Pregnant Women Should Take Greater Care of Novel H1N1 (“Swine Flu”) Virus

A recent study indicates that pregnant women are more severely impacted by a new H1N1 flu virus and should seek immediate treatment with antivirals.

Pregnant women infected with 2009 novel H1N1 had a higher rate of hospitalization and greater risk of death than the general population due to the H1N1 flu.

The data collected and analyzed by the Centers for Disease Control and Prevention (CDC) are the most comprehensive available to date on the impact of this novel H1N1 flu virus among pregnant women.

“The death of a pregnant woman is always heartbreaking, and unfortunately we have been hearing reports of otherwise healthy women dying from H1N1. If a pregnant woman feels like she may have influenza, she needs to call her healthcare provider right away,” said CDC′s Dr. Denise Jamieson, lead author of the study. “Clinicians who treat pregnant women should have a system in place for triaging pregnant women with influenza-like symptoms and they should not delay in initiating appropriate antiviral therapy. Some clinicians hesitate treating pregnant women with antiviral medications because of concerns for the developing fetus, but this is the wrong approach. It is critical that pregnant women, in particular, be treated promptly. ”

Six deaths of pregnant women with H1N1 were reported to CDC between April 15 and June 16, 2009, representing 13 percent of the total 45 deaths reported to CDC during that time period. All were healthy prior to infection of H1N1 and subsequently developed primary viral pneumonia leading to acute respiratory distress requiring mechanical ventilation. All pregnant women who died did not receive antivirals soon enough to benefit their treatment. CDC recommends that pregnant women with suspected or confirmed influenza infection receive prompt treatment with antiviral medication.

Based on past influenza pandemics and on seasonal influenza epidemics, pregnant women have increased rates of illness and death from influenza infection.

Despite recommendations from the Advisory Committee on Immunization Practices and the American College of Obstetricians and Gynecologists for inactivated flu vaccine for all pregnant women, seasonal flu vaccine coverage among pregnant women is very low (less than 14 percent).

Source: Centers for Disease Control (CDC), July 29, 2009; Lancet, August 8, 2009.

Onglyza, a New Type 2 Diabetes Drug Approved by FDA

The U.S. Food and Drug Administration (FDA) today approved Onglyza (saxagliptin), a once-daily tablet to treat Type 2 diabetes in adults. The medication is intended to be used with diet and exercise to control high blood sugar levels.

The hormone insulin keeps blood sugar (glucose) levels within a narrow range in people who don’t have diabetes. People with Type 2 diabetes are either resistant to insulin or do not produce enough insulin to maintain normal blood sugar levels.

Onglyza is in a class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors which stimulate the pancreas to make more insulin after eating a meal.

“Keeping blood sugar levels in adequate control is essential to the good health of the 24 million people in the United States with Type 2 diabetes,” said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “High blood sugar levels can cause blurry vision and excessive urination and eventually result in such serious conditions as kidney and eye disease.”

The most common side effects observed with Onglyza are upper respiratory tract infection, urinary tract infection, and headache. Other side effects include allergic-like reactions such as rash and hives.

Approval of Onglyza was primarily based on the results of eight clinical trials. The application seeking FDA approval was submitted before December 2008 when the agency recommended that manufacturers of new diabetes drugs carefully design and evaluate their clinical trials for cardiovascular safety. Although Onglyza was not associated with an increased risk for cardiovascular events in patients who were mainly at low risk for these events, the FDA is requiring a postmarket study that will specifically evaluate cardiovascular safety in a higher risk population.

Onglyza is manufactured by Bristol-Myers Squibb Co. of Princeton, N.J., and marketed by Bristol-Myers and AstraZeneca Pharmaceuticals LP, of Wilmington, Del.

Source: FDA, July 31, 2009

HIV May Be Transmitted via Pre-Chewed Food

Researchers have uncovered the first cases in which HIV almost certainly was transmitted from mothers or other caregivers to children through pre-chewed food. The source of HIV in the pre-chewed food was most likely the infected blood in the saliva of the people who pre-chewed the food before giving it to the children. The researchers said their findings suggest that HIV-infected mothers or other caregivers should be warned against giving infants pre-chewed food and directed toward safer feeding options.

The cases indicate that physicians and clinics should routinely include questions about pre-chewing food in their health screening of infant caregivers who have HIV or are suspected of the infection. Also, possible cases of HIV transmission through pre-chewed food should be reported to public health agencies to help increase understanding of the prevalence of such transmission.

Led by Aditya Gaur, M.D., of St. Jude Children’s Research Hospital, with colleagues from St. Jude (Marion Donohoe, CPNP), the University of Miami (Charles Mitchell, M.D., and Delia Rivera, M.D.) and the Centers for Disease Control and Prevention (Kenneth Dominguez, M.D., Marcia Kalish, Ph.D., and John Brooks, M.D.), the researchers published their findings in the August 2009 issue of the journal Pediatrics. Gaur is an assistant member of the St. Jude Infectious Diseases department.

Giving infants pre-chewed food has been reported to transmit infections such as streptococcus and the hepatitis B virus, Gaur said. However, until these cases there was no evidence that the blood-borne HIV could be similarly transmitted. The source of blood in the saliva of the person pre-chewing the food for the child may likely have been visible or microscopic bleeding from the gums or some other part of the mouth, he added.

In their paper, the researchers described three cases in which pre-chewed food was likely the source of HIV transmission to infants.

The case that led to this published report was a 9-month-old infant who was referred to St. Jude because she was HIV positive after earlier tests had been negative.

“Her HIV-positive mother had not breastfed her, and further investigation had ruled out transmission by blood transfusion, injury or sexual abuse,” Gaur said. Also, genetic testing, led by Kalish at the CDC, showed that the daughter had been infected with the same HIV strain as the mother.

“Fortunately, the St. Jude nurse practitioner, Marion Donohoe, was very thorough in her questioning about feeding practices, and she asked about pre-mastication. It turned out this mother had fed her daughter pre-chewed food,” Gaur said.

When Gaur contacted Dominguez at the CDC about the possible case of transmission via pre-chewed food, the center alerted him to two similar cases previously reported by senior author Mitchell and colleague Rivera from the University of Miami. Those cases were not reported to the public at the time because of the lack of sufficient evidence of transmission via pre-chewed food. One case involved pre-chewing by an HIV-infected mother, and the other an HIV-infected aunt who was the caregiver.

Gaur said that information in the three cases suggests that one factor aiding such transmission was mouth bleeding in the caregiver, as well as in the infant due to teething or infection. He also said caregivers’ lack of adherence to their own drug-treatment regimens probably increased their blood HIV levels, increasing the likelihood of transmission.

“These three cases are persuasive enough that they justify cautioning HIV-positive caregivers against giving infants pre-chewed foods,” Gaur said. “Also, we hope increased awareness of this possible mode of transmission will bring more cases to light and more thorough studies, which can either substantiate or refute this transmission route.” Also important, Gaur said, will be the results of surveys now being conducted in collaboration with other research groups in the United States and abroad to determine the extent of infant feeding using pre-chewed food.

The findings do not warrant a blanket recommendation against pre-chewed food for infants, the researchers emphasized. The practice, which has been reported from many parts of the world including the United States may be integral to providing adequate infant nutrition and grounded in culture and tradition. On a global level, educating HIV-positive caregivers will require cognizance of culturally sensitive issues and potential nutritional consequences linked to pre-chewing, the investigators said. The findings also do not imply that HIV can be transmitted through saliva during oral contact such as kissing. In the cases the researchers studied, HIV transmission was likely enabled by bleeding gums or open mouth sores.

“Importantly, this report does not challenge the accepted belief that saliva does not carry HIV and that transmission does not occur in kissing,” Gaur said. “The exception is that transmission can occur when the people involved have damaged mucosa in their mouths, and blood is mixed with the saliva.”

Source: St. Jude Children’s Research Hospital; Pediatrics, August, 2009

Targeted Therapy Delivers Chemo Directly to Ovarian Cancer Cells

With a novel therapeutic delivery system, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center has successfully targeted a protein that is over-expressed in ovarian cancer cells. Using the EphA2 protein as a molecular homing mechanism, chemotherapy was delivered in a highly selective manner in preclinical models of ovarian cancer, the researchers report in the July 29 issue of the Journal of the National Cancer Institute.

EphA2 is attractive for such molecularly targeted therapy because it has increased expression in ovarian and other cancers, including breast, colon, prostate and non-small cell lung cancers and in aggressive melanomas, and its expression has been associated with a poor prognosis.

“One of our goals has been to develop more specific ways to deliver chemotherapeutic drugs,” said senior author Anil K. Sood, M.D., professor and in the Departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson. “Over the last several years we have shown that EphA2 is a target that is present quite frequently in ovarian and other cancers, but is either present in low levels or is virtually absent from most normal adult tissues. EphA2’s preferential presence on tumor cells makes it an attractive therapeutic target.”

The researchers used a carrier system to deliver chemotherapy directly to ovarian cancer cells. The immunoconjugate contains an anti-EphA2 monoclonal antibody linked to the chemotherapy drug monomethyl auristatin phenylalanine (MMAF) through the non-cleavable linker maleimidocaproyl. Research has shown that auristatins induce cell cycle arrest at the G – M border, disrupt microtubules and induce apoptosis (programmed cell death) in cancer cells.

The investigators evaluated the delivery system’s specificity in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells through antibody-binding and internalization assays. They also assessed viability and apoptosis in ovarian cancer cell lines and tumor models and examined anti-tumor activity in orthotopic mouse models with mice bearing HeyA8-luc and SKOV3ip1 ovarian tumors.

According to Sood, who is also co-director of both the Center for RNA Interference and Non-Coding RNA and the Blanton-Davis Ovarian Cancer Research Program at M. D. Anderson, the immunoconjugate was highly specific in delivering MMAF to the tumor cells that expressed EphA2 while showing minimal uptake in cells that did not express the protein. In the models, the therapy inhibited tumor growth in treated mice by 85 percent – 98 percent compared to control mice.

“Once we optimized the dosing regimen, the drug was highly effective in reducing tumor growth and in prolonging survival in preclinical animal models,” Sood said. “We actually studied bulkier masses because that is what one would see in a clinical setting where there are pre-existent tumors, and even in this setting the drug was able to reduce or shrink the tumors.”

As for future research with the EphA2-silencing therapy, Sood said, “We are gearing up to bring it to phase I clinical trials. A lot of the safety studies are well under way or nearing completion and we anticipate that this drug will enter clinical trials within the next few months.”

He added that his group is simultaneously conducting preclinical testing on other chemotherapy drugs to determine which agents might combine well with the immunoconjugate used in the current study.

“There is growing interest in molecularly targeted therapy so that we are not indiscriminately killing normal cells,” Sood noted. “The goal is to make the delivery of chemotherapy more specific. The immunoconjugate we used is in a class of drugs that is certainly quite attractive from that perspective.”

Source: University of Texas M. D. Anderson Cancer Center

40% of Emergency Room Visits Billed to Public Insurance, Says Report

More than 40 percent of the 120 million visits that Americans made to hospital emergency departments in 2006 were billed to public insurance, according to the latest News and Numbers from the Agency for Healthcare Research and Quality.

According to the analysis by the federal agency, about 50 million emergency department visits were billed to Medicaid and Medicare. The uninsured accounted for another 18 percent of visits for emergency care, while 34 percent of the visits were billed to private insurance companies and the rest were billed to workers compensation, military health plan administrator Tricare and other payers.

The agency’s study of hospital emergency department use in 2006 also found that:

  • About 38 percent of the 24.2 million visits billed to Medicare ended with the patients being admitted, compared with 11 percent of the 41.5 million visits billed to private insurers, 9.5 percent of the 26 million visits billed to Medicaid and 7 percent of the 21.2 million visits by the uninsured.
  • The uninsured were the most frequent users of hospital emergency departments. Their rate was 1.2 times greater than that of people with public or private insurance – 452 visits per 1,000 population vs. 367 visits per 1,000 population, respectively.
  • The uninsured were also the most likely to be treated and released – a possible indication of their use of hospital emergency departments as their usual source of care. Their "treat-and-release" rate was 421 visits per 1,000 population vs. 301 per 1,000 population for the insured.

Source: Agency for Healthcare Research and Quality (AHRQ)

Sun Exposure May Trigger Auto Immune Disease in Women

Ultraviolet (UV) radiation from sunlight may be associated with the development of certain autoimmune diseases, particularly in women, according to a study by researchers at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.

“This study found that women who lived in areas with higher levels of UV exposure when they developed an autoimmune muscle disease called myositis were more likely to develop the form known as dermatomyositis, which weakens the muscles and causes distinctive rashes, instead of the form called polymyositis that does not have a rash,” said Frederick W. Miller, M.D., Ph.D., chief of the Environmental Autoimmunity Group, Program of Clinical Research, at NIEHS. “Although we have not shown a direct cause and effect link between UV exposure and this particular autoimmune disease, this study confirms the association between UV levels and the frequency of dermatomyositis that we found in a previous investigation,” said Miller.

The study, published in the August issue of Arthritis & Rheumatism, is also the first to evaluate and find a possible UV radiation association in autoimmune diseases in women.

According to Miller, women are more likely than men to develop many autoimmune diseases, but the reasons for this have not been clear. “We only found the association between UV exposure and dermatomyositis in women and not in men, and it could be that inherent differences in how women and men respond to UV radiation may play a role in the development of certain autoimmune diseases,” said Dr. Miller. Miller also noted that other researchers have shown that female mice develop more skin inflammation after UV light exposure compared to male mice and these effects may be related to the new findings in dermatomyositis.

The study was designed to determine if there was a relationship between the level of UV exposure at the onset of the disease and the type of myositis and autoantibodies that people developed. Dermatomyositis and polymyositis are the two major forms of myositis and both are considered autoimmune diseases, in which the body’s immune system attacks muscle or skin and sometimes other tissues. Dermatomyositis is typically accompanied by a distinctive reddish-purple rash on the upper eyelids or over the knuckles and is often made worse with sun exposure.

To conduct the study, the NIEHS researchers collaborated with myositis centers across the country that had seen 380 patients who had been diagnosed with dermatomyositis or polymyositis and determined their autoantibodies. “Patients with autoimmune diseases make a variety of autoantibodies that are unique to different conditions. One autoantibody specifically associated with dermatomyositis is called the anti-Mi-2 autoantibody and we know from our previous research that UV radiation increases levels of the Mi-2 protein that this autoantibody binds to,” said Miller.

In addition to finding an association between the level of UV radiation and the proportion of women who developed dermatomyositis compared to polymyositis, the researchers found an association between UV levels and the proportion of women with the anti-Mi-2 autoantibody. “More research is clearly needed to understand the potential links between UV radiation and the development of autoimmune diseases and autoantibodies in women,” said Miller.

“While the causes of autoimmune diseases are not known, we suspect from emerging research that they develop after one or more environmental exposures in genetically susceptible people,” said NIEHS Director Linda Birnbaum, Ph.D. “This study adds UV radiation to the growing list of environmental exposures possibly important in the development of autoimmune diseases.”

Source: National Institute of Environmental Health Sciences (NIEHS), July 30, 2009

Hair Loss Treatment for Women

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

Hormonal Therapies and Acne

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

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

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