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Patients with type 2 diabetes or prediabetes are more likely to develop congestive heart failure (CHF) when given rosiglitazone or pioglitazone, as compared with controls. However these drugs did not increase the risk of cardiovascular death (CVD) for these patients.

These are the conclusions of authors of an Article published in The Lancet.

Additionally, a linked Editorial and two accompanying Comments discuss the importance of basing clinical decisions on trials which assess outcomes which most matter to patients - such as micro- and macro-vascular complications and quality and quantity of life - rather than simply the “surrogate outcome” of blood glucose control which all trials in the Article’s analysis are based.

In the Article, Dr Richard Nesto, Lahey Clinic Medical Centre, Burlington, MA, USA and colleagues did a meta-analysis (a combined analysis of previous studies) of seven randomised double-blind clinical trials of drug related congestive heart failure in patients with type 2 diabetes or prediabetes, who were given rosiglitazone or pioglitazone, from a family of drugs known as thiazolidinediones (TZDs). These trials featured 20191 patients. The main outcome measures were development of CHF and the risk of CVD.

The researchers found that the 72% increase in relative risk for CHF was observed across a wide background of cardiovascular risk - in patients with prediabetes, those with type 2 diabetes but no cardiovascular disease, those with both type 2 diabetes and cardiovascular disease, and those with type 2 diabetes and documented CHF. According to the authors, the absolute risk for CFH varied a great deal across these patient groups which should help clinicians select appropriate patients for TZDs when these drugs are prescribed.

The authors say that since the drug exposures in these trials were relatively short, and most patients did not have previous histories of CHF or evidence of left ventricular dysfunction at entry, the excess of CHF events related to TZDs was probably the result of TZD-related fluid retention and diastolic dysfunction in susceptible patients. They add, however, that the natural history of congestive heart failure when caused by TZD-related fluid retention is unknown.

They say: “Despite the glucose-lowering effect of TZDs, our data indicate that these drugs should not be used in patients with heart failure and should be cautiously used for glycaemic control in patients with cardiovascular disease who do not have heart failure. In patients with type 2 diabetes without cardiovascular disease in whom the absolute risk for CHF is much lower, the use of TZDs should be weighed against the risks and benefits of other antidiabetic medications.”

They conclude with a note of caution, saying: “Insufficient follow-up durations could have affected our conclusions about the association between CHF and cardiovascular mortality. We also did not have sufficient data to assess whether the risk of congestive heart failure differed between the two TZDs. We need longer follow-up and better characterisation of patients in whom CHF develops because of fluid retention to determine the effect of TZDs on overall cardiovascular outcome and whether CHF should be regarded as an adverse event or a characteristic cardiovascular endpoint.”

In the first Comment, Dr John Cleland and Dr Stephen Atkin, Department of Cardiology, Castle Hill Hospital, University of Hull, UK, say: “All the meta-analyses fail to spot the elephant in the room. Treatments should be effective, rather than merely innocuous. Improved glycaemic control is not a surrogate for effective care of patients who have diabetes, which should be to reduce disability and increase lifespan?the regulatory authorities need greater emphasis on ensuring that drugs have effects that are clinically relevant, both in their actions and extent, without stifling innovation in an industry that is valuable to society.”

In the second Comment, Dr Victor Montori, Mayo Clinic of Medicine, MN, USA, and colleagues say drugs based on trials with surrogate outcomes represent a false economy despite saving money initially and allowing new drugs more rapid access to the market. They say: “Any savings are quickly overwhelmed by expenses associated with potentially ineffective or even harmful (yet heavily advertised) expensive therapies?.patients and society may end up paying dearly for drugs that cause more harm than good.

“The medical community should insist that we invest the resources needed to do trials that ascertain the effect of interventions on patient-important outcomes.”

The linked Editorial says that future trials need to be designed with the issues pointed out by the commentators in mind. It concludes: “Manufacturers must do - in a timely fashion - postmarketing studies that assess the long-term safety of their drugs, and regulatory agencies must hold manufacturers’ feet to the fire to ensure that these are performed, performed properly, and thoroughly evaluated and made available to guide decisions about prescribing?unless limitations on the understanding, analysis, and communication of drug safety issues are addressed, the TZDs will simply become the latest in a series of preventable drug disasters.”

http://www.lancet.com

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The part of the prostate that is biopsied may matter more than the number of biopsy samples taken for accurately diagnosing prostate cancer, according to a study by researchers at SUNY Upstate Medical University.

The study is published in the Oct. 3 edition of the Journal of the National Cancer Institute .

It is difficult to know whether prostate biopsies are correctly identifying prostate cancer because men with prostate biopsies do not usually undergo surgery to have their prostates removed.

To determine the accuracy of prostate biopsies, Gabriel Haas, M.D., professor of urology at SUNY Upstate Medical University in Syracuse and colleagues performed biopsies on prostates from 164 deceased men who had no history of prostate cancer. Biopsies were taken from various areas of the prostate in an attempt to mirror the way biopsies are performed on live patients.

Almost 30 percent of the prostates had cancer cells, and 43 percent of those were clinically significant cancers as defined by tissue characteristics. Cancer detection depended more on the part of the prostate that was biopsied than on the number of samples that were taken.

“This information ? can assist the clinician to design the appropriate biopsy regimen to detect clinically significant cancers that pose biologic risk and avoid the overdiagnosis of clinically insignificant cancers that would be unlikely to have an adverse effect on the patient,” the authors write.

http://www.upstate.edu/

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Researchers at the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH) may have discovered a second molecular “switch” responsible for turning off the immune system’s response against HIV.

Last year members of the same team identified a molecule called PD-1 that suppresses the activity of HIV-specific CD8 T cells that should destroy virus-infected cells. Now the researchers describe how a regulatory protein called CTLA-4 inhibits the action of HIV-specific CD4 T cells that control the overall response against the virus. The report will appear in the journal Nature Immunology and is receiving early online release.

“We’ve shown that a known regulator of the immune system, CTLA-4, is present in elevated levels on the virus-specific CD4 cells that should be managing the body’s response against HIV, says Daniel Kaufmann, MD, of PARC and the MGH Infectious Disease Unit, a co-first author of the paper. “We also found that CTLA-4 expression rises as HIV infection progresses and that the molecule switches off CD4 cell function in a way that appears to be reversible.”

Expression of the CTLA-4 protein is known to be elevated on activated T cells, those that have encountered a pathogen and are multiplying rapidly to mount an immune response. Studies in cancer patients have shown that the molecule serves to dampen the immune response, and some preliminary investigations in animals and humans have suggested a potential role in HIV infection. The current study was designed to examine how CTLA-4 may be involved in the dysfunction of HIV-specific T cells that leads to the immune-system breakdown of AIDS.

The researchers first found that CTLA-4 was overexpressed on the HIV-specific CD4 T cells of infected individuals who had not yet received antiviral treatment. Levels were highest in those with symptoms of acute infection and second highest in chronically infected participants. CTLA-4 expression was lowest among a group of participants whose immune systems were naturally able to suppress HIV replication without antiviral medications - “elite controllers” in whom viral levels are too low to be detected.

Elevated CTLA-4 expression also correlated with signs of disease progression - increased viral load and reduced overall CD4 count. While antiviral treatment caused viral loads to drop significantly after treatment began, it resulted in only modest and slow drops in CTLA-4 expression. In vitro tests of the effects of blocking the CTLA-4 molecule improved the function of HIV-specific CD4 cells. Comparing the effects of blocking CTLA-4 with those of blocking PD-1 or both molecules produced functional improvements that varied considerably between participants, signifying a complex relationship between the pathways controlled by the two molecules.

“Both of these pathways contribute to dysfunction of HIV-specific T cells and both may be considered targets for therapeutic intervention. But since their mechanisms are so complicated, further study is needed before clinical trials can be planned,” says Kaufmann, an instructor in Medicine at Harvard Medical School (HMS).

“Understanding why the immune system fails to control HIV is essential for development of vaccines and new therapies” said Bruce Walker, MD, director of PARC-MGH and senior author of the study. “These studies suggest that the immune system is turning itself off prematurely in HIV-infected persons, and the big challenge now is to figure out if we can turn it back on, getting it to do what it is supposed to do, without causing collateral damage in the process.” Walker is a professor of Medicine at HMS and a Howard Hughes Medical Institute (HHMI) investigator.

http://www.mgh.harvard.edu/

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A popular prostate cancer treatment called androgen deprivation therapy may encourage prostate cancer cells to produce a protein that makes them more likely to spread throughout the body, a new study by Johns Hopkins researchers suggests.

Although the finding could eventually lead to changes in this standard treatment for a sometimes deadly disease, the Johns Hopkins researchers caution that their discovery is far too preliminary for prostate cancer patients or physicians to stop using it. The therapy is effective at slowing tumor growth, they emphasized.

David Berman, an assistant professor of pathology, urology and oncology at The Johns Hopkins University School of Medicine, and his colleagues identified the unsuspected potential problem with treatments that suppress testosterone after discovering that the gene that codes for the protein, called nestin, was active in lab-grown human prostate cancer cells.

Curious about whether prostate cancer cells in people also produce nestin, the researchers looked for it in cells taken from men who had surgery to remove locally confined cancers of their prostates and found none. But when they looked for nestin in prostate cancer cells isolated from patients who had died of metastatic prostate cancer - in which cancer cells spread out from the prostate tumor - they found substantial evidence that the nestin gene was active.

What was different, Berman speculated, is that androgen deprivation therapy, a treatment that reduces testosterone in the body, is generally given only when prostate cancers become aggressive and likely to metastasize.

Because prostate cancer growth is typically stimulated by testosterone, the treatment is thought to slow tumor growth and weaken the disease. Patients who eventually die because their disease metastasizes are almost certain to have received this type of therapy, he says.

Speculating that depriving cells of androgens might also, however, affect nestin expression, the researchers experimented on a prostate cancer cell line that depends on androgens to grow. When they removed androgens from the chemical mixture that the cells live in, their production of nestin increased.

Aware that the nestin gene has long been suggested to play some role in cell growth and development, Berman and his colleagues used a bit of laboratory sabotage called RNA interference to decrease the genetic expression of nestin and found that these cells weren’t able to move around and through other cells nearly as well as cells with normal nestin levels.

Prostate cancer cells with hampered nestin expression were also less likely than normal prostate cancer cells to migrate to other parts of the body when transplanted into mice. However, while nestin expression seemed pivotal for metastasis in these experiments, it didn’t seem to make a difference in tumor growth.

“What all this suggests is that nestin levels increased when prostate cancer cells are deprived of androgens and may encourage the cells to metastasize,” says Berman.

http://www.hopkinsmedicine.org/

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Surgeons at the Methodist DeBakey Heart Center in Houston have begun a new trial that will seek to protect patients from stroke by reversing blood flow in the brain during carotid stenting.

“By reversing blood flow in the brain, we hope to prevent small particles from reaching the brain and causing a stroke or problems with speech, memory or pain,” said Dr. Imran Mohuiddin, principal investigator and vascular surgeon at the Methodist DeBakey Heart Center.

During a typical carotid stenting procedure, a tiny metal scaffold is placed in a narrowed carotid artery to prop it open and ensure sufficient blood flow from the heart to the brain. During the stenting process, tiny bits of atherosclerotic debris can come loose and flow into the brain, restricting or blocking oxygenated blood from reaching the brain. By reversing the flow, this debris will not flow towards the brain, so risk of injury may be reduced.

The Gore Neuroprotection System is an investigational device that employs tiny balloons to reverse blood flow. This neuroprotective device will be inserted via catheter in the patient’s groin. One tiny balloon will be inflated in the common carotid artery, the main artery of the neck. Another tiny balloon will be inflated in the outer branch of the main artery, the external carotid artery. This causes blood to flow away from the head, allowing loose particles will flow away from the brain.

While the blood flow reversal is active, the surgeon will place the stent in the diseased carotid artery via a catheter in the groin. When the stent is in place, the two balloons will be deflated and blood flow will return to normal.

The EMPiRE (Embolic Protection with Reverse Flow) study is a multi-site trial supported by W.L. Gore & Associates. The study targets patients who are at high risk for carotid endarterectomy, the alternative open surgical procedure that does not use less-invasive catheter-based technology. Fifteen people will take part in this study at Methodist.

http://www.debakeyheartcenter.com

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The Society for Women’s Health Research gathered three lung cancer experts on Capitol Hill on September 17, 2007 to inform Congress on the need for increased funding to research lung cancer and its impact on women.

“We focused on lung cancer today because lung cancer is the leading cause of cancer death for both women and men in America,” said Phyllis Greenberger, M.S.W, president and CEO of the Society, a Washington, D.C. based advocacy organization. “A growing body of research is showing differences in susceptibility, progression and responsiveness to treatment in lung cancer between women and men.”

Laurie Fenton Ambrose, president and CEO of the Lung Cancer Alliance said, “More people are recognizing lung cancer, which has been stigmatized for so long as a self-imposed condition, as a disease. That’s the good news.” The bad news is that the five-year survival rate has only grown from 12 percent in 1971 to 15 percent today.

According to the Lung Cancer Alliance, lung cancer kills over 70,800 women a year, 30,000 more than breast cancer. Yet lung cancer research is severely under funded. In 2006, the National Cancer Institute spent approximately $13,519 for research on breast cancer per death compared to only $1,638 on research per lung cancer death.

Joan Schiller, M.D., chief of the Division of Hematology and Oncology and deputy director of the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center in Dallas, pointed to the changing face of lung cancer.

The death of actress and nonsmoker Dana Reeve in 2006 drew attention to the disturbing fact that nonsmokers account for 13-15 percent of new lung cancer cases each year. Unfortunately, there is little information on why nonsmokers develop lung cancer. Air pollution and exposure radon or asbestos have been linked to lung cancer risk, but most experts believe that second hand smoke is the leading risk for lung cancer among individuals who have never smoked.

There is conflicting data about whether women nonsmokers are more susceptible to lung cancer than men, but a study in the Journal of Clinical Oncology last February found that about 20 percent of lung cancer cases in women occur in nonsmokers, compared to eight percent in men.

Research is underway to examine whether the biological traits of being a woman or a man impacts lung cancer susceptibility.

Jill Siegfried, Ph.D., professor and vice chair of pharmacology at the University of Pittsburg School of Medicine and co-director of the Lung and Esophageal Cancer program at the Pittsburgh Cancer Institute, spoke at the briefing about her research involving estrogen’s role in lung cancer development.

“We’ve learned that lung tumors have the ability to use estrogen pathways to stimulate growth,” Siegfried said. “Anti-estrogens and aromatase inhibitors, drugs that prevent the body from responding to or making estrogen, may benefit lung cancer patients who have an active estrogen pathway.”

All of the experts agreed that more research is needed so that we can save lives with improved diagnosis and treatment.

http://www.womenshealthresearch.org/

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A research paper confirms what medical charity Group B Strep Support has been saying for years - that testing pregnant women for group B strep would save lives and save the government money.

The article in the British Medical Journal reports that most group B Streptococcal (GBS) infection in newborn babies could be prevented by changing current best practice. The report found that offering testing for group B Strep carriage to all pregnant women was the most cost effective option, with antibiotics being offered in labour where GBS is found.

The research estimates that this will save the Government GBP37 million a year.

Jane Plumb, Chairman of Group B Strep Support said:

“It would be madness to ignore this crucial piece of research. It will save money. It will save babies’ lives. And it will save parents having to stand by as their baby suffers needlessly. That’s got to be a win-win strategy, which the Government has to implement and now!”

Group B Strep causes infections such as meningitis, septicaemia and pneumonia. It affects 700 babies every year in the UK, killing 75 and leaving 40 with serious long-term mental or physical problems. GBS infection can usually be prevented by giving antibiotics during labour to women whose babies are most at risk of developing these infections.

The research paper evaluates the cost-effectiveness of various strategies for preventing neonatal infection with GBS and other bacteria. The authors say that current best practice is not cost-effective. Current best practice involves offering intravenous antibiotics only to women in high risk situations - who have previously had a baby with a GBS infection, who have incidentally tested positive for GBS during pregnancy or who have a fever in labour.

The research results show the most cost-effective option that minimises antibiotic usage is to treat all women in premature labour as well as all those in high risk situations, and to test all other pregnant women and then treat those found to carry GBS. The report recommends immediate extension of current practice.

Jane Plumb continues: ‘We need to offer women testing for group B Strep carriage late in pregnancy and, if GBS is found, then they need to decide, with their health professionals, what action if any to take in labour”.

http://www.gbss.org.uk

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Fetal cells that persist in a woman’s body long after pregnancy - a common occurrence known in scientific circles as fetal microchimerism - in some cases may reduce the woman’s risk of breast cancer, according to researchers at Fred Hutchinson Cancer Research Center.

The findings, published in the Oct. 1 issue of Cancer Research, add to the Jekyll and Hyde characteristics of fetal microchimerism, or FMc, which has been found to be both detrimental and beneficial to women’s health.

In this latest prospective study, scientists V.K. Gadi, M.D., Ph.D. and J. Lee Nelson, M.D., examined the blood of 82 women post-pregnancy, 35 of whom had had breast cancer. They looked for male DNA in the blood, presuming it was present due to a prior pregnancy. Fetal microchimerism (FMc) was found significantly more often in healthy women than women with a history of breast cancer, 43 percent versus 14 percent respectively. The scientists concluded that FMc may contribute to reduction of breast cancer based on the hypothesis that residual fetal cells may provide immune surveillance of malignant cells in the mother. They caution that further studies are needed to confirm the theory.

“To our knowledge, the current results provide the first indication that FMc could impart a protective effect against breast cancer,” Gadi said.

Prior research into FMc, some of it performed at the Hutchinson Center, indicates that while the presence of fetal cells in women may confer immune protection and promote cell repair, such cells also may be harbingers of some autoimmune diseases.

Two observations provided a rationale for the study hypothesis of the potential beneficial role of fetal cells, according to the authors. It is well established that women who have given birth have a lower risk of breast cancer. And, allogeneic (from another individual) stem-cell transplants are used to treat many types of blood cancers by replacing a diseased immune system with a healthy one

Additionally, fetal cells are commonly found in the circulating blood of healthy women who have given birth. Fetal cells represent a naturally acquired source of allogeneic immune cells; in prior studies the prevalence of T, B, natural-killer (NK) and antigen-presenting cells of fetal origin in healthy women ranged from 30 percent to 70 percent, depending on the cell type. The research was funded by the National Institutes of Health and Amgen Inc.

http://www.fhcrc.org/

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As policy makers debate what levels of ozone in the air are safe for humans to breathe, studies in mice are revealing that the inhaled pollutant impairs the body’s first line of defense, making it more susceptible to subsequent foreign invaders, such as bacteria.

While it has long been known that exposure to ozone, a major component of urban air pollution, is associated with increased cardiovascular and pulmonary hospitalizations and deaths, the actual mechanisms involved remain unclear. New studies by Duke University Medical Center pulmonary researchers on the effects of ozone on the innate immune system, the body’s “tripwire” for foreign invaders, may provide part of the answer.

The Duke-led team found that ozone exposure in mice at levels approximating unhealthy levels for humans appears to enhance lung injury in response to bacterial toxins, but more importantly, it also appears to enhance programmed cell death in critical innate immune system cells that gobble up foreign invaders, keeping the airways clear.

“Small amounts of inhaled foreign material can be relatively harmless, since they stimulate an appropriate innate immune response that protects the lungs,” said John Hollingsworth, M.D., pulmonologist and lead author of study whose results appear Oct. 1 in the Journal of Immunology. “However, it appears that ozone causes the innate immune system to overreact, killing key immune system cells, and possibly making the lung more susceptible to subsequent invaders, such as bacteria.”

The innate immune system is the most primitive aspect of the body’s defenses. Its cells react indiscriminately to any invader. One of the key cells in the innate immune system is known as a macrophage, Greek for “big eater.”

For their experiments, the researchers had mice breathe either room air or air with levels of ozone meant to mirror what an exercising human would experience on a high, or unhealthy, ozone level day. After exposing all mice to the active portion of E. coli bacteria in aerosol form, the researchers studied how the innate immune system responded.

“In the mice exposed to ozone, the airways of the lungs were hyperactive and we found higher concentrations of inflammatory cells,” Hollingsworth said. “But more significantly, ozone pre-exposure reduced the number of macrophages in the lung after secondary exposure to inhaled bacterial endotoxin. Exposure to ozone in this context had stimulated them to undergo programmed cell death, or apoptosis.”

The researchers also found that the effect of the inhaled ozone was not limited to just the lungs. Mice exposed to ozone were also found to have lower levels of immune system cells circulating in the blood.

The Duke team plans further studies on the mechanisms behind ozone’s ability to induce cell death in macrophages in the lungs. They will also focus on the pollutant’s ability to interfere with system-wide immune responses.

The Environmental Protection Agency is in the final phases of reviewing and possibly updating the standards for allowable levels of ozone in the air. The current standard says that any amount greater than 85 parts per billion can be unhealthy for those at risk. Many medical groups, including the American Thoracic Society, recommend setting a stricter standard of 60 parts per billion, citing studies showing ozone’s adverse effects on health, especially in children and those with compromised health.

http://www.dukehealth.org/

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In the October 1 issue of G&D, Dr. Guillermo Oliver (St. Jude Children’s Research Hospital) and colleagues present new evidence to resolve a century-old debate over the origin of the mammalian lymphatic vasculature.

Understanding the development of the lymphatic vasculature is integral to understanding its function in both health (mediating immunity and maintaining tissue fluid levels) and disease (lymphedema and spreading tumor metastasis).

The adult mammalian lymphatic vasculature is derived from a few embryonic lymph sacs. The debate has surrounded the cellular origin of the lymphatic vasculature: Does it arise from venous endothelial cells or does it arise in the mesenchyme and then establish venous connection later on in development”

Dr. Oliver and colleagues used genetically modified mice to perform elegant lineage tracing experiments, from which they concluded, quite definitively, that the mammalian lymphatic vasculature is venous-derived.

“Identifying the origin of any specific cell type is critical to understand the basic processes guiding the development of an organ. The detailed characterization of the formation of a normal healthy lymphatic vasculature is central to our efforts to prevent, diagnose, and hopefully cure lymphatic vasculature disorders,” explains Dr. Oliver.

http://www.cshl.org/

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