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Tuberculosis (TB) Drug Doses Too Low for Today’s Obese Populations, Says Study

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The typical dose of a medication considered pivotal in treating tuberculosis effectively is much too low to account for modern-day physiques, UT Southwestern Medical Center researchers said.

The finding, reported online and in the August edition of Antimicrobial Agents and Chemotherapy, is particularly important for those living in societies plagued by obesity, said Dr. Tawanda Gumbo, associate professor of internal medicine at UT Southwestern and the study’s lead author.

“What really drives the variability of this particular drug is patient weight and gender, so in our simulations we took that into account,” Dr. Gumbo said. “What we found is that we’re really using doses for very skinny people – 105 to 110 pounds. I haven’t met many adults who are at that weight.”

About one-third of the world’s population is infected with Mycobacterium tuberculosis, the bacterium that causes TB, and as many as 2 million people die from the disease each year. TB, which is the leading cause of death among people infected with HIV/AIDS, kills more people than any other disease caused by a single infectious agent, according to the National Institutes of Health. Treatment usually lasts six to 12 months and includes a combination of antibiotics such as Pyrazinamide, the drug examined in this study.

Because treatment typically includes multiple drugs, introducing new ones to existing regimens has made it harder to identify which, if any, of the drugs are working at the current dosage levels. Researchers also have struggled to identify the needed dosage as well as exactly where in the body these drugs work to combat the bacterium.

The new model developed at UT Southwestern uses cultured cells to gauge the effectiveness and proper dosage of anti-tuberculosis drugs.

“With this model, we can directly test molecules that have the potential to shorten therapy and go straight to coming up with the doses that you would use in patients,” Dr. Gumbo said. “What that means is that if you have a molecule that could cure TB in one month in this model, it stands a good chance that it would do the same in patients.”

For this study, the researchers gave patients Pyrazinamide – an older drug generally used in combination with other drugs – daily for one month. The researchers then used the data collected to calculate how much bacteria the drug killed before resistance emerged. They opted to focus on Pyrazinamide because physicians once used it alone to treat the disease, so there are many studies documenting precisely how the drug behaves in patients – something that is unclear for some newer drugs.

When the UT Southwestern researchers began testing Pyrazinamide in the lab, they found that the concentration of the drug declined at a rate that matches the rate seen in patients.

“In patients, unlike in test tubes, it’s not a constant concentration. A patient given multiple drugs degrades each of them at different rates,” he said. “Using this model, we can actually copy this concentration profile of the drugs to human-like exposures.”

Dr. Gumbo said his team’s finding that the doses traditionally given to tuberculosis patients are much too low suggests that different doses are probably needed in different countries. “Most of the patients we see here in Dallas are not 110 pounds unless they have some other severe disease,” he added.

The next step, Dr. Gumbo said, is to continue researching drug combinations in order to devise the optimum treatment regimen for tuberculosis patients.

“We’ve rationally and scientifically come up with a dose that depends not just on the kinetics or the concentration time profile of patients, but also how the bug itself responds to that particular drug,” he said. “So, instead of using the average patient or a mean patient, we can now project how a drug combination will fare in actual patients. With this model, researchers can use these simulations to determine the duration of therapy, which could shorten from years to months.”

Source: Antimicrobial Agents and Chemotherapy, August, 2009.

Hair Loss Treatment for Women

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For many women, hair loss can be very difficult to deal with.

“Hair loss is a very misunderstood condition, both in terms of how people see their own hair loss and how physicians who are not dermatologists approach hair loss,” said Dr. McMichael. “It is important for women to be evaluated by a dermatologist, who specializes in hair loss, at the first signs of a problem – whether she notices that her ponytail is smaller than it used to be, she sees more hair in the shower, or if her part is widening. Determining the cause of the hair loss is the first step in treating it and preventing future hair loss.”

Female-Pattern Hair Loss
The most common form of hair loss in women is female-pattern hair loss, which is a hereditary condition also referred to as androgenetic alopecia. While pattern hair loss affects both men and women, it is very different in women and does not display the classic receding hairline or bald spot on top of the scalp as it does in men. In women, the frontal hairline is usually maintained, but there is
visible thinning over the crown. Dr. McMichael explained that in both male- and female-pattern hair loss, the hair stays on the head for a shorter time due to a short growth phase, resulting in baby fine hairs that do not reach their full length or diameter.

Fortunately, several treatment options are effective for women with hair loss. Minoxidil 2% is the only topical medication approved by the U.S. Food and Drug Administration (FDA) for female-pattern hair loss. Minoxidil 5% is only FDA-approved for male-pattern hair loss, but it has been shown to be very effective in women as well. Both the 2% and 5% solutions are available over-the-counter. While minoxidil does not grow new hair, it works by prolonging the growth phase of hair – providing more time for hair to grow out to its full density.

“Minoxidil is a wonderful option for women with thinning hair, as it only treats the hair you want to keep that is not reaching its maximum growth and is an easy way to fill in hair density,” said Dr. McMichael. “Although minoxidil is an over-the-counter treatment, women should consult their dermatologist who is experienced with the product and can explain how it works and off-set any known side effects – such as irritation or fine facial hair that could develop along the cheeks and jaw line.”

In some cases, other medications may be used off-label to treat female hair loss, including finasteride (which is FDA-approved for male-pattern hair loss) for women of non-childbearing age only, and the anti-androgens spironolactone and flutamide that work by blocking the male hormone testosterone at the cellular level of the hair follicle. These oral medications also may be an option for women who may not want to spend time applying minoxidil every day. Dr. McMichael also noted that hair transplantation is an extremely effective procedure for women who want to fully restore their lost hair and works best in conjunction with topical or oral medications to prevent further hair loss.

Telogen Effluvium
Another common form of hair loss in both men and women, telogen effluvium, refers to an increase in the number of hairs in the telogen, or rest, phase of the hair cycle, which typically lasts three months in the normal growth
cycle. However, telogen effluvium occurs as a result of the body’s natural physiologic response to some form of stress, causing more hair to enter the rest phase than the normal 10 percent. For example, surgery, childbirth, dramatic weight loss (including gastric bypass surgery), the death of a loved one, starting
or stopping oral contraceptives, iron deficiency, and chronic thyroid diseases can trigger this type of hair loss.

“When I evaluate patients’ hair and their recent medical history, I am able to determine if their hair loss is a result of telogen effluvium. I always tell women to be patient and that their hair needs to grow back on its own,” said Dr. McMichael. “In these cases, I would only recommend minoxidil to less than 50 percent of women and oral medications would not be effective. Once the trigger is removed, the hair simply needs to return to normal – which could take anywhere from three to nine months. The key is determining the trigger and when it occurred in relation to the hair loss.”

Alopecia Areata
An autoimmune form of hair loss that can affect men and women, alopecia areata, occurs when the body’s white blood cells attack the hair follicles and put them to sleep. This results in either a small patch of complete hair loss on the scalp that may be easy to cover or complete hair loss on the scalp (similar to the effects of chemotherapy in cancer patients) and/or other areas of the body.

While not as common as other forms of hair loss, this condition can be very psychologically upsetting for women and its manifestations are unpredictable from person to person. For example, alopecia areata can happen overnight or occur gradually over the course of several years. Dr. McMichael noted that typically, alopecia areata is initially seen in children and young adults.

Although there are no FDA-approved treatments for alopecia areata, Dr. McMichael explained that dermatologists may use combination therapies off-label such as injectable steroids, topical steroids or minoxidil 5% to try to regrow hair in patches of bald spots. However, she cautioned that not all patients will experience hair regrowth even with treatment – which could have a significant negative impact on their quality of life.

“Studies examining quality of life issues show that women with hair loss are much more bothered by their condition than men,” said Dr. McMichael. “With men, it has become socially acceptable to be bald, but the same is not true for women. Many of my patients report not going to church because they don’t want
people in the pew behind them to see their thinning hair, or they stop exercising because they don’t want to mess up their hair that they’ve spent so much time styling to try to hide their hair loss. It really can affect many aspects of their lives.”

Dr. McMichael is optimistic that research in hair loss will continue to expand in the future. She also suggested that in addition to seeing their dermatologist for proper evaluation and treatment, women who are bothered by their hair loss can find help through the many support groups that are available to patients on the Internet.

Source: American Academy of Dermatology (AAD), July 29, 2009

Alternative Therapies for Eczema Treatments, With a Caveat

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Despite having access to some of the best health care in the world, many Americans with the most common form of eczema, known as atopic dermatitis, have sought relief from “alternative medicines.” However, dermatologists caution that patients seeking alternative treatments to alleviate symptoms of this common, chronic, inflammatory skin disease marked by red, itchy rashes, risk developing more severe symptoms by delaying treatment.

At the American Academy of Dermatology’s Summer Academy Meeting 2009 in Boston, dermatologist Peter A. Lio, MD, FAAD, assistant professor of dermatology and pediatrics at Northwestern University Feinberg School of Medicine in Chicago, discussed why eczema patients try alternative therapies and how certain therapies used in conjunction with clinically tested medical treatments could hold promise in further improving the condition.

“Part of the difficulty in understanding why people seek alternative medicine lies in defining this term,” said Dr. Lio. “Broadly speaking, it encompasses treatments such as acupuncture, homeopathy and holistic medicine outside of the form of medicine taught in most U.S. medical schools. But people use the term for anything from chicken soup to any lotion or potion sold on the Internet to a new dietary supplement. Unfortunately, a great deal of snake oil can hide under the umbrella of alternative medicine.”

Dr. Lio believes there are two main reasons that patients try alternative therapies for eczema. The first reason is that since the cause of eczema is not fully understood nor why it occurs in some people and not others, treatments are
based on controlling the symptoms rather than fixing the root cause. Secondly, an increasing number of patients are looking for natural non-medical therapies that do not pose the known side effects of some of the traditional medications.

However, many non-medical therapies, especially herbal treatments, marketed for treating eczema are not governed by the U.S. Food and Drug Administration (FDA) or any agency, and contaminants could cause health problems or drug interactions could occur when used with other medications.

“The biggest risk posed by alternative medicines is worsening symptoms due to delayed treatment. In my practice, most of my patients have used some form of alternative therapy, but largely with little or no measurable improvement,” said Dr. Lio. “In fact, one large-scale study found more than half of the eczema patients participating reported using one or more forms of alternative medicine for their disease. The study concluded that the majority of patients reported no improvement or even worsening of their condition after using these alternative treatments.”

While topical corticosteroids (the mainstay in the treatment of eczema), antibacterial agents, topical calcineurin inhibitors and moisturizers are among the most effective medical treatments dermatologists prescribe to treat eczema, Dr. Lio suggested certain alternative therapies may be beneficial for some patients, perhaps by reducing stress.

For example, studies show that physical or emotional stress can worsen atopic dermatitis, and one study concluded that stress directly slows the healing of the skin barrier – or its protective outer layer. In another study, psychosocial stress and sleep deprivation were found to disrupt skin barrier function in healthy patients.

“It is possible that some forms of alternative medicine, such as hypnosis and acupuncture, may help eczema patients by reducing stress,” said Dr. Lio. “The areas of stress reduction and behavior modification are promising and deserve further exploration as a means to complement traditional medical therapies.”

In his practice, some of Dr. Lio’s patients report improvement in their condition with acupuncture, but there are no scientific studies examining this potential benefit. Currently, Dr. Lio is trying to initiate a study on the effects of acupuncture on eczema patients at his institution to examine why acupuncture reportedly benefits some patients but not others.

“I think it is important for patients to inform their dermatologist if they are using alternative therapies, as some could cause dangerous drug interactions with traditional medicine,” said Dr. Lio. “I always tell my patients that the fact that there are thousands of alternative treatments for eczema suggests that not one of them works really well. But if patients are committed to trying alternative medications, they should consult their dermatologist and not forgo their recommended medical regimen.”

Source: American Academy of Dermatology (AAD), July 29, 2009

Hormone Replacement Therapy (HRT) and Its Effects on Skin Appearance

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For many women, hormone replacement therapy (HRT) can alleviate the physical symptoms associated with the change of life. But despite the initial hype generated by post-menopausal women who noticed a marked improvement in their skin’s appearance while on HRT, dermatologists argue that scientific studies of estrogen do not show definitive improvements for skin rejuvenation of photodamaged skin and the potential risks when used long-term outweigh any potential skin benefits.

At the American Academy of Dermatology’s Summer Academy Meeting 2009 in Boston, dermatologist Margaret E. Parsons, MD, FAAD, assistant clinical professor of dermatology at the University of California at Davis in Sacramento, reviewed studies that demonstrate mixed results when examining whether or not estrogen improves the appearance of the skin and why patients should opt for tried-and-true cosmetic therapies instead.

“Based on the research conducted thus far, it does not appear that topical or oral estrogens are a viable long-term solution for improving sun-damaged or aging skin,” said Dr. Parsons. “In my practice, I do not prescribe estrogens for skin rejuvenation because of the lack of consistent data to support their use and the known risks of prolonged estrogen therapy – including an increased risk of breast cancer.”

Estrogens are a group of hormones that play a key role in regulating many aspects of a woman’s overall health, including reproduction. Certain parts of the body contain cells that are more receptive to the effects of estrogen than others, including the face. Dr. Parsons noted that estrogens benefit the skin in many ways, including an increase in collagen content, water retention and elasticity.

During pregnancy when estrogen levels are at their highest, women experience thicker hair and glowing skin. On the other hand, post-menopausal women may
notice that their skin does not have the same elasticity as it once did and that it is drier than normal.

In order to treat the most common symptoms associated with menopause – including hot flashes, mood swings and vaginal changes – physicians often prescribe hormone replacement therapy (HRT) to boost the body’s estrogen levels that drop dramatically during this change of life. However, when the results of the Women’s Health Initiative (WHI) study were announced in 2002, the way HRT was viewed to treat post-menopausal women changed significantly. For example, the WHI study found that women on long-term HRT could be at an increased risk for breast cancer and that the overall health risks of this therapy could outweigh the possible benefits. From that point on, HRT was prescribed more conservatively with lower dosing options and individualization based on each woman’s own health history.

Since there were reports of some women on HRT noticing an improvement in their skin, studies were conducted to determine if these results could be validated. Dr. Parsons explained that results of multiple studies examining the relationship between estrogens and skin improvement were inconclusive.

For example, one study examined whether low-dose hormone therapy improved aging skin in 485 women who were on average five years post-menopausal. Published in the September 2008 issue of the Journal of the American Academy of Dermatology, the study concluded that estrogen supplementation did not provide any significant improvement in sun-damaged skin.

“Although this study found no obvious skin benefits in this particular group of women, another study that looked at women who began HRT at the onset of menopause – and did not wait to start treatment like the other group – did experience noticeable improvements in their skin,” said Dr. Parsons. “These
studies pose unanswered questions as to the timing and duration of prescribing HRT to produce skin benefits. For this reason, the jury is still out as to whether estrogens can be effective for aging skin.”

In addition, another study showed that applying topical estrogen to sun-damaged facial skin and sun-protected skin on the hip of post-menopausal women resulted in stimulated collagen production and less wrinkling in the sun-
protected hip skin, but no noticeable improvement in the sun-damaged facial skin.

Dr. Parsons added that more research will likely continue in the future to examine the possible benefits of estrogen for improving aging skin. Until then, she stressed that there are many effective therapies that dermatologists regularly use to address the common signs of aging – including retinoids, alpha-hydroxy acids and other topical therapies, as well as chemical peels, lasers, botulinum toxin and skin fillers, to name a few.

“The best advice I can offer my patients to improve their overall skin health is to wear sunscreen with a sun protection factor (SPF) of at least 30, don’t smoke and use a topical retinoid,” said Dr. Parsons. “When it comes to minimizing the cumulative effects of sun damage, an ounce of prevention really does go a long way.”

Colchicine for Acute Gout, Familial Mediterranean Fever Approved by FDA

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The U.S. Food and Drug Administration (FDA) has approved Mutual Pharmaceutical Company’s drug, Colcrys, to treat acute flairs in patients with gout, a recurrent and painful form of arthritis, and patients with familial Mediterranean fever (FMF), an inherited inflammatory disorder.

The medication’s active ingredient is colchicine, a complex compound derived from the dried seeds of a plant known as the autumn crocus or meadow saffron (Colchicum autumnale).

Colchicine has been used by healthcare practitioners for many years to treat gout but had not been approved by the FDA. The FDA has an initiative underway to bring unapproved, marketed products like colchicine under its regulatory framework. This initiative promotes the goal of assuring that all marketed drugs meet modern standards for safety, effectiveness, quality and labeling.

Physicians historically have given colchicine hourly for acute gout flares until the flare subsided or they had to stop treatment because the patient began experiencing gastrointestinal problems. A dosing study required as part of FDA approval demonstrated that one dose initially and a single additional dose after one hour was just as effective as continued hourly dosing for acute gout flares, but much less toxic. As a result, the drug is being approved for acute gout flares with the lower recommended dosing regimen.

The FDA is alerting healthcare professionals to this new dosing regimen and also warning about the potential for severe drug interactions when patients take colchicine.

The medicinal value of using colchicum was first identified in the first century A.D. and its use for treating acute gout dates back to 1810. Physicians have prescribed the medication since then. Although single-ingredient colchicine has not been approved by the FDA until now, a combination product containing colchicine and an agent that increased the excretion of uric acid in the urine was approved by the FDA in 1939.

FMF is the most common of the hereditary periodic fever syndromes and is characterized by recurrent episodes of fever, arthritis and painful inflammation of the lining layers of the lungs and abdomen. Though rare in the United States, it is more common in Mediterranean countries. Physicians have prescribed colchicine for FMF for many years based on studies showing that it reduced the frequency of attacks but use of colchicine for FMF had never been approved. With this approval, Colcrys becomes the first drug approved to treat FMF.

Colcrys is manufactured by Mutual Pharmaceutical Company, Inc., Philadelphia.

Hormonal Therapies and Acne

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Although acne traditionally has been considered a disease of teenagers, it is also extremely common in adult women. Studies show that acne affects more than 50 percent of women between the ages of 20-29 and more than 25 percent of women between the ages of 40-491. In fact, after age 20, women are far more likely to report having acne than men. While there is no cure for acne, dermatologists are finding that hormonal therapies can help some women fight bothersome acne that occurs in adulthood.

At the American Academy of Dermatology’s Summer Academy Meeting 2009 in Boston, dermatologist Bethanee J. Schlosser, MD, PhD, FAAD, assistant professor of dermatology and director of the Women’s Skin Health Program at Northwestern University Feinberg School of Medicine in Chicago, discussed the most widely used hormonal therapies available for women with acne and the best candidates for this type of treatment.

Factors that contribute to the formation of acne include excess oil gland production, skin inflammation, abnormal maturation of skin cells lining the hair follicle and an increased number of the acne-causing bacteria Propionibacterium acnes. However, hormones also influence both oil gland production and the maturation of skin cells thereby contributing to the formation of acne lesions. For example, when androgens (the male hormones present in both men and women) over-stimulate the oil glands and hair follicles in the skin, hormonal acne flares can occur.

“Women over the age of 20 may experience worsening of their acne or a change in the nature of their acne. This can include increased lesions on the lower one-third of the face (including the jaw line and upper neck), pre-menstrual flares, and resistance to oral antibiotics and other traditional acne therapies,” said
Dr. Schlosser. “For these women, hormonal therapy in the form of combination oral contraceptives and/or anti-androgen medications, such as spironolactone, flutamide and dutasteride that work by reducing the activity of the male hormone testosterone, may provide significant benefit.”

Dr. Schlosser noted that the use of hormonal therapies for acne, including combination oral contraceptives, requires careful screening of patients. For example, there are numerous contraindications (or factors that increase the risks of a particular medication) that must be considered before hormonal therapy is prescribed for treating acne. Such contraindications for combination oral contraceptives include a personal history of breast cancer, heart attack or stroke, uncontrolled high blood pressure, migraines with neurological symptoms, or abnormal vaginal bleeding, to name a few. Dermatologists will review these factors with patients to determine if hormonal acne therapy poses any potential risks for patients.

Based on a physical examination, a patient’s medical history and the success or failure of previously prescribed acne treatments, dermatologists may recommend hormonal therapy to enhance the results of acne treatment in women. Hormonal therapy in the form of combination oral contraceptive pills has been shown to help treat both inflammatory acne lesions (the papules, pustules and painful nodules under the skin), and non-inflammatory acne lesions (blackheads and whiteheads). Dr. Schlosser suggests that hormonal therapy should not be used in isolation but instead recommends that combination oral contraceptives or anti-androgen medications be used in conjunction with topical retinoids for optimal results.

While there are numerous types of oral contraceptives available that can be used to treat acne in women, three combination oral contraceptive pills have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acne. All combination oral contraceptives contain an estrogen (ethinyl estradiol for most contraceptive pills) and a progestin. The estrogen component decreases the production of testosterone and other androgens by the ovaries and decreases the amount of active testosterone in the body.

Some progestins may actually mimic the activity of testosterone on the oil gland and thereby worsen acne. Therefore, Dr. Schlosser primarily recommends oral contraceptives that contain one of the following progestins: norgestimate, desogestrel, or drospirenone, all of which demonstrate low or no risk of increasing the activity of the testosterone receptor.

“Combination oral contraceptives can be very beneficial in the treatment of acne in appropriately selected women, and several different oral contraceptives have been shown to be effective in clinical studies,” said Dr. Schlosser. “But the treatment of acne with combination oral contraceptives needs to be targeted to each patient’s individual needs, and patients should be monitored regularly to ensure the safety and effectiveness of their particular therapy.”

Dr. Schlosser cautioned that improvement of acne with hormonal therapy does not occur overnight and requires at least three months of continuous use before a judgment about effectiveness should be made. In many cases, patients need to continue using oral contraceptives to sustain their results over time. However, some patients can stop hormonal therapy and maintain clear skin with the regular use of a topical retinoid.

“For many women with adult-onset acne, combination hormonal therapy can provide excellent results,” added Dr. Schlosser. “Women who think they might be good candidates should discuss their options with their dermatologist who can offer a customized treatment regimen and continual monitoring to ensure optimal results.”

Source: American Academy of Dermatology (AAD), July 29, 2009

Multiple Scleroris (MS) Disease Progression Risk Predictors

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Cognitive testing may help people with inactive or benign multiple sclerosis (MS) better predict their future with the disease, according to a study published in the July 29, 2009, online issue of Neurology®, the medical journal of the American Academy of Neurology. Gender and brain lesions may also determine the risk of progression of MS years after diagnosis.

By current definition, people with benign MS are those who remain “fully functional” after 15 or more years from disease onset. However, people with benign MS occasionally develop renewed disease activity or progression, and can experience severe symptoms.

For the study, researchers looked at the cognitive test results and brain scans of 63 people with benign MS during a period of five years. Of those, 43 were women and 20 were men.

The cognitive tests included verbal and visual memory, attention, concentration and the speed at which the participant processed information. Brain scans revealed the number of lesions associated with MS on the person’s brain. Follow-up neurologic exams were done every six months.

The study found that nearly 30 percent of people with benign MS significantly worsened over the course of five years. People who failed more than two cognitive tests (out of 10 total) were 20 percent more likely to progress over time. Men with benign MS were nearly three times more likely to later experience signs of MS compared to women. People with more brain lesions detected on scans were also more likely to develop signs of the disease.

“Our findings strongly suggest that a person’s gender, cognitive state and amount of lesions on the brain are important factors for predicting MS progression,” said study author Maria Pia Amato, MD, with the University of Florence in Italy. “Our study highlights the importance of cognitively testing people with benign MS who appear to be healthy. This information might be important in tailoring the patient’s treatment.”

Source: Neurology; American Academy of Neurology (AAN), July 29, 2009

Researches Find Method to Block Genetic Flaw that Can Cause Muscular Dystrophy

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Researchers have found a way to block the genetic flaw at the heart of a common form of muscular dystrophy. The results of the study, which were published today in the journal Science, could pave the way for new therapies that essentially reverse the symptoms of the disease.

The researchers used a synthetic molecule to break up deposits of toxic genetic material and re-establish the cellular activity that is disrupted by the disease. Because scientists believe that potentially all of the symptoms of myotonic dystrophy – the most common form of muscular dystrophy in adults – flow from this single genetic flaw, neutralizing it could potentially restore muscle function in people with the disease.

“This study establishes a proof of concept that could be followed to develop a successful treatment for myotonic dystrophy,” said neurologist Charles Thornton, M.D., the senior author of the study and co-director of the University of Rochester Medical Center’s Wellstone Muscular Dystrophy Cooperative Research Center. “It also demonstrates the potential to reverse established symptoms of the disease after they have developed, as opposed to simply preventing them from getting worse.”

Myotonic dystrophy is a degenerative disease characterized by progressive muscle wasting and weakness. People with myotonic dystrophy have prolonged muscle tensing (myotonia) and are not able to relax certain muscles after use. The condition is particularly severe in the hand muscles and can cause a person’s grip to lock making it difficult to perform rapid, repeated movements. Currently there is no medication to halt the progression of the disease.

Toxic RNA Holds Proteins Hostage
Although the genetic flaw that causes myotonic dystrophy was discovered in 1992, researchers studied the defect for many years before they had a clear understanding of the molecular events that ultimately produce the symptoms of the disease. Over time it became apparent that a central player in myotonic dystrophy was RNA, a versatile molecule that is very similar to DNA. RNA serves a vital function by relaying the genetic information from the nucleus – the protected area of the cell that houses DNA –out to the main body of the cell, where the instructions are used to build proteins. Every gene produces its own RNA, usually in multiple copies, and every RNA is a genetic blueprint of its parent gene.

The surprising aspect of myotonic dystrophy was that the genetic defect leads to production of a toxic RNA – the first example in human genetics in which RNA was cast in the role of molecular perpetrator. The errant RNA has a toxic effect because it grabs onto and holds hostage certain proteins, preventing them from carrying out their normal functions. For example, the capture of a protein called “muscleblind” causes the locking grip phenomenon that is a hallmark of the disease, a sign of faulty electrical control in muscle cells. Over time, the toxic RNA is produced in abundance and the captive proteins accumulate in deposits – or inclusions – that are visible in the cell’s nucleus.

“An unexpected byproduct of research on myotonic dystrophy was that we were forced to change our ideas about the role of RNA in genetic disease,” said Thornton. “Once we adjusted to this new concept, we realized that the prospects for developing treatment might be unusually good. No essential component of muscle is missing, but some important proteins are in the wrong place, stuck on the toxic RNA.”

New Tools to Tackle Genetic Flaws
The Rochester team used a synthetic molecule – called an antisense morpholino oligonucleotide – that mimics a segment of the genetic code. In this case the morpholino was specifically designed to bind to the toxic RNA and neutralize its harmful effects by releasing the captured proteins. When injected into the muscle cells of mice with myotonic dystrophy the molecule found its way to the cell nucleus, broke up the deposits of toxic RNA, freed the captive muscleblind proteins, and ultimately improved the function of the muscle cells.

The researchers specifically observed a restoration of proper electrical control in the cells, which is a convenient way to monitor the condition. However, because the hostage proteins play a role in a myriad of other cellular functions, they believe that this treatment will ultimately alleviate other aspects of the disease as well.

“Based on our current understanding we would predict that by releasing the proteins held hostage, many of the symptoms of the disease may potentially be corrected by this approach,” said URMC neurologist Thurman Wheeler, M.D., co-author of the study.

These genetic tools are relatively new and have provided researchers with a heretofore unprecedented ways to precisely target and manipulate genetic activity. “The current textbooks for medical students do not have chapters on antisense oligonucleotides, but this will change in the near future,” said Thornton. “As compared to conventional drugs that work on proteins, antisense oligonucleotides work on RNA. They have been around for 20 years, but only recently is their full potential being realized. They provide great flexibility and they can be developed rapidly.”

The authors are quick to point out that major hurdles must be overcome before this compound can be tested in humans. Specifically, a better delivery system must be developed to get this or a similar compound to where it needs to go in the body, and the potential side effects must be carefully analyzed. However, having established a general concept of what a treatment for myotonic dystrophy may look like, researchers believe that the next steps in developing an effective drug should go faster.

Source: Science, July 16, 2009

Discovery May Help Prevent Rotavirus Epidemics

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New Vaccines Shift the Course of Childhood Diarrhea-Causing Disease and Could Have Big Global Impact

New vaccines have the potential to prevent or temper epidemics of the childhood diarrhea-causing disease rotavirus, protect the unvaccinated and raise the age at which the infection first appears in children, federal researchers reported in a study today.

The findings were based on changing patterns of rotavirus transmission in the United States, where the disease is rarely fatal, and they have implications for combating epidemics in other countries where the death toll is much higher.

The research, published in the July 17 issue of the journal Science, is based on mathematical modeling that takes into account regional birth rates and predicted vaccination levels and effectiveness. The model suggests that when 80 percent or more of children in a given population are vaccinated, annual epidemics may occur on a less regular basis and more unvaccinated children will be protected. Data from 2007-2008, when vaccination first reached appreciable coverage levels in the United States, validate the model′s predictions.

“Rotavirus vaccines have rapidly and dramatically reduced hospitalizations and emergency room visits for gastroenteritis in American children,” said investigator Umesh D. Parashar, M.B.B.S., M.P.H., of the Centers for Disease Control and Prevention′s National Center for Immunization and Respiratory Diseases. “This research not only explains the effects of the U.S. rotavirus vaccination program, but also lays the foundation for understanding the tremendous life-saving benefits of vaccination in the developing world, where more than half a million children die from rotavirus each year.”

The study showed for the first time that the timing of rotavirus epidemics is dependent on the birth rate in the population because they are driven by infants who have never been infected before. In the United States, winter outbreaks would typically occur sooner in the higher birth rate states of the Southwest and later in the Northeast, where birth rates tend to be lower.

But with the introduction of two vaccines, the first in 2006, rotavirus outbreaks may become less frequent and less pronounced. They also may make their first appearance in children when they are older than the previous norm of less than 5 years of age, according to the research.

In older children, later onset would likely mean fewer cases and less severity of diarrhea.

The modeling and analysis were done by a team of researchers from the Fogarty International Center of the National Institutes of Health, the CDC, the Agency for Healthcare Research and Quality, the Pennsylvania State University, Princeton University and the George Washington University.

“When you can observe the immediate effects of vaccination and compare them to what the model predicted, you have a head start on stopping this preventable disease in countries where rotavirus unnecessarily kills hundreds of thousands of children,” said Roger I. Glass, M.D., Ph.D., one of the study authors and director of the Fogarty Center.

Lead author Virginia Pitzer, Sc.D., of Penn State and the Fogarty Center, said, “Each population is going to have a different demographic makeup, and there may be conditions we cannot predict with certainty, but we believe introducing vaccination in the developing world will decrease the terrible burden of rotavirus.”

Source: CDC, July 16, 2009

Blacks Have Highest Obesity Rate, Says CDC

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Blacks had 51 percent higher prevalence of obesity, and Hispanics had 21 percent higher obesity prevalence compared with whites, according to researchers with the Centers for Disease Control and Prevention.

Greater prevalences of obesity for blacks and whites were found in the South and Midwest than in the West and Northeast. Hispanics in the Northeast had lower obesity prevalence than Hispanics in the Midwest, South or West. The study, in CDC′s Morbidity and Mortality Weekly Report, examined data from 2006-2008.

“This study highlights that in the United States, blacks and Hispanics are disproportionately affected by obesity,” said Dr. William H. Dietz, Director of CDC′s Division of Nutrition, Physical Activity, and Obesity, “If we have any hope of stemming the rise in obesity, we must intensify our efforts to create an environment for healthy living in these communities.”

The study uses data from the Behavioral Risk Factor Surveillance System (BRFSS), of the Centers for Disease Control and Prevention. BRFSS is an ongoing, state-based, random-digit–dialed telephone survey of the U.S. civilian, noninstitutionalized population aged 18 years and older.

The study found that in 40 states, obesity prevalence among blacks was 30 percent or more. In five of those states, Alabama, Maine, Mississippi, Ohio, and Oregon, obesity prevalence among blacks was 40 percent or greater.

For blacks, the prevalence of obesity ranged from 23 percent to 45.1 percent among all states and the District of Columbia; among Hispanics in 50 states and DC, the prevalence of obesity ranged from 21 percent to 36.7 percent, with 11 states having an obesity prevalence of 30 percent or higher. Among whites in 50 states and the District of Columbia, the prevalence of obesity ranged from 9 percent to 30.2 percent, with only West Virginia having a prevalence of 30 percent or more.

“We know that racial and ethnic differences in obesity prevalence are likely due to both individual behaviors, as well as differences in the physical and social environment,” said Liping Pan, M.D., M.P.H., lead author and epidemiologist. “We need a combination of policy and environmental changes that can create opportunities for healthier living.”

For this study analysis, CDC analyzed the 2006−2008 BRFSS data.

Source: CDC, July 16, 2009