Medtronic’s CoreValve tested in US

Heart experts at Johns Hopkins have begun testing a new device designed to replace blocked aortic valves in patients for whom traditional open-heart surgery is considered too risky, such as elderly patients and those with other serious medical conditions. The testing is part of a nationwide study to evaluate the device, which is deployed in a minimally invasive way.

The new device, known as CoreValve, is a self-expanding valve made of a compressed metal scaffold with three flexible tissue leaflets attached. It is put in place inside the patient’s damaged valve through a catheter that is threaded through a leg artery to the aorta.

Once the device is in place, a sheath covering the valve is removed via the same catheter, allowing the leaflets to open and close, directing blood flow to the rest of the body and the brain.

The device is already approved for use in Europe. During the European tests, patients experienced a more than doubling of blood flow, in some cases showing ejection fractions rising from 20% to between 50% and 60%.

“The people most likely to benefit from this approach are incredibly weak, often bedridden because of their severely narrowed, aortic valve,” says interventional cardiologist Jon Resar, MD, who along with cardiac surgeon John Conte, MD, is leading the Johns Hopkins portion of the study. Hopkins is among 40 medical centers that are participating in the Medtronic CoreValve U.S. Pivotal trial. Medtronic is the device manufacturer and is funding the tests.

“For many of our patients, this procedure is their only hope,” says Resar, an associate professor and director of the adult cardiac catheterization laboratory at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute.

Because it doesn’t involve open heart surgery, the approach is known as transcatheter aortic valve implantation, or TAVI for short. Even though it is a minimally invasive procedure, Resar cautions that the device is not a cure-all, noting that about 30 percent of patients who have the procedure may die within a year from disease-related complications in the kidneys, liver or lungs. But for patients whose only treatment option is medication to manage their aortic disease, up to half may die within a year.

Resar adds that many TAVI patients in Europe are living longer than five years after placement of the device, and says the potential risks are far less than with conventional surgery.



Half-matched transplants widen pool of donors for leukaemia, lymphoma

Identifying a suitable donor for leukaemia and lymphoma patients who need bone marrow transplants may be far easier now that results of two clinical trials show transplant results with half-matched bone marrow or umbilical cord blood are comparable to fully matched tissue, thanks in large part to the availability of effective antirejection drugs and special post-transplant chemotherapy.

The finding means that nearly all patients in need of a transplant can find donors.

Plans are under way for a four-year randomized trial for so-called haploidentical marrow or cord blood transplants in 380 patients to begin late this year or early next year.

Johns Hopkins researchers involved in the trials, say the results are good news because they address the problem faced by patients when no family members are a complete match for the patient’s tissue type.

In the clinical trials, investigators from the Blood and Marrow Transplant Clinical Trials Network at 27 medical centres in tested two types of transplants, those from half-matched (or haploidentical) bone marrow or cord blood, and published their results in the 14 July issue of Blood. Some 50 adult leukaemia or lymphoma patients with advanced disease or at high risk for relapse were included in each of the Phase II trials. Six of the participating centres conducted both types of transplants.

Bone marrow tissue is extracted by needle from the hip bone of donors. Marrow that is half-identical to a patient’s tissue type can be obtained from parents, children and most siblings.

Results of the two trials show one-year survival rates of 54% for cord blood transplant and 62% for haploidentical marrow. Survival without disease progression at one year was 46% for cord blood and 48% for haploidentical marrow. The investigators say this is comparable to survival achieved by similar patients undergoing transplants from fully matched siblings or unrelated adult donors.

Relapse rate after one year was 45% for haploidentical marrow transplants and 31% for cord blood. No patients had severe graft versus host disease (GVHD) – an attack on the patient’s normal tissues by immune cells of the donor – after bone marrow transplant.

At one year, deaths not caused by relapse occurred in 7% of haploidentical patients and 24% of cord blood transplants.

Bone marrow transplant expert Ephraim Fuchs, MD, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center, says that in the past, haploidentical transplants failed more often because the transplanted cells caused severe GVHD, especially in older patients. Half of the patients enrolled in the current trials were 50 and older.

“Ten years ago, it was unthinkable to do a haploidentical transplant,” says Dr Fuchs, who led the haploidentical transplant clinical trial. doi:10.1182/blood-2011-03-344853



Stem cells trials in humans for MS set to begin

The first clinical trial in humans to test whether stem cells can cure Multiple Sclerosis (MS) is set to begin in about six months. More than 150 patients across Europe will be involved in the trial.

Dr Paolo Muraro from Imperial College London, said: “There is very strong preclinical evidence that stem cells might be an effective treatment.”

The phase II trials are expected to begin in six months’ time and will run for five years following which there will be an assessment of the results and perhaps phase III trials.

Researchers will collect stem cells from the bone marrow of patients, grow them in the laboratory and then re-inject them into their blood with the expectation they will make their way to the brain and repair the damage caused by MS.

Drugs are currently available to alleviate the symptoms, but they do not prevent the progression of the condition.



New marker found for hereditary colon cancer – familial adenomatous polyposis

Researchers have found that a hereditary colon cancer syndrome, familial adenomatous polyposis (FAP), is associated with abnormally dense blood vessel growth in the skin lining the mouth.

The finding, reported in the June issue of Familial Cancer, could lead to a quick screening test for FAP, which is normally diagnosed with expensive DNA tests and colonoscopies, and sometimes goes unnoticed until cancer develops.

“This higher blood vessel density in the mouth may reflect an abnormal state of cells lining the digestive tract – including the oral cavity – that predisposes people to colorectal cancer and precancerous polyps,” says Francis M. Giardiello, M.D., Johns G. Rangos Sr. Professor of Medicine at Johns Hopkins and director of Hopkins’ Hereditary Colorectal Cancer Program.

People who have even one copy of the mutant gene that causes FAP develop hundreds of precancerous colorectal polyps, also known as adenomas, in their teens. Most have their colons removed after diagnosis to avoid what would otherwise be a near-100 percent risk of colon cancer by middle age. doi:10.1007/s10689-011-9432-3



New marker identified to predict kidney failure

A high level of a hormone that regulates phosphate is associated with an increased risk of kidney failure and death among chronic kidney disease (CKD) patients, according to a recent study led by researchers at the University of Miami. The results are published in the 15 June 2011 issue of the Journal of the American Medical Association and funded by the US National Institute of Diabetes and Digestive Diseases and Kidney Diseases (NIDDK).

In a previous study of patients beginning haemodialysis for treatment of kidney failure, individuals with elevated blood levels of the hormone fibroblast growth factor 23 (FGF23) were found to be at nearly six times greater risk of death compared to those with lower levels. However, the hormone had not been tested in the much larger population of patients with less advanced CKD. Researchers now report that patients with earlier stage kidney disease and high FGF23 are at nearly two times higher risk of kidney failure if their baseline estimated glomerular filtration rate (eGFR) is 45 millilitres or higher, while all CKD patients are at three times higher risk of death compared to patients with lower levels of the hormone. The eGFR is a measure of kidney function.

Senior study author Myles Wolf, MD, MMSc, at the University of Miami, believes this discovery could lead to earlier diagnosis and treatment of phosphate problems. Treatment typically consists of dietary phosphate restriction and phosphate binders.

“Since FGF23 rises before phosphate in people with early or intermediate-stage chronic kidney disease, this hormone could be an early marker pointing to patients who may benefit from early management of phosphate levels, which may help preserve kidney function and reduce deaths,” he said.

The findings are based on data from 3,879 racially diverse participants with CKD who enrolled in the NIDDKsupported, multi-center, observational Chronic Renal Insufficiency Cohort (CRIC) Study between June 2003 and September 2008. During a median follow up period of 3.5 years, 266 patients died and 410 developed kidney failure.

The study of FGF23 in the CRIC Study is part of a major effort supported by the NIDDK to identify markers that can better predict the fate of patients with CKD. doi:10.1001/jama.2011.826



Surgical complications 12 times more likely in obese patients

Obese patients are nearly 12 times more likely to suffer a complication following elective plastic surgery than their normalweight counterparts, according to new research by Johns Hopkins scientists.

“Our data demonstrate that obesity is a major risk factor for complications following certain kinds of elective surgery,” says Marty Makary, MD, MPH, an associate professor of surgery at the Johns Hopkins University School of Medicine and leader of the study published online in the journal Plastic and Reconstructive Surgery.

Not only are these findings relevant to physicians who need to pay special heed to issues such as potential surgical site infections in heavier patients but, the authors argue, they are relevant to policymakers whose increasingly applied metrics for surgical quality and reimbursement do not account for the higher risk of worse outcomes in the obese.

Operations on obese patients are more taxing, says Makary, a surgeon himself. These surgeries usually take longer, the operating fields are deeper, the spaces in which an infection can set in are often greater and blood flow in fat tissue is less than in other types of tissue, which results in slower healing, he says.

In the study, Makary and his colleagues examined insurance claims data from seven Blue Cross and Blue Shield plans and identified patients who underwent elective breast procedures covered by insurance between 2002 and 2006. There were 2,403 patients in the obese group and 5,597 patients in the normal weight control group. The most common procedure, by far, was breast reduction, followed by breast reconstruction, augmentation and mastopexy (breast lift). Within 30 days of surgery, 18.3% of the obese group experienced at least once complication, compared to 2.2% of patients in the control group. The differences between the two groups were most pronounced in complications, such as inflammation (with obese patients 22 times more likely to suffer a complication), infection (13 times) and pain (11 times). doi:10.1097/PRS.0b013e3182284c05



fMRI a good objective diagnostic tool for autism

Functional magnetic resonance imaging (fMRI) may provide an early and objective indicator of autism, according to researchers at Columbia University in New York City, who used the technique to document language impairment in autistic children. Results of their study appear online and in the August issue of Radiology.

Autism is a spectrum disorder characterised by repetitive behaviours and impaired language, communication and social interactions. According to the US Centers for Disease Control and Prevention, it is estimated that as many as one in every 110 children is affected by autism.

“With the extraordinarily high prevalence of autism, you would think there would be an objective diagnosis for the disorder,” said Joy Hirsch, PhD, a professor at Columbia University Medical Center and director of the Functional MRI Laboratory. “However, the diagnosis of autism currently remains limited to parent and clinician observation of missed developmental milestones.”

In the study, researchers performed fMRI exams on 15 control children (mean age: 12.1) and 12 language-impaired and agematched autistic children (mean age: 12.4). Using fMRI, the researchers were able to measure neural activity in working brain tissues, while the children listened to recordings of their parents talking to them.

Activation levels during passive stimulation were measured within two regions of the brain: the primary auditory cortex (A1) and superior temporal gyrus (STG), a region associated with sentence comprehension. Brain activation maps for each patient were then computed using statistical linear modeling.

Activity in the A1 region of the brain did not differ between autistic and control patients. However, activation within the STG was greater for control children relative to autistic patients.

“These findings first tell us that the autistic children in our study appeared normal with respect to the primary auditory system,” Dr Hirsch said. “But it appears that the STG in the autistic brains was not as sensitive to the language narratives as was the STG in the brains of the typical children.”

An additional 27 autistic children undergoing routine MRI exams with sedation were also included in the study. Using a similar analysis of sedation-adjusted values from the control group, the researchers identified 26 of 27 (96%) sedated autistic patients with autism.

“This study suggests that fMRI acquired during listening to a language narrative can be used to distinguish children with autism from those without,” Dr Hirsch said. “Based on these initial findings, future studies using these or similar fMRI methods may result in an early and objective imaging indicator for autism.”

Some children with autism spectrum disorders can benefit from intensive behaviour therapy, but early intervention is key.

“The need for an early, objective diagnosis is enormous,” Dr Hirsch said. doi:10.1148/radiol.11101576



Increasing awareness contributes to lowering childhood obesity

Increasing public awareness of the childhood obesity epidemic may be contributing to evidence of overall reductions in body mass index (BMI) in children, according to the results of a US nationwide study published in Childhood Obesity.

The HEALTHY Study tested the effects of a public health intervention strategy for lowering BMI among middle school students. Half of the schools participating underwent no changes (the control group), while the other half (the intervention group) instituted changes in their nutritional and physical education programs as well as promotional events and educational activities intended to bring about behaviour change. doi:10.1089/chi.2011.0044



Metabolic analysis suggests need for gender-specific therapies

Analyses of the metabolic profile of blood serum reveal significant differences between men and women. From their tests, scientists at the Helmholtz Zentrum München have concluded that there is a need for gender-specific therapies. The study is published in PLoS Genetics.

Gender-specific therapies may be required for some diseases as there are significant differences between male and female metabolism. The differences affect 101 of the 131 metabolites tested in this study – above all lipid and amino acid species – in the serum of more than 3,000 volunteers who took part in the population- based KORA study. Professor Thomas Illig, head of the Research Unit of Molecular Epidemiology, and Dr Kirstin Mittelstrass see this as proof that “in terms of molecular profiles, men and women have to be assigned to two completely different categories. That means that we also need gender-specific approaches to the treatment of diseases.” For their recent study, the scientists at the

Helmholtz Zentrum München combined genetic data with metabolic profiles which were established in the Metabolomics Platform of the Genome Analysis Center. The genetic analysis was conducted by Professor Thomas Meitinger, director of the Institute of Human Genetics.

In the next phase, the scientists will increase the number of metabolites and also evaluate further studies from a genderspecific point of view. “Through the combination of gender-specific evaluation, genetic association studies and metabolomics we will gain a detailed understanding of how the major widespread diseases such as diabetes mellitus develop,” Professor Illig says. doi:10.1371/journal.pgen.1002215



Researchers show profound changes in brain of adult stutterers

Hearing Beethoven while reciting Shakespeare can suppress even a King’s stutter, as recently illustrated in the movie The King’s Speech. This dramatic but shortlived effect of hiding the sound of one’s own speech indicates that the integration of hearing and motor functions plays some role in the fluency (or dysfluency) of speech. New research has shown that in adults who have stuttered since childhood the processes of auditory-motor integration are indeed located in a different part of the brain to those in adults who do not stutter. The findings are reported in the September 2011 issue of Cortex.

Dr Nicole Neef and Dr. Martin Sommer from the University of Goettingen, together with Dr Bettina Pollok from the University of Duesseldorf, studied the performance of a group of adults who stutter, as well as a control group of adults who do not stutter, in a finger tapping exercise. They used Transcranial Magnetic Stimulation (TMS) to interfere temporarily with brain activity in the dorsolateral premotor cortex while the participants tapped their fingers in time with the clicks of a metronome. In control subjects, disturbing the left premotor cortex impaired the finger tapping, but disturbing the right premotor cortex had no effect. In stuttering adults, the pattern was reversed: the accuracy of finger tapping was affected by disturbing the right hemisphere, and unaffected when disturbing the left.

Previous research has already linked stuttering with a right-shifted cerebral blood flow in the motor and premotor areas during speech. In this new study, a shift of auditory-motor integration to the right side of the brain occurred even in a task not directly involving speech. Thus, in the brains of adults who stutter there appears to be a profound reorganization possibly compensating for subtle white matter disturbances in other parts of the brain – the left inferior frontal regions. These findings shed light on the extent of the reorganization of brain functions in persistent developmental stuttering.

Ref: Neef Ne, et al. Right-shift for nonspeech motor processing in adults who stutter. Cortex. 2011 Sep;47(8):945-54. Epub 2010 Jun 30. PMID: 20822768



Safety concerns raised over Chantix use

A meta-analysis of 14 clinical trials involving popular anti-smoking drug – Varenicline – raises safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with its use among tobacco users.

The meta-analysis shows the chance of a serious cardiac event increases by 72% compared to people on placebo.

The US FDA warned in June on thebasis of a 700-person study that the drug, made by Pfizer and sold in some countries under the name Chantix, could be cause for a slightly elevated risk of a heart attack or other cardiovascular event in people with existing heart disease.

However, Sonal Singh, MD, MPH, an assistant professor of general internal medicine at the Johns Hopkins University School of Medicine and the lead author of the metaanalysis, thinks the drug substantially increases the risk of a cardiovascular event even among smokers without heart disease.

“I think our new research shifts the riskbenefit profile of varenicline,” Singh says. “People should be concerned. They don’t need Chantix to quit and this is another reason to consider avoiding Chantix altogether.”

In the study, published 4 July 2011 in the Canadian Medical Association Journal, Singh and his colleagues reviewed and analysed 14 double-blind, randomised, controlled clinical trials involving more than 8,200 healthy people who received either varenicline or a placebo. Whereas the number of people who died in each group was the same (seven), the increased risk of a major harmful cardiovascular event requiring hospitalisation such as a heart attack or arrhythmia was 72% in the varenicline arms. None of the studies followed people for longer than a year. The average age of study participants was less than 45 years and the majority were men.

Singh says questions about the drug’s cardiovascular disease risks have been raised since varenicline went on the market in 2006, but no study has clarified the magnitude of these risks to the extent found in the new study. doi: 10.1503/cmaj. 110218
 
Controversy

The study has sparked considerable controversy in the medical community with a wide range of responses from opposing sides. In one of the responses, Larry Samuels, Senior Medical Director, Pfizer, says: “Serious methodological issues limit the reliability and relevance of the results of the analysis by Singh et al.” These letters can be read here: http://tinyurl.com/ 3op5dta

                                  
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