Heart News and Ailments

Note : All these latest medical breadkthroughs have been extracted from Breakthrough digest.

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Exercise helps repair muscle damage in heart failure patients

American Heart Association meeting report ORLANDO, Nov. 7 — Exercise increased the growth of new muscle cells and blood vessels in the weakened muscles of people with heart failure, according to two studies reported today at the American Heart Association’s Scientific Sessions 2007.
“If you have heart failure, exercise training can improve your health status, increase your ability to exercise and reverse patterns of muscle damage that are common in heart failure,” said Axel Linke, M.D., assistant professor of medicine at the University of Leipzig, Germany, and a co-author on both studies.
In chronic heart failure, the heart can’t pump enough blood to other organs in the body.
“In addition to getting out of condition because it becomes difficult to exercise, people with heart failure have cellular-level changes in their muscles that make them weaker, more prone to fatigue, and in later stages results in actual muscle shrinkage,” he said.

In one study (abstract 3797), researchers investigated whether exercise training could activate progenitor cells, a pool of immature cells in skeletal muscle that can divide into various mature cells as needed for muscle repair.
Compared with healthy people, those with heart failure have about a 50 percent reduction in the number of progenitor cells in their muscles, Linke said.
Researchers examined biopsies of the vastus lateralis, the largest quadricep muscle in the outer thigh, in 50 men, average age 56, with moderate to severe heart failure — a level at which any exercise is uncomfortable. Researchers took the biopsies before and after a six-month period in which 25 men remained inactive and the other 25 participated in an individualized, physician-supervised endurance exercise program.

Study participants rode a stationary bicycle at least 30 minutes a day (usually divided into two sessions) at about half their peak exercise capacity.
At the end of the six-month study, levels of progenitor cells stayed the same in the inactive group but changed significantly in the exercisers:
Total number of progenitor cells (identified by c-kit+ protein marker on the cell surface) increased by 109 percent.
Progenitor cells differentiating into muscle cells (identified by c-kit/MEF2+ marker) increased by 166 percent.
Progenitor cells actively dividing to form
new cells and repair muscle damage (identified by c-kit/Ki67+ protein marker) significantly increased six-fold.

“With exercise, the number of progenitor cells became almost normal, the cells started to divide again, and they began to differentiate into myocytes (muscle cells). And that’s exactly what patients with heart failure need — replacement of muscle cells,” Linke said.
Participants in the exercise program also felt better and increased their exercise capacity 20 percent during the six-month study, Linke said.
Whether exercise can induce similar changes in heart muscle is not known, researchers said.
“We also have c-kit+ cells in the heart but we don’t know whether they are similar to those in skeletal muscle,” Linke said.
In the second study (abstract 3796), researchers tracked endothelial progenitor cells that are created in bone marrow and circulate through the bloodstream. The cells help repair damaged blood vessel linings and spur new vessels to form in a process called vasculogenesis.
In heart failure, the linings of blood vessels are damaged, blood vessels in muscle do not dilate normally, and the number of small blood vessels (capillaries) in muscle tissue is reduced.

Researchers randomly assigned 37 men, average age 65, with severe heart failure to receive either 12 weeks of exercise training or to remain inactive. They took blood tests and biopsies of the quadricep muscle before and after the program. After 12 weeks, researchers found no changes in men assigned to the control group. In contrast, exercisers changed significantly:
Circulating progenitor cells (identified by CD34+ marker) increased 47 percent.

Circulating progenitor cells beginning to mature into endothelial cells (identified by CD34/KDR+ marker) significantly increased 199 percent.
Functional activity of the circulating progenitor cells (measured by migratory capacity) significantly increased 149 percent.
The density of capillaries in skeletal tissue significantly increased 17 percent.
“Whether you have moderate or severe heart failure, you can benefit from exercise therapy,” Linke said. “These studies show that the benefits come from both the regeneration of muscle cells and the formation of blood vessels.”
More than 5 million people in the United States have heart failure. About 1 percent of people over age 65 start having heart failure annually.

Headache - Migraine

New treatment effective for most severe kind of headache A nasal spray is safe and effective at rapidly treating cluster headaches, which are considered to be the most painful kind of headache with few treatment options, according to a study published in the August 28, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology. The double-blind trial involved 52 people with cluster headache who used five or 10 milligrams of zolmitriptan nasal spray or placebo to treat 151 separate cluster headache attacks. The study found 63 percent of people treated with the drug at the higher dose reported headache relief at 30 minutes, compared to 50 percent of people taking the lower dose of zolmitriptan nasal spray and 30 percent in the placebo group. “This is a significant finding and the main endpoint of our study,” said study author Alan M. Rapoport, MD, with The New England Center for Headache in Stamford, CT, and Clinical Professor of Neurology at The David Geffen School of Medicine at UCLA in Los Angeles. Rapoport is a Fellow of the American Academy of Neurology. “The 10 milligram dose worked as quickly as 10 minutes in some patients.” “Cluster headache is an extremely severe headache disorder with enormous unmet treatment needs,” said Rapoport. “Few medications for cluster headache have been systematically tested, and only one, which involves an injection of sumatriptan, has been FDA approved.” Cluster headache is relatively rare, occurring in less than one-tenth of one percent of the U.S. population. Men are three to four times more likely to suffer from cluster headaches than women. The pain is considered to be the most severe of the primary headache disorders and often peaks within five minutes and remains severe for about one and up to three hours. The pain is usually associated with neurological findings such as a droopy eyelid, small pupil, red and tearing eye, and stuffed and running nostril. All of the symptoms usually occur on the same side as the headache pain. “Because a cluster headache attack builds up to a crescendo within five to 15 minutes, treatment must be rapid and offer significant relief,” said Rapoport. “While the FDA has not approved zolmitriptan nasal spray for use in cluster headaches, it may someday be considered a first-line therapy.” Side effects were mild and no serious adverse events were reported during the study.

Gastrointestinal - IBD

Scientists discover a direct route from the brain to the immune It used to be dogma that the brain was shut away from the actions of the immune system, shielded from the outside forces of nature. But that’s not how it is at all. In fact, thanks to the scientific detective work of Kevin Tracey, MD, it turns out that the brain talks directly to the immune system, sending commands that control the body’s inflammatory response to infection and autoimmune diseases. Understanding the intimate relationship is leading to a novel way to treat diseases triggered by a dangerous inflammatory response. Dr. Tracey, director and chief executive of The Feinstein Institute for Medical Research, will be giving the 2007 Stetten Lecture on Wednesday, Oct. 24, at the National Institutes of Health in Bethesda, MD. His talk – Physiology and Immunology of the Cholinergic Anti-inflammatory Pathway – will highlight the discoveries made in his laboratory and the clinical trials underway to test the theory that stimulation of the vagus nerve could block a rogue inflammatory response and treat a number of diseases, including life-threatening sepsis. With this new understanding of the vagus nerve’s role in regulating inflammation, scientists believe that they can tap into the body’s natural healing defenses and calm the sepsis storm before it wipes out its victims. Each year, 750,000 people in the United States develop severe sepsis, and 215,000 will die no matter how hard doctors fight to save them. Sepsis is triggered by the body’s own overpowering immune response to a systemic infection, and hospitals are the battlegrounds for these potentially lethal conditions. The vagus nerve is located in the brainstem and snakes down from the brain to the heart and on through to the abdomen. Dr. Tracey and others are now studying ways of altering the brain’s response or targeting the immune system itself as a way to control diseases. Dr. Tracey is a neurosurgeon who came into research through the back door of the operating room. More than two decades ago, he was treating a young girl whose body had been accidentally scorched by boiling water and she was fighting for her life to overcome sepsis. She didn’t make it. Dr. Tracey headed into the laboratory to figure out why the body makes its own cells that can do fatal damage. Dr. Tracey discovered that the vagus nerve speaks directly to the immune system through a neurochemical called acetylcholine. And stimulating the vagus nerve sent commands to the immune system to stop pumping out toxic inflammatory markers. “This was so surprising to us,” said Dr. Tracey, who immediately saw the potential to use vagus stimulation as a way to shut off abnormal immune system responses. He calls this network “the inflammatory reflex.” Research is now underway to see whether tweaking the brain’s acetylcholine system could be a natural way to control the inflammatory response. Inflammation is key to many diseases - from autoimmune conditions like Crohn’s disease and rheumatoid arthritis to Alzheimer’s, where scientists have identified a strong inflammatory component. Dr. Tracey has presented his work to the Dalai Lama, who has shown a great interest in the neurosciences and the mind-body connection. He has also written a book called “Fatal Sequence,” about the double-edge sword of the immune system.

Head and Neck Cancer

Smoking Increases Head and Neck Cancer Risk Smoking is often associated with lung cancer, but a new study reveals smoking is associated with head and neck cancers as well. Smoking plays a greater role in the development of head and neck cancer in women than men. Cancers of the head and neck include cancers of the larynx, nasal passages/nose, oral cavity and pharynx. Worldwide, more than 500,000 people are diagnosed with these cancers every year. These cancers are three-times more common in men than women, and men are twice as likely to die from head and neck cancer then women.Researchers from the National Cancer Institute analyzed data from more than 476,000 men and women. They wanted to assess the gender differences in the risk for cancer in the head and neck sites. They report the research confirmed these cancers are more common in men than women. However, they found only 45 percent of these cancers could be attributed to smoking in men, while 75 percent of these cancers could be attributed to smoking in women. Study authors conclude, to reduce the incidence of head and neck cancers, public health efforts should be aimed at eliminating smoking in both women and men. This article was reported by Ivanhoe.com, which offers Medical Alerts by e-mail every day of the week.

Ovarian Cancer...

Keeping Ovarian Cancer Away This year, about 22,000 women will be diagnosed with ovarian cancer. The good news is many of these patients respond to treatments and go into remission quickly. The bad news is the cancer often comes back with deadly consequences. But now, a new treatment aims to keep the cancer away for good. She’s needed the good times after being diagnosed with stage four ovarian cancer. “My first thought was, ‘Oh my God, I have ovarian cancer. That’s like one of the worst cancers you can possibly have,’” Lee says. After chemotherapy and radiation, Lee went into remission. Good news, but Robert Holloway, M.D., a gynecologic oncologist at the Florida Hospital Cancer Institute in Orlando, Fla., says 75 percent of patients in remission have their cancer return. “Some of the most intense areas of research right now are to try and figure out how to take women who are in remission and keep them there,” Dr. Holloway says. Now, researchers are studying a new therapy that may do just that. Catumaxomab — or CAT for short — is infused right into the abdomen through a port. It links immune cells to cancer cells. The body then creates an immune response to seek out and destroy the cancer cells. “I can say in the patients that I treated, we have seen the immune response,” Dr. Holloway says. Patients are given four injections over a month. Doctors have treated about 36 patients in a clinical trial. It’s still early, but so far, all the women have remained in remission. Lee had the injections and has been in remission for nine months. “I hope that this clinical trial prevents me from ever having a relapse again, and I’ll stay in remission forever,” Lee says. She says she wants to enjoy each and every moment with her little pups. Side effects of the therapy include a flu-like condition since the drug affects the body’s immune system. Currently, there are 36 patients enrolled in this clinical trial nationally, but researchers are now enrolling more.

Breast Cancer...

Researchers announce new methods of beating breast cancer University of Manchester researchers will reveal new ways of controlling and treating breast cancer at the National Cancer Research Institute conference in Birmingham today (Monday 1 October 2007). Dr Robert Clarke and his team at the University’s Cancer Studies research group have been investigating human breast cancers for the presence of stem cells - cells that generate new tumours and can cause the cancer to recur - in a series of studies funded by the charity Breast Cancer Campaign. One third of women who are successfully treated for breast cancer find that the disease recurs some years later because some of these cancer cells survive the treatment and begin to grow again. The team’s research into these ‘breast cancer stem cells’ revealed that the cells are stimulated by the Notch gene. The team, who published the study in Journal of the National Cancer Institute, is now hoping to develop new drug therapies to target this gene and thus stop the growth of any surviving breast cancer stem cells. One drug that is known to attack Notch is already used for the treatment of Alzheimer’s Disease so, having undergone health and safety checks, its clinical trial for use on breast cancer patients could be speeded up and lead to a treatment in hospital clinics within a few years. Herceptin, by contrast, took more than 15 years to go from the discovery of its gene target to treatment. The team is also aiming to identify other new pathways of controlling breast cancer stem cells by using a genetic library to shut down other genes at random to see how it affects them, in a study with Rene Bernards at the Netherlands Cancer Institute. The team, along with Professor Tony Whetton, are using a state-of-the-art mass-spectrometry based proteomics facility at the Paterson Institute of Cancer Research to identify proteins that control breast cancer stem cells. The facility - one of only a few in the UK - enables them to break up breast cancer stem cell proteins and analyse the sequence of amino acids to identify novel proteins that control the cells’ growth. Dr Clarke says: “Our work has revealed the importance of several pathways not previously known to regulate stem cell survival and self-renewal, which is tremendously exciting. Inhibitors of signalling pathways that regulate cancer stem cells could represent a new therapeutic modality in breast cancer, to be used in combination with current treatments in the near future.”

Brain News and Ailments

Scientists discover a direct route from the brain to the immune system It used to be dogma that the brain was shut away from the actions of the immune system, shielded from the outside forces of nature. But that’s not how it is at all. In fact, thanks to the scientific detective work of Kevin Tracey, MD, it turns out that the brain talks directly to the immune system, sending commands that control the body’s inflammatory response to infection and autoimmune diseases. Understanding the intimate relationship is leading to a novel way to treat diseases triggered by a dangerous inflammatory response. Dr. Tracey, director and chief executive of The Feinstein Institute for Medical Research, will be giving the 2007 Stetten Lecture on Wednesday, Oct. 24, at the National Institutes of Health in Bethesda, MD. His talk – Physiology and Immunology of the Cholinergic Anti-inflammatory Pathway – will highlight the discoveries made in his laboratory and the clinical trials underway to test the theory that stimulation of the vagus nerve could block a rogue inflammatory response and treat a number of diseases, including life-threatening sepsis. With this new understanding of the vagus nerve’s role in regulating inflammation, scientists believe that they can tap into the body’s natural healing defenses and calm the sepsis storm before it wipes out its victims. Each year, 750,000 people in the United States develop severe sepsis, and 215,000 will die no matter how hard doctors fight to save them. Sepsis is triggered by the body’s own overpowering immune response to a systemic infection, and hospitals are the battlegrounds for these potentially lethal conditions. The vagus nerve is located in the brainstem and snakes down from the brain to the heart and on through to the abdomen. Dr. Tracey and others are now studying ways of altering the brain’s response or targeting the immune system itself as a way to control diseases. Dr. Tracey is a neurosurgeon who came into research through the back door of the operating room. More than two decades ago, he was treating a young girl whose body had been accidentally scorched by boiling water and she was fighting for her life to overcome sepsis. She didn’t make it. Dr. Tracey headed into the laboratory to figure out why the body makes its own cells that can do fatal damage. Dr. Tracey discovered that the vagus nerve speaks directly to the immune system through a neurochemical called acetylcholine. And stimulating the vagus nerve sent commands to the immune system to stop pumping out toxic inflammatory markers. “This was so surprising to us,” said Dr. Tracey, who immediately saw the potential to use vagus stimulation as a way to shut off abnormal immune system responses. He calls this network “the inflammatory reflex.” Research is now underway to see whether tweaking the brain’s acetylcholine system could be a natural way to control the inflammatory response. Inflammation is key to many diseases - from autoimmune conditions like Crohn’s disease and rheumatoid arthritis to Alzheimer’s, where scientists have identified a strong inflammatory component. Dr. Tracey has presented his work to the Dalai Lama, who has shown a great interest in the neurosciences and the mind-body connection. He has also written a book called “Fatal Sequence,” about the double-edge sword of the immune system.

Brain News and Ailments

Scientists discover a direct route from the brain to the immune system

It used to be dogma that the brain was shut away from the actions of the immune system, shielded from the outside forces of nature. But that’s not how it is at all. In fact, thanks to the scientific detective work of Kevin Tracey, MD, it turns out that the brain talks directly to the immune system, sending commands that control the body’s inflammatory response to infection and autoimmune diseases. Understanding the intimate relationship is leading to a novel way to treat diseases triggered by a dangerous inflammatory response.
Dr. Tracey, director and chief executive of The Feinstein Institute for Medical Research, will be giving the 2007 Stetten Lecture on Wednesday, Oct. 24, at the National Institutes of Health in Bethesda, MD. His talk – Physiology and Immunology of the Cholinergic Anti-inflammatory Pathway – will highlight the discoveries made in his laboratory and the clinical trials underway to test the theory that stimulation of the vagus nerve could block a rogue inflammatory response and treat a number of diseases, including life-threatening sepsis.
With this new understanding of the vagus nerve’s role in regulating inflammation, scientists believe that they can tap into the body’s natural healing defenses and calm the sepsis storm before it wipes out its victims. Each year, 750,000 people in the United States develop severe sepsis, and 215,000 will die no matter how hard doctors fight to save them. Sepsis is triggered by the body’s own overpowering immune response to a systemic infection, and hospitals are the battlegrounds for these potentially lethal conditions.
The vagus nerve is located in the brainstem and snakes down from
the brain to the heart and on through to the abdomen. Dr. Tracey and others are now studying ways of altering the brain’s response or targeting the immune system itself as a way to control diseases.
Dr. Tracey is a neurosurgeon who came into research through the back door of the operating room. More than two decades ago, he was treating a young girl whose body had been accidentally scorched by boiling water and she was fighting for her life to overcome sepsis. She didn’t make it. Dr. Tracey headed into the laboratory to figure out why the body makes its own cells that can do fatal damage. Dr. Tracey discovered that the vagus nerve speaks directly to the immune system through a neurochemical called acetylcholine. And stimulating the vagus nerve sent commands to the immune system to stop pumping out toxic inflammatory markers. “This was so surprising to us,” said Dr. Tracey, who immediately saw the potential to use vagus stimulation as a way to shut off abnormal immune system responses. He calls this network “the inflammatory reflex.”
Research is now underway to see whether tweaking the brain’s acetylcholine system could be a natural way to control the inflammatory response. Inflammation is key to many diseases - from autoimmune conditions like Crohn’s disease and rheumatoid arthritis to Alzheimer’s, where scientists have identified a strong inflammatory component.
Dr. Tracey has presented his work to the Dalai Lama, who has shown a great interest in the neurosciences and the mind-body connection. He has also written a book called “Fatal Sequence,” about the double-edge sword of the immune system.

Bone Cancer...Myeloma

Know the signs and symptoms of myeloma The American Cancer Society estimates that approximately 16,600 new cases of myeloma are diagnosed each year in the United States. Bone pain is the most common early symptom of myeloma. Most patients feel pain in their back or ribs, but it can occur in any bone. The pain is usually made worse by movement. Patients fatigue more easily and often feel weak. They may additionally have a pale complexion from anemia which is a common medical problem for patients with myeloma and may contribute to the fatigue. whether the disease progresses, the concentration of normal cells in the blood may additionally decrease. Headaches, bruising, nose bleeding, gastrointestinal bleeding, and tingling or numbness in extremities are all symptoms of myeloma. Patients may have repeated infections considering antibodies to invading viruses, bacteria or other disease agents are not made efficiently of in adequate amounts. Urinary tract, bronchial, lung, skin, or other sites of infection may be the first sign of the disease. In addition, recurrent infections may complicate the course of the disease.

Bladder Cancer...

Increased risk of bladder cancer associated with chlorinated water A new study shows that whether you drink, bathe or swim in chlorinated water it may increase the risk of bladder cancer. The chemicals, mostly chlorine, used to disinfect water can be harmful when they are inhaled or absorbed through the skin. The chemical by-product produced, called trihalomethanes (THM), can be a supreme carcinogenic considering it does not get detoxified by the liver. The researchers analyzed the average water THM levels in the 123 municipalities in the study. public living in households with an average household water THM of more than 49 micrograms per liter had double the bladder cancer risk of those living in households where water THM concentration was below 8 micrograms per liter. They noted that levels of about 50 micrograms per liter are common in industrialized societies. Those who drank chlorinate water were at a 35 percent greater risk of bladder cancer than those who didn’t and the use of swimming pools boosted bladder cancer risk by 57 percent. Something else we need to distress about–great! I am not losing sleep by that one. I cannot take back all those years swimming in the backyard pool!

Osteoarthritis

New insights into inflammation in osteoarthritis Study indicates role of inflammatory mechanism distinct from joint cartilageThe most common degenerative joint disease, osteoarthritis (OA) is marked by the breakdown of articular cartilage, which is the type of cartilage that lines the ends of most limb bones. It can afflict any joint—fingers, toes, wrists, ankles, elbows, shoulders, and the spine, as well as the weight-bearing knees and hips. As OA progresses, sufferers often experience inflammation around the affected joint. This inflammation has been attributed to bits of cartilage breaking off and aggravating the synovium, the thin, smooth membrane lining a joint. Yet, MRI detection of prominent synovitis in early OA—when joint cartilage appears normal—suggests that other joint structures may be involved in triggering this inflammation. Recent studies of inflammation in spinal arthritis implicate the enthesis, which is the attachment site of ligament or tendon to bone as being a potential driving factor in joint inflammation. Intrigued by the potential role of tendon or ligament attachment sites in synovitis, Professors Michael Benjamin of Cardiff University and Dennis McGonagle of the University of Leeds decided to investigate the extent to which different entheses could contribute to inflammation by forming a functional unit and destructive partnership with adjacent synovium. Featured in the November 2007 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), their findings shed light on a potential novel mechanism for synovial inflammation in degenerative arthritis. This is based on a structure that the authors have called the “synovial-entheseal complex” (SEC). Basically insertions have a different type of cartilage called fibrocartilage near the bone. Although this is different from articular cartilage that lines the ends of bones, the authors speculated that this type of cartilage could also derive nourishment from synovium. However, this close integration although desirable in health could have unfortunate consequences if the enthesis was damaged. To validate the widespread formation and to explore further, the possible inflammatory function of SECs, researchers collected ligament and tendon attachment samples from 60 cadavers, 35 male and 25 female, with a mean age of 84 years at death. 49 different entheses—19 from the arms, 26 from the legs, and 4 from the spinal column—were preserved for examination. To exclude cartilage degeneration as a trigger for synovial inflammation, 17 of the selected entheses were not immediately adjacent to joint cartilage. Each sample was studied for evidence of inflammatory cells and soft tissue microdamage, as well as for the composition of SECs. At 82 percent of the entheses, the formation of a SEC was found. As expected, this occurred in entheses very close to joint cartilage, where the synovium was often part of the joint itself. However, a SEC was also detected in 47 percent of the sites separated from joint cartilage. For example, the SEC found at the Achilles tendon was formed with synovium that protruded from a cavity called a “bursa”, located a considerable distance from the ankle joint. Joint insertions are sites of high mechanical stressing and the authors speculated that this could lead to damage within them, including their fibrocartilage This is exactly what the authors found. Degenerative changes—at least one and sometimes several—were detected on the soft tissue side of attachment sites. Most notably, cell clustering and/or fissuring was found in 76 percent of entheses. In 85 percent of SECs, the synovial component also showed evidence of mild inflammatory change. Finally, in 73 percent of the attachments, small numbers of inflammatory cells were present in the enthesis itself. Therefore the authors suggest that joint degeneration of fibrocartilage at insertions could trigger inflammation within SECs. As Professors Benjamin and McGonagle note, one their most striking findings was the large number of attachment sites with evidence of changes in the entheses mirroring those typically seen in joint cartilage in OA—fibrocartilage cell clusters, cell hypertrophy, and fissuring among them. “Such changes at certain entheses could be directly relevant to older subjects with joint symptoms due to degenerative disease,” Professor McGonagle observes, “and some of the symptoms could be emanating from the SEC.” Affirming the concept of a “synovio-etheseal complex” as widely applicable at many sites in the body, both right next to and removed from joint cartilage, this study also supports the idea that biomechanical factors related to the enthesis could play an important role in synovial inflammation in both degenerative and inflammatory arthritis.

HIV .. Aids

Second pathway behind HIV-associated immune system dysfunction identified Potential treatment target needs further investigation before clinical testing 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. ###Co-first author of the Nature Immunology report is Daniel Kavanagh, PhD, also of PARC and MGH. Additional co-authors are Florencia Pereyra, MD, Elizabeth Mackey, Toshiyuki Miura, PhD, DM; Mark Brockman, Almas Rathod, Alicja Piechocka-Trocha, Brett Baker, Sylvie Le Gall, PhD, Michael Waring, Ryan Ahern, Kristen Moss, and Eric Rosenberg, MD, of PARC-MGH; John Zaunders and Anthony Kelleher, MBBS, PhD, St. Vincent’s Hospital, Darlington, NSW, Australia; Sarah Palmer, PhD, and John Coffin, PhD, National Cancer Institute; Baogong Zhu, MD, and Gordon Freeman, PhD, Dana-Farber Cancer Institute. External support for the study came from the National Institutes of Health, HHMI and the Mark and Lisa Schwartz Foundation. Massachusetts General Hospital (www.massgeneral.org), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine

Aging

Einstein Researchers Use Novel Approach to Uncover Genetic Components of Aging People who live to 100 or more are known to have just as many—and sometimes even more—harmful gene variants compared with younger people. Now, scientists at the Albert Einstein College of Medicine of Yeshiva University have discovered the secret behind this paradox: favorable “longevity” genes that protect very old people from the bad genes’ harmful effects. The novel method used by the researchers could lead to new drugs to protect against age-related diseases. “We hypothesized that people living to 100 and beyond must be buffered by genes that interact with disease-causing genes to negate their effects,” says Dr. Aviv Bergman, a professor in the departments of pathology and neuroscience at Einstein and senior author of the study, which appears in the August 31 issue of PLoS Computational Biology. To test this hypothesis, Dr. Bergman and his colleagues examined individuals enrolled in Einstein’s Longevity Genes Project, initiated in 1998 to investigate longevity genes in a selected population: Ashkenazi (Eastern European) Jews. They are descended from a founder group of just 30,000 or so people. So they are relatively genetically homogenous, which simplifies the challenge of associating traits (in this case, age-related diseases and longevity) with the genes that determine them. Participating in the study were 305 Ashkenazi Jews more than 95 years old and a control group of 408 unrelated Ashkenazi Jews. (Centenarians are so rare in human populations—only one in 10,000 people live to be 100—that “longevity” genes probably wouldn’t turn up in a typical control group. Longevity runs in families, so 430 children of centenarians were added to the control group to increase the number of favorable genes.) All participants were grouped into cohorts representing each decade of lifespan from the 50’s on up. Using DNA samples, the researchers determined the prevalence in each cohort of 66 genetic markers present in 36 genes associated with aging. As expected, some disease-related gene variants were as prevalent or even more prevalent in the oldest cohorts of Ashkenazi Jews than in the younger ones. And as Dr. Bergman had predicted, genes associated with longevity also became more common in each succeeding cohort. “These results indicate that the frequency of deleterious genotypes may increase among people who live to extremely old ages because their protective genes allow these disease-related genes to accumulate,” says Dr. Bergman.The Einstein researchers were able to construct a network of gene interactions that contributes to the understanding of longevity. In particular, they found that the favorable variant of the gene CETP acts to buffer the harmful effects of the disease-causing gene Lp(a). If future research finds that a single longevity gene buffers against several disease-causing genes, then drugs that mimic the action of the longevity gene could help protect against cardiovascular disease and other age-related diseases. “This study shows that our approach, which was inspired by a theoretical model, can reveal underlying mechanisms that explain seemingly paradoxical observations in a complex trait such as aging,” says Dr. Bergman. “So we’re hopeful that this method could also help uncover the mechanisms—the gene interactions—responsible for other complex biological traits such as cancer and diabetes.” Meanwhile, the Einstein researchers are greatly expanding their longevity research: From the 66 genetic markers examined in this study, they are now using a high-throughput technology that allows them to assay one million genetic markers throughout the human genome. The goal is to find additional genetic networks that are involved in the process of aging. Other Einstein researchers involved in the study were Gil Atzmon, Kenny Ye, Thomas McCarthy and Nir Barzilai.

Acromegaly

FDA Approves New Drug to Treat Rare Disease, Acromegaly FDA NEWS DIGEST, Acromegaly The U.S. Food and Drug Administration today approved Somatuline Depot (lanreotide acetate injection) for the treatment of acromegaly, a rare and potentially life threatening disease in adults caused by abnormal secretion of growth hormone (GH), commonly from a benign tumor located in the pituitary gland located in the brain. “This type of therapy provides an alternative for patients who have not responded to other therapies,” said Steven Galson, M.D., M.P.H., director, Center for Drug Evaluation and Research. “The new approval reflects FDA’s goals for making effective and safe treatments available to patients with rare diseases under the Orphan Drugs program.” FDA has approved Somatuline Depot for the long-term treatment of patients with acromegaly who have had inadequate response to or can not be treated with surgery and/or radiation therapy. This new treatment lowers the levels of certain hormones in the body, including GH and insulin-like growth factor. Excessive GH secretion, working through insulin-like growth factor, can cause enlargement of the hands, feet, facial bones, and enlargement of internal organs such as the heart and liver. If untreated, patients with acromegaly often have a shortened life span because of heart and respiratory diseases, diabetes mellitus, and colon cancer. The safety and effectiveness of Somatuline Depot (administered through injection) was determined in two pivotal clinical trials involving a total of 400 patients. Common side effects include diarrhea, gallstones, skin reactions such as itching, slow heart rate, and change in blood sugar levels. Patients with diabetes who receive treatment with Somatuline Depot may need to have their diabetes medication adjusted. FDA designated Somatuline Depot orphan status because the drug treats a rare disease and meets other criteria. Orphan products are developed to treat rare diseases or conditions that affect fewer than 200,000 people in the United States. The Orphan Drug Act provides a seven-year period of exclusive marketing to the first manufacturer who obtains marketing approval for a designated orphan product. Acromegaly affects approximately 15,000 people in the United States and Canada and is most commonly found in middle-aged adults. Patients with acromegaly have reduction in life expectancy of 5 to 10 years. The drug will be marketed by Tercica, Inc. in Brisbane, CA.