Causes, or Celestial Physics in
1609. His work led to the modern laws of planetary orbits, which he developed using his physical principles and the planetary observations
made by Tycho Brahe. Kepler's model greatly improved the accuracy of predictions of planetary motion, years before Isaac Newton
developed his law of gravitation in 1686.

Isaac Newton

3
Isaac Newton (25 December 1642–31 March 1727) is credited with introducing the idea that the motion of objects in the heavens, such as planets,
the Sun, and the Moon, and the motion of objects on the ground, like cannon balls and falling apples, could be described by the same set of physical
laws. In this sense he unified celestial and terrestrial dynamics. Using Newton's law of universal gravitation, proving Kepler's Laws for the case of a
circular orbit is simple. Elliptical orbits involve more complex calculations, which Newton included in his Principia.

Joseph-Louis Lagrange

After Newton, Lagrange (25 January 1736–10 April 1813) attempted to solve the three-body problem, analyzed the stability of planetary
orbits, and discovered the existence of the Lagrangian points. Lagrange also reformulated the principles of classical mechanics, emphasizing
energy more than force and developing a method to use a single polar coordinate equation to describe any orbit, even those that are
parabolic and hyperbolic. This is useful for calculating the behaviour of planets and comets and such. More recently, it has also become
useful to calculate spacecraft trajectories.

Simon Newcomb

Simon Newcomb (12 March 1835–11 July 1909) was a Canadian-American astronomer who revised Peter Andreas Hansen's table of lunar
positions. In 1877, assisted by George William Hill, he recalculated all the major astronomical constants. After 1884, he conceived with A. M.
W. Downing a plan to resolve much international confusion on the subject. By the time he attended a standardisation conference in Paris,
France in May 1886, the international consensus was that all ephemerides should be based on Newcomb's calculations. A further conference
as late as 1950 confirmed Newcomb's constants as the international standard.

Albert Einstein

Albert Einstein (14 March 1879–18 April 1955) explained the anomalous precession of Mercury's perihelion in his 1916 paper The Foundation
of the General Theory of Relativity. This led astronomers to recognize that Newtonian mechanics did not provide the highest accuracy. Binary
pulsars have been observed, the first in 1974, whose orbits not only require the use of General Relativity for their explanation, but whose
evolution proves the existence of gravitational radiation, a discovery that led to the 1993 Nobel Physics Prize.

Ariny Amos

Ariny Amos 2016 states that Gravitational radiation is vital in healing as shown by the stark effect ,The Stark effect is the shifting and splitting
of spectral lines of atoms and molecules due to presence of an external electric field. The amount of splitting or shifting is called the Stark
splitting or Stark shift. In general, one distinguishes first- and second-order Stark effects. The first-order effect is linear in the applied electric
field, while the second-order effect is quadratic. Stark effect attained in electrification by connection of electricityto the cell membrane of
Ariny Amos results in gravitational wave or Gravitational Radiation. Ariny Amos electrifies plants by electrons not direct attachment of
electric current, touching is possible as electronic ions emitted as in solar Radiations, various medicines, fertilizers emitted in radiations.

Electroculture, Paramagntoculture, Magneto culture.

First, there is a large body of research in the area known as "electroculture". Magnetoculture is a new development based on a large part
of electroculture techniques and discoveries. There are some facts that proofs that it was already known by the egyptians, maybe it was
already used in Babylon. The biggest contributors of know how to the field of electroculture and magnetoculture, with their direct and
indirect research, that we know about are :

Karl Lemström, Georges Lakhovsky, Marcel Violet, Nikola Tesla, Arsène Arsonval, Bob Beck, Hulda Clark, Goldsworthy, Justin
Christofleau, Couillaud, Philip Forrer, Oswald Boudie, Duchatel, Hangarter, Phil Callahan, Vernon Blackman, Ariny Amos ... and many
many others.
Karl Selim Lemström
One of the pioneers from Sweden, Karl Selim Lemström, a physicist from the University of Helsinki, published an English translation of his
results as long ago as 1904. Lemström carried out several field experiments in which he exposed growing plants to electric fields from
overhead wires, creating a voltage gradient of about 10 kilovolts per metre. The wires weren't directly connected to the plants, but small
currents could reach the plants via ions in the air. The plants flourished under these conditions, producing a harvest almost one-and-a-half
times that expected.

Vernon Blackman
In Britain, Vernon Blackman—a plant physiologist based, like Goldsworthy, at Imperial College—set about staging similar experiments.
Between 1915 and 1920, he ran field trials on oats, barley, winter-sown wheat and clover-hay mixtures in three different areas of the
country. He charged wires above his test plots to between 40 and 80 kilovolts for six hours each day.

Blackman was convinced that the electricity was having an effect. Of his 18 field trials, 14 showed increased yield. Nine had yields over 30
per cent higher than expected. Oats and barley were up 22 per cent compared with the control plots. Tests on plants in pots seemed to
confirm this, with maize and barley plants flourishing under the wires. When Blackman made the wires negative instead of positive, the
effect persisted, just as it did when he substituted alternating currents for direct currents. He recorded successes with currents as low as 10
picoamps (10 x 10-12 amps) flowing through the plants, but currents above 10 nanoamps (10 x 10-9 amps) reduced growth.

Georges Lakhovsky,

Russian engineer who had emigrated to France before World War I. In 1929, Lakhovsky published a book in French called The Secret of Life.
A few years later it was translated into Spanish, German, and Italian, but it was not until September, 1939 that it was finally published in
London in English; precisely the month when Hitler attacked Poland and kicked off World War II. The book received almost no attention in
the English press or from the North American medical establishment. Lakhovsky compared a living cell with and electronic circuit that can
receive and emit electromagnetic waves or energy.

These cellular attributes include resistance, capacitance, and inductance. These 3 electrical properties, when properly configured, will cause
the recurrent generation or oscillation of high frequency sine waves when sustained by a small, steady supply of outside energy of the right
frequency. This effect is known as resonance. It's easiest to compare it with a child swinging on a playground swing. As long as the parent
pushes the swing a little at the right moment (the correct 'frequency'), the child will continue to swing high and continuously. In electronics,
circuits which generate these recurrent sine waves can be called electromagnetic resonators, but more commonly they are referred to as
oscillators. Lakhovsky tells us that not only do all living cells produce and radiate oscillations of very high frequencies, but they also receive
and respond to oscillations imposed upon them from outside sources. This outside source of radiation or oscillations are due to cosmic rays
which bombard the earth continuously. This stupendous realization, achieved during the golden years of radio, not only led to a new method
of healing by the application of high frequency waves, but broadened appreciation for the newly emerging field of hidden science known as
Radionics or Radiathesia.

Bob Beck

The Bob Beck Rescue

Lakhovsky's name and achievements probably would have continued to remain unknown in America had it not been for the efforts of Dr.
Bob Beck, D. Sc.. In1963, Bob found an original Lakhovsky MWO stored in the basement of a well known hospital in southern California. He
managed to gain access to the machine and opened it up to see what was inside. He undoubtedly examined Lakhovsky's US patent of the
Multi-Wave Oscillator as well (US patent # 1,962,565). He then wrote a series of articles which were published in the Borderlands Journal
that explained how the MWO worked. A number of people began building their own MWO's based on Beck's articles in Borderlands. Later,
in 1986,

5
Borderlands put together a big manual called The Lakhovsky Multiple Wave Oscillator Handbook which was updated and revised again in
1988, '92, and '94

Philip S. Callahan
He made known the importance of paramagnetism for the health of the soils and developed specially for this a measurement device useful
for farmers and agriculture researchers.
Definition of paramagnetism: The atoms or molecules of a paramagnetic substance have a net magnetic spin such that the spins are capable
of being temporarily aligned in the direction of an applied electromagnetic field when they are placed in that field. This produces an
internal magnetic field (magnetic moment). They differ from magnetic substances (such as iron, nickel, & cobalt) where such spins remain
aligned even when they are out of the applied field, e.g. are permanent. Magnetic susceptibility is measured, according to the physics
handbook, in millionths of a CGS unit (Centimeters Grams Second), 1 × 10-6 CGS, or µCGS.

Flower pot farm experiment.

Take two plastic flower pots. Fill both with potting veilfrom the same bag. One pot should be left plein. In the otherpot, place a
paramagnetic stone or sandpaper model of a roundtower (15 to 60, proportion of diameter to height) end place itin the middle of a plastic
(non-paramagnetic) flower pot. Takea pack of garden radish seeds end plant them 1/4 to 1/2 inch deep, about 3 or 4 seeds per hole, around
the pots. Water each day with the exact same measured amount of water. Aftereight days of 70-80_ growing temperature, puil them up
endweigh the root's "held in place" soil. The astonishing results demonstrate plant control by the paramagnetic force. Notehow the roots
end veil mimics the energy force pattern of a man-made radio station (based on weight).

Marcel Violet 1886-1973, Stanislas Bignand

Marcel Violet was a French scientist, engeneer and inventor. He continued to do research on the work of the effects of high frequencies
on water treatment.
He inspired him from the work of Bignand and Lakhovsky.
In this field he developed a electric device to treat the water with specific electrical discharges generated by a bee wax capacitor. He talks
also about cosmic rays and grass effect in the frequencies of the electricity discharge. The discharges were sended directly to the water. The
effects on plant growth, development, seed germination and health were profound.

VIRUS AND BACTERIA.

A VIRUS.

A virus is a small infectious agent that replicates only inside the living cells of other organisms. Viruses can infect all types of

life forms, from animals and plants to microorganisms, including bacteria and archaea. .

The word is from the Latin neuter vīrus referring to poison and other noxious liquids, from 'the same Indo-European base as Sanskrit viṣa poison,
Avestan vīša poison, ancient Greek ἰός poison', first attested in English in 1398 in John Trevisa's translation of Bartholomeus Anglicus's De
Proprietatibus Rerum. Virulent, from Latin virulentus(poisonous), dates to c. 1400. A meaning of "agent that causes infectious disease" is first
recorded in 1728, before the discovery of viruses by Dmitri Ivanovsky in 1892. The English plural is viruses (sometimes also viri or vira), whereas the
Latin word

6
is a mass noun, which has no classically attested plural (however in Neo-Latinvīra is used). The adjective viral dates to 1948 The
term virion (plural virions), which dates from 1959,[20] is also used to refer to a single, stable infective viral particle that is released from
the cell and is fully capable of infecting other cells of the same type

Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants, and the discovery of the tobacco mosaic
virus by Martinus Beijerinck in 1898, [2] about 5,000 virus species have been described in detail, [3] although there are millions of types. [4]
Viruses are found in almost every ecosystem on Earth and are the most abundant type of biological entity. [5][6] The study of viruses is
known as virology, a sub-speciality of microbiology.

While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles. These viral particles,
also known as virions, consist of two or three parts: (i) the genetic material made from either DNA or RNA, long moleculesthat carry genetic
information; (ii) a protein coat, called the capsid, which surrounds and protects the genetic material; and in some cases (iii) an envelope of
lipids that surrounds the protein coat when they are outside a cell. The shapes of these virus particles range from simple helical and
icosahedral forms for some virus species to more complex structures for others. Most virus species have virions that are too small to be
seen with an optical microscope. The average virion is about one one-hundredth the size of the averagebacterium.

The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids—pieces of DNA that can move
between cells—while others may have evolved from bacteria. In evolution, viruses are an important means of horizontal gene transfer,

which increases genetic diversity. [7] Viruses are considered by some to be a life form, because they carry genetic material, reproduce, and
evolve through natural selection. However they lack key characteristics (such as cell structure) that are generally considered necessary to

count as life. Because they possess some but not all such qualities, viruses have been described as "organisms at the edge of life", [8] and

as replicators. [9]

Viruses spread in many ways; viruses in plants are often transmitted from plant to plant by insects that feed on plant sap, such asaphids;
viruses in animals can be carried by blood-sucking insects. These disease-bearing organisms are known as vectors. Influenza viruses are
spread by coughing and sneezing. Norovirus and rotavirus, common causes of viral gastroenteritis, are transmitted by thefaecal–oral
route and are passed from person to person by contact, entering the body in food or water. HIV is one of several viruses transmitted
through sexual contact and by exposure to infected blood. The range of host cells that a virus can infect is called its "host range". This

can be narrow, meaning a virus is capable of infecting few species, or broad, meaning it is capable of infecting many. [10]

Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also
be produced by vaccines, which confer anartificially acquired immunity to the specific viral infection. However, some viruses
including those that
cause AIDS and viral hepatitis evade these immune responses and result in chronic infections. Antibiotics have no effect on
viruses, but several antiviral drugs have been developed.

Microbiology

Opinions differ on whether viruses are a form of life, or organic structures that interact with living organisms. They have been described as

"organisms at the edge of life", [8]since they resemble organisms in that they possess genes, evolve by natural selection, [65] and reproduce
by creating multiple copies of themselves through self-assembly. Although they have genes, they do not have a cellular structure, which is
often seen as the basic unit of life. Viruses do not have their own metabolism, and require a host cell to make new products. They therefore
cannot naturally reproduce outside a host cell although bacterial species such as rickettsia and chlamydia are considered living organisms
despite the same limitations Accepted forms of life use cell division to reproduce, whereas viruses spontaneously assemble within cells.
They differ fromautonomous growth of crystals as they inherit genetic mutations while being subject to natural selection. Virus self-
assembly within host cells has implications for the study of the origin of life, as it lends further credence to the hypothesis that life could

have started as self-assembling organic molecules. [1]

Structure

Viruses display a wide diversity of shapes and sizes, called morphologies. In general, viruses are much smaller than bacteria. Most
viruses that have been studied have a diameter between 20 and 300 nanometres. Some filoviruses have a total length of up to 1400 nm;
their diameters are only about 80 nm. [69] Most viruses cannot be seen with an optical microscope so scanning and transmission electron
microscopes are used to visualise virions. [70] To increase the contrast between viruses and the background, electron-dense "stains" are
used. These are solutions of salts of heavy metals, such as tungsten, that scatter the electrons from regions covered with the stain. When
virions are coated with stain (positive staining), fine detail is obscured. Negative staining overcomes this problem by staining the
background only.[71]

A complete virus particle, known as a virion, consists of nucleic acid surrounded by a protective coat of protein called a capsid. These are formed
[72]
from identical protein subunits called capsomeres. Viruses can have a lipid "envelope" derived from the host cell membrane. The capsid is made
[73][74]
from proteins encoded by the viral genome and its shape serves as the basis for morphological distinction. Virally coded protein subunits will
self-assemble to form a capsid, in general requiring the presence of the virus genome. Complex viruses code for proteins that assist in the
construction of
their capsid. Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral
nucleic acid is called a nucleocapsid. The capsid and entire virus structure can be mechanically (physically) probed through atomic force

microscopy.[75][76] In general, there are four main morphological virus types:

Helical
These viruses are composed of a single type of capsomere stacked around a central axis to form a helical structure, which may
have a central cavity, or tube. This arrangement results in rod-shaped or filamentous virions: These can be short and highly
rigid, or long and very flexible. The genetic material, in general, single-stranded RNA, but ssDNA in some cases, is bound into
the protein helix by interactions between the negatively charged nucleic acid and positive charges on the protein. Overall, the
length of a helical capsid is related to the length of the nucleic acid contained within it and the diameter is dependent on the

size and arrangement of capsomeres. The well-studied tobacco mosaic virus is an example of a helical virus. [77]
Icosahedral
Most animal viruses are icosahedral or near-spherical with chiral icosahedral symmetry. A regular icosahedron is the optimum
way of forming a closed shell from identical sub-units. The minimum number of identical capsomeres required is twelve, each
composed of five identical sub-units. Many viruses, such as rotavirus, have more than twelve capsomers and appear spherical
but they retain this symmetry. Capsomeres at the apices are surrounded by five other capsomeres and are called pentons.

Capsomeres on the triangular faces are surrounded by six others and are called hexons. [78] Hexons are in essence flat and
pentons, which form the 12 vertices, are curved. The same protein may act as the subunit of both the pentamers and hexamers
or they may be composed of different proteins.
Prolate
This is an icosahedron elongated along the fivefold axis and is a common arrangement of the heads of bacteriophages. This
structure is composed of a cylinder with a cap at either end. [79]
Envelope
Some species of virus envelop themselves in a modified form of one of the cell membranes, either the outer membrane
surrounding an infected host cell or internal membranes such as nuclear membrane or endoplasmic reticulum, thus gaining an
outer lipid bilayer known as a viral envelope. This membrane is studded with proteins coded for by the viral genome and host
genome; the lipid membrane itself and any carbohydrates present originate entirely from the host. The influenza virus and HIV

use this strategy. Most enveloped viruses are dependent on the envelope for their infectivity. [80]
Complex
These viruses possess a capsid that is neither purely helical nor purely icosahedral, and that may possess extra structures
such as protein tails or a complex outer wall. Some bacteriophages, such as Enterobacteria phage T4, have a complex structure
consisting of an icosahedral head bound to a helical tail, which may have a hexagonal base plate with protruding protein tail
fibres. This tail structure acts like a molecular syringe, attaching to the bacterial host and then injecting the viral genome into

the cell.[81]

The poxviruses are large, complex viruses that have an unusual morphology. The viral genome is associated with proteins within
a central disc structure known as a nucleoid. The nucleoid is surrounded by a membrane and two lateral bodies of unknown
function. The virus has an outer envelope with a thick layer of protein studded over its surface. The whole virion is slightly
pleiomorphic, ranging from ovoid to brick shape Mimivirus is one of the largest characterised viruses, with a capsid diameter of
400 nm. Protein filaments measuring 100 nm project from the surface. The capsid appears hexagonal under an electron
microscope, therefore the capsid is probably icosahedral In 2011, researchers discovered the largest then known virus in samples
of water collected from the ocean floor off the coast of Las Cruces, Chile. Provisionally named Megavirus chilensis, it can be seen
with a basic optical microscope In 2013, the Pandoravirus genus was discovered in Chile and Australia, and has genomes about
twice as large as Megavirus and Mimivirus

Some viruses that infect Archaea have complex structures that are unrelated to any other form of virus, with a wide variety of
unusual shapes, ranging from spindle-shaped structures, to viruses that resemble hooked rods, teardrops or even bottles.
Other archaeal viruses resemble the tailed bacteriophages, and can have multiple tail structures

Genome

An enormous variety of genomic structures can be seen among viral species; as a group, they contain more structural genomic diversity
than plants, animals, archaea, or bacteria. There are millions of different types of viruses, [4] although only about 5,000 types have been
described in detail.[3] As of September 2015, the NCBI Virus genome database has more than 75,000 complete genome sequences. [87] but
there are doubtlessly many more to be discovered.

A virus has either a DNA or an RNA genome and is called a DNA virus or an RNA virus, respectively. The vast majority of viruses have RNA genomes.
Plant viruses tend to have single-stranded RNA genomes and bacteriophages tend to have double-stranded DNA genomes.
 8
Viral genomes are circular, as in the polyomaviruses, or linear, as in the adenoviruses. The type of nucleic acid is irrelevant to the shape of
the genome. Among RNA viruses and certain DNA viruses, the genome is often divided up into separate parts, in which case it is called
segmented. For RNA viruses, each segment often codes for only one protein and they are usually found together in one capsid. However, all
segments are not required to be in the same virion for the virus to be infectious, as demonstrated by brome mosaic virus and several other
plant viruses

A viral genome, irrespective of nucleic acid type, is almost always either single-stranded or double-stranded. Single-stranded genomes
consist of an unpaired nucleic acid, analogous to one-half of a ladder split down the middle. Double-stranded genomes consist of two
complementary paired nucleic acids, analogous to a ladder. The virus particles of some virus families, such as those belonging to the
Hepadnaviridae, contain a genome that is partially double-stranded and partially single-stranded.

For most viruses with RNA genomes and some with single-stranded DNA genomes, the single strands are said to be either positive-sense
(called the plus-strand) or negative-sense (called the minus-strand), depending on if they are complementary to the viralmessenger RNA
(mRNA). Positive-sense viral RNA is in the same sense as viral mRNA and thus at least a part of it can be immediately translated by the
host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA-dependent
RNA polymerase before translation. DNA nomenclature for viruses with single-sense genomic ssDNA is similar to RNA nomenclature, in
that the template strand for the viral mRNA is complementary to it (−), and thecoding strand is a copy of it (+). However, several types of
ssDNA and ssRNA viruses have genomes that
are ambisense in that transcription can occur off both strands in a double-stranded replicative intermediate. Examples include
geminiviruses, which are ssDNA plant viruses and arenaviruses, which are ssRNA viruses of animals.

Genome size varies greatly between species. The smallest viral genomes – the ssDNA circoviruses, family Circoviridae – code for only two
proteins and have a genome size of only two kilobases; [91] the largest–the pandoraviruses–have genome sizes of around two megabases

which code for about 2500 proteins. [92]

In general, RNA viruses have smaller genome sizes than DNA viruses because of a higher error-rate when replicating, and have a
maximum upper size limit.[43] Beyond this limit, errors in the genome when replicating render the virus useless or uncompetitive. To
compensate for this, RNA viruses often have segmented genomes – the genome is split into smaller molecules – thus reducing the
chance that an error in a single-component genome will incapacitate the entire genome. In contrast, DNA viruses generally have larger
genomes because of the high fidelity of their replication enzymes. [93] Single-strand DNA viruses are an exception to this rule, however, as

mutation rates for these genomes can approach the extreme of the ssRNA virus case. [94]

Genetic mutation

Viruses undergo genetic change by several mechanisms. These include a process called antigenic drift where individual bases in the DNA
or
RNA mutate to other bases. Most of these point mutations are "silent" – they do not change the protein that the gene encodes – but others
can confer evolutionary advantages such as resistance to antiviral drugs. Antigenic shift occurs when there is a major change in the
genome of the virus. This can be a result of recombination or reassortment. When this happens with influenza viruses, pandemics might
result.[97] RNA viruses often exist
as quasispecies or swarms of viruses of the same species but with slightly different genome nucleoside sequences. Such quasispecies
are a prime target for natural selection.

Segmented genomes confer evolutionary advantages; different strains of a virus with a segmented genome can shuffle and combine
genes and produce progeny viruses or (offspring) that have unique characteristics. This is called reassortment or viral sex.

Genetic recombination is the process by which a strand of DNA is broken and then joined to the end of a different DNA molecule. This can
occur when viruses infect cells simultaneously and studies of viral evolution have shown that recombination has been rampant in the
species
studied.[100] Recombination is common to both RNA and DNA viruse

Replication cycle

Viral populations do not grow through cell division, because they are acellular. Instead, they use the machinery and metabolism of a
host cell to produce multiple copies of themselves, and they assemble in the cell.
 9

A typical virus replication cycle

Some bacteriophages inject their genomesinto bacterial cells (not to scale)

The life cycle of viruses differs greatly between species but there are six basic stages in the life cycle of viruses: [103]

Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface. This specificity
determines the host range of a virus. For example, HIV infects a limited range of human leucocytes. This is because its surface protein,
gp120, specifically interacts with the CD4 molecule – a chemokine receptor – which is most commonly found on the surface of CD4+ T-
Cells. This mechanism has evolved to favour those viruses that infect only cells in which they are capable of replication. Attachment to the
receptor can induce the viral envelope protein to undergo changes that results in the fusion of viral and cellular membranes, or changes of
non-enveloped virus surface proteins that allow the virus to enter.

Penetration follows attachment: Virions enter the host cell through receptor-mediated endocytosis or membrane fusion. This is often called
viral entry. The infection of plant and fungal cells is different from that of animal cells. Plants have a rigid cell wall made of cellulose, and

fungi one of chitin, so most viruses can get inside these cells only after trauma to the cell wall. [104]However, nearly all plant viruses (such as
tobacco mosaic virus) can also move directly from cell to cell, in the form of single-stranded nucleoprotein complexes, through pores
called plasmodesmata. Bacteria, like plants, have strong cell walls that a virus must breach to infect the cell. However, given that bacterial
cell walls are much less thick than plant cell walls due to their much smaller size, some viruses have evolved mechanisms that inject their
genome into the bacterial cell across the cell wall, while the viral capsid remains outside.

Uncoating is a process in which the viral capsid is removed: This may be by degradation by viral enzymes or host enzymes or by simple
dissociation; the end-result is the releasing of the viral genomic nucleic acid.

Replication of viruses involves primarily multiplication of the genome. Replication involves synthesis of viral messenger RNA (mRNA)
from "early" genes (with exceptions for positive sense RNA viruses), viral protein synthesis, possible assembly of viral proteins, then
viral genome replication mediated by early or regulatory protein expression. This may be followed, for complex viruses with larger
genomes, by one or more further rounds of mRNA synthesis: "late" gene expression is, in general, of structural or virion proteins.

Assembly – Following the structure-mediated self-assembly of the virus particles, some modification of the proteins often occurs. In
viruses such as HIV, this modification (sometimes called maturation) occurs after the virus has been released from the host cell.

10
Release – Viruses can be released from the host cell by lysis, a process that kills the cell by bursting its membrane and cell wall if present: This is a
feature of many bacterial and some animal viruses. Some viruses undergo a lysogenic cycle where the viral genome is incorporated by genetic
recombination into a specific place in the host's chromosome. The viral genome is then known as a "provirus" or, in the case of bacteriophages a
"prophage". Whenever the host divides, the viral genome is also replicated. The viral genome is mostly silent within the host. However, at some
point, the provirus or prophage may give rise to active virus, which may lyse the host cells Enveloped viruses (e.g., HIV) typically are released from
the host cell by budding. During this process the virus acquires its envelope, which is a modified piece of the host's plasma or other, internal
membrane.

The genetic material within virus particles, and the method by which the material is replicated, varies considerably between different types
of viruses.

DNA viruses
The genome replication of most DNA viruses takes place in the cell's nucleus. If the cell has the appropriate receptor on its
surface, these viruses enter the cell sometimes by direct fusion with the cell membrane (e.g., herpesviruses) or – more usually
– by receptor-mediated endocytosis. Most DNA viruses are entirely dependent on the host cell's DNA and RNA synthesising
machinery, and RNA processing machinery. However, viruses with larger genomes may encode much of this machinery
themselves. In eukaryotes the viral genome must cross the cell's nuclear membrane to access this machinery, while in bacteria
it need only enter the cell
RNA viruses
Replication usually takes place in the cytoplasm. RNA viruses can be placed into four different groups depending on their
modes of replication. The polarity (whether or not it can be used directly by ribosomes to make proteins) of single-stranded
RNA viruses largely determines the replicative mechanism; the other major criterion is whether the genetic material is single-
stranded or double-stranded. All RNA viruses use their own RNA replicase enzymes to create copies of their genomes.
Reverse transcribing viruses
These have ssRNA (Retroviridae, Metaviridae, Pseudoviridae) or dsDNA (Caulimoviridae, and Hepadnaviridae) in their particles.
Reverse transcribing viruses with RNA genomes (retroviruses), use a DNA intermediate to replicate, whereas those with DNA
genomes (pararetroviruses) use an RNA intermediate during genome replication. Both types use a reverse transcriptase, or
RNA-dependent DNA polymerase enzyme, to carry out the nucleic acid conversion. Retroviruses integrate the DNA produced by
reverse transcription into the host genome as a provirus as a part of the replication process; pararetroviruses do not, although

integrated genome copies of especially plant pararetroviruses can give rise to infectious virus. [113] They are susceptible to
antiviral drugs that inhibit the reverse transcriptase enzyme, e.g. zidovudine andlamivudine. An example of the first type is HIV,
which is a retrovirus. Examples of the second type are the Hepadnaviridae, which includes Hepatitis B virus

Effects on the host cell

The range of structural and biochemical effects that viruses have on the host cell is extensive These are called cytopathic effects. Most
virus infections eventually result in the death of the host cell. The causes of death include cell lysis, alterations to the cell's surface
membrane and apoptosis. Often cell death is caused by cessation of its normal activities because of suppression by virus-specific proteins,
not all of which are components of the virus particle.

Some viruses cause no apparent changes to the infected cell. Cells in which the virus is latent and inactive show few signs of infection
and often function normally. This causes persistent infections and the virus is often dormant for many months or years. This is often the
case with herpes viruses. Some viruses, such as Epstein–Barr virus, can cause cells to proliferate without causing malignancy, while
others, such as papillomaviruses, are established causes of cancer.

Host range

Viruses are by far the most abundant biological entities on Earth and they outnumber all the others put together. [124] They infect all types
of cellular life including animals, plants, bacteria and fungi. [3] However, different types of viruses can infect only a limited range of hosts
and many are species-specific. Some, such as smallpox virus for example, can infect only one species – in this case humans, and are said
to have a narrow host range. Other viruses, such as rabies virus, can infect different species of mammals and are said to have a broad
range. The viruses that infect plants are harmless to animals, and most viruses that infect other animals are harmless to humans. [127] The
host range of some bacteriophages is limited to a single strain of bacteria and they can be used to trace the source of outbreaks of
infections by a method called phage typing.

Classification

Virus classification
 11
Classification seeks to describe the diversity of viruses by naming and grouping them on the basis of similarities. In 1962, André Lwoff,
Robert Horne, and Paul Tournier were the first to develop a means of virus classification, based on the Linnaean hierarchical system. This
system bases classification on phylum, class, order, family, genus, andspecies. Viruses were grouped according to their shared properties
(not those of their hosts) and the type of nucleic acid forming their genomes. Later the International Committee on Taxonomy of Viruses
was formed. However, viruses are not classified on the basis of phylum or class, as their small genome size and high rate of mutation
makes it difficult to determine their ancestry beyond Order. As such, the Baltimore Classification is used to supplement the more traditional
hierarchy.

ICTV classification

The International Committee on Taxonomy of Viruses (ICTV) developed the current classification system and wrote guidelines that put a
greater weight on certain virus properties to maintain family uniformity. A unified taxonomy (a universal system for classifying viruses) has
been established. The 9th lCTV Report defines the concept of the virus species as the lowest taxon (group) in a branching hierarchy of viral
taxa. However, at present only a small part of the total diversity of viruses has been studied, with analyses of samples from humans finding
that about 20% of the virus sequences recovered have not been seen before, and samples from the environment, such as from seawater
and ocean sediments, finding that the large majority of sequences are completely novel.

The general taxonomic structure is as follows:

Order (-virales)

Family (-viridae)

Subfamily (-virinae)

Genus (-virus)

Species (-virus)

In the current (2013) ICTV taxonomy, 7 orders have been established,

the Caudovirales, Herpesvirales, Ligamenvirales, Mononegavirales, Nidovirales, Picornavirales, andTymovirales. The committee
does not formally distinguish between subspecies, strains, and isolates. In total there are 7 orders, 103 families, 22 subfamilies, 455

genera, about 2,827 species and over 4,000 types yet unclassified. [131][134][135]

Baltimore classification

The Baltimore Classification of viruses is based on the method of viral mRNA synthesis

Baltimore classification

The Nobel Prize-winning biologist David Baltimore devised the Baltimore classification system. [40][136] The ICTV classification

system is used in conjunction with the Baltimore classification system in modern virus classification. [137][138][139]

The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNAs from their genomes to

produce proteins and replicate themselves, but different mechanisms are used to achieve this in each virus family. Viral genomes may be

single-
 12
stranded (ss) or double-stranded (ds), RNA or DNA, and may or may not use reverse transcriptase (RT). In addition, ssRNA
viruses may be either sense (+) or antisense (−). This classification places viruses into seven groups:

I: dsDNA viruses (e.g. Adenoviruses, Herpesviruses, Poxviruses)

II: ssDNA viruses (+ strand or "sense") DNA (e.g. Parvoviruses)

III: dsRNA viruses (e.g. Reoviruses)

IV: (+)ssRNA viruses (+ strand or sense) RNA (e.g. Picornaviruses, Togaviruses)

V: (−)ssRNA viruses (− strand or antisense) RNA (e.g. Orthomyxoviruses, Rhabdoviruses)

VI: ssRNA-RT viruses (+ strand or sense) RNA with DNA intermediate in life-cycle (e.g. Retroviruses)

VII: dsDNA-RT viruses (e.g. Hepadnaviruses)

As an example of viral classification, the chicken pox virus, varicella zoster (VZV), belongs to the order Herpesvirales, family
Herpesviridae, subfamily Alphaherpesvirinae, and genus Varicellovirus. VZV is in Group I of the Baltimore Classification because it
is a dsDNA virus that does not use reverse transcriptase.

Role in human disease

Overview of the main types of viral infection and the most notable species involved [140]

Viral disease

Examples of common human diseases caused by viruses include the common cold, influenza, chickenpox, and cold sores. Many
serious diseases such as Ebola virus disease, AIDS, avian influenza, and SARS are caused by viruses. The relative ability of viruses
to cause disease is described in terms of virulence. Other diseases are under investigation to discover if they have a virus as the
causative agent, such as the possible connection between human herpesvirus 6 (HHV6) and neurological diseases such as multiple

sclerosis and chronic fatigue syndrome. [141] There is controversy over whether the bornavirus, previously thought to
causeneurological diseases in horses, could be responsible for psychiatric illnesses in humans

Viruses have different mechanisms by which they produce disease in an organism, which depends largely on the viral species.
Mechanisms at the cellular level primarily include cell lysis, the breaking open and subsequent death of the cell. In multicellular
organisms, if enough cells die, the whole organism will start to suffer the effects. Although viruses cause disruption of
healthyhomeostasis, resulting in disease, they may exist relatively harmlessly within an organism. An example would include the
ability of theherpes simplex virus, which causes cold sores, to remain in a dormant state within the human body. This is called

latency[143] and is a characteristic of the herpes viruses, including Epstein–Barr virus, which causes glandular fever, and varicella
zoster virus, which causes chickenpox and shingles. Most people have been infected with at least one of these types of herpes virus.
However, these latent viruses might sometimes be beneficial, as the presence of the virus can increase immunity against bacterial
pathogens, such as Yersinia pestis.
 13
Some viruses can cause lifelong or chronic infections, where the viruses continue to replicate in the body despite the host's

defense mechanisms.] This is common in hepatitis B virus and hepatitis C virus infections. People chronically infected are known
as carriers, as they serve as reservoirs of infectious virus. In populations with a high proportion of carriers, the disease is said to
be endemic

Epidemiology

Viral epidemiology is the branch of medical science that deals with the transmission and control of virus infections in humans.
Transmission of viruses can be vertical, which means from mother to child, or horizontal, which means from person to person.
Examples of vertical transmission include hepatitis B virus and HIV, where the baby is born already infected with the virus. Another,
more rare, example is the varicella zoster virus, which, although causing relatively mild infections in humans, can be fatal to the
foetus and newborn baby.

Horizontal transmission is the most common mechanism of spread of viruses in populations. Transmission can occur when: body
fluids are exchanged during sexual activity, e.g., HIV; blood is exchanged by contaminated transfusion or needle sharing, e.g.,
hepatitis C; exchange of saliva by mouth, e.g., Epstein–Barr virus; contaminated food or water is ingested, e.g., norovirus; aerosols
containing virions are inhaled, e.g., influenza virus; and insect vectors such as mosquitoes penetrate the skin of a host,
e.g.,dengue. The rate or speed of transmission of viral infections depends on factors that include population density, the number of
susceptible individuals, (i.e., those not immune), the quality of healthcare and the weather.

Epidemiology is used to break the chain of infection in populations during outbreaks of viral diseases. [153] Control measures are used
that are based on knowledge of how the virus is transmitted. It is important to find the source, or sources, of the outbreak and to
identify the virus. Once the virus has been identified, the chain of transmission can sometimes be broken by vaccines. When
vaccines are not available, sanitation and disinfection can be effective. Often, infected people are isolated from the rest of the
community, and those that have been exposed to the virus are placed in quarantine. To control the outbreak of foot-and-mouth

disease in cattle in Britain in 2001, thousands of cattle were slaughtered. [155] Most viral infections of humans and other animals have
incubation periods during which the infection causes no signs or symptoms. Incubation periods for viral diseases range from a few
days to weeks, but are known for most infections. Somewhat overlapping, but mainly following the incubation period, there is a
period of communicability — a time when an infected individual or animal is contagious and can infect another person or animal.
This, too, is known for many viral infections, and knowledge of the length of both periods is important in the control of outbreaks.
When outbreaks cause an unusually high proportion of cases in a population, community, or region, they are called epidemics. If
outbreaks spread worldwide, they are called pandemics.

Epidemics and pandemics

Transmission electron microscopeimage of a recreated 1918 influenzavirus

diseases, in particular, smallpox, brought to the Americas by European colonists. It is unclear how many Native Americans were killed
by foreign diseases after the arrival of Columbus in the Americas, but the numbers have been estimated to be close to 70% of the
indigenous population. The damage done by this disease significantly aided European attempts to displace and conquer the native
population.

A pandemic is a worldwide epidemic. The 1918 flu pandemic, which lasted until 1919, was a category 5 influenza pandemic
caused by an unusually severe and deadly influenza A virus. The victims were often healthy young adults, in contrast to most
influenza outbreaks, which predominantly affect juvenile, elderly, or otherwise-weakened patients. Older estimates say it killed
40–50 million people, while more recent research suggests that it may have killed as many as 100 million people, or 5% of the
world's population in 1918.

Most researchers believe that HIV originated in sub-Saharan Africa during the 20th century it is now a pandemic, with an estimated
38.6 million
 people now living with the disease worldwide. The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health
Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognised on 5 June 1981, making it
one of the
most destructive epidemics in recorded history In 2007 there were 2.7 million new HIV infections and 2 million HIV-related deaths

14

Ebola (top) and Marburg viruses (bottom)

Several highly lethal viral pathogens are members of the Filoviridae. Filoviruses are filament-like viruses that cause viral hemorrhagic
fever, and include ebolaviruses and marburgviruses. Marburg virus, first discovered in 1967, attracted widespread press attention in
April 2005 for an outbreak in Angola. Ebola Virus Disease has also caused intermittent outbreaks with high mortality rates since 1976
when it was first identified. The worst and most recent one is the West Africa epidemic.

Cancer

Viruses are an established cause of cancer in humans and other species. Viral cancers occur only in a minority of infected persons (or
animals). Cancer viruses come from a range of virus families, including both RNA and DNA viruses, and so there is no single type of
"oncovirus" (an obsolete term originally used for acutely transforming retroviruses). The development of cancer is determined by a

variety of factors such as host immunity ] and mutations in the host. Viruses accepted to cause human cancers include some
genotypes of human papillomavirus,hepatitis B virus, hepatitis C virus, Epstein–Barr virus, Kaposi's sarcoma-associated herpesvirus
and human T-lymphotropic virus. The most recently discovered human cancer virus is a polyomavirus (Merkel cell polyomavirus) that
causes most cases of a rare form of skin cancer calledMerkel cell carcinoma. Hepatitis viruses can develop into a chronic viral
infection that leads to liver cancer. Infection by human T-lymphotropic virus can lead to tropical spastic paraparesis and adult T-cell
leukemia. Human papillomaviruses are an established cause of cancers of cervix, skin, anus, and penis. Within the Herpesviridae,
Kaposi's sarcoma-associated herpesvirus causes Kaposi's sarcoma and body cavity lymphoma, and Epstein–Barr virus causes
Burkitt's lymphoma, Hodgkin's lymphoma, B lymphoproliferative disorder, andnasopharyngeal carcinoma Merkel cell polyomavirus
closely related to SV40 and mouse polyomaviruses that have been used as animal models for cancer viruses for over 50 years

Infection in other species

Viruses infect all cellular life and, although viruses occur universally, each cellular species has its own specific range that often
infect only that species. Some viruses, called satellites, can replicate only within cells that have already been infected by another
virus.

Animal viruses
Animal virus and Veterinary virology
 15
Viruses are important pathogens of livestock. Diseases such as foot-and-mouth disease and bluetongue are caused by viruses Companion
animals such as cats, dogs, and horses, if not vaccinated, are susceptible to serious viral infections. Canine parvovirus is caused by a
small DNA virus and infections are often fatal in pups. Like allinvertebrates, the honey bee is susceptible to many viral infections However,
most viruses co-exist harmlessly in their host and cause no signs or symptoms of disease

PLANT VIRUSES

: Plant virus

There are many types of plant virus, but often they cause only a loss of yield, and it is not economically viable to try to control them. Plant
viruses are often spread from plant to plant by organisms, known as vectors. These are normally insects, but some fungi,nematode worms,
and single-celled organisms have been shown to be vectors. When control of plant virus infections is considered economical, for perennial

fruits, for example, efforts are concentrated on killing the vectors and removing alternate hosts such as weeds. ] Plant viruses cannot infect
humans and other animals because they can reproduce only in living plant cells.

Peppers infected by mild mottle virus

Plants have elaborate and effective defence mechanisms against viruses. One of the most effective is the presence of so-called resistance
(R) genes. Each R gene confers resistance to a particular virus by triggering localised areas of cell death around the infected cell, which
can often be seen with the unaided eye as large spots. This stops the infection from spreading. RNA interference is also an effective
defence in plants. When they are infected, plants often produce natural disinfectants that kill viruses, such as salicylic acid, nitric oxide,
and reactive oxygen molecules.

Plant virus particles or virus-like particles (VLPs) have applications in both biotechnology and nanotechnology. The capsids of most plant
viruses are simple and robust structures and can be produced in large quantities either by the infection of plants or by expression in a
variety of heterologous systems. Plant virus particles can be modified genetically and chemically to encapsulate foreign material and can
be incorporated into supramolecular structures for use in biotechnology.

BACTERIAL VIRUSES,

Any member of a unique class of infectious agents, which were originally distinguished by their smallness (hence, they
were described as “filtrable” because of their ability to pass through fine ceramic filters that blocked all cells, including
bacteria) and their inability to replicate outside of and without assistance of a living host cell. Because these properties
are shared by certain bacteria (RICKETTSIAE, CHLAMYDIAE), viruses are now characterized by their simple organization and
their unique mode of replication. A virus consists of genetic material, which may be either DNA or RNA, and is surrounded
by a protein coat and, in some viruses, by a membranous envelope.

Unlike cellular organisms, viruses do not contain all the biochemical mechanisms for their own replication; they replicate
by using the biochemical mechanisms of a host cell to synthesize and assemble their separate components. (Some do
contain or produce essential enzymes when there is no cellular enzyme that will serve.) When a complete virus particle
(VIRION) comes in contact with a

16
REVERSE TRANSCRIPTASE

host cell, only the viral nucleic acid and, in some viruses, a few enzymes are injected into the host cell.

Within the host cell the genetic material of a DNA virus is replicated and transcribed into messenger RNA by host cell
enzymes, and proteins coded for by viral genes are synthesized by host cell ribosomes. These are the proteins that form
the CAPSID (protein coat); there may also be a few enzymes or regulatory proteins involved in assembling the capsid
around newly synthesized viral nucleic acid, in controlling the biochemical mechanisms of the host cell, and in lysing the
host cell when new virions have been assembled. Some of these may already have been present within the initial virus,
and others may be coded for by the viral genome for production within the host cell.

Because host cells do not have the ability to replicate “viral RNA” but are able to transcribe messenger RNA, RNA viruses
must
contain enzymes to produce genetic material for new virions. For certain viruses the RNA is replicated by a viral enzyme
(TRANSCRIPTASE) contained in the virion, or produced by the host cell using the viral RNA as a messenger. In other viruses a
contained in the virion transcribes the genetic message on the viral RNA into DNA, which is then
replicated
by the host cell. Reverse transcriptase is actually a combination of two enzymes: a POLYMERASE that assembles the new
DNA copy and an RNASE that degrades the source RNA.

In viruses that have membranes, membrane-bound viral proteins are synthesized by the host cell and move, like host cell
membrane proteins, to the cell surface. When these proteins assemble to form the capsid, part of the host cell membrane
is pinched off to form the envelope of the virion.

Some viruses have only a few genes coding for capsid proteins. Other more complex ones may have a few hundred
genes. But no virus has the thousands of genes required by even the simplest cells. Although in general viruses “steal”
their lipid envelope from the host cell, virtually all of them produce “envelope proteins” that penetrate the envelope and
serve as receptors. Some envelope proteins facilitate viral entry into the cell, and others have directly pathogenic effects.

Some viruses do not produce rapid lysis of host cells, but rather remain latent for long periods in the host before the
appearance of clinical symptoms. This carrier state can take any of several different forms. The term LATENCY is used to
denote the interval from infection to clinical manifestations. In the LENTIVIRUSES, it was formerly mistakenly believed that
virus was inactive during this period. The true situation is that lentiviruses are rapidly replicating and spawning dozens of
quasi-species until a particularly effective one overruns the ability of the host's IMMUNE SYSTEM to defeat it. Other viruses,
however, such as the HERPESVIRUSES, actually enter a time known as “viral latency,” when little or no replication is taking
place until further replication is initiated by a specific trigger. For many years all forms of latency were thought to be
identical, but now it has been discovered that there are different types with basic and important distinctions.

In viral latency, most of the host cells may be protected from infection by immune mechanisms involving antibodies to
the viral particles or INTERFERON. Cell-mediated immunity is essential, especially in dealing with infected host cells.
Cytotoxic LYMPHOCYTES may also act as antigen-presenting CELLS to better coordinate the IMMUNE RESPONSE. Containment of
virus in mucosal tissues is far more complex, involving follicular dendritic cells and Langerhans CELLS.

Some enveloped RNA viruses can be produced in infected cells that continue growing and dividing without being killed.
This probably involves some sort of intracellular regulation of viral growth. It is also possible for the DNA of some viruses
to be incorporated into the host cell DNA, producing a carrier state. These are almost always RETROVIRUSES, which are
called PROVIRUSES before and after integration of viral DNA into the host genome.

Few viruses produce toxins, although viral infections of bacteria can cause previously innocuous bacteria to become
much more pathogenic and toxic. Other viral proteins, such as some of the human immunodeficiency VIRUS, appear to
be actively toxic, but
 17
those are the exception, not the rule.

However, viruses are highly antigenic. Mechanisms of pathologic injury to cells include cell LYSIS; induction of cell
PROLIFERATION (as in certain WARTS and MOLLUSCUM CONTAGIOSUM); formation of giant cells, syncytia, or intracellular inclusion
bodies caused by the virus; and perhaps most importantly, symptoms caused by the host's IMMUNE RESPONSE, such as
inflammation or the deposition of antigen-antibody complexes in tissues.

Because viral reproduction is almost completely carried out by host cell mechanisms, there are few points in the process
where stopping viral reproduction will not also kill host cells. For this reason there are no chemotherapeutic agents for
most viral diseases. ACYCLOVIR is an antiviral that requires viral proteins to become active. Some viral infections can be
prevented by vaccination (active IMMUNIZATION), and others can be treated by passive IMMUNIZATION with immune GLOBULIN,
although this has been shown to be effective against only a few dozen viruses.

Comparison of shapes and sizes of viruses.

attenuated virus one whose pathogenicity has been reduced by serial animal passage or other means.
B19 virus a species belonging to the genus Erythrovirus that binds to the erythrocyte P blood group antigen and is the
cause of ERYTHEMA INFECTIOSUM. In patients with HEMOLYTIC ANEMIA or SICKLE CELL DISEASE it causes aplastic CRISIS; it can also
cause acute ARTHRITIS. Fetal infection can cause HYDROPS FETALIS and spontaneous ABORTION or death in utero. Persistent
infection in IMMUNOCOMPROMISED patients can lead to chronic bone marrow failure. Called also human parvovirus B19.
bacterial virus one that is capable of producing transmissible lysis of bacteria; see also BACTERIOPHAGE.

coryza virus rhinovirus.

Coxsackie virus coxsackievirus.
defective virus one that cannot be completely replicated or cannot form a protein coat; in some cases replication can
proceed if missing gene functions are supplied by other viruses; see also helper VIRUS.
dengue virus a flavivirus, existing as four antigenically related but distinct types (designated 1, 2, 3, and 4), that causes
both the classic and hemorrhagic forms of DENGUE.
DNA virus a virus whose GENOME consists of DNA.
Ebola virus an RNA virus almost identical to the Marburg virus but serologically distinct; it causes a disease similar to
that caused by the Marburg virus.
EB virus Epstein-Barr virus.
encephalomyocarditis virus an enterovirus that causes mild aseptic meningitis and encephalomyocarditis.
enteric v's enterovirus.

18
 HEPATITIS E.
enteric orphan v's orphan viruses isolated from the intestinal tract of humans and other animals. Epstein-Barr virus
(EBV) a herpeslike virus that causes infectious mononucleosis and is associated with Burkitt's lymphoma and
nasopharyngeal carcinoma; see also EPSTEIN-BARR VIRUS.
fixed virus a virus whose virulence and incubation period have been stabilized by serial passage and have remained
fixed during further transmission, as opposed to a street virus.
helper virus one that aids in the development of a defective virus by supplying or restoring the activity of the viral gene
or enabling it to form a protein coat.
hepatitis A virus (HAV) any virus of the genus Hepatovirus that causes HEPATITIS A. This has the most rapid onset of the
hepatitis viruses affecting humans; transmission is easier than for the hepatitis B and C VIRUSES, but infection generally
does not persist. While infection with this virus alone is usually not life-threatening, coincident infection with hepatitis C
VIRUS is generally rapidly fatal.
hepatitis B virus (HBV) a species of genus Orthohepadnavirus that causes HEPATITIS B.
hepatitis C virus a species of genus Hepacivirus that causes HEPATITIS C; its latency period may last 30 years or more.
hepatitis D virus (HDV) (hepatitis delta virus) an unclassified defective RNA virus, thought of as a parasite of the hepatitis
B VIRUS and transmitted in the same manner; it requires enzymes and other assistance from HBV to replicate. This virus
magnifies the pathogenicity of hepatitis B virus many times and is the etiologic agent of HEPATITIS D. hepatitis E virus an
enterically transmitted calicivirus that causes

hepatitis G virus (HGV) a parenterally transmitted flavivirus originally isolated from a patient with chronic hepatitis; most
infections are benign, and it is uncertain what role, if any, HGV plays in the etiology of liver disease.
hepatotropic virus a virus that primarily affects the liver, such as the hepatitis VIRUSES.

herpes virus herpesvirus.

herpes simplex virus former name for any virus that causes HERPES SIMPLEX, now called human herpesviruses; see
HERPESVIRUS. human immunodeficiency virus (HIV) either of two species of LENTIVIRUSES that cause ACQUIRED IMMUNODEFICIENCY
SYNDROME (AIDS). HIV-1 is found around the world and HIV-2 is found primarily in West Africa. Progression of HIV-2
infection to AIDS is generally slower and less extreme than that of HIV-1. The virus is believed to induce permanent
infection and has a propensity toward a subset of T LYMPHOCYTES called the CD4 CELLS. The infected cells become
dysfunctional and eventually the host's IMMUNE SYSTEM is overwhelmed or exhausted; death ensues, usually as a result of
infection. The virus is not transmitted through casual contact; the most common routes of transmission are through
sexual intercourse, direct exposure to contaminated blood, and transplacental transmission from mother to fetus.
19
MARBURG VIRUS DISEASE.
Human immunodeficiency virus: retrovirus particle. From Copstead, 1995.

human T-cell leukemia virus (human T-cell lymphotropic virus) former names for human T-lymphotropic virus.
human T-lymphotropic virus (HTLV) either of two related species of RETROVIRUSES that have an affinity for the helper CELL
type of T lymphocytes. HTLV-1 causes chronic infection and is associated with adult T-cell LEUKEMIA and a type of
MYELOPATHY. HTLV-2 has been isolated from an atypical variant of hairy cell LEUKEMIA and from patients with other
hematological disorders, but no clear association with disease has been established.
influenza virus any of a group of ORTHOMYXOVIRUSES that cause INFLUENZA; there are at least three serotypes or species (A,
B, and C). Serotype A viruses are subject to major antigenic changes (antigenic SHIFTS) as well as minor gradual
antigenic changes (antigenic DRIFT) and cause widespread epidemics and pandemics. Serotypes B and C are chiefly
associated with sporadic epidemics.
influenza A virus (influenza B virus) (influenza C virus) species in the genera Influenzavirus A, Influenzavirus B,
and Influenzavirus C; see influenza VIRUS.
La Crosse virus a virus of the California serogroup of the genus Bunyavirus, the etiologic agent of La Crosse ENCEPHALITIS.
latent virus one that ordinarily occurs in a noninfective state and is demonstrable by indirect methods that activate it.
lytic virus one that is replicated in the host cell and causes death and lysis of the cell.
maedi/visna virus a LENTIVIRUS that is the etiologic agent of a type of PNEUMONIA in sheep.
Marburg virus an RNA virus occurring in Africa, transmitted by insect bites, and
causing masked virus latent virus.
measles virus a paramyxovirus that is the cause of measles.
mumps virus a paramyxovirus that causes mumps and sometimes tenderness and swelling of the testes, pancreas,
ovaries, or other organs.
Norwalk virus a CALICIVIRUS that is common cause of epidemics of acute GASTROENTERITIS, with diarrhea and vomiting that
last 24 to 48 hours.

20
 ACQUIRED IMMUNODEFICIENCY SYNDROME

oncogenic v's an epidemiologic class of viruses that are acquired by close contact or injection and cause usually
persistent infection; they may induce cell transformation and malignancy.
orphan v's viruses isolated in tissue culture, but not found specifically associated with any disease.
parainfluenza virus any of various PARAMYXOVIRUSES that cause upper respiratory tract disease of varying severity.
poliomyelitis virus see POLIOVIRUS.
pox virus poxvirus.
rabies virus an RNA virus of the rhabdovirus group that causes RABIES.

respiratory syncytial virus (RSV) any of a genus of single-stranded PARAMYXOVIRUSES; the name is derived from the type of
disease produced (respiratory infection) and the microscopic appearance of the viruses in cell cultures. RSV can cause a
wide
variety of respiratory disorders ranging from a mild cold to serious or even fatal disease of the lung in the very young and
very old. It
regularly produces an outbreak of infection each winter and virtually disappears in the summer months. The most severe
infections
in children are in the very young, especially those who are preterm, immunologically compromised, or suffering from a
congenital
heart defect or preexisting lung disorder. Adults at risk for infection include parents and others who are repeatedly
exposed to young
children, for example, pediatric nurses and day care attendants. The course of infection tends to be milder in adults than in
children
and about 15 per cent of affected adults have no symptoms. In the very elderly these infections may have the same degree
of
seriousness and clinical manifestations as in the very young.
RNA virus a virus whose GENOME consists of RNA.
rubella virus a togavirus that is the etiologic agent of rubella.
satellite virus a strain of virus unable to replicate except in the presence of helper VIRUS; considered to be deficient in
coding for CAPSID formation.
simian-human immunodeficiency virus a chimeric, engineered virus with the ENVELOPE of human immunodeficiency VIRUS
and the CYTOPLASM and NUCLEUS of simian immunodeficiency VIRUS; it is used in animal models because it is a better mimic
of HIV than SIV is.
simian immunodeficiency virus (SIV) a LENTIVIRUS closely related to human immunodeficiency VIRUS that causes inapparent
infection in African green monkeys and a disease resembling in macaques and

chimpanzees.
slow virus any virus that remains latent for long periods in the infected host before the appearance of clinical symptoms.
smallpox virus variola virus.
street virus virus from a naturally infected animal, as opposed to a laboratory-adapted strain of the virus.
vaccinia virus a species of ORTHOPOXVIRUS that does not occur in nature and has been propagated for many years only
in the laboratory for use as an active vaccine against SMALLPOX. The present virus is derived from the original one
used by Jenner, obtained from the lesions of COWPOX, but the origin of the original virus remains unclear. varicella-
zoster virus former name for human herpesvirus 3; see HERPESVIRUS.
variola virus the virtually extinct ORTHOPOXVIRUS that is the etiologic agent of SMALLPOX. No natural infection has occurred
since 1977, and no reservoir of the virus now exists.
West Nile virus a virus of the genus Flavivirus, the cause of West Nile ENCEPHALITIS; it is transmitted by Culex
mosquitoes, with wild birds serving as the reservoir. It was originally endemic in Africa, Asia, and Europe, but recently
spread to North America.
wild-type virus street virus.

BACTERIOPHAGE.

Bacteriophages are viruses that infect bacteria. Many types of bacteriophage exist, some simply infect and lyse their host bacteria, while
others insert into the bacterial chromosome. A bacteriophage can contain genes that contribute to its host's phenotype: for example, in
the evolution of Escherichia coli O157:H7 and Clostridium botulinum, the toxin genes in an integrated phage converted a harmless
ancestral bacterium into a lethal
pathogen.] Bacteria resist phage infection through restriction modification systems that degrade foreign DNA, and a system that
 21
uses CRISPR sequences to retain fragments of the genomes of phage that the bacteria have come into contact with in the past, which
allows them to block virus replication through a form of RNA interference. This CRISPR system provides bacteria with acquired immunity
to infection.

Bacteriophages are a common and diverse group of viruses and are the most abundant form of biological entity in aquatic environments –
there are up to ten times more of these viruses in the oceans than there are bacteria reaching levels of 250,000,000 bacteriophages
permillilitre of seawater. These viruses infect specific bacteria by binding to surface receptor molecules and then entering the cell. Within a
short amount of time, in some cases just minutes, bacterial polymerase starts translating viral mRNA into protein. These proteins go on to
become either new virions within the cell, helper proteins, which help assembly of new virions, or proteins involved in cell lysis. Viral
enzymes aid in the breakdown of the cell membrane, and, in the case of the T4 phage, in just over twenty minutes after injection over three
hundred phages could be released.

Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall

The major way bacteria defend themselves from bacteriophages is by producing enzymes that destroy foreign DNA. These enzymes,
calledrestriction endonucleases, cut up the viral DNA that bacteriophages inject into bacterial cells. Bacteria also contain a system that
usesCRISPR sequences to retain fragments of the genomes of viruses that the bacteria have come into contact with in the past, which
allows them to block the virus's replication through a form of RNA interference. This genetic system provides bacteria with acquired
immunity to infection.

Archaean viruses

Some viruses replicate within archaea: these are double-stranded DNA viruses with unusual and sometimes unique shapes. These viruses
have been studied in most detail in the thermophilic archaea, particularly the orders Sulfolobales and Thermoproteales. Defences against
these viruses involve RNA interference from repetitive DNAsequences within archaean genomes that are related to the genes of the viruses
Most archaea have CRISPR– Cas systems as an adaptive defense against viruses. These enable archaea to retain sections of viral DNA,
which are then used to target and eliminate subsequent infections by the virus using a process similar to RNA interference.

Role in aquatic ecosystems

Marine bacteriophage

A teaspoon of seawater contains about one million viruses Most of these are bacteriophages, which are harmless to plants and animals, and
are in fact essential to the regulation of saltwater and freshwater ecosystems They infect and destroy bacteria in aquatic microbial
communities, and are the most important mechanism of recycling carbon in the marine environment. The organic molecules released from
the dead bacterial cells stimulate fresh bacterial and algal growth Viral activity may also contribute to the biological pump, the process
whereby carbon is sequestered in the deep ocean.

Microorganisms constitute more than 90% of the biomass in the sea. It is estimated that viruses kill approximately 20% of this biomass
each day and that there are 15 times as many viruses in the oceans as there are bacteria and archaea. Viruses are the main agents
responsible for the rapid destruction of harmful algal blooms which often kill other marine life.The number of viruses in the oceans
decreases further offshore and deeper into the water, where there are fewer host organisms.
Like any organism, marine mammals are susceptible to viral infections. In 1988 and 2002, thousands of harbor seals were killed in Europe by phocine
[228]
distemper virus. Many other viruses, including caliciviruses, herpesviruses, adenoviruses and parvoviruses, circulate in marine mammal
populations.

Role in evolution
 22
Viruses are an important natural means of transferring genes between different species, which increases genetic diversity and drives
evolution. It is thought that viruses played a central role in the early evolution, before the diversification of bacteria, archaea and
eukaryotes, at the time of the last universal common ancestor of life on Earth Viruses are still one of the largest reservoirs of unexplored
genetic diversity on Earth.

BACTERIA.

Bacteria (singular: bacterium) constitute a large domain of prokaryotic microorganisms. Typically a fewmicrometres in length, bacteria have
a number of shapes, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth, and are present
in most of its habitats. Bacteria inhabit soil, water, acidic hot springs,radioactive waste, [4] and the deep portions of Earth's crust. Bacteria
also live
in symbiotic and parasitic relationships with plants and animals.

Etymology of Bacteria.

The word bacteria is the plural of the New Latin bacterium, which is the latinisation of the Greek (bakterion) the diminutive of,

meaning "staff, cane",] because the first ones to be discovered were rod-shaped.

Bacteria were first observed by the Dutch microscopist Antonie van Leeuwenhoek in 1676, using a single-lens microscope of his own
design. He then published his observations in a series of letters to the Royal Society of London. Bacteria were Leeuwenhoek's most
remarkable microscopic discovery. They were just at the limit of what his simple lenses could make out and, in one of the most striking
hiatuses in the history of science, no one else would see them again for over a century. Only then were his by-then-largely-forgotten
observations of bacteria — as opposed to his famous "animalcules" (spermatozoa) — taken seriously.

Christian Gottfried Ehrenberg introduced the word "bacterium" in 1828. In fact, his Bacterium was a genus that contained non-spore-

forming rod-shaped bacteria, ] as opposed to Bacillus, a genus of spore-forming rod-shaped bacteria defined by Ehrenberg in 1835.

Louis Pasteur demonstrated in 1859 that the growth of microorganisms causes the fermentation process, and that this growth
is not due to spontaneous generation. (Yeasts and molds, commonly associated with fermentation, are not bacteria, but rather
fungi.) Along with his contemporary Robert Koch, Pasteur was an early advocate of the germ theory of disease.

Robert Koch, a pioneer in medical microbiology, worked on cholera, anthrax and tuberculosis. In his research into tuberculosis Koch
finally proved the germ theory, for which he received a Nobel Prize in 1905. In Koch's postulates, he set out criteria to test if an organism is
the cause of a disease, and these postulates are still used today.

There are typically 40 million bacterial cells in a gram of soil and a million bacterial cells in a millilitre of fresh water. There are

approximately 5×10 bacteria on Earth,] forming a biomass which exceeds that of all plants and animals. Bacteria are vital in recycling
nutrients, with many of the stages in nutrient cycles dependent on these organisms, such as thefixation of nitrogen from the atmosphere
and putrefaction. In the biological communities surrounding hydrothermal ventsand cold seeps, bacteria provide the nutrients needed to
sustain life by converting dissolved compounds, such as hydrogen sulphide and methane, to energy. On 17 March 2013, researchers
reported data that suggested bacterial life forms thrive in
the Mariana Trench, which with a depth of up to 11 kilometres is the deepest part of the Earth's oceans. Other researchers reported related
studies that microbes thrive inside rocks up to 580 metres below the sea floor under 2.6 kilometres of ocean off the coast of the
northwestern United
States. According to one of the researchers, "You can find microbes everywhere — they're extremely adaptable to conditions, and
survive wherever they are.

Most bacteria have not been characterized, and only about half of the bacterial phyla have species that can be grown in the laboratory.
The study of bacteria is known as bacteriology, a branch of microbiology.

There are approximately ten times as many bacterial cells in the human flora as there are human cells in the body, with the largest number
of the human flora being in the gut flora, and a large number on the skin The vast majority of the bacteria in the body are rendered harmless
by the protective effects of the immune system, and some are beneficial. However, several species of bacteria are pathogenic and cause
infectious diseases, including cholera, syphilis, anthrax,leprosy, and bubonic plague. The most common fatal bacterial diseases are
respiratory infections,
with tuberculosis alone killing about 2 million people per year, mostly in sub-Saharan Africa. ] In developed countries, antibiotics are used to

23
treatbacterial infections and are also used in farming, making antibiotic resistance a growing problem. In industry, bacteria are important
in sewage treatment and the breakdown of oil spills, the production of cheese and yogurt through fermentation, and the recovery of gold,
palladium, copper and other metals in the mining sector as well as in biotechnology, and the manufacture of antibiotics and other
chemicals.

Once regarded as plants constituting the class Schizomycetes, bacteria are now classified as prokaryotes. Unlike cells of animals and
other eukaryotes, bacterial cells do not contain a nucleus and rarely harbour membrane-bound organelles. Although the term bacteria
traditionally included all prokaryotes, the scientific classification changed after the discovery in the 1990s that prokaryotes consist of
two very different groups of organisms that evolved from an ancient common ancestor. These evolutionary domains are called Bacteria
and Archaea

: Bacterial morphological plasticity

Bacteria display many cell morphologies and arrangements

Bacteria display a wide diversity of shapes and sizes, calledmorphologies. Bacterial cells are about one-tenth the size of eukaryotic cells
and are typically 0.5–5.0 micrometres in length. However, a few species are visible to the unaided eye — for example, Thiomargarita
namibiensis is up to half a millimetre long and Epulopiscium fishelsonireaches 0.7 mm. Among the smallest bacteria are members of the
genus Mycoplasma, which measure only 0.3 micrometres, as small as the largest viruses. Some bacteria may be even smaller, but
theseultramicrobacteria are not well-studied.

Most bacterial species are either spherical, called cocci (sing. coccus, from Greek kókkos, grain, seed), or rod-shaped, called bacilli (sing.
bacillus, from Latin baculus, stick). Elongation is associated with swimming. Some bacteria, called vibrio, are shaped like slightly curved
rods or comma-shaped; others can be spiral-shaped, calledspirilla, or tightly coiled, called spirochaetes. A small number of species even

have tetrahedral or cuboidal shapes.] More recently, some bacteria were discovered deep under Earth's crust that grow as branching
filamentous types with a star-shaped cross-section. The large surface area to volume ratio of this morphology may give these bacteria an
advantage in nutrient-poor environments. This wide variety of shapes is determined by the bacterial cell wall and cytoskeleton, and is
important because it can influence the ability of bacteria to acquire nutrients, attach to surfaces, swim through liquids and escape
predators.
24
A biofilm of thermophilic bacteria in the outflow of Mickey Hot Springs,Oregon, approximately 20 mm thick.

Many bacterial species exist simply as single cells, others associate in characteristic patterns: Neisseria form diploids (pairs),
Streptococcus form chains, and Staphylococcus group together in "bunch of grapes" clusters. Bacteria can also be elongated to form
filaments, for example
the Actinobacteria. Filamentous bacteria are often surrounded by a sheath that contains many individual cells. Certain types, such as
species of the genus Nocardia, even form complex, branched filaments, similar in appearance to fungal mycelia.

Bacteria often attach to surfaces and form dense aggregations called biofilms or bacterial mats. These films can range from a few
micrometers in thickness to up to half a meter in depth, and may contain multiple species of bacteria, protists and archaea. Bacteria living
in biofilms display a complex arrangement of cells and extracellular components, forming secondary structures, such as microcolonies,
through which there are networks of channels to enable better diffusion of nutrients. In natural environments, such as soil or the surfaces of
plants, the majority of bacteria are bound to surfaces in biofilms. Biofilms are also important in medicine, as these structures are often
present during chronic bacterial infections or in infections of implanted medical devices, and bacteria protected within biofilms are much
harder to kill than individual isolated bacteria.

Even more complex morphological changes are sometimes possible. For example, when starved of amino acids, Myxobacteria detect
surrounding cells in a process known asquorum sensing, migrate toward each other, and aggregate to form fruiting bodies up to 500
micrometres long and containing approximately 100,000 bacterial cells In these fruiting bodies, the bacteria perform separate tasks; this
type of cooperation is a simple type of multicellular organisation. For example, about one in 10 cells migrate to the top of these fruiting
bodies and differentiate into a specialised dormant state called myxospores, which are more resistant to drying and other adverse
environmental conditions than are ordinary cells

Cellular structure

Further information: Bacterial cell structure

Structure and contents of a typicalgram-positive bacterial cell (seen by the fact that only one cell membrane is present).
25
Intracellular structures

The bacterial cell is surrounded by a cell membrane (also known as a lipid, cytoplasmic or plasma membrane). This membrane encloses the contents
of the cell and acts as a barrier to hold nutrients, proteins and other essential components of the cytoplasmwithin the cell. As they are prokaryotes,
bacteria do not usually have membrane-bound organelles in their cytoplasm, and thus contain few large intracellular structures. They lack a
true nucleus, mitochondria, chloroplasts and the other organelles present in eukaryotic cells. Bacteria were once seen as simple bags of
cytoplasm, but structures such as the prokaryotic cytoskeleton and the localization of proteins to specific locations within the cytoplasm
that give bacteria some complexity have been discovered. These subcellular levels of organization have been called "bacterial
hyperstructures"

Bacterial microcompartments, such as carboxysomes, ] provide a further level of organization; they are compartments within
bacteria that are surrounded by polyhedral protein shells, rather than by lipid membranes These "polyhedral organelles" localize
and compartmentalize bacterial metabolism, a function performed by the membrane-bound organelles in eukaryotes.

Many important biochemical reactions, such as energy generation, use concentration gradients across membranes. The general lack of
internal membranes in bacteria means reactions such as electron transport occur across the cell membrane between the cytoplasm and the
periplasmic space. However, in many photosynthetic bacteria the plasma membrane is highly folded and fills most of the cell with layers of
light-gathering membrane. These light-gathering complexes may even form lipid-enclosed structures calledchlorosomes in green sulfur
bacteria. Other proteins import nutrients across the cell membrane, or expel undesired molecules from the cytoplasm.

Carboxysomes are protein-enclosed bacterial organelles. Top left is anelectron microscope image of carboxysomes in Halothiobacillus
neapolitanus, below is an image of purified carboxysomes. On the right is a model of their structure. Scale bars are 100 nm.

Bacteria do not have a membrane-bound nucleus, and their genetic material is typically a single circular DNA chromosome located in the
cytoplasm in an irregularly shaped body called thenucleoid. The nucleoid contains the chromosome with its associated proteins and RNA.
The
phylum Planctomycetes[55] and candidate phylum Poribacteria may be exceptions to the general absence of internal membranes in
bacteria, because they appear to have a double membrane around their nucleoids and contain other membrane-bound cellular structures.
Like allliving organisms, bacteria contain ribosomes, often grouped in chains called polyribosomes, for the production of proteins, but the
structure of the bacterial ribosome is different from that ofeukaryotes and Archaea. [ Bacterial ribosomes have a sedimentation rate of 70S
(measured inSvedberg units): their subunits have rates of 30S and 50S. Some antibiotics bind specifically to 70S ribosomes and inhibit
bacterial protein synthesis. Those antibiotics kill bacteria without affecting the larger 80S ribosomes of eukaryotic cells and without
harming the host.

Some bacteria produce intracellular nutrient storage granules for later use, such as glycogen,polyphosphate or polyhydroxyalkanoates.
Certain bacterial species, such as thephotosynthetic Cyanobacteria, produce internal gas vesicles, which they use to regulate their
buoyancy – allowing them to move up or down into water layers with different light intensities and nutrient levels Intracellular membranes
called chromatophores are also found in membranes of phototrophic bacteria. Used primarily for photosynthesis, they contain
bacteriochlorophyll pigments and carotenoids. An early idea was that bacteria might contain membrane folds termed mesosomes, but
these were later shown to be artifacts produced by the chemicals used to prepare the cells for electron microscopy.Inclusions are
considered to be nonliving components of the cell that do not possess metabolic activity and are not bounded by membranes. The most
common inclusions are glycogen, lipid droplets, crystals, and pigments. Volutin granules are cytoplasmic inclusions of complexed
inorganic polyphosphate. These granules are called metachromatic granules due to their displaying the metachromatic effect; they appear
red or blue when stained with the blue dyes methylene blue or toluidine blue. Gas vacuoles, which are freely permeable to gas, are
membrane-bound vesicles present in some species of Cyanobacteria. They allow the bacteria to control their buoyancy.
Microcompartments are widespread, membrane-bound organelles that are made of a protein shell that surrounds and encloses various
enzymes. Carboxysomes are bacterial

26
microcompartments that contain enzymes involved in carbon fixation. Magnetosomes are bacterial microcompartments, present in
magnetotactic bacteria, that contain magnetic crystals.

Extracellular structures
Cell envelope

In most bacteria, a cell wall is present on the outside of the cell membrane. The cell membrane and cell wall comprise the cell envelope.
A common bacterial cell wall material is peptidoglycan (called "murein" in older sources), which is made from polysaccharide chains
cross-linked
by peptides containing D-amino acids Bacterial cell walls are different from the cell walls of plants and fungi, which are made of cellulose
and chitin, respectively. The cell wall of bacteria is also distinct from that of Archaea, which do not contain peptidoglycan. The cell wall is
essential to the survival of many bacteria, and the antibiotic penicillin is able to kill bacteria by inhibiting a step in the synthesis of
peptidoglycan.

There are broadly speaking two different types of cell wall in bacteria, a thick one in the gram-positives and a thinner one in the gram-
negatives. The names originate from the reaction of cells to the Gram stain, a test long-employed for the classification of bacterial
species

Gram-positive bacteria possess a thick cell wall containing many layers of peptidoglycan and teichoic acids. In contrast, gram-negative
bacteria have a relatively thin cell wall consisting of a few layers of peptidoglycan surrounded by a second lipid
membrane containing lipopolysaccharides and lipoproteins. Lipopolysaccharides, also calledendotoxins, are composed of
polysaccharides and lipid A that is responsible for much of the toxicity of gram-negative bacteria. Most bacteria have the gram-negative
cell wall, and only
the Firmicutes and Actinobacteria have the alternative gram-positive arrangement. These two groups were previously known as the low
G+C and high G+C gram-positive bacteria, respectively. These differences in structure can produce differences in antibiotic susceptibility;
for instance, vancomycin can kill only gram-positive bacteria and is ineffective against gram-negative pathogens, such as Haemophilus
influenzae or Pseudomonas aeruginosa. If the bacterial cell wall is entirely removed, it is called aprotoplast, whereas if it is partially
removed, it is called a spheroplast. β-Lactam antibiotics, such as penicillin, inhibit the formation of peptidoglycan cross-links in the
bacterial cell wall. The enzyme lysozyme, found in human tears, also digests the cell wall of bacteria and is the body's main defense against
eye infections.

Acid-fast bacteria, such as Mycobacteria, are resistant to decolorization by acids during staining procedures. The high mycolic acid content
of Mycobacteria, is responsible for the staining pattern of poor absorption followed by high retention. The most common staining
technique used to identify acid-fast bacteria is the Ziehl-Neelsen stain or acid-fast stain, in which the acid-fast bacilli are stained bright-red
and stand out clearly against a blue background. L-form bacteria are strains of bacteria that lack cell walls. The main pathogenic bacteria in
this class is Mycoplasma (not to be confused with Mycobacteria).

In many bacteria, an S-layer of rigidly arrayed protein molecules covers the outside of the cell. This layer provides chemical and physical
protection for the cell surface and can act as a macromolecular diffusion barrier. S-layers have diverse but mostly poorly understood
functions, but are known to act as virulence factors in Campylobacter and contain surface enzymes in Bacillus stearothermophilus.

Helicobacter pylori electron micrograph, showing multiple flagella on the cell surface

Flagella are rigid protein structures, about 20 nanometres in diameter and up to 20 micrometres in length, that are used for motility.
Flagella are driven by the energy released by the transfer of ions down an electrochemical gradient across the cell membrane.

Fimbriae (sometimes called "attachment pili") are fine filaments of protein, usually 2–10 nanometres in diameter and up to several
micrometers in length. They are distributed over the surface of the cell, and resemble fine hairs when seen under the electron microscope.
Fimbriae are believed to be involved in attachment to solid surfaces or to other cells, and are essential for the virulence of some bacterial

pathogens.[71] Pili (sing. pilus) are cellular appendages, slightly larger than fimbriae, that can transfer genetic materialbetween bacterial
cells in a process called conjugation where they are called conjugation pili or "sex pili" (see bacterial genetics, below). They can also
generate movement where they are called type IV pili (see movement, below).

27
Glycocalyx are produced by many bacteria to surround their cells, and vary in structural complexity: ranging from a disorganised slime
layer of extra-cellular polymer to a highly structured capsule. These structures can protect cells from engulfment by eukaryotic cells such
as macrophages (part of the human immune system) They can also act as antigens and be involved in cell recognition, as well as aiding
attachment to surfaces and the formation of biofilms

The assembly of these extracellular structures is dependent on bacterial secretion systems. These transfer proteins from the
cytoplasm into the periplasm or into the environment around the cell. Many types of secretion systems are known and these
structures are often essential for the virulence of pathogens, so are intensively studied.

Endospores
: Endospore

Bacillus anthracis (stained purple) growing in cerebrospinal fluid

Certain genera of gram-positive bacteria, such as Bacillus, Clostridium, Sporohalobacter, Anaerobacter, and Heliobacterium, can form
highly resistant, dormant structures called endospores. In almost all cases, one endospore is formed and this is not a reproductive
process, although Anaerobacter can make up to seven endospores in a single cell. Endospores have a central core of cytoplasmcontaining
DNA and ribosomes surrounded by a cortex layer and protected by an impermeable and rigid coat. Dipicolinic acid is a chemical compound
that composes 5% to 15% of the dry weight of bacterial spores. It is implicated as responsible for the heat resistance of the endospore.

Endospores show no detectable metabolism and can survive extreme physical and chemical stresses, such as high levels of UV
light,gamma radiation, detergents, disinfectants, heat, freezing, pressure, and desiccation. In this dormant state, these organisms may
remain viable for millions of years and endospores even allow bacteria to survive exposure to the vacuum and radiation in space. [81]
According to scientist Dr. Steinn Sigurdsson, "There are viable bacterial spores that have been found that are 40 million years old on
Earth — and we know they're very hardened to
radiation." Endospore-forming bacteria can also cause disease: for example, anthrax can be contracted by the inhalation
of Bacillus anthracis endospores, and contamination of deep puncture wounds with Clostridium tetani endospores
causes tetanus.

Metabolism

Microbial metabolism

Bacteria exhibit an extremely wide variety of metabolic types. The distribution of metabolic traits within a group of bacteria has
traditionally been used to define theirtaxonomy, but these traits often do not correspond with modern genetic classifications. Bacterial
metabolism is classified into nutritional groups on the basis of three major criteria: the kind of energy used for growth, the source of
carbon, and the electron donors used for growth. An additional criterion of respiratory microorganisms are theelectron acceptors used for
aerobic or anaerobic respiration.

Carbon metabolism in bacteria is either heterotrophic, where organic carbon compounds are used as carbon sources, or autotrophic,
meaning that
cellular carbon is obtained by fixing carbon dioxide. Heterotrophic bacteria include parasitic types. Typical autotrophic bacteria are
phototrophic cyanobacteria, green sulfur-bacteria and some purple bacteria, but also many chemolithotrophic species, such as nitrifying or
sulfur-
[87]
oxidising bacteria. Energy metabolism of bacteria is either based on phototrophy, the use of light through photosynthesis, or based on
chemotrophy,
28
the use of chemical substances for energy, which are mostly oxidised at the expense of oxygen or alternative electron acceptors
(aerobic/anaerobic respiration).

Filaments of photosyntheticcyanobacteria

Bacteria are further divided into lithotrophs that use inorganic electron donors and organotrophs that use organic compounds as electron
donors. Chemotrophic organisms use the respective electron donors for energy conservation (by aerobic/anaerobic respiration or
fermentation) and biosynthetic reactions (e.g., carbon dioxide fixation), whereas phototrophic organisms use them only for biosynthetic
purposes. Respiratory organisms use chemical compounds as a source of energy by taking electrons from the reduced substrate and
transferring them to a terminal electron acceptor in a redox reaction. This reaction releases energy that can be used to synthesise ATP and
drive metabolism. In aerobic organisms, oxygen is used as the electron acceptor. In anaerobic organisms other inorganic compounds, such
as nitrate, sulfate or carbon dioxide are used as electron acceptors. This leads to the ecologically important processes of denitrification,
sulfate reduction, and acetogenesis, respectively.

Another way of life of chemotrophs in the absence of possible electron acceptors is fermentation, wherein the electrons taken from the
reduced substrates are transferred to oxidised intermediates to generate reduced fermentation products (e.g., lactate, ethanol,
hydrogen,butyric acid). Fermentation is possible, because the energy content of the substrates is higher than that of the products, which
allows the organisms to synthesise ATP and drive their metabolism.

These processes are also important in biological responses to pollution; for example, sulfate-reducing bacteria are largely responsible

for the production of the highly toxic forms of mercury (methyl- and dimethylmercury) in the environment. ] Non-respiratory anaerobes
use fermentation to generate energy and reducing power, secreting metabolic by-products (such as ethanol in brewing) as waste.
Facultative anaerobes can switch between fermentation and different terminal electron acceptors depending on the environmental
conditions in which they find themselves.

Lithotrophic bacteria can use inorganic compounds as a source of energy. Common inorganic electron donors are hydrogen, carbon
monoxide, ammonia (leading tonitrification), ferrous iron and other reduced metal ions, and several reduced sulfur compounds. In unusual
circumstances, the gas methane can be used by methanotrophicbacteria as both a source of electrons and a substrate for carbon
anabolism. In both aerobic phototrophy and chemolithotrophy, oxygen is used as a terminal electron acceptor, whereas under anaerobic
conditions inorganic compounds are used instead. Most lithotrophic organisms are autotrophic, whereas organotrophic organisms are
heterotrophic.

In addition to fixing carbon dioxide in photosynthesis, some bacteria also fix nitrogen gas (nitrogen fixation) using the enzyme
nitrogenase. This environmentally important trait can be found in bacteria of nearly all the metabolic types listed above, but is not
universal

Regardless of the type of metabolic process they employ, the majority of bacteria are able to take in raw materials only in the form of
relatively small molecules, which enter the cell by diffusion or through molecular channels in cell membranes. The Planctomycetes are the
exception (as they are in possessing membranes around their nuclear material). It has recently been shown that Gemmata obscuriglobus is
able to take in large molecules via a process that in some ways resembles endocytosis, the process used by eukaryotic cells to engulf
external items.

Growth and reproduction

29
Many bacteria reproduce through binary fission, which is compared to mitosis andmeiosis in this image.

Further information: Bacterial growth

Unlike in multicellular organisms, increases in cell size (cell growth) and reproduction by cell division are tightly linked in unicellular
organisms. Bacteria grow to a fixed size and then reproduce through binary fission, a form of asexual reproduction. Under optimal
conditions, bacteria can grow and divide extremely rapidly, and bacterial populations can double as quickly as every 9.8 minutes. In cell
division, two identical clone daughter cells are produced. Some bacteria, while still reproducing asexually, form more complex reproductive
structures that help disperse the newly formed daughter cells. Examples include fruiting body formation by Myxobacteria and aerial hyphae
formation by Streptomyces, or budding. Budding involves a cell forming a protrusion that breaks away and produces a daughter cell.

A colony ofEscherichia coli

In the laboratory, bacteria are usually grown using solid or liquid media. Solid growth media, such as agar plates, are used to isolate pure
cultures of a bacterial strain. However, liquid growth media are used when measurement of growth or large volumes of cells are required.
Growth in stirred liquid media occurs as an even cell suspension, making the cultures easy to divide and transfer, although isolating single
bacteria from liquid media is difficult. The use of selective media (media with specific nutrients added or deficient, or with antibiotics
added) can help identify specific organisms.

Most laboratory techniques for growing bacteria use high levels of nutrients to produce large amounts of cells cheaply and quickly.
However, in natural environments, nutrients are limited, meaning that bacteria cannot continue to reproduce indefinitely. This nutrient
limitation has led the evolution of different growth strategies (see r/K selection theory). Some organisms can grow extremely rapidly when
nutrients become available, such as the formation of algal (and cyanobacterial) blooms that often occur in lakes during the summer. Other
organisms have adaptations to harsh environments, such as the production of multiple antibiotics by Streptomyces that inhibit the growth
of competing microorganisms. In nature, many organisms live in communities (e.g., biofilms) that may allow for increased supply of
nutrients and protection from environmental stresses. These relationships can be essential for growth of a particular organism or group of
organisms (syntrophy).

Bacterial growth follows four phases. When a population of bacteria first enter a high-nutrient environment that allows growth, the cells need to adapt
to their new environment. The first phase of growth is the lag phase, a period of slow growth when the cells are adapting to the high-nutrient
environment and preparing for fast growth. The lag phase has high biosynthesis rates, as proteins necessary for rapid growth are produced. The
second phase of growth is the log phase, also known as thelogarithmic or exponential phase. The log phase is marked by rapid exponential growth.
The rate at which
30
cells grow during this phase is known as the growth rate (k), and the time it takes the cells to double is known as the generation time (g).
During log phase, nutrients are metabolised at maximum speed until one of the nutrients is depleted and starts limiting growth. The third
phase of growth is the stationary phase and is caused by depleted nutrients. The cells reduce their metabolic activity and consume non-
essential cellular proteins. The stationary phase is a transition from rapid growth to a stress response state and there is increased
expression of genes involved in DNA repair,antioxidant metabolism and nutrient transport. The final phase is the death phase where the
bacteria run out of nutrients and die.

Genetics

Further information: Plasmid and Genome

Most bacteria have a single circular chromosome that can range in size from only 160,000 base pairs in the endosymbiotic bacteria
Candidatus Carsonella ruddii, to 12,200,000 base pairs in the soil-dwelling bacteria Sorangium cellulosum. Spirochaetes of the genus
Borrelia are a notable exception to this arrangement, with bacteria such as Borrelia burgdorferi, the cause of Lyme disease, containing a
single linear chromosome. The genes in bacterial genomes are usually a single continuous stretch of DNA and although several different
types of introns do exist in bacteria, these are much rarer than in eukaryotes.

Bacteria may also contain plasmids, which are small extra-chromosomal DNAs that may contain genes for antibiotic resistance or
virulence factors. Plasmids replicate independently of chromosomes, so it is possible that plasmids could be lost in bacterial cell

division. Against this possibility is the fact that a single bacterium can contain hundreds of copies of a single plasmid. [107]

Bacteria, as asexual organisms, inherit identical copies of their parent's genes (i.e., they are clonal). However, all bacteria can evolve by
selection on changes to their genetic material DNA caused by genetic recombination or mutations. Mutations come from errors made
during the replication of DNA or from exposure to mutagens. Mutation rates vary widely among different species of bacteria and even
among different clones of a single species of bacteria. Genetic changes in bacterial genomes come from either random mutation during
replication or "stress-directed mutation", where genes involved in a particular growth-limiting process have an increased mutation rate.

DNA transfer

Some bacteria also transfer genetic material between cells. This can occur in three main ways. First, bacteria can take up exogenous DNA from their
environment, in a process called transformation. Genes can also be transferred by the process of transduction, when the integration of a
bacteriophage introduces foreign DNA into the chromosome. The third method of gene transfer is conjugation, whereby DNA is transferred through
direct cell contact.

Transduction of bacterial genes by bacteriophage appears to be a consequence of infrequent errors during intracellular assembly of
virus particles, rather than a bacterial adaptation. Conjugation, in the much-studied E. coli system is determined by plasmid genes, and
is an adaptation for transferring copies of the plasmid from one bacterial host to another. It is seldom that a conjugative plasmid
integrates into the host bacterial chromosome, and subsequently transfers part of the host bacterial DNA to another bacterium. Plasmid-
mediated transfer of host bacterial DNA also appears to be an accidental process rather than a bacterial adaptation.

Transformation, unlike transduction or conjugation, depends on numerous bacterial gene products that specifically interact to perform this
complex process and thus transformation is clearly a bacterial adaptation for DNA transfer. In order for a bacterium to bind, take up and
recombine donor DNA into its own chromosome, it must first enter a special physiological state termed competence (see Natural
competence). In Bacillus subtilis, about 40 genes are required for the development of competence.The length of DNA transferred during B.
subtilis transformation can be between a third of a chromosome up to the whole chromosome. Transformation appears to be common
among bacterial species, and thus far at least 60 species are known to have the natural ability to become competent for transformation The
development of competence in nature is usually associated with stressful environmental conditions, and seems to be an adaptation for
facilitating repair of DNA damage in recipient cells.

In ordinary circumstances, transduction, conjugation, and transformation involve transfer of DNA between individual bacteria of the same
species, but occasionally transfer may occur between individuals of different bacterial species and this may have significant
consequences, such as the transfer of antibiotic resistance. In such cases, gene acquisition from other bacteria or the environment is
called horizontal gene transfer and may be common under natural conditions. Gene transfer is particularly important in antibiotic
resistance as it allows the rapid transfer of resistance genes between different pathogens.

Bacteriophages
: Bacteriophage

Bacteriophages are viruses that infect bacteria. Many types of bacteriophage exist, some simply infect and lyse their host bacteria, while others

insert into the bacterial chromosome. A bacteriophage can contain genes that contribute to its host's phenotype: for example, in the evolution of

Escherichia
31
coli O157:H7 and Clostridium botulinum, the toxin genes in an integrated phage converted a harmless ancestral bacterium
into a lethal pathogen.] Bacteria resist phage infection through restriction modification systems that degrade foreign DNA,
and a system that
uses CRISPR sequences to retain fragments of the genomes of phage that the bacteria have come into contact with in the past, which
allows them to block virus replication through a form of RNA interference. This CRISPR system provides bacteria with acquired immunity
to infection.

Behavior

Secretion

Bacteria frequently secrete chemicals into their environment in order to modify it favorably. The secretions are often proteins and may act
as enzymes that digest some form of food in the environment.

Bioluminescence
Milky seas effect

A few bacteria have chemical systems that generate light. This bioluminescence often occurs in bacteria that live in association with fish,
and the light probably serves to attract fish or other large animals.

Multicellularity
Prokaryote § Sociality

Bacteria often function as multicellular aggregates known as biofilms, exchanging a variety of molecular signals for inter-cell
communication, and engaging in coordinated multicellular behavior.

The communal benefits of multicellular cooperation include a cellular division of labor, accessing resources that cannot effectively be
utilized by single cells, collectively defending against antagonists, and optimizing population survival by differentiating into distinct cell
types. For example, bacteria in biofilms can have more than 500 times increased resistance to antibacterial agents than individual
"planktonic" bacteria of the same species.

One type of inter-cellular communication by a molecular signal is called quorum sensing, which serves the purpose of determining
whether there is a local population density that is sufficiently high that it is productive to invest in processes that are only successful if
large numbers of similar organisms behave similarly, as in excreting digestive enzymes or emitting light.

Quorum sensing allows bacteria to coordinate gene expression, and enables them to produce, release and detect autoinducers or
pheromones which accumulate with the growth in cell population.

Movement
Chemotaxis, Flagellum, and Pilus

Many bacteria can move using a variety of mechanisms: flagella are used for swimming through fluids; bacterial gliding and twitching
motility move bacteria across surfaces; and changes of buoyancy allow vertical motion.
32
Flagellum of gram-negative bacteria. The base drives the rotation of the hook and filament.

Swimming bacteria frequently move near 10 body lengths per second and a few as fast as 100. This makes them at least as fast as fish, on
a relative scale.

In bacterial gliding and twitching motility, bacteria use their type IV pili as a grappling hook, repeatedly extending it, anchoring it and then
retracting it with remarkable force (>80 pN).

"Our observations redefine twitching motility as a rapid, highly organized mechanism of bacterial translocation by which Pseudomonas
aeruginosa can disperse itself over large areas to colonize new territories. It is also now clear, both morphologically and genetically, that
twitching motility and social gliding motility, such as occurs in Myxococcus xanthus, are essentially the same process."

— "A re-examination of twitching motility in Pseudomonas aeruginosa" – Semmler, Whitchurch & Mattick (1999)

Flagella are semi-rigid cylindrical structures that are rotated and function much like the propeller on a ship. Objects as small as
bacteria operate a low Reynolds number and cylindrical forms are more efficient than the flat, paddle-like, forms appropriate at human-
size scale.

Bacterial species differ in the number and arrangement of flagella on their surface; some have a single flagellum (monotrichous), a
flagellum at each end (amphitrichous), clusters of flagella at the poles of the cell (lophotrichous), while others have flagella distributed
over the entire surface of the cell (peritrichous). The bacterial flagella is the best-understood motility structure in any organism and is
made of about 20 proteins, with approximately another 30 proteins required for its regulation and assembly. The flagellum is a rotating
structure driven by a reversible motor at the base that uses the electrochemical gradient across the membrane for power.This motor
drives the motion of the filament, which acts as a propeller.

Many bacteria (such as E. coli) have two distinct modes of movement: forward movement (swimming) and tumbling. The tumbling allows
them to reorient and makes their movement a three-dimensional random walk. (See external links below for link to videos.) The flagella
of a unique group of bacteria, the spirochaetes, are found between two membranes in the periplasmic space. They have a distinctive

helical body that twists about as it moves.]

Motile bacteria are attracted or repelled by certain stimuli in behaviors called taxes: these include chemotaxis, phototaxis, energy taxis,
and magnetotaxis. In one peculiar group, the myxobacteria, individual bacteria move together to form waves of cells that then
differentiate to form fruiting bodies containing spores. Themyxobacteria move only when on solid surfaces, unlike E. coli, which is
motile in liquid or solid media.

Several Listeria and Shigella species move inside host cells by usurping the cytoskeleton, which is normally used to move organelles inside
the cell. By promoting actinpolymerization at one pole of their cells, they can form a kind of tail that pushes them through the host cell's
cytoplasm.

Classification and identification

33
Streptococcus mutans visualized with a Gram stain

Bacterial taxonomy

: Scientific classification, Systematics, Bacterial phyla, and Clinical pathology

Classification seeks to describe the diversity of bacterial species by naming and grouping organisms based on similarities. Bacteria can
be classified on the basis of cell structure, cellular metabolism or on differences in cell components, such as DNA, fatty acids,
pigments, antigens and quinones. While these schemes allowed the identification and classification of bacterial strains, it was unclear
whether these differences represented variation between distinct species or between strains of the same species. This uncertainty was due

to the lack of distinctive structures in most bacteria, as well as lateral gene transfer between unrelated species. ] Due to lateral gene
transfer, some closely related bacteria can have very different morphologies and metabolisms. To overcome this uncertainty, modern
bacterial classification emphasizes molecular systematics, using genetic techniques such asguanine cytosine ratio determination,
genome-genome hybridization, as well as sequencing genes that have not undergone extensive lateral gene transfer, such as the rRNA
gene.Classification of bacteria is determined by publication in the International Journal of Systematic Bacteriology, and Bergey's Manual of
Systematic Bacteriology. The International Committee on Systematic Bacteriology (ICSB) maintains international rules for the naming of
bacteria and taxonomic categories and for the ranking of them in the International Code of Nomenclature of Bacteria.

The term "bacteria" was traditionally applied to all microscopic, single-cell prokaryotes. However, molecular systematics showed
prokaryotic life to consist of two separatedomains, originally called Eubacteria and Archaebacteria, but now called Bacteria and Archaea
that evolved independently from an ancient common ancestor. The archaea and eukaryotes are more closely related to each other than
either is to the bacteria. These two domains, along with Eukarya, are the basis of the three-domain system, which is currently the most
widely used classification system in
microbiolology. However, due to the relatively recent introduction of molecular systematics and a rapid increase in the number of genome
sequences that are available, bacterial classification remains a changing and expanding field. For example, a few biologists argue that the
Archaea and Eukaryotes evolved from gram-positive bacteria.

The identification of bacteria in the laboratory is particularly relevant in medicine, where the correct treatment is determined by the
bacterial species causing an infection. Consequently, the need to identify human pathogens was a major impetus for the development of
techniques to identify bacteria.

34
Phylogenetic tree showing the diversity of bacteria, compared to other organisms. Eukaryotes are colored red, archaea green and bacteria
blue.

The Gram stain, developed in 1884 by Hans Christian Gram, characterises bacteria based on the structural characteristics of their cell walls. [
The thick layers of peptidoglycan in the "gram-positive" cell wall stain purple, while the thin "gram-negative" cell wall appears pink. By
combining morphology and Gram-staining, most bacteria can be classified as belonging to one of four groups (gram-positive cocci, gram-
positive bacilli, gram-negative cocci and gram-negative bacilli). Some organisms are best identified by stains other than the Gram stain,
particularly mycobacteria or Nocardia, which show acid-fastness onZiehl–Neelsen or similar stains. Other organisms may need to be
identified by their growth in special media, or by other techniques, such as serology.

Culture techniques are designed to promote the growth and identify particular bacteria, while restricting the growth of the other bacteria in
the sample. Often these techniques are designed for specific specimens; for example, a sputum sample will be treated to identify organisms
that cause pneumonia, while stool specimens are cultured on selective media to identify organisms that cause diarrhoea, while preventing
growth of non-pathogenic bacteria. Specimens that are normally sterile, such as blood, urineor spinal fluid, are cultured under conditions
designed to grow all possible organisms. Once a pathogenic organism has been isolated, it can be further characterised by its morphology,
growth patterns (such as aerobic or anaerobic growth), patterns of hemolysis, and staining.

As with bacterial classification, identification of bacteria is increasingly using molecular methods. Diagnostics using DNA-based tools, such
]
as polymerase chain reaction, are increasingly popular due to their specificity and speed, compared to culture-based methods. These methods also
allow the detection and identification of "viable but nonculturable" cells that are metabolically active but non-dividing. However, even using these
improved methods, the total number of bacterial species is not known and cannot even be estimated with any certainty. Following present
[149]
classification, there are a little less than 9,300 known species of prokaryotes, which includes bacteria and archaea; but attempts to estimate the
7 9
true number of bacterial diversity have ranged from 10 to 10 total species – and even these diverse estimates may be off by many orders of
magnitude.

Interactions with other organisms

Despite their apparent simplicity, bacteria can form complex associations with other organisms. These symbiotic associations can be
divided
into parasitism, mutualism andcommensalism. Due to their small size, commensal bacteria are ubiquitous and grow on animals and
plants exactly as they will grow on any other surface. However, their growth can be increased by warmth and sweat, and large populations
of these organisms in humans are the cause of body odor.

Predators

Some species of bacteria kill and then consume other microorganisms, these species are called predatory bacteria. These include
organisms such as Myxococcus xanthus, which forms swarms of cells that kill and digest any bacteria they encounter. Other bacterial
predators either attach to their prey in order to digest them and absorb nutrients, such as Vampirovibrio chlorellavorus or invade another
cell and multiply inside the cytosol, such as Daptobacter. These predatory bacteria are thought to have evolved from saprophages that
consumed dead microorganisms, through adaptations that allowed them to entrap and kill other organisms.

35
Mutualists

Certain bacteria form close spatial associations that are essential for their survival. One such mutualistic association, called interspecies
hydrogen transfer, occurs between clusters of anaerobic bacteria that consume organic acids, such as butyric acid or propionic acid,
and produce hydrogen, and methanogenic Archaea that consume hydrogen. The bacteria in this association are unable to consume the
organic acids as this reaction produces hydrogen that accumulates in their surroundings. Only the intimate association with the
hydrogen-consuming Archaea keeps the hydrogen concentration low enough to allow the bacteria to grow.

In soil, microorganisms that reside in the rhizosphere (a zone that includes the root surface and the soil that adheres to the root after gentle shaking)
carry out nitrogen fixation, converting nitrogen gas to nitrogenous compounds. This serves to provide an easily absorbable form of nitrogen for many
plants, which cannot fix nitrogen themselves. Many other bacteria are found as symbionts in humans and other organisms. For example, the
presence of over 1,000 bacterial species in the normal human gut flora of the intestines can contribute to gut immunity, synthesise vitamins, such as
folic
acid, vitamin K and biotin, convert sugars to lactic acid (see Lactobacillus), as well as fermenting complex undigestible carbohydrates. The
presence of this gut flora also inhibits the growth of potentially pathogenic bacteria (usually throughcompetitive exclusion) and these
beneficial bacteria are consequently sold as probiotic dietary supplements.

Color-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading cultured human cells

Pathogens
Main article: Pathogenic bacteria

If bacteria form a parasitic association with other organisms, they are classed as pathogens. Pathogenic bacteria are a major cause of
human death and disease and cause infections such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosyand
tuberculosis. A pathogenic cause for a known medical disease may only be discovered many years after, as was the case withHelicobacter
pylori and peptic ulcer disease. Bacterial diseases are also important in agriculture, with bacteria causing leaf spot, fire blight and wilts in
plants, as well as Johne's disease, mastitis, salmonella and anthrax in farm animals.

Each species of pathogen has a characteristic spectrum of interactions with its human hosts. Some organisms, such
asStaphylococcus or Streptococcus, can cause skin infections, pneumonia, meningitis and even overwhelming sepsis, a
systemicinflammatory response producing shock, massive vasodilation and death Yet these organisms are also part of the normal human
flora and usually exist on the skin or in the nose without causing any disease at all. Other organisms invariably cause disease in humans,
such as the Rickettsia, which are obligate intracellular parasites able to grow and reproduce only within the cells of other organisms. One
species of Rickettsia causes typhus, while another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate
intracellular parasites, contains species that can cause pneumonia, or urinary tract infection and may be involved in coronary heart disease
Finally, some species, such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium avium, are opportunistic
pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis.

36
Overview of bacterial infections and main species involved.

Bacterial infections may be treated with antibiotics, which are classified as bacteriocidal if they kill bacteria, orbacteriostatic if they just
prevent bacterial growth. There are many types of antibiotics and each class inhibitsa process that is different in the pathogen from that
found in the host. An example of how antibiotics produce selective toxicity are chloramphenicol and puromycin, which inhibit the bacterial
ribosome, but not the structurally different eukaryotic ribosome. Antibiotics are used both in treating human disease and inintensive
farming to promote animal growth, where they may be contributing to the rapid development ofantibiotic resistance in bacterial
populations. Infections can be prevented by antiseptic measures such as sterilizing the skin prior to piercing it with the needle of a syringe,
and by proper care of indwelling catheters. Surgical and dental instruments are also sterilized to prevent contamination by bacteria.
Disinfectants such as bleach are used to kill bacteria or other pathogens on surfaces to prevent contamination and further reduce the risk
of infection.

Significance in technology and industry

Economic importance of bacteria

Bacteria, often lactic acid bacteria, such as Lactobacillus and Lactococcus, in combination with yeasts andmolds, have been used for
thousands of years in the preparation of fermented foods, such as cheese,pickles, soy sauce, sauerkraut, vinegar, wine and yogurt.

The ability of bacteria to degrade a variety of organic compounds is remarkable and has been used in waste processing and
bioremediation. Bacteria capable of digesting the hydrocarbons in petroleum are often used to clean up oil spills. Fertilizer was added to
some of the beaches in Prince William Sound in an attempt to promote the growth of these naturally occurring bacteria after the 1989
Exxon Valdez oil spill. These efforts were effective on beaches that were not too thickly covered in oil. Bacteria are also used for the
bioremediation of industrial toxic wastes. In the chemical industry, bacteria are most important in the production of enantiomerically pure
chemicals for use as pharmaceuticals or agrichemicals.

Bacteria can also be used in the place of pesticides in the biological pest control. This commonly involves Bacillus thuringiensis (also
called BT), a gram-positive, soil dwelling bacterium. Subspecies of this bacteria are used as a Lepidopteran-specific insecticides under
trade names such as Dipel and Thuricide Because of their specificity, these pesticides are regarded as environmentally friendly, with little
or no effect on humans, wildlife, pollinators and most other beneficial insects

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Because of their ability to quickly grow and the relative ease with which they can be manipulated, bacteria are the workhorses for the fields
of molecular biology, genetics andbiochemistry. By making mutations in bacterial DNA and examining the resulting phenotypes,
scientists can determine the function of genes, enzymes and metabolic pathways in bacteria, then apply this knowledge to more
complex organisms This aim of understanding the biochemistry of a cell reaches its most complex expression in the synthesis of huge
amounts of enzyme kinetic and gene expression data into mathematical models of entire organisms. This is achievable in some well-
studied bacteria, with models of Escherichia
coli metabolism now being produced and tested. This understanding of bacterial metabolism and genetics allows the use of
biotechnology to bioengineer bacteria for the production of therapeutic proteins, such as insulin, growth factors, or antibodies

Because of their importance for research in general, samples of bacterial strains are isolated and preserved in Biological Resource
Centers. This ensures the availability of the strain to scientists worldwide.

The scope of neuroscience has broadened to include different approaches used to study the molecular, cellular, developmental, structural,
functional, evolutionary, computational, and medical aspects of the nervous system. The techniques used by neuroscientists have also
expanded enormously, from molecular and cellular studies of individual nerve cells to imaging of sensory and motor tasks in the brain.
Recent theoretical advances in neuroscience have also been aided by the study of neural networks.

The operations of individual brain cells are now understood in considerable detail but the way they cooperate in ensembles of millions is
yet to be solved.Recent models in modern neuroscience treat the brain as a biological computer, very different in mechanism from an
electronic computer, but similar in the sense that it acquires information from the surrounding world, stores it, and processes it in a variety
of ways, analogous to the central processing unit (CPU) in a computer.

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CROSS SECTIONAL STRUCTURE OF THE HUMAN BRAIN

Structure features of the human brain.

General features

The adult human brain weighs on average about 1.3–1.5 kg (2.9–3.3 lb), or about 2% of total body weight, with a volume of around 1260
cm3 in men and 1130 cm3 in women, although there is substantial individual variation. Neurological differences between the sexes have not
been shown to correlate in any simple way with IQ or other measures of cognitive performance.

The human brain is composed of neurons, glial cells, and blood vessels. The number of neurons is estimated at roughly 100 billion.The
adult human brain is estimated to contain 86±8 billion neurons, with a roughly equal number (85±10 billion) of non-neuronal cells. Out of
these, 16 billion (or 19% of all brain neurons) are located in the cerebral cortex (including subcortical white matter), 69 billion (or 80% of
all brain neurons) are in the cerebellum.

The cerebral hemispheres (the cerebrum) form the largest part of the human brain and are situated above other brain structures. They are covered
with a cortical layer (the cerebral cortex) which has a convoluted topography. Underneath the cerebrum lies the brainstem, resembling a stalk on
which the cerebrum is attached. At the rear of the brain, beneath the cerebrum and behind the brainstem, is the cerebellum, a structure with a
horizontally furrowed surface, the cerebellar cortex, that makes it look different from any other brain area. The same

39
structures are present in other mammals, although they vary considerably in relative size. As a rule, the smaller the cerebrum, the less
convoluted the cortex. The cortex of a rat or mouse is almost perfectly smooth. The cortex of a dolphin or whale, on the other hand, is
more convoluted than the cortex of a human.

The living brain is very soft, having a gel-like consistency similar to soft tofu. Although referred to as grey matter, the live cortex is pinkish-
beige in color and slightly off-white in the interior.

The shape and size of the brain varies greatly in different species, and identifying common features is often difficult. Nevertheless, there are
a number of principles of brain architecture that apply across a wide range of species. Some aspects of brain structure are common to
almost the entire range of animal species; others distinguish "advanced" brains from more primitive ones, or distinguish vertebrates from
invertebrates.

The simplest way to gain information about brain anatomy is by visual inspection, but many more sophisticated techniques have been
developed. Brain tissue in its natural state is too soft to work with, but it can be hardened by immersion in alcohol or other fixatives, and
then sliced apart for examination of the interior. Visually, the interior of the brain consists of areas of so-called grey matter, with a dark
color, separated by areas of white matter, with a lighter color. Further information can be gained by staining slices of brain tissue with a
variety of chemicals that bring out areas where specific types of molecules are present in high concentrations. It is also possible to
examine the microstructure of brain tissue using a microscope, and to trace the pattern of connections from one brain area to another.

The human brain has many properties that are common to all vertebrate brains, including a basic division into three parts called the forebrain,

midbrain, and hindbrain, with interconnected fluid-filled ventricles, and a set of generic vertebrate brain structures including the medulla oblongata

and pons of the brainstem, the cerebellum, optic tectum, thalamus, hypothalamus, basal ganglia, olfactory bulb, and many others.

As a mammalian brain, the human brain has special features that are common to all mammalian brains, most notably a six-layered
cerebral cortex and a set of associated structures, including the hippocampus and amygdala. The upper surface of the forebrain of other
vertebrates is covered in a layer of neural tissue called the pallium. The pallium is a relatively simple three-layered cell structure. The
hippocampus and the amygdala originate from the pallium but in mammals they are much more complex.

As a primate brain, the human brain has a much larger cerebral cortex, in proportion to body size, than most mammals, and a very
highly developed visual system. The shape of the brain within the skull is also altered somewhat as a consequence of the upright
position in which primates hold their heads.

As a hominid brain, the human brain is substantially enlarged even in comparison to the brain of a typical monkey. The sequence of
evolution from Australopithecus (four million years ago) to Homo sapiens (modern man) was marked by a steady increase in brain size,
particularly in the frontal lobes, which are associated with a variety of high-level cognitive functions.

Humans and other primates have some differences in gene sequence, and genes are differentially expressed in many brain regions. The

functional differences between the human brain and the brains of other animals also arise from many gene–environment interactions.

The neuroimmune system of the brain is structurally distinct from the peripheral immune system which protects the rest of the body;
in particular, the immune system is composed primarily of hematopoietic cells and anatomical barriers, while the neuroimmune
system is composed of glia, mast cells, and various brain barriers (e.g., blood–brain barrier and blood-cerebrospinal fluid barrier).

CEREBRAL CORTEX

The dominant feature of the human brain is corticalization. The cerebral cortex in humans is so large that it overshadows every other part of the

brain. A few subcortical structures show alterations reflecting this trend. The cerebellum, for example, has a medial zone connected mainly to

subcortical motor areas, and a lateral zone connected primarily to the cortex. In humans the lateral zone takes up a much larger fraction of

40
the cerebellum than in most other mammalian species. Corticalization is reflected in function as well as structure. In a rat, surgical
removal of the entire cerebral cortex leaves an animal that is still capable of walking around and interacting with the environment.

In a human, comparable cerebral cortex damage produces a permanent state of coma. The amount of association cortex, relative to the
other two categories of sensory and motor, increases dramatically as one goes from simpler mammals, such as the rat and the cat, to more
complex ones, such as the chimpanzee and the human. A gene present in the human genome but not in the chimpanzee (ArhGAP11B)
seems to play a major role in corticalization. ArhGAP11B and human encephalisationThe cerebral cortex is essentially a sheet of neural
tissue, folded in a way that allows a large surface area to fit within the confines of the skull. When unfolded, each cerebral hemisphere has
a total surface area of about 1.3 square feet (0.12 m2). Each cortical ridge is called a gyrus, and each groove or fissure separating one gyrus
from another is called a sulcus

CORTICAL DIVISIONS

The cerebral cortex is nearly symmetrical with left and right hemispheres that are approximate mirror images of each other. Each
hemisphere is conventionally divided into four "lobes", the frontal lobe, parietal lobe, occipital lobe, and temporal lobe. With one exception,
this division into lobes does not derive from the structure of the cortex, though the lobes are named after the bones of the skull that overlie
them, the frontal bone, parietal bone, temporal bone, and occipital bone. The borders between lobes lie beneath the sutures that link the
skull bones together. The exception is the border between the frontal and parietal lobes, which lies behind the corresponding suture; instead
it follows the anatomical boundary of the central sulcus, a deep fold in the brain's structure where the primary somatosensory cortex and
primary motor cortex meet.

Because of the arbitrary way most of the borders between lobes are demarcated, they have little functional significance. With the exception
of the occipital lobe, a small area that is entirely dedicated to vision, each of the lobes contains a variety of brain areas that have minimal
functional relationship. The parietal lobe, for example, contains areas involved in somatosensation, hearing, language, attention, and spatial
cognition. In spite of this heterogeneity, the division into lobes is convenient for reference. The main functions of the frontal lobe are to
control attention, abstract thinking, behavior, problem solving tasks, and physical reactions and personality. The occipital lobe is the smallest
lobe; its main functions are visual reception, visual-spatial processing, movement, and color recognition. The temporal lobe controls
auditory and visual memories, language, and some hearing and speech.

Although there are enough variations in the shape and placement of gyri and sulci (cortical folds) to make every brain unique, most
human brains show sufficiently consistent patterns of folding that allow them to be named. Many of the gyri and sulci are named

according to the location on the lobes or other major folds on the cortex. These include:

Superior, Middle, Inferior frontal gyrus: in reference to the frontal lobe

Medial longitudinal fissure, which separates the left and right cerebral hemispheres
Precentral and Postcentral sulcus: in reference to the central sulcus, which separates the frontal lobe from the parietal
lobe Lateral sulcus, which divides the frontal lobe and parietal lobe above from the temporal lobe below
Parieto-occipital sulcus, which separates the parietal lobes from the occipital lobes, is seen to some small extent on the
lateral surface of the hemisphere, but mainly on the medial surface.
Trans-occipital sulcus: in reference to the occipital lobe

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Functions of the Cortex.

Functions of the cortex are divided it into three categories of regions: One consists of the primary sensory areas, which receive signals from
the sensory nerves and tracts by way of relay nuclei in the thalamus. Primary sensory areas include the visual area of the occipital lobe, the
auditory area in parts of the temporal lobe and insular cortex, and the somatosensory cortex in the parietal lobe. A second category is the
primary motor cortex, which sends axons down to motor neurons in the brainstem and spinal cord. This area occupies the rear portion of the
frontal lobe, directly in front of the somatosensory area. The third category consists of the remaining parts of the cortex, which are called the
association areas. These areas receive input from the sensory areas and lower parts of the brain and are involved in the complex processes of
perception, thought, and decision-making.

Cytoarchitecture

Different parts of the cerebral cortex are involved in different cognitive and behavioral functions. The differences show up in a number of ways: the
effects of localized brain damage, regional activity patterns exposed when the brain is examined using functional imaging techniques, connectivity
with subcortical areas, and regional differences in the cellular architecture of the cortex. Neuroscientists describe most of the cortex—the part they
call the neocortex—as having six layers, but not all layers are apparent in all areas, and even when a layer is present, its thickness and cellular
organization may vary. Scientists have constructed maps of cortical areas on the basis of variations in the appearance of the layers as seen with a
microscope. One of the most widely used schemes came from KorbinianBrodmann, who split the cortex into 51 different areas and assigned each a
number (many of these Brodmann areas have since been subdivided). For example, Brodmann area 1 is the primary somatosensory cortex, Brodmann
area 17 is the primary visual cortex, and Brodmann area 25 is the anterior cingulate cortex.

Many of the brain areas Brodmann defined have their own complex internal structures. In a number of cases, brain areas are organized into
"topographic maps", where adjoining bits of the cortex correspond to adjoining parts of the body, or of some more abstract entity. A simple
example of this type of correspondence is the primary motor cortex, a strip of tissue running along the anterior edge of the central sulcus, shown in
the image to the right. Motor areas innervating each part of the body arise from a distinct zone, with neighboring body parts represented by
neighboring zones. Electrical stimulation of the cortex at any point causes a muscle-contraction in the represented body part. This "somatotopic"
representation is not evenly distributed, however. The head, for example, is represented by a region about three times as large as the zone for the
entire back and trunk. The size of any zone correlates to the precision of motor control and sensory discrimination possible. The areas for the lips,
fingers, and tongue are particularly large, considering the proportional size of their represented body parts.

In visual areas, the maps are retinotopic—that is, they reflect the topography of the retina, the layer of light-activated neurons lining the
back of the eye. In this case too the representation is uneven: the fovea—the area at the center of the visual field—is greatly
overrepresented compared to the periphery. The visual circuitry in the human cerebral cortex contains several dozen distinct retinotopic
maps, each devoted to analyzing the visual input stream in a particular way. The primary visual cortex , which is the main recipient of direct
input from the visual part of the thalamus, contains many neurons that are most easily activated by edges with a particular orientation
moving across a particular point in the visual field. Visual areas farther downstream extract features such as color, motion, and shape.

In auditory areas, the primary map is tonotopic. Sounds are parsed according to frequency (i.e., high pitch vs. low pitch) by subcortical
auditory areas, and this parsing is reflected by the primary auditory zone of the cortex. As with the visual system, there are a number of
tonotopic cortical maps, each devoted to analyzing sound in a particular way.

Within a topographic map there can sometimes be finer levels of spatial structure. In the primary visual cortex, for example, where the
main organization is retinotopic and the main responses are to moving edges, cells that respond to different edge-orientations are
spatially segregated from one another.

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Development of the Human Brain.

Studies report that three primary structures are formed in the sixth gestational week. These are the forebrain, the midbrain, and the
hindbrain, also known as the prosencephalon, mesencephalon, and the rhombencephalon respectively. Five secondary structures from
these in the seventh gestational week. These are the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon
which later become the lateral ventricles, third ventricles, aqueduct, and upper and lower parts of the fourth ventricle from the
telencephalon to the myelencephalon, during adulthood. Cortical white matter increases from childhood (~9 years) to adolescence (~14
years), most notably in the frontal and parietal cortices. Cortical grey matter development peaks at ~12 years of age in the frontal and
parietal cortices, and 17 years in the temporal lobes (with the superior temporal cortex being last to mature). In terms of grey matter loss,
the sensory and motor regions mature first, followed by other cortical regions. One of the most intriguing facts of human brains is the
appearance of cortical folds which first takes place during 24 and 32 weeks of gestation.

Neural Development.

Neural development refers to the processes that generate, shape, and reshape the nervous system, from the earliest stages of
embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to
address the underlying mechanisms. The field draws on both neuroscience and developmental biology to provide insight into the cellular and
molecular mechanisms by which complex nervous systems develop. Defects in neural development can lead to cognitive and motor
impairment, as well as neurological disorders such as Rett syndrome, and intellectual disability.

OVERVIEW OF THE BRAIN DEVELOPMENT.

The nervous system is derived from the ectoderm—the outermost tissue layer—of the embryo. In the third week of development the
neuroectoderm appears and forms the neural plate along the dorsal side of the embryo. This neural plate is the source of the majority of
neurons and glial cells in the mature human. A groove forms in the neural plate and, by week four of development, the neural plate wraps in
on itself to make a hollow neural tube. Because this neural tube later gives rise to the brain and spinal cord any mutations at this stage in
development can lead to lethal deformities like anencephaly or lifelong disabilities like spina bifida. Later development yields areas known
as the two lateral ventricles and the third ventricle. The telencephalon, which eventually encompasses the two lateral ventricles, gives rise to
areas of the brain known as the Basal Ganglia and the Limbic System. Gradually some of the cells stop dividing and differentiate into neurons
and glial cells, which are the main cellular components of the brain. The newly generated neurons migrate to different parts of the
developing brain to self-organize into different brain structures. Once the neurons have reached their regional positions, they extend axons
and dendrites, which allow them to communicate with other neurons via synapses. Synaptic communication between neurons leads to the
establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior. The human brain does most of
its development within the first 20 years of life.

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OVERVIEW OF THE BRAIN DEVELOPMENT.

Aspects of neural development

Some landmarks of neural development include the birth and differentiation of neurons from stem cell precursors, the migration of
immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons and dendrites from neurons, guidance
of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their
postsynaptic partners, and finally the lifelong changes in synapses, which are thought to underlie learning and memory.

Typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independent mechanisms and activity-
dependent mechanisms. Activity-independent mechanisms are generally believed to occur as hardwired processes determined by genetic
programs played out within individual neurons. These include differentiation, migration and axon guidance to their initial target areas.
These processes are thought of as being independent of neural activity and sensory experience. Once axons reach their target areas,
activity-dependent mechanisms come into play. Although synapse formation is an activity-independent event, modification of synapses
and synapse elimination requires neural activity.

Developmental neuroscience uses a variety of animal models including mice Musmusculus, the fruit fly Drosophila melanogaster,
the zebrafishDaniorerio, Xenopuslaevis tadpoles and the worm Caenorhabditiselegans, among others.

Neural induction

During early embryonic development the ectoderm becomes specified to give rise to the epidermis (skin) and the neural plate. The
conversion of undifferentiated ectoderm to neuro-ectoderm requires signals from the mesoderm. At the onset of gastrulation presumptive
mesodermal cells move through the dorsal blastopore lip and form a layer in between the endoderm and the ectoderm. These mesodermal
cells that migrate along the dorsal midline give rise to a structure called the notochord. Ectodermal cells overlying the notochord develop
into the neural plate in response to a diffusible signal produced by the notochord. The remainder of the ectoderm gives rise to the
epidermis (skin). The ability of the mesoderm to convert the overlying ectoderm into neural tissue is called neural induction.

The neural plate folds outwards during the third week of gestation to form the neural groove. Beginning in the future neck region, the
neural folds of this groove close to create the neural tube. The formation of the neural tube from the ectoderm is called neurulation. The
ventral part of the neural tube is called the basal plate; the dorsal part is called the alar plate. The hollow interior is called the neural canal.
By the end of the fourth week of gestation, the open ends of the neural tube, called the neuropores, close off.

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A transplanted blastopore lip can convert ectoderm into neural tissue and is said to have an inductive effect. Neural inducers are molecules
that can induce the expression of neural genes in ectoderm explants without inducing mesodermal genes as well. Neural induction is often
studied in xenopus embryos since they have a simple body pattern and there are good markers to distinguish between neural and non-neural
tissue. Examples of neural inducers are the molecules noggin and chordin.

When embryonic ectodermal cells are cultured at low density in the absence of mesodermal cells they undergo neural differentiation
(express neural genes), suggesting that neural differentiation is the default fate of ectodermal cells. In explant cultures (which allow direct
cell-cell interactions) the same cells differentiate into epidermis. This is due to the action of BMP4 (a TGF-β family protein) that induces
ectodermal cultures to differentiate into epidermis. During neural induction, noggin and chordin are produced by the dorsal mesoderm
(notochord) and diffuse into the overlying ectoderm to inhibit the activity of BMP4. This inhibition of BMP4 causes the cells to differentiate
into neural cells. Inhibition of TGF-β and BMP (bone morphogenetic protein) signaling can efficiently induce neural tissue from human
pluripotent stem cells,[5] a model of early human development.

Regionalization

Late in the fourth week, the superior part of the neural tube flexes at the level of the future midbrain—the mesencephalon. Above
the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain).

The optical vesicle (which eventually become the optic nerve, retina and iris) forms at the basal plate of the prosencephalon. The alar plate
of the prosencephalon expands to form the cerebral hemispheres (the telencephalon) whilst its basal plate becomes the diencephalon.
Finally, the optic vesicle grows to form an optic outgrowth.

Patterning of the nervous system

In chordates, dorsal ectoderm forms all neural tissue and the nervous system. Patterning occurs due to specific environmental
conditions - different concentrations of signaling molecules

Dorsoventral axis

The ventral half of the neural plate is controlled by the notochord, which acts as the 'organiser'. The dorsal half is controlled by the
ectoderm plate, which flanks either side of the neural plate.

Ectoderm follows a default pathway to become neural tissue. Evidence for this comes from single, cultured cells of ectoderm, which go on
to form neural tissue. This is postulated to be because of a lack of BMPs, which are blocked by the organiser. The organiser may produce
molecules such as follistatin, noggin and chordin that inhibit BMPs.

The ventral neural tube is patterned by Sonic Hedgehog (Shh) from the notochord, which acts as the inducing tissue. Notochord-derived Shh
signals to the floor plate, and induces Shh expression in the floor plate. Floor plate-derived Shh subsequently signals to other cells in the
neural tube, and is essential for proper specification of ventral neuron progenitor domains. Loss of Shh from the notochord and/or floor
plate prevents proper specification of these progenitor domains. Shh binds Patched1, relieving Patched-mediated inhibition of Smoothened,
leading to activation of Gli family of transcription factors (Gli1, Gli2, and Gli3) transcription factors.

In this context Shh acts as a morphogen - it induces cell differentiation dependent on its concentration. At low concentrations it forms
ventral interneurones, at higher concentrations it induces motor neuron development, and at highest concentrations it induces floor plate
differentiation. Failure of Shh-modulated differentiation causes holoprosencephaly.

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The dorsal neural tube is patterned by BMPs from the epidermal ectoderm flanking the neural plate. These induce sensory interneurones
by activating Sr/Thr kinases and altering SMAD transcription factor levels.

Rostrocaudal (Anteroposterior) axis

Signals that control anteroposterior neural development include FGF and retinoic acid, which act in the hindbrain and spinal cord. The
hindbrain, for example, is patterned by Hox genes, which are expressed in overlapping domains along the anteroposterior axis under the
control of retinoic acid. The 3' genes in the Hox cluster are induced by retinoic acid in the hindbrain, whereas the 5' Hox genes are not
induced by retinoic acid and are expressed more posteriorly in the spinal cord. Hoxb-1 is expressed in rhombomere 4 and gives rise to the
facial nerve. Without this Hoxb-1 expression, a nerve similar to the trigeminal nerve arises.

Neuronal migration

Neuronal migration is the method by which neurons travel from their origin or birthplace to their final position in the brain. There are several
ways they can do this, e.g. by radial migration or tangential migration. This time lapse displays sequences of radial migration (also known as
glial guidance) and somal translocation.

Radial migration

Neuronal precursor cells proliferate in the ventricular zone of the developing neocortex. The first postmitotic cells to migrate from the
preplate, which are destined to become Cajal-Retzius cells and subplate neurons. These cells do so by somal translocation. Neurons
migrating with this mode of locomotion are bipolar and attach the leading edge of the process to the pia. The soma is then transported to
the pial surface by nucleokinesis, a process by which a microtubule "cage" around the nucleus elongates and contracts in association with
the centrosome to guide the nucleus to its final destination. Radial glia, whose fibers serve as a scaffolding for migrating cells, can itself
divide or translocate to the cortical plate and differentiate either into astrocytes or neurons.Somal translocation can occur at any time during
development.

Subsequent waves of neurons split the preplate by migrating along radial glial fibres to form the cortical plate. Each wave of migrating
cells travel past their predecessors forming layers in an inside-out manner, meaning that the youngest neurons are the closest to the
surface. It is estimated that glial guided migration represents 90% of migrating neurons in human and about 75% in rodents.

Tangential migration

Most interneurons migrate tangentially through multiple modes of migration to reach their appropriate location in the cortex. An example of

tangential migration is the movement of interneurons from the ganglionic eminence to the cerebral cortex. One example of ongoing tangential

migration in a mature organism, observed in some animals, is the rostral migratory stream connecting subventricular zone and olfactory bulb.

Axophilic migration

Many neurons migrating along the anterior-posterior axis of the body use existing axon tracts to migrate along; this is called axophilic
migration. An example of this mode of migration is in GnRH-expressing neurons, which make a long journey from their birthplace in the
nose, through the forebrain, and into the hypothalamus. Many of the mechanisms of this migration have been worked out, starting with
the extracellular guidance cues that trigger intracellular signaling. These intracellular signals, such as calcium signaling, lead to actin and
microtubule cytoskeletal dynamics, which produce cellular forces that interact with the extracellular environment through cell adhesion
proteins to cause the movement of these cells.

Other modes of migration

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There is also a method of neuronal migration called multipolar migration. This is seen in multipolar cells, which are abundantly present in
the cortical intermediate zone. They do not resemble the cells migrating by locomotion or somal translocation. Instead these multipolar
cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers.

Neurotrophic factors

The survival of neurons is regulated by survival factors, called trophic factors. The neurotrophic hypothesis was formulated by Victor
Hamburger and Rita Levi Montalcini based on studies of the developing nervous system. Victor Hamburger discovered that implanting an
extra limb in the developing chick led to an increase in the number of spinal motor neurons. Initially he thought that the extra limb was
inducing proliferation of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during
normal development, and the extra limb prevented this cell death. According to the neurotrophic hypothesis, growing axons compete for
limiting amounts of target-derived trophic factors and axons that fail to receive sufficient trophic support die by apoptosis. It is now clear
that factors produced by a number of sources contribute to neuronal survival.

Nerve Growth Factor (NGF): Rita Levi Montalcini and Stanley Cohen purified the first trophic factor, Nerve Growth Factor (NGF), for
which they received the Nobel Prize. There are three NGF-related trophic factors: BDNF, NT3, and NT4, which regulate survival of various
neuronal populations. The Trk proteins act as receptors for NGF and related factors. Trk is a receptor tyrosine kinase. Trk dimerization
and phosphorylation leads to activation of various intracellular signaling pathways including the MAP kinase, Akt, and PKC pathways.

CNTF: Ciliaryneurotrophic factor is another protein that acts as a survival factor for motor neurons. CNTF acts via a receptor complex that
includes CNTFRα, GP130, and LIFRβ. Activation of the receptor leads to phosphorylation and recruitment of the JAK kinase, which in turn
phosphorylates LIFRβ. LIFRβ acts as a docking site for the STAT transcription factors. JAK kinase phosphorylates STAT proteins, which
dissociate from the receptor and translocate to the nucleus to regulate gene expression.

GDNF: Glial derived neurotrophic factor is a member of the TGFb family of proteins, and is a potent trophic factor for striatal neurons.
The functional receptor is a heterodimer, composed of type 1 and type 2 receptors. Activation of the type 1 receptor leads to
phosphorylation of Smad proteins, which translocate to the nucleus to activate gene expression.

Synapse formation

Neuromuscular junction

Much of our understanding of synapse formation comes from studies at the neuromuscular junction. The transmitter at this synapse is
acetylcholine. The acetylcholine receptor (AchR) is present at the surface of muscle cells before synapse formation. The arrival of the nerve
induces clustering of the receptors at the synapse. McMahan and Sanes showed that the synaptogenic signal is concentrated at the basal
lamina. They also showed that the synaptogenic signal is produced by the nerve, and they identified the factor as Agrin. Agrin induces
clustering of AchRs on the muscle surface and synapse formation is disrupted in agrin knockout mice. Agrin transduces the signal via MuSK
receptor to rapsyn. Fischbach and colleagues showed that receptor subunits are selectively transcribed from nuclei next to the synaptic site.
This is mediated by neuregulins.

In the mature synapse each muscle fiber is innervated by one motor neuron. However, during development many of the fibers are
innervated by multiple axons. Lichtman and colleagues have studied the process of synapses elimination. This is an activity-dependent
event. Partial blockage of the receptor leads to retraction of corresponding presynaptic terminals.

CNS synapses

47
Agrin appears not to be a central mediator of CNS synapse formation and there is active interest in identifying signals that mediate CNS
synaptogenesis. Neurons in culture develop synapses that are similar to those that form in vivo, suggesting that synaptogenic signals can function
properly in vitro. CNS synaptogenesis studies have focused mainly on glutamatergic synapses. Imaging experiments show that dendrites are highly
dynamic during development and often initiate contact with axons. This is followed by recruitment of postsynaptic proteins to the site of contact.
Stephen Smith and colleagues have shown that contact initiated by dendritic filopodia can develop into synapses.

Induction of synapse formation by glial factors: Barres and colleagues made the observation that factors in glial conditioned media
induce synapse formation in retinal ganglion cell cultures. Synapse formation in the CNS is correlated with astrocyte differentiation
suggesting that astrocytes might provide a synaptogenic factor. The identity of the astrocytic factors is not yet known.

Neuroligins and SynCAM as synaptogenic signals: Sudhof, Serafini, Scheiffele and colleagues have shown that neuroligins and SynCAM can
act as factors that induce presynaptic differentiation. Neuroligins are concentrated at the postsynaptic site and act via neurexins
concentrated in the presynaptic axons. SynCAM is a cell adhesion molecule that is present in both pre- and post-synaptic membranes.

Activity dependent mechanisms in the assembly of neural circuits

The processes of neuronal migration, differentiation and axon guidance are generally believed to be activity-independent mechanisms and
rely on hard-wired genetic programs in the neurons themselves. New research findings however have implicated a role for activity-
dependent mechanisms in mediating some aspects of the aforementioned processes such as the rate of neuronal migration, aspects of
neuronal differentiation and axon pathfinding. Activity-dependent mechanisms influence neural circuit development and are crucial for
laying out early connectivity maps and the continued refinement of synapses which occurs during development. There are two distinct
types of neural activity we observe in developing circuits -early spontaneous activity and sensory-evoked activity. Spontaneous activity
occurs early during neural circuit development even when sensory input is absent and is observed in many systems such as the developing
visual system,auditory system, motor system,hippocampus,cerebellum and neocortex

Experimental techniques such as direct electrophysiological recording, fluorescence imaging using calcium indicators and optogenetic
techniques have shed light on the nature and function of these early bursts of activity. They have distinct spatial and temporal patterns
during development and their ablation during development has been known to result in deficits in network refinement in the visual system.
In the immature retina, waves of spontaneous action potentials arise from the retinal ganglion cells and sweep across the retinal surface in
the first few postnatal weeks. These waves are mediated by neurotransmitter acetylcholine in the initial phase and later on by glutamate.
They are thought to instruct the formation of two sensory maps- the retinotopic map and eye-specific segregation.Retinotopic map
refinement occurs in downstream visual targets in the brain-the superior colliculus (SC) and dorsal lateral geniculate nucleus (LGN).
Pharmacological disruption and mouse models lacking the β2 subunit of the nicotinic acetylcholine receptor has shown that the lack of
spontaneous activity leads to marked defects in retinotopy and eye-specific segregation.

In the developing auditory system, developing cochlea generate bursts of activity which spreads across the inner hair cells and spiral ganglion
neurons which relay auditory information to the brain. ATP release from supporting cells triggers action potentials in inner hair cells. In the
auditory system, spontaneous activity is thought to be involved in tonotopic map formation by segregating cochlear neuron axons tuned to
high and low frequencies. In the motor system, periodic bursts of spontaneous activity are driven by excitatory GABA and glutamate during
the early stages and by acetylcholine and glutamate at later stages. In the developing zebrafish spinal cord, early spontaneous activity is
required for the formation of increasingly synchronous alternating bursts between ipsilateral and contralateral regions of the spinal cord and
for the integration of new cells into the circuit.In the cortex, early waves of activity have been observed in the cerebellum and cortical
slices.Once sensory stimulus becomes available, final fine-tuning of sensory-coding maps and circuit refinement begins to rely more and
more on sensory-evoked activity as demonstrated by classic experiments about the effects of sensory deprivation during critical periods.

Synapse elimination

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Synaptic pruning

Several motorneurons compete for each neuromuscular junction, but only one survives until adulthood. Competition in vitro has been
shown to involve a limited neurotrophic substance that is released, or that neural activity infers advantage to strong post-synaptic
connections by giving resistance to a toxin also released upon nerve stimulation. In vivo, it is suggested that muscle fibres select the
strongest neuron through a retrograde signal.

ELECTRICAL ACTIVITY OF THE HUMAN BRAIN.

Brain electrical activity recorded from a human patient during an epileptic seizure

Electrodes and magnetic fields

By placing electrodes on the scalp, it is possible to record the summed electrical activity of the cortex using a methodology known as
electroencephalography (EEG). EEG records average neuronal activity from the cerebral cortex and can detect changes in activity over
large areas but with low sensitivity for sub-cortical activity. EEG recordings are sensitive enough to detect tiny electrical impulses lasting
only a few milliseconds. Most EEG devices have good temporal resolution, but low spatial resolution.

Electrodes can also be placed directly on the surface of the brain (usually during surgical procedures that require removal of part of the
skull). This technique, called electrocorticography (ECoG), offers finer spatial resolution than electroencephalography, but is very invasive. In
addition to measuring the electric field directly via electrodes placed over the skull, it is possible to measure the magnetic field that the
brain generates using a method known as magnetoencephalography (MEG).This technique also has good temporal resolution like EEG but
with much better spatial resolution. The greatest disadvantage of MEG is that, because the magnetic fields generated by neural activity are
very subtle, the neural activity must be relatively close to the surface of the brain to detect its magnetic field. MEGs can only detect the
magnetic signatures of neurons located in the depths of cortical folds (sulci) that have dendrites oriented in a way that produces a field.

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HYPOTHALAMUS.

Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important
functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland (hypophysis).

The hypothalamus is located at the base of the forebrain, bounded by the optic chiasm rostrally and the midbrain tegmentum caudally. It
forms the floor and ventral walls of the third ventricle and is continuous through the infundibular stalk with the posterior pituitary gland, as
illustrated in figure A. Because of its central position in the brain and its proximity to the pituitary, it is not surprising that the hypothalamus
integrates information from the forebrain, brainstem, spinal cord, and various endocrine systems, being particularly important in the central
control of visceral motor functions.

The hypothalamus comprises a large number of distinct nuclei, each with its own complex pattern of connections and functions. The
nuclei, which are intricately interconnected, can be grouped in three longitudinal regions referred to as periventricular, medial, and lateral.
They can also be grouped along the anterior—posterior dimension, which are referred to as the anterior (or preoptic), tuberal, and
posterior regions (figure B). The anterior periventricular group contains the suprachiasmatic nucleus, which receives direct retinal input
and drives circadian rhythms (see Chapter 28). More scattered neurons in the periventricular region (located along the wall of the third
ventricle) manufacture peptides known as releasing or inhibiting factors that control the secretion of a variety of hormones by the
anterior pituitary. The axons of these neurons project to the median eminence, a region at the junction of the hypothalamus and pituitary
stalk, where the peptides are secreted into the portal circulation that supplies the anterior pituitary.

Nuclei in the anterior-medial region include the paraventricular and supra- optic nuclei, which contain the neurosecretory neurons whose
axons extend into the posterior pituitary. With appropriate stimulation, these neurons secrete oxytocin or vasopressin (antidiuretic
hormone) directly into the bloodstream. Other neurons in the paraventricular nucleus project to the preganglionic neurons of the
sympathetic and parasympathetic divisions in the brainstem and spinal cord. It is these cells that are thought to exert hypothalamic control
over the visceral motor system and to modulate the activity of the poorly defined nuclei in the brainstem tegmentum that organize specific
autonomic reflexes such as respiration and vomiting. The paraventricular nucleus, like other hypothalamic nuclei, receives inputs from the
other hypothalamic zones, which are in turn related to the cortex, hippocampus, amygdala, and other central structures that, as noted in the
text, are all capable of influencing visceral motor function.

The medial-tuberal region nuclei (tuberal refers to the tuber cinereum, the anatomical name given to the middle portion of the inferior
surface of the hypothalamus) include the dorsomedial and ventromedial nuclei, which are involved in feeding, reproductive and parenting
behavior, thermoregulation, and water balance. These nuclei receive inputs from structures of the limbic system, as well as from visceral
sensory nuclei in the brainstem (e.g., the nucleus of the solitary tract).

Finally, the lateral region of the hypothalamus is really a rostral continuation of the midbrain reticular formation. Thus, the neurons of
the lateral region are not grouped into nuclei, but are scattered among the fibers of the medial forebrain bundle, which runs through the
lateral hypothalamus. These cells control behavioral arousal and shifts of attention, especially as related to reproductive activities.

In summary, the hypothalamus regulates an enormous range of physiological and behavioral activities, including control of body
temperature, sexual activity, reproductive endocrinology, and attack-and-defense (aggressive) behavior. It is not surprising, then, that this
intricate structure is the key controlling center for visceral motor activity and for homeostatic functions generally which the principle of
relativity works.

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The hypothalamus is located below the thalamus and is part of the limbic system. In the terminology of neuroanatomy, it forms the ventral
part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is the size of an almond.

The hypothalamus is responsible for certain metabolic processes and other activities of the autonomic nervous system. It synthesizes and
secretes certain neurohormones, called releasing hormones or hypothalamic hormones, and these in turn stimulate or inhibit the secretion
of pituitary hormones. The hypothalamus controls body temperature, hunger, important aspects of parenting and attachment behaviors,
thirst, fatigue, sleep, and circadian rhythms.

Structure of hypothalamus

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The hypothalamus is a brain structure made up of distinct nuclei as well as less anatomically distinct areas. It is found in all vertebrate
nervous systems. In mammals, magnocellularneurosecretory cells in the paraventricular nucleus and the supraoptic nucleus of the
hypothalamus produce neurohypophysial hormones, oxytocin and vasopressin. These hormones are released into the blood in the posterior
pituitary. Much smaller parvocellularneurosecretory cells, neurons of the paraventricular nucleus, release corticotropin-releasing hormone
and other hormones into the hypophyseal portal system, where these hormones diffuse to the anterior pituitary.

Neural connections

Major neural connections include Lateral hypothalamus Orexinergic projection system and Tuberomammillary nucleus Histaminergic outputs

Lateral hypothalamus

The lateral hypothalamus, also called the lateral hypothalamic area, contains the primary orexinergic nucleus within the hypothalamus that
widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as
promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood
pressure, among many others.Clinically significant disorders that involve dysfunctions of the orexinergic projection system include
narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity (e.g., irritable bowel syndrome),
and eating disorders.

The neurotransmitter glutamate and the endocannabinoids (e.g., anandamide) and the orexin neuropeptides orexin-A and orexin-B are
the primary signaling neurochemicals in orexin neurons; pathway-specific neurochemicals include GABA, melanin-concentrating
hormone, nociceptin, glucose, the dynorphin peptides, and the appetite-regulating peptide hormones leptin and ghrelin, among others.
Notably, cannabinoid receptor 1 (CB1) is colocalized on orexin projection neurons in the lateral hypothalamus and many output
structures, where the CB1 and orexin receptor 1 (OX1) receptors form the CB1–OX1 receptor heterodimer.

Orexinergic projection system

The orexin projection system innervates the entirety of the remainder of the hypothalamus, with robust projections to the posterior hypothalamus,
tuberomammillary nucleus (the histamine projection nucleus), the arcuate nucleus, and the paraventricular hypothalamic nucleus. In addition to the
histaminergic nucleus, the orexin system also projects onto the ventral tegmental area dopamine nucleus, locus ceruleus noradrenergic nucleus, the
serotonergic raphe nuclei, and cholinergic pedunculopontine nucleus and laterodorsal tegmental nucleus.

Other output regions include: the ventromedial hypothalamus, medial and lateral septal nuclei, central medial amygdala, zonaincerta,
periaqueductal gray matter, lateral habenula, diagonal band, substantiainnominata (contains the nucleus basalis), striaterminalis,
prefrontal cortex, various brain stem substructures, including the rostral ventromedial medulla, rostral ventrolateral medulla, nucleus
ambiguus, solitary nucleus, spinal trigeminal nucleus, pontine micturition center, ventral respiratory group, and pontine respiratory group),
area postrema, and dorsal nucleus of vagus nerve.

Cannabinoid receptor 1 (CB1) is colocalized on orexin projection neurons in the lateral hypothalamus and many output structures, where the
CB1 and orexin receptor 1 (OX1) receptors physically and functionally join together to form the CB1–OX1 receptor heterodimer.[4][9][10]
There is substantial anatomical and functional overlap and systemic cross-talk between the endocannabinoid system and orexinergic
projection system within the central nervous system.

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Tuberomammillary nucleus

The tuberomammillary nucleus is a histaminergic nucleus located within the posterior third of the hypothalamus.[1] It consists of,
largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, learning, memory, sleep
and energy balance.

The tuberomammillary nucleus is the sole source of histamine pathways in the human brain. The densest axonal projections from the
tuberomammillary nucleus are sent to the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and other parts of the
hypothalamus. The projections to the cerebral cortex directly increase cortical activation and arousal, and projections to acetylcholinergic neurons
of the basal forebrain and dorsal pons do so indirectly, by increasing the release of acetylcholine in the cerebral cortex

The hypothalamus is highly interconnected with other parts of the central nervous system, in particular the brainstem and its reticular
formation. As part of the limbic system, it has connections to other limbic structures including the amygdala and septum, and is also
connected with areas of the autonomous nervous system.

The hypothalamus receives many inputs from the brainstem, the most notable from the nucleus of the solitary tract, the locus coeruleus,
and the ventrolateral medulla.

Most nerve fibres within the hypothalamus run in two ways (bidirectional).

Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and
the dorsal longitudinal fasciculus.
Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and terminal stria.
Projections to areas of the sympathetic motor system (lateral horn spinal segments T1-L2/L3) are carried by the
hypothalamospinal tract and they activate the sympathetic motor pathway.

Sexual dimorphism

Several hypothalamic nuclei are sexually dimorphic; i.e., there are clear differences in both structure and function between
males and females.[citation needed]

Some differences are apparent even in gross neuroanatomy: most notable is the sexually dimorphic nucleus within the
preoptic area. However most of the differences are subtle changes in the connectivity and chemical sensitivity of particular
sets of neurons.[citation needed]

The importance of these changes can be recognised by functional differences between males and females. For instance, males of most species prefer

the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. If the sexually dimorphic

53
nucleus is lesioned, this preference for females by males diminishes. Also, the pattern of secretion of growth hormone is sexually
dimorphic, and this is one reason why in many species, adult males are much larger than females.

Responsiveness to ovarian steroids

Other striking functional dimorphisms are in the behavioral responses to ovarian steroids of the adult. Males and females respond to
ovarian steroids in different ways, partly because the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic;
i.e., estrogen receptors are expressed in different sets of neurons.[citation needed]

Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase
activation, leading to diverse non-genomic cellular functions. Estrogen and progesterone bind to their cognate nuclear hormone receptors,
which translocate to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to
another transcription factor's binding site. Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner,
despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. In general, ERs and progesterone
receptors (PRs) are gene activators, with increased mRNA and subsequent protein synthesis following hormone exposure.

Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal
steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly in neurons in the anterior and mediobasal
hypothalamus, notably:[citation needed]

the preoptic area (where LHRH neurons are located)

the periventricular nucleus (where somatostatin neurons are located)
the ventromedial hypothalamus (which is important for sexual behavior).

Development

In neonatal life, gonadal steroids influence the development of the neuroendocrine hypothalamus. For instance, they determine the ability
of females to exhibit a normal reproductive cycle, and of males and females to display appropriate reproductive behaviors in adult life.
[citation needed]

If a female rat is injected once with testosterone in the first few days of postnatal life (during the "critical period" of sex-steroid influence),
the hypothalamus is irreversibly masculinized; the adult rat will be incapable of generating an LH surge in response to estrogen (a
characteristic of females), but will be capable of exhibiting male sexual behaviors (mounting a sexually receptive female).

By contrast, a male rat castrated just after birth will be feminized, and the adult will show female sexual behavior in response to
estrogen (sexual receptivity, lordosis behavior).

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In primates, the developmental influence of androgens is less clear, and the consequences are less understood. Within the brain,
testosterone is aromatized to (estradiol), which is the principal active hormone for developmental influences. The human testis secretes
high levels of testosterone from about week 8 of fetal life until 5–6 months after birth (a similar perinatal surge in testosterone is observed
in many species), a process that appears to underlie the male phenotype. Estrogen from the maternal circulation is relatively ineffective,
partly because of the high circulating levels of steroid-binding proteins in pregnancy.

Sex steroids are not the only important influences upon hypothalamic development; in particular, pre-pubertal stress in early life (of rats)
determines the capacity of the adult hypothalamus to respond to an acute stressor. Unlike gonadal steroid receptors, glucocorticoid
receptors are very widespread throughout the brain; in the paraventricular nucleus, they mediate negative feedback control of CRF
synthesis and secretion, but elsewhere their role is not well understood.

Functions of hypothalamus

Hormone release

Endocrine glands in the human head and neck and their hormones

The hypothalamus has a central neuroendocrine function, most notably by its control of the anterior pituitary, which in turn regulates
various endocrine glands and organs. Releasing hormones (also called releasing factors) are produced in hypothalamic nuclei then
transported along axons to either the median eminence or the posterior pituitary, where they are stored and released as needed.

Anterior pituitary

In the hypothalamic–adenohypophyseal axis, releasing hormones, also known as hypophysiotropic or hypothalamic hormones, are
released from the median eminence, a prolongation of the hypothalamus, into the hypophyseal portal system, which carries them to the
anterior pituitary where they exert their regulatory functions on the secretion ofadenohypophyseal hormones. These hypophysiotropic
hormones are stimulated by parvocellularneurosecretory cells located in the periventricular area of the hypothalamus. After their release
into the capillaries of the third ventricle, the hypophysiotropic hormones travel through what is known as the hypothalamo-pituitary portal
circulation. Once they reach their destination in the anterior pituitary, these hormones bind to specific receptors located on the surface of
pituitary cells. Depending on which cells are activated through this binding, the pituitary will either begin secreting or stop secreting
hormones into the rest of the bloodstream.

It is also known that hypothalamic-pituitary-adrenal axis (HPA) hormones are related to certain skin diseases and skin homeostasis.
There is evidence linking hyperactivity of HPA hormones to stress-related skin diseases and skin tumors.

Stimulation

The hypothalamus coordinates many hormonal and behavioural circadian rhythms, complex patterns of neuroendocrine outputs,
complex homeostatic mechanisms, and important behaviours. The hypothalamus must, therefore, respond to many different signals,
some of which generated externally and some internally. Delta wave signalling arising either in the thalamus or in the cortex influences
the secretion of releasing hormones; GHRH and prolactin are stimulated whilst TRH is inhibited.

55
The hypothalamus is responsive to:

I. Light: daylength and photoperiod for regulating circadian and seasonal rhythms
II. Olfactory stimuli, including pheromones
III.Steroids, including gonadal steroids and corticosteroids
IV. Neurally transmitted information arising in particular from the heart, the stomach, and the reproductive tract
V. Autonomic inputs
Blood-borne stimuli, including leptin, ghrelin, angiotensin, insulin, pituitary hormones, cytokines, plasma concentrations of
VI. glucose
and osmolarity etc.
VII. Stress
VIII. Invading microorganisms by increasing body temperature, resetting the body's thermostat upward.

Olfactory stimuli

Olfactory stimuli are important for sexual reproduction and neuroendocrine function in many species. For instance if a pregnant mouse is
exposed to the urine of a 'strange' male during a critical period after coitus then the pregnancy fails (the Bruce effect). Thus, during coitus, a
female mouse forms a precise 'olfactory memory' of her partner that persists for several days. Pheromonal cues aid synchronisation of
oestrus in many species; in women, synchronised menstruation may also arise from pheromonal cues, although the role of pheromones in
humans is disputed.

Blood-borne stimuli.

Peptide hormones have important influences upon the hypothalamus, and to do so they must pass through the blood–brain barrier. The
hypothalamus is bounded in part by specialized brain regions that lack an effective blood–brain barrier; the capillary endothelium at these
sites is fenestrated to allow free passage of even large proteins and other molecules. Some of these sites are the sites of neurosecretion - the
neurohypophysis and the median eminence. However, others are sites at which the brain samples the composition of the blood. Two of
these sites, the SFO (subfornical organ) and the OVLT (organumvasculosum of the lamina terminalis) are so-called circumventricular organs,
where neurons are in intimate contact with both blood and CSF. These structures are densely vascularized, and contain osmoreceptive and
sodium-receptive neurons that control drinking, vasopressin release, sodium excretion, and sodium appetite. They also contain neurons
with receptors for angiotensin, atrial natriuretic factor, endothelin and relaxin, each of which important in the regulation of fluid and
electrolyte balance. Neurons in the OVLT and SFO project to the supraoptic nucleus and paraventricular nucleus, and also to preoptic
hypothalamic areas. The circumventricular organs may also be the site of action of interleukins to elicit both fever and ACTH secretion, via
effects on paraventricular neurons.

It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of prolactin and leptin, there is
evidence of active uptake at the choroid plexus from the blood into the cerebrospinal fluid (CSF). Some pituitary hormones have a negative
feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus, but how it enters the
brain is not clear. There is also evidence for central actions of prolactin.

Findings have suggested that thyroid hormone (T4) is taken up by the hypothalamic glial cells in the infundibular nucleus/ median eminence,
and that it is here converted into T3 by the type 2 deiodinase (D2). Subsequent to this, T3 is transported into the thyrotropin-releasing
hormone

56
(TRH)-producing neurons in the paraventricular nucleus. Thyroid hormone receptors have been found in these neurons, indicating that they
are indeed sensitive to T3 stimuli. In addition, these neurons expressed MCT8, a thyroid hormone transporter, supporting the theory that T3
is transported into them. T3 could then bind to the thyroid hormone receptor in these neurons and affect the production of thyrotropin-
releasing hormone, thereby regulating thyroid hormone production.

The hypothalamus functions as a type of thermostat for the body. It sets a desired body temperature, and stimulates either heat production
and retention to raise the blood temperature to a higher setting or sweating and vasodilation to cool the blood to a lower temperature. All
fevers result from a raised setting in the hypothalamus; elevated body temperatures due to any other cause are classified as hyperthermia.
Rarely, direct damage to the hypothalamus, such as from a stroke, will cause a fever; this is sometimes called a hypothalamic fever.
However, it is more common for such damage to cause abnormally low body temperatures.

Steroids

The hypothalamus contains neurons that react strongly to steroids and glucocorticoids – (the steroid hormones of the adrenal gland,
released in response to ACTH). It also contains specialized glucose-sensitive neurons (in the arcuate nucleus and ventromedial
hypothalamus), which are important for appetite. The preoptic area contains thermosensitive neurons; these are important for TRH
secretion.

Neural

Oxytocin secretion in response to suckling or vagino-cervical stimulation is mediated by some of these pathways; vasopressin secretion in
response to cardiovascular stimuli arising from chemoreceptors in the carotid body and aortic arch, and from low-pressure atrial volume
receptors, is mediated by others. In the rat, stimulation of the vagina also causes prolactin secretion, and this results in pseudo-
pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of
high levels of estrogen can induce maternal behavior in a virgin ewe. These effects are all mediated by the hypothalamus, and the
information is carried mainly by spinal pathways that relay in the brainstem. Stimulation of the nipples stimulates release of oxytocin and
prolactin and suppresses the release of LH and FSH.

Cardiovascular stimuli are carried by the vagus nerve. The vagus also conveys a variety of visceral information, including for instance signals
arising from gastric distension or emptying, to suppress or promote feeding, by signalling the release of leptin or gastrin, respectively. Again
this information reaches the hypothalamus via relays in the brainstem.

In addition hypothalamic function is responsive to—and regulated by—levels of all three classical monoamine neurotransmitters,
noradrenaline, dopamine, and serotonin (5-hydroxytryptamine), in those tracts from which it receives innervation. For example,
noradrenergic inputs arising from the locus coeruleus have important regulatory effects upon corticotropin-releasing hormone (CRH) levels.

Control of food intake

Peptide hormones and neuropeptides that regulate feeding.

The extreme lateral part of the ventromedial nucleus of the hypothalamus is responsible for the control of food intake. Stimulation of this
area causes increased food intake. Bilateral lesion of this area causes complete cessation of food intake. Medial parts of the nucleus have a
controlling effect on the lateral part. Bilateral lesion of the medial part of the ventromedial nucleus causes hyperphagia and obesity of the
animal. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake.

There are different hypotheses related to this regulation:

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 I. Lipostatic hypothesis: This hypothesis holds that adipose tissue produces a humoral signal that is proportionate to the amount of
fat and acts on the hypothalamus to decrease food intake and increase energy output. It has been evident that a hormone leptin
acts on the hypothalamus to decrease food intake and increase energy output.
II. Gutpeptide hypothesis: gastrointestinal hormones like Grp, glucagons, CCK and others claimed to inhibit food intake. The
food entering the gastrointestinal tract triggers the release of these hormones, which act on the brain to produce satiety.
The brain contains both CCK-A and CCK-B receptors.
III. Glucostatic hypothesis: The activity of the satiety center in the ventromedial nuclei is probably governed by the glucose
utilization in the neurons. It has been postulated that when their glucose utilization is low and consequently when the
arteriovenous blood glucose difference across them is low, the activity across the neurons decrease. Under these conditions, the
activity of the feeding center is unchecked and the individual feels hungry. Food intake is rapidly increased by intraventricular
administration of 2-deoxyglucose therefore decreasing glucose utilization in cells.
IV. Thermostatic hypothesis: According to this hypothesis, a decrease in body temperature below a given set-point stimulates
appetite,
whereas an increase above the set-point inhibits appetite.

Fear processing

The medial zone of hypothalamus is part of a circuitry that controls motivated behaviors, like defensive behaviors. Analyses of Fos-labeling
showed that a series of nuclei in the "behavioral control column" is important in regulating the expression of innate and conditioned
defensive behaviors.

c-Fos

In the fields of molecular biology and genetics, c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It was
first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkins murine osteogenic sarcoma virus). It is a part
of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2 as well as smaller FosB splice variants, FosB2 and
ΔFosB. It has been mapped to chromosome region 14q21→q31. C-fos encodes a 62 kDa protein, which forms heterodimer with c-jun (part of
Jun family of transcription factors), resulting in the formation of AP-1 (Activator Protein-1) complex which binds DNA at AP-1 specific sites at
the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important
role in many cellular functions and has been found to be overexpressed in a variety of cancers.

Structure and function of c - Fos

c-fos is a 380 amino acid protein with a basic leucine zipper region for dimerisation and DNA-binding and a transactivation domain at
C-terminus. Unlike Jun proteins, it cannot form homodimers, only heterodimers with c-jun. In vitro studies have shown that Jun–Fos
heterodimers are more stable and have stronger DNA-binding activity than Jun–Jun homodimers.

A variety of stimuli, including serum, growth factors, tumor promoters, cytokines, and UV radiation induce their expression. The c-fos mRNA and
protein is generally among the first to be expressed and hence referred to as an immediate early gene. It is rapidly and transiently induced, within 15
minutes of stimulation. Its activity is also regulated by posttranslational modification caused by phosphorylation by different kinases, like MAPK,
cdc2, PKA or PKC which influence protein stability, DNA-binding activity and the trans-activating potential of the transcription factors. It can cause
gene repression as well as gene activation, although different domains are believed to be involved in both processes.

It is involved in important cellular events, including cell proliferation, differentiation and survival; genes associated with hypoxia; and
angiogenesis; which makes its dysregulation an important factor for cancer development. It can also induce a loss of cell polarity and
epithelial-mesenchymal transition, leading to invasive and metastatic growth in mammary epithelial cells.

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The importance of c-fos in biological context has been determined by eliminating endogenous function by using anti-sense mRNA, anti-c-
fos antibodies, a ribozyme that cleaves c-fos mRNA or a dominant negative mutant of c-fos. The transgenic mice thus generated are
viable, demonstrating that there are c-fos dependent and independent pathways of cell proliferation, but display a range of tissue-
specific developmental defects, including osteoporosis, delayed gametogenesis, lymphopenia and behavioral abnormalities.

Clinical significance

The AP-1 complex has been implicated in transformation and progression of cancer. In osteosarcoma and endometrial carcinoma, c-Fos
overexpression was associated with high-grade lesions and poor prognosis. Also, in a comparison between precancerous lesion of the
cervix uteri and invasive cervical cancer, c-Fos expression was significantly lower in precancerous lesions. C-Fos has also been identified
as independent predictor of decreased survival in breast cancer.

It was found that overexpression of c-fos from class I MHC promoter in transgenic mice leads to the formation of osteosarcomas due to
increased proliferation of osteoblasts whereas ectopic expression of the other Jun and Fos proteins does not induce any malignant
tumors. Activation of the c-Fos transgene in mice results in overexpression of cyclin D1, A and E in osteoblasts and chondrocytes, both in
vitro and in vivo, which might contribute to the uncontrolled growth leading to tumor. Human osteosarcomas analyzed for c-fos
expression have given positive results in more than half the cases and c-fos expression has been associated with higher frequency of
relapse and poor response to chemotherapy.

Several studies have raised the idea that c-Fos may also have tumor-suppressor activity, that it might be able to promote as well as
suppress tumorigenesis. Supporting this is the observation that in ovarian carcinomas, loss of c-Fos expression correlates with disease
progression. This double action could be enabled by differential protein composition of tumour cells and their environment, for example,
dimerisation partners, co-activators and promoter architecture. It is possible that the tumor suppressing activity is due to a proapoptotic
function. The exact mechanism by which c-Fos contributes to apoptosis is not clearly understood, but observations in human hepatocellular
carcinoma cells indicate that c-Fos is a mediator of c-myc-induced cell death and might induce apoptosis through the p38 MAP kinase
pathway. Fas ligand (FASLG or FasL) and the tumour necrosis factor-related apoptosis-inducing ligand (TNFSF10 or TRAIL) might reflect an
additional apoptotic mechanism induced by c-Fos, as observed in a human T-cell leukaemia cell line. Another possible mechanism of c-Fos
involvement in tumour suppression could be the direct regulation of BRCA1, a well established factor in familial breast and ovarian cancer.

In addition, role of c-fos and other Fos family proteins has also been studied in endometrial carcinoma, cervical cancer,
mesotheliomas, colorectal cancer, lung cancer, melanomas, thyroid carcinomas, esophageal cancer, hepatocellular carcinomas, etc.

Cocaine, methamphetamine, heroin, and other psychoactive drugs have been shown to increase c-fos production in the mesocortical
pathway (prefrontal cortex) as well as in the mesolimbic reward pathway (nucleus accumbens). Accumbal c-Fos repression by ΔFosB's AP-1
complex acts as a molecular switch for the long-term induction of ΔFosB, thus allowing it to accumulate in dopamine D1-type medium spiny
neurons. As such, the c-Fos promoter finds utilization in drug addiction research in general, as well as with context-induced relapse to drug-
seeking and other behavioral changes associated with chronic drug taking.

An increase in c-Fos production in androgen receptor-containing neurons has been observed in rats after mating.

Applications of c-FOS ;Expression of c-fos is an indirect marker of neuronal activity because c-fos is often expressed when neurons fire
action potentials.Upregulation of c-fos mRNA in a neuron indicates recent activity

Antipredatory defensive behavior

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Exposure to a predator (such as a cat) elicits defensive behaviors in laboratory rodents, even when the animal has never been exposed to a
cat. In the hypothalamus, this exposure causes an increase in Fos-labeled cells in the anterior hypothalamic nucleus, the dorsomedial part of
the ventromedial nucleus, and in the ventrolateral part of the premammillary nucleus (PMDvl). The premammillary nucleus has an important
role in expression of defensive behaviors towards a predator, since lesions in this nucleus abolish defensive behaviors, like freezing and flight.
The PMD does not modulate defensive behavior in other situations, as lesions of this nucleus had minimal effects on post-shock freezing
scores. The PMD has important connections to the dorsal periaqueductal gray, an important structure in fear expression. In addition, animals
display risk assessment behaviors to the environment previously associated with the cat. Fos-labeled cell analysis showed that the PMDvl is
the most activated structure in the hypothalamus, and inactivation with muscimol prior to exposure to the context abolishes the defensive
behavior. Therefore, the hypothalamus, mainly the PMDvl, has an important role in expression of innate and conditioned defensive
behaviors to a predator.

Social defeat

Social defeat refers to losing a confrontation among conspecific animals, or any kind of hostile dispute among humans, in either a dyadic or
in a group-individual context, potentially generating very significant practical and psychological consequences in terms of control over
resources, access to mates and social positions.Likewise, the hypothalamus has a role in social defeat: Nuclei in medial zone are also
mobilized during an encounter with an aggressive conspecific. The defeated animal has an increase in Fos levels in sexually dimorphic
structures, such as the medial pre-optic nucleus, the ventrolateral part of ventromedial nucleus, and the ventral premammilary nucleus.
Such structures are important in other social behaviors, such as sexual and aggressive behaviors. Moreover, the premammillary nucleus also
is mobilized, the dorsomedial part but not the ventrolateralpart.Lesions in this nucleus abolish passive defensive behavior, like freezing and
the "on-the-back" posture

HYPOTHALAMIC DYSFUNCTION.

Hypothalamic dysfunction is a problem with part of the brain called the hypothalamus. The hypothalamus helps control the pituitary gland
and regulates many body functions.

Causes of hypothalamic dysfunction

The hypothalamus helps control the pituitary gland. The pituitary is a small gland at the base of the brain. The pituitary, in turn, controls the:

Adrenal glands, Ovaries, Teste, Thyroid gland .The hypothalamus also helps regulate: Body temperature, Childbirth, Emotion,
Growth, Production of breast milk, Salt and water balance, Sleep, Weight and appetite

CAUSES OF HYPOTHALAMIC DYSFUNCTION

The most common causes of hypothalamic dysfunction are;

Emesis;Vomiting, also known as emesis and throwing up, among other terms, is the involuntary, forceful expulsion of the contents of
one's stomach through the mouth and sometimes the nose.

Vomiting can be caused by a wide variety of conditions; it may present as a specific response to ailments like gastritis or poisoning, or as a non-

specific sequela of disorders ranging from brain tumors and elevated intracranial pressure to overexposure to ionizing radiation. The feeling

60
that one is about to vomit is called nausea, which often precedes, but does not always lead to, vomiting. Antiemetics are sometimes
necessary to suppress nausea and vomiting. In severe cases, where dehydration develops, intravenous fluid may be required.

Surgery;Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate
and/or treat a pathological condition such as disease or injury, to help improve bodily function or appearance or to repair unwanted
ruptured areas (for example, a perforated ear drum).

An act of performing surgery may be called a surgical procedure, operation, or simply surgery. In this context, the verb operate means to
perform surgery. The adjective surgical means pertaining to surgery; e.g. surgical instruments or surgical nurse. The patient or subject on
which the surgery is performed can be a person or an animal. A surgeon is a person who practices surgery

traumatic brain injury; intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity,

mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). Head injury usually

refers to TBI, but is a broader category because it can involve damage to structures other than the brain, such as the scalp and skull.

TBI is a major cause of death and disability worldwide, especially in children and young adults. Males sustain traumatic brain injuries
more frequently than do females. Causes include falls, vehicle accidents, and violence. Prevention measures include use of technology
to protect those suffering from automobile accidents, such as seat belts and sports or motorcycle helmets, as well as efforts to reduce
the number of automobile accidents, such as safety education programs and enforcement of traffic laws.

Brain trauma can occur as a consequence of a focal impact upon the head, by a sudden acceleration/deceleration within the cranium or by
a complex combination of both movement and sudden impact. In addition to the damage caused at the moment of injury, brain trauma
causes secondary injury, a variety of events that take place in the minutes and days following the injury. These processes, which include
alterations in cerebral blood flow and the pressure within the skull, contribute substantially to the damage from the initial injury.

TBI can cause a host of physical, cognitive, social, emotional, and behavioral effects, and outcome can range from complete recovery to
permanent disability or death. The 20th century saw critical developments in diagnosis and treatment that decreased death rates and
improved outcome. Some of the current imaging techniques used for diagnosis and treatment include computed tomography and MRIs
(magnetic resonance imaging). Depending on the injury, treatment required may be minimal or may include interventions such as
medications

Tumor orNeoplasm;Neoplasm is an abnormal growth of tissue and when it also forms a mass is commonly referred to as a
tumor.This abnormal growth (neoplasia) usually but not always forms a mass.

The World Health Organization (WHO) classifies neoplasms into four main groups: benign neoplasms, in situ neoplasms, malignant
neoplasms, and neoplasms of uncertain or unknown behavior. Malignant neoplasms are also simply known as cancers.

Prior to the abnormal growth of tissue, as neoplasia, cells often undergo an abnormal pattern of growth, such as metaplasia or dysplasia.
[6] However, metaplasia or dysplasia do not always progress to neoplasia. The word is means plasma "formation, creation".

A neoplasm can be benign, potentially malignant, or malignant (cancer).

Benign tumors include uterine fibroids and melanocytic nevi (skin moles). They are circumscribed and localized and do not transform
into cancer.

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 Potentially-malignant neoplasms include carcinoma in situ. They are localised, do not invade and destroy but in time, may transform
into a cancer.

Malignant neoplasms are commonly called cancer. They invade and destroy the surrounding tissue, may form metastases and, if untreated
or unresponsive to treatment, will prove fatal.

Secondary neoplasm refers to any of a class of cancerous tumor that is either a metastatic offshoot of a primary tumor, or an
apparently unrelated tumor that increases in frequency following certain cancer treatments such as chemotherapy or radiotherapy.

Rarely there can be a metastatic neoplasm with no known site of the primary cancer and this is classed as a cancer of unknown primary
origin

Clonality;Neoplastic tumors are often heterogeneous and contain more than one type of cell, but their initiation and continued growth is
usually dependent on a single population of neoplastic cells. These cells are presumed to be clonal – that is, they are derived from the same
cell, and all carry the same genetic or epigenetic anomaly – evident of clonality. For lymphoid neoplasms, e.g. lymphoma and leukemia,
clonality is proven by the amplification of a single rearrangement of their immunoglobulin gene (for B cell lesions) or T cell receptor gene
(for T cell lesions). The demonstration of clonality is now considered to be necessary to identify a lymphoid cell proliferation as neoplastic.

It is tempting to define neoplasms as clonal cellular proliferations but the demonstration of clonality is not always possible. Therefore,
clonality is not required in the definition of neoplasia.

Radiation;In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a
material medium.This includes:

electromagnetic radiation, such as radio waves, visible light, x-rays, and gamma radiation (γ)
particle radiation, such as alpha radiation (α), beta radiation (β), and neutron radiation (particles of non-zero rest
energy) acoustic radiation, such as ultrasound, sound, and seismic waves (dependent on a physical transmission
medium)
gravitational radiation, radiation that takes the form of gravitational waves, or ripples in the curvature of spacetime.

Radiation is often categorized as either ionizing or non-ionizing depending on the energy of the radiated particles. Ionizing radiation
carries more than 10 eV, which is enough to ionize atoms and molecules, and break chemical bonds. This is an important distinction due
to the large difference in harmfulness to living organisms. A common source of ionizing radiation is radioactive materials that emit α, β, or
γ radiation, consisting of helium nuclei, electrons or positrons, and photons, respectively. Other sources include X-rays from medical
radiography examinations and muons, mesons, positrons, neutrons and other particles that constitute the secondary cosmic rays that are
produced after primary cosmic rays interact with Earth's atmosphere.

Gamma rays, X-rays and the higher energy range of ultraviolet light constitute the ionizing part of the electromagnetic spectrum. The
lower-energy, longer-wavelength part of the spectrum including visible light, infrared light, microwaves, and radio waves is non-ionizing;
its main effect when interacting with tissue is heating. This type of radiation only damages cells if the intensity is high enough to cause
excessive heating. Ultraviolet radiation has some features of both ionizing and non-ionizing radiation. While the part of the ultraviolet
spectrum that penetrates the Earth's atmosphere is non-ionizing, this radiation does far more damage to many molecules in biological
systems than can be
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accounted for by heating effects, sunburn being a well-known example. These properties derive from ultraviolet's power to alter
chemical bonds, even without having quite enough energy to ionize atom

Anorexia nervosa or bulimia;Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by a low weight, fear
of gaining weight, a strong desire to be thin, and food restriction. Many people with anorexia see themselves as overweight even though
they are in fact underweight. If asked they usually deny they have a problem with low weight. Often they weigh themselves frequently, eat
only small amounts, and only eat certain foods. Some will exercise excessively, force themselves to vomit, or use laxatives to produce weight
loss. Complications may include osteoporosis, infertility and heart damage, among others.

Signs and symptoms

Anorexia nervosa is an eating disorder characterized by attempts to lose weight, to the point of starvation. A person with anorexia nervosa
may exhibit a number of signs and symptoms, the type and severity of which may vary and may be present but not readily apparent.

Anorexia nervosa, and the associated malnutrition that results from self-imposed starvation, can cause complications in every major organ
system in the body.Hypokalaemia, a drop in the level of potassium in the blood, is a sign of anorexia nervosa. A significant drop in
potassium can cause abnormal heart rhythms, constipation, fatigue, muscle damage and paralysis. Some individuals may lack awareness
that they are ill.

Symptoms of hypothalamic dysfunction include:

Refusal to maintain a normal body mass index

Amenorrhea, a symptom that occurs after prolonged weight loss; causes menses to stop, hair becomes brittle, and skin
becomes yellow and unhealthy.
Fear of even the slightest weight gain; taking all precautionary measures to avoid weight gain or becoming
overweight Obvious, rapid, dramatic weight loss to at least 15% under normal body weight
Lanugo: soft, fine hair growing on the face and body

Obsession with calories and fat content of food

Preoccupation with food, recipes, or cooking; may cook elaborate dinners for others, but not eat the food
themselves Food restriction despite being underweight
Food rituals, such as cutting food into tiny pieces, refusing to eat around others, hiding or discarding food
Purging: May use laxatives, diet pills, ipecac syrup, or water pills; may engage in self-induced vomiting; may run to the
bathroom after eating in order to vomit and quickly get rid of ingested calories
Excessive exercise including micro-exercising, for example making small persistent movements of fingers or
toes. Perception of self as overweight despite being told by others they are too thin
Intolerance to cold and frequent complaints of being cold; body temperature may lower (hypothermia) in an effort to
conserve energy
Hypotension or orthostatic
hypotension Bradycardia or
tachycardia
Depression
Solitude: may avoid friends and family; becomes withdrawn and
secretive Abdominal distension
Halitosis (from vomiting or starvation-induced
ketosis) Dry hair and skin, as well as hair thinning

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 Chronic fatigue
Rapid mood swings

Bleeding;Bleeding, technically known as hemorrhaging or haemorrhaging (see American and British spelling differences), is blood escaping
from the circulatory system. Bleeding can occur internally, where blood leaks from blood vessels inside the body, or externally, either
through a natural opening such as the mouth, nose, ear, urethra, vagina or anus, or through a break in the skin. Hypovolemia is a massive
decrease in blood volume, and death by excessive loss of blood is referred to as exsanguination. Typically, a healthy person can endure a loss
of 10–15% of the total blood volume without serious medical difficulties (by comparison, blood donation typically takes 8–10% of the
donor's blood volume). The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery.

Blood loss

Hemorrhaging is broken down into four classes by the American College of Surgeons' advanced trauma life support (ATLS).

Class I Hemorrhage involves up to 15% of blood volume. There is typically no change in vital signs and fluid resuscitation is not
usually necessary.

Class II Hemorrhage involves 15-30% of total blood volume. A patient is often tachycardic (rapid heart beat) with a narrowing of the
difference between the systolic and diastolic blood pressures. The body attempts to compensate with peripheral vasoconstriction. Skin
may start to look pale and be cool to the touch. The patient may exhibit slight changes in behavior. Volume resuscitation with
crystalloids (Saline solution or Lactated Ringer's solution) is all that is typically required. Blood transfusion is not typically required.

Class III Hemorrhage involves loss of 30-40% of circulating blood volume. The patient's blood pressure drops, the heart rate increases,
peripheral hypoperfusion (shock), such as capillary refill worsens, and the mental status worsens. Fluid resuscitation with crystalloid and
blood transfusion are usually necessary.

Class IV Hemorrhage involves loss of >40% of circulating blood volume. The limit of the body's compensation is reached and
aggressive resuscitation is required to prevent death.

This system is basically the same as used in the staging of hypovolemic shock.

Individuals in excellent physical and cardiovascular shape may have more effective compensatory mechanisms before experiencing
cardiovascular collapse. These patients may look deceptively stable, with minimal derangements in vital signs, while having poor peripheral
perfusion. Elderly patients or those with chronic medical conditions may have less tolerance to blood loss, less ability to compensate, and
may take medications such as betablockers that can potentially blunt the cardiovascular response. Care must be taken in the assessment of
these patients

The World Health Organization made a standardized grading scale to measure the severity of bleeding.

Grade 0 no bleeding

Grade 1 petechial bleeding;

Grade 2 mild blood loss (clinically significant);

Grade 3 gross blood loss, requires transfusion (severe);

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Grade 4 debilitating blood loss, retinal or cerebral associated with fatality

Origin

Mouth

Hematemesis – vomiting fresh blood

Hemoptysis – coughing up blood from the lungs

Anus

Hematochezia – rectal blood

Urinary tract

Hematuria – blood in the urine from urinary bleeding

Upper head

Intracranial hemorrhage – bleeding in the skull.

Cerebral hemorrhage – a type of intracranial hemorrhage, bleeding within the brain tissue itself.

Intracerebral hemorrhage – bleeding in the brain caused by the rupture of a blood vessel within the head. See also hemorrhagic stroke.

Subarachnoid hemorrhage (SAH) implies the presence of blood within the subarachnoid space from some pathologic process. The
common medical use of the term SAH refers to the nontraumatic types of hemorrhages, usually from rupture of a berry aneurysm or
arteriovenous malformation(AVM). The scope of this article is limited to these nontraumatic hemorrhages.

Lungs

Pulmonary hemorrhage

Gynecologic

Vaginal bleeding

Postpartum hemorrhage

Breakthrough bleeding

Ovarian bleeding. This is a potentially catastrophic and not so rare complication among lean patients with polycystic ovary
syndrome undergoing transvaginal oocyte retrieval.

Gastrointestinal

Upper gastrointestinal bleed

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 Lower gastrointestinal bleed

Occult gastrointestinal bleed

Causes of bleeding.

Bleeding arises due to either traumatic injury, underlying medical condition, or a combination.

Traumatic Injury

Traumatic bleeding is caused by some type of injury. There are different types of wounds which may cause traumatic bleeding. These include:

Abrasion - Also called a graze, this is caused by transverse action of a foreign object against the skin, and usually does not penetrate
below the epidermis

Excoriation - In common with Abrasion, this is caused by mechanical destruction of the skin, although it usually has an
underlying medical cause
Hematoma - Caused by damage to a blood vessel that in turn causes blood to collect under the skin.
Laceration - Irregular wound caused by blunt impact to soft tissue overlying hard tissue or tearing such as in childbirth. In
some instances, this can also be used to describe an incision.
Incision - A cut into a body tissue or organ, such as by a scalpel, made during surgery.
Puncture Wound - Caused by an object that penetrated the skin and underlying layers, such as a nail, needle or
knife Contusion - Also known as a bruise, this is a blunt trauma damaging tissue under the surface of the skin
Crushing Injuries - Caused by a great or extreme amount of force applied over a period of time. The extent of a crushing injury
may not immediately present itself.
Ballistic Trauma - Caused by a projectile weapon such as a firearm. This may include two external wounds (entry and exit)
and a contiguous wound between the two

The pattern of injury, evaluation and treatment will vary with the mechanism of the injury. Blunt trauma causes injury via a shock effect;
delivering energy over an area. Wounds are often not straight and unbroken skin may hide significant injury. Penetrating trauma follows
the course of the injurious device. As the energy is applied in a more focused fashion, it requires less energy to cause significant injury. Any
body organ, including bone and brain, can be injured and bleed. Bleeding may not be readily apparent; internal organs such as the liver,
kidney and spleen may bleed into the abdominal cavity. The only apparent signs may come with blood loss. Bleeding from a bodily orifice,
such as the rectum, nose, or ears may signal internal bleeding, but cannot be relied upon. Bleeding from a medical procedure also falls into
this category.

Medical condition

'Medical bleeding' denotes hemorrhage as a result of an underlying medical condition (i.e. causes of bleeding that are not directly
due to trauma). Blood can escape from blood vessels as a result of 3 basic patterns of injury:

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 Intravascular changes - changes of the blood within vessels (e.g. ↑ blood pressure, ↓ clo ng factors)

Intramural changes - changes arising within the walls of blood vessels (e.g. aneurysms, dissections, AVMs, vasculitides)

Extravascular changes - changes arising outside blood vessels (e.g. H pylori infection, brain abscess, brain tumor)

The underlying scientific basis for blood clotting and hemostasis is discussed in detail in the articles, Coagulation, hemostasis and
related articles. The discussion here is limited to the common practical aspects of blood clot formation which manifest as bleeding.

Some medical conditions can also make patients susceptible to bleeding. These are conditions that affect the normal hemostatic
(bleeding-control) functions of the body. Such conditions either are, or cause, bleeding diatheses. Hemostasis involves several
components. The main components of the hemostatic system include platelets and the coagulation system.

Platelets are small blood components that form a plug in the blood vessel wall that stops bleeding. Platelets also produce a variety of
substances that stimulate the production of a blood clot. One of the most common causes of increased bleeding risk is exposure to non-
steroidal anti-inflammatory drugs (or "NSAIDs"). The prototype for these drugs is aspirin, which inhibits the production of thromboxane.
NSAIDs inhibit the activation of platelets, and thereby increase the risk of bleeding. The effect of aspirin is irreversible; therefore, the
inhibitory effect of aspirin is present until the platelets have been replaced (about ten days). Other NSAIDs, such as "ibuprofen" (Motrin) and
related drugs, are reversible and therefore, the effect on platelets is not as long-lived.

There are several named coagulation factors that interact in a complex way to form blood clots, as discussed in the article on coagulation.
Deficiencies of coagulation factors are associated with clinical bleeding. For instance, deficiency of Factor VIII causes classic Hemophilia A
while deficiencies of Factor IX cause "Christmas disease"(hemophilia B). Antibodies to Factor VIII can also inactivate the Factor VII and
precipitate bleeding that is very difficult to control. This is a rare condition that is most likely to occur in older patients and in those with
autoimmune diseases. vonWillebrand disease is another common bleeding disorder. It is caused by a deficiency of or abnormal function of
the "von Willebrand" factor, which is involved in platelet activation. Deficiencies in other factors, such as factor XIII or factor VII are
occasionally seen, but may not be associated with severe bleeding and are not as commonly diagnosed.

In addition to NSAID-related bleeding, another common cause of bleeding is that related to the medication, warfarin ("Coumadin" and
others). This medication needs to be closely monitored as the bleeding risk can be markedly increased by interactions with other
medications. Warfarin acts by inhibiting the production of Vitamin K in the gut. Vitamin K is required for the production of the clotting
factors, II, VII, IX, and X in the liver. One of the most common causes of warfarin-related bleeding is taking antibiotics. The gut bacteria make
vitamin K and are killed by antibiotics. This decreases vitamin K levels and therefore the production of these clotting factors.

Deficiencies of platelet function may require platelet transfusion while deficiencies of clotting factors may require transfusion of either
fresh frozen plasma or specific clotting factors, such as Factor VIII for patients with hemophilia.

Genetic disorders that cause iron buildup in the body; A genetic disorder is a genetic problem caused by one or more abnormalities in
the genome, especially a condition that is present from birth (congenital). Most genetic disorders are quite rare and affect one person in
every several thousands or millions.

Genetic disorders may be hereditary, passed down from the parents' genes. In other genetic disorders, defects may be caused by new mutations

or changes to the DNA. In such cases, the defect will only be passed down if it occurs in the germ line. The same disease, such as some forms of

cancer, may be caused by an inherited genetic condition in some people, by new mutations in other people, and mainly by

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environmental causes in other people. Whether, when and to what extent a person with the genetic defect or abnormality will actually
suffer from the disease is almost always affected by the environmental factors and events in the person's development.

Some types of recessive gene disorders confer an advantage in certain environments when only one copy of the gene is present.

Single Gene,

A single-gene disorder is the result of a single mutated gene. Over 4000 human diseases are caused by single-gene defects. Single-gene
disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparentaldisomy, however, may affect
inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between
autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For
example, achondroplasia is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe skeletal
disorder of which achondroplasics could be viewed as carriers. Sickle-cell anemia is also considered a recessive condition, but heterozygous
carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple
where one partner or both are sufferers or carriers of a single-gene disorder wish to have a child, they can do so through in vitro
fertilization, which means they can then have a preimplantation genetic diagnosis to check whether the embryo has the genetic disorder.

Autosomal dominant

Autosomal dominant and Autosomal dominant gene

Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person
usually has one affected parent. The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have
reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to
develop the disease. Examples of this type of disorder are Huntington's disease, neurofibromatosis type 1, neurofibromatosis type 2,
Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant
disorder),Tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.

Autosomal recessive

Autosomal dominant § Autosomal recessive allele

Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has
unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Two unaffected people who each
carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of
disorder are Albinism, Medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Niemann-Pick
disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in
an autosomal recessive fashion.

X-linked dominant

Main article: X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern,
with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically
being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentiapigmenti type 2, and
Aicardi

68
syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this
finding are extremely rare cases in which boys with Klinefelter syndrome (47,XXY) also inherit an X-linked dominant condition and exhibit
symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs
between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y
chromosome), and his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an
affected fetus with each pregnancy, although it should be noted that in cases such as incontinentiapigmenti, only female offspring are
generally viable. In addition, although these conditions do not alter fertility per se, individuals with Rett syndrome or Aicardi syndrome
rarely reproduce.[citation needed]

X-linked recessive

X-linked recessive inheritance

X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females,
and the chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not
be affected, and his daughters will carry one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has
a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene and are
therefore carriers. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch-Nyhan
syndrome, as well as common and less serious conditions such as male pattern baldness and red-green color blindness. X-linked recessive
conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).

Y-linked

Y linkage

Y-linked disorders, also called holandric disorders, are caused by mutations on the Y chromosome. These conditions display may only be
transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders
in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.

Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is
only possible through the circumvention of infertility by medical intervention.

Mitochondrial

Mitochondrial disease

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Because only egg cells
contribute mitochondria to the developing embryo, only mothers can pass on mitochondrial conditions to their children. An example
of this type of disorder is Leber's hereditary optic neuropathy.

Many genes

Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in
combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex
disorders

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often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting
or passing on these disorders. Complex disorders are also difficult to study and treat, because the specific factors that cause most of these
disorders have not yet been identified. Studies which aim to identify the cause of complex disorders can use several methodological
approaches to determine genotype-phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants
within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first
approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.

On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases.
But this does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many
of them (e.g., blood pressure).

Asthma, autoimmune diseases such as multiple sclerosis, cancers, ciliopathies, cleft palate, diabetes, heart disease,
hypertension, inflammatory bowel disease, intellectual disability, mood disorder, obesity, refractive error, infertility

Head trauma; terms traumatic brain injury and head injury are often used interchangeably in the medical literature.This broad classification
includes neuronal injuries, hemorrhages, vascular injuries, cranial nerve injuries, and subduralhygromas, among many others. These
classifications can be further categorized as open (penetrating) or closed head injuries. This depends on if the skull was broken or not.
Because head injuries cover such a broad scope of injuries, there are many causes—including accidents, falls, physical assault, or traffic
accidents—that can cause head injuries. Many of these are minor, but some can be severe enough to require hospitalization.

The incidence (number of new cases) of head injury is 1.7 million people in the United States alone each year. About 3% of these incidents
lead to death. Adults suffer head injuries more frequently than any age group. Their injuries tend to be due to falls, motor vehicle crashes,
colliding or being struck by an object, and assaults. Children, however, tend to experience head injuries due to accidental falls and
intentional causes (such as being struck or shaken). Head injury often occurs in toddlers as they learn to walk. Head trauma is a common
cause of childhood hospitalization.

Unlike a broken bone where trauma to the body is obvious, head trauma can sometimes be conspicuous or inconspicuous. In the case of
an open head injury, the skull is cracked and broken by an object that makes contact with the brain. This leads to bleeding. Other obvious
symptoms can be neurological in nature. The person may become sleepy, behave abnormally, lose consciousness, vomit, develop a
severe headache, have mismatched pupil sizes, and/or be unable to move certain parts of the body. While these symptoms happen right
after head injury occurs, many problems can develop later in life. Alzheimer’s disease, for example, is much more likely to develop in a
person who has experienced a head injury.

Classification of head trauma

Head injuries include both injuries to the brain and those to other parts of the head, such as the scalp and skull.Head injuries can be closed
or open. A closed (non-missile) head injury is where the dura mater remains intact. The skull can be fractured, but not necessarily. A
penetrating head injury occurs when an object pierces the skull and breaches the dura mater. Brain injuries may be diffuse, occurring over a
wide area, or focal, located in a small, specific area.A head injury may cause skull fracture, which may or may not be associated with injury
to the brain. Some patients may have linear or depressed skull fractures.If intracranial hemorrhage occurs, a hematoma within the skull can
put pressure on the brain. Types of intracranial hemorrage include subdural, subarachnoid, extradural, and intraparenchymal hematoma.
Craniotomy surgeries are used in these cases to lessen the pressure by draining off blood.

Brain injury can be at the site of impact, but can also be at the opposite side of the skull due to a contrecoup effect (the impact to the head can cause

the brain to move within the skull, causing the brain to impact the interior of the skull opposite the head-impact).If the impact causes the

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head to move, the injury may be worsened, because the brain may ricochet inside the skull causing additional impacts, or the brain may
stay relatively still (due to inertia) but be hit by the moving skull (both are contrecoup injuries).

Private Patrick Hughes, Co. K, 4th New York Volunteers, wounded at the Battle of Antietam on September 17, 1862.

Specific problems after head injury can include

Skull fracture

Lacerations to the scalp and resulting hemorrhage of the skin

Traumatic subdural hematoma, a bleeding below the dura mater which may develop slowly

Traumatic extradural, or epidural hematoma, bleeding between the dura mater and the skull

Traumatic subarachnoid hemorrhage

Cerebral contusion, a bruise of the brain

Concussion, a loss of function due to trauma

Dementia pugilistica, or "punch-drunk syndrome", caused by repetitive head injuries, for example in boxing or other contact sports

A severe injury may lead to a coma or death

Shaken baby syndrome — a form of child abuse

Concussion

Traumatic brain injury (TBI) is an exchangeable word used for the word concussion. This term refers to a mild brain injury. This injury is a
result due to a blow to the head that could make the person’s physical, cognitive, and emotional behaviors irregular.Symptoms may
include:Clumsiness, Fatigue, Confusion, Nausea, Blurry Vision, Headaches, and others.Mild concussions are associated with sequelae.
Severity is measured using various concussion grading systems.

A slightly greater injury is associated with both anterograde and retrograde amnesia (inability to remember events before or after the
injury). The amount of time that the amnesia is present correlates with the severity of the injury. In all cases the patients develop
postconcussion syndrome, which includes memory problems, dizziness, tiredness, sickness and depression.Cerebral concussion is the most
common head injury seen in children.

Intracranial hemorrhage

Types of intracranial hemorrhage are roughly grouped into intra-axial and extra-axial. The hemorrhage is considered a focal brain injury; that
is, it occurs in a localized spot rather than causing diffuse damage over a wider area.

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Intra-axial hemorrhage

Cerebral hemorrhage

Intra-axial hemorrhage is bleeding within the brain itself, or cerebral hemorrhage. This category includes intraparenchymal hemorrhage,
or bleeding within the brain tissue, and intraventricular hemorrhage, bleeding within the brain's ventricles (particularly of premature
infants). Intra-axial hemorrhages are more dangerous and harder to treat than extra-axial bleeds.

Extra-axial hemorrhage

Extra-axial hemorrhage, bleeding that occurs within the skull but outside of the brain tissue, falls into three subtypes:

Epidural hemorrhage (extradural hemorrhage) which occur between the dura mater (the outermost meninx) and the skull, is caused by
trauma. It may result from laceration of an artery, most commonly the middle meningeal artery. This is a very dangerous type of injury
because the bleed is from a high-pressure system and deadly increases in intracranial pressure can result rapidly. However, it is the least
common type of meningeal bleeding and is seen in 1% to 3% cases of head injury .

Patients have a loss of consciousness (LOC), then a lucid interval, then sudden deterioration (vomiting, restlessness, LOC)

Head CT shows lenticular (convex) deformity.

Subdural hemorrhage results from tearing of the bridging veins in the subdural space between the dura and arachnoid mater.

Head CT shows crescent-shaped deformity

Subarachnoid hemorrhage, which occur between the arachnoid and pia meningeal layers, like intraparenchymal hemorrhage, can result
either from trauma or from ruptures of aneurysms or arteriovenous malformations. Blood is seen layering into the brain along sulci and
fissures, or filling cisterns (most often the suprasellar cistern because of the presence of the vessels of the circle of Willis and their
branchpoints within that space). The classic presentation of subarachnoid hemorrhage is the sudden onset of a severe headache (a
thunderclap headache). This can be a very dangerous entity, and requires emergent neurosurgical evaluation, and sometimes urgent
intervention.

Cerebral contusion

Cerebral contusion is bruising of the brain tissue. The majority of contusions occur in the frontal and temporal lobes. Complications may
include cerebral edema and transtentorial herniation. The goal of treatment should be to treat the increased intracranial pressure. The
prognosis is guarded.

Mechanism of Cerbral contusion.

Unlike brain trauma that occurs due to direct impact and deformation of the brain, DAI is the result of traumatic shearing forces that occur
when the head is rapidly accelerated or decelerated, as may occur in auto accidents, falls, and assaults. It usually results from rotational
forces or severe deceleration. Vehicle accidents are the most frequent cause of DAI; it can also occur as the result of child abuse such as in
shaken baby syndrome.

The major cause of damage in DAI is the disruption of axons, the neural processes that allow one neuron to communicate with another.
Tracts of axons, which appear white due to myelination, are referred to as white matter. Acceleration causes shearing injury: damage
inflicted as tissue slides over other tissue. When the brain is accelerated, parts of differing densities and distances from the axis of rotation
slide over each

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other, stretching axons that traverse junctions between areas of different density, especially at junctions between white and grey
matter.Two thirds of DAI lesions occur in areas where grey and white matter meet.

Characteristics

Lesions typically exist in the white matter of brains injured by DAI; these lesions vary in size from about 1–15 mm and are distributed
in a characteristic way. DAI most commonly affects white matter in areas including the brain stem, the corpus callosum, and the
cerebral hemispheres.

The lobes of the brain most likely to be injured are the frontal and temporal lobes. Other common locations for DAI include the white matter
in the cerebral cortex, the superior cerebral peduncles, basal ganglia, thalamus, and deep hemispheric nuclei. These areas may be more
easily damaged because of the difference in density between them and the rest of the brain.

Diffuse axonal injury ;

Diffuse axonal injury (DAI) is a brain injury in which damage in the form of extensive lesions in white matter tracts occurs over a widespread
area. DAI is one of the most common and devastating types of traumatic brain injury, and is a major cause of unconsciousness and
persistent vegetative state after severe head trauma. It occurs in about half of all cases of severe head trauma and may be the primary
damage that occurs in concussion. The outcome is frequently coma, with over 90% of patients with severe DAI never regaining
consciousness. Those who do wake up often remain significantly impaired.

DAI can occur in every degree of severity from very mild or moderate to very severe.[4] Concussion may be a milder type of diffuse
axonal injury.

Diffuse axonal injury, or DAI, usually occurs as the result of an acceleration or deceleration motion, not necessarily an impact. Axons are
stretched and damaged when parts of the brain of differing density slide over one another. Prognoses vary widely depending on the extent
of damage.

Signs and symptoms

Presentation varies according to the injury. Some patients with head trauma stabilize and other patients deteriorate. A patient may present
with or without neurological deficit.Patients with concussion may have a history of seconds to minutes unconsciousness, then normal
arousal. Disturbance of vision and equilibrium may also occur.Common symptoms of head injury include coma, confusion, drowsiness,
personality change, seizures, nausea and vomiting, headache and a lucid interval, during which a patient appears conscious only to
deteriorate later.[8]

Symptoms of skull fracture can include:

leaking cerebrospinal fluid (a clear fluid drainage from nose, mouth or ear) may be and is strongly indicative of basilar skull
fracture and the tearing of sheaths surrounding the brain, which can lead to secondary brain infection.
visible deformity or depression in the head or face; for example a sunken eye can indicate a maxillar fracture
an eye that cannot move or is deviated to one side can indicate that a broken facial bone is pinching a nerve that innervates
eye muscles

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 wounds or bruises on the scalp or face.
Basilar skull fractures, those that occur at the base of the skull, are associated with Battle's sign, a subcutaneous bleed over
the mastoid, hemotympanum, and cerebrospinal fluid rhinorrhea and otorrhea.

Because brain injuries can be life-threatening, even people with apparently slight injuries, with no noticeable signs or complaints, require
close observation; They have a chance for severe symptoms later on. The caretakers of those patients with mild trauma who are released
from the hospital are frequently advised to rouse the patient several times during the next 12 to 24 hours to assess for worsening
symptoms.

The Glasgow Coma Scale (GCS) is a tool for measuring degree of unconsciousness and is thus a useful tool for determining severity of injury.
The Pediatric Glasgow Coma Scale is used in young children. The widely used PECARN Pediatric Head Injury/Trauma Algorithm helps
physicians weigh risk-benefit of imaging in a clinical setting given multiple factors about the patient - including mechanism/location of injury,
age of patient, and GCS score.

Infections;Infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host
tissues to these organisms and the toxins they produce. Infectious disease, also known as transmissible disease or communicable disease, is
illness resulting from an infection.

Infections are caused by infectious agents including viruses, viroids, prions, bacteria, nematodes such as parasitic roundworms and
pinworms, arthropods such as ticks, mites, fleas, and lice, fungi such as ringworm, and other macroparasites such as tapeworms and other
helminths.

Hosts can fight infections using their immune system. Mammalian hosts react to infections with an innate response, often
involving inflammation, followed by an adaptive response.

Specific medications used to treat infections include antibiotics, antivirals, antifungals, antiprotozoals, and antihelminthics. Infectious
diseases resulted in 9.2 million deaths in 2013 (about 17% of all deaths). The branch of medicine that focuses on infections is referred to as
infectious disease.

Classification of infections

Symptomatic infections are apparent, whereas an infection that is active but does not produce noticeable symptoms may be called inapparent, silent,

subclinical or occult. An infection that is inactive or dormant is called a latent infection.[6] An example of a latent bacterial infection is latent

tuberculosis. Some viral infections can also be latent, examples of latent viral infections are any of those from the Herpesviridae family.

A short-term infection is an acute infection. A long-term infection is a chronic infection. Infections can be further classified by causative
agent (bacterial, viral, fungal, parasitic), and by the presence or absence of systemic symptoms (sepsis).

Primary versus opportunistic

Among the many varieties of microorganisms, relatively few cause disease in otherwise healthy individuals.[7] Infectious disease results from
the interplay between those few pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from
any pathogen, depends upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen.
However a host's immune system can also cause damage to the host itself in an attempt to control the infection. Clinicians therefore classify
infectious microorganisms or microbes according to the status of host defenses - either as primary pathogens or as opportunistic pathogens:

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 Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the
severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common
primary pathogens of humans only infect humans, however many serious diseases are caused by organisms acquired from the environment
or that infect non-human hosts.

Opportunistic pathogens can cause an infectious disease in a host with depressed resistance. Opportunistic infection may be caused by
microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract, and
they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridium difficile colitis) or from the
environment as a result of traumatic introduction (as in surgical wound infections or compound fractures). An opportunistic disease requires
impairment of host defenses, which may occur as a result of genetic defects (such as Chronic granulomatous disease), exposure to
antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy), exposure to ionizing
radiation, or as a result of an infectious disease with immunosuppressive activity (such as with measles, malaria or HIV disease). Primary
pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host.

Infectious or not

One way of proving that a given disease is "infectious", is to satisfy Koch's postulates (first proposed by Robert Koch), which demands that
the infectious agent be identified only in patients and not in healthy controls, and that patients who contract the agent also develop the
disease. These postulates were first used in the discovery that Mycobacteria species cause tuberculosis. Koch's postulates can not be
applied ethically for many human diseases because they require experimental infection of a healthy individual with a pathogen produced
as a pure culture.
Often, even clearly infectious diseases do not meet the infectious criteria. For example, Treponemapallidum, the causative spirochete of
syphilis, cannot be cultured in vitro - however the organism can be cultured in rabbit testes. It is less clear that a pure culture comes from an
animal source serving as host than it is when derived from microbes derived from plate culture. Epidemiology is another important tool
used to study disease in a population. For infectious diseases it helps to determine if a disease outbreak is sporadic (occasional occurrence),
endemic (regular cases often occurring in a region), epidemic (an unusually high number of cases in a region), or pandemic (a global
epidemic).

Contagiousness

Infectious diseases are sometimes called contagious disease when they are easily transmitted by contact with an ill person or their secretions (e.g.,
influenza). Thus, a contagious disease is a subset of infectious disease that is especially infective or easily transmitted. Other types of
infectious/transmissible/communicable diseases with more specialized routes of infection, such as vector transmission or sexual transmission, are
usually not regarded as "contagious", and often do not require medical isolation (sometimes loosely called quarantine) of victims. However, this
specialized connotation of the word "contagious" and "contagious disease" (easy transmissibility) is not always respected in popular use.

By anatomic location

Infections can be classified by the anatomic location or organ system infected, including:

Urinary tract infection

Skin infection

Respiratory tract infection

Odontogenic infection (an infection that originates within a tooth or in the closely surrounding tissues)

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 Vaginal infections

Intra-amniotic infection

In addition, locations of inflammation where infection is the most common cause include pneumonia, meningitis and salpingitis.

Signs and symptoms

The symptoms of an infection depend on the type of disease. Some signs of infection affect the whole body generally, such as fatigue, loss
of appetite, weight loss, fevers, night sweats, chills, aches and pains. Others are specific to individual body parts, such as skin rashes,
coughing, or a runny nose.

In certain cases, infectious diseases may be asymptomatic for much or even all of their course in a given host. In the latter case, the
disease may only be defined as a "disease" (which by definition means an illness) in hosts who secondarily become ill after contact with
an asymptomatic carrier. An infection is not synonymous with an infectious disease, as some infections do not cause illness in a host.

Bacterial or viral

Viral infection

In general , caused by pathogenic viruses ; Symptoms of viral infections are systemic. This means they involve many different parts of the
body or more than one body system at the same time; i.e. a runny nose, sinus congestion, cough, body aches etc. They can be local at times
as in viral conjunctivitis or "pink eye" and herpes. Only a few viral infections are painful, like herpes. The pain of viral infections is often
described as itchy or burning

Bacterial infection

Bacterial infection are caused by Bacterial infection, The classic symptoms of a bacterial infection are localized redness, heat, swelling and
pain. One of the hallmarks of a bacterial infection is local pain, pain that is in a specific part of the body. For example, if a cut occurs and is
infected with bacteria, pain occurs at the site of the infection. Bacterial throat pain is often characterized by more pain on one side of the
throat. An ear infection is more likely to be diagnosed as bacterial if the pain occurs in only one ear. A cut that produces pus and milky-
colored liquid is most likely infected.

Bacterial and viral infections can both cause the same kinds of symptoms. It can be difficult to distinguish which is the cause of a
specific infection.It's important to distinguish, because viral infections cannot be cured by antibiotics.

Pathophysiology

There is a general chain of events that applies to infections. The chain of events involves several steps—which include the infectious agent,
reservoir, entering a susceptible host, exit and transmission to new hosts. Each of the links must be present in a chronological order for an
infection to develop. Understanding these steps helps health care workers target the infection and prevent it from occurring in the first
place. Colonization

Infection of a toe with an ingrown toenail; there is pus (yellow) and resultant inflammation (redness and swelling around the nail).

Infection begins when an organism successfully enters the body, grows and multiplies. This is referred to as colonization. Most humans are
not easily infected. Those who are weak, sick, malnourished, have cancer or are diabetic have increased susceptibility to chronic or
persistent infections. Individuals who have a suppressed immune system are particularly susceptible to opportunistic infections. Entrance
to the host at

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host-pathogen interface, generally occurs through the mucosa in orifices like the oral cavity, nose, eyes, genitalia, anus, or the microbe can
enter through open wounds. While a few organisms can grow at the initial site of entry, many migrate and cause systemic infection in
different organs. Some pathogens grow within the host cells (intracellular) whereas others grow freely in bodily fluids.

Wound colonization refers to nonreplicating microorganisms within the wound, while in infected wounds, replicating organisms exist and
tissue is injured. All multicellular organisms are colonized to some degree by extrinsic organisms, and the vast majority of these exist in
either a mutualistic or commensal relationship with the host. An example of the former is the anaerobic bacteria species, which colonizes
the mammalian colon, and an example of the latter is various species of staphylococcus that exist on human skin. Neither of these
colonizationsare considered infections. The difference between an infection and a colonization is often only a matter of circumstance. Non-
pathogenic organisms can become pathogenic given specific conditions, and even the most virulent organism requires certain circumstances
to cause a compromising infection. Some colonizing bacteria, such as Corynebacteria sp. and viridans streptococci, prevent the adhesion and
colonization of pathogenic bacteria and thus have a symbiotic relationship with the host, preventing infection and speeding wound healing.

A fluorescence micrograph of cells in Drosophila larvae healing after a puncture wound. The arrow points to cells that have fused to
form syncytia, and the arrowheads point to cells that are oriented to face the wound.

The variables involved in the outcome of a host becoming inoculated by a pathogen and the ultimate outcome include:

the route of entry of the pathogen and the access to host regions that it
gains the intrinsic virulence of the particular organism
the quantity or load of the initial inoculant
the immune status of the host being colonized
As an example, the staphylococcus species remains harmless on the skin, but, when present in a normally sterile space, such
as in the capsule of a joint or the peritoneum, multiplies without resistance and causes harm.

Because it is normal to have bacterial colonization, it is difficult to know which chronic wounds are infected. Despite the huge number of
wounds seen in clinical practice, there are limited quality data for evaluated symptoms and signs. A review of chronic wounds in the
Journal of the American Medical Association's "Rational Clinical Examination Series" quantified the importance of increased pain as an
indicator of infection. The review showed that the most useful finding is an increase in the level of pain [likelihood ratio (LR) range, 11-20]
makes infection much more likely, but the absence of pain (negative likelihood ratio range, 0.64-0.88) does not rule out infection (summary
LR 0.64-0.88).

Disease

Disease can arise if the host's protective immune mechanisms are compromised and the organism inflicts damage on the host. Microorganisms can

cause tissue damage by releasing a variety of toxins or destructive enzymes. For example, Clostridium tetani releases a toxin that paralyzes

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muscles, and staphylococcus releases toxins that produce shock and sepsis. Not all infectious agents cause disease in all hosts. For example,
less than 5% of individuals infected with polio develop disease. On the other hand, some infectious agents are highly virulent. The prion
causing mad cow disease and Creutzfeldt–Jakob disease invariably kills all animals and people that are infected.

Persistent infections occur because the body is unable to clear the organism after the initial infection. Persistent infections are characterized
by the continual presence of the infectious organism, often as latent infection with occasional recurrent relapses of active infection. There
are some viruses that can maintain a persistent infection by infecting different cells of the body. Some viruses once acquired never leave the
body. A typical example is the herpes virus, which tends to hide in nerves and become reactivated when specific circumstances arise.

Persistent infections cause millions of deaths globally each year. Chronic infections by parasites account for a high morbidity and
mortality in many underdeveloped countries.

Transmission

Main article: Transmission (medicine)

For infecting organisms to survive and repeat the infection cycle in other hosts, they (or their progeny) must leave an existing reservoir
and cause infection elsewhere. Infection transmission can take place via many potential routes:

Droplet contact, also known as the respiratory route, and the resultant infection can be termed airborne disease. If an infected person
coughs or sneezes on another person the microorganisms, suspended in warm, moist droplets, may enter the body through the nose, mouth
or eye surfaces.

Fecal-oral transmission, wherein foodstuffs or water become contaminated (by people not washing their hands before preparing food,
or untreated sewage being released into a drinking water supply) and the people who eat and drink them become infected. Common
fecal-oral transmitted pathogens include Vibrio cholerae, Giardia species, rotaviruses, Entamebahistolytica, Escherichia coli, and tape
worms. Most of these pathogens cause gastroenteritis.

Sexual transmission, with the resulting disease being called sexually transmitted disease

Oral transmission, Diseases that are transmitted primarily by oral means may be caught through direct oral contact such as kissing, or
by indirect contact such as by sharing a drinking glass or a cigarette.

Transmission by direct contact, Some diseases that are transmissible by direct contact include athlete's foot, impetigo and warts

Vertical transmission, directly from the mother to an embryo, fetus or baby during pregnancy or childbirth. It can occur when the mother
gets an infection as an intercurrent disease in pregnancy.

Iatrogenic transmission, due to medical procedures such as injection or transplantation of infected material.

Culex mosquitos (Culexquinquefasciatus shown) are biological vectors that transmit West Nile Virus.

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 Vector-borne transmission, transmitted by a vector, which is an organism that does not cause disease itself but that transmits infection
by conveying pathogens from one host to another.

The relationship between virulence versus transmissibility is complex; if a disease is rapidly fatal, the host may die before the microbe can
be passed along to another host.

Diagnosis

Diagnosis of infectious disease sometimes involves identifying an infectious agent either directly or indirectly. In practice most minor
infectious diseases such as warts, cutaneous abscesses, respiratory system infections and diarrheal diseases are diagnosed by their clinical
presentation and treated without knowledge of the specific causative agent. Conclusions about the cause of the disease are based upon the
likelihood that a patient came in contact with a particular agent, the presence of a microbe in a community, and other epidemiological
considerations. Given sufficient effort, all known infectious agents can be specifically identified. The benefits of identification, however, are
often greatly outweighed by the cost, as often there is no specific treatment, the cause is obvious, or the outcome of an infection is benign.

Diagnosis of infectious disease is nearly always initiated by medical history and physical examination. More detailed identification
techniques involve the culture of infectious agents isolated from a patient. Culture allows identification of infectious organisms by examining
their microscopic features, by detecting the presence of substances produced by pathogens, and by directly identifying an organism by its
genotype. Other techniques (such as X-rays, CAT scans, PET scans or NMR) are used to produce images of internal abnormalities resulting
from the growth of an infectious agent. The images are useful in detection of, for example, a bone abscess or a spongiform encephalopathy
produced by a prion.

Malnutrition; Malnutrition or malnourishment is a condition that results from eating a diet in which nutrients are either not enough or are
too much such that the diet causes health problems. It may involve calories, protein, carbohydrates, vitamins or minerals. Not enough
nutrients is called undernutrition or undernourishment while too much is called overnutrition. Malnutrition is often used specifically to refer
to undernutrition where there is not enough calories, protein, or micronutrients. If undernutrition occurs during pregnancy, or before two
years of age, it may result in permanent problems with physical and mental development. Extreme undernourishment, known as starvation,
may have symptoms that include: a short height, thin body, very poor energy levels, and swollen legs and abdomen.People also often get
infections and are frequently cold. The symptoms of micronutrient deficiencies depend on the micronutrient that is lacking.

Undernourishment is most often due to not enough high-quality food being available to eat. This is often related to high food prices and
poverty. A lack of breastfeeding may contribute, as may a number of infectious diseases such as: gastroenteritis, pneumonia, malaria, and
measles, which increase nutrient requirements. There are two main types of undernutrition: protein-energy malnutrition and dietary
deficiencies. Protein-energy malnutrition has two severe forms: marasmus (a lack of protein and calories) and kwashiorkor (a lack of just
protein). Common micronutrient deficiencies include: a lack of iron, iodine, and vitamin A. During pregnancy, due to the body's increased
need, deficiencies may become more common. In some developing countries, overnutrition in the form of obesity is beginning to present
within the same communities as undernutrition. Other causes of malnutrition include anorexia nervosa and bariatric surgery.

Definition by Gomez

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In 1956, Gómez and Galvan studied factors associated with death in a group of malnourished (undernourished) children in a hospital in
Mexico City, Mexico and defined categories of malnutrition: first, second, and third degree. The degrees were based on weight below a
specified percentage of median weight for age. The risk of death increases with increasing degree of malnutrition. An adaptation of
Gomez's original classification is still used today. While it provides a way to compare malnutrition within and between populations, the
classification has been criticized for being "arbitrary" and for not considering overweight as a form of malnutrition. Also, height alone may
not be the best indicator of malnutrition; children who are born prematurely may be considered short for their age even if they have good
nutrition.

Degree of PEM % of desired body weight for age and sex

Normal 90%-100%

Mild: Grade I (1st degree) 75%-89%

Moderate: Grade II (2nd degree) 60%-74%

Severe: Grade III (3rd degree) <60%

SOURCE:"Serum Total Protein and Albumin Levels in Different Grades of Protein Energy Malnutrition"[

Definition by Waterlow

John Conrad Waterlow established a new classification for malnutrition. Instead of using just weight for age measurements, the
classification established by Waterlow combines weight-for-height (indicating acute episodes of malnutrition) with height-for-age to show
the stunting that results from chronic malnutrition. One advantage of the Waterlow classification over the Gomez classification is that
weight for height can be examined even if ages are not known.

Degree of PEM Stunting (%) Height for age Wasting (%) Weight for height

Normal: Grade 0 >95% >90%

Mild: Grade I 87.5-95% 80-90%

Moderate: Grade II 80-87.5% 70-80%

Severe: Grade III <80% <70%

SOURCE: "Classification and definition of protein-calorie malnutrition." by Waterlow, 1972

These classifications of malnutrition are commonly used with some modifications by WHO

Undernutrition and overnutrition

Malnutrition is caused by eating a diet in which nutrients are not enough or are too much such that it causes health problems. It is a
category of diseases that includes undernutrition and overnutrition.Overnutrition can result in obesity and being overweight. In some
developing countries, overnutrition in the form of obesity is beginning to present within the same communities as undernutrition.

However, the term malnutrition is commonly used to refer to undernutrition only. This applies particularly to the context of development
cooperation. Therefore, "malnutrition" in documents by the World Health Organization, UNICEF, Save the Children or other international
non-governmental organizations (NGOs) usually is equated to undernutrition.

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Protein-energy malnutrition

Undernutrition is sometimes used as a synonym of protein–energy malnutrition (PEM). While other include both micronutrient deficiencies
and protein energy malnutrition in its definition. It differs from calorie restriction in that calorie restriction may not result in negative health
effects. The term hypoalimentation means underfeeding.

The term "severe malnutrition" or "severe undernutrition" is often used to refer specifically to PEM. PEM is often associated with
micronutrient deficiency. Two forms of PEM are kwashiorkor and marasmus, and they commonly coexist.

Kwashiorkor

Kwashiorkor (‘displaced child’) is mainly caused by inadequate protein intake resulting in a low concentration of amino acids. The main
symptoms are edema, wasting, liver enlargement, hypoalbuminaemia, steatosis, and possibly depigmentation of skin and hair.
Kwashiorkor is identified by swelling of the extremities and belly, which is deceiving of actual nutritional status.

Marasmus

Marasmus (‘to waste away’) is caused by an inadequate intake of protein and energy. The main symptoms are severe wasting, leaving little
or no edema, minimal subcutaneous fat, severe muscle wasting, and non-normal serum albumin levels. Marasmus can result from a
sustained diet of inadequate energy and protein, and the metabolism adapts to prolong survival. It is traditionally seen in famine, significant
food restriction, or more severe cases of anorexia. Conditions are characterized by extreme wasting of the muscles and a gaunt expression.

Undernutrition, hunger

Undernutrition encompasses stunted growth (stunting), wasting, and deficiencies of essential vitamins and minerals (collectively referred to
as micronutrients). The term hunger, which describes a feeling of discomfort from not eating, has been used to describe undernutrition,
especially in reference to food insecurity

Swelling(medical); In medical parlance, swelling, turgescence or tumefaction is a transient abnormal enlargement of a body part or area
not caused by proliferation of cells.[1] It is caused by accumulation of fluid in tissues. It can occur throughout the body (generalized), or a
specific part or organ can be affected (localized). Swelling is usually not dangerous and is a common reaction to a inflammation or a
bruise.

Swelling is considered one of the five characteristics of inflammation; along with pain, heat, redness, and loss of function.

In a general sense, the suffix "-megaly" is used to indicate a growth, as in hepatomegaly, acromegaly, and splenomegaly.

A body part may swell in response to injury, infection, or disease. Swelling, especially of the ankle, can occur if the body is not
circulating fluid well. If water retention progresses to a symptomatic extent, swelling results.

Generalized swelling, or massive edema (also called anasarca), is a common sign in severely ill people. Although slight edema may be
difficult to detect to the untrained eye, especially in an overweight person, massive edema is very obvious.

Types of swelling

Traumatic swellings develop immediately after trauma, like a hematoma or dislocation.

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Congenital swellings are present since birth, such as a hemangioma or meningocele. Some congenital swellings may not be discovered
until later in life, such as a branchial cyst, dermoid cyst or thyroglossal cyst.

Inflammatory swelling may be either acute or chronic. The presentations of acute swellings are redness, local fever, pain and
impairment of function of the affected organ. The related lymph nodes will be affected and will show signs of acute lymphadenitis.
Chronic inflammatory swellings will show the signs of acute inflammatory swellings, but in subdued form. In this case, edema might
not occur. Chronic swellings can be differentiated from neoplastic swellings by the fact that neoplastic swellings never recede in size,
but inflammatory swellings may show occasional diminution.

Causes of swelling.

Allergic reaction Eczema Insect sting

Parasitic
Cellulitis Hives Infection

Contact dermatitis Insect bite Skin infection

Causes of generalized swelling:

Beri-beri Congestive heart Heart failure Lymphatic Preeclampsia

Celiac failure Kidney obstruction Pregnancy

disease Edema conditions Malabsorption Premenstrual

Certain Excessive IV therapy Kidney failure Malnutrition syndrome

medications Filariasis Liver condition Nephritis Protein

Cirrhosis of Glomerulonephritis Lymphedema Nephrotic deficiency

the liver syndrome Thyroid
Chronic condition

hepatitis Ulcerative
colitis

Varicose veins

Some possible causes of a swollen limb include:

Lymphatic
Allergic reaction obstruction

Cancer Sunburn

Venous thrombosis

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SYMPTOMS OF HYPOTHALAMI DYSFUNCTION

Symptoms are usually due to the hormones that are missing. In children, there may be growth problems, either too much or too little growth.

In other children, puberty occurs too early or too late.

Tumor symptoms may include headache or loss of vision.

Hypothyroidism symptoms may include feeling cold all the time, constipation, fatigue, or weight gain, among others.

Low adrenal function symptoms may include dizziness or weakness.

Kallmann syndrome is a genetic type of hypothalamic dysfunction. Symptoms include:

Lowered function of sexual hormones (hypogonadism)

Inability to smell (in some people)

BRAIN TUMORS

Permanent blindness

Problems related to the brain area where the tumor occurs

Vision disorders

Problems controlling salt and water balance

HYPOTHYROIDISM

Heart problems

High cholesterol

ADRENAL INSUFFICIENCY

Inability to deal with stress (such as surgery or infection), which can be life-threatening by causing low blood pressure

GONADAL DEFICIENCY

Heart disease

Erection problems

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 Infertility

Thin bones (osteoporosis)

Problems breast feeding

GROWTH HORMONE DEFICIENCY

High cholesterol

Osteoporosis

Short stature (in children)

Weakness

TREATMENT

EXAMS AND TESTS

Blood or urine tests may be ordered to determine levels of hormones such as:

Cortisol, Estrogen, Growth hormone, Pituitary hormones, Prolactin, Testosterone, Thyroid

Other possible tests include: Hormone injections followed by timed blood samples MRI or CT scans of the brain, Visual field eye exam (if there is

a tumor)

TREATMENT

Treatment depends on the cause of the hypothalamic dysfunction:

Outlook (Prognosis)

Many causes of hypothalamic dysfunction are treatable. Most of the time, missing hormones can be replaced.

Possible Complications

Complications of hypothalamic dysfunction depend on the cause.

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ELECTROTHERAPY TREATMENT METHOD.

Electrotherapy is a form of medical treatment, which uses small electrical impulses to repair tissue, stimulate muscles and increase
sensations and muscle strength. Or Electrotherapy is the use of electrical energy as a medical treatment. In medicine, the term
electrotherapy can apply to a variety of treatments, including the use of electrical devices such as deep brain stimulators for neurological
disease. The term has also been applied specifically to the use of electric current to speed wound healing. Additionally, the term
"electrotherapy" or "electromagnetic therapy" has also been applied to a range of alternative medical devices and treatments.

There are several different forms of electrotherapy; these include ultrasound, interferential therapy, transcutaneous electrical nerve
stimulation (TENS), laser therapy and muscle stimulation. Ultrasound uses sound waves to speed up the healing process, while
interferential therapy and TENS reduce pain by manipulating the nerves which reduces the sensation of pain and produces a tingling
feeling. Laser therapy is sometimes used to repair damaged tissue; using lasers means the treatment can be both accurate and intense.

Muscel stimulation

alternating was superior to direct current for electrotherapeutic triggering of muscle contractions. What he called the 'warming affect' of
direct currents irritated the skin, since, at voltage strengths needed for muscle contractions, they cause the skin to blister (at the anode) and
pit (at the cathode). Furthermore, with DC each contraction required the current to be stopped and restarted. Moreover, alternating current
could produce strong muscle contractions regardless of the condition of the muscle, whereas DC-induced contractions were strong if the
muscle was strong, and weak if the muscle was weak.

investigating the application of electrical stimulation not just to retard and prevent atrophy but to restore muscle mass and strength,
employed what was termed galvanic exercise on the atrophied hands of patients who had an ulnar nerve lesion from surgery upon a wound.
[5] These galvanic exercises employed a monophasic wave form, direct current.

Cancer treatment

In the field of cancer treatment, DC electrotherapy showed, when a study published in the journal Science reported total destruction of
tumor in 60% of subjects, which was very noteworthy for an initial study. the journal Cancer Research published the most remarkable such
study, reporting shrinkage of tumor in animal subjects on being treated with DC electrotherapy .The mechanism for the effectiveness of DC
electrotherapy in treating cancer The free-radical (unpaired electron) containing active-site of enzyme RibonucleotideReductase, RnR—
which controls the rate-limiting step in the synthesis of DNA—can be disabled by a stream of passing electrons.

Central Control of the Visceral Motor Functions

The visceral motor system is regulated in part by circuitry in the cerebral cortex: Involuntary visceral reactions such as blushing in response
to consciously embarrassing stimuli, vasoconstriction and pallor in response to fear, and autonomic responses to sexual situations make this
plain. Indeed, autonomic function is intimately related to emotional experience and expression. In addition, the hippocampus, thalamus,
basal ganglia, cerebellum, and reticular formation all influence the visceral motor system. The major center in the control of the visceral
motor system.The hypothalamic nuclei relevant to visceral motor function project to the nuclei in the brainstem that organize many visceral
reflexes (e.g., respiration, vomiting, urination), to the cranial nerve nuclei that contain parasympathetic preganglionic neurons, and to the
sympathetic and parasympathetic preganglionic neurons in the spinal cord. The general organization of this central autonomic control is
summarized below, and some important clinical manifestations of damage to this descending system

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Although the hypothalamus is the key structure in the overall organization of visceral function, and in homeostasis generally, the visceral
motor system continues to function independently if disease or injury impedes the influence of this controlling center. The major subcortical
centers for the ongoing regulation of the autonomic function in the absence of hypothalamic control are a series of poorly understood nuclei
in the brainstem tegmentum that organize specific visceral functions such as cardiac reflexes, reflexes that control the bladder, and reflexes
related to sexual function, as well as other critical autonomic reflexes such as respiration and vomiting.

The afferent information from the viscera that drives these brainstem centers is, as noted already, received by neurons in the nucleus of
the solitary tract, which relays these signals to the hypothalamus and to the various autonomic centers in the brainstem tegmentum.

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Coronal sections through the human hypothalamus.

Coronal sections through the human hypothalamus (see figure A for location of sections 1–4). Color coding of the nuclei illustrates the two
dimensions by which hypothalamic nuclei are subdivided (see text). Blue, red, and green illustrate nuclei in the anterior, tuberal, and
posterior regions, respectively. The relative shading of these hues illustrates the three mediolateral zones: Lighter shading represents nuclei
in the periventricular zone, whereas darker shades represent medial zone nuclei. Nuclei in the lateral zone are stippled. (1) Section through
the anterior region illustrating the preoptic and suprachiasmatic nuclei. (2) Rostral tuberal region. (3) Caudal tuberal region. (4) Section
through the posterior region illustrating the mammillary bodies.

SYMPATHETIC TRUNK ELECTRIFICATION

The sympathetic nervous system is one of the two main divisions of the autonomic nervous system, the other being the parasympathetic
nervous system. The autonomic nervous system functions to regulate the body's unconscious actions. The sympathetic nervous system's
primary process is to stimulate the body's fight-or-flight response. It is, however, constantly active at a basic level to maintain
homeostasis.The sympathetic nervous system is described as being complementary to the parasympathetic nervous system which
stimulates the body to "rest-and-digest" or "Feed and breed".

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The sympathetic trunks (sympathetic chain, gangliated cord) are a paired bundle of nerve fibers that run from the base of the skull to
the coccyx.

Organization

The sympathetic nervous system extends from the thoracic to lumbar vertebrae and has connections with the thoracic, abdominal, and
pelvic plexuses.

Sympathetic nerves arise from near the middle of the spinal cord in the intermediolateral nucleus of the lateral grey column, beginning at
the first thoracic vertebra of the vertebral column and are thought to extend to the second or third lumbar vertebra. Because its cells begin
in the thoracic and lumbar regions of the spinal cord, the sympathetic nervous system is said to have a thoracolumbar outflow. Axons of
these nerves leave the spinal cord through the anterior root. They pass near the spinal (sensory) ganglion, where they enter the anterior
rami of the spinal nerves. However, unlike somatic innervation, they quickly separate out through white rami connectors (so called from the
shiny white sheaths of myelin around each axon) that connect to either the paravertebral (which lie near the vertebral column) or
prevertebral (which lie near the aortic bifurcation) ganglia extending alongside the spinal column.

To reach target organs and glands, the axons must travel long distances in the body, and, to accomplish this, many axons relay their message
to a second cell through synaptic transmission. The ends of the axons link across a space, the synapse, to the dendrites of the second cell.
The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic
cell). The message is then carried to the final destination.

Presynaptic nerves' axons terminate in either the paravertebral ganglia or prevertebral ganglia. There are four different ways an axon can
take before reaching its terminal. In all cases, the axon enters the paravertebral ganglion at the level of its originating spinal nerve. After
this, it can then either synapse in this ganglion, ascend to a more superior or descend to a more inferior paravertebral ganglion and
synapse there, or it can descend to a prevertebral ganglion and synapse there with the postsynaptic cell.

The postsynaptic cell then goes on to innervate the targeted end effector (i.e. gland, smooth muscle, etc.). Because paravertebral
and prevertebral ganglia are relatively close to the spinal cord, presynaptic neurons are generally much shorter than their
postsynaptic counterparts, which must extend throughout the body to reach their destinations.

A notable exception to the routes mentioned above is the sympathetic innervation of the suprarenal (adrenal) medulla. In this case,
presynaptic neurons pass through paraverterbral ganglia, on through prevertebral ganglia and then synapse directly with suprarenal tissue.
This tissue consists of cells that have pseudo-neuron like qualities in that when activated by the presynaptic neuron, they will release their
neurotransmitter (epinephrine) directly into the blood stream.

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In the sympathetic nervous system and other components of the peripheral nervous system, these synapses are made at sites called
ganglia. The cell that sends its fiber is called a preganglionic cell, while the cell whose fiber leaves the ganglion is called a postganglionic
cell. As mentioned previously, the preganglionic cells of the sympathetic nervous system are located between the first thoracic segment
and third lumbar segments of the spinal cord. Postganglionic cells have their cell bodies in the ganglia and send their axons to target
organs or glands.

The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle and inferior), which sends sympathetic
nerve fibers to the head and thorax organs, and the celiac and mesenteric ganglia (which send sympathetic fibers to the gut)

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The sympathetic trunk lies just lateral to the vertebral bodies for the entire length of the vertebral column. It interacts with the anterior rami
of spinal nerves by way of rami communicantes. The sympathetic trunk permits preganglionic fibers of the sympathetic nervous system to
ascend to spinal levels superior to T1 and descend to spinal levels inferior to L2/3.

Abdominal portion of the sympathetic trunk (Yellow), with the celiac plexus and hypogastric plexus. (Sympathetic trunk labeled at center
left.)

The superior end of it is continued upward through the carotid canal into the skull, and forms a plexus on the internal carotid artery; the
inferior part travels in front of the coccyx, where it converges with the other trunk at a structure known as the ganglion impar. Along the
length of the sympathetic trunk are sympathetic ganglia known as paravertebral ganglia

The sympathetic trunk is a fundamental part of the sympathetic nervous system, part of the autonomic nervous system. It allows nerve
fibres to travel to spinal nerves that are superior and inferior to the one in which they originated. Also, a number of nerves, such as most
of the splanchnic nerves, arise directly from the trunks.

ARINY AMOS ELECTRIFICATION TREATMENT METHOD.

ARINY AMOS TREATS THE FOLLOWING DISEASES WITH ELECTRIFICATION.

Ariny Amos never charged fee for treatment, Electrical Cures are God Given, contended that electrification may have curative powers when no other
medicines have been able to help. He made the observation:Electric Fire in Cases of this kind and of many other Kinds, dilates the minute Vessels,
and capillary Passages, as well as separates the cloggi Due to slavery, debtors' imprisonment, poor working conditions, and unsanitary living
conditions.ng Particles of the stagnating Fluids. By accelerating likewise the Motion of the Blood, it removes many Obstructions.

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John Wesley Pioneered and continued in the advancement of electricity for healing. In John wesleys work, Ariny Amos accepts that
electricity is the soul of the universe. Treatment is possible for instances where no Medicines discovered to treat such a disease, additional
facilitated by universal gravitation of Celestial bodies or Celestial Objects or heavenly bodies or heavenly objects or Astronomical objects or
Astronomical bodies with the assistance of Lorentz Force. Ariny Amos obtained an electrical apparatus and began experimenting by shocking
himself for several of the following diseases and found offering cures without medicines.

ELECTRIFICATION APARATUS;

Ariny Amos exercised this Experiment with himself and some People in Public several times, It consists of a hollow glass cylinder (7 1/2 in.
long by 4 1/2 in. diameter) supported on two wooden uprights. Through it runs a metal bar to which a handle is attached, by means of which
the cylinder can be freely rotated. A leather pad (to which is firmly attached a piece of black silk) is pressed against the cylinder. It is
controlled, very simply, by a thumbscrew.

On an attached platform (8 in. long by 5 in. wide) and mounted on a glass insulating column, is a metal arm with a thin rod (9 1/2 in. long)
attached to it, at the end of which is a small metal ball 1 in. diameter. The whole machine is mounted on four glass insulating legs (4 1/2
in. in height).

Altaernative is Electric wire measuring 60cm, open in both ends as sealed by rubber, connection to electric circuit and attached to the
cell membrane of the patient, any system of the body can be electrified.

BIOPHYSICS OF ELECTRIFICATION

ACTION POTENTIAL

In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls,
following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons,
muscle cells, and endocrine cells, as well as in some plant cells. Neurons play a central role in cell-to-cell communication. In other types
of cells, their main function is to activate intracellular processes. In muscle cells, for example, an action potential is the first step in the
chain of events leading to contraction. In beta cells of the pancreas, they provoke release of insulin.Action potentials in neurons are also
known as "nerve impulses" or "spikes", and the temporal sequence of action potentials generated by a neuron is called its "spike
train". A neuron that emits an action potential is often said to "fire".

Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane. These channels
are shut when the membrane potential is near the resting potential of the cell, but they rapidly begin to open if the membrane potential
increases to a precisely defined threshold value. When the channels open (in response to depolarization in transmembrane voltagethey
allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane
potential. This then causes more channels to open, producing a greater electric current across the cell membrane, and so on. The process
proceeds explosively until all of the available ion channels are open, resulting in a large upswing in the membrane potential. The rapid
influx of sodium ions causes the polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As the sodium
channels close, sodium ions can no longer enter the neuron, and then they are actively transported back out of the plasma membrane.
Potassium channels are then activated, and there is an outward current of potassium ions, returning the electrochemical gradient to the
resting state. After an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization or refractory
period, due to additional potassium currents. This mechanism prevents an action potential from traveling back the way it just came.

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In animal cells, there are two primary types of action potentials. One type is generated by voltage-gated sodium channels, the other by
voltage-gated calcium channels. Sodium-based action potentials usually last for under one millisecond, whereas calcium-based action
potentials may last for 100 milliseconds or longer, In some types of neurons, slow calcium spikes provide the driving force for a long burst
of rapidly emitted sodium spikes. In cardiac muscle cells, on the other hand, an initial fast sodium spike provides a "primer" to provoke
the rapid onset of a calcium spike, which then produces muscle contraction

OVER VIEW OF ACTION POTENTIAL

Nearly all cell membranes in animals, plants and fungi maintain a voltage difference between the exterior and interior of the cell, called
the membrane potential. A typical voltage across an animal cell membrane is –70 mV; this means that the interior of the cell has a
negative voltage of approximately one-fifteenth of a volt relative to the exterior. In most types of cells the membrane potential usually
stays fairly constant. Some types of cells, however, are electrically active in the sense that their voltages fluctuate over time. In some types
of electrically active cells, including neurons and muscle cells, the voltage fluctuations frequently take the form of a rapid upward spike
followed by a rapid fall. These up-and-down cycles are known as action potentials. In some types of neurons the entire up-and-down
cycle takes place in a few thousandths of a second. In muscle cells, a typical action potential lasts about a fifth of a second. In some other
types of cells, and in plants, an action potential may last three seconds or more.

The electrical properties of a cell are determined by the structure of the membrane that surrounds it. A cell membrane consists of a lipid
bilayer of molecules in which larger protein molecules are embedded. The lipid bilayer is highly resistant to movement of electrically
charged ions, so it functions as an insulator. The large membrane-embedded proteins, in contrast, provide channels through which ions
can pass across the membrane. Action potentials are driven by channel proteins whose configuration switches between closed and open
states as a function of the voltage difference between the interior and exterior of the cell. These voltage-sensitive proteins are known as
voltage-gated ion channels

Shape of a typical action potential. The membrane potential remains near a baseline level until at some point in time it abruptly
spikes upward and then rapidly falls.

PROCESS OF ELECTRIFICATION IN A TYPICAL NEURON.

All cells in animal body tissues are electrically polarized – in other words, they maintain a voltage difference across the cell's plasma
membrane, known as the membrane potential. This electrical polarization results from a complex interplay between protein structures
embedded in the membrane called ion pumps and ion channels. In neurons, the types of ion channels in the membrane usually vary
across different parts of the cell, giving the dendrites, axon, and cell body different electrical properties. As a result, some parts of the
membrane of a neuron may be excitable (capable of generating action potentials), whereas others are not. Recent studies have shown
that the most excitable part of a neuron is the part after the axon hillock (the point where the axon leaves the cell body), which is called
the initial segment, but the axon and cell body are also excitable in most cases.

Each excitable patch of membrane has two important levels of membrane potential: the resting potential, which is the value the
membrane potential maintains as long as nothing perturbs the cell, and a higher value called the threshold potential. At the axon hillock
of a typical neuron, the resting potential is around –70 millivolts (mV) and the threshold potential is around –55 mV. Synaptic inputs to a
neuron cause the membrane to depolarize or hyperpolarize; that is, they cause the membrane potential to rise or fall. Action potentials
are triggered when enough depolarization accumulates to bring the membrane potential up to threshold. When an action potential is
triggered, the membrane potential abruptly shoots upward and then equally abruptly shoots back downward, often ending below the
resting level, where it remains for some period of time. The shape of the action potential is stereotyped; that is, the rise and fall usually
have approximately the same amplitude and time course for all action potentials in a given cell. (Exceptions are discussed later in the
article.) In most neurons, the entire process takes place in about a

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thousandth of a second. Many types of neurons emit action potentials constantly at rates of up to 10–100 per second; some types,
however, are much quieter, and may go for minutes or longer without emitting any action potentials

Approximate plot of a typical action potential shows its various phases as the action potential passes a point on a cell membrane. The
membrane potential starts out at -70 mV at time zero. A stimulus is applied at time = 1 ms, which raises the membrane potential above -55
mV (the threshold potential). After the stimulus is applied, the membrane potential rapidly rises to a peak potential of +40 mV at time = 2
ms. Just as quickly, the potential then drops and overshoots to -90 mV at time = 3 ms, and finally the resting potential of -70 mV is
reestablished at time = 5

BIOPHYSICAL BASIS

Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels. A voltage-gated ion
channel is a cluster of proteins embedded in the membrane that has three key properties:

1. It is capable of assuming more than one conformation.

2. At least one of the conformations creates a channel through the membrane that is permeable to specific types of ions.
3. The transition between conformations is influenced by the membrane potential.

Thus, a voltage-gated ion channel tends to be open for some values of the membrane potential, and closed for others. In most cases,
however, the relationship between membrane potential and channel state is probabilistic and involves a time delay. Ion channels switch
between conformations at unpredictable times: The membrane potential determines the rate of transitions and the probability per unit
time of each type of transition.

Voltage-gated ion channels are capable of producing action potentials because they can give rise to positive feedback loops: The membrane
potential controls the state of the ion channels, but the state of the ion channels controls the membrane potential. Thus, in some situations, a rise
in the membrane potential can cause ion channels to open, thereby causing a further rise in the membrane potential. An action potential occurs
when this positive feedback cycle proceeds explosively. The time and amplitude trajectory of the action potential are determined by the
biophysical properties of the voltage-gated ion channels that produce it. Several types of channels that are capable of producing the positive
feedback necessary to generate an action potential exist. Voltage-gated sodium channels are responsible for the fast action potentials involved in

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nerve conduction. Slower action potentials in muscle cells and some types of neurons are generated by voltage-gated calcium channels.
Each of these types comes in multiple variants, with different voltage sensitivity and different temporal dynamics.

The most intensively studied type of voltage-dependent ion channels comprises the sodium channels involved in fast nerve conduction.
These are
sometimes known as Hodgkin-Huxley sodium channels because they were first characterized by Alan Hodgkin and Andrew Huxley in
their
Nobel Prize-winning studies of the biophysics of the action potential, but can more conveniently be referred to as Na V channels. (The "V"
stands
for "voltage".) AnNaV channel has three possible states, known as deactivated, activated, and inactivated. The channel is permeable only
to
sodium ions when it is in the activated state. When the membrane potential is low, the channel spends most of its time in the deactivated
(closed)
state. If the membrane potential is raised above a certain level, the channel shows increased probability of transitioning to the activated
(open)
state. The higher the membrane potential the greater the probability of activation. Once a channel has activated, it will eventually
transition to the
inactivated (closed) state. It tends then to stay inactivated for some time, but, if the membrane potential becomes low again, the channel
will
eventually transition back to the deactivated state. During an action potential, most channels of this type go through a cycle
deactivated→activated→inactivated→deactivated. This is only the population average behavior, however — an individual channel can in
principle make any transition at any time. However, the likelihood of a channel's transitioning from the inactivated state directly to the
activated
state is very low: A channel in the inactivated state is refractory until it has transitioned back to the deactivated state.

The outcome of all this is that the kinetics of the NaV channels are governed by a transition matrix whose rates are voltage-dependent
in a complicated way. Since these channels themselves play a major role in determining the voltage, the global dynamics of the system
can be quite difficult to work out. Hodgkin and Huxley approached the problem by developing a set of differential equations for the
parameters that govern the ion channel states, known as the Hodgkin-Huxley equations. These equations have been extensively
modified by later research, but form the starting point for most theoretical studies of action potential biophysics.

As the membrane potential is increased, sodium ion channels open, allowing the entry of sodium ions into the cell. This is followed by
the opening of potassium ion channels that permit the exit of potassium ions from the cell. The inward flow of sodium ions increases the
concentration of positively charged cations in the cell and causes depolarization, where the potential of the cell is higher than the cell's
resting potential. The sodium channels close at the peak of the action potential, while potassium continues to leave the cell. The efflux of
potassium ions decreases the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium
current exceeds the sodium current and the voltage returns to its normal resting value, typically −70 mV. However, if the voltage
increases past a critical threshold, typically 15 mV higher than the resting value, the sodium current dominates. This results in a
runaway condition whereby the positive feedback from the sodium current activates even more sodium channels. Thus, the cell fires,
producing an action potential. The frequency at which cellular action potentials are produced is known as its firing rate.
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Action potential propagation along an axon

Currents produced by the opening of voltage-gated channels in the course of an action potential are typically significantly larger than the
initial stimulating current. Thus, the amplitude, duration, and shape of the action potential are determined largely by the properties of
the excitable membrane and not the amplitude or duration of the stimulus. This all-or-nothing property of the action potential sets it
apart from graded potentials such as receptor potentials, electrotonic potentials, and synaptic potentials, which scale with the magnitude
of the stimulus. A variety of action potential types exist in many cell types and cell compartments as determined by the types of voltage-
gated channels, leak channels, channel distributions, ionic concentrations, membrane capacitance, temperature, and other factors.

The principal ions involved in an action potential are sodium and potassium cations; sodium ions enter the cell, and potassium ions
leave, restoring equilibrium. Relatively few ions need to cross the membrane for the membrane voltage to change drastically. The ions
exchanged during an action potential, therefore, make a negligible change in the interior and exterior ionic concentrations. The few
ions that do cross are pumped out again by the continuous action of the sodium–potassium pump, which, with other ion transporters,
maintains the normal ratio of ion concentrations across the membrane. Calcium cations and chlorideanions are involved in a few types
of action potentials, such as the cardiac action potential and the action potential in the single-cell algaAcetabularia, respectively.

Although action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger action potentials
on neighboring stretches of membrane, precipitating a domino-like propagation. In contrast to passive spread of electric potentials
(electrotonic potential), action potentials are generated anew along excitable stretches of membrane and propagate without decay. [7]
Myelinated sections of axons are not excitable and do not produce action potentials and the signal is propagated passively as electrotonic
potential. Regularly spaced unmyelinated patches, called the nodes of Ranvier, generate action potentials to boost the signal. Known as
saltatory conduction, this type of signal propagation provides a favorable tradeoff of signal velocity and axon diameter. Depolarization
of axon terminals, in general, triggers the release of neurotransmitter into the synaptic cleft. In addition, backpropagating action
potentials have been recorded in the dendrites of pyramidal neurons, which are ubiquitous in the neocortex. .These are thought to have a
role in spike-timing-dependent plasticity

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ANATOMY OF NEURON

NEURON

Neuron also known as a neurone or nerve cell) is an electrically excitable cell that processes and transmits information through electrical
and chemical signals. These signals between neurons occur via synapses, specialized connections with other cells. Neurons can connect to
each other to form neural networks. Neurons are the core components of the brain and spinal cord of the central nervous system (CNS),
and of the ganglia of the peripheral nervous system (PNS). Specialized types of neurons include: sensory neurons which respond to
touch, sound, light and all other stimuli affecting the cells of the sensory organs that then send signals to the spinal cord and brain, motor
neurons that receive signals from the brain and spinal cord to cause muscle contractions and affect glandular outputs, and interneurons
which connect neurons to other neurons within the same region of the brain, or spinal cord in neural networks.

A typical neuron consists of a cell body (soma), dendrites, and an axon. The term neurite is used to describe either a dendrite or an axon,
particularly in its undifferentiated stage. Dendrites are thin structures that arise from the cell body, often extending for hundreds of
micrometres and branching multiple times, giving rise to a complex "dendritic tree". An axon (also called a nerve fiber when
myelinated) is a special cellular extension (process) that arises from the cell body at a site called the axon hillock and travels for a
distance, as far as 1 meter in humans or even more in other species. Nerve fibers are often bundled into fascicles, and in the peripheral
nervous system, bundles of fascicles make up nerves (like strands of wire make up cables). The cell body of a neuron frequently gives rise
to multiple dendrites, but never to more than one axon, although the axon may branch hundreds of times before it terminates. At the
majority of synapses, signals are sent from the axon of one neuron to a dendrite of another. There are, however, many exceptions to these
rules: neurons that lack dendrites, neurons that have no axon, synapses that connect an axon to another axon or a dendrite to another
dendrite, etc.

All neurons are electrically excitable, maintaining voltage gradients across their membranes by means of metabolically driven ion
pumps, which combine with ion channels embedded in the membrane to generate intracellular-versus-extracellular concentration
differences of ions such as sodium, potassium, chloride, and calcium. Changes in the cross-membrane voltage can alter the function of
voltage-dependent ion channels. If the voltage changes by a large enough amount, an all-or-none electrochemical pulse called an action
potential is generated, which travels rapidly along the cell's axon, and activates synaptic connections with other cells when it arrives.

In most cases, neurons are generated by special types of stem cells. It is generally believed that neurons do not undergo cell division
but recent research in dogs shows that in some instances in the retina they do.[1]Astrocytes are star-shaped glial cells that have also
been observed to turn into neurons by virtue of the stem cell characteristic pluripotency. In humans, neurogenesis largely ceases
during adulthood; but in two brain areas, the hippocampus and olfactory bulb, there is strong evidence for generation of substantial
numbers of new neurons

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Neurons are highly specialized for the processing and transmission of cellular signals. Given their diversity of functions performed in
different parts of the nervous system, there is, as expected, a wide variety in their shape, size, and electrochemical properties. For
instance, the soma of a neuron can vary from 4 to 100 micrometers in diameter.The soma is the body of the neuron. As it contains the
nucleus, most protein synthesis occurs here. The nucleus can range from 3 to 18 micrometers in diameter.The dendrites of a neuron are
cellular extensions with many branches. This overall shape and structure is referred to metaphorically as a dendritic tree. This is where
the majority of input to the neuron occurs via the dendritic spine.

The axon is a finer, cable-like projection that can extend tens, hundreds, or even tens of thousands of times the diameter of the
soma in length. The axon carries nerve signals away from the soma (and also carries some types of information back to it). Many
neurons have only one axon, but this axon may—and usually will—undergo extensive branching, enabling communication with
many target cells. The part of the axon where it emerges from the soma is called the axon hillock. Besides being an anatomical
structure, the axon hillock is also the part of the neuron that has the greatest density of voltage-dependent sodium channels. This
makes it the most easily excited part of the neuron and the spike initiation zone for the axon: in electrophysiological terms it has
the most negative action potential threshold. While the axon and axon hillock are generally involved in information outflow, this
region can also receive input from other neurons.

The axon terminal contains synapses, specialized structures where neurotransmitter chemicals are released to communicate
with target neurons.

The canonical view of the neuron attributes dedicated functions to its various anatomical components; however dendrites and axons
often act in ways contrary to their so-called main function.

Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the peripheral nervous
system are much thicker. The soma is usually about 10–25 micrometers in diameter and often is not much larger than the cell nucleus it
contains. The longest axon of a human motor neuron can be over a meter long, reaching from the base of the spine to the toes.

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Sensory neurons can have axons that run from the toes to the posterior column of the spinal cord, over 1.5 meters in adults. Giraffes
have single axons several meters in length running along the entire length of their necks. Much of what is known about axonal function
comes from studying the squid giant axon, an ideal experimental preparation because of its relatively immense size (0.5–1 millimeters
thick, several centimeters long).

Fully differentiated neurons are permanently postmitotic;[6] however, research starting around 2002 shows that additional neurons
throughout the brain can originate from neural stem cells through the process of neurogenesis. These are found throughout the brain,
but are particularly concentrated in the subventricular zone and subgranular zone

INTERNAL STRUCTRE OF NEURON

Numerous microscopic clumps called Nissl substance (or Nissl bodies) are seen when nerve cell bodies are stained with a basophilic
("base-loving") dye. These structures consist of rough endoplasmic reticulum and associated ribosomal RNA. Named after German
psychiatrist and neuropathologist Franz Nissl (1860–1919), they are involved in protein synthesis and their prominence can be
explained by the fact that nerve cells are very metabolically active. Basophilic dyes such as aniline or (weakly) haematoxylinhighlight
negatively charged components, and so bind to the phosphate backbone of the ribosomal RNA.

The cell body of a neuron is supported by a complex mesh of structural proteins called neurofilaments, which are assembled into larger
neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment that is byproduct of
synthesis of catecholamines), and lipofuscin (a yellowish-brown pigment), both of which accumulate with age.Other structural proteins
that are important for neuronal function are actin and the tubulin of microtubules. Actin is predominately found at the tips of axons
and dendrites during neuronal development.

There are different internal structural characteristics between axons and dendrites. Typical axons almost never contain ribosomes,
except some in the initial segment. Dendrites contain granular endoplasmic reticulum or ribosomes, in diminishing amounts as the
distance from the cell body increases

Neurons in the brain

The number of neurons in the brain varies dramatically from species to species.One estimate (published in 1988) puts the human brain

at about 100 billion (1011) neurons and 100 trillion (1014) synapses. A lower estimate (published in 2009) is 86 billion neurons, of which
16.3 billion are in the cerebral cortex, and 69 billion in the cerebellum. By contrast, the nematode wormCaenorhabditis elegans has just
302 neurons, making it an ideal experimental subject as scientists have been able to map all of the organism's neurons. The fruit fly
Drosophila melanogaster, a common subject in biological experiments, has around 100,000 neurons and exhibits many complex
behaviors. Many properties of neurons, from the type of neurotransmitters used to ion channel composition, are maintained across
species, allowing scientists to study processes occurring in more complex organisms in much simpler experimental systems.

Neurological disorders

Neurology

Demylination.

Demyelination is the act of demyelinating, or the loss of the myelin sheath insulating the nerves. When myelin degrades, conduction of
signals along the nerve can be impaired or lost, and the nerve eventually withers. This leads to certain neurodegenerative disorders like
multiple sclerosis and chronic inflammatory demyelinating polyneuropathy.

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Axonal degeneration

Although most injury responses include a calcium influx signaling to promote resealing of severed parts, axonal injuries initially lead to acute
axonal degeneration, which is rapid separation of the proximal and distal ends within 30 minutes of injury. Degeneration follows with swelling of
the axolemma, and eventually leads to bead like formation. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after
axolemma degradation. Early changes include accumulation of mitochondria in the paranodal regions at the site of injury. Endoplasmic
reticulum degrades and mitochondria swell up and eventually disintegrate. The disintegration is dependent on ubiquitin and calpainproteases
(caused by influx of calcium ion), suggesting that axonal degeneration is an active process. Thus the axon undergoes complete fragmentation. The
process takes about roughly 24 hrs in the PNS, and longer in the CNS. The signaling pathways leading to axolemma degeneration are currently
unknown.

Nerve regeneration

Charcot–Marie–Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), hereditary sensorimotor
neuropathy and peroneal muscular atrophy, is a heterogeneous inherited disorder of nerves (neuropathy) that is characterized by loss
of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of
disease. Presently incurable, this disease is one of the most common inherited neurological disorders, with 37 in 100,000 affected.

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by progressive cognitive
deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most
striking early symptom is loss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily
more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive
(intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and
functions such as decision-making and planning become impaired.

Parkinson's disease (PD), also known as Parkinson disease, is a degenerative disorder of the central nervous system that often impairs
the sufferer's motor skills and speech. Parkinson's disease belongs to a group of conditions called movement disorders. It is
characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical
movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia,
normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.
Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

Myasthenia gravis is a neuromuscular disease leading to fluctuating muscle weakness and fatigability during simple activities. Weakness
is typically caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting
the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants, cholinesterase inhibitors
and, in selected cases, thymectomy

Neuroregeneration

It has been demonstrated that neurogenesis can sometimes occur in the adult vertebrate brain, a finding that led to controversy in 1999.
[35]
However, later studies of the age of human neurons suggest that this process occurs only for a minority of cells, and the
overwhelming majority of neurons comprising the neocortex were formed before birth and persist without replacement.It is often
possible for peripheral axons to regrow if they are severed. Recent studies have also shown that the body contains a variety of stem cell
types that have the capacity to differentiate into

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neurons. A report in Nature suggested that researchers had found a way to transform human skin cells into working nerve cells using
a process called transdifferentiation in which "cells are forced to adopt new identities

CLASSIFICATION OF NEURONS

Neurons exist in a number of different shapes and sizes and can be classified by their morphology and function. The anatomist Camillo
Golgi grouped neurons into two types; type I with long axons used to move signals over long distances and type II with short axons,
which can often be confused with dendrites. Type I cells can be further divided by where the cell body or soma is located. The basic
morphology of type I neurons, represented by spinal motor neurons, consists of a cell body called the soma and a long thin axon covered
by the myelin sheath. Around the cell body is a branching dendritic tree that receives signals from other neurons. The end of the axon
has branching terminals (axon terminal) that release neurotransmitters into a gap called the synaptic cleft between the terminals and the
dendrites of the next neuron.

STRUCTURAL CLASSIFICATION OF NEURONS

Polarity

Different kinds of neurons:

1 Unipolar neuron
2 Bipolar neuron
3 Multipolar neuron
4 Pseudounipolar neuron

Most neurons can be anatomically characterized as:

Unipolar or pseudounipolar: dendrite and axon emerging from same process.

Bipolar: axon and single dendrite on opposite ends of the soma.

Multipolar: two or more dendrites, separate from the axon:

o Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinje cells, and anterior
horn cells.

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 o Golgi II: neurons whose axonal process projects locally; the best example is the granule cell.
Anaxonic: where axon cannot be distinguished from dendrites

Several types of cells support an action potential, such as plant cells, muscle cells, and the specialized cells of the heart (in which
occurs the cardiac action potential). However, the main excitable cell is the neuron, which also has the simplest mechanism for the
action potential.

Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single soma, a single axon and one or more axon
terminals. Dendrites are cellular projections whose primary function is to receive synaptic signals. Their protrusions, or spines, are
designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of ligand-gated ion
channels. These spines have a thin neck connecting a bulbous protrusion to the dendrite. This ensures that changes occurring inside the
spine are less likely to affect the neighboring spines. The dendritic spine can, with rare exception (see LTP), act as an independent unit.
The dendrites extend from the soma, which houses the nucleus, and many of the "normal" eukaryotic organelles. Unlike the spines, the
surface of the soma is populated by voltage activated ion channels. These channels help transmit the signals generated by the dendrites.
Emerging out from the soma is the axon hillock. This region is characterized by having a very high concentration of voltage-activated
sodium channels. In general, it is considered to be the spike initiation zone for action potentials. Multiple signals generated at the spines,
and transmitted by the soma all converge here. Immediately after the axon hillock is the axon. This is a thin tubular protrusion traveling
away from the soma. The axon is insulated by a myelin sheath. Myelin is composed of either Schwann cells (in the peripheral nervous
system) or oligodendrocytes (in the central nervous system), both of which are types of glial cells. Although glial cells are not involved
with the transmission of electrical signals, they communicate and provide important biochemical support to neurons. To be specific,
myelin wraps multiple times around the axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the
axon. This insulation prevents significant signal decay as well as ensuring faster signal speed. This insulation, however, has the restriction
that no channels can be present on the surface of the axon. There are, therefore, regularly spaced patches of membrane, which have no
insulation. These nodes of Ranvier can be considered to be "mini axon hillocks", as their purpose is to boost the signal in order to
prevent significant signal decay. At the furthest end, the axon loses its insulation and begins to branch into several axon terminals. These
presynaptic terminals, or synaptic boutons, are a specialized area within the axon of the presynaptic cell that contains neurotransmitters
enclosed in small membrane-bound spheres called synaptic vesicles.

Furthermore, some unique neuronal types can be identified according to their location in the nervous system and distinct shape. Some
examples are:

Basket cells, interneurons that form a dense plexus of terminals around the soma of target cells, found in the cortex and

cerebellum. Betz cells, large motor neurons.

Lugaro cells, interneurons of the cerebellum.

Medium spiny neurons, most neurons in the corpus striatum.

Purkinje cells, huge neurons in the cerebellum, a type of Golgi I multipolar

neuron. Pyramidal cells, neurons with triangular soma, a type of Golgi I.

Renshaw cells, neurons with both ends linked to alpha motor neurons.

Unipolar brush cells, interneurons with unique dendrite ending in a brush-like

tuft. Granule cells, a type of Golgi II neuron.

Anterior horn cells, motoneurons located in the spinal cord.

Spindle cells, interneurons that connect widely separated areas of the brain

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Functional classification

Direction

Afferent neurons convey information from tissues and organs into the central nervous system and are sometimes also called
sensory neurons.

Efferent neurons transmit signals from the central nervous system to the effector cells and are sometimes called motor

neurons. Interneurons connect neurons within specific regions of the central nervous system.

Afferent and efferent also refer generally to neurons that, respectively, bring information to or send information from the brain region.

Action on other neurons

A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors. The effect upon the postsynaptic
neuron is determined not by the presynaptic neuron or by the neurotransmitter, but by the type of receptor that is activated. A
neurotransmitter can be thought of as a key, and a receptor as a lock: the same type of key can here be used to open many different
types of locks. Receptors can be classified broadly as excitatory (causing an increase in firing rate), inhibitory (causing a decrease in
firing rate), or modulatory (causing long-lasting effects not directly related to firing rate).

The two most common neurotransmitters in the brain, glutamate and GABA, have actions that are largely consistent. Glutamate acts on
several different types of receptors, and have effects that are excitatory at ionotropic receptors and a modulatory effect at metabotropic
receptors. Similarly GABA acts on several different types of receptors, but all of them have effects (in adult animals, at least) that are
inhibitory. Because of this consistency, it is common for neuroscientists to simplify the terminology by referring to cells that release
glutamate as "excitatory neurons", and cells that release GABA as "inhibitory neurons". Since over 90% of the neurons in the brain
release either glutamate or GABA, these labels encompass the great majority of neurons. There are also other types of neurons that have
consistent effects on their targets, for example "excitatory" motor neurons in the spinal cord that release acetylcholine, and "inhibitory"
spinal neurons that release glycine.

The distinction between excitatory and inhibitory neurotransmitters is not absolute, however. Rather, it depends on the class of chemical
receptors present on the postsynaptic neuron. In principle, a single neuron, releasing a single neurotransmitter, can have excitatory
effects on some targets, inhibitory effects on others, and modulatory effects on others still. For example, photoreceptor cells in the retina
constantly release the neurotransmitter glutamate in the absence of light. So-called OFF bipolar cells are, like most neurons, excited by
the released glutamate. However, neighboring target neurons called ON bipolar cells are instead inhibited by glutamate, because they
lack the typical ionotropicglutamate receptors and instead express a class of inhibitory metabotropic glutamate receptors. When light is
present, the photoreceptors cease releasing glutamate, which relieves the ON bipolar cells from inhibition, activating them; this
simultaneously removes the excitation from the OFF bipolar cells, silencing them.

It is possible to identify the type of inhibitory effect a presynaptic neuron will have on a postsynaptic neuron, based on the proteins the
presynaptic neuron expresses. Parvalbumin-expressing neurons typically dampen the output signal of the postsynaptic neuron in the
visual cortex, whereas somatostatin-expressing neurons typically block dendritic inputs to the postsynaptic neuron.Discharge patterns

Neurons can be classified according to their electrophysiological characteristics:

Tonic or regular spiking. Some neurons are typically constantly (or tonically) active. Example: interneurons in

neurostriatum. Phasic or bursting. Neurons that fire in bursts are called phasic.

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 Fast spiking. Some neurons are notable for their high firing rates, for example some types of cortical inhibitory interneurons, cells
in globus pallidus, retinal ganglion cells.Classification by neurotransmitter production

Cholinergic neurons—acetylcholine. Acetylcholine is released from presynaptic neurons into the synaptic cleft. It acts as a ligand for both

ligand-gated ion channels and metabotropic (GPCRs) muscarinic receptors. Nicotinic receptors, are pentameric ligand-gated ion

channels composed of alpha and beta subunits that bind nicotine. Ligand binding opens the channel causing influx of Na +
depolarization and increases the probability of presynaptic neurotransmitter release. Acetylcholine is synthesized from choline
and acetyl coenzyme A.
GABAergic neurons—gamma aminobutyric acid. GABA is one of two neuroinhibitors in the CNS, the other being Glycine. GABA has a

homologous function to ACh, gating anion channels that allow Cl − ions to enter the post synaptic neuron. Cl− causes
hyperpolarization within the neuron, decreasing the probability of an action potential firing as the voltage becomes more
negative (recall that for an action potential to fire, a positive voltage threshold must be reached). GABA is synthesized from
glutamate neurotransmitters by the enzyme glutamate decarboxylase.
Glutamatergic neurons—glutamate. Glutamate is one of two primary excitatory amino acid neurotransmitter, the other being
Aspartate. Glutamate receptors are one of four categories, three of which are ligand-gated ion channels and one of which is a
G-protein coupled receptor (often referred to as GPCR).

1. AMPA and Kainate receptors both function as cation channels permeable to Na+ cation channels mediating fast
excitatory synaptic transmission
2. NMDA receptors are another cation channel that is more permeable to Ca 2+. The function of NMDA receptors is
dependant on Glycine receptor binding as a co-agonist within the channel pore. NMDA receptors do not function
without both ligands present.
3. Metabotropic receptors, GPCRs modulate synaptic transmission and postsynaptic excitability.

Glutamate can cause excitotoxicity when blood flow to the brain is interrupted, resulting in brain damage. When blood flow
is suppressed, glutamate is released from presynaptic neurons causing NMDA and AMPA receptor activation more so than

would normally be the case outside of stress conditions, leading to elevated Ca 2+ and Na+ entering the post synaptic neuron
and cell damage. Glutamate is synthesized from the amino acid glutamine by the enzyme glutamate synthase.

Dopaminergic neurons—dopamine. Dopamine is a neurotransmitter that acts on D1 type (D1 and D5) Gs coupled receptors, which
increase cAMP and PKA, and D2 type (D2, D3, and D4) receptors, which activate Gi-coupled receptors that decrease cAMP and
PKA. Dopamine is connected to mood and behavior, and modulates both pre and post synaptic neurotransmission. Loss of
dopamine neurons in the substantia nigra has been linked to Parkinson's disease. Dopamine is synthesized from the amino acid
tyrosine. Tyrosine is catalyzed into levadopa (or L-DOPA) by tyrosine hydroxlase, and levadopa is then converted into dopamine by
amino acid decarboxylase.

Serotonergic neurons—serotonin. Serotonin (5-Hydroxytryptamine, 5-HT) can act as excitatory or inhibitory. Of the four 5-HT
receptor classes, 3 are GPCR and 1 is ligand gated cation channel. Serotonin is synthesized from tryptophan by tryptophan
hydroxylase, and then further by aromatic acid decarboxylase. A lack of 5-HT at postsynaptic neurons has been linked to
depression. Drugs that block the presynaptic serotonin transporter are used for treatment, such as Prozac and Zoloft.

MECHANISMS FOR PROPAGATING ACTION POTENTIAL.

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In 1937, John Zachary Young suggested that the squid giant axon could be used to study neuronal electrical properties. Being larger
than but similar in nature to human neurons, squid cells were easier to study. By inserting electrodes into the giant squid axons,
accurate measurements were made of the membrane potential.

Ariny Amos cell membrane of the axon and soma contain voltage-gated ion channels that allow the neuron to generate and propagate an
electrical signal (an action potential). These signals are generated and propagated by charge-carrying ions including sodium (Na +),

potassium (K+), chloride (Cl−), and calcium (Ca2+).

A signal propagating down an axon to the cell body and dendrites of the next cell

There are several stimuli that can activate a neuron leading to electrical activity, including pressure, stretch, chemical transmitters, and
changes of the electric potential across the cell membrane. Stimuli cause specific ion-channels within the cell membrane to open, leading
to a flow of ions through the cell membrane, changing the membrane potential.

Thin neurons and axons require less metabolic expense to produce and carry action potentials, but thicker axons convey impulses more
rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons have insulating sheaths of myelin around
their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral
nervous system. The sheath enables action potentials to travel faster than in unmyelinated axons of the same diameter, whilst using less
energy. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed
nodes of Ranvier, which contain a high

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density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder that results from demyelination of axons in the central
nervous system.

Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes graded
neurotransmitter release. Such nonspiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long
distances.

Neural coding

Neural coding is concerned with how sensory and other information is represented in the brain by neurons. The main goal of studying
neural coding is to characterize the relationship between the stimulus and the individual or ensemble neuronal responses, and the
relationships amongst the electrical activities of the neurons within the ensemble. It is thought that neurons can encode both digital and
analog information.All-or-none principle

The conduction of nerve impulses is an example of an all-or-none response. In other words, if a neuron responds at all, then it must
respond completely. Greater intensity of stimulation does not produce a stronger signal but can produce a higher frequency of firing.
There are different types of receptor response to stimulus, slowly adapting or tonic receptors respond to steady stimulus and produce a
steady rate of firing. These tonic receptors most often respond to increased intensity of stimulus by increasing their firing frequency,
usually as a power function of stimulus plotted against impulses per second. This can be likened to an intrinsic property of light where
to get greater intensity of a specific frequency (color) there have to be more photons, as the photons can't become "stronger" for a
specific frequency.

There are a number of other receptor types that are called quickly adapting or phasic receptors, where firing decreases or stops with
steady stimulus; examples include: skin when touched by an object causes the neurons to fire, but if the object maintains even pressure
against the skin, the neurons stop firing. The neurons of the skin and muscles that are responsive to pressure and vibration have
filtering accessory structures that aid their function.

The pacinian corpuscle is one such structure. It has concentric layers like an onion, which form around the axon terminal. When
pressure is applied and the corpuscle is deformed, mechanical stimulus is transferred to the axon, which fires. If the pressure is
steady, there is no more stimulus; thus, typically these neurons respond with a transient depolarization during the initial
deformation and again when the pressure is removed, which causes the corpuscle to change shape again. Other types of adaptation
are important in extending the function of a number of other neurons.

INITIATION OFACTION POTENTIAL

Initiation

In electric shock from Ariny Amos Cell Membrane then considering the propagation of action potentials along axons and their
termination at the synaptic knobs, it is helpful to consider the methods by which action potentials can be initiated at the axon hillock.
The basic requirement is that the membrane voltage at the hillock be raised above the threshold for firing. There are several ways in
which this depolarization can occur.

The axon hillock is a specialized part of the cell body (or soma) of a neuron that connects to the axon.The axon hillock is the last site in
the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many
years, it had been believed that the axon hillock was the usual site of action potential initiation. It is now thought that the earliest site of
action potential initiation is found just adjacent, in the initial (unmyelinated) segment of the axon. However, the positive point, at which
the action potential starts, varies between cells. It can also be altered by hormonal stimulation of the neuron, or by second messenger
effects of neurotransmitters.
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The axon hillock also functions as a tight junction, since it acts as a barrier for lateral diffusion of transmembrane proteins, GPI
anchored proteins such as thy1, and lipids embedded in the plasma membrane.

Dynamics

Action potentials are most commonly initiated by excitatory postsynaptic potentials from a presynaptic neuron. Typically,
neurotransmitter molecules are released by the presynapticneuron. These neurotransmitters then bind to receptors on the postsynaptic
cell. This binding opens various types of ion channels. This opening has the further effect of changing the local permeability of the cell
membrane and, thus, the membrane potential. If the binding increases the voltage (depolarizes the membrane), the synapse is excitatory.
If, however, the binding decreases the voltage (hyperpolarizes the membrane), it is inhibitory. Whether the voltage is increased or
decreased, the change propagates passively to nearby regions of the membrane (as described by the cable equation and its refinements).
Typically, the voltage stimulus decays exponentially with the distance from the synapse and with time from the binding of the
neurotransmitter. Some fraction of an excitatory voltage may reach the axon hillock and may (in rare cases) depolarize the membrane
enough to provoke a new action potential. More typically, the excitatory potentials from several synapses must work together at nearly
the same time to provoke a new action potential. Their joint efforts can be thwarted, however, by the counteracting inhibitory
postsynaptic potentials.

Neurotransmission can also occur through electrical synapses. Due to the direct connection between excitable cells in the form of gap
junctions, an action potential can be transmitted directly from one cell to the next in either direction. The free flow of ions between cells
enables rapid non-chemical-mediated transmission. Rectifying channels ensure that action potentials move only in one direction
through an electrical synapse.Electrical synapses are found in all nervous systems, including the human brain, although they are a
distinct minority.

When an action potential arrives at the end of the pre-synaptic axon (top), it causes the release of neurotransmitter molecules that open
ion channels in the post-synaptic neuron (bottom). The combined excitatory and inhibitory postsynaptic potentials of such inputs can begin
a new action potential in the post-synaptic neuron.

"All-or-none" principle

The all-or-none law is the principle that the strength by which a nerve or muscle fiber responds to a stimulus is independent of the strength of the
stimulus. If that stimulus exceeds the threshold potential, the nerve or muscle fiber will give a complete response; otherwise, there is no response.

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It was first established by the American physiologist Henry Pickering Bowditch in 1871 for the contraction of heart muscle. According to
him,
describing the relation of response to stimulus,

“An induction shock produces a contraction or fails to do so according to its strength; if it does so at all, it produces the greatest
contraction that can be produced by any strength of stimulus in the condition of the muscle at the time.” The individual fibers of both
skeletal muscle and nerve
respond to stimulation according to the all-or-none principle
The amplitude of an action potential is independent of the amount of current that produced it. In other words, larger currents

do not create larger action potentials. Therefore, action potentials are said to be all-or-none signals, since either they occur

fully or they do not occur at all. This is in contrast to receptor potentials, whose amplitudes are dependent on the intensity of

a stimulus. In both cases, the frequency of action potentials is correlated with the intensity of a stimulus.

Sensory neurons

In sensory neurons, an external signal such as pressure, temperature, light, or sound is coupled with the opening and closing of ion
channels, which in turn alter the ionic permeabilities of the membrane and its voltage. These voltage changes can again be excitatory
(depolarizing) or inhibitory (hyperpolarizing) and, in some sensory neurons, their combined effects can depolarize the axon hillock
enough to provoke action potentials. Examples in humans include the olfactory receptor neuron and Meissner's corpuscle, which are
critical for the sense of smell and touch, respectively. However, not all sensory neurons convert their external signals into action
potentials; some do not even have an axonInstead, they may convert the signal into the release of a neurotransmitter, or into continuous
graded potentials, either of which may stimulate subsequent neuron(s) into firing an action potential. For illustration, in the human ear,
hair cells convert the incoming sound into the opening and closing of mechanically gated ion channels, which may cause
neurotransmitter molecules to be released. In similar manner, in the human retina, the initial photoreceptor cells and the next layer of
cells (comprising bipolar cells and horizontal cells) do not produce action potentials; only some amacrine cells and the third layer, the
ganglion cells, produce action potentials, which then travel up the optic nerve.

PACEMAKER POTENTIALS

In sensory neurons, action potentials result from an external stimulus. However, some excitable cells require no such stimulus to fire: They
spontaneously depolarize their axon hillock and fire action potentials at a regular rate, like an internal clock. The voltage traces of such cells
are known as pacemaker potentials. The cardiac pacemaker cells of the sinoatrial node in the heart provide a good example.Although such
pacemaker potentials have a natural rhythm, it can be adjusted by external stimuli; for instance, heart rate can be altered by
pharmaceuticals as well as signals from the sympathetic and parasympathetic nerves. The external stimuli do not cause the cell's repetitive
firing, but merely alter its timing. In some cases, the regulation of frequency can be more complex, leading to patterns of action potentials,
such as bursting.

In pacemaker potentials, the cell spontaneously depolarizes (straight line with upward slope) until it fires an action potential.
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Phases in Action Potential.

The course of the action potential can be divided into five parts: the rising phase, the peak phase, the falling phase, the undershoot phase,
and the refractory period. During the rising phase the membrane potential depolarizes (becomes more positive). The point at which
depolarization stops is called the peak phase. At this stage, the membrane potential reaches a maximum. Subsequent to this, there is a
falling phase. During this stage the membrane potential becomes more negative, returning towards resting potential. The undershoot, or
afterhyperpolarization, phase is the period during which the membrane potential temporarily becomes more negatively charged than
when at rest (hyperpolarized). Finally, the time during which a subsequent action potential is impossible or difficult to fire is called the

refractory period, which may overlap with the other phases.[21]

The course of the action potential is determined by two coupled effects. First, voltage-sensitive ion channels open and close in response
to changes in the membrane voltageVm. This changes the membrane's permeability to those ions. Second, according to the Goldman
equation, this change in permeability changes in the equilibrium potential Em, and, thus, the membrane voltage Vm. Thus, the
membrane potential affects the permeability, which then further affects the membrane potential. This sets up the possibility for positive
feedback, which is a key part of the rising phase of the action potential. A complicating factor is that a single ion channel may have
multiple internal "gates" that respond to changes in Vm in opposite ways, or at different rates. For example, although raising Vmopens
most gates in the voltage-sensitive sodium channel, it also closes the channel's "inactivation gate", albeit more slowly.Hence, when V m is
raised suddenly, the sodium channels open initially, but then close due to the slower inactivation.

The voltages and currents of the action potential in all of its phases were modeled accurately by Alan Lloyd Hodgkin and Andrew
Huxley in 1952, for which they were awarded the Nobel Prize in Physiology or Medicine in 1963 However, their model considers
only two types of voltage-sensitive ion channels, and makes several assumptions about them, e.g., that their internal gates open and
close independently of one another. In reality, there are many types of ion channels, and they do not always open and close
independently.

Stimulation and rising phase

A typical action potential begins at the axon hillockwith a sufficiently strong depolarization, e.g., a stimulus that increases V m. This
depolarization is often caused by the injection of extra sodium cations into the cell; these cations can come from a wide variety of
sources, such as chemical synapses, sensory neurons or pacemaker potentials.

For a neuron at rest, there is a high concentration of sodium and chlorine ions in the extracellular fluid compared to the intracellular fluid while
there is a high concentration of potassium ions in the intracellular fluid compared to the extracellular fluid. This concentration gradient along

with potassium leak channels present on the membrane of the neuron causes an efflux of potassium ions making the resting potential close to E K≈
–
75 mV. The depolarization opens both the sodium and potassium channels in the membrane, allowing the ions to flow into and out of the
axon, respectively. If the depolarization is small (say, increasing Vm from −70 mV to −60 mV), the outward potassium current
overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential around −70 mV.However, if
the depolarization is large enough, the inward sodium current increases more than the outward potassium current and a runaway
condition (positive feedback) results: the more inward current there is, the more V m increases, which in turn further increases the
inward current. A sufficiently strong depolarization (increase in Vm) causes the voltage-sensitive sodium channels to open; the increasing
permeability to sodium drives Vm closer to the sodium equilibrium voltage ENa≈ +55 mV. The increasing voltage in turn causes even
more sodium channels to open, which pushes Vm still further towards ENa. This positive feedback continues until the sodium channels
are fully open and Vm is close to ENa. The sharp rise in Vm and sodium permeability correspond to the rising phase of the action
potential.

The critical threshold voltage for this runaway condition is usually around −45 mV, but it depends on the recent activity of the axon. A
membrane that has just fired an action potential cannot fire another one immediately, since the ion channels have not returned to the
deactivated state. The period during which no new action potential can be fired is called the absolute refractory period. At longer times,
after some but not all of the ion
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channels have recovered, the axon can be stimulated to produce another action potential, but with a higher threshold, requiring a much stronger
depolarization, e.g., to −30 mV. The period during which action potentials are unusually difficult to evoke is called the relative refractory period.

Peak and falling phase

The positive feedback of the rising phase slows and comes to a halt as the sodium ion channels become maximally open. At the peak of
the action potential, the sodium permeability is maximized and the membrane voltage Vm is nearly equal to the sodium equilibrium

voltage ENa. However, the same raised voltage that opened the sodium channels initially also slowly shuts them off, by closing their pores;
the sodium channels become inactivated. This lowers the membrane's permeability to sodium relative to potassium, driving the
membrane voltage back towards the resting value. At the same time, the raised voltage opens voltage-sensitive potassium channels; the
increase in the membrane's potassium permeability drives Vm towards EK. Combined, these changes in sodium and potassium

permeability cause Vm to drop quickly, repolarizing the membrane and producing the "falling phase" of the action potential.

Afterhyperpolarization

The raised voltage opened many more potassium channels than usual, and some of these do not close right away when the membrane
returns to its normal resting voltage. In addition, further potassium channels open in response to the influx of calcium ions during the
action potential. The potassium permeability of the membrane is transiently unusually high, driving the membrane voltage V m even
closer to the potassium equilibrium voltage EK. Hence, there is an undershoot or hyperpolarization, termed an afterhyperpolarization in
technical language, that persists until the membrane potassium permeability returns to its usual value.

Refractory period

Each action potential is followed by a refractory period, which can be divided into an absolute refractory period, during which it is
impossible to evoke another action potential, and then a relative refractory period, during which a stronger-than-usual stimulus is

required.[29][30][31] These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. When
closing after an action potential, sodium channels enter an "inactivated" state, in which they cannot be made to open regardless of the
membrane potential—this gives rise to the absolute refractory period. Even after a sufficient number of sodium channels have
transitioned back to their resting state, it frequently happens that a fraction of potassium channels remains open, making it difficult for
the membrane potential to depolarize, and thereby giving rise to the relative refractory period. Because the density and subtypes of
potassium channels may differ greatly between different types of neurons, the duration of the relative refractory period is highly
variable.

The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along axons. [35] At any given
moment, the patch of axon behind the actively spiking part is refractory, but the patch in front, not having been activated recently, is
capable of being stimulated by the depolarization from the action potential.

Propagation

Nerve conduction velocity

The action potential generated at the axon hillock propagates as a wave along the axon. The currents flowing inwards at a point on the
axon during an action potential spread out along the axon, and depolarize the adjacent sections of its membrane. If sufficiently strong,
this depolarization provokes a similar action potential at the neighboring membrane patches. This basic mechanism was demonstrated
by Alan Lloyd Hodgkin in 1937. After crushing or cooling nerve segments and thus blocking the action potentials, he showed that an
action potential arriving on one side of the block could provoke another action potential on the other, provided that the blocked segment
was sufficiently short.
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Once an action potential has occurred at a patch of membrane, the membrane patch needs time to recover before it can fire again. At the
molecular level, this absolute refractory period corresponds to the time required for the voltage-activated sodium channels to recover
from inactivation, i.e., to return to their closed state. There are many types of voltage-activated potassium channels in neurons, some of
them inactivate fast (A-type currents) and some of them inactivate slowly or not inactivate at all; this variability guarantees that there
will be always an available source of current for repolarization, even if some of the potassium channels are inactivated because of
preceding depolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate within several millisecond during
strong depolarization, thus making following depolarization impossible until a substantial fraction of sodium channels have returned to
their closed state. Although it limits the frequency of firing, the absolute refractory period ensures that the action potential moves in only
one direction along an axon. The currents flowing in due to an action potential spread out in both directions along the axon. However,
only the unfired part of the axon can respond with an action potential; the part that has just fired is unresponsive until the action
potential is safely out of range and cannot restimulate that part. In the usual orthodromic conduction, the action potential propagates
from the axon hillock towards the synaptic knobs (the axonal termini); propagation in the opposite direction—known as antidromic
conduction—is very rare. However, if a laboratory axon is stimulated in its middle, both halves of the axon are "fresh", i.e., unfired; then
two action potentials will be generated, one traveling towards the axon hillock and the other traveling towards the synaptic knobs.

Myelin and Saltatory Conduction

In order to enable fast and efficient transduction of electrical signals in the nervous system, certain neuronal axons are covered with
myelin sheaths. Myelin is a multilamellar membrane that enwraps the axon in segments separated by intervals known as nodes of
Ranvier. It is produced by specialized cells: Schwann cells exclusively in the peripheral nervous system, and oligodendrocytes exclusively
in the central nervous system. Myelin sheath reduces membrane capacitance and increases membrane resistance in the inter-node
intervals, thus allowing a fast, saltatory movement of action potentials from node to node. Myelination is found mainly in vertebrates,
but an analogous system has been discovered in a few invertebrates, such as some species of shrimp. Not all neurons in vertebrates are
myelinated; for example, axons of the neurons comprising the autonomous nervous system are not, in general, myelinated.

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Comparison of the conduction velocities of myelinated and unmyelinated∝ axons in the Ariny Amos. The conduction velocity v of myelinated
neurons∝ varies roughly linearly with axon diameter d (that is, v d), whereas the speed of unmyelinated neurons varies roughly as the square
root (v √d). The red and blue curves are fits of experimental data, whereas the dotted lines are their theoretical extrapolations.

Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general rule, myelination increases the
conduction velocity of action potentials and makes them more energy-efficient. Whether saltatory or not, the mean conduction velocity
of an action potential ranges from 1 meter per second (m/s) to over 100 m/s, and, in general, increases with axonal diameter.

Action potentials cannot propagate through the membrane in myelinated segments of the axon. However, the current is carried by the cytoplasm,
which is sufficient to depolarize the first or second subsequent node of Ranvier. Instead, the ionic current from an action potential at one node of
Ranvier provokes another action potential at the next node; this apparent "hopping" of the action potential from node to node is known as
saltatory conduction. Although the mechanism of saltatory conduction was suggested in 1925 by Ralph Lillie, the first experimental evidence for
saltatory conduction came from Ichiji Tasaki and Taiji Takeuchi and from Andrew Huxley and Robert Stämpfli. By contrast, in unmyelinated
axons, the action potential provokes another in the membrane immediately adjacent, and moves continuously down the axon like a wave.

Myelin has two important advantages: fast conduction speed and energy efficiency. For axons larger than a minimum diameter
(roughly 1 micrometre), myelination increases the conduction velocity of an action potential, typically tenfold. Conversely, for a given
conduction velocity, myelinated fibers are smaller than their unmyelinated counterparts. For example, action potentials move at roughly
the same speed (25 m/s) in a myelinated frog axon and an unmyelinated squid giant axon, but the frog axon has a roughly 30-fold
smaller diameter and 1000-fold smaller cross-sectional area. Also, since the ionic currents are confined to the nodes of Ranvier, far fewer
ions "leak" across the membrane, saving metabolic energy. This saving is a significant selective advantage, since the human nervous
system uses approximately 20% of the body's metabolic energy.The length of axons' myelinated segments is important to the success of
saltatory conduction. They should be as long as possible to maximize the speed of conduction, but not so long that the arriving signal is
too weak to provoke an action potential at the next node of Ranvier. In nature, myelinated segments are generally long enough for the
passively propagated signal to travel for at least two nodes while retaining enough amplitude to fire an action potential at the second or
third node. Thus, the safety factor of saltatory conduction is high, allowing transmission to bypass nodes in case of injury. However,
action potentials may end prematurely in certain places where the safety factor is low, even in unmyelinated neurons; a common
example is the branch point of an axon, where it divides into two axons.

Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of action potentials. The most well-
known of these is multiple sclerosis, in which the breakdown of myelin impairs coordinated movement.

CABLE THEORY

Classical cable theory uses mathematical models to calculate the electric current (and accompanying voltage) along passive neurites, particularly
the dendrites that receive synaptic inputs at different sites and times. Estimates are made by modeling dendrites and axons as cylinders composed
of segments with capacitancesand resistancescombined in parallel The capacitance of a neuronal fiber comes about because electrostatic forces
are acting through the very thin lipid bilayer . The resistance in series along the fiber is due to the axoplasm's significant resistance to movement

of electric charge.

The flow of currents within an axon can be described quantitatively by cable theory and its elaborations, such as the compartmental
model.[45] Cable theory was developed in 1855 by Lord Kelvin to model the transatlantic telegraph cable and was shown to be
relevant to neurons by Hodgkin and Rushton in 1946. In simple cable theory, the neuron is treated as an electrically passive,
perfectly cylindrical transmission cable, which can be described by a partial differential equation

111
whereV(x, t) is the voltage across the membrane at a time t and a position x along the length of the neuron, and where λ and τ are the
characteristic length and time scales on which those voltages decay in response to a stimulus. Referring to the circuit diagram on the
right, these scales can be determined from the resistances and capacitances per unit length.

Cable theory's simplified view of a neuronal fiber. The connected RC circuits correspond to adjacent segments of a passive
neurite. The extracellular resistances r e (the counterparts of the intracellular resistances r i) are not shown, since they are usually

negligibly small; the extracellular medium may be assumed to have the same voltage everywhere .

Fiber capacitance

These time and length-scales can be used to understand the dependence of the conduction velocity on the diameter of the neuron in
unmyelinated fibers. For example, the time-scale τ increases with both the membrane resistance r m and capacitance cm. As the
capacitance increases, more charge must be transferred to produce a given transmembrane voltage (by the equation Q=CV); as the
resistance increases, less charge is transferred per unit time, making the equilibration slower. In similar manner, if the internal
resistance per unit length ri is lower in one axon than in another (e.g., because the radius of the former is larger), the spatial decay
length λ becomes longer and the conduction velocity of an action potential should increase. If the transmembrane resistance r m is
increased, that lowers the average "leakage" current across the membrane, likewise causing λ to become longer, increasing the
conduction velocity.

Cable theory in computational neuroscience has roots leading back to the 1850s, when Professor William Thomson (later known as Lord
Kelvin) began developing mathematical models of signal decay in submarine (underwater) telegraphic cables. The models resembled the
partial differential equations used by Fourier to describe heat conduction in a wire.

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The 1870s saw the first attempts by Hermann to model neuronalelectrotonic potentials also by focusing on analogies with heat
conduction. However, it was Hoorweg who first discovered the analogies with Kelvin's undersea cables in 1898 and then Hermann and
Cremer who independently developed the cable theory for neuronal fibers in the early 20th century. Further mathematical theories of
nerve fiber conduction based on cable theory were developed by Cole and Hodgkin (1920s–1930s), Offner et al. (1940), and Rushton
(1951).

Experimental evidence for the importance of cable theory in modeling the behavior of axons began surfacing in the 1930s from work
done by Cole, Curtis, Hodgkin, Sir Bernard Katz, Rushton, Tasaki and others. Two key papers from this era are those of Davis and
Lorente de Nó (1947) and Hodgkin and Rushton (1946), Ariny Amos (2016)

The 1950s saw improvements in techniques for measuring the electric activity of individual neurons. Thus cable theory became
important for analyzing data collected from intracellular microelectrode recordings and for analyzing the electrical properties of
neuronal dendrites. Scientists like Coombs, Eccles, Fatt, Frank, Fuortes and others now relied heavily on cable theory to obtain
functional insights of neurons and for guiding them in the design of new experiments.

Later, cable theory with its mathematical derivatives allowed ever more sophisticated neuron models to be explored by workers such
as Jack, Ariny Amos,Rall, Redman, Rinzel, Idan Segev, Tuckwell, Bell, and Iannella.

DISORDERS THAT ARINY AMOS TREATED WITH ELECTRIFICATION.

Consumption (tuberculosis) and HIV/ Aids;Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis
(MTB). Tuberculosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, known
as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected.
The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss. The historical
term "consumption" came about due to the weight loss. Infection of other organs can cause a wide range of symptoms.

Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze. People with latent TB do
not spread the disease. Active infection occurs more often in people with HIV/AIDS and in those who smoke. Diagnosis of active TB is based
on chest X-rays, as well as microscopic examination and culture of body fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST)
or blood tests.

Prevention of TB involves screening those at high risk, early detection and treatment of cases, and vaccination with the bacillus
Calmette-Guérin vaccine. Those at high risk include household, workplace, and social contacts of people with active TB. Treatment
requires the use of multiple antibiotics over a long period of time. Antibiotic resistance is a growing problem with increasing rates of
multiple drug-resistant tuberculosis (MDR-TB).

Contractions of the limbs;

A muscle contracture is a permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity
in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spastic cerebral palsy.

Contractures are essentially muscles or tendons that have remained too tight for too long, thus becoming shorter. Once they occur, it is
often argued that they cannot be stretched or exercised away (they must be released with orthopedic surgery). Most of the physical
therapy, occupational therapy, and other exercise regimens targeted towards people with spasticity focuses on trying to prevent
contractures from happening in the first place. However, research on sustained traction of connective tissue in approaches such as
adaptive yoga has demonstrated that contracture can be reduced, at the same time that tendency toward spasticity is addressed.

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Contractures can also be due to ischemia, as in Volkmann's contracture. Excessive matrix metalloproteinase and myofibroblast
accumulation in the wound margins can result in contracture.

Cramp;

A cramp is a sudden, and involuntary muscle contraction or over-shortening; while generally temporary and non-damaging, they can cause
mild-to-excruciating pain, and a paralysis-like immobility of the affected muscle(s). Onset is usually sudden, and it resolves on its own over
a period of several seconds, minutes, or hours. Cramps may occur in a skeletal muscle or smooth muscle. Skeletal muscle cramps may be
caused by muscle fatigue or a lack of electrolytes (e.g., low sodium, low potassium, or low magnesium)[citation needed]. Cramps of smooth
muscle may be due to menstruation or gastroenteritis.

Differential diagnosis

Causes of cramping include hyperflexion, hypoxia, exposure to large changes in temperature, dehydration, or low blood salt. Muscle
cramps may also be a symptom or complication of pregnancy, kidney disease, thyroid disease, hypokalemia, hypomagnesemia or
hypocalcaemia (as conditions), restless-leg syndrome, varicose veins, and multiple sclerosis.

Electrolyte disturbance may cause cramping and muscle tetany, particularly hypokalemia and hypocalcaemia. This disturbance arises as the
body loses large amounts of interstitial fluid through sweat. This interstitial fluid comprises mostly water and salt (sodium chloride). The
loss of osmotically active particles outside of muscle cells leads to a disturbance of the osmotic balance and therefore shrinking of muscle
cells, as these contain more osmotically active particles. This causes the calcium pump between the muscle sarcoplasm and sarcoplasmic
reticulum to short circuit; the calcium ions remain bound to the troponin, continuing muscle contraction.

As early as 1965, researchers observed that leg cramps and restless-leg syndrome result from excess insulin, sometimes
called hyperinsulinemia.

Skeletal muscle cramps

Skeletal muscles can be voluntarily controlled, under normal circumstances. Skeletal muscles that cramp the most often are the calves,
thighs, and arches of the foot, and are sometimes called a "Charley horse" or a "corkie". Such cramping is associated with strenuous
physical activity and can be intensely painful; however, they can even occur while inactive/relaxed. Around 40% of people who experience
skeletal cramps are likely to endure extreme muscle pain, and may be unable to use the entire limb that contains the "locked-up" muscle
group. It may take up to seven days for the muscle to return to a pain-free state.

Nocturnal leg cramps

Nocturnal leg cramps are involuntary muscle contractions that occur in the calves, soles of the feet, or other muscles in the body during
the night or (less commonly) while resting.

The duration of nocturnal leg cramps is variable with cramps lasting anywhere from a few seconds to several minutes. Muscle soreness may
remain after the cramp itself ends. These cramps are more common in older people. They happen quite frequently in teenagers and in some
people while exercising at night. The precise cause of these cramps is unclear. Potential contributing factors include dehydration, low levels
of certain minerals (magnesium, potassium, calcium, and sodium), and reduced blood flow through muscles attendant in prolonged sitting
or lying down. Nocturnal leg cramps (almost exclusively calf cramps) are considered 'normal' during the late stages of pregnancy. They can,
however, vary in intensity from mild to extremely painful.

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A lactic acid buildup around muscles can trigger cramps; however, these happen during anaerobic respiration when a person is exercising or
engaging in an activity where the heart beat speeds up. Medical conditions associated with leg cramps are cardiovascular disease,
hemodialysis, cirrhosis, pregnancy, and lumbar canal stenosis.

Differential diagnosis includes restless legs syndrome, claudication, myositis, peripheral neuropathy. All of which can be differentiated
through careful history and physical examination.

Gentle stretching and massage, putting some pressure on the affected leg by walking or standing, or taking a warm bath or shower may help
to end the cramp.

If the cramp is in the calf muscle, pulling the big toe gently backwards will stretch the muscle and, in some cases, cause almost
immediate relief. There are limited evidence supporting the use of Magnesium, Calcium channel blockers, carisoprodol and Vitamin
B12. Quinine is no longer recommended for treatment of nocturnal leg cramps due to potential fatal hypersensitivity reactions and
thrombocytopenia. Arrhythmias, cinchonism, hemolytic uremic syndrome can also occur at higher dosages.

Smooth muscle cramps

Smooth muscle contractions may be symptomatic of endometriosis or other health problems. Menstrual cramps may also occur both
before and during a menstrual cycle.

Iatrogenic causes

Various medications may cause nocturnal leg cramps:

Diuretics, especially potassium

sparing IV iron sucrose
Conjugated
estrogens
Teriparatide
Naproxen

Raloxifene

Long acting adrenergic beta-agonists (LABAs)

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (HMG-CoA inhibitors or statins)

Besides being painful, a nocturnal leg cramp can cause much distress and anxiety. Statins may sometimes cause myalgia and cramps among
other possible side effects. Raloxifene (Evista) is a medication associated with a high incidence of leg cramps. Additional factors, which
increase the probability for these side effects, are physical exercise, age, female gender, history of cramps, and hypothyroidism. Up to 80% of
athletes using statins suffer significant adverse muscular effects, including cramps; the rate appears to be approximately 10–25% in a typical
statin-using population. In some cases, adverse effects disappear after switching to a different statin; however, they should not be ignored if
they persist, as they can, in rare cases, develop into more serious problems. Coenzyme Q10 supplementation can be helpful to avoid some
statin-related adverse effects, but currently there is not enough evidence to prove the effectiveness in avoiding myopathy or myalgia

Deafness;

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Hearing loss, also known as hearing impairment, is a partial or total inability to hear. A deaf person has little to no hearing. Hearing loss
may occur in one or both ears. In children hearing problems can affect the ability to learn language and in adults it can cause work
related difficulties. In some people, particularly older people, hearing loss can result in loneliness. Hearing loss can be temporary or
permanent.

Hearing loss may be caused by a number of factors, including: genetics, ageing, exposure to noise, some infections, birth complications,
trauma to the ear, and certain medications or toxins. A common condition that results in hearing loss is chronic ear infections. Certain
infections during pregnancy such as rubella may also cause problems. Hearing loss is diagnosed when hearing testing finds that a person is
unable to hear 25 decibels in at least one ear. Testing for poor hearing is recommended for all newborns. Hearing loss can be categorised as
mild, moderate, severe, or profound.

Dropsy or Edema.

Edema (also oedema, dropsy, and hydropsy) "swelling" is an abnormal accumulation of fluid in the interstitium, located beneath the skin
and in the cavities of the body which can cause severe pain. Clinically, edema manifests as swelling; the amount of interstitial fluid is
determined by the balance of fluid homeostasis, and the increased secretion of fluid into the interstitium, or the impaired removal of the
fluid can cause edema.

Classifications

Cutaneous edema is referred to as "pitting" when, after pressure is applied to a small area, the indentation persists after the release of the
pressure. Peripheral pitting edema, as shown in the illustration, is the more common type, resulting from water retention. It can be caused
by systemic diseases, pregnancy in some women, either directly or as a result of heart failure, or local conditions such as varicose veins,
thrombophlebitis, insect bites, and dermatitis.

Non-pitting edema is observed when the indentation does not persist. It is associated with such conditions as lymphedema, lipedema,
and myxedema.

Edema caused by malnutrition defines kwashiorkor, an acute form of childhood protein-energy malnutrition characterized by edema,
irritability, anorexia, ulcerating dermatoses, and an enlarged liver with fatty infiltrates. The insufficient protein consumption, but with
sufficient calorie intake, distinguishes it from marasmus. Kwashiorkor cases occur in areas of famine or poor food supply. Cases in the
developed world are rare.

Generalized

A rise in hydrostatic pressure occurs in cardiac failure. A fall in osmotic pressure occurs in nephrotic syndrome and liver failure.

Causes of edema which are generalized to the whole body can cause edema in multiple organs and peripherally. For example, severe
heart failure can cause pulmonary edema, pleural effusions, ascites and peripheral edema. In rare cases, a Parvovirus B19 infection may
cause generalized edemas.

Although a low plasma oncotic pressure is widely cited for the edema of nephrotic syndrome, most physicians note that the edema may occur

before there is any significant protein in the urine (proteinuria) or fall in plasma protein level. Most forms of nephrotic syndrome are due to

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biochemical and structural changes in the basement membrane of capillaries in the kidney glomeruli, and these changes occur, if to a lesser
degree, in the vessels of most other tissues of the body. Thus the resulting increase in permeability that leads to protein in the urine can
explain the edema if all other vessels are more permeable as well.

As well as the previously mentioned conditions, edemas often occur during the late stages of pregnancy in some women. This is more
common with those of a history of pulmonary problems or poor circulation also being intensified if arthritis is already present in that
particular woman. Women that already have arthritic problems most often have to seek medical help for pain caused from over-reactive
swelling. Edemas that occur during pregnancy are usually found in the lower part of the leg, usually from the calf down.

Organ-specific

An edema will occur in specific organs as part of inflammations, tendonitis or pancreatitis, for instance. Certain organs develop edema
through tissue specific mechanisms.

Examples of edema in specific organs:

Cerebral edema is extracellular fluid accumulation in the brain. It can occur in toxic or abnormal metabolic states and
conditions such as systemic lupus or reduced oxygen at high altitudes. It causes drowsiness or loss of consciousness.

Pulmonary edema occurs when the pressure in blood vessels in the lung is raised because of obstruction to the removal of blood
via the pulmonary veins. This is usually due to failure of the left ventricle of the heart. It can also occur in altitude sickness or on
inhalation of toxic chemicals. Pulmonary edema produces shortness of breath. Pleural effusions may occur when fluid also
accumulates in the pleural cavity.

Edema may also be found in the cornea of the eye with glaucoma, severe conjunctivitis or keratitis or after surgery. Sufferers
may perceive coloured haloes around bright lights.

Edema surrounding the eyes is called periorbital edema or eye puffiness. The periorbital tissues are most noticeably
swollen immediately after waking, perhaps as a result of the gravitational redistribution of fluid in the horizontal
position.

Common appearances of cutaneous edema are observed with mosquito bites, spider bites, bee stings (wheal and flare), and
skin contact with certain plants such as Poison Ivy or Western Poison Oak,[6] the latter of which are termed contact
dermatitis.

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 Another cutaneous form of edema is myxedema, which is caused by increased deposition of connective tissue. In myxedema (and
a variety of other rarer conditions) edema is caused by an increased tendency of the tissue to hold water within its extracellular
space. In myxedema this is because of an increase in hydrophilic carbohydrate-rich molecules (perhaps mostly hyaluronan)
deposited in the tissue matrix. Edema forms more easily in dependent areas in the elderly (sitting in chairs at home or on
aeroplanes) and this is not well understood. Estrogens alter body weight in part through changes in tissue water content. There
may be a variety of poorly understood situations in which transfer of water from tissue matrix to lymphatics is impaired because
of changes in the hydrophilicity of the tissue or failure of the 'wicking' function of terminal lymphatic capillaries.

In lymphedema abnormal removal of interstitial fluid is caused by failure of the lymphatic system. This may be due to
obstruction from, for example, pressure from a cancer or enlarged lymph nodes, destruction of lymph vessels by radiotherapy,
or infiltration of the lymphatics by infection (such as elephantiasis). It is most commonly due to a failure of the pumping action
of muscles due to immobility, most strikingly in conditions such as multiple sclerosis, or paraplegia. It has been suggested that
the edema that occurs in some people following use of aspirin-like cyclo-oxygenase inhibitors such as ibuprofen or
indomethacin may be due to inhibition of lymph heart action.
Hydrops fetalis is a condition of the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments.

Epilepsy;

Epilepsy is a group of neurological diseases characterized by epileptic seizures. Epileptic seizures are episodes that can vary from brief and
nearly undetectable to long periods of vigorous shaking. These episodes can result in physical injuries including occasionally broken
bones. In epilepsy, seizures tend to recur, and have no immediate underlying cause. Isolated seizures that are provoked by a specific cause
such as poisoning are not deemed to represent epilepsy. People with epilepsy in some areas of the world experience stigma due to the
condition.

The cause of most cases of epilepsy is unknown, although some people develop epilepsy as the result of brain injury, stroke, brain tumors,
infections of the brain, and birth defects. Known genetic mutations are directly linked to a small proportion of cases. Epileptic seizures are
the result of excessive and abnormal nerve cell activity in the cortex of the brain. The diagnosis involves ruling out other conditions that
might cause similar symptoms such as fainting and determining if another cause of seizures is present such as alcohol withdrawal or
electrolyte problems. This may be partly done by imaging the brain and performing blood tests. Epilepsy can often be confirmed with an
electroencephalogram (EEG), but a normal test does not rule out the condition.

Felons (abscesses);

An abscess (Latin: abscessus) is a collection of pus that has built up within the tissue of the body. Signs and symptoms of abscesses
include redness, pain, warmth, and swelling. The swelling may feel fluid filled when pressed. The area of redness often extends beyond
the swelling. Carbuncles and boils are types of abscess that often involve hair follicles with carbuncles being larger.

They are usually caused by a bacterial infection. Often many different types of bacteria are involved in a single infection. In the United
States and many other areas of the world the most common bacteria present is methicillin-resistant Staphylococcus aureus. Rarely,
parasites can

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cause abscesses and this is more common in the developing world. Diagnosis of a skin abscess is usually made based on what it looks like
and is confirmed by cutting it open. Ultrasound imaging may be useful in cases in which the diagnosis is not clear. In abscesses around the
anus, computer tomography (CT) may be important to look for deeper infection.

Agues (fevers-malaria);

Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans (a group of single-celled
microorganisms) belonging to the Plasmodium type. Malaria causes symptoms that typically include fever, fatigue, vomiting, and
headaches. In severe cases it can cause yellow skin, seizures, coma, or death. Symptoms usually begin ten to fifteen days after being bitten.
If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection,
reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing
exposure to malaria.

The disease is most commonly transmitted by an infected female Anopheles mosquito. The mosquito bite introduces the parasites from
the mosquito's saliva into a person's blood. The parasites travel to the liver where they mature and reproduce. Five species of Plasmodium
can infect and be spread by humans. Most deaths are caused by P. falciparum because P. vivax, P. ovale, and P. malariae generally cause a
milder form of malaria. The species P. knowlesi rarely causes disease in humans. Malaria is typically diagnosed by the microscopic
examination of blood using blood films, or with antigen-based rapid diagnostic tests. Methods that use the polymerase chain reaction to
detect the parasite's DNA have been developed, but are not widely used in areas where malaria is common due to their cost and
complexity

St Anthony's Fire (burning sensation in limbs and extremities caused by a fungus);

Blindness;

Visual impairment, also known as vision impairment or vision loss, is a decreased ability to see to a degree that causes problems not
fixable by usual means, such as glasses. Some also include those who have a decreased ability to see because they do not have access to
glasses or contact lenses. Visual impairment is often defined as a best corrected visual acuity of worse than either 20/40 or 20/60.The term
blindness is used for complete or nearly complete vision loss. Visual impairment may cause people difficulties with normal daily activities
such as driving, reading, socializing, and walking.

The most common causes of visual impairment globally are uncorrected refractive errors (43%), cataracts (33%), and glaucoma (2%).
Refractive errors include near sighted, far sighted, presbyopia, and astigmatism. Cataracts are the most common cause of blindness. Other
disorders that may cause visual problems include age related macular degeneration, diabetic retinopathy, corneal clouding, childhood
blindness, and a number of infections.[5] Visual impairment can also be caused by problems in the brain due to stroke, prematurity, or
trauma among others.These cases are known as cortical visual impairment.[6] Screening for vision problems in children may improve future
vision and educational achievement. Screening adults without symptoms is of uncertain benefit. Diagnosis is by an eye exam.

Gutta serena or Amaurosis;

(Greek meaning darkening, dark, or obscure) is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may
result from either a medical condition or from excess acceleration, as in flight. The term is the same as the Latin gutta serena.

Types of Amaurosis.

Leber's congenital amaurosis is an inherited disease resulting in optic atrophy and secondary severe vision loss or blindness. It was
first described by Theodore Leber in the 19th century.

Amaurosis fugax (Latin: fugax meaning fleeting) is a temporary loss of vision in one eye caused by decreased blood flow (ischemia) to the
retina.[citation needed] It may also be caused by embolization from atherosclerotic plaques in the ipsilateral (same side) internal carotid
artery.
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It is a type of transient ischaemic attack (TIA).[citation needed] Those experiencing amaurosis usually experience complete symptom resolution
within a few minutes. In a small minority of those who experience amaurosis, stroke or permanent vision loss results. Diabetes, hypertension and
smoking are factors known to increase the risks of suffering this condition. It also can be the result of surgical repair to the mitral valve, when very
small emboli may break away from the site of the repair, while the patient's tissue grows to cover the plastic annuloplasty band.

Quinidine toxicity can lead to cinchonism and also to quinine amaurosis.

Bronchocele (goiter);

A goitre (British English) or goiter (American English) (from the Latin gutteria, struma) is a swelling of the neck or larynx resulting
from enlargement of the thyroid gland (thyromegaly), associated with a thyroid gland that is not functioning properly.

Worldwide, over 90.54% cases of goitre are caused by iodine deficiency.

Signs and symptoms

Goitre which is associated with hypothyroidism or hyperthyroidism may be present with symptoms of the underlying disorder. For
hyperthyroidism, the most common symptoms are associated with adrenergic stimulation: tachycardia, palpitations, nervousness, tremor,
increased blood pressure and heat intolerance. Clinical manifestations are often related to hypermetabolism, including increased
metabolism, excessive thyroid hormone, an increase in oxygen consumption, metabolic changes in protein metabolism, immunologic
stimulation of diffuse goitre, and ocular changes (exophthalmos). Hypothyroid individuals may have weight gain despite poor appetite, cold
intolerance, constipation and lethargy. However, these symptoms are often nonspecific and hard to diagnose.

Morphology

Regarding morphology, goitres may be classified either as the growth pattern or as the size of the growth:

Growth pattern

Uninodular (struma uninodosa): can be either inactive or a toxic nodule

Multinodular (struma nodosa): can likewise be inactive or toxic, the latter called toxic multinodular goitre
Diffuse (struma diffuse): the whole thyroid appearing to be enlarged.

Size

Class I (palpation struma): in normal posture of the head, it cannot be seen; it is only found by palpation.
Class II: the struma is palpative and can be easily seen.
Class III: the struma is very large and is retrosternal; pressure results in compression marks.

Chlorosis (iron-deficiency anemia);Anemia, also spelled anaemia, is usually defined as a decrease in the amount of red blood cells (RBCs) or
hemoglobin in the blood. It can also be defined as a lowered ability of the blood to carry oxygen. When anemia comes on slowly, the
symptoms are often vague and may include: feeling tired, weakness, shortness of breath or a poor ability to exercise. Anemia that comes on
quickly often has greater symptoms, which may include: confusion, feeling like one is going to pass out, loss of consciousness, or increased
thirst. Anemia must be significant before a person becomes noticeably pale. Additional symptoms may occur depending on the underlying
cause.

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There are three main types of anemia: that due to blood loss, that due to decreased red blood cell production, and that due to increased
red blood cell breakdown. Causes of blood loss include trauma and gastrointestinal bleeding, among others. Causes of decreased
production include iron deficiency, a lack of vitamin B12, thalassemia, and a number of neoplasms of the bone marrow. Causes of
increased breakdown include a number of genetic conditions such as sickle cell anemia, infections like malaria, and certain autoimmune
diseases. It can also be classified based on the size of red blood cells and amount of hemoglobin in each cell. If the cells are small, it is
microcytic anemia. If they are large, it is macrocytic anemia while if they are normal sized, it is normocytic anemia. D

Coldness of the feet - (Raynaud's syndrome);

In medicine, Raynaud's disease or Raynaud's phenomenon is excessively reduced blood flow in response to cold or emotional stress,
causing discoloration of the fingers, toes, and occasionally other areas. This condition may also cause nails to become brittle with
longitudinal ridges. Named after French physician Maurice Raynaud (1834–1881), the phenomenon is believed to be the result of
vasospasms that decrease blood supply to the respective regions.

When the disorder's cause is idiopathic, it is referred to as Raynaud's disease (also called primary Raynaud's); if the syndrome is secondary
to another disease such as systemic sclerosis, Scleroderma, or other connective tissue disorders, it is correctly referred to as Raynaud's
phenomenon (secondary Raynaud's). If Raynaud's phenomenon is suspected to be secondary to systemic sclerosis, one tool which may help
aid in the prediction of systemic sclerosis is thermography.

Its pathophysiology includes hyperactivation of the sympathetic nervous system causing extreme vasoconstriction of the peripheral blood
vessels, leading to tissue hypoxia. Chronic, recurrent cases of Raynaud's phenomenon can result in atrophy of the skin, subcutaneous
tissues, and muscle. In rare cases it can cause ulceration and ischemic gangrene

Fistula Lacrymalis (obstruction of the flow of tears);

In medicine, a fistula is an abnormal connection between two hollow spaces (technically, two epithelialized surfaces), such as blood
vessels, intestines, or other hollow organs. Fistulas are usually caused by injury or surgery, but they can also result from an infection or
inflammation. Fistulas are generally a disease condition, but they may be surgically created for therapeutic reasons

In botany, the term is most common in its adjectival forms, where it is used in binomial names to refer to species that are distinguished
by hollow or tubular structures. Monarda fistulosa, for example, has tubular flowers; Eutrochium fistulosum has a tubular stem; and
Allium fistulosum has hollow or tubular leLocations

Fistulas can develop in various parts of the body. The following list is sorted by the International Statistical Classification of Diseases and
Related Health Problems.

H: Diseases of the eye, adnexa, ear, and mastoid process

(H04.6) Lacrimal
fistula (H70.1)
Mastoid fistula
Craniosinus fistula: between the intracranial space and a paranasal
sinus (H83.1) Labyrinthine fistula
Perilymph fistula: tear between the membranes between the middle and inner
ears Preauricular fistula
Preauricular fistula: usually on the top of the cristae helicis ears

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I: Diseases of the circulatory system

(I25.4) Coronary arteriovenous fistula, acquired

(I28.0) Arteriovenous fistula of pulmonary vessels

Pulmonary arteriovenous fistula: between an artery and vein of the lungs, resulting in shunting of blood. This results in
improperly oxygenated blood.
(I67.1) Cerebral arteriovenous fistula,
acquired (I77.0) Arteriovenous fistula,
acquired
(I77.2) Fistula of artery

J: Diseases of the respiratory system

(J86.0) Pyothorax with fistula

(J95.0) Tracheoesophageal fistula, between the trachea and the esophagus. This may be congenital or acquired, for example
as a complication of a tracheostomy.

K: Diseases of the digestive systemaves.

(K11.4) Salivary gland fistula

(K31.6) Fistula of stomach and
duodenum (K31.6) Gastrocolic fistula
(K31.6) Gastrojejunocolic fistula - after a Billroth II a fistula forms between the transverse colon and the upper jejunum (which,
post Billroth II, is attached to the remainder of the stomach). Fecal matter passes improperly from the colon to the stomach and
causes halitosis.
Enterocutaneous fistula: between the intestine and the skin surface, namely from the duodenum or the jejunum or the ileum.
This definition excludes the fistulas arising from the colon or the appendix.
Gastric fistula: from the stomach to the skin
surface (K38.3) Fistula of appendix
(K60) Anal and rectal fissures and
fistulas (K60.3) Anal fistula
(K60.5) Anorectal fistula (fecal fistula, fistula-in-ano): connecting the rectum or other anorectal area to the skin surface. This
results in abnormal discharge of feces through an opening other than the anus.
(K63.2) Fistula of intestine
Enteroenteral fistula: between two parts of the
intestine (K82.3) Fistula of gallbladder
(K83.3) Fistula of bile duct

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 Biliary fistula: connecting the bile ducts to the skin surface, often caused by gallbladder surgery
Pancreatic fistula: between the pancreas and the exterior via the abdominal wall

M: Diseases of the musculoskeletal system and connective tissue

(M25.1) Fistula of joint

N: Diseases of the urogenital system

(N32.1) Vesicointestinal
fistula (N36.0) Urethral fistula
Innora:between the prostatic utricle and the outside of the
body (N64.0) Fistula of nipple
(N82) Fistulae involving female genital tract / Obstetric fistula
(N82.0) Vesicovaginal fistula: between the bladder and the
vagina (N82.1) Other female urinary-genital tract fistulae
Cervical fistula: abnormal opening in the cervix

(N82.2) Fistula of vagina to small intestine

Enterovaginal fistula: between the intestine and the

vagina (N82.3) Fistula of vagina to large intestine
Rectovaginal: between the rectum and the vagina
(N82.4) Other female intestinal-genital tract
fistulae (N82.5) Female genital tract-skin fistulae
(N82.8) Other female genital tract fistulae
(N82.9) Female genital tract fistula, unspecified

Q: Congenital malformations, deformations and chromosomal abnormalities

(Q18.0) Sinus, fistula and cyst of branchial cleft

Congenital preauricular fistula: A small pit in front of the ear. Also known as an ear pit or preauricular
sinus. (Q26.6) Portal vein-hepatic artery fistula
(Q38.0) Congenital fistula of lip
(Q38.4) Congenital fistula of salivary gland
(Q42.0) Congenital absence, atresia and stenosis of rectum with fistula

(Q42.2) Congenital absence, atresia and stenosis of anus with fistula

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 (Q43.6) Congenital fistula of rectum and anus
(Q51.7) Congenital fistulae between uterus and digestive and urinary
tracts (Q52.2) Congenital rectovaginal fistula

T: External causes

(T14.5) Traumatic arteriovenous

fistula (T81.8) Persistent
postoperative fistula

Types of fistula.

Various types of fistulas include:

Types Name Definition

Blind with only one open end

Complete with both external and internal openings

Incomplete a fistula with an external skin opening, which does not connect to any internal organ

Although most fistulas are in forms of a tube, some can also have multiple branches.

Fits or Seizure;

A seizure, also known as a fit, is caused by a disturbance in the electrical activity of the brain, which can be due to conditions such as
epilepsy. A person having a seizure may not show any obvious symptoms, but in severe cases they may lose consciousness or experience
convulsions. Seizures usually begin suddenly but are often different in their duration and severity.

A person may have one seizure and no further symptoms, or they may have further seizures.

Not everyone who has a seizure will be diagnosed with epilepsy.

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Causes of non-epileptic seizures include diabetes, heart conditions and mental health conditions

Types of seizure:

Generalised seizures involve both sides of the brain from the start of the attack. Common subtypes include tonic-clonic (grand
mal) and absence seizures (petit mal). Febrile and infantile spasms are two types of generalised seizures that occur almost
exclusively in young children.

Partial (or focal) seizures are the second major seizure type. These begin in a specific area of the brain and may be contained
there. Or they may spread to the entire brain.

With simple partial seizures, the person remains conscious.

Complex partial seizures involve impaired consciousness.

Causes seizures

Often the cause of a seizure is unknown. Many conditions can provoke seizures, including:

Stroke
Brain tumour

Head injuries

Electrolyte imbalance

Very low blood sugar

Repetitive sounds or flashing lights, such as in video games

Medications, such as anti-psychotics and some asthma
drugs
Withdrawal from medications, such as certain tranquillisers or narcotics, or
alcohol Use of drugs such as cocaine and heroin
Cancer
Brain infections, such as meningitis

Symptoms of seizures vary widely, depending on the part of the brain affected by the electrical misfiring. If a very small part of the
brain is affected, you might sense only an odd smell or taste. In other cases, you could have hallucinations or convulsions, or you could
lose consciousness.

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 Generalised tonic-clonic: This is sometimes preceded by an aura (awareness of a strange odour, taste, or vision). You might lose
consciousness and fall, and experience muscle rigidity (stiffness) or convulsions (jerking movements of the arms and legs). You
might also lose bladder control or bite your tongue. After regaining consciousness, you might feel confused and fall asleep.

Generalised absence: This involves loss of awareness and blank stares or eyelid fluttering for up to 20 seconds. You feel well
enough to resume activity immediately after the seizure.

Simple partial: Although you don’t lose consciousness, you have involuntary movements, sensations, or psychic experiences such
as awareness of a smell or a sense of déjà vu lasting several seconds.

Complex partial: Initial disorientation is followed by strange movements of the arms or legs or odd vocalisations for one to
three minutes, as well as loss of consciousness.

Jacksonian: Muscle twitching begins in a single area and then progresses, for example, from the hand to the arm.

Febrile: Preceded by fever in young children, these seizures can be very brief tonic-clonic type seizures or partial seizures
lasting more than 15 minutes. Most children who have a fever-induced seizure never experience a second seizure.

Infantile spasms (West Syndrome): Lasting just a few seconds, bending of limbs, neck, and torso while lying down may occur often
during a single day. This usually only strikes children younger than three, often those with developmental delays or disabilities.

Ganglions (cysts around joints and tendons)

Gout; Gout is usually characterized by recurrent attacks of inflammatory arthritis—a red, tender, hot, and swollen joint. Pain
typically comes on rapidly in less than twelve hours. The joint at the base of the big toe is affected in about half of cases. It may
also result in tophi, kidney stones, or urate nephropathy.

The cause is a combination of diet and genetic factors. It occurs more commonly in those who eat a lot of meat, drink a lot of
beer, or are overweight. The underlying mechanisms involves elevated levels of uric acid in the blood. When the uric acid
crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, an attack of gout occurs. Diagnosis may be
confirmed by seeing the characteristic crystals in joint fluid or tophus. Blood uric acid levels may be normal during an attack.

Gravel (small kidney stones);

A kidney stone is a hard, crystalline mineral material formed within the kidney or urinary tract.

Nephrolithiasis is the medical term for kidney stones.

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One in every 20 people develop kidney stones at some point in their life.

Kidney stones form when there is a decrease in urine volume and/or an excess of stone-forming substances in the urine.

Dehydration is a major risk factor for kidney stone formation.

Symptoms of a kidney stone include flank pain (the pain can be quite severe) and blood in the urine (hematuria).

People with certain medical conditions, such as gout, and those who take certain medications or supplements are at risk for kidney stones.

Diet and hereditary factors are also related to stone formation.

Diagnosis of kidney stones is best accomplished using an ultrasound, intravenous pyleography (IVP), or a CT scan.

Most kidney stones will pass through the ureter to the bladder on their own with time.

Treatment includes pain-control medications and, in some cases, medications to facilitate the passage of urine.

lithotripsy or surgical techniques may be used for stones which do not pass through the ureter to the bladder on their own.

Ganglion cysts disease;

A ganglion cyst, or a synovial cyst, also known as Gideon's Disease, a Bible Cyst, or a Bible Bump, is a non-neoplastic soft tissue lump that
may occur in any joint, but most often occurs on, around, or near joints and tendons in the hands or feet. These cysts are caused by leakage
of fluid from the joint into the surrounding tissue.

Head-Ache;

Headache, also known as cephalalgia, is the symptom of pain anywhere in the region of the head or neck. It occurs in migraines, tension-
type headaches, and cluster headaches. Frequent headaches can affect relationships and employment. There is also an increased risk of
depression in those with severe headaches.

Headaches can occur as a result of many conditions whether serious or not. There are a number of different classification systems for
headaches. The most well-recognized is that of the International Headache Society. Causes of headaches may include fatigue, sleep
deprivation, stress, the effects of medications, the effects of recreational drugs, viral infections, common colds, head injury, rapid ingestion of
a very cold food or beverage,and dental or sinus issues.

Treatment of a headache depends on the underlying cause, but commonly involves pain medication. Some form of headache is one of the
most commonly experienced of all physical discomforts.

Hysterics;

Usually, hysterics.a fit of uncontrollable laughter or weeping; hysteria.Hysteria, in its colloquial use, describes ungovernable emotional
excess. Generally, modern medical professionals have abandoned using the term "hysteria" to denote a diagnostic category, replacing it
with more precisely defined categories, such as somatization disorder. In 1980, the American Psychiatric Association officially changed the
diagnosis of "hysterical neurosis, conversion type" (the most extreme and effective type) to "conversion disorder"

Inflammations;

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Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants,
and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate
the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to
initiate tissue repair.

The classical signs of acute inflammation are calor, dolor, rubor, tumor (heat, pain, redness and swelling) and loss of function. Inflammation
is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific
for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and
compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, periodontitis,
atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma). Inflammation is therefore normally closely regulated by
the body.

Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is
achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A series of
biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and
various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of
cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the
tissue from the inflammatory process.

Mycobacterial cervical lymphadenitis;

Also known as scrofula or King's evil, refers to a lymphadenitis of the cervical lymph nodes associated with tuberculosis as well as
non-tuberculous (atypical) mycobacteria. Disease

Scrofula is the term used for lymphadenopathy of the neck, usually as a result of an infection in the lymph nodes, known as
lymphadenitis. It can be caused by tuberculous or non tuberculous mycobacteria. About 95% of the scrofula cases in adults are caused by
Mycobacterium tuberculosis, most often in immunocompromised patients (about 50% of cervical tuberculous lymphadenopathy). In
immunocompetent children, scrofula is often caused by atypical mycobacteria (Mycobacterium scrofulaceum) and other nontuberculous
mycobacteria (NTM). Unlike the adult cases, only 8% of cases in children are tuberculous.

With the stark decrease of tuberculosis in the second half of the 20th century, scrofula became a less common disease in adults, but
remained common in children. With the appearance of AIDS, however, it has shown a resurgence, and presently affects about 5% of
severely immunocompromised patients

Knots in flesh;

Necrotizing soft tissue infection is a rare but very severe type of bacterial infection. It can destroy the muscles, skin, and underlying tissue.
The word "necrotizing" refers to something that causes body tissue to die.

Causes of knots

Many different types of bacteria can cause this infection. A very severe and usually deadly form of necrotizing soft tissue infection is due
to Streptococcus pyogenes, which is sometimes called "flesh-eating bacteria."

Necrotizing soft tissue infection develops when the bacteria enters the body, usually through a minor cut or scrape. The bacteria begins to
grow and release harmful substances (toxins) that kill tissue and affect blood flow to the area. As the tissue dies, the bacteria enters the
blood and rapidly spreads throughout the body.

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Lameness;

Lameness is an abnormal gait or stance of an animal that is the result of dysfunction of the locomotor system. In the horse, it is most
commonly caused by pain, but can be due to neurologic or mechanical dysfunction. Lameness is a common veterinary problem in
racehorses, sport horses, and pleasure horses. It is one of the most costly health problems for the equine industry, both monetarily for the
cost of diagnosis and treatment, and for the cost of time off resulting in loss-of-use

Throat-sore;

A sore throat (or throat pain) is pain or irritation of the throat. A common physical symptom, it is usually caused by acute
pharyngitis (inflammation of the throat), although it can also appear as a result of trauma, diphtheria, or other conditions.

Differential diagnosis

A sore throat is usually from irritation or inflammation. The most common cause (80%) is acute viral pharyngitis, a viral infection of the
throat. Other causes include other infections (such as streptococcal pharyngitis), trauma, and tumors. Gastroesophageal (acid) reflux disease
can cause stomach acid to back up into the throat and also cause the throat to become sore.In children streptococcal pharyngitis is the cause
of 37% of sore throats.

Toe hurt;

Pain in the toe can arise due to abnormalities or injury to any of the structures in the toe, including skin, nerves, bones, blood vessels, and
soft tissues. Toe pain is a fairly common symptom, since our feet are constantly exposed to injury by walking, running, or other athletic
activity, and moving around. Some types of toe pain can be accompanied by numbness, burning, warmth, or other symptoms. The most
common causes of toe pain include ingrown toenails, bunions, cuts or scrapes, other injuries, blisters, and corns and calluses. Arthritis
(including rheumatoid arthritis, gout, and other types of arthritis) and infections are additional causes of toe pain.

Tooth-ache;

Toothache, also known as dental pain, is pain in the teeth and/or their supporting structures, caused by dental diseases or pain referred to
the teeth by non-dental diseases.

Common causes include inflammation of the pulp, usually in response to tooth decay, dental trauma, or other factors, dentin
hypersensitivity (short, sharp pain, usually associated with exposed root surfaces), apical periodontitis (inflammation of the periodontal
ligament and alveolar bone around the root apex), dental abscesses (localized collections of pus, such as apical abscess, pericoronal
abscess, and periodontal abscess), alveolar osteitis ("dry socket", a possible complication of tooth extraction, with loss of the blood clot
and exposure of bone), acute necrotizing ulcerative gingivitis (a gum infection, also called "trenchmouth"), and others.

Pulpitis is classified as reversible when the pain is mild to moderate and lasts for a short time after a stimulus (for instance, cold or sweet);
or irreversible when the pain is severe, spontaneous, and lasts a long time after a stimulus. Left untreated, pulpitis may become irreversible,
then progress to pulp necrosis (death of the pulp) and apical periodontitis. Abscesses usually cause throbbing pain. The apical abscess
usually occurs after pulp necrosis, the pericoronal abscess is usually associated with acute pericoronitis of a lower wisdom tooth, and
periodontal abscesses usually represent a complication of chronic periodontitis (gum disease). Much less commonly, non-dental conditions
can cause toothache, such as maxillary sinusitis, which can cause pain in the upper back teeth, or angina pectoris, which can cause pain in
the lower teeth.

Toothache is the most common type of orofacial pain:125–135 and, when severe, it is considered a dental emergency

Wen (sebaceous cysts) orA trichilemmal cyst;

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Also known as a wen, pilar cyst or isthmus-catagen cyst, is a common cyst that forms from a hair follicle. They are most often found on the
scalp. The cysts are smooth, mobile and filled with keratin, a protein component found in hair, nails, skin, and horns. They are, however,
clinically and histologically distinct from Trichilemmal Horns[clarification needed], which are much more rare and not limited to the scalp.
Trichilemmal cysts may run in families and they may or may not be inflamed and tender, often depending on whether or not they've
ruptured. Rarely, these cysts may grow more extensively and form rapidly multiplying trichilemmal tumors, also called proliferating
trichilemmal cysts, which are benign but may grow aggressively at the cyst site. Very rarely, trichilemmal cysts can become cancerous.

Leprosy;Leprosy, also known as Hansen's disease (HD), is a long term infection caused by the bacteria Mycobacterium leprae and
Mycobacterium lepromatosis. Initially, infections are without symptoms and typically remain this way from 5 to as long as 20 years.
Symptoms that develop include granulomas of the nerves, respiratory tract, skin, and eyes. This may result in a lack of ability to feel pain
and thus loss of parts of extremities due to repeated injuries or infection due to unnoticed wounds.Weakness and poor eyesight may also
be present.

Leprosy is spread between people. It is believed to occur through a cough or contact with fluid from the nose of an infected person. Leprosy
occurs more commonly among those living in poverty and is believed to be transmitted by respiratory droplets. Contrary to popular belief,
it is not highly contagious.The two main types of disease are based on the number of bacteria present: paucibacillary and multibacillary.
The two types are differentiated by the number of poorly pigmented, numb skin patches present, with paucibacillary having five or fewer
and multibacillary having more than five. The diagnosis is confirmed by finding acid-fast bacilli in a biopsy of the skin or by detecting the
DNA using polymerase chain reaction.

Mortification (gangrene);

Gangrene (or gangrenous necrosis) is a type of necrosis caused by a critically insufficient blood supply. This potentially life-threatening
condition may occur after an injury or infection, or in people suffering from any chronic health problem affecting blood circulation. The
primary cause of gangrene is reduced blood supply to the affected tissues, which results in cell death. Diabetes and long-term smoking
increase the risk of suffering from gangrene.

Gangrene is a non-communicable disease. It does not spread from person to person. There are different types of gangrene with different
symptoms, such as dry gangrene, wet gangrene, gas gangrene, internal gangrene and necrotizing fasciitis. Treatment depends on the
underlying cause, and can include resection, debridement (or, in severe cases, amputation) of the affected body parts, antibiotics,
revascularization (via a vascular bypass or angioplasty), or hyperbaric oxygen therapy. It can rarely include medical therapy to stop
vascular spasm or the production of cold-induced vascular obstruction by cold-precipitated cryoglobulins.

Types gangrene

Dry gangrene

Dry gangrene is a form of coagulative necrosis that develops in ischemic tissue, where the blood supply is inadequate to keep tissue viable.
Dry gangrene is often due to peripheral artery disease, but can be due to acute limb ischemia. The limited oxygen in the ischemic limb limits
putrefaction and bacteria fail to survive. The affected part is dry, shrunken and dark reddish-black. The line of separation usually brings
about complete separation, with eventual falling off of the gangrenous tissue if it is not removed surgically, a process called
autoamputation.

Dry gangrene is the end result of chronic ischemia without infection. If ischemia is detected early, when there are ischemic wounds rather
than gangrene, the process can be treated by revascularization (via vascular bypass or angioplasty). However, once gangrene has developed,
the affected tissues are not salvageable.

Diabetes mellitus is a risk-factor for peripheral vascular disease and thus for dry gangrene, but also a risk factor for wet gangrene,
particularly in patients with poorly controlled blood-sugars, as elevated serum glucose creates a favorable environment for bacterial
infection.
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Wet gangrene

Wet, or infected, gangrene is characterized by thriving bacteria and has a poor prognosis (compared to dry gangrene) due to sepsis resulting
from the free communication between infected fluid and circulatory fluid. In wet gangrene, the tissue is infected by saprogenic
microorganisms (Clostridium perfringens or Bacillus fusiformis, for example), which cause tissue to swell and emit a fetid smell. Wet
gangrene usually develops rapidly due to blockage of venous (mainly) and/or arterial blood flow. The affected part is saturated with
stagnant blood, which promotes the rapid growth of bacteria. The toxic products formed by bacteria are absorbed, causing systemic
manifestation of sepsis and finally death. The affected part is edematous, soft, putrid, rotten and dark.

Because of the high mortality associated with infected gangrene, an emergency salvage amputation, such as a guillotine amputation, is
often needed to limit systemic effects of the infection. Such an amputation can be converted to a formal amputation, such as a below or
above knee amputation.

Gas gangrene

Gas gangrene is a bacterial infection that produces gas within tissues. It can be caused by Clostridium, most commonly alpha toxin
producing Clostridium perfringens, or various non-clostridial species. Infection spreads rapidly as the gases produced by bacteria expand
and infiltrate healthy tissue in the vicinity. Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated
as a medical emergency.

Gas gangrene is caused by bacterial exotoxin-producing clostridial species, which are mostly found in soil, and other anaerobes such as
Bacteroides and anaerobic streptococci. These environmental bacteria may enter the muscle through a wound and subsequently proliferate
in necrotic tissue and secrete powerful toxins. These toxins destroy nearby tissue, generating gas at the same time. A gas composition of
5.9% hydrogen, 3.4% carbon dioxide, 74.5% nitrogen, and 16.1% oxygen was reported in one clinical case.

Gas gangrene can cause necrosis, gas production, and sepsis. Progression to toxemia and shock is often very rapid.

Other

Necrotizing fasciitis is an infection that spreads deep into the body along tissue
planes. Noma is a gangrene of the face.
Fournier gangrene is a type of necrotizing fasciitis that usually affects the genitals and groin.
Venous limb gangrene may be caused by heparin-induced thrombocytopenia and thrombosis
(HITT). Severe mesenteric ischemia may result in gangrene of the small intestine.
Severe ischemic colitis may result in gangrene of the large intestine.

Pain in the Back, in the stomach; An irritation or problem with any of these structures can cause lower back pain and/or pain that radiates
or is referred to other parts of the body. Many lower back problems also cause back muscle spasms, which don't sound like much but can
cause severe pain and disability.

While lower back pain is extremely common, the symptoms and severity of lower back pain vary greatly. A simple lower back muscle
strain might be excruciating enough to necessitate an emergency room visit, while a degenerating disc might cause only mild,
intermittent discomfortCertain causes of lower back pain have a tendency to occur more often in younger individuals versus older
adults:

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 Younger adults (30 to 60 year olds) are more likely to experience back pain from the disc space itself (e.g. lumbar disc herniation
or degenerative disc disease) or from a back muscle strain or other soft tissue strain.
Older adults (over 60) are more likely to suffer from pain related to joint degeneration (such as osteoarthritis or spinal stenosis)
or from a compression fracture.

Palpitation of the Heart;Heart palpitations are a feeling that your heart is beating too hard or too fast, skipping a beat, or fluttering. You
may notice heart palpitations in your chest, throat, or neck.

Heart palpitations can be bothersome or frightening. They usually aren't serious or harmful, though, and often go away on their own.
Most of the time, they're related to stress and anxiety or to consumption of stimulants such as caffeine, nicotine, or alcohol. Palpitations
also often occur during pregnancy.

In rare cases, palpitations can be a sign of a more serious heart condition. Therefore, if you have heart palpitations, make arrangements to
see your doctor. And seek immediate medical attention if along with palpitations, you experience shortness of breath, dizziness, chest pain,
or fainting.

After taking your medical history and conducting a physical exam, your doctor may order tests that can either confirm or rule out an
underlying cause. If an underlying cause is found, the right treatment can reduce or eliminate palpitations. If your palpitations are not
related to an underlying cause, lifestyle changes, including stress management and the avoidance of common triggers, can help prevent
them.

Causes of Heart Palpitations

Many things can cause heart palpitations. In the vast majority of cases, the cause is either related to your heart or is unknown. Non-
heart-related causes of palpitations include:

Strong emotions such as anxiety, fear, or stress; palpitations often occur during panic
attacks. Vigorous physical activity
Caffeine, nicotine, alcohol, or illegal street drugs such as cocaine and amphetamines
Medical conditions, including thyroid disease, a low blood sugar level, anemia, low blood pressure, fever, and dehydration
Hormonal changes during menstruation, pregnancy, or the perimenopausal period; sometimes, palpitations during pregnancy
are signs of anemia.
Medications, including diet pills, decongestants, asthma inhalers, and some drugs used to prevent arrhythmias (a serious
heart rhythm problem) or treat an underactive thyroid
Certain herbal and nutritional
supplements Abnormal electrolyte levels

Some people experience palpitations after eating heavy meals that are rich in carbohydrates, sugar, or fat. Sometimes, eating
foods with high levels of monosodium glutamate (MSG), nitrates, or sodium can bring them on.

If you have heart palpitations after eating certain foods, the problem could be food sensitivity. Keeping a food diary can help
you identify which foods to avoid.

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 Palpitations can also be related to underlying heart disease. When they are, palpitations are more likely to represent
arrhythmia. Heart conditions associated with palpitations include:
Prior heart attack
Coronary artery disease
Other heart problems such as congestive heart failure, heart valve problems, or heart muscle problems

Palsy;Palsy is a medical term which refers to various types of paralysis, often accompanied by weakness and the loss of feeling and
uncontrolled body movements such as shaking

In some editions, the Bible passage of Luke 5:18 is translated to refer to "a man which was taken with a palsy". More modern editions
simply refer to a man who is paralyzed. Although the term has historically been associated with paralysis generally, "is now almost always
used in connection to the word “cerebral”—meaning the brain".

Specific kinds of palsy include:

Bell's palsy, partial facial paralysis

Bulbar palsy, impairment of cranial nerves
Cerebral palsy, a neural disorder caused by intracranial lesions
Conjugate gaze palsy, a disorder affecting the ability to move the
eyes Erb's palsy, also known as brachial palsy, involving paralysis of
an arm Spinal muscular atrophy, also known as wasting palsy
Squatter's palsy, a common name for bilateral peroneal nerve palsy that may be triggered by sustained squatting[3][4]
[5] Third nerve palsy, involving cranial nerve III

Rheumatism;

Rheumatism or rheumatic disorder is an umbrella term for conditions causing chronic, often intermittent pain affecting the joints and/or
connective tissue. The study of, and therapeutic interventions in, such disorders is called rheumatology. The term "rheumatism", however,
does not designate any specific disorder, but covers at least 200 different conditions.

Types of Rheumatism.

The major rheumatic disorders currently recognized include

Ankylosing
spondylitis Back pain
Bursitis/Tendinitis, Shoulder pain, wrist, biceps, leg, knee (patellar), ankle, hip, and
Achilles Capsulitis
Neck pain
Osteoarthritis
Palindromic rheumatism has been theorized to be a form of rheumatoid arthritis.

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Although these disorders probably have little in common in terms of their epidemiology, they do share two characteristics: they cause
chronic (though often intermittent) pain, and they are difficult to treat. They are also, collectively, very common.

Other rheumatic diseases which are caused by autoimmunity include:

Relapsing polychondritis[
systemic lupus erythematosus
rheumatoid arthritis (see also gout, inflammatory arthritis,
pseudogout) juvenile arthritis
Sjögren
syndrome
scleroderma
Polymyositis
Dermatomyositi
s Behçet's
disease Reactive
arthritis
Psoriatic
arthritis

Sources dealing with rheumatism tend to focus on arthritis,[citation needed] but "rheumatism" may also refer to other conditions
causing chronic pain, grouped as "non-articular rheumatism", also known as "regional pain syndrome" or "soft tissue rheumatism".The
term "Rheumatic Diseases" is used in MeSH to refer to connective tissue disorders.

Ringworms orDermatophytosis;

More commonly known as as ringworm, is a fungal infection of the skin. Ringworm is a misnomer. The infection isn’t caused by a worm.
It’s caused by a fungus.

Ringworm infection can affect both humans and animals. The infection initially presents itself with red patches on affected areas of the skin
and later spreads to other parts of the body. The infection may affect the skinThree different types of fungi can cause this infection. They are
called trichophyton, microsporum, and epidermophyton. It’s possible that these fungi may live for an extended period as spores in soil.
Humans and animals can contract ringworm after direct contact with this soil. The infection can also spread through contact with infected
animals or humans. The infection is commonly spread among children and by sharing items that may not be clean. of the scalp, feet, groin,
beard, or other areas.

Sciatica (pain, tingling in leg);Sciatica is a medical condition of pain going down the leg from the lower back.This pain may go down the
back, outside, or front of the leg. Typically, symptoms are only on one side of the body. Certain causes, however, may result in pain on
both sides. Lower back pain is sometimes but not always present. Weakness or numbness may occur in various parts of the leg and foot.

About 90% of the time sciatica is due to a spinal disc herniation pressing on one of the lumbar or sacral nerve roots.Other problems that
may result in sciatica include spondylolisthesis, spinal stenosis, piriformis syndrome, pelvic tumors, and compression by a baby's head
during pregnancy. The straight-leg-raising test is often helpful in diagnosis. The test is positive if, when the leg is raised while a person is
lying on their back, pain shoots below the knee. In most cases medical imaging is not needed. Exceptions to this are when bowel or bladder
function is affected, there is significant loss of feeling or weakness, symptoms are long standing, or there is a concern of a tumor or
infection.Conditions that may present similarly are diseases of the hip and early herpes zoster before the rash appears.
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Shingles;

Shingles is a viral infection that causes a painful rash. Although shingles can occur anywhere on your body, it most often appears as a
single stripe of blisters that wraps around either the left or the right side of your torso.

Shingles is caused by the varicella-zoster virus — the same virus that causes chickenpox. After you've had chickenpox, the virus lies inactive
in nerve tissue near your spinal cord and brain. Years later, the virus may reactivate as shingles. While it isn't a life-threatening condition,
shingles can be very painful.

Sprain;

A sprain, more commonly known as a torn ligament, is damage to one or more ligaments in a joint, often caused by trauma or the joint
being taken beyond its functional range of motion. The severity of sprain ranges from a minor injury which resolves in a few days to a
major rupture of one or more ligaments requiring surgical fixation and a period of immobilisation. Sprains can occur in any joint but are
most common in the ankle and wrist

A diagnosis of a sprain can often be made with a good degree of certainty by physical examination based on the clinical presentation and
method of injury. In some cases, X-rays are obtained to ensure that there is no fracture. In some cases, particularly if the injury is prolonged
or does not appear to be resolving as expected, magnetic resonance imaging (MRI) is performed to look at surrounding soft tissues and the
ligament.

Classification

First degree sprain – the fibres of the ligament are stretched but intact.
Second degree sprain – is a tear of part of a ligament, from a third to almost all its fibres.
Third degree sprain – is a complete rupture of the ligament, sometimes avulsing a piece of bone.

Joints involved

Although any joint can experience a sprain, some of the more common include:

The ankle. It is the most common, and has been said that sprains such as serious ankle sprains are more painful and take longer
to heal than actually breaking the bones in that area.
The knee. One of the more talked about sprains is that to the anterior cruciate ligament (ACL) of the knee. This is a disabling
sprain common to athletes, especially in American football, football (soccer), basketball, pole vaulting, softball, baseball and
some styles of martial arts. See Anterior cruciate ligament injury.
Ligaments between the spinal
vertebrae The fingers.
The wrist.

The toes.

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Typhoid;

Typhoid fever, also known simply as typhoid, is a bacterial infection due to Salmonella typhi that causes symptoms. Symptoms may vary
from mild to severe and usually begin six to thirty days after exposure. Often there is a gradual onset of a high fever over several days.
Weakness, abdominal pain, constipation, and headaches also commonly occur. Diarrhea is uncommon and vomiting is not usually severe.
Some people develop a skin rash with rose colored spots. In severe cases there may be confusion. Without treatment symptoms may last
weeks or months. Other people may carry the bacterium without being affected; however, they are still able to spread the disease to
others.Typhoid fever is a type of enteric fever along with paratyphoid fever.

The cause is the bacterium Salmonella typhi, also known as Salmonella enterica serotype typhi, growing in the intestines and blood.Typhoid
is spread by eating or drinking food or water contaminated with the feces of an infected person. Risk factors include poor sanitation and poor
hygiene. Those who travel to the developing world are also at risk and only humans can be infected. Diagnosis is by either culturing the
bacteria or detecting the bacterium's DNA in the blood, stool, or bone marrow. Culturing the bacterium can be difficult. Bone marrow testing
is the most accurate. Symptoms are similar to that of many other infectious diseases. Typhus is a different disease.

Surfeit (over-indulgence);Excess eating of food, overspeech, overdrunk.

Vomiting;

Vomiting, also known as emesis and throwing up, among other terms, is the involuntary, forceful expulsion of the contents of one's
stomach through the mouth and sometimes the nose.

Vomiting can be caused by a wide variety of conditions; it may present as a specific response to ailments like gastritis or poisoning, or as a
non-specific sequela of disorders ranging from brain tumors and elevated intracranial pressure to overexposure to ionizing radiation. The
feeling that one is about to vomit is called nausea, which often precedes, but does not always lead to, vomiting. Antiemetics are sometimes
necessary to suppress nausea and vomiting. In severe cases, where dehydration develops, intravenous fluid may be required.

Vomiting is different from regurgitation, although the two terms are often used interchangeably. Regurgitation is the return of undigested
food back up the esophagus to the mouth, without the force and displeasure associated with vomiting. The causes of vomiting and
regurgitation are generally different.

Dehydration and electrolyte imbalance

Prolonged and excessive vomiting depletes the body of water (dehydration), and may alter the electrolyte status. Gastric vomiting leads to
the loss of acid (protons) and chloride directly. Combined with the resulting alkaline tide, this leads to hypochloremic metabolic alkalosis
(low chloride levels together with high HCO−

3 and CO

2 and increased blood pH) and often hypokalemia (potassium depletion). The hypokalemia is an indirect result of the kidney compensating
for the loss of acid. With the loss of intake of food the individual may eventually become cachectic. A less frequent occurrence results from
a vomiting of intestinal contents, including bile acids and HCO−

3, which can cause metabolic acidosis.

Mallory–Weiss tear

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Repeated or profuse vomiting may cause erosions to the esophagus or small tears in the esophageal mucosa (Mallory–Weiss tear). This
may become apparent if fresh red blood is mixed with vomit after several episodes.

Dentistry

Recurrent vomiting, such as observed in bulimia nervosa, may lead to destruction of the tooth enamel due to the acidity of the vomit.
Digestive enzymes can also have a negative effect on oral health, by degrading the tissue of the gums

Pathophysiology of vomiting.

Receptors on the floor of the fourth ventricle of the brain represent a chemoreceptor trigger zone, known as the area postrema, stimulation
of which can lead to vomiting. The area postrema is a circumventricular organ and as such lies outside the blood–brain barrier; it can
therefore be stimulated by blood-borne drugs that can stimulate vomiting or inhibit it.

There are various sources of input to the vomiting center:

The chemoreceptor trigger zone at the base of the fourth ventricle has numerous dopamine D2 receptors, serotonin 5-HT3
receptors, opioid receptors, acetylcholine receptors, and receptors for substance P. Stimulation of different receptors are involved
in different pathways leading to emesis, in the final common pathway substance P appears involved.
The vestibular system, which sends information to the brain via cranial nerve VIII (vestibulocochlear nerve), plays a major
role in motion sickness, and is rich in muscarinic receptors and histamine H1 receptors.
The cranial nerve X (vagus nerve) is activated when the pharynx is irritated, leading to a gag reflex.
The vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system. Irritation of
the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these
inputs.
The CNS mediates vomiting that arises from psychiatric disorders and stress from higher brain centers.

The vomiting act encompasses three types of outputs initiated by the chemoreceptor trigger zone: Motor, parasympathetic nervous
system (PNS), and sympathetic nervous system (SNS). They are as follows:

Increased salivation to protect tooth enamel from stomach acids. (Excessive vomiting leads to dental erosion). This is part of the
PNS output.
The body takes a deep breath to avoid aspirating vomit.
Retroperistalsis starts from the middle of the small intestine and sweeps up digestive tract contents into the stomach, through
the relaxed pyloric sphincter.
Intrathoracic pressure lowers (by inspiration against a closed glottis), coupled with an increase in abdominal pressure as the
abdominal muscles contract, propels stomach contents into the esophagus as the lower esophageal sphincter relaxes. The
stomach itself does not contract in the process of vomiting except for at the angular notch, nor is there any retroperistalsis in the
esophagus.
Vomiting is ordinarily preceded by retching.
Vomiting also initiates an SNS response causing both sweating and increased heart rate.

The neurotransmitters that regulate vomiting are poorly understood, but inhibitors of dopamine, histamine, and serotonin are all used to
suppress vomiting, suggesting that these play a role in the initiation or maintenance of a vomiting cycle. Vasopressin and neurokinin may
also participate.

137
Disorders due to ununderstood nuclei, nerves in the body can easily be destroyed by electric signals , These objections were explained by
Ariny Amos theory of general relativity, in which gravitation is an attribute of curved spacetime instead of being due to a force propagated
between bodies, fictitious force becomes stronger than any other force in the universe. In Einstein's theory, energy and momentum distort
spacetime in their vicinity, and other particles move in trajectories determined by the geometry of spacetime. This allowed a description of
the motions of light and mass that was consistent with all available observations. In general relativity, the gravitational force is a fictitious
force due to the curvature of spacetime, because the gravitational acceleration of a body in free fall is due to its world line being a geodesic
of spacetime.

Umbilicus disorders;

The embryology of the umbilicus and the developmental basis for surgical abnormalities has been well described for more than 100
years.
Umbilical hernias, abdominal wall defects, umbilical polyps and drainage,[1] and omphalomesenteric remnants are well described.

A stark contrast is observed between the physiologic importance of the umbilicus during development and its importance after birth.
During development, the umbilicus functions as a channel that allows blood flow between the placenta and fetus. It also serves an
important role in the development of the intestine and the urinary system. After birth, once the umbilical cord falls off, no evidence of
these connections should be present.

Nevertheless, umbilical disorders are frequently encountered in pediatric surgery. An understanding of the anatomy and
embryology of the abdominal wall and umbilicus is important for identifying and properly treating these conditions.

Patients with umbilical disorders present with drainage, a mass, or both. Most umbilical disorders result from failure of normal
embryologic or physiologic processes. Unusual umbilical anatomy, such as a single umbilical artery or abnormal position of the
umbilicus, may be associated with other congenital anomalies or syndromes. Omphalocele and gastroschisis, which are common
abdominal wall defects associated with the umbilicus, are discussed further elsewhere (see Pediatric Omphalocele and Gastroschisis).

Masses of the umbilicus may be related to lesions of the skin, embryologic remnants, or an umbilical hernia. Masses associated with
the skin include dermoid cysts, hemangiomas, and inclusion cysts. Umbilical drainage is associated with granulomas and
embryologic remnants. The following should be noted:

Delayed separation of the umbilical cord - The umbilical cord usually separates from the umbilicus 1-8 weeks postnatally; topical
antimicrobials are usually applied after delivery, followed by isopropyl alcohol until cord separation; delayed separation may
signify an underlying immune disorder

Umbilical granuloma - Granulation tissue may persist at the base of the umbilicus after cord separation; the tissue is composed
of fibroblasts and capillaries and can grow to more than 1 cm; umbilical granulomas must be differentiated from umbilical
polyps and from granulomas secondary to a patent urachus, both of which do not respond to silver nitrate cauterization

Umbilical infections - Patients with omphalitis may present with purulent umbilical discharge or periumbilical cellulitis;
although infections may be associated with retained umbilical cord or ectopic tissue, they were often, in the past, related to
poor hygiene; current aseptic practices and the routine use of antimicrobials on the umbilical cord have reduced the incidence
to less than 1%; cellulitis may become severe and rapidly progess within hours to necrotizing fasciitis and generalized sepsis,
and thus, prompt attention and treatment are critical

Omphalomesenteric remnants - Persistence of all or portions of the omphalomesenteric duct can result in fistulas, sinus tracts, cysts,

congenital bands, and mucosal remnants; patients with mucosal remnants can present with an umbilical polyp or an umbilical cyst

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 Urachal remnants - The developing bladder remains connected to the allantois through the urachus, and remnants of this
connection include a patent urachus, urachal sinus, and urachal cyst; umbilical polyps and granulomas can also be observed
in association with a urachal remnant

Umbilical hernias - These result when persistence of a patent umbilical ring occurs; some umbilical hernias close spontaneously,

but many require surgical repair [2]

Methods of management in some disorders, such as treating umbilical granulomas with silver nitrate, have changed little over the last
century. In the early 1900s, umbilical hernia repair was a challenging procedure. Spontaneous closure of these hernias and preservation
of the appearance of the natural umbilicus were recognized. Today, umbilical hernia repair is one of the most common procedures
performed by pediatric surgeons.

Pleurisy (inflammation of the membrane surrounding lungs); Pleurisy (also known as pleuritis) is an inflammation of the pleurae, the
membranes of the pleural cavity surrounding the lungs. There are many possible causes of pleurisy but viral infections spreading from the
lungs to the pleural cavity are the most common. The inflamed pleural layers rub against each other every time the lungs expand to breathe
in air. This can cause sharp pain when breathing, also called pleuritic chest pain. The condition may either be primary or secondary and is
often associated with a pleural effusion.Signs and symptoms

The defining symptom of pleurisy is a sudden sharp, stabbing, burning or dull pain in the right or left side of the chest during breathing,
especially when one inhales and exhales. It feels worse with deep breathing, coughing, sneezing, or laughing. The pain may stay in one
place, or it may spread to the shoulder or back. Sometimes, it becomes a fairly constant dull ache.

Depending on its cause, pleuritic chest pain may be accompanied by other symptoms:

Dry cough
Fever and chills
Rapid, shallow breathing

Shortness of breath

Tachycardia
Sore throat followed by pain and swelling in the joints

Pleural space can be invaded by fluid, air, and particles from different parts of the body which fairly complicates the diagnosis. Viral
infection (coxsackievirus, RSV, CMV, adenovirus, EBV, parainfluenza, influenza) is the most common cause of pleurisy. However, many
other different conditions can cause pleuritic chest pain:

Aortic dissections
Autoimmune disorders such as systemic lupus erythematosus (or drug-induced lupus erythematosus), Autoimmune hepatitis
(AIH) and rheumatoid arthritis
Bacterial infections associated with pneumonia and
tuberculosis Chest injuries (blunt or penetrating)

139
 Familial Mediterranean fever, an inherited condition that often causes fever and swelling in the abdomen or the
lungs Fungal or parasitic infections
Heart surgery, especially coronary-artery bypass
grafting Cardiac problems (ischemia, pericarditis)
Inflammatory bowel
disease Lung cancer and
lymphoma
Other lung diseases like cystic fibrosis, sarcoidosis, asbestosis, lymphangioleiomyomatosis, and
mesothelioma Pneumothorax
Pulmonary embolisms, which are blood clots that enter the lungs

When the space between two layers of pleura starts to fill with fluid in a case of pleural effusion, it can ease the chest pain, but instead
creates a shortness of breath, since the lungs need room to expand during breathing. Some cases of pleuritic chest pain are idiopathic,
which means that the exact cause cannot be determined.

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 CONCLUSION.

In medicine , Electric signals with immune system destroys the un understood nuclei, Protein of the virus and bacteria, nerves in the
Brain of human and plant tissue and vertebrates resulting to cure of patient , and plant tissues . Ariny Amos Cell Membrane then
considering the propagation of action potentials along axons and their termination at the synaptic knobs, it is helpful to consider the
methods by which action potentials can be initiated at the axon hillock. The basic requirement is that the membrane voltage at the
hillock be raised above the threshold for firing. There are several ways in which this depolarization can occur.

The axon hillock is a specialized part of the cell body (or soma) of a neuron that connects to the axon.The axon hillock is the last site in
the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many
years, it had been believed that the axon hillock was the usual site of action potential initiation. It is now thought that the earliest site of
action potential initiation is found just adjacent, in the initial (unmyelinated) segment of the axon. However, the positive point, at which
the action potential starts, varies between cells. It can also be altered by hormonal stimulation of the neuron, or by second messenger
effects of neurotransmitters.The axon hillock also functions as a tight junction, since it acts as a barrier for lateral diffusion of
transmembrane proteins, GPI anchored proteins such as thy1, and lipids embedded in the plasma membrane

Ariny Amos concludes that Death occurs, cure fails is due to failures of the, gravitational force, universal gravitational of celestial
bodies or heavenly bodies due to Neurological disorders triggered by a fictitious force.Celestial body often acts as antibody (Ab), also
known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to
identify and neutralize pathogens such as bacteria and viruses.

Demyelination is the act of demyelinating, or the loss of the myelin sheath insulating the nerves. When myelin degrades, conduction of
signals along the nerve can be impaired or lost, and the nerve eventually withers. This leads to certain neurodegenerative disorders like
multiple sclerosis and chronic inflammatory demyelinating polyneuropathy.
Although most injury responses include a calcium influx signaling to promote resealing of severed parts,

axonal injuriesAxonal degeneration,initiallyleadto acute axonal degeneration, which is rapid separation of the proximal and

distal ends within 30 minutes of injury. Degeneration follows with swelling of the axolemma, and eventually leads to bead like

formation. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. Early

changes include accumulation of mitochondria in the paranodal regions at the site of injury. Endoplasmic reticulum degrades

and mitochondria swell up and eventually disintegrate. The disintegration is dependent on ubiquitin and calpainproteases

(caused by influx of calcium ion), suggesting that axonal degeneration is an active process. Thus the axon undergoes complete

fragmentation. The process takes about roughly 24 hrs in the PNS, and longer in the CNS. The signaling pathways leading to

axolemma degeneration are currently unknown.

Nerve regeneration; Charcot–Marie–Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), hereditary
sensorimotor neuropathy and peroneal muscular atrophy, is a heterogeneous inherited disorder of nerves (neuropathy) that is
characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the
advanced stages of disease. Presently incurable, this disease is one of the most common inherited neurological disorders, with 37 in
100,000 affected.

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by progressive cognitive
deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most
striking early symptom is loss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily
more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive
(intellectual) impairment extends to the
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domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and functions such as decision-making and
planning become impaired.

Parkinson's disease (PD), also known as Parkinson disease, is a degenerative disorder of the central nervous system that often impairs
the sufferer's motor skills and speech. Parkinson's disease belongs to a group of conditions called movement disorders. It is
characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical
movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia,
normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.
Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

Myasthenia gravis is a neuromuscular disease leading to fluctuating muscle weakness and fatigability during simple activities. Weakness
is typically caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting
the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants, cholinesterase inhibitors
and, in selected cases, thymectomy

Neuroregeneration.It has been demonstrated that neurogenesis can sometimes occur in the adult vertebrate brain, a finding that led to

controversy in 1999. However, later studies of the age of human neurons suggest that this process occurs only for a minority of cells, and the
overwhelming majority of neurons comprising the neocortex were formed before birth and persist without replacement. It is often possible
for peripheral axons to regrow if they are severed. Recent studies have also shown that the body contains a variety of stem cell types that
have the capacity to differentiate into neurons. A report in Nature suggested that researchers had found a way to transform human skin cells
into working nerve cells using a process called transdifferentiation in which "cells are forced to adopt new identities

Electric signals will act in fictitious force in Antigen-antibody interaction, or antigen-antibody reaction in afictitious force, Antigen –Antibody
reaction is a specific chemical interaction between antibodies produced by B cells of the white blood cells and antigens during immune reaction. It
is the fundamental reaction in the body by which the body is protected from complex foreign molecules, such as pathogens and their chemical
toxins. In the blood, the antigens are specifically and with high affinity bound by antibodies to form an antigen-antibody complex. The immune
complex is then transported to cellular systems where itcan be destroyed or deactivated.Heavenly bodies or elestial bodies where by electrical
force which is particle attracts every other particle in the body using a force that is directly proportional to the product of their masses but also
inversely proportional to the square of the distance between them, general physical law.

Disorders due to ununderstood nuclei, nerves in the body can easily be destroyed by electric signals , These objections were explained by
Ariny Amos theory of general relativity, in which gravitation is an attribute of curved spacetime instead of being due to a force propagated
between bodies. In Einstein's theory, energy and momentum distort spacetime in their vicinity, and other particles move in trajectories
determined by the geometry of spacetime. This allowed a description of the motions of light and mass that was consistent with all available
observations. In general relativity, the gravitational force is a fictitious force due to the curvature of spacetime, because the gravitational
acceleration of a body in free fall is due to its world line being a geodesic of spacetime.

A fictitious force, also called a pseudo force,d'Alembert force or inertial force, is an apparent force that acts on all masses whose
motion is described using a non-inertial frame of reference, such as a rotating reference frame.The force F does not arise from any
physical interaction between two objects, but rather from the acceleration a of the non-inertial reference frame itself. Such an
additional force due to nonuniform relative motion of two reference frames is called a pseudo-force.

Assuming Newton's second law in the form F = ma, fictitious forces are always proportional to the mass m.

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Afictitious force explains why people die in hospitals, accidents,failto curein that, A fictitious force on an object arises when the frame
of reference used to describe the object's motion is accelerating compared to a non-accelerating frame. As a frame can accelerate in any
arbitrary way, so can fictitious forces be as arbitrary (but only in direct response to the acceleration of the frame). However, four
fictitious forces are defined for frames accelerated in commonly occurring ways: one caused by any relative acceleration of the origin
in a straight line (rectilinear acceleration); two involving rotation: centrifugal force and Coriolis force; and a fourth, called the Euler
force, caused by a variable rate of rotation, should that occur. Gravitational force would also be a fictitious force based upon a field
model in which particles distort spacetime due to their mass which clearly illustrates cure by electricity and in medicine

The surface of the Earth is a rotating reference frame. To solve classical mechanics problems exactly in an Earth-bound reference frame,
three fictitious forces must be introduced such that celestial bodies or Heavenly bodies fall on earth depending on the conditions of each
person on earth, the Coriolis force, the centrifugal force and the Euler force. The Euler force is typically ignored because the variations in
the angular velocity of the rotating Earth surface are usually insignificant. All of the other fictitious forces are strong compared to most
typical forces in everyday life, but they can be detected under careful conditions. For example, Léon Foucault shows the Coriolis force
that results from the Earth's rotation using the Foucault pendulum. If the Earth were to rotate a thousand times faster (making each day
only ≈86 seconds long), people could easily get the impression that such fictitious forces are pulling on them and do not die for thousand
years, as on a spinning carousel.

Recommendations;

Two commonly used targets, also approved by the FDA, are the internal segment of the globus pallidus (GPi)
and subthalamic nucleus (STN). FDA-Approved Brain Stimulation Targets.Modern brain research.physical
control of the mind,future brain creation,

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