What A Seminar
What A Seminar
What A Seminar
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HISTORY AND BACKGROUND
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History
• 1872 George Huntington was one of three generations of medical
practitioners in Long Island. With their combined experience of
several generations of a family with the same symptoms, he realised
their conditions were linked and set about describing it. A year after
leaving medical school , in 1872, he presented his accurate definition
of the disease to a medical society in Middleport, Ohio.
• c1923 Smith Ely Jelliffe (1866-1945) and Frederick Tilney (1875-
1938) began analyzing the history of Huntington's sufferers in New
England.
• 1932 P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a
thousand people with Huntington's back to two brothers and their
families who left Bures in Essex for Suffolk bound for Boston in
1630.
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George Huntington
George Huntington
His father, George Lee Huntington 1811-1881) and grandfather, Dr. Abel
Huntington (1778-1858), were also physicians in the same family practice.
Their observations combined with his own were invaluable in precisely
describing this disease, which afflicted several generations of a family in
East Hampton on Long Island.
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Frequency:
• In the US: Several epidemiological studies in the United States,
conducted from 1945-1980, show consistent statistics stating that
approximately 30,000 people have HD.
Race:
• No significant differences exist among national and ethnic groups in
the number of CAG repeats; however, the higher frequency of HD
among white persons and its lower prevalence in other populations,
including black persons and Japanese persons, has led to the
hypothesis that the mutation responsible for the disease was carried to
different parts of the world by immigrant European settlers.
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CAUSES AND MECHANISM
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Causes
The product of this gene is a 348 kDa cytoplasmic protein called huntingtin.
Huntingtin has a characteristic sequence of fewer than 40 glutamine amino
acid residues (encoded by CAG trinucleotide repeats) in the normal form,
more than this and a mutated form of huntingtin that causes the disease is
produced. The severity of the disease is generally proportional to the number
of extra residues.
If the gene is inherited from the mother the count is usually similar, but
tends to increase if inherited from the father. Because of the progressive
increase in length of the repeats, the disease tends to increase in severity and
have an earlier onset in successive generations. This is known as anticipation
PROTIEN AGGREGATES
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selected regions of the brain. Certain neurons appear to be more vulnerable
in HD.
Free radicals
Apoptosis
Another theory to explain the death of nerve cells postulates that the cells
actually kill themselves in response to chemical changes caused by HD. The
theory proposes that HD triggers the early death of neurons by accelerating a
normal process called apoptosis, or “programmed cell death.”
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cause cell death, which is one possible explanation of how HD nerve cells
die.
Mechanism
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inclusions.The continuous aggregation of the abnormal huntingtin molecules
in neuronal cells causes cell death, especially in the frontal lobes and the
basal ganglia (mainly in the caudate nucleus).Huntingtin aggregates form
through a nucleation dependent polymerization.
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Effect of huntington disease on brain
HD affects the basal ganglia, large masses of gray matter located deep
within the cerebral hemispheres that regulate and coordinate cortically
originated movement. The corpus striatum includes the globus pallidus and
the striatum, which contains the caudate nucleus and the putamen.
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causes problems with voluntary movement. Neurons that project to the
lateral globus pallidus are preferentially lost. Although the lateral portion of
the globus pallidus is more severely affected than the medial portion during
the early and middle phases of HD, all areas of the striatum are depleted in
advanced stages. The cannabinoid receptors of striatal nerve terminals in
lateral GP are lost more than those of the medial GP. These abnormalities
produce the clinical manifestations of HD.
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1. Corona radiata 2. Sagittal stratum 3. Head of caudate nucleus 4. Body of caudate
nucleus 5. Tail of caudate nucleus 6. Connecting piece between lentiform nucleus
and taiI of caudate nucleus 7. Amygdaloid body 8. Anterior commissure 9. Stria
terminalis 10. Internal capsule 11. Cut surface of basis pedunculi
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1. Corona radiata 2. Internal capsule 3. Globus pallidus 4. Sagittal stratum 5.Olfactory
bulb 6. Olfactory tract 7. Straight gyrus 8. Anterior (rostral) commissure 9. Optic chiasma
10. Optic nerve Figure 4: The left hemisphere from the lateral aspect
The exact link between CAG repeats (huntingtin) and mitochondrial failure
is that aggregates may trap critical enzymes that are involved in energy
metabolism. Some think that the cause of cell death is the splitting of the
lysosome so that the hydrolytic enzymes within it are released. This will
cause the cell membrane to split and the cell to die.
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DIAGNOSIS
DIAGNOSIS
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Genetic Testing
With the discovery of the gene a simple and accurate genetic test became
available. The HD gene test usually requires a blood sample, but can be
performed on other tissues, such as skin, amniocytes or chorionic villus
cells, or autopsy material. The test requires special moleculardiagnostic
facilities.
Genetic testing for HD is potentially useful in three clinical situations:
diagnostic or confirmatory testing; predictive or presymptomatic testing; and
prenatal testing.
• Confirmatory testing
Confirmatory testing should be performed in a patient who appears to have
HD if no other affected family members have previously had a gene test, to
be sure that the “family disease” is really HD and not some other condition.
A small blood sample is taken, and DNA from it is analyzed to determine the
CAG repeat number. A person with a repeat number of 30 or below will not
develop Huntington's disease. A person with a repeat number between 35
and 40 may not develop the disease within their normal lifespan. A person
with a very high number of repeats (70 or above) is likely to develop the
juvenile-onset form.
• Predictive testing
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for competent adults who have participated in a careful discussion of
their genetic risks and the potential risks and benefits of the test itself.
• Prenatal testing
NEUROIMAGING STUDIES
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Figure 7: Positron emission tomography image of a patient with Huntingdon's
disease
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SIGNS AND SYMPTOMS
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Congnitive Disorder
Introduction
The cognitive disorder in HD is considered a “sub-cortical” syndrome. The
most prominent cognitive impairments in HD involve the so-called
“executive functions”- abilities such as organization, regulation and
perception. These fundamental abilities can affect performance in many
cognitive areas, including speed, reasoning, planning, judgement, decision
making, emotional engagement, perseveration, impulse control, temper
control, perception, awareness, attention, language, learning, memory and
timing.
• Disorganization
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• Lack of Initiation
Some family members complain that the person with HD “just sits around
all day and won’t do anything”. A lack of initiation is often misinterpreted as
laziness, apathy or lack of interest, and may be a reason for poor
performance at work. Once started, persons with HD may be able to execute
the behaviors adequately (i.e., compute taxes, calculate sales, administrate
employees, teach school), but may be unable to organize and initiate the
behaviors at the appropriate time.
External initiation often helps the person with HD remain active and
participate in both social and work activities. Keeping a daily routine can
minimize the need for internal initiation. Maintaining the desired behavior is
usually less of a problem for persons with HD.
• Perseveration
Perseveration or being fixed on a specific thought or action can occur when
behaviors are inadequately regulated by the brain. Patients become
behaviorally rigid, and tend to get stuck on an idea or task. Established
routines and gentle reminders of changing tasks can help avoid problems.
• Impulsivity
Some persons with HD experience difficulties with impulse control and may
develop problem behaviors such as irritability, temper outbursts, sexual
promiscuity and acting without thinking. Some degree of impulsivity and
dysregulation of behaviors is quite common in HD. Some strategies to help
family members and caregivers cope with impulsivity are addressed below.
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• Irritability and Temper Outbursts
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Physical Movement Disorder
Introduction
There are two parts to the movement disorder associated with
Huntington’s disease: the presence of involuntary movements, and the
impairment of voluntary movements.
The involuntary movements are called chorea and consist of irregular
jerking or writhing movements referred to as Huntington’s chorea.
Abnormal eye movements ,movements of neck ,lips etc.
• Chorea
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A variety of medications have been used to treat rigidity, spasticity, and
dystonia, all with modest success at best.
Consultation with a physiotherapist or physiatrist to design a program to
mobilize the patient and prevent contractures may be an important
component to the management of rigidity and spasticity. Botulinum toxin
injections have been used rarely, but might be beneficial if severe rigidity
of a small muscle or group of muscles is disturbing function.
Swallowing Difficulties
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during and after meals, to take small bites, and to clear the mouth of food
after each bite by taking sips of liquid.
Drinking fluid through a straw may be easier than drinking directly from a
cup, and the use of a covered cup or mug, like a “sippy cup” used by young
children ,may prevent spillage due to chorea. Grainy items, such as ground
beef or rice, may irritate the pharynx and cause choking. Foods such as
steak, which are hard to chew, should also be avoided.Patients may have
difficulty adjusting to different textures of food, and may do better if they
finish each item on the plate in turn.
Self-feeding may be prolonged by having the patient eat more frequent, but
smaller meals,and by using“finger foods”. The transition to assisted feeding
does not have to be all or nothing, as patients may still be able to eat
unassisted at certain times and be fed at other times.
Choking may decrease once self-feeding is stopped, because the caregiver
will have greater controlover the size and frequency of the bites. The
caregiver should still promote eating slowly, and not talkingwhile eating,
and should make sure the mouth is empty before each bite. With supervision,
mostpatients are able to assist with feeding and to take adequate amounts of
food by mouth quite far into the illness. However, before dysphagia and
communication difficulties become severe, the issue of feeding tubes should
be discussed with the patient and family, to ensure that appropriate nutrition
can be maintained throughout the illness. A gastrostomy tube can clearly
improve nutritional status in a debilitated person with severe dysphagia, and
may prolong life. However, patients and families may not desire this
intervention late in thecourse of HD.
Nutrition
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such as adding oil to soups, drinking cream instead of skim milk, adding
margarine liberally as a condiment, and focusing on easily eaten, high-
calorie foods such as pasta with cream based sauce.
Dysarthria
Falls
Falls are common in persons with HD, and can be a source of significant
morbidity. Usually seen more in the moderate to advanced stages,often result
from combination of spasticity, rigidity, chorea, and loss of balance.
Pharmacotherapy to prevent falls could includetreatment of chorea, rigidity,
spasticity and dystonia, while minimizing the use of drugs such as
neurolepticsand benzodiazepines, whose side effects include sedation,
ataxia, or parkinsonism. Installing handrails in key locations and minimizing
the use of stairs can help to reduce falls.Some families convert a ground
floor office or den into a bedroom. Furniture such as tables and desks,
particularly items with sharp corners, should be arrayed along the periphery
of the room, where they will present less of an obstacle. Floors should be
carpeted to lessen the impact when falls do occur. Patients who fall out of
bed may have a mattress placed beside the bed at night, or may sleep on a
mattress placed directly on the floor.
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Psychiatric Disorder
Introduction
Patients with Huntington’s disease who have psychiatric disorders suffer
from conditions such as Major Depression, Bipolar Disorder or Obsessive-
Compulsive Disorder which are specific well-described syndromes, found in
all sorts of patients. Most of these psychiatric problems are believed to be
related directly to the central nervous system injury caused by HD.
• Depression
Because depression in HD appears directly related to the brain disease,
pharmacotherapy is usually indicated.
Major Depression is a clinical syndrome, a constellation of signs and
symptoms which, taken together, suggest the diagnosis. Use of diagnostic
criteria helps to distinguish major depression from demoralization, transient
changes in mood caused by negative life events, such as bereavement, and
from some of the symptoms of HD itself, such as weight loss, trouble with
concentration, and apathy. Patients with Major Depression have a sustained
low mood, often accompanied by changes in self-attitude, such as feelings of
worthlessness or guilt, a loss of interest or pleasure in activities, changes in
sleep, particularly early morning awakening, and appetite, loss of energy,
and hopelessness. Depressed patients often feel worse in the morning than in
the afternoon.
A specific complaint of depressed mood is not necessary to make the
diagnosis if the patient has the other symptoms. In fact patients with HD
often have trouble identifying or describing their emotional state. Depression
in such a patient may be characterized by changes in sleep or appetite
patterns, agitation, tearfulness, or a drop-off in functional abilities. In such
circumstances the diagnosis should be considered.
In evaluating an HD patient with depression the physician also needs to
consider whether some physical problem, other than HD, might be the cause.
The patient’s medical history should be reviewed for conditions such as
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hypothyroidism, stroke, or exposure to certain drugs associated with mood
changes, such as steroids, reserpine, beta-blockers, and particularly alcohol.
Suicide
Depressed patients should always be asked about suicide, and this should be
regularly reassessed.
If the patient acknowledges these feelings, the clinician needs to ask more
questions to evaluate their severity and decide on the best course of action.
Some patients, although having suicidal thoughts, may be at low risk if they
have a good relationship with their doctor, have family support, and have no
specific plans. Others may be so dangerous to themselves that they require
emergency hospitalization.
A physician should listen supportively to these concerns, realizing that most
patients will be able to adapt if they are not suffering from depression.
Mania
Obsessive-Compulsive Disorders
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and the patient may struggle to put them aside, whereas the acting out of
compulsions generally relieves anxiety and may not be as strongly resisted.
Serotonergic antidepressants are used to treat OCD and may ameliorate
obsessions and compulsions in HD patients that do not meet the criteria for
the full syndrome.
Schizophrenia-Like Disorders
Delirium
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Psychiatric Symptoms not Belonging
to a Specific Disorder
Apathy
Apathy is common in HD and is probably related to frontal lobe
dysfunction. Apathetic patients become unmotivated and uninterested in
their surroundings. They lose enthusiasm and spontaneity. Performance at
work or school becomes sluggish. While apathetic patients have trouble
initiating actions, they will often participate if someone else suggests an
activity and works along with them to sustain energy and attention. For
example, a man with HD had always loved fishing, but when his brother
came to take him fishing for his birthday he wanted to stay home in front of
the television. The brother insisted, and when they left the house, he had a
good time fishing all day. When he returned, he immediately turned the
television back on.
Anxiety
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DRUGS FOR TREATMENT
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Drugs for treating huntington disease.
• Flavonoids
The flavonoids contribute to Ginkgo’s antioxidant properties. They have
been found to reduce the levels of free radicals(hydrogen peroxide), which
are highly reactive molecules with unpaired electrons. One way by which
flavonoids protect the cell is by reducing cell membrane lipid peroxidation.
Lipid peroxidation is defined as the process whereby free radicals “steal”
electrons from the lipids in our cell membranes, resulting in cell damage and
increased production of free radicals. Lipids include molecules such as fatty
acids, cholesterol, and other related compounds. As antioxidants, the
flavonoids neutralize the free radicals in our cell, lowering the levels of free
radicals available for lipid peroxidation.
. Terpenoids
The terpenoids include bilobalide and the ginkgolides A, B, C, M, and J.
Bilobalides have been proposed to have protective effects on nerve cells and
on the nervous tissue through their role in motor nerve cell regeneration.
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binds to a special kind of protein called a heat shock protein. All cells
produce a common set of heat shock proteins (Hsp’s) in response to a variety
of stresses, including heat, exposure to toxic compounds, or other conditions
that cells normally do not experience.
Most, but not all, heat shock proteins play the role of “molecular
chaperones.” Molecular chaperones are substances inside the cell that bind
and stabilize proteins at intermediate stages of folding, assembly, movement
across membranes, and degradation.
When GA is absent in cells, Hsp 90 and HSF 1(Heat Shock Factor 1).
commonly bind together and perform various functions as a unit. When GA
is added to cells, it binds to Hsp 90, making Hsp 90 unable to associate with
HSF 1. The free HSF 1 is then able to enter the cell nucleus where it initiates
the production of other heat shock proteins, specifically Hsp 70 and Hsp 40.
Once Hsp 70 and Hsp 40 are produced, they associate with the misfolded
huntingtin protein and prevent its aggregation.
In summary, recent research suggests that GA works against huntingtin
aggregations by triggering the following chain of events: (1) GA binds to the
heat stress protein Hsp 90, creating free HSF 1 within HD neurons; (2) the
free HSF 1 triggers increased production of Hsp 70 and Hsp 40 within the
cells; and (3) high levels of Hsp 70 and Hsp 40 then prevent the aggregation
of mutant huntingtin.
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Cystamine (Mechanism: Protein Aggregation)
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Rapamycin, also known as sirolimus, is an FDA-approved antibiotic and
immunosuppressant.
Rapamycin inhibits the activity of a protein called mTOR which, among its
other functions, inhibits a process called autophagy. Autophagy is the
process by which a cell breaks down its own molecules and other
components that are no longer needed. Since mTOR functions to inhibit
autophagy, by inhibiting mTOR, rapamycin promotes autophagy, allowing
for the breakdown of unnecessary components of the cell.
The part of the cell that is to be degraded is first engulfed by a double
membrane to separate it from the rest of the cell; the resulting membrane-
enclosed bubble of cytosol (and the proteins it contains) becomes what is
called the autophagosome. The autophagosome eventually fuses with a
cellular organelle called a lysosome, a much larger membrane-enclosed
bubble that contains a variety of enzymes that can break down all sorts of
cellular components (which is why lysosomes are sometimes referred to as
the “garbage disposals” of the cell). In order to protect the rest of the cell
from being degraded, these enzymes only work in a very acidic
environment, so the pH inside lysosomes is much lower than the neutral pH
in the rest of the cell.
In this process, the proteins are gathered up and transported to the lysosome,
where they are broken down and their component amino acids recycled.
Studies of nerve cells have shown that huntingtin can often be found in
autophagosomes, the membrane-bound sacs that carry cell parts to the
lysosome for degradation
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Minocycline (Mechanism: Inflammation)
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Creatine (Mechanism: Abnormalities in Energy
Metabolism)
Riluzole
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associated cell death might eventually be delayed.
HDAC inhibitors
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OTHER DRUGS
Medical care:
Drugs used to manage psychosis and agitation in patients with dementia are
intended to decrease psychotic symptoms (eg, paranoia, delusions,
hallucinations) and associated or independent agitation, screaming,
combativeness, or violence. The therapeutic goal is increased comfort and
safety of patients, families, and caregivers.
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(Risperdal not to hypotension, tachycardia, and arrhythmias
exceed 16
mg/d
Carbamaz 100 mg
epine not to <1 year: Drowsiness, dizziness, and blurred vision;
(Tegretol) exceed 100-200 caution while driving or performing other
1200 mg qd mg/d tasks requiring alertness; history of
1-5 years: cardiac, hepatic, renal, or hematopoietic
200-400 dysfunction .
mg/d
6-10 years:
400-600
mg/d
11-15
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years: 600-
1000 mg/d
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PROGNOSIS
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PROGNOSIS
Gene knockdown
A gene knockdown is either a genetically modified organism that carries one
or more genes in its chromosomes that has been made less active or had its
"expression" reduced or is the use of a reagent such as a short DNA or RNA
(oligonucleotide) with seqeuence complementary to an active gene or its
mRNA transcript. This oligonucleotide will bind to this active gene (or its
transcripts) to decrease expression of a specific gene, copying the effects of
such a genetic modification. So far such organisms have been engineered
chiefly for research purposes. Also known as knockdown organisms or
simply knockdowns, their most direct use is for learning about a gene that
has been sequenced, but has an unknown or incompletely known function,
an experimental approach known as reverse genetics. Researchers draw
inferences from how the knockdown differs from individuals in which the
gene of interest has not been made inoperative. Knockdown includes the
processes of modifying an organism or of using a reagent to suppress gene
expression, as in "knocking down a gene."
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Popular reagent-based methods of knocking down the expression of a gene
include suppression of translation using small interfering RNA (siRNA) or
Morpholino oligos.
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene
regulation. The term gene silencing is generally used to describe the
"switching off" of a gene by a mechanism other than genetic mutation. That
is, a gene which would be expressed (turned on) under normal circumstances
is switched off by machinery in the cell.Genes are regulated at either the
transcriptional or post-transcriptional level.
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Transcriptional gene silencing is the result of histone modifications, creating
an environment of heterochromatin around a gene that makes it inaccessible
to transcriptional machinery (RNA polymerase, transcription factors, etc.).
Before RNAi was well characterized, it was called by other names, including
post transcriptional gene silencing and transgene silencing. Only after these
phenomena were characterized at the molecular level was it obvious that
they were the same phenomenon
Cellular mechanism
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The native cellular purpose of the RNA interference machinery is not well
characterized, but it is known to be involved in microRNA (miRNAs)
processing and the resulting translational repression. MicroRNAs, which are
encoded in the genome and have a role in gene regulation, typically have
incomplete base pairing and only inhibit the translation of the target mRNA;
by contrast, RNA interference as used in the laboratory typically involves
perfectly base-paired dsRNA molecules that induce mRNA cleavage. After
integration into the RISC, siRNAs base pair to their target mRNA and
induce the RISC component protein argonaute to cleave the mRNA, thereby
preventing it from being used as a translation template.
Organisms vary in their cells' ability to take up foreign dsRNA and use it in
the RNAi pathway. The effects of RNA interference are both systemic and
heritable in plants and in C. elegans, although not in Drosophila or mammals
due to the absence of RNA replicase in these organisms. In plants, RNAi is
thought to propagate through cells via the transfer of siRNAs through
plasmodesmata.
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STEM CELLS
Stem cells are the primitive cells that are responsible for creating
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the various tissues of the body. There are skin stem cells, blood
stem cells and, most recently discovered, brain and spinal cord
stem cells.
Studies have shown that the brain stem cells in adult mice and
monkeys are usually making new neurons that participate in
olfaction (the ability to smell) and memory. So, it seems as though
the stem cells in mammals are regenerating two principal functions
- the ability to smell odour and to remember things - which may
tell us that these are the most important functions for our species.
REFERENCES
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2.WLISON & GISVOLD’S Textbook of Oganic Medicinal & Pharmaceutical
Chemistry By John H Block & John M Beale Jr Pg .nos 496 to 508,
514 to 520.
5. www.wikipedia.com
6. www.stanford.edu/grp/hopes/causes html
7. depts.washington.edu/mucholab/research.html
8. http--www_tcd_ie-tsmj-2003-images-hoseyfig3_gif.htm
10. http://www.stat.washington.edu/www/seminars/
11. www.dnaftb.org/ygyh/index.html
13. http://www.mdvu.org/library/disease/hd/hd_sym.html
14.http://www.disability.vic.gov.au/bhcv2/bhcsubmit.nsf/maxsearch?openagen
t&c=top&v=1&j=.2702187&jz=.8787732&tx=huntington_disease
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