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In Vivo
Breakthrough

Blacks, Hispanics Fare Worse During Wait For Lung Transplant
Idiopathic pulmonary fibrosis (IPF) is a terrible disease with no known cause and a median survival rate of only three years. Lung transplantation is the only treatment.
   Black and Hispanic patients on the waiting list for a new lung, however, have a 30 percent greater mortality rate than white patients, according to a CUMC study of 2,635 IPF patients. The disparity could not be explained by increased age (black and Hispanic patients were actually four to five years younger than whites), the presence of other diseases, the rate of lung transplantation, or socioeconomic factors.
   The only difference that explained the disparity was disease severity, says the study’s lead author, David Lederer, M.D., assistant professor of clinical medicine. Blacks and Hispanics were sicker than whites when placed on the waiting list.
   “We now need to sort out why minorities have more severe disease at the time of listing,” Dr. Lederer says. To get on the lung transplant list, patients must be referred to lung transplant centers by their primary physicians. Because the symptoms of IPF can mimic those of heart failure, asthma, and chronic obstructive pulmonary disease, many people are misdiagnosed, especially if they don’t have access to good health care, Dr. Lederer says. He and his colleagues are starting a five-year prospective study at CUMC’s lung transplant center to determine the reasons for the disparity in mortality.
Amer J Transplant 2006 6: 2436-2442
The research was supported by the NIH, the Martin and Ellen Strahl Research
Fund, the Jean Muir-Katz Research Fund, and the Health Resources and Services Administration.


Continuous HIV Treatment Most Effective
Long-term use of HIV antiretroviral therapy is associated with a risk of waning adherence and development of HIV resistance. Studies have also shown that antiretroviral therapy may be associated with side effects including those affecting the heart, kidneys, and liver. Thus, it was hypothesized that intermittent therapy used only during specific times and based on the CD4 cell count – a key indicator of immune function – might lessen these side effects while maintaining the benefits of these drugs. A trial of more than 5,000 HIV patients in 30 countries shows, however, that intermittent treatment increases the risk of death or developing an AIDS-related disease 2.6 times compared with continuous treatment. Surprisingly, patients receiving intermittent treatment also experienced more heart, kidney and liver side effects than the intermittent treatment.
   The study, conducted by an international group of researchers, and co-chaired by Wafaa El-Sadr, M.D., M.P.H., professor of clinical medicine and epidemiology and chief of infectious diseases at Harlem Hospital, originally was supposed to follow the patients for an average of six years. It was stopped after an average patient follow-up of only 16 months, however, when it became apparent that intermittent therapy was not working.
   “Our findings provide clear and compelling evidence that the episodic strategy, guided by CD4+ cell count, should not be recommended,” Dr. El-Sadr says.
NEJM 2006 355(22): 2283-2296
The study was funded by the National Institute of Allergy and Infectious Diseases.


Parkinson’s Gene Therapy Successful in Mice
An experimental gene therapy for Parkinson’s disease has generated the best response seen to date among therapies designed to prevent the death of neurons in animals. Parkinson’s selectively kills dopamine neurons in the substantia nigra, a region of the mid-brain. The gene therapy delivers a cell-survival gene, Akt, to the dopamine neurons. Like other experimental therapies designed to increase cell survival, the Akt therapy prevented neuronal death in mice with a form of Parkinson’s. Unlike similar therapies, however, the Akt therapy also saved nearly all axons that reach into the striatum, a part of the brain that plans movements.
   “Without their axons, dopamine neurons can not send messages to the striatum, so it’s very exciting to see such a high level of protection,” says Robert Burke, M.D., lead author and director of the Morris K. Udall Parkinson’s Disease Research Center of Excellence at CUMC.
   The new Akt therapy is designed to activate the same cell survival pathways activated by a neurotrophic factor called GDNF. Much optimism had surrounded GDNF therapy because of successful primate studies and small, open label clinical trials. But a 2006 clinical trial found GDNF did not improve patients’ symptoms. In the trial, GDNF was pumped through a catheter into the brain, and researchers think this method may have failed to deliver enough of the drug to the substantia nigra.
   The Akt treatment attempts to solve the delivery problem by using a viral vector to directly activate neurotrophic signaling pathways within dopamine neurons. Dr. Burke and colleagues are now working to adapt the vector for human clinical trials.
PNAS 2006 103(49):18757-62
The research was funded by the NIH,
the Parkinson’s Disease Foundation, the Lowenstein Foundation, and the Michael J. Fox Foundation.


What’s Bad for Atherosclerosis May be Good for TB
   Atherosclerosis and TB – two diseases that seem quite different – share an underlying commonality that may lead to better treatments for both. The connection lies within macrophages, cells important in both diseases.
   In atherosclerosis, macrophages congregate in the fatty lesions that line arteries. Macrophage death promotes lesion rupture, which can lead to heart attack or stroke.
   A new study shows that macrophages die when two cell surface receptors – Toll-like receptor 4 (TLR4) and type A scavenger receptor (SRA) – are activated by other molecules in the lesion. The findings may lead to new ways to treat atherosclerosis by preventing macrophage death, says lead author, Ira Tabas, M.D., Ph.D., Richard J. Stock Professor and vice chair of research in the Department of Medicine and professor of cellular biophysics.
   Surprisingly, the two receptors may also play a critical role in TB. Virulent strains of TB bacteria are dangerous because they hijack and then hide inside living lung macrophages, only to emerge later and cause disease. However, less virulent TB strains fail to do much harm because they kill the macrophages and thus lose their safe haven. Evidence from the literature suggests that these weak strains may kill lung macrophages because they activate TLR4 and SRA. Current studies by Dr. Tabas’ group and their collaborators are testing this idea. In theory, a drug that activated TLR4 and SRA and killed the TB-infected lung macrophages could be an effective treatment for people infected with virulent TB strains. Dr. Tabas says that care is needed to ensure macrophages in atherosclerotic plaques are not targeted by such a drug.
PNAS 2006 103(52): 19794-19799
The research was supported by the NIH.

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