Day: 03/10/2011

The great debate: haploidentical or cord blood transplant

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One of the truly revolutionary advances in hematopoietic cell transplantation (HCT) is the increasingly successful use of alternative donors, thereby allowing the delivery of a potentially curative transplant to ~75% of patients who do not have an HLA-matched sibling donor. A substantial proportion of the need has been met by HLA-matched volunteer unrelated donors, but an unmet need still exists, particularly among minority populations and for people who need a more immediate source of hematopoietic cells. Two such sources, umbilical cord blood (UCB) and haploidentical related donors, have filled most of this need, and outcomes following transplants from these donor sources are very promising. UCB has the advantages of ready availability and is less capable of causing GVHD but hematological recovery and immune reconstitution are slow. Haploidentical HCT is characterized by the nearly uniform and immediate availability of a donor and the availability of the donor for post transplant cellular immunotherapy, but is complicated by a high risk of GVHD and poor immune reconstitution when GVHD is prevented by vigorous ex vivo or in vivo T-cell depletion. This review will discuss the pertinent issues that affect the choice of one donor source over another and offer recommendations regarding the optimal utilization of these donor sources.

source: nature

 

New Genetic Links to Heart Disease Risk

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Researchers Identify New Gene Regions Associated With Coronary Artery Disease

March 8, 2011 — Three studies have identified a large number of genes linked to the development of heart disease among Europeans, South Asians, and Chinese people.

The discoveries more than double the number of genes previously associated with heart disease, the No. 1 one killer in Western countries and a major health threat in China and other parts of Asia.

The studies are published in the online edition of Nature Genetics.

In the study focusing on Europeans, the genes of more than 135,000 people were analyzed. Researchers compared healthy people with those who had been diagnosed with coronary artery disease (CAD). They found, in addition to the 10 previously known gene regions for CAD, 13 new gene regions. The findings were unexpected.

“The majority reside in gene regions that were not previously suspected in the pathogenesis of CAD,” the researchers write.

Genetics play a major role in the development of heart disease. Identifying genes that put people at increased risk could aid in the development of both prevention strategies and new treatments. But first, more study is needed to determine how the genes contribute to CAD.

“Understanding their mechanisms will not only improve our understanding of the disease process but could also ultimately help to develop new treatments,” Nilesh Samani, cardiologist and co-lead of the project from the University of Leicester in the U.K., says in a news release.

Six of the 23 confirmed genes in the study could be linked to known risk factors for CAD such as cholesterol and high blood pressure.

A Visual Guide to Heart Disease

Europeans and South Asians Share Similar Genetic Risks

In a separate study, researchers comparing the genetic risks to CAD carried by Europeans and South Asians (primarily from India and Pakistan) found another five gene regions linked to the disease. What they weren’t able to find were risk factors unique to either population; both shared the same genetic susceptibility.

The study researchers also report that the five newly discovered gene regions play a smaller role in heart disease than the gene regions that had already been identified. They speculate that the major heart disease genes may already have been found, but that there may be many less potent — and as yet unknown — genes that contribute to the disease, a goal of future studies.

“Even broader collaborations would identify additional variants that influence CAD risk,” the researchers suggest.

Chinese May Have Unique Genetic Risk

The third study was a first of its kind: a genome-wide association study of Chinese, in particular Han Chinese. Like the other two studies, this one sought to identify genetic risk factors for heart disease, which kills an estimated 700,000 Chinese each year.

The research team identified a single previously unsuspected genetic risk factor, one that is not associated with heart disease in Europeans. They believe that it is possible that it might be a risk unique to Chinese, though how it works is unknown. One theory they offer is that environmental and lifestyle differences — the two other major determinants of heart disease risk — may explain why the gene region is triggered among Chinese but not in people in other parts of the world.

“Further studies may be needed to identify the causative variant(s) for CAD [in this gene region],” the researchers conclude.

source: webMD

Olmesartan Delays Microalbuminuria in Diabetes

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Olmesartan Delays Microalbuminuria in Diabetes, but with Risks
Olmesartan, an angiotensin-receptor blocker, delays the development of microalbuminuria in patients with type 2 diabetes and well-controlled blood pressure, but its use is associated with an increased risk of death from cardiovascular events, according to a New England Journal of Medicine study.
The ROADMAP trial, sponsored by the drug’s manufacturer, randomized some 4500 diabetic patients with normoalbuminuria to daily olmesartan or placebo. In addition, participants’ blood pressures were treated to maintain values under 130/80 mm Hg.
After a median 3-year follow-up, the olmesartan group showed a significant advantage over placebo in delaying time to onset of microalbuminuria (the primary outcome). However, fatal cardiovascular events were more common with olmesartan.
An editorialist writes that the finding of delayed microalbuminuria was not unanticipated. And given the increased cardiovascular mortality found with olmesartan, she asks why wouldn’t other renin-angiotensin blocking drugs be prescribed if they are not associated with fatal complications?

Source:NEJM article

First New Lupus Drug in a Half-Century Approved

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The FDA has approved belimumab (Benlysta) to treat patients with systemic lupus erythematosus who are already receiving standard treatment. Belimumab, a fully human monoclonal antibody that targets the B-lymphocyte stimulator protein, is the first new lupus therapy in over 50 years.
In two trials comprising some 1700 patients with lupus, those treated with belimumab plus standard therapy had less disease activity than patients who receive placebo plus standard therapy. The belimumab group may have had fewer severe flares, but the studies were not conclusive. Patients taking belimumab had a higher rate of death and serious infection than the placebo group.
In these studies, the treatment did not seem effective in people of African or African American heritage, but the study populations weren’t large enough to make definitive conclusions. The FDA has asked the manufacturer to undertake another trial in this subgroup.

Source:FDA news release

Nano-sized vaccines

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MIT engineers have designed a new type of nanoparticle that could safely and effectively deliver vaccines for diseases such as HIV and malaria.

The new particles, described in the Feb. 20 issue of Nature Materials, consist of concentric fatty spheres that can carry synthetic versions of proteins normally produced by viruses. These synthetic particles elicit a strong immune response — comparable to that produced by live virus vaccines — but should be much safer, says Darrell Irvine, author of the paper and an associate professor of materials science and engineering and biological engineering.

Such particles could help scientists develop vaccines against cancer as well as infectious diseases. In collaboration with scientists at the Walter Reed Army Institute of Research, Irvine and his students are now testing the nanoparticles’ ability to deliver an experimental malaria vaccine in mice.

Vaccines protect the body by exposing it to an infectious agent that primes the immune system to respond quickly when it encounters the pathogen again. In many cases, such as with the polio and smallpox vaccines, a dead or disabled form of the virus is used. Other vaccines, such as the diphtheria vaccine, consist of a synthetic version of a protein or other molecule normally made by the pathogen.

When designing a vaccine, scientists try to provoke at least one of the human body’s two major players in the immune response: T cells, which attack body cells that have been infected with a pathogen; or B cells, which secrete antibodies that target viruses or bacteria present in the blood and other body fluids.

For diseases in which the pathogen tends to stay inside cells, such as HIV, a strong response from a type of T cell known as “killer” T cell is required. The best way to provoke these cells into action is to use a killed or disabled virus, but that cannot be done with HIV because it’s difficult to render the virus harmless.

To get around the danger of using live viruses, scientists are working on synthetic vaccines for HIV and other viral infections such as hepatitis B. However, these vaccines, while safer, do not elicit a very strong T cell response. Recently, scientists have tried encasing the vaccines in fatty droplets called liposomes, which could help promote T cell responses by packaging the protein in a virus-like particle. However, these liposomes have poor stability in blood and body fluids.

Irvine, who is a member of MIT’s David H. Koch Institute for Integrative Cancer Research, decided to build on the liposome approach by packaging many of the droplets together in concentric spheres. Once the liposomes are fused together, adjacent liposome walls are chemically “stapled” to each other, making the structure more stable and less likely to break down too quickly following injection. However, once the nanoparticles are absorbed by a cell, they degrade quickly, releasing the vaccine and provoking a T cell response.

In tests with mice, Irvine, postdoctoral associate James Moon (lead author of the paper) and their colleagues used the nanoparticles to deliver a protein called ovalbumin, an egg-white protein commonly used in immunology studies because biochemical tools are available to track the immune response to this molecule. They found that three immunizations of low doses of the vaccine produced a strong T cell response — after immunization, up to 30 percent of all killer T cells in the mice were specific to the vaccine protein.

That is one of the strongest T cell responses generated by a protein vaccine, and comparable to strong viral vaccines, but without the safety concerns of live viruses, says Irvine. Importantly, the particles also elicit a strong antibody response. Niren Murthy, associate professor at Georgia Institute of Technology, says the new particles represent “a fairly large advance,” though he says that more experiments are needed to show that they can elicit an immune response against human disease, in human subjects. “There’s definitely enough potential to be worth exploring it with more sophisticated and expensive experiments,” he says.

In addition to the malaria studies with scientists at Walter Reed, Irvine is also working on developing the nanoparticles to deliver cancer vaccines and HIV vaccines. Translation of this approach to HIV is being done in collaboration with colleagues at the Ragon Institute of MIT, Harvard and Massachusetts General Hospital. The institute, which funded this study along with the Gates Foundation, Department of Defense and National Institutes of Health, was established in 2009 with the goal of developing an HIV vaccine.

source: MIT

Exploiting cancer cells’ weaknesses

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When designing new cancer drugs, biologists often target specific gene mutations found only in cancer cells, or in a subset of cancer cells. A team of MIT biologists is now taking a slightly different approach, targeting a trait shared by nearly all cancer cells — they have too many chromosomes.

MIT biology professor Angelika Amon has been studying this peculiarity, known as aneuploidy, for several years. In developing fetuses, aneuploidy causes death or birth defects. However, in cancer cells, aneuploidy appears to confer a survival advantage.

“We’re interested in this because the vast majority of human cancers are aneuploid,” says Amon, a member of the David H. Koch Institute for Integrative Cancer Research. “The question arises, can we exploit the fact that all tumor cells are aneuploid for treatment? Compounds that selectively kill aneuploid cells would be effective against a broad spectrum of human tumors.”

In a study published Feb. 18 in the journal Cell, Amon and her colleagues identified three such compounds, and they are now running a large-scale screen of thousands of compounds, with researchers from Harvard, to identify even more drug candidates. Lead author of the paper is Yun-Chi Tang, a postdoctoral fellow at the Koch Institute.

Cell stress

Amon has previously shown that aneuploid cells divide very slowly and grow too large. Aneuploidy also puts significant stress on cells: It takes a lot of energy to replicate all of that extra genetic material, and to produce the proteins encoded by those extra genes. Furthermore, the cells then have to break down all those proteins, since they’re not needed. “Cells have a limited number of tools available to deal with extra proteins,” Amon says. “These pathways get stressed and they can’t keep up.”

In the Cell study, Amon selected about 20 potential drug compounds that might exploit those weaknesses. “We said, maybe we can enhance those stresses and induce lethality. The hope is to enhance it to a level that does not affect normal cells but would affect aneuploid cells more,” she says.

The researchers tested the compounds in mouse embryonic fibroblasts that have an extra chromosome, and then in human cancer cells. They identified three compounds that preferentially targeted the aneuploid cells (both human and mouse): chloroquine, a drug commonly used to treat malaria, and two other compounds called AICAR and 17-AAG.

AICAR stresses cells by activating an enzyme called AMPK, which cranks up cellular metabolism. 17-AAG inhibits the production of a protein involved in stabilizing other proteins that cancer cells need to grow. Chloroquine acts by blocking a cancer cell’s ability to rid itself of damaged proteins and cell structures.

Amon says she believes the drugs are exaggerating the stresses of aneuploidy, but more experiments are needed to show that.

All three compounds induce human cancer cells to kill themselves, but they work much better when two are used together. 17-AAG is already in clinical trials for leukemia, but these new data suggest that it would be better used in combination with other drugs, Amon says.

AICAR is not approved for human use, but a similar drug called metformin is used to treat diabetes. However, metformin did not perform as well in this study as AICAR.

Pumin Zhang, professor of molecular physiology at Baylor College of Medicine, says the results represent a significant step toward finding drugs that specifically target cancer cells, unlike most of the chemotherapy drugs now available. “It shows there is a clear difference between normal cells and aneuploid cancer cells, and we can exploit that difference,” says Zhang, who was not involved in this research.

source MIT

Harmful Immune Reactions Might One Day Be Curbed with Cell-Based Therapy

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A team of researchers led by Memorial Sloan-Kettering immunologist Alexander Rudensky has gained new understanding about regulatory T cells — a subtype of immune cells that suppresses the immune system’s reactivity. Their findings, published in Science, raise hope that these cells could be used as therapy in patients with immune-system-related conditions. [PubMed Abstract]

Regulatory T cells are critical for life, Dr. Rudensky explained. “In their absence, the immune system — instead of attacking foreign intruders — strikes against normal cells and tissues, causing inflammatory responses that can be fatal.”

In recent years, he and other scientists have studied the cells closely, positing that regulatory T cells one day could be manipulated in the clinic — for example, to prevent dangerous immune reactions in patients with autoimmune disorders such as multiple sclerosis or rheumatoid arthritis, or in cancer patients who have received bone marrow transplants from donors.

But it remained to be established that regulatory T cells could be exploited safely. “Concerns have been raised that regulatory T cells under certain conditions — for example, in a disease setting — might be induced to transform into other T cell types of the immune system,” explained Dr. Rudensky, “in effect changing the cells’ function.” If such change of function occurred in a patient whose immune system was already overactive, the cells could potentially boost that immune system even further, instead of calming it down.

By performing experiments in genetically engineered mice, the researchers were able to examine the lifespan of regulatory T cells in a mouse’s body. The study showed that the cells are constantly being replenished as they divide to yield identical copies and so remain stable, their function unchanged — both under normal conditions and when a mouse’s immune system had been challenged by infection or autoimmune reaction. “Our findings give reassurance that future therapies based on regulatory T cells could provide a durable and safe way to control a patient’s immune system,” Dr. Rudensky noted.

source: MSKCC

Shiatsu

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Shiatsu is a form of bodywork, which uses hand pressure and
manipulative techniques to eliminate energy imbalances within organ
systems and maintain health. Shiatsu is a Japanese word “shi” means
finger and “atsu” means pressure. The practice of shiatsu is
characterized by its great simplicity and to an untrained observer it
may appear as though very little is happening. During a shiatsu
session the practitioner stimulates various pressure points on the
body with his or her hands or thumb. They may also include applying
pressure with the elbows or a simple rotation of a limb. While it
appears as though little is happening on a physical level there is a
lot happening internally to the body’s energy. The traditional
Japanese word ki is used to describe the bodys vital energy. In
Oriental medicine, harmony of ki within the human body is essential
to health. As the shiatsu practitioner stimulates points on the body
it opens energy pathways and moves stagnant ki. When Ki become
sluggish it can manifest into a physical imbalance so by stimulating
ki it prevents physical symptoms. Research has shown that shiatsu is
helpful in relieving back pain and muscle tension, as well as
improving sleep patterns.

Early practitioners of Shiatsu had the creativity and integrity to
develop their own styles. Some styles concentrate on acupressure
points, others emphasize on the five-element approach or another
aspect of traditional Chinese medicine. Acupressure Shiatsu focuses
specifically upon acupuncture points. Five Element Style Shiatsu
relies mainly upon the Five Element theory of Traditional Chinese
Medicine, especially in relation to the emotions, and incorporates
some macrobiotic principles. Macrobiotic Shiatsu incorporates the
acupuncture meridians. Nippon Style Shiatsu places great emphasis on
Western physiology, but with the addition of Chinese medical theory
and the classical energy channels. Zen Shiatsu uses tonification and
sedation principals, an extended energy channel system, and a
condensed synthesis of Traditional Chinese Medicine, Western
physiology and psychology. Oha Shiatsu incorporates aspects of Zen
Shiatsu, and the use of classical acupoints and channels. The styles
of shiatsu may vary but ultimately the effectiveness depends upon the
attitude, proficiency and attunement of the practitioner.

Tokojiro Namikoshi developed the Namaikoshi Shiatsu style and has
helped establish shiatsu as an international therapy. Tokujiro
Namikoshi was born on November 3, 1905 on the Japanese Island of
Shikoku. When Namikoshi was 7 years old he and his family moved to
the northern Island of Hokkaido, which had a much cooler climate.
Once there, Namikoshi’s mother began suffering from what is known
today as rheumatoid arthritis. To alleviate the growing pain
Namikoshi began stroking and pressing the painful parts of her body.
This reduced his mother’s pain and allowed his hands to develop a
sensitivity to the condition of her body. Soon the young therapist
realized the greatest healing benefit was achieved when he pressed
the body 80% of the time and rubbed it 20%. In time he cured his
mother’s condition. This experience intrigued Namikoshi to study the
human body and eventually he systemized his thumb pressure into the
Namikoshi shiatsu method. In 1925 he opened the Shiatsu Institute of
Therapy on Hokkaido. In 1953 Master Tokujiro Namikoshi Sensei and his
son introduced shiatsu to North America when he taught the healing art
at the Palmer Chiropractic School in Iowa. Now shiatsu has become
internationally accepted as an effective natural healing art form
throughout the world, including Europe, Canada, Australia, and New
Zealand.

source: GCNM

Clostridium difficile: Risk Factors for Infection

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Two studies highlight contamination of the hospital environment with C. difficile spores as a major risk factor.

The clinical and financial burdens of Clostridium difficile infection (CDI) are substantial and have been increasing over the last decade. Findings from two recent retrospective cohort studies provide further insights into the risk factors for such infection and could aid in preventive efforts.

Dubberke and colleagues collected data on all patients hospitalized for ≥48 hours at a Missouri medical center in 2003. After exclusion of patients in the bone marrow transplant and leukemia units and individuals with CDI during the preceding 60 days, 35,350 patients remained, including 329 with CDI. Significant risk factors for CDI included higher CDI pressure score (a measure of an individual’s total exposure to infectious CDI patients; odds ratio, 13.0), ≥2 hospitalizations within the preceding 60 days (OR, 2.7), older age (OR, 2.5), receipt of a gastric acid suppressor (OR, 2.1) or an antimotility drug (OR, 2.1), higher number of days receiving high-risk antibiotics (OR, 1.9), albumin level ≤3.5 g/dL on admission (OR, 1.7), and admission to an intensive care unit (ICU; OR, 1.6). A CDI risk prediction model developed using these variables appeared to have excellent but not perfect predictive accuracy, based on statistical measures that evaluate model discrimination.

Shaughnessy and colleagues assessed the effect of room assignment on CDI incidence at a 20-bed ICU in a Michigan medical center from January 2005 through June 2006. Among the 1770 patients with records available for analysis, 87 were determined to have acquired CDI after admission to the ICU. The incidence of CDI was significantly higher among patients admitted to a room in which the previous occupant had had CDI than among patients admitted to a room in which the previous occupant had not had CDI (11.0% vs. 4.6%; P=0.002). This risk factor remained significant after adjustment for age, Apache III score, proton-pump inhibitor use, and antibiotic exposure.

Comment: These studies are limited by their retrospective design and by the potential effect of variables that were not analyzed (nicely demonstrated by the absence of room assignment in Dubberke and colleagues’ model). Notably, however, both studies raise the issue of contamination of the hospital environment with C. difficile spores as a — if not the — major risk factor for nosocomial CDI. This issue deserves much greater attention than it has received in the past.

— Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases March 9, 2011

Wireless Monitoring of Pulmonary Artery Pressure in Patients with Heart Failure

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An implantable sensor reduced the rate of hospitalization for HF, but the difference in out-of-hospital time was slight.
Intense interest surrounds the development of implantable hemodynamic monitoring systems, designed to improve outcomes and reduce hospitalization rates in patients with heart failure (HF) by enabling management of derangements in physiologic parameters before they become clinically apparent. In a manufacturer-sponsored trial, researchers tested the effects of the Champion heart sensor on HF-related hospitalizations. Eligible patients had New York Heart Association class III HF of 3 months’ duration and a hospitalization for HF within the past year. A wireless pulmonary artery sensor was placed in all patients. Sensor data were available only to physicians caring for patients randomized to treatment; control patients received usual care.
About one third of the 550 participants (average age, 61; approximately 70% men) had a cardiac resynchronization therapy device. At 6 months, the rate of HF-related hospitalizations was significantly lower in the treatment group than in the control group (31% vs. 43%; P<0.001). The number of days alive outside the hospital was similar in the two groups (174 vs. 172), although the difference was statistically significant (P=0.02). During a total mean follow-up of 15 months, 15 sensor- or procedure-related complications occurred.
Comment: Despite the demonstrated benefit of this device with regard to HF-related hospitalization, the total number of days alive outside the hospital was not much different in the two groups, which may dampen the enthusiasm for this technology. All hospitalizations, not just those related to HF, constitute the endpoint of greatest interest to patients and policymakers.
— Harlan M. Krumholz, MD, SM
Dr. William T. Abraham, the senior author of this study and a founder of the sponsoring manufacturer, is a Contributing Editor for Journal Watch Cardiology. Dr. Abraham had no role in the selection of this article for summarization or in its review.
Published in Journal Watch Cardiology March 9, 2011