Researchers Identify Gene Mutations Underlying Risk for Most Common Form of Parkinson's Disease

Two genes containing mutations known to cause rare familial forms of parkinsonism are also associated with the more common, sporadic form of the disease where there is no family history, researchers have found.
The finding came in the largest genome-wide association study (GWAS) reported to date involving Parkinson's disease. GWAS studies look in the DNA on all of the chromosomes in a specific population of individuals for common genetic associations with a disease. To date, such studies have been done on relatively small numbers of samples and have not been able to identify genetic variations of smaller effect in Parkinson's disease. But now, GWAS studies in very large sample sets are able to identify these elusive genetic variations.

Collaborating scientists in the United States and Europe pooled nearly 14,000 DNA samples and data to confirm that mutations in the alpha-synuclein (SNCA) gene and microtubule associated protein tau (MAPT), both present in the general population, are risk factors for sporadic Parkinson's disease.

In an independent study from Japan, researchers also identified a different combination of genetic variants as risk factors in people of Japanese descent, a finding that highlights the power of GWAS in comparing risk factors among different populations.

The findings presented in the Nov. 15, 2009, online issue of  were supported in Nature Genetics part by the National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke, National Cancer Institute, and the National Institute of Environmental Health Sciences, all components of the National Institutes of Health.

Parkinson's disease, which affects about 1.5 million Americans, is a progressive neurologic disorder caused by the degeneration of nerve cells in the portion of the brain that controls movement. The likelihood of developing the disorder increases with age and involves a combination of environmental risk factors and genetic susceptibility. GWAS studies require large numbers of DNA samples — a hurdle the international team of researchers overcame through collaboration.

"Because previous Parkinson's GWAS were too small and lacked power, we worked together to compile and analyze the large data sets needed to identify the elusive genetic variations that play a role in this complex disease," said Andrew B. Singleton, Ph.D., chief of the NIA Laboratory of Neurogenetics, who co-led the study with Thomas Gasser, M.D., of the Hertie Institute for Clinical Brain Research, University of Tubingen, and the German Center for Neurodegenerative Disease, of Tubingen, Germany. "With this better understanding of the underlying genetic variants involved in the progress of this disorder, we have more insight into the causes and underlying biology of this disease. We hope this new understanding will one day provide us with strategies to delay, or even prevent, the development of Parkinson's disease."

The two-phase GWAS first analyzed DNA samples of 1,713 people with the disease and 3,978 free of the disorder, all of whom were Europeans. The findings were then replicated in a similar group of 3,361 people with Parkinson's disease and 4,573 without the disorder. Following the initial findings implicating SNCA and MAPT variants as risk factors for typical Parkinson's disease, the team then compared results with researchers performing a GWAS study in a group of Japanese people (2,816 with Parkinson's disease and 3,401 free of the disorder). This second GWAS also strong association for SNCA but not for MAPT.

Additionally, both GWAS studies found evidence for two additional risk variants; the first, which was strongest in the Japanese population, was namerevealed the d Park16; the second is close to a gene, LRRK2, which Dr. Singleton's and Dr. Gasser's groups previously found contains mutations that cause an inherited form of Parkinson's disease.

"These findings support the notion that the sporadic and rare familial forms of the disease are related and that common genetic variability plays a role in developing the disorder," said NIA Director Richard J. Hodes, M.D. "Future GWAS involving greater numbers of DNA samples will likely reveal additional common genetic risk factors. As we continue to use these and other novel approaches to understand complex diseases, we move closer to a complete understanding of the genetic basis of Parkinson's disease."

Source : National Institutes of Health

Smart phones allow quick diagnosis of acute appendicitis

Radiologists can accurately diagnose acute appendicitis from a remote location with the use of a handheld device or mobile phone equipped with special software, according to a study presented today at the annual meeting of the Radiological Society of North America (RSNA).

"The goal is to improve the speed and accuracy of medical diagnoses, as well as to improve communications among different consulting physicians," said the study's lead author, Asim F. Choudhri, M.D., fellow physician in the Division of Neuroradiology at Johns Hopkins University in Baltimore. "When we can make these determinations earlier, the appropriate surgical teams and equipment can be assembled before the surgeon even has the chance to examine the patient." 

Appendicitis, or inflammation and infection of the appendix, is a medical emergency requiring surgical removal of the organ. Undiagnosed or left untreated, the inflamed appendix will rupture, causing toxins to spill into the abdominal cavity and potentially causing a life-threatening infection.

Appendicitis can occur at any age but is most common in people between the ages of 10 and 30, according to the National Institutes of Health.

Typically, a patient arriving at the emergency room with suspected appendicitis will undergo computed tomography (CT) and a physical examination. If a radiologist is not immediately available to interpret the CT images or if consultation with a specialist is needed, diagnosis is delayed, increasing the risk of rupture. Transmitting the images over a mobile device allows for instant consultation and diagnosis from a remote location. It can also aid in surgical planning.

"This new technology can expedite diagnosis and, therefore, treatment," Dr. Choudhri said.

For the study performed at the University of Virginia in Charlottesville, CT examinations of the abdomen and pelvis of 25 patients with pain in the right lower abdomen were reviewed over an encrypted wireless network by five radiologists using an iPhone G3 equipped with OsiriX Mobile medical image viewing software. All of the patients had surgical confirmation or follow-up evaluations to confirm whether or not they had appendicitis.

"The scans can be read in full resolution with very little panning, and the software allows the reader to zoom and adjust the contrast and brightness of the image," Dr. Choudhri said. "The radiologist is evaluating actual raw image data, not snapshots." 

Fifteen of the 25 patients were correctly identified as having acute appendicitis on 74 (99 percent) of 75 interpretations, with one false negative. There were no false positive readings. In eight of the 15 patients who had appendicitis, calcified deposits within the appendix were correctly identified in 88 percent of the interpretations. All 15 patients had signs of inflammation near the appendix that were correctly identified in 96 percent of interpretations, and 10 of the 15 had fluid near the appendix, which was correctly identified in 94 percent of the interpretations. Three abscesses were correctly identified by all five readers. 

"The iPhone interpretations of the CT scans were as accurate as the interpretations viewed on dedicated picture archiving and communication system (PACS) workstations," Dr. Choudhri said. 

Dr. Choudhri pointed out that patient privacy concerns would have to be addressed before any handheld mobile device could be considered practical for clinical use, but noted that this technique has great potential for improving emergency room care. 

"We hope that this will result in improved patient outcomes, as evidenced by decreased rates of ruptured appendicitis, shorter hospital stays and fewer complications," he said.

Source: Radiological Society of North America

New stem cell technology leads to better treatment for complicated bone fractures

    A novel technology involving use of stem cells, developed by Hebrew University of Jerusalem researchers, has been applied to provide better and rapid healing for patients suffering from complicated bone fractures.

The technology, involving isolation of the stem cells from bone marrow, was developed by Dr. Zulma Gazit, Dr. Gadi Pelled, Prof. Dan Gazit and their research team at the Skeletal Biotechnology Laboratory at the Hebrew University Faculty of Dental Medicine and was given public exposure in an article that appeared in the prestigious journal Stem Cells. The technology has now successfully been used to treat complicated fractures in seven patients at the Hadassah University Hospital in Ein Kerem, Jerusalem.

To date, in clinical orthopedics, standard treatment for severe bone loss has involved either amputation or a prolonged period of disability. The use of prosthetic implants tends to fail in the long term. Excessive bone loss may result in non-uniting fractures, which are observed in more than one million new cases per year in the US alone.

In recent years, the use of mesenchymal stem cells (MSCs, or multipotent stem cells that can differentiate into a variety of cell types) has been claimed to be a promising biological therapy that could be used to treat complicated fractures and other disorders in the skeleton. These cells constitute a unique population of adult stem cells that can readily be isolated from various sites in the human body, especially from bone marrow and adipose (fat) tissues. Following isolation, MSCs can be utilized to repair a variety of injured tissues including bone, cartilage, tendon, intervertebral discs and even the heart muscle.

The conventional method of MSC isolation, using prolonged periods of growth in designated incubators, has proved to be laborious, costly and also possibly injurious to the therapeutic quality of the cells. Therefore, an alternative method involving the immediate use of these stem cells was an unmet need in the field of regenerative medicine.

Now, the Hebrew University group has developed a technology called immuno-isolation in which MSCs are sorted out from the other cells residing in a bone marrow sample, using a specific antibody. In the Stem Cell paper it was shown that the immuno-isolated cells could be immediately used to form new bone tissue when implanted in laboratory animals, without having to undergo a prolonged incubator growth period.



Following this breakthrough, a unique and close collaboration was established among clinicians (Prof. Meir Liebergall, head of orthopedics, Hadassah University Hospital), the Good Manufacturing Practice (GMP) facility at Hadassah (Headed by Prof. Eithan Galun) and the Gazit group at the Faculty of Dental Medicine.
Within this collaborative effort, a clinical-grade protocol for the use of immuno-isolated MSCs was established. Subsequently a clinical trial was initiated at Hadassah, aimed at establishing the foundation for the use of immuno-isolated MSCs in orthopedic surgery. 

To date, seven patients suffering from complicated fractures have been treated successfully with a combination of their own immuno-isolated MSCs and blood products. The entire procedure lasted a few hours and without any need to grow the cells for weeks in a laboratory.


It is anticipated that future development of the current endeavor will extend to treat other injuries in the skeleton, such as degenerated intervertebral discs or torn tendons. The Gazit group believes that further clinical trials will demonstrate that the immuno-isolation technology is useful in overcoming morbidity in patients suffering from skeletal fractures and diseases, and might restore function and quality of life to sick and injured people.

In this regard, Yissum Research Development Company of the Hebrew University of Jerusalem, the technology transfer arm of the university, licensed the immuno-isolation technology to TheraCell Inc. of California in July 2009. TheraCell aims to further develop and commercialize the technology for advanced regenerative medicine procedures such as spinal fusion.

New genetic cause of cardiac failure discovered

Over the course of a lifetime, the heart pumps some 250 million liters of blood through the body. In the order to do this, the muscle fibers of the heart have to be extremely durable. The research group headed by Dr. Wolfgang Rottbauer, vice chair of the Department of Medicine III at Heidelberg University Hospital (Germany), has discovered a protein that is responsible for the stability of the smallest muscular unit, the sarcomere.

In cooperation with other researchers within the National Genome Research Network they proved that mutations of this protein are the cause of a new type of heart failure. The results have been published in the November issue of Nature Medicine.
Primary heart muscle disease with decreased cardiac pump function leading to enlargement of the heart chambers (dilated cardiomyopathy) is one of the most frequent causes of chronic heart failure. Six new cases per 100,000 people occur each year; 20 percent of these cases are genetic. The heart disease weakens cardiac cells and the heart can no longer pump efficiently which leads to dilation of the cardiac chambers.

Muscle activity takes place in the smallest unit of muscle fiber, the sarcomere. In the presence of an appropriate stimulus, actin and myosin filaments interact and contract the muscle. These movable elements are anchored in what are known as Z-disks. With every heartbeat, enormous forces act on the Z-disks.
Torn Z disks weaken the heart.


"In our studies of zebrafish, we discovered a protein that is needed to stabilize the Z-disk. If this protein (nexilin) is mutated, the movable muscle elements are no longer anchored firmly enough. The muscles then lose strength and the heart is weakened," explains Dr. Tillman Dahme, resident and co-author of the study. The researchers examined the genetic material of affected patients and verified a mutated Z-disk protein in 9 of 1000 participants. They showed that in these patients, the defective nexilin was the major cause of heart disease. "The nexilin dilated cardiomyopathy allowed us for the first time to describe a new form of heart muscle dilatation and define the mechanism causing it, namely destabilization of the Z-disk," says Dahme.
The studies also showed that the extent of the damage to the Z-disk is directly related to the workload. This insight has an influence on clinical therapy. "Patients with a nexilin mutation might benefit from early treatment with medications that reduce cardiac stress. This could lower the mechanical stress on the Z-disks and prevent progressive damage to the heart," said Dr. Rottbauer.