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

Pilates: A Low-Impact Way to Build Core Strength, Endurance and Flexibility

The June issue of Mayo Clinic Women’s HealthSource addresses this increasingly popular low-impact fitness technique. Pilates emphasizes mind-body connection and breath control to build strength, endurance and flexibility, particularly in the trunk muscles.

Many women opt for Pilates because it can provide a nicely toned look without adding bulk. Practiced regularly, Pilates can assist with weight loss and help alleviate low back pain.

Pilates isn’t new. In the early 20th century, Joseph Pilates, a German citizen, developed a system to help his fellow inmates at a World War I internment camp stay physically conditioned. He later opened a studio in New York where his teaching gained a following in the dance and performance arts communities.

Today, Pilates classes are widely available at health clubs, studios, community centers and senior centers. Pilates can be done on a floor mat or using specialized equipment, such as stability balls, resistance bands or most often, a Reformer. This piece of equipment consists of a sliding seat and a series of springs and pulleys that allow progressive exercises to strengthen all muscle groups.

A typical Pilates session includes a set of controlled stretches and movements, with participants concentrating on breathing, precision and flowing movements. Instead of emphasizing quantity, Pilates focuses on quality — doing a few, extremely precise repetitions.

The best way to start is to enroll in a class taught by a qualified instructor. Success with Pilates depends on precision of movement and effort. Proper instruction is key to knowing how to exercise and achieve the benefits.

Total Laparoscopic Aortic Surgery Is Feasible, Shows Satisfactory Results

Recently the use of laparoscopy for vascular procedures has been limited by difficulties in aortic exposure and anastomosis techniques, as well as the concurrent competitive progress of endovascular surgery. For aortic repair, best results (in terms of long-term patency) have been obtained by conventional surgery which has been associated short-term morbidity and mortality.

Endovascular techniques (which are noninvasive but have less reliable long-term results) as well as video-endoscopic aortic surgery are alternatives to conventional surgery. Minimally invasive surgery benefits include reduced time in intensive care and a shorter hospital stay; a quicker resumption of intestinal transit; less abdominal wall complications; and reduced requirements for anelgesics.

“The goal of total laparoscopic aortic repair is to achieve the same outcome as open repair without invasive laparotomy,” said Jérôme Cau, MD, professor at Poitiers University Hospital in Poitiers, France. “However, specialized training is required to master the procedure and get acquainted with coelioscopic practice necessary for laparoscopic suture.”

Dr. Cau said he and fellow researchers performed a study that completed a retrospective analysis of laparoscopic techniques for vascular procedures in a series of 219 patients, to determine its feasibility for treatment and outcomes with respect to aortic occlusive disease (AOD), abdominal aortic aneurysms (AAA) and aorto-renal bypass in the endovascular era. These findings were presented today at the 63rd Annual Meeting of the Society for Vascular Surgery.

One hundred and twenty-seven AODs; 80 AAAs and 12 aorto-renal bypasses were studied from the hospital; this series did not include 110 aortic bypass patients operated on in others centers by this team. The mean patient age was 61 years and the gender ratio was three men to one woman. The mean operative time of procedures for AOD was 223 (±50) minutes, with a mean clamp time of 56 (±21) minutes. A total of 3.6 percent of AOD procedures had to be converted to open surgeries.

For laparoscopic AAA procedures, the mean operative time was 262 (±57) minutes and the mean “clamp time was 103 (±15) minutes. Eight AAAs had to be converted to an open procedure. The 30-day mortality rate was 0.9 percent. Overall mortality rate was 13.4 percent during a mean follow-up time of 16.2 months. The primary assisted patency rate for AAAs and occlusive disease was 100 percent.

Dr. Cau added that as any in any relatively new technique, laparoscopy’s place in vascular surgery remains to be defined. He noted that for aortoiliac occlusive diseases, this technique has shown excellent results and should compete with open repair for the treatment of TASC C & D occlusive diseases.

“Aneurysm repair in laparoscopy has been demonstrated to be feasible and reliable, and in our experience showed promising and satisfactory results,” noted Dr. Cau. “In the aneurysmal pathology we can predict that the competition with endovascular aortic repair (which is becoming the standard) will make laparoscopy more difficult to ‘find its place’ and make room for hybrid techniques. Specific training remains particularly important to reach technical success in laparoscopy and needs to be presented to the young generation of vascular surgeons in university pilot center.”

“Precise indications for this kind of surgery, compared to endovascular and open surgery, remain to be determined by randomized studies,” added Dr. Cau. “Nevertheless, it is a difficult technique. Further development will rely on effective training, advances in technique and instrumentation.”

Source: Society for Vascular Surgery, June 12, 2009

Adults Should Consider Re-Vaccination for Whooping Cough

“Vaccines are not just for children any more.”

That is the important, and potentially life-saving message, that Geisinger Health System pediatric gastroenterologist William Cochran, M.D., vice chairman of the Janet Weis Children’s Hospital, wants to deliver. And this is a message that comes from personal experience.

“I am a physician, and I didn’t realize that adults needed to be revaccinated for what are considered childhood diseases such as pertussis (whooping cough),” said Dr. Cochran. “And I found that out the hard way – by contracting that very disease.”

According to the Centers for Disease Control and Prevention, pertussis is an acute, infectious cough illness that remains prevalent in the United States despite longstanding routine childhood pertussis vaccination. It is characterized by the unforgettable “whoop” sound made when gasping for breath after a coughing fit. It creates a sticky, thick mucous that makes it difficult to eat, drink and breathe.

This remains an issue because immunity wanes approximately five to 10 years after completion of childhood vaccination, leaving adolescents and adults susceptible to the disease. The CDC reports that since the 1980s, the number of reported pertussis cases has increased steadily, especially among adolescents and adults. And, between 2000-2003 and 2004-2007, there was a 100-percent increase in reported cases of pertussis; there may be as many as 800,000 to 3.3 million adult and adolescent cases of pertussis in any given year.

“This is considered the 100-day cough,” said Lisa Esolen, M.D., system director of Geisinger Infection Control. “This is not a cough that goes away after a few days. At Geisinger alone, we’ve had two pertussis outbreaks within a span of a year, one of which required delivering antibiotics to 105 people who were exposed. That is a significant number. And all it takes is awareness and revaccination to control.”

Dr. Cochran’s experience with the disease, and lengthy and painful recovery, has inspired him to educate adults about the importance of revaccination. “The coughing gets so bad that I can’t get any air. My airway closes until the ‘whoop’ end of the cough occurs. It’s very frightening and extremely painful,” he said. “The CDC recommends that all adults between the ages of 19-64 should be revaccinated, along with healthcare providers. If more adults get their vaccines, then we’ll have more power to stop this horrible disease in its tracks.”

See the CDC website for a schedule of recommended adult vaccinations (PDF).

Source: Geisinger Health System, June 12, 2009

New Treatment Offers Hope to Patients Debilitated by Stroke

Researchers in the Neuroimaging and Stroke Recovery Laboratory at Beth Israel Deaconess Medical Center / Harvard Medical School are using a novel treatment for chronic stroke patients.

The non-invasive technique of dual-hemisphere transcranial direct current stimulation (tDCS) uses electrical stimulation to modulate brain activity while simultaneous engaging the paretic arm/hand in sensorimotor activities. They studied chronic stroke patients who had movement problems after a stroke in a randomized clinical trial.

The patients were divided into groups receiving either the electrical stimulation or placebo stimulation while receiving occupational therapy (OT) at the same time. After only 5 treatment sessions, patients receiving real stimulation and OT significantly improved in their motor functions, while control patients (receiving placebo stimulation and OT) showed no significant improvement.

Functional magnetic resonance imaging showed increased brain activity in areas that control limb movement on the affected side for patients who received the real tDCS. It is important to notice that these changes were found in patients whose strokes had occurred on average about 3 years prior to the study, when patients are typically considered to be stable and unlikely to experience further improvement. This new treatment offers hope for patients debilitated by strokes.

Authors: R Lindenberg, LL Zhu, V Renga, D Nair, G Schlaug, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Source: Organization for Human Brain Mapping, June 12, 2009

Autism Drug Citalopram Is Ineffective, Says Study

A drug commonly given to autistic children to reduce repetitive behaviors is ineffective compared to placebo and, in some children, may actually increase repetitive behaviors, the largest study of autistic children to date has found.

“What we found, much to our surprise, is that there was no significant difference in positive response between kids treated with citalopram and kids who received the placebo. And the kids treated with citalopram tended to have more side effects,” said Linmarie Sikich, M.D., a co-author of the study and associate professor of psychiatry in the University of North Carolina at Chapel Hill School of Medicine.

“I cannot emphasize this enough: This was not at all what we expected to see,” Sikich said.

Results of the study, a randomized controlled clinical trial of the drug citalopram, are published in the June 29, 2009 issue of Archives of General Psychiatry. It was funded by the National Institutes of Health and took place at six academic medical centers across the country. Principal investigator and lead author of the study is Bryan H. King, M.D., who began the study at Dartmouth and continued to oversee it there after he moved to the University of Washington, where he is currently director of psychiatry and behavioral medicine at Seattle Children’s Hospital.

Citalopram, which is sold under the brand name Celexa, is one of a class of antidepressant drugs called selective serotonin reuptake inhibitors, or SSRIs. SSRIs are the most frequently used medications for children with autism. They are also used to treat depression, anxiety and obsessive compulsive disorder in both adults and children. Prior to this study there was very little scientific evidence to support the use of SSRIs in autistic children, but some preliminary studies showed promising results for citalopram, Sikich said.

Hypothesizing that citalopram would improve the overall functioning of autistic children and adolescents by reducing repetitive behavior, Sikich and colleagues recruited 149 children ages 5 to 17 to take part in the 12-week trial. Seventy-three received daily doses of liquid citalopram while 76 received daily doses of liquid placebo. Researchers measured the children’s’ response to treatment using the Clinical Global Impression-Improvement scale (CGI-I). They also recorded measures of repetitive behavior and side effects.

At the end of the trial, some children in both groups showed a positive response. However, there was no significant difference between the groups: the positive response in the citalopram group was 32.9 percent versus 34.2 percent in the placebo group. In addition, children in the citalopram group were significantly more likely to experience adverse side effects such as increased energy level, impulsiveness, decreased concentration, hyperactivity, increased repetitive movements and behaviors, diarrhea, insomnia, and dry itchy skin.

The researchers concluded that citalopram “is not an effective treatment” for autistic children with repetitive behaviors. In addition, they wrote, this trial shows that the use of SSRIs in autistic children “is not without risk” and “at present there is insufficient research evidence to merit a clear recommendation regarding the use of SSRIs as a class” for the treatment of repetitive behavior in children with autism spectrum disorders.

“The obvious short term message is, this treatment didn’t work. And that surprised us a great deal,” Sikich says. “But the really important take-home message is that we have to do large, scientifically-sound comparative studies like this to really know whether a specific treatment works and is safe. Simply relying on doctors’ and families’ impressions often leads us to use medications that really don’t work and may do more harm than good” says Sikich.

Safe and effective medication and behavioral treatments are desperately needed to help children with autism realize their potentials and keep from harming themselves or others, Sickish says.

“Well-done studies, using methods like the ones in this study, have shown that another drug, risperidone, is useful in reducing irritability and aggression in children with autism,” she says. “Thus, this study shouldn’t be interpreted as saying all medications don’t help people with autism and are harmful. Instead it says that citalopram doesn’t help most children with autism and is harmful to some children. Clearly we need more research to develop and test other interventions for this important problem.”

People with autism are severely impaired by the disorder and experience major problems with highly repetitive behaviors, often including self-injurious behaviors, communicating and interacting appropriately with others. Frequently the repetitive behaviors keep children with autism from learning in school or participating in age appropriate activities. When it is time to stop the repetitive behavior and begin a new, functional activity, many children with autism become distraught and aggressive. These repetitive behaviors also contribute to the difficulties that make it hard for most people with autism to live independently or work as adults, Sikich says.

In addition to UNC, academic medical centers taking part in the study were Mt. Sinai School of Medicine, North Shore-Long Island Jewish Health System, Dartmouth, UCLA and Yale University.

The study was conducted as part of the NIH-sponsored Studies to Advance Autism Research and Treatment network.

Source: University of North Carolina at Chapel Hill School of Medicine , May 28, 2009

Ophthalmologist calls for cataract surgery prior to starting Flomax treatment

East Hanover, NJ – May, 26 2009 – A drug commonly used to treat prostate problems is linked to serious complications after cataract surgery, according to new research. In this week’s issue of JAMA, a study looked at a group of 96,128 men, ages 66 and older, who had cataract surgery. Among those who had taken Flomax in the two weeks before surgery, 7.5% had a serious complication like retinal detachment or inflammation of the eye. Only 2.7% of patients who hadn’t recently taken Flomax experienced such complications. The authors concluded: “Flomax exposure is associated with an increased risk of postoperative complications concurs with prior studies of intraoperative adverse events. We believe that this is the first large study with an adequate study design to describe this effect and provide a population-based risk estimate. It is unclear whether drug discontinuation prior to surgery reduces this risk. Because the combination of cataract surgery and tamsulosin exposure is relatively common, patients should be properly apprised of the risks of drug therapy and preoperative systems should focus on the identification of tamsulosin use by patients. In this way, surgeons can plan and prepare for a potentially more complicated procedure or refer to someone with more experience.” Cary M Silverman, MD, Medical Director of EyeCare 20/20 in East Hanover, NJ calls for a change in the practice patterns associated with the prescribing of Flomax and similar medications. In a letter to the Editor in this month’s issue of EyeNet, a publication of the American Academy of Ophthalmology, he asks that: “ If the urologist is considering starting a patient on an alpha blocker to treat urinary symptoms, a baseline exam from the ophthalmologist should be considered prior to treatment. If a cataract is detected, it might make sense to treat the cataract prior to the initiation of alpha blocker therapy. This would go a long way toward minimizing the morbidity in these patients.” Silverman has started a petition among ophthalmologists in an attempt to bring about this change in practice patterns. EyeCare 20/20 Medical Director, Cary M. Silverman, M.D. specializes in innovative LASIK vision correction, state-of-the-art refractive cataract surgery, as well as an array of other refractive surgery options for patients who are not candidates for LASIK.

Researchers Develop DNA Compounds that May Help Treat Lupus

A research team led by a University of Iowa investigator has generated DNA-like compounds that effectively inhibit the cells responsible for systemic lupus erythematosus — the most common and serious form of lupus. There currently is no cure for this chronic autoimmune condition that damages the skin, joints and internal organs and affects an estimated one million Americans.

The team, which included researchers at Boston University School of Medicine, demonstrated the anti-inflammatory effects of class R inhibitory oligonucleotides in laboratory experiments. The findings, which could eventually lead to new treatments, appear May 28 in BioMed Central’s open access journal Arthritis Research and Therapy.

“The increased potency of class R inhibitory oligonucleotides for certain cells involved in lupus flare-ups could help patients by providing specific inhibition, yet allowing them to generate a protective immune response when needed,” said the study’s lead author, Petar Lenert, M.D., Ph.D., assistant professor of internal medicine at the University of Iowa Roy J. and Lucille A. Carver College of Medicine.

During periodic flare-ups in people with lupus, the immune system overreacts and mistakenly attacks cells and tissues throughout the body, resulting in a range of symptoms including inflammation, pain and a characteristic “butterfly rash” across the cheeks.

Using human cell lines and isolated mouse cells, Lenert and his colleagues showed that the DNA-like compounds were able to selectively reduce the activity of two types of immune cells called autoreactive B cells and dendritic cells. When given to mice with lupus, the compounds delayed death and reduced kidney damage, proving their effectiveness.

“With further testing, we hope that class R inhibitory oligonucleotides may become another weapon in the fight against lupus,” Lenert said.

Lupus prevalence varies by country and ethnicity. It is much more common in women than men; nine out of 10 people with lupus are female. Lupus also is three times more common in African-American women than in Caucasian women and is more prevalent in women of Latino, Asian and Native American descent.

The study received grants from the National Institutes of Health and the Alliance for Lupus Research.

Source: University of Iowa Health Sciences, May 27, 2009

Genetic Link Between Heart Disease and Gum Disease

BBC News reports that a genetic link between gum disease and heart attacks has been found by researchers in Germany.
Periodontitis (gum disease) is known to be associated with heart disease but how exactly they are linked is unknown.

Now the University of Kiel team has found a common gene mutation in people with periodontitis and heart attack patients, a conference heard.

Source: BBC, May 25, 2009

Prilosec, Nexium and Prevacid Tied to Higher Risk of Pneumonia

A new study has found that hospital patients who are given proton pump inhibitors–drugs that help prevent acid reflux–are at higher risk for pneumonia than those who are not given these medications.

The drugs — including Nexium, Prilosec and Prevacid — are often recommended for intensive-care patients to prevent stress ulcers, and in recent years they have been given to many other hospital patients, in large part because they are widely perceived to be safe. Experts estimate that 40 percent to 70 percent of inpatients now receive acid-suppressive drugs during a hospital stay, with about half receiving them for the first time.

Source: New York Times, May 26, 2009