On Target

ON TARGET
COMPLIMENTARY NEWS LETTER OF TARGET HEALTH® INC.

12 August 2007

I. WHAT'S NEW?
History of Medicine and Quiz Volumes Available
II. QUIZ - (Fill In The Blanks)
Glaucoma & Alzheimer’s Share Protein Fragment
III. HISTORY OF MEDICINE
Meditation
IV. PSYCHIATRY
Gene Implicated in ADHD
V. PUBLIC HEALTH
Non-Pharmaceutical Interventions Saved Lives in the Flu Pandemic of 1918
VI. OPHTHALMOLOGY
The Complement System and Age-Related Macular Degeneration
VII. REGULATORY AFFAIRS
Consumer Warning - Oyster Alert
VIII. TARGET HEALTH

I. WHAT'S NEW

History of Medicine and Quiz Volumes Available

In response to reader requests, we have been collating all of the Quiz Questions and History of Medicine Articles. History of Medicine Volume 1 is complete. While Volume 1 of the Quiz Questions and Volume 2 of History of Medicine are still in development, all are currently available by request.

For more information about Target Health, please contact Dr. Jules T. Mitchel or Joyce Hays. Visit our Blog and Website.

II. QUIZ (Fill In The Blanks)

Glaucoma & Alzheimer’s Share Protein Fragment

A new study in rats, published in the Proceedings of the National Academy of Sciences, shows that a protein fragment that litters the brains of people with Alzheimer's disease may also bear responsibility for some of the 1) ___ loss in glaucoma. Glaucoma patients typically have abnormal fluid pressure within the eye, but it remains unknown how this stress kills the nerve cells at the back of the 2) ___. While there is no current cure for glaucoma, easing eye 3) ___ with drugs or surgery helps prevent vision loss in many patients. Some glaucoma patients, however, experience vision loss even with normal eye pressure, indicating that other factors are sometimes involved. The new research suggests that one hidden assailant is 4) ___, the same protein fragment that accumulates in the brains of Alzheimer's patients. An earlier rodent study of glaucoma had found the substance in the animals' eyes, but other evidence of amyloid-beta in glaucoma is scarce. In the new study, glaucoma was induced in 60 rats by injecting 5) ___ into the animals' eyes. Within weeks, amyloid-beta deposits showed up in dying retinal-nerve cells. The researchers then gave another round of eye injections to some of the rats. In one eye, the animals received a synthetic antibody that absorbs amyloid-beta. The other eye got a 6) ___. After 3 weeks, the medicated eyes showed only one-fourth as much retinal-cell death as did the untreated eyes. The effect remained 13 weeks later. Next, the scientists repeated the experiment on other rats with glaucoma, this time using a cocktail that included the 7) ___ and two other drugs with anti–amyloid-beta effects: a dye called Congo red and an enzyme deactivator called beta-secretase inhibitor. The triple combination worked even better than the antibody alone, reducing cell 8) ___ by 84%.

ANSWERS: 1) vision; 2) retina; 3) pressure; 4) amyloid-beta; 5) saline; 6) placebo; 7) antibody; 8) death

III. HISTORY OF MEDICINE

Meditation

Meditation describes a state of concentrated attention on some object or thought or awareness. It usually involves turning the attention inward to the mind itself. Meditation is often recognized as a component of Eastern religions, where it has been practiced for over 5,000 to 8,000 years. In recent years there has been a growing interest within the medical community to study the physiological effects of meditation. Many concepts of meditation have been applied to clinical settings in order to measure its effect on somatic motor function as well as cardiovascular and respiratory function. Also the hermeneutic and phenomenological aspects of meditation are areas of growing interest. Meditation has entered the mainstream of health care as a method of stress and pain reduction. In an early study in 1972, Transcendental Meditation was shown to affect human metabolism by lowering the biochemical byproducts of stress, such as lactate, decreasing heart rate and blood pressure and inducing favorable brain waves. In 1976, the Australian psychiatrist Ainslie Meares, reported in the Medical Journal of Australia, the regression of cancer following intensive meditation. As a method of stress reduction, meditation is often used in hospitals in cases of chronic or terminal illness to reduce complications associated with increased stress including a depressed immune system. There is growing agreement in the medical community that mental factors such as stress, significantly contribute to a lack of physical health. The NIH has established 5 research centers to research the mind-body aspects of disease. Dr. James Austin, a neurophysiologist at the University of Colorado, reported that Zen meditation rewires the circuitry of the brain. This has been confirmed using functional MRI imaging which examines the activity of the brain. The Mind Body Medical Institute, affiliated with Harvard and several Boston hospitals, reports that meditation induces a host of biochemical and physical changes in the body collectively referred to as the relaxation response. The relaxation response includes changes in metabolism, heart rate, respiration, blood pressure and brain chemistry.

IV. PSYCHIATRY

Gene Implicated in ADHD

According to an article published in Archives of General Psychiatry 2007;64:921-931, brain areas that control attention were thinnest in children with attention deficit hyperactivity disorder (ADHD) who carried a particular version of a gene. However, the areas, on the right side of the brain's outer mantle, or cortex, normalized in thickness during the teen years in these children, coinciding with clinical improvement. Although this particular gene version increased risk for ADHD, it also predicted better clinical outcomes and higher IQ than two other common versions of the same gene in youth with ADHD. According to the authors, since this gene version had similar structural effects in healthy children as in children with the disorder, the findings suggest that ADHD is at the far end of a continuum of normal traits and likely stems from interactions between several such genes and non-genetic factors. It has been established that the dopamine D4 receptor gene, called the 7-repeat variant, accounts for about 30% of the genetic risk for ADHD, making it by far the strongest candidate gene implicated in the disorder. It's called the 7-repeat because it contains the same repeating sequence in its genetic code seven times. Everyone inherits two copies of the D4 receptor gene, one from each parent, so some people have two copies of the same version while others may carry two different versions. For the current study, the D4 gene types were scanned and determined for 105 children with ADHD and 103 healthy controls at the baseline visit and then re-scanned through the teen years. Results showed that nearly one-fourth of youth with ADHD and in about one-sixth of the healthy controls had at least one copy of the 7-repeat version. Nearly two thirds of the ADHD youth and three-fourths of the healthy controls had the most common 4-repeat version; fewer than one-tenth in each group had a 2-repeat version. While the 7-repeat version was linked to thinner attention-controlling cortex in both ADHD and healthy subjects, it appeared to confer advantage only among youth with ADHD. For example, participants with ADHD who lacked at least one copy of this 7-repeat variant had significantly lower IQs, and more than half of them still had pronounced ADHD symptoms when followed-up about six years later, compared to only 21% of those with at least one copy of the 7-repeat variant. There was also a trend toward better overall functioning among those with at least one copy of the 7-repeat variant at follow-up. The MRI scans revealed that 7-repeat carriers with ADHD started out with the thinnest cortex areas important for controlling attention (right orbitofrontal and posterior parieto-occipital). The next thinnest were children with ADHD who did not have the 7-repeat version, followed by healthy children with the 7-repeat. Healthy children lacking the 7-repeat had the thickest cortex, but this did not appear to affect their IQ. In 7-repeat carriers with ADHD, the attention-controlling areas thickened to normal by age 16. Gene variants of two other dopamine system components showed few such anatomic correlates, confirming that the findings were specific to the D4 receptor gene. A time-lapse MRI graphic shows the cortex normalizing from ages 8-16 in youth with ADHD who have the 7-repeat version of the dopamine D4 receptor gene.
See: <http://www.nimh.nih.gov/press/adhdcortex.cfm#cortex>.

V. PUBLIC HEALTH

Non-Pharmaceutical Interventions Saved Lives in the Flu Pandemic of 1918

A critical question in pandemic influenza planning is the role nonpharmaceutical interventions (1. school closure; 2. cancellation of public gatherings; and 3. isolation and quarantine) might play in delaying the temporal effects of a pandemic, reducing the overall and peak attack rate, and reducing the number of cumulative deaths. Such measures could potentially provide valuable time for pandemic-strain vaccine and antiviral medication production and distribution. Optimally, appropriate implementation of nonpharmaceutical interventions would decrease the burden on health care services and critical infrastructure. As a result, a study published in the Journal of the American Medical Association (2007;298:644-654), was performed to examine the implementation of nonpharmaceutical interventions for epidemic mitigation in 43 cities in the continental United States from September 8, 1918, through February 22, 1919, and to determine whether city-to-city variation in mortality was associated with 1) the timing, duration, and combination of nonpharmaceutical interventions; 2) altered population susceptibility associated with prior pandemic waves; 3) age and gender distribution; and population size and density. The study utilized historical archival research, and statistical and epidemiological analyses. Nonpharmaceutical interventions were grouped into 3 major categories: school closure; cancellation of public gatherings; and isolation and quarantine. The main outcome measures were 1) weekly excess death rate (EDR); 2) time from the activation of nonpharmaceutical interventions to the first peak EDR; 3) the first peak weekly EDR; and 4) cumulative EDR during the entire 24-week study period. Results showed that there were 115,340 excess pneumonia and influenza deaths in the 43 cities during the 24 weeks analyzed. Every city adopted at least 1 of the 3 major categories of nonpharmaceutical interventions. School closure and public gathering bans activated concurrently represented the most common combination implemented in 34 cities (79%). This combination had a median duration of 4 weeks (range, 1-10 weeks) and was significantly associated with reductions in weekly EDR. The cities that implemented nonpharmaceutical interventions earlier had greater delays in reaching peak mortality, lower peak mortality rates, and lower total mortality. There was a statistically significant association between increased duration of nonpharmaceutical interventions and a reduced total mortality burden (Spearman r = –0.39, P = .005). According to the authors, the findings demonstrate a strong association between early, sustained, and layered application of nonpharmaceutical interventions and mitigating the consequences of the 1918-1919 influenza pandemic in the United States, and that in planning for future severe influenza pandemics, nonpharmaceutical interventions should be considered for inclusion as companion measures to developing effective vaccines and medications for prophylaxis and treatment.

VI. OPHTHALMOLOGY

The Complement System and Age-Related Macular Degeneration

Age-related macular degeneration (ARMD) is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation has been implicated in the pathogenesis. As a result, a study published in the New England Journal of Medicine Volume (2007;357:553-561), tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5, in case subjects and control subjects. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, a set of Scottish cases and controls were genotyped. Results showed that the common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls) and the Scottish group (244 cases and 351 controls). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7; for F/F homozygotes, the odds ratio was 2.6. The estimated population attributable risk for C3F was 22%. According to the authors, complement C3 is important in the pathogenesis of ARMD and that .the findings further underscore the influence of the complement pathway in the pathogenesis of ARMD.

VII. REGULATORY AFFAIRS

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

Consumer Warning - Oyster Alert

Those with weakened immune systems, including people affected by AIDS, chronic alcohol abuse, liver, stomach, or blood disorders, cancer, diabetes, or kidney disease should avoid eating raw oysters, regardless of where they are harvested.

The FDA is warning consumers not to eat raw oysters harvested from an area of the southern tip of Hood Canal in Washington after an outbreak of illness caused by Vibrio parahaemolyticus bacteria. Symptoms of the illness, called vibriosis, include watery diarrhea, often with abdominal cramping, nausea, vomiting, fever, and chills. Usually these symptoms occur within 24 hours of ingestion and last no more than three days. Severe disease is rare and occurs most commonly in people with weakened immune systems. Those who believe they have experienced these symptoms after consuming raw oysters should consult their health care provider and contact their local health department. Raw oysters harvested from “growing area 6” in Hood Canal from July 3, 2007 and after, have caused at least six people to become ill in California and Washington. Additional reports of illness are being investigated by the states. To date, records indicate that raw oysters from the area were distributed to California, Florida, Hawaii, Idaho, New York, Oregon, Washington, British Columbia (Canada), Hong Kong, Malaysia, and Singapore. The Washington State Department of Health has closed the growing area associated with the illness and has asked commercial oyster harvesters and dealers who obtained oysters from this area to recall them. Consumers who have recently purchased oysters should check with the place of purchase and ask if they were harvested from the affected growing area.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

VIII. TARGET HEALTH

TARGET HEALTH INC. (www.targethealth.com)is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND, IDE, NDA, PMA and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, Web Trials, utilizing Target e*CRF®, our proprietary Internet-based Clinical Trial System, and Medical Writing. TARGET HEALTH's Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

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