Monday, August 13, 2007


Epilepsy is a much misunderstood medical disorder, inspite of the illness being known to mankind for over 3000 years. There are many myths and fears about this eminently treatable condition. One of the common myths is that epilepsy is a mental illness which is not so.
We now know that with the available antiepileptic drugs, epilepsy can be well controlled in about 75 to 80% of patients and the drugs can be withdrawn if a person is fit-free for to 2-5 years period. However the disease which can be so well controlled is perceived as a great setback and great cause for misery, simply because of the wrong notions. To make matters worse the doctors have very little time to convey the total picture of epilepsy and they concentrate more on procedures and prescription of the drugs. In order to facilitate patients to gain information about various non-medical aspects of epilepsy, an organization known as International Bureau for Epilepsy (IBE) was formed in 1961 by Mr. George.Burden who was a non-medical person and who recognized the necessity of such an organization.

As written by Dr. K.K. Sinha

Dr. B S Singhal, Prof & Head - Dept of Neurology

Epilepsy is common. The treatment goal is to achieve total freedom from epileptic epileptic attacks. Failure to comply with treatment regimes is a common cause of seizure recurrence. In this case of antiepileptic drugs ( AEDs) non compliance means not taking the drug or not taking the recommended dosage or not taking the drug for the duration specified. Besides, there may also be noncompliant behaviour such as not altering the life style activities known to trigger seizures ( e.g not getting enough sleep and overindulgence in alcohol )
There can be several reasons for non compliance. Failure to educate the patient regarding the nature of illness, the drugs prescribed with their side effects and the need for regular and prolonged medication is an important cause for noncompliance. Regrettably this aspect is often neglected in our country. Being busy in patient care cannot be an excuse. Also the patients seek multiple consultations and the new doctor may presume that the patient has been briefed by the previous physician. In the past availability of the AED was an issue. Today a particular brand may not be available at all places. It would therefore be desirable to write the generic name and alternative brand names so that the patient gets the drug. The high cost of the drug can be a factor for discontinuation of AED and this should always be taken into consideration. Frequent dosing can be another cause for missing the drug, especially the afternoon dose. Fortunately many drugs are now available with controlled release preparations which enable them to be given in a convenient single or twice a day schedule. Complex drug regimens withmultiple drugs ( at times result in missing the all important AED. Patients also tend to become noncompliant when they feel better due to a good seizure control. On occasions, the patients discontinue the drug to see is they are cured. Fortunately in India the mother ensures that the child is given the drug at the scheduled time, but there can be a lapse on the part of the teenagers and mildly forgetful elderly patient.
Many a patient has apprehension about the long - term toxicity of AED which need to be dispelled. In particular, newly married women may have fear regarding the effect of AED on fertility and pregnancy and they need proper counseling. Regrettably too often, the firls get married ( in case of arranged marriages ) without disclosing the illness. After marriage the girl tries to avoid taking the drug at the scheduled time or in appropriate dose resulting in seizure recurrence. Many patients in India have faith in ayurvedic or homeopathic medication. Practitioners or alternative medicine often gives false assurance to the patients of achieving a ' cure' from epilepsy. There is unfortunately no governmental control for such persons. The results in switching to other drugs with recurrence of the seizures.
To conclude, non compliance is a major factors in seizure recurrence. In such a case, one should always enquire if the individual has missed the drug before escalating the dose or switching to another drug. One may also get some idea regarding non compliance by doing the pill count and going serum drug level. We can hope to achieve better seizure control by improving compliance through education of the patient, use of memory aids such as pill boxes, reinforcing good physician - patient relationship, by providing good family support, and help from the support groups.

Dr Sunil K Pandya, Neurosurgeon
Drugs used in the treatment of epilepsy in India : need for reappraisal
Fashions in drug therapy
There has been a marked increase in the number of drugs available for the treatment of epilepsy and new drugs are being added each year. At first sight this appears to be a reason for celebration. Drug companies introducing the latest drugs certainly lost no time extolling their virtues and marketing them aggressively to doctors likely to use them. Doctors, keen to follow the dictates of fashion, soon switch over from old, time-tested chemicals to the drug that is the ' flavour of the month'. In this in the best interests of patients ?
Drug manufacturers spend small fortunes highlighting the superiority of their latest offerings over those of rivals and denigrating the now unfashionable older drugs. Unfortunately, the majority of doctors accept what is dished our to them by the companies, their critical faculties having been dulled by years spent without visiting a medical library or studying recent issues of indexed medical journals. Sweeteners offered by pharmaceutical companies make acceptance easier. Visit any annual conference and you will see a variety of gifts on offer to doctors. These range from bags to suitcases, to trips, to tourist attractions within the state where the conference is being held. These companies also host liberal cocktail parties and gala dinners. Blatant advertisement of new drugs on conference screens and all around conference halls is not the norm.
The patient pays the price in more ways than one.Newer drugs are invariably much more expensive then those of yesteryear. Manufacturers are now reluctant to produce the 'cheap' drug, as the profit margin on them is much lower then that on the latest product. Over time, costs o f patients escalate as the inexpensive drugs become 'orphans' and are phased out.
The side effects or 'adverse reactions produced by drugs in use over decades are well documented, understood and easily detected. The unwelcome effects produced by the newer drugs are underplayed by the manufacturer and are poorly understood by the doctors. It is years before these become public knowledge in the medical fraternity. As a consequence, they may be missed. This is harmful to the patient. By the time these side-effects become public knowledge, the company has made profits from this drug and has shifted its spotlight on to its latest offering.
Why is a reappraisal of the prescription of drugs against epilepsy necessary ?
Most of our patients are poor. It is unfair to them and their families to foist expensive new drugs on them when an older preparation will suffice to control fits without causing harm. A case in point is the adult whose fits are controlled by phenobarbitone tablets without any side effects. Why should a more modern expensive drug be substituted in his case ? Why should phenobarbitone or phenytoin not be tried as the first drug when its use is appropriate on medical grounds ?
Where possible, the inexpensive drug must be preferred provided it is equally effective and causes no harmful effects.
The newer drugs against epilepsy - like new antibiotics - must be reserved for use in those patients where the older drugs are ineffective or have caused complications. The use of sodium valproate in a patient in whom phenytoin has produced the Steven-Johnson syndrome is unchallengeable.
New epilepsy prevention study findings have been reported by scientists at University of Bonn
August 10, 2007
Pain & Central Nervous System Week via NewsEdge Corporation :
2007 AUG 13 - ( -- Investigators publish new data in the report "Diminished response of CA1 neurons to antiepileptic drugs in chronic epilepsy." According to a study from Bonn, Germany, "A substantial proportion of epilepsy patients (approximately 30%) continue to have seizures despite carefully optimized treatment with antiepileptic drugs (AEDs). One key concept to explain the development of pharmacoresistance is that epilepsy-related changes in the properties of CNS drug targets result in AED-insensitivity of these targets."
"These changes then contribute to drug-resistance on a clinical level. We have tested this hypothesis in hippocampal CA1 neurons in experimental epilepsy. Using patch-clamp techniques, we thoroughly examined the effects of carbamazepine (CBZ) and phenytoin (PHT) on voltage-gated Na( ) currents (I(Na)) in hippocampal CA1 neurons of sham-control and chronically epileptic rats. We find that there were significant changes in the effects of PHT, but not CBZ on the voltage-dependence of inactivation, resulting in a significant reduction in voltage-dependent blocking effects in chronically epileptic animals. Conversely, CBZ effects on the time course of recovery from inactivation of I(Na) were significantly less pronounced in epileptic compared to sham-control animals, whereas PHT effects remained unaltered. Our findings indicate that AED-sensitivity of Na( ) currents is reduced in chronic epilepsy. The reduction in sensitivity is due to different biophysical mechanisms for CBZ and PHT. Furthermore, comparison to published work suggests that the loss of AED-sensitivity is less pronounced in CA1 neurons than in dentate granule neurons. Thus, these results suggest that target mechanisms of drug resistance are cell type and AED specific," wrote C. Schaub and colleagues, University of Bonn.
The researchers concluded: "Unraveling these complex mechanisms is likely to be important for a better understanding of the cellular basis of drug-resistant epilepsy."
Schaub and colleagues published the results of their research in Epilepsia (Diminished response of CA1 neurons to antiepileptic drugs in chronic epilepsy. Epilepsia, 2007;48(7):1339-50).
For additional information, contact C. Schaub, University of Bonn Medical Center, Dept. of Epileptology, Bonn, Germany.
The publisher of the journal Epilepsia can be contacted at: Blackwell Publishing Inc., 350 Main St., Malden, MA 02148, USA.

Sunday, January 14, 2007

Traumatic brain injury

Traumatic brain injury (TBI), traumatic injuries to the brain, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. TBI can result from a closed head injury or a penetrating head injury and is one of two subsets of acquired brain injury (ABI). The other subset is non-traumatic brain injury (i.e. stroke, meningitis, anoxia). Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem (see brain damage). Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain. Outcome can be anything from complete recovery to permanent disability or death. A coma can also affect a child's brain.


TBI is a major public health problem, especially among males ages 15 to 24, and among elderly people of both sexes 75 years and older. Children aged 5 and younger are also at high risk for TBI.
Each year in the United States:
approximately 1 million head-injured people are treated in hospital emergency rooms,
approximately 270,000 people experience a moderate or severe TBI,
approximately 60,000 new cases of epilepsy occur as a result of head trauma,
approximately 230,000 people are hospitalized for TBI and survive,
approximately 80,000 of these survivors live with significant disabilities as a result of the injury, and
approximately 70,000 people die from head injury.

Signs and Symptoms of TBI

Some symptoms are evident immediately, while others do not surface until several days or weeks after the injury.
With mild TBI, the patient may remain conscious or may lose consciousness for a few seconds or minutes. The person may also feel dazed or not like him- or herself for several days or weeks after the initial injury. Other symptoms include:

  • headache,

  • mental confusion,

  • lightheadedness,

  • dizziness,

  • double vision, blurred vision, or tired eyes,

  • ringing in the ears,

  • bad taste in the mouth,

  • fatigue or lethargy,

  • a change in sleep patterns,

  • behavioral or mood changes, and

  • trouble with memory, concentration, attention, or thinking
symptoms remain the same or get better; worsening symptoms indicate a more severe injury.
With moderate or severe TBI, the patient may show these same symptoms, but may also have:

  • loss of consciousness

  • personality change

  • a severe, persistent, or worsening headache,

  • repeated vomiting or nausea,

  • seizures,

  • inability to awaken,

  • dilation (widening) of one or both pupils,

  • slurred speech,

  • weakness or numbness in the extremities,

  • loss of coordination, and/or
    increased confusion, restlessness, or agitation
    vomiting and neurological deficit (e.g. weakness in a limb) together are important indicators of prognosis and their presence may warrant early CT scanning and neurosurgical intervention.

Small children with moderate to severe TBI may show some of these signs as well as signs specific to young children, including:

  • persistent crying,

  • inability to be consoled, and/or

  • refusal to nurse or eat.
Anyone with signs of moderate or severe TBI should receive immediate emergency medical attention.

Causes of and risk factors for TBI

Half of all TBIs are due to transportation accidents involving automobiles, motorcycles, bicycles, and pedestrians. These accidents are the major cause of TBI in people under age 75.
For those 75 and older, falls cause the majority of TBIs.
Approximately 20 % of TBIs are due to violence, such as firearm assaults and child abuse, and about 3 % are due to sports injuries. Fully half of TBI incidents involve alcohol use.

Types of TBI

The damage from TBI can be focal, confined to one area of the brain, or diffuse, involving more than one area of the brain. Diffuse trauma to the brain is frequently associated with concussion (a shaking of the brain in response to sudden motion of the head), diffuse axonal injury, or coma. Localized injuries may be associated with neurobehavioral manifestations, hemiparesis or other focal neurologic deficits.
Types of focal brain injury include bruising of brain tissue called a contusion and intracranial hemorrhage or hematoma, heavy bleeding in the skull. Hemorrhage, due to rupture of a blood vessel in the head, can be extra-axial, meaning it occurs within the skull but outside of the brain, or intra-axial, occurring within the brain. Extra-axial hemorrhages can be further divided into subdural hematoma, epidural hematoma, and subarachnoid hemorrhage. An epidural hematoma involves bleeding into the area between the skull and the dura. With a subdural hematoma, bleeding is confined to the area between the dura and the arachnoid membrane. A subarachnoid hemorrhage involves bleeding into the space between the surface of the brain and the arachnoid membrane that lies just above the surface of the brain, usually resulting from a tear in a blood vessel on the surface of the brain. Bleeding within the brain itself is called an intracerebral hematoma. Intra-axial bleeds are further divided into intraparenchymal hemorrhage which occurs within the brain tissue itself and intraventricular hemorrhage which occurs into the ventricular system.
TBI can result from a closed head injury or a penetrating head injury. A closed injury occurs when the head suddenly and violently hits an object but the object does not break through the skull. A penetrating injury occurs when an object pierces the skull and enters brain tissue.
As the first line of defense, the skull is particularly vulnerable to injury. Skull fractures occur when the bone of the skull cracks or breaks. A depressed skull fracture occurs when pieces of the broken skull press into the tissue of the brain. A penetrating skull fracture occurs when something pierces the skull, such as a bullet, leaving a distinct and localized traumatic injury to brain tissue. Skull fractures can cause cerebral contusion.
Another insult to the brain that can cause injury is anoxia. Anoxia is a condition in which there is an absence of oxygen supply to an organ's tissues, even if there is adequate blood flow to the tissue. Hypoxia refers to a decrease in oxygen supply rather than a complete absence of oxygen, and ischemia is inadequate blood supply, as is seen in cases in which the brain swells. In any of these cases, without adequate oxygen, a biochemical cascade called the ischemic cascade is unleashed, and the cells of the brain can die within several minutes. This type of injury is often seen in near-drowning victims, in heart attack patients (particularly those who have suffered a cardiac arrest, or in people who suffer significant blood loss from other injuries that then causes a decrease in blood flow to the brain due to circulatory (hypovolemic) shock.

Effects on consciousness

Generally, there are six abnormal states of consciousness that can result from a TBI: stupor, coma, persistent vegetative state, minimally conscious state, locked-in syndrome, and brain death.
Stupor is a state in which the patient is unresponsive but can be aroused briefly by a strong stimulus, such as sharp pain. Coma is a state in which the patient is totally unconscious, unresponsive, unaware, and unarousable.
Patients in a persistent vegetative state are unconscious and unaware of their surroundings, but they continue to have a sleep-wake cycle and can have periods of alertness. A vegetative state can result from diffuse injury to the cerebral hemispheres of the brain without damage to the lower brain and brainstem. Anoxia, or lack of oxygen to the brain, which is a common complication of cardiac arrest, can also bring about a vegetative state.
Patients in a minimally conscious state have a reduced level of arousal and may appear, on the surface, to be in a persistent vegetative state but are capable of demonstrating the ability to actively process information. In the minimally conscious state a patient exhibits deliberate, or cognitively mediated, behavior often enough, or consistently enough, for clinicians to be able to distinguish it from the entirely unconscious, reflexive responses that are seen in the persistent vegetative state. Differentiating a patient in a persistent vegetative state from one in a minimally conscious state can be challenging but remains a critically important clinical task.
Locked-in syndrome is a condition in which a patient is aware and awake, but cannot move or communicate due to complete paralysis of the body.
Brain death is the lack of measurable brain function due to diffuse damage to the cerebral hemispheres and the brainstem, with loss of any integrated activity among distinct areas of the brain. Brain death is irreversible. Removal of assistive devices will result in immediate cardiac arrest and cessation of breathing.

Disabilities Resulting From TBI

Disabilities resulting from a TBI depend upon the severity of the injury, the location of the injury, and the age and general health of the patient. Some common disabilities include problems with cognition (thinking, memory, and reasoning), sensory processing (sight, hearing, touch, taste, and smell), communication (expression and understanding), and behavior or mental health (depression, anxiety, personality changes, aggression, acting out, and social inappropriateness).
Within days to weeks of the head injury approximately 40 % of TBI patients develop a host of troubling symptoms collectively called postconcussion syndrome (PCS). A patient need not have suffered a concussion or loss of consciousness to develop the syndrome and many patients with mild TBI suffer from PCS. Symptoms include headache, dizziness, memory problems, trouble concentrating, sleeping problems, restlessness, irritability, apathy, depression, and anxiety. These symptoms may last for a few weeks after the head injury. The syndrome is more prevalent in patients who had psychiatric symptoms, such as depression or anxiety, before the injury. Treatment for PCS may include medicines for pain and psychiatric conditions, and psychotherapy and occupational therapy.
Most patients with severe TBI, if they recover consciousness, suffer from cognitive disabilities, including the loss of many higher level mental skills. The most common cognitive impairment among severely head-injured patients is memory loss, characterized by some loss of specific memories and the partial inability to form or store new ones. Some of these patients may experience post-traumatic amnesia (PTA), either anterograde or retrograde. Anterograde PTA is impaired memory of events that happened after the TBI, while retrograde PTA is impaired memory of events that happened before the TBI.
Many patients with mild to moderate head injuries who experience cognitive deficits become easily confused or distracted and have problems with concentration and attention. They also have problems with higher level, so-called executive functions, such as planning, organizing, abstract reasoning, problem solving, and making judgments, which may make it difficult to resume pre-injury work-related activities. Recovery from cognitive deficits is greatest within the first 6 months after the injury and more gradual after that.
Patients with moderate to severe TBI have more problems with cognitive deficits than patients with mild TBI, but a history of several mild TBIs may have an additive effect, causing cognitive deficits equal to a moderate or severe injury.
Many TBI patients have sensory problems, especially problems with vision. Patients may not be able to register what they are seeing or may be slow to recognize objects. Also, TBI patients often have difficulty with hand-eye coordination. Because of this, TBI patients may seem clumsy or unsteady. Other sensory deficits may include problems with hearing, smell, taste, or touch. Some TBI patients develop tinnitus, a ringing or roaring in the ears. A person with damage to the part of the brain that processes taste or smell may develop a persistent bitter taste in the mouth or perceive a persistent noxious smell. Damage to the part of the brain that controls the sense of touch may cause a TBI patient to develop persistent skin tingling, itching, or pain. These conditions are rare and hard to treat.
Language and communication problems are common disabilities in TBI patients. Some may experience aphasia, defined as difficulty with understanding and producing spoken and written language; others may have difficulty with the more subtle aspects of communication, such as body language and emotional, non-verbal signals.
In non-fluent aphasia, also called Broca's aphasia or motor aphasia, TBI patients often have trouble recalling words and speaking in complete sentences. They may speak in broken phrases and pause frequently. Most patients are aware of these deficits and may become extremely frustrated.
Patients with fluent aphasia, also called Wernicke's aphasia or sensory aphasia, display little meaning in their speech, even though they speak in complete sentences and use correct grammar. Instead, they speak in flowing gibberish, drawing out their sentences with non-essential and invented words. Many patients with fluent aphasia are unaware that they make little sense and become angry with others for not understanding them. Patients with global aphasia have extensive damage to the portions of the brain responsible for language and often suffer severe communication disabilities.
TBI patients may have problems with spoken language if the part of the brain that controls speech muscles is damaged. In this disorder, called dysarthria, the patient can think of the appropriate language, but cannot easily speak the words because they are unable to use the muscles needed to form the words and produce the sounds. Speech is often slow, slurred, and garbled. Some may have problems with intonation or inflection, called prosodic dysfunction.
TBI patients have been described as the "walking wounded"owing to psychological problems. Most TBI patients have emotional or behavioral problems that fit under the broad category of psychiatric health. Family members of TBI patients often find that personality changes and behavioral problems are the most difficult disabilities to handle. Psychiatric problems that may surface include depression, apathy, anxiety, irritability, anger, paranoia, confusion, frustration, agitation, insomnia or other sleep problems, and mood swings. Problem behaviors may include aggression and violence, impulsivity, disinhibition, acting out, noncompliance, social inappropriateness, emotional outbursts, childish behavior, impaired self-control, impaired self-awareness, inability to take responsibility or accept criticism, egocentrism, inappropriate sexual activity, and alcohol or drug abuse/addiction. Some patients' personality problems may be so severe that they are diagnosed with organic personality disorder, a psychiatric condition characterized by many of the problems mentioned above. Sometimes TBI patients suffer from developmental stagnation, meaning that they fail to mature emotionally, socially, or psychologically after the trauma. This is a serious problem for children and young adults who suffer from a TBI. Attitudes and behaviors that are appropriate for a child or teenager become inappropriate in adulthood. Many TBI patients who show psychiatric or behavioral problems can be helped with medication and psychotherapy, although the effectiveness of psychotherapy may be limited by the residual neurocognitive impairment. Technological improvements and excellent emergency care have diminished the incidence of devastating TBI while increasing the numbers of patients with mild or moderate TBI. Such patients are more adversely affected by their emotional problems than by their residual physical disabilities.

Other Long-Term Problems Associated With TBI

Other long-term problems that can develop after a TBI include Parkinson's disease and other motor problems, Alzheimer's disease, dementia pugilistica, and post-traumatic dementia.
Alzheimer's disease (AD) - AD is a progressive, neurodegenerative disease characterized by dementia, memory loss, and deteriorating cognitive abilities. Recent research suggests an association between head injury in early adulthood and the development of AD later in life; the more severe the head injury, the greater the risk of developing AD. Some evidence indicates that a head injury may interact with other factors to trigger the disease and may hasten the onset of the disease in individuals already at risk. For example, people who have a particular form of the protein apolipoprotein E (apoE4) and suffer a head injury fall into this increased risk category. (ApoE4 is a naturally occurring protein that helps transport cholesterol through the bloodstream.)
Parkinson's disease and other motor problems - Movement disorders as a result of TBI are rare but can occur. Parkinson's disease may develop years after TBI as a result of damage to the basal ganglia. Symptoms of Parkinson's disease include tremor or trembling, rigidity or stiffness, slow movement (bradykinesia), inability to move (akinesia), shuffling walk, and stooped posture. Despite many scientific advances in recent years, Parkinson's disease remains a chronic and progressive disorder, meaning that it is incurable and will progress in severity until the end of life. Other movement disorders that may develop after TBI include tremor, ataxia (uncoordinated muscle movements), and myoclonus (shock-like contractions of muscles).
Dementia pugilistica - Also called chronic traumatic encephalopathy, dementia pugilistica primarily affects career boxers. The most common symptoms of the condition are dementia and parkinsonism caused by repetitive blows to the head over a long period of time. Symptoms begin anywhere between 6 and 40 years after the start of a boxing career, with an average onset of about 16 years.
Post-traumatic dementia - The symptoms of post-traumatic dementia are very similar to those of dementia pugilistica, except that post-traumatic dementia is also characterized by long-term memory problems and is caused by a single, severe TBI that results in a coma.

A Window of hope after Research/Studies

  • A 23 year old woman in a vegetative state was able to communicate with a team of British researchers at Cambridge University in England led by Neurologist Adrian Owen via functional magnetic resonance imaging (FMRI)(scan)[1]. Some researchers were cautious but note that the research was groundbreaking. "It's the first time we've ever seen something like this. It really is kind of shocking," said Nicholas Schiff, a neurologist at the Weill Cornell Medical College in New York.

  • Brain injury patient While Wallis showed few outward signs of consciousness, his brain was methodically rebuilding the white-matter infrastructure necessary for him to interact with the outside world, researchers reported Monday in the Journal of Clinical Investigation.Using PET scans and an advanced imaging technique called diffusion tensor imaging, the researchers examined Wallis' brain after he regained full consciousness and found that cells in the relatively undamaged areas had formed new axons, the long nerve fibers that transmit messages between neurons.

Label for the figure on the top left side: Coronal MRI, brain (level: insert line D): AH-ant horn, BC-body caudate n, CC-corpus cal, CT-corticospinal tr, F-fornix, IH-inf horn, INC-int capsule, IR-intercerb v, L1-putamen, L2-ext seg gl pall, L3-int seg gl pall, MCA-mid cereb a, P-pons, SCA-sup cer a, SN-subst n, T-thalamus, TT-tent cereb.

How Brain Injury Leads To Seizures & Memory Problems

In a finding that may provide a scientific basis for eventual treatment, neurology researchers have shown that traumatic brain injury reduces the level of a protein that helps keep brain activity in balance. The resulting abnormal activity, in turn, is thought to be an underlying reason for seizures and memory defects experienced by people who have suffered a traumatic brain injury (TBI).

"A traumatic brain injury occurs to someone in the United States every 23 seconds," said study team leader Akiva S. Cohen, Ph.D., of The Children's Hospital of Philadelphia, adding that, "TBI is the leading cause of death among children and young adults in this country. There are no cures known for traumatic brain injury. Our hope is that our research may contribute to potential therapies for TBI patients."
Transportation accidents such as car crashes are responsible for the majority of TBIs in people under age 75. According to the National Institutes of Health, over 5 million Americans currently have permanent disabilities resulting from TBIs.
The study, which was done in animals, appears in the journal Neurobiology of Disease, published online on Oct. 10.
Using mice, the researchers showed for the first time that TBI reduces the levels of a protein called potassium-chloride co-transporter 2 (KCC2) within a portion of the brain called the dentate gyrus. The dentate gyrus controls overactivity from reaching seizure-prone brain cells further along the circuit.
The dentate gyrus is a gatekeeper in maintaining a balance between two systems of neurotransmitters in the brain: the glutamate system and the gamma-aminobutyric acid system, abbreviated GABA(A). Glutamate stimulates neurons to fire, while GABA(A) inhibits that activity. "When lower levels of the KCC2 transporter weaken the dentate gyrus's ability to act as a gatekeeper," said Dr. Cohen, "neurons become more excitable, and seizures can occur."
In addition to its role in inhibiting seizures, the dentate gyrus is also believed to be important in memory formation. Therefore, said Dr. Cohen, "Interfering with normal function in the dentate gyrus may impair memory formation--especially antegrade memory, the ability to learn new things." Epileptic seizures and impaired memory are two of the disabilities caused by TBI.
Further animal studies, said Dr. Cohen, will investigate whether supplying KCC2 directly to the dentate gyrus will restore normal functioning in that structure, and whether it may improve symptoms in brain-injured mice. If this proves to be the case, the protein may someday be used as a medical treatment for patients with TBI.
The National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, supported this study. Dr. Cohen's co-authors were David P. Bonislawski and Elizabeth P. Schwarzbach. All three are from the University of Pennsylvania School of Medicine.

Note: This story has been adapted from a news release issued by Children's Hospital of Philadelphia.

Saturday, January 13, 2007

Famous People with Epilepsy

Famous people with epileptic seizures Epilepsy has nothing to do with mental disease or retardation. This has been proved beyond all doubt by the "epileptic geniuses", people who achieved great things in spite of suffering from epilepsy.The following selection shows people who had epileptic seizures at a certain stage in their life or who suffered from a chronic form of epilepsy for many years. Some historical researchers believe there is evidence to suggest that the following famous figures may have also suffered from seizure disorders:

Some historical researchers believe there is evidence to suggest that the following famous figures may have also suffered from seizure disorders:-

  • Alexander the Great, king of Macedonia
  • Aristotle, Greek philosopher/scientist
  • Napoleon Bonaparte, French general/emperor
  • Buddha, founder of Buddhism
  • Julius Caesar, Roman emperor
  • Hannibal, Carthaginian general
  • Michelangelo, Italian painter/sculptor
  • Mohammed, prophet of Islam
  • Sir Isaac Newton, British mathematician
  • Pythagoras, Greek mathematician
  • Saint Paul the Apostle, a father of the early Catholic Church
  • Socrates, Greek philosopher
  • Leonardo da Vinci, Italian painter, draftsman, sculptor, architect and engineer

Many famous people have suffered from the disorder and excelled in spite of it. They include:-

  • Bud Abbott, American comedian of Abbott and Costello fame
  • Richard Burton, Welsh actor
  • Truman Capote, American author
  • Lewis Carroll, English author and mathematician
  • Dante Alighieri, Italian author
  • Charles Dickens, English author
  • Fyodor Dostoyevsky, Russian author
  • Danny Glover, American actor
  • Vincent van Gogh, Dutch painter
  • Margaux Hemingway, American actress, granddaughter of author Ernest Hemingway
  • Elton John, English pop singer
  • James Madison, fourth U.S. president
  • Guy de Maupassant, French author
  • Alfred Nobel, Swedish chemist, engineer and founder of the Nobel Prize awards
  • Niccolo Paganini, Italian violinist
  • Peter the Great, Russian czar
  • Edgar Allen Poe, American author
  • Neil Young, Canadian rock musician
  • Jonathan Swift, English author
  • Peter Ilich Tchaikovsky, Russian composer
  • Alfred Lord Tennyson, English poet
  • Lord Byron, English poet
  • Vladimir Ilyich Lenin, Russian Revolutionist
  • Socrates, Greek Philosopher
  • Hansjakob

Research done on the information available about the 'famous people with epilepsy' who are usually listed in literature on the subject has shown that some of them definitely did suffer from epilepsy (e.g. Caesar, Grand Duke Karl, Pope Pius IX., Flaubert, Dostoyevsky). Other people (e.g. King Saul, Napoleon, van Gogh, St. Paul) are suspected of having had epilepsy, but research cannot prove this definitively.It is clear that some famous people (e.g. Lord Byron, Nobel) did not have a chronic form of epilepsy but temporarily suffered epileptic seizures at certain periods in their lives.

The interest shown in famous people who had epilepsy once again makes it clear that people with the chronic disease epilepsy or who suffer occasional epileptic seizures can still be highly intelligent and achieve great things.

Tuesday, October 31, 2006

Commonplace sugar compound silences seizures

Though in clinical use for decades, a small, sweet-tasting compound is revealing a startling new face as a potential cure for epilepsy.
2-deoxy-glucose, or 2DG, has long been used in radio labeling, medical scanning and cancer imaging studies in humans. But now, researchers at the University of Wisconsin-Madison have found the substance also blocks the onset of epileptic seizures in laboratory rats.

Reported in the journal Nature Neuroscience, the findings have potentially huge implications for up to half of all epileptic patients who currently have no access to treatment, says senior author Avtar Roopra, a UW-Madison assistant professor of neurology."We pumped the rats full [of 2DG] and still saw no side effects," says Roopra, who estimates that the compound may be available for human use within five years. "I see 2DG as an epilepsy management treatment much like insulin is used to treat diabetes." "All the available epilepsy treatments have focused on suppressing seizures," says co-author and renowned epilepsy expert Tom Sutula, a UW-Madison professor of neurology. "There has been hope that [new drugs] will not only suppress seizures, but modify their consequences. [2DG] appears to be a novel treatment that offers great promise to achieve that vision." About 1 percent of the world's population suffers from epilepsy, a neurological condition that makes people susceptible to seizures. Scientists believe that seizures, of which there are many kinds, occur due to sudden changes in how brain cells send electrical signals to each other. In about 30 to 50 percent of epilepsy patients, available treatments - including the removal of parts of the brain's temporal lobe - are largely ineffective.2DG is essentially a more palatable version of the "ketogenic," or sugar-free, diets that some researchers have long recommended to epilepsy patients. Indeed, the notion of a sugar-free diet actually stretches back thousands of years to Biblical times, when healers sometimes prescribed starvation as a potent way to fend off seizures. UW-Madison researchers first began to investigate the role of sugar in controlling seizures after early experiments showed that children on sugar-free diets can rapidly experience seizures when they consume even a small dose of carbohydrates, such as a cookie or a little piece of bread.But ketogenic regimens can be a miserable experience. "The kids can't eat any sugar at all. Imagine no bread or Christmas cake," says Roopra. But 2DG would work as an effective substitute because it enters cells and clogs up certain cellular enzymes. As a result, the body can't use its own glucose.Though ketogenic diets seem to work in many epilepsy patients in whom existing treatments have been unsuccessful, scientists have struggled to understand the exact cellular connection between no sugar and no seizures. The UW-Madison work for the first time clears up some of that mystery. Roopra has long explored how certain proteins known as "transcription factors" turn neuronal genes on or off. He has been particularly intrigued by one transcription factor known as NRSF, which is thought to control up to 1,800 genes in the brain, including many that are implicated in epilepsy. Like an electrical motherboard, NRSF ensures that neuronal genes switch "on" in the body's neurons, while remaining switched "off" in other regions where they normally play no role. Roopra found that NRSF binds to another protein called CTBP. The finding "immediately raised alarm bells," Roopra says, because CTBP also binds to a free-floating molecule - NADH - that emerges when sugars break down in cells. To his surprise, Roopra found that CTBP binds to either NRSF or NADH. In other words, a cell with a lot of glucose generates a lot of NADH, so CTBP is more likely to bind with the sugar byproduct than NRSF. But without CTBP, NRSF most likely derails the normal function of certain neuronal genes - including those connected to epilepsy.Scientists believe that NSRF also controls genes that potentially play a role in cancer. Roopra is planning future studies to test whether 2DG holds promise for combating breast cancer, or fast-spreading glioblastomas. The UW-Madison team has patented 2DG for its use against epilepsy in collaboration with the Wisconsin Alumni Research Foundation, UW-Madison's technology transfer arm.

Friday, October 13, 2006


First of all, We have to know what is Memory?

When an event happens, when you learn something, or when you meet someone, your brain determines whether that information needs to be saved. If your brain judges the information important, it places it in your memory as like "files." You probably know your brain has different analitical parts. Some of them are important for memory. The hippocampus (say: hih-puh-kam-pus) is one of the more important parts of the brain that processes memories. Old information and new information, or memories, are thought to be processed and stored away in different areas of the cerebral cortex, or the "gray matter" of the brain - the largest, outermost part of the brain.
Let us know more about hippocampus.
The hippocampus is a part of the brain located inside the temporal lobe (humans and other mammals have two hippocampi, one in each side of the brain). It forms a part of the limbic system and plays a part in memory and spatial navigation. The name derives from its curved shape in coronal sections of the brain, which resembles a seahorse (Greek: hippo=horse, kampos=sea monster). In Alzheimer's disease, the hippocampus becomes one of the first regions of the brain to suffer damage; memory problems and disorientation appear amongst the first symptoms. Damage to the hippocampus can also result from oxygen starvation (anoxia) and encephalitis. In the anatomy of animals, the hippocampus is among the phylogenetically oldest parts of the brain. The hippocampal emergence from the archipallium is most pronounced in primates and Cetacean sea mammals. Nonetheless, in primates the hippocampus occupies less of the cerebrum in proportion to cerebral cortex among the youngest species, especially humans. The significant development of hippocampal volume in primates correlates more with overall increase of brain mass than with neocortical development.


Although there is a lack of consensus relating to terms describing the hippocampus and the adjacent cortex, the term hippocampal formation generally applies to the dentate gyrus, the Cornu Ammonis fields CA1-CA3 (and CA4, frequently called the hilus and considered part of the dentate gyrus), and the subiculum. The CA1, CA2 and CA3 fields make up the hippocampus proper.
Information flow through the hippocampus proceeds from dentate gyrus to CA3 to CA1 to the subiculum, with additional input information at each stage and outputs at each of the two final stages. CA2 represents only a very small portion of the hippocampus and its presence is often ignored in accounts of hippocampal function, though it is notable that this small region seems unusually resistant to conditions that usually cause large amounts of cellular damage, such as epilepsy.
The perforant path, which brings information primarily from entorhinal cortex (but also perirhinal cortex, among others), is generally considered the main source of input to the hippocampus. Layer II of entorhinal cortex (EC) brings input to the dentate gyrus and field CA3, while EC layer III brings input to field CA1 and the subiculum. The main output pathways of the hippocampus are the cingulum bundle and the fimbria/fornix, which arise from field CA1 and the subiculum.

Diagram of hippocampus
Perforant path input from EC layer II enters the dentate gyrus and is relayed to region CA3 (and to mossy cells, located in the hilus of the dentate gyrus, which then send information to distant portions of the dentate gyrus where the cycle is repeated). Region CA3 combines this input with signals from EC layer II and sends extensive connections within the region and also sends connections to region CA1 through a set of fibers called the Schaffer collaterals. Region CA1 receives input from the CA3 subfield, EC layer III and the nucleus reuniens of the thalamus (which project only to the terminal apical dendritic tufts in the stratum lacunosum-moleculare). In turn, CA1 projects to the subiculum as well as sending information along the aforementioned output paths of the hippocampus. The subiculum is the final stage in the pathway, combining information from the CA1 projection and EC layer III to also send information along the output pathways of the hippocampus.
The hippocampus also receives a number of subcortical inputs. In Macaca fascicularis, these inputs include the amygdala (specifically the anterior amygdaloid area, the basolateral nucleus, and the periamygdaloid cortex), the medial septum and the diagonal band of Broca, the claustrum, the substantia innominata and the basal nucleus of Meynert, the thalamus (including the anterior nuclear complex, the laterodorsal nucleus, the paraventricular and parataenial nuclei, the nucleus reuniens, and the nucleus centralis medialis), the lateral preoptic and lateral hypothalamic areas, the supramammillary and retromammillary regions, the ventral tegmental area, the tegmental reticular fields, the raphe nuclei (the nucleus centralis superior and the dorsal raphe nucleus), the nucleus reticularis tegementi pontis, the central gray, the dorsal tegmental nucleus, and the locus coeruleus.
It is widely accepted that each of these regions has a unique functional role in the information processing of the hippocampus, but to date the specific contribution of each region is poorly understood.

Role of Hippocampus in General Memory

Drawing of the neural circuitry of the rodent hippocampus. S. Ramón y Cajal, 1911.Psychologists and neuroscientists dispute the precise role of the hippocampus, but, in general, agree that it has an essential role in the formation of new memories about experienced events (episodic or autobiographical memory). Some researchers prefer to consider the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory (memories that can be explicitly verbalized — these would include, for example, memory for facts in addition to episodic memory). Some evidence supports the idea that, although these forms of memory often last a lifetime, the hippocampus ceases to play a crucial role in the retention of the memory after a period of consolidation. Damage to the hippocampus usually results in profound difficulties in forming new memories (anterograde amnesia), and normally also affects access to memories prior to the damage (retrograde amnesia). Although the retrograde effect normally extends some years prior to the brain damage, in some cases older memories remain - this sparing of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain. However, experimentation has difficulties in testing the sparing of older memories; and, in some cases of retrograde amnesia, the sparing appears to affect memories formed decades before the damage to the hippocampus occurred, so its role in maintaining these older memories remains controversial. Damage to the hippocampus does not affect some aspects of memory, such as the ability to learn new skills (playing a musical instrument, for example), suggesting that such abilities depend on a different type of memory (procedural memory) and different brain regions. And there is evidence (e.g., O'Kane et al 2004) to suggest that patient HM (who had his medial temporal lobes removed bilaterally as a treatment for epilepsy) can form new semantic memories.

Role of Hippocampus in spatial memory and navigation

Some evidence implicates the hippocampus in storing and processing spatial information. Studies in rats have shown that neurons in the hippocampus have spatial firing fields. These cells are called place cells. Some cells fire when the animal finds itself in a particular location, regardless of direction of travel, while most are at least partially sensitive to head direction and direction of travel. In rats, some cells, termed context-dependent cells, may alter their firing depending on the animal's recent past (retrospective) or expected future (prospective). Different cells fire at different locations, so that, by looking at the firing of the cells alone, it becomes possible to tell where the animal is. Place cells have now been seen in humans involved in finding their way around in a virtual reality town. The findings resulted from research with individuals that had electrodes implanted in their brains as a diagnostic part of surgical treatment for serious epilepsy. The discovery of place cells led to the idea that the hippocampus might act as a cognitive map — a neural representation of the layout of the environment. Recent evidence has cast doubt on this perspective, indicating that the hippocampus might be crucial for more fundamental processes within navigation. Regardless, studies with animals have shown that an intact hippocampus is required for simple spatial memory tasks (for instance, finding the way back to a hidden goal). Without a fully-functional hippocampus, humans may not successfully remember where they have been and how to get where they are going. Researchers believe that the hippocampus plays a particularly important role in finding shortcuts and new routes between familiar places. Some people exhibit more skill at this sort of navigation than do others, and brain imaging shows that these individuals have more active hippocampi when navigating. London's taxi drivers must learn a large number of places — and know the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs). A study at University College London (Maguire et al, 2000) showed that part of the hippocampus is larger in taxi drivers than in the general public, and that more-experienced drivers have bigger hippocampi. Whether having a bigger hippocampus helps an individual to become a cab driver or finding shortcuts for a living makes an individual's hippocampus grow is yet to be elucidated. A study on rats at Indiana University suggested that the sexual dimorphism in the hippocampus morphology is tied to a sexual dimorphism in repeated maze performance. Males seem to be better at contexualizing their whereabouts because they have more hippocampus to work with.

Now let us know more about cerebral cortex

The cerebral cortex is a brain structure in vertebrates. In non-living, preserved brains, the outermost layers of the cerebrum has a grey color, hence the name "grey matter". Grey matter is formed by neurons and their unmyelinated fibers while the white matter below the grey matter of the cortex is formed predominantly by myelinated axons interconnecting different regions of the central nervous system. The human cerebral cortex is 2-4 mm (0.08-0.16 inches) thick and plays a central role in many complex brain functions including memory, attention, perceptual awareness, "thinking", language and consciousness. The surface of the cerebral cortex is folded in large mammals like humans, where more than two thirds of the cortical surface is buried in the grooves, called "sulci". The phylogenetically more ancient part of the cerebral cortex, the hippocampus, is differentiated in five layers, while the more recent neo-cortex is differentiated in six basic layers. Relative variations in thickness or cell type (among other parametres) allows us to distinguish among different neocortical architectonic fields. The geometry of these fields seems to be related to the anatomy of the cortical folds and, for example, layers in the upper part of the cortical grooves (called gyri) are more clearly differentiated than in its deeper parts (called sulcal "fundi").
Now what can go wrong with Memory?
As wonderful as memory is, it isn't always perfect. It's normal to occasionally forget the name of somebody you just met or where you put your shoes[U said Chromosome, may be]. And of course, everyone has forgotten an answer on a test. Darn! You knew that one, too! It's also typical for people to forget more things as they grow older. Your parents or grandparents might joke about having a "senior moment." That's when they forget something. But some memory problems are serious, such as when a person has Alzheimer's disease. Strokes, which also affect older people, are another medical problem that can affect someone's memory. A stroke is when the blood supply to the brain is temporarily stopped or when a blood vessel bursts. Another problem could occuer, that is TBI or Traumatic Brain Injury which can impair your memory for forever.

Wednesday, October 11, 2006

Andrew Fire & Mello shares Nobel Prize for discovering how double-stranded RNA can switch off genes

Andrew Fire took his first look around at Stanford and started screaming. His response wasn't unusual—for a newborn, that is. The molecular biologist was born at Stanford Hospital, attended public schools in Sunnyvale and graduated from the University of California-Berkeley, after being turned down by his only other college choice: Stanford.
All pretty normal, he hastens to point out—not mentioning that he completed high school at age 15 and college at age 19. But as of 2:30 a.m. Monday, the quiet Stanford medical school professor with the self-deprecating air will have to work a little harder to convince the world that he's nothing special. He won this year's Nobel Prize in Physiology or Medicine, and it will be a long time before he sees "normal" again.
Linda Cicero
Andrew Fire
Fire shares the prize with Craig Mello of the University of Massachusetts Medical School. The announcement from the Nobel Assembly at Karolinska Institutet came a mere eight years after they published their breakthrough discovery of RNA interference. The relatively rapid recognition is unusual in the rarified Nobel world, which often rewards researchers decades after their initial findings.
"I was very surprised," said Fire, professor of pathology and of genetics, of the early morning phone call from the committee. "At first I thought that maybe they had a wrong number, or that I was dreaming. But I guess it's real." Such prompt accolades are one indication of how their finding has turned the field of molecular biology on its head—and how it hasn't yet stopped spinning.

"This is an extraordinary achievement for Andy Fire and Craig Mello, for science and for Stanford," said Philip Pizzo, MD, dean of the School of Medicine. "It affirms the importance of basic fundamental research, which often yields new insights into human biology. Their discovery is already unfolding in new directions that may translate into discoveries of new diagnostic and therapeutic approaches for a variety of human disorders."
Fire, PhD, 47, and Mello, PhD, 45, are part of a team of researchers credited with recognizing that certain RNA molecules can be used to turn off specific genes in animal cells. The discovery, made while Fire was at the Carnegie Institution's Department of Embryology in Baltimore, marked the first time that biologists were able to selectively "silence" the voice of one gene in the cacophony of the tens of thousands that give a cell its marching orders from development to death. Their description of the process, called RNA interference or RNAi, in Nature in 1998, jumpstarted a new biological field by opening up previously inaccessible areas of research.
"It was clear from the first week that I met Andy that he was destined to do something great," said a longtime friend and Carnegie Institution colleague David Schwartz, PhD, professor of genetics and of chemistry at the University of Wisconsin-Madison. "He was just such a natural about it. There are people who are excellent at sports, you just put a baseball bat in their hands and the ball flies. Andy is like that with science; without a fuss, it just happens."
Before the discovery, the only method of removing a gene's influence from a population of cells involved a laborious and time-consuming series of experiments with no guarantee of success. It was virtually impossible to "knock-out" even a small fraction of genetic suspects in a particular pathway. Now researchers around the world are using RNAi techniques to quickly and randomly silence one gene at a time in swaths of cells. By plucking out those that act abnormally with regard to the pathway in question, they are able to identify even previously unknown genes involved in the pathway.
Linda Cicero
Andrew Fire (right), with Stanford President John Hennessy, became the third member of the medical school faculty to win a Nobel Prize.
The technique has also shown remarkable clinical promise. RNAi-based treatments are being tested in many animal models of disease—high cholesterol, HIV, cancer and hepatitis, among others—and clinical trials have been launched in humans with specific types of macular degeneration and pneumonia. The potential applications of the research are vast.
Despite some intriguing hints that RNA was more than just an assembly manual for proteins, much of this process remained a mystery until Fire and Mello published their findings in the nematode C. elegans, a tiny worm about the width of a No. 2 pencil lead. But Fire emphasizes that much of the preliminary legwork had already been done by other plant and animal researchers.
"We came into a field where a lot was already known," said Fire. "It was a complex jigsaw puzzle, and we were able to contribute one piece. Fortunately for us it was a very nice piece, but it would be really disingenuous to say we did the whole puzzle."
Such demurring is standard for Fire; colleagues often describe him as remarkably modest. Monday, Fire lived up to that reputation. After reluctantly agreeing to participate in numerous media interviews and press conferences, he made sure to credit "insightful and dedicated colleagues and students" with whom he has worked and "whose ideas and efforts are very much the subject of the prize." And he noted that scientists have a responsibility to society at large. "All of us in science look forward to sharing with the public both the responsibilities and opportunities that arise as we understand more about the human body," he said.
Fire added, "For me personally, the occasion of such an award is an opportunity to thank the many patient teachers and mentors who have opened doors to science and research, and especially my family, who have made everything possible.
"This day is a wonderful chance to acknowledge that science is a group effort," Fire continued. "The advances cited in the Nobel award grew from original scientific inquiry from numerous research groups throughout the world." He also thanked the National Institute of General Medical Sciences for providing the grants that made the research possible and continues to support both scientists.
Others were just a little more effervescent. "My wife and I have known him for 20 years, and we were jumping and hooting and hollering when we found out," said Schwartz, who is also the director of the Genomic Sciences Training Program at Madison's Laboratory for Molecular and Computational Genomics. "I spoke to him a couple of weeks ago and told him he was going to win the prize. With his typical understated personality, he said 'Let's talk about something else.'" In fact, Fire is so unassuming that he first suspected his early morning phone call was a prank by his old friend.
Fire will officially receive the award on Dec. 10 in Stockholm, and he and Mello will share the $1.4 million prize. He is the medical school's third Nobel laureate, joining emeritus professors Paul Berg, PhD, and Arthur Kornberg, MD.
"Professor Fire's contributions to his field have been of enormous importance and the recognition by the Nobel committee is a remarkable achievement at this early point in his career," said President John Hennessy. "The RNA research of professors Fire and Mello represents the very best of the collaborative nature of university scholarship. The fact that this basic discovery is already impacting the development of new therapies is a wonderful reminder of the importance of fundamental research."
As any graduate student can attest, fundamental research often means long hours of tedium. Although Fire is careful to credit others, he's no stranger to such drudgery. "I'd be working in the middle of the night," recalled Schwartz, "and Andy would be hunched over his microscope next door, feeding his worms. They had a mutation that made them so uncoordinated that he had to push food their way with a tiny brush." But the work paid off. "This is just gorgeous work that stands a chance to really change medicine, as well as being a remarkable tool for biology," said Schwartz. "Anyone who knows him will not be surprised that he won."
After Fire received his PhD from MIT, he was accepted as a Helen Hay Whitney Postdoctoral Fellow in Cambridge, England, in a laboratory headed by Nobel laureate Sydney Brenner, PhD. He conducted his initial work on gene silencing by double-stranded RNA between 1986 and 2003 while at the Carnegie Institution. He was an adjunct professor in the Department of Biology at Johns Hopkins University starting in 1989 and joined the Stanford faculty in 2003. Throughout his career, all of the major work in Fire's lab has been supported by research grants from the US National Institutes of Health.
Fire is a member of the National Academy of Sciences and of the American Academy of Arts & Sciences. He serves on the Board of Scientific Counselors and the NIH's National Center for Biotechnology. He has received and shared numerous awards, including the Maryland Distinguished Young Scientist Award, Meyenburg Prize, Genetics Society of America Medal, National Academy of Sciences Award in Molecular Biology, Passano Family Foundation Award, Wiley Prize, H.P. Heineken Prize in Biochemistry and Biophysics, Warren Triennial Prize, Rosenstiel Award, Gairdner Award, Massry Prize and Ehrlich/Darmstaedter Prize.
None of this has gone to Fire's head—and the Nobel Prize doesn't appear to be either. "I like what I do," he said when asked how the Nobel might affect his life. "I like teaching, I like research and I like talking to colleagues. This brings another dimension: an opportunity to have a voice beyond my own lab and field. That's a big responsibility, and I look forward to using that voice as needed. At the same time, I still want to do interesting and unusual experiments, while also making sure I don't get too much credit."


Mutation in (mt)DNA causes Human diseases

A number of human diseases are caused by mutations in genes in our mitochondria: cytochrome b 12S rRNA ATP synthase subunits of NADH dehydrogenase several tRNA genes Although many different organs may be affected, disorders of the brain and muscles are the most common. Perhaps this reflects the great demand for energy of both these organs. Some of these disorders are inherited in the germline. In every case, the mutant gene is received from the mother because none of the mitochondria in sperm survives in the fertilized egg. Other disorders are somatic; that is, the mutation occurs in the somatic tissues of the individual. Example: exercise intolerance A number of humans who suffer from easily-fatigued muscles turn out to have a mutations in their cytochrome b gene. Curiously, only the mitochondria in their muscles have the mutation; the mtDNA of their other tissues is normal. Presumably, very early in their embryonic development, a mutation occurred in a cytochrome b gene in the mitochondrion of a cell destined to produce their muscles. The severity of mitochondrial diseases varies greatly. The reason for this is probably the extensive mixing of mutant DNA and normal DNA in the mitochondria as they fuse with one another. A mixture of both is called heteroplasmy. The higher the ratio of mutant to normal, the greater the severity of the disease. In fact by chance alone, cells can on occasion end up with all their mitochondria carrying all-mutant genomes — a condition called homoplasmy (a phenomenon resembling genetic drift).


Sunday, October 08, 2006


It is a boon to the genetical students and epileptic patients that Harvard Medical School found a new gene causes epilepsy.

Here the report goes, "Boston--Harvard Medical School affiliate Beth Israel Deaconess Medical Center--Scientists studying the genetic basis of epilepsy have discovered a gene that is not only required for proper brain development, but which also may play an important role in vascular disease and stroke. Researchers at Boston's Beth Israel Deaconess Medical Center for the first time have found that the gene filamin 1 (Flnl), which has previously been implicated in platelet function and cell motility outside the central nervous system, plays a critical role in human brain development and causes epilepsy when its normal function is disrupted. They also report that patients with F1n1 mutations are prone to suffering strokes and often are born with a serious vascular anomaly called patent ductus arteriosus. Their findings are the cover story of the December Neuron. "No one realized until now that this gene played a role in the brain" says Christopher A. Walsh, MD, PhD, director of the neurogenetics laboratory at Beth Israel Deaconess Medical Center, and principal investigator of the Neuron study, "Mutations in Filamin 1 Prevent Migration of Cerebral Cortical Neurons in Human Periventricular Heterotopia." "We are, of course excited about the role this gene is playing in the developing brain, but we are also interested in F1n1's connections to stroke and vascular development," continues Walsh. Periventricular heterotopia (PH) is a disorder in which neurons in the brain fail to migrate to their proper location during development, and which results in epilepsy in affected females. Mutations in F1n1 cause this disorder in females, while males with F1n1 mutations die before birth, presumably due to an essential role F1n1 has in the development of the embryo. Walsh and colleagues first homed in on the gene for PH by studying families in which the disorder is inherited. Using gene mapping techniques they narrowed down their search from a possible 60,000 genes to approximately 100 genes. They then studied about a dozen of these genes to determine if any were mutated in their PH patients. Walsh estimates that he and his team spent about six person-years mapping and testing genes before mutations in F1n1 were identified. This gene-hunt has been a full time job for the past three and a half years for the first author of the Neuron paper, Jeremy Fox. "This kind of work is very unpredictable. What pays off in the end is persistence," comments Fox. Walsh speculates that F1n1 acts as an engine that initiates cell migration from deep within the brain to the area where development of the cortex takes place. With some of this migration blocked by F1n1 mutations, many neurons remain deep within the brain and possibly cause epilepsy by making inappropriate connections. Patients with PH mutations also often suffer from strokes and vasculature defects, and Walsh believes that more subtle F1n1 mutations may be found in many people with these other problems. His group plans to collaborate with colleagues at Harvard Medical School to study the non-neuronal roles of F1n1, while continuing studies into the precise role of F1n1 in migrating neurons in the developing brain."