Children with HIV/AIDS falling through the cracks of treatment scale-up efforts

Published: Thursday, December 1, 2011 - 13:33 in Health & Medicine Less than one-quarter (23%) of children with HIV/AIDS who need treatment are getting it, according to a report released by the World Health Organization (WHO) on the occasion of World AIDS Day (1 December 2011). Although treatment coverage for adults has been steadily climbing and has now reached approximately half of those in need, coverage for children is lagging far behind, highlighted the Drugs for Neglected Diseases initiative (DNDi), a non-profit research and development organization that has recently launched a new paediatric HIV drug development programme. 'Children with HIV/AIDS are falling through the cracks', said Dr Bernard Pcoul, Executive Director of the DNDi. '250,000 children died of HIV-related complications in 2010 -- that's nearly 700 each day. This is simply unacceptable.' There are several reasons for this situation -- including lack of access for pregnant women to antenatal care, HIV testing, and antiretrovirals (ARVs) to prevent mother-to-child transmission and treat expecting mothers, as well as difficulties diagnosing HIV in infants. But one of the most important, and overlooked, is the lack of suitable formulations of ARVs adapted for children, particularly babies and toddlers. The reason for this neglect lies, ironically, with the success of the virtual elimination of HIV among newborns in wealthy countries. 'There's little profit to be made from developing treatments for the millions of children with HIV/AIDS, 90% of whom are the poorest of the poor in sub-Saharan Africa, and the lack of market incentive means pharmaceutical companies do not develop ARVs adapted to their needs', Dr Pcoul continued. 'Without treatment, half of the children born with HIV die before their second birthday.' WHO recommends immediate ART for all HIV-positive children less than two years old, but the safety and correct dosing have not been established in very young children for the majority of ARVs approved for adults. In addition, key existing paediatric ARV formulations taste bad, require impractical multiple liquid preparations and refrigeration, and have undesirable interactions with tuberculosis (TB) drugs. DNDi's new paediatric HIV programme aims to develop an improved first-line therapy for children under three years of age. Ideally, this ARV combination therapy needs to be easy to administer and better tolerated by children than current drugs, as well as heat stable and easily dispersible (dissolvable in water or breast milk). It must also carry minimal risk for developing resistance and require minimum weight adjustments. Finally, any new formulations must be compatible with TB drugs. 'Given the current funding crisis, we are deeply concerned that children with HIV/AIDS -who are already invisible and largely voiceless -- will fall even further down on the agenda', said Dr Marc Lallemant, Head of DNDi's Paediatric HIV Programme. 'And while everything possible needs to be done to achieve the long-term goal of "eliminating" new infections among infants, including through scale-up of prevention of mother-to-child transmission programmes, a more serious response is urgently needed for HIV-positive children today.'

MAKS: Drug-free prevention of dementia decline

Published: Thursday, December 1, 2011 - 02:33 in Health & Medicine There are many different causes of dementia and, although its progression can be fast or slow, it is always degenerative. Symptoms of dementia include confusion, loss of memory, and problems with speech and understanding. It can be upsetting for both the affected person and their relatives and carers. New research published in BioMed Central's open access journal BMC Medicine shows that a regime of behavioral and mental exercises was able to halt the progression of dementia. Researchers led by Prof. Graessel, from Friedrich-Alexander-Universitt Erlangen, included in their study patients with dementia from five nursing homes in Bavaria. After random selection, half the patients were included on the year-long MAKS 'intervention' consisting of two hours of group therapy, six days a week. In addition all patients maintained their normal treatment and regular activities provided by the nursing home. The MAKS system consists of motor stimulation(M), including games such as bowling, croquet, and balancing exercises; cognitive stimulation (K), in the form of individual and group puzzles; and practicing 'daily living' activities (A), including preparing snacks, gardening and crafts. The therapy session began with a ten minute introduction, which the researchers termed a 'spiritual element' (S), where the participants discussed topics like 'happiness', or sang a song or hymn. After 12 months of therapy the MAKS group maintained their level on the Alzheimer's Disease Assessment Scale (ADAS) and, even more importantly maintained their ability to carry out activities of daily living, while the control group all showed a decrease in cognitive and functional ability. Prof. Graessel explained, "While we observed a better result for patients with mild to moderate dementia, the result of MAKS therapy on ADAS (cognitive function) was at least as good as treatment with cholinesterase inhibitors. Additionally we found that the effect on the patients' ability to perform daily living tasks (as measured by the Erlanger Test of Daily Living (E-ADL)) was twice as high as achieved by medication. This means that MAKS therapy is able to extend the quality of, and participation in, life for people with dementia within a nursing home environment. We are currently in the process of extending these preliminary results to see if this prevention of dementia decline can be maintained over a longer time period."

Early sign of Alzheimer's reversed in lab

Published: Wednesday, November 30, 2011 - 23:34 in Health & Medicine One of the earliest known impairments caused by Alzheimer's disease -- loss of sense of smell -- can be restored by removing a plaque-forming protein in a mouse model of the disease, a study led by a Case Western Reserve University School of Medicine researcher finds. The study confirms that the protein, called amyloid beta, causes the loss. "The evidence indicates we can use the sense of smell to determine if someone may get Alzheimer's disease, and use changes in sense of smell to begin treatments, instead of waiting until someone has issues learning and remembering," said Daniel Wesson, assistant professor of neuroscience at Case Western Reserve and lead investigator. "We can also use smell to see if therapies are working."

A description of the research is published in the Nov. 2 issue of The Journal of Neuroscience. Smell loss can be caused by a number of ailments, exposures and injuries; but since the 1970s, it has been identified as an early sign of this disease. The new research shows how and where in the brain this happens, and that the impairment it can be treated. "Understanding smell loss, we think, will hold some clues about how to slow down this disease," Wesson said. There is currently no effective treatment or cure for the disease, marked by eroding senses, cognition and coordination, leading to death. Currently 5.3 million Americans suffer from Alzheimer's and the number is expected to triple to 16 million by 2050, according to the Alzheimer's Association. Wesson worked with Anne H. Borkowski, a researcher at the Nathan S. Kline Institute in Orangeburg, N.Y., Gary E. Landreth, professor of neuroscience at Case Western Reserve School of Medicine, and Ralph A. Nixon, Efrat Levy and Donald A. Wilson, of the New York University School of Medicine. They found that just a tiny amount of amyloid beta -- too little to be seen on today's brain scans -- causes smell loss in mouse models. Amyloid beta plaque accumulated first in parts of the brain associated with smell, well before accumulating in areas associated with cognition and coordination. Early on, the olfactory bulb, where odor information from the nose is processed, became hyperactive. Over time, however, the level of amyloid beta increased in the olfactory bulb and the bulb became hypoactive. Despite spending more time sniffing, the mice failed to remember smells and became incapable of telling the difference between odors. The same pattern is seen in people with the disease. They become unresponsive to smells as they age. While losses in the olfactory system occurred, the rest of the mouse model brain, including the hippocampus, which is a center for memory, continued to act normally early in the disease stage. "This shows the unique vulnerability of the olfactory system to the pathogenesis of Alzheimer's disease," Wesson said. The team then sought to reverse the effects. Mice were given a synthetic liver x-receptor agonist, a drug that clears amyloid beta from the brain. After two weeks on the drug, the mice could process smells normally. After withdrawal of the drug for one week, impairments returned. Wesson and his team are now following-up on these discoveries to determine how amyloid spreads throughout the brain, to learn methods to slow disease progression.

Eating fish reduces risk of Alzheimer's disease

Published: Wednesday, November 30, 2011 - 14:37 in Health & Medicine People who eat baked or broiled fish on a weekly basis may be improving their brain health and reducing their risk of developing mild cognitive impairment (MCI) and Alzheimer's disease, according to a study presented November 30 at the annual meeting of the Radiological Society of North America (RSNA). "This is the first study to establish a direct relationship between fish consumption, brain structure and Alzheimer's risk," said Cyrus Raji, M.D., Ph.D., from the University of Pittsburgh Medical Center and the

University of Pittsburgh School of Medicine. "The results showed that people who consumed baked or broiled fish at least one time per week had better preservation of gray matter volume on MRI in brain areas at risk for Alzheimer's disease." Alzheimer's disease is an incurable, progressive brain disease that slowly destroys memory and cognitive skills. According to the National Institute on Aging, as many as 5.1 million Americans may have Alzheimer's disease. In MCI, memory loss is present but to a lesser extent than in Alzheimer's disease. People with MCI often go on to develop Alzheimer's disease. For the study, 260 cognitively normal individuals were selected from the Cardiovascular Health Study. Information on fish consumption was gathered using the National Cancer Institute Food Frequency Questionnaire. There were 163 patients who consumed fish on a weekly basis, and the majority ate fish one to four times per week. Each patient underwent 3-D volumetric MRI of the brain. Voxel-based morphometry, a brain mapping technique that measures gray matter volume, was used to model the relationship between weekly fish consumption at baseline and brain structure 10 years later. The data were then analyzed to determine if gray matter volume preservation associated with fish consumption reduced risk for Alzheimer's disease. The study controlled for age, gender, education, race, obesity, physical activity, and the presence or absence of apolipoprotein E4 (ApoE4), a gene that increases the risk of developing Alzheimer's. Gray matter volume is crucial to brain health. When it remains higher, brain health is being maintained. Decreases in gray matter volume indicate that brain cells are shrinking. The findings showed that consumption of baked or broiled fish on a weekly basis was positively associated with gray matter volumes in several areas of the brain. Greater hippocampal, posterior cingulate and orbital frontal cortex volumes in relation to fish consumption reduced the risk for five-year decline to MCI or Alzheimer's by almost fivefold. "Consuming baked or broiled fish promotes stronger neurons in the brain's gray matter by making them larger and healthier," Dr. Raji said. "This simple lifestyle choice increases the brain's resistance to Alzheimer's disease and lowers risk for the disorder." The results also demonstrated increased levels of cognition in people who ate baked or broiled fish. "Working memory, which allows people to focus on tasks and commit information to short-term memory, is one of the most important cognitive domains," Dr. Raji said. "Working memory is destroyed by Alzheimer's disease. We found higher levels of working memory in people who ate baked or broiled fish on a weekly basis, even when accounting for other factors, such as education, age, gender and physical activity." Eating fried fish, on the other hand, was not shown to increase brain volume or protect against cognitive decline.

Genetic sequencing could help match patients with biomarker-driven cancer trials, treatments
Published: Wednesday, November 30, 2011 - 22:33 in Health & Medicine As cancer researchers continue to identify genetic mutations driving different cancer subtypes, they are also creating a catalog of possible targets for new treatments. The University of Michigan Comprehensive Cancer Center and Michigan Center for

Translational Pathology (MCTP) recently completed a pilot study aimed at solving the practical challenges involved in quickly and systematically sequencing genetic material from patients with advanced or treatment-resistant cancer in order to match them with existing clinical trials based on the biomarkers identified. "We're talking about more than just examining a few genes where mutations are known to occur, or even about a hundred genes," says co-lead investigator Dan Robinson, Ph.D., a post-doctoral fellow at MCTP. "We're talking about the ability to sequence more than 20,000 genes and look not just for individual genetic mutations, but at combinations of mutations." The exploratory study, known as the Michigan Oncology Sequencing Project (MIONCOSEQ), found that identifying a patient's "mutational landscape" provides a promising approach for identifying which trials may best help a patient, the researchers say. Their findings were recently published in Science Translational Medicine. "High-throughput sequencing harnesses the latest technological advances to process millions of pieces of genetic information, allowing us to map a cancer's genetic aberrations," says co-lead investigator Sameek Roychowdhury, M.D., Ph.D., a clinical lecturer in hematology and oncology at the U-M Medical School. "Using this technique to identify biomarker-driven treatment options really opens the door for personalized oncology, but it also presents a number of logistical challenges, chief among them making the results available cost-effectively and in a clinically relevant timeframe." "A decade or two ago, this type of sequencing would have cost many millions or even billions of dollars, but the technology is advancing so rapidly, we're now talking in terms of thousands -- which makes widespread use a real possibility," he adds. Cancer can arise from a variety of genetic alterations including rearrangements, additions, deletions and substitutions within the genetic code. "Different sequencing processes are required to find different types of alterations," Roychowdhury says. "But to be cost-effective, there must be a balancing act between a broad analysis and a deep analysis." The study began by testing the researchers' sequencing strategy on prostate cancer tumors that had been grown in mice. Later, two patients were enrolled in a clinical pilot: one with colorectal cancer and one with melanoma. Potential clinical trials were identified for both patients. However, the researchers caution, not all patients will match an existing study. Some patients with a given mutation may be excluded because they have, for example, prostate cancer, but a trial is only enrolling breast cancer patients. The researchers believe that this approach also provides an opportunity to approach clinical trials in a new way, moving from a tissue-specific focus toward genetic aberrations shared across cancer types. Still, enrolling in a trial does not guarantee a patient will benefit from the treatment, the researchers caution. Hurdles to widespread implementation include the need for a multidisciplinary Sequencing Tumor Board to interpret the complex sequencing results, management of the necessary computational resources, and a process for dealing with incidental genetic findings revealed by the sequencing -- such as a risk for hemochromatosis, a genetic disorder that causes the body to absorb too much iron. Achieving a four-week turnaround time for results is important because that's how long patients are usually required to wait for unsuccessful treatments to leave their systems before starting a clinical trial. "Once some of the practical and technological hurdles are cleared, we envision an array of mutation and pathway-based trials for available targeted therapies, with eligibility

based on molecular assessment," says senior investigator Arul Chinnaiyan, M.D., Ph.D., director of MCTP, Howard Hughes Medical Institute Investigator, and S.P. Hicks Professor of Pathology at the U-M Medical School. "Moreover, if patients are treated with matching targeted therapies and develop secondary resistance, it could also help reveal the mechanisms of resistance and inform future trials for combination therapies." Chinnaiyan says the work was made possible only by collaboration and teamwork. U-M physicians Moshe Talpaz, M.D., Stephen Gruber, M.D., Ph.D., and Kenneth Pienta, M.D. played key roles in the clinical implementation of this exploratory protocol, he notes. Researchers hope this type of sequencing will become more widely available over the next 5 to 10 years. Cancer patients are encouraged to speak to their doctors about clinical trial opportunities.

New study shows biopsy of recurrent breast cancer can alter treatment
Published: Monday, November 28, 2011 - 19:32 in Health & Medicine A second, larger clinical research study led by breast cancer specialists at Princess Margaret Hospital (PMH) has again proven that comparing a new biopsy of progressing or recurring cancer with that of the original cancer can dictate a change in treatment. The results are published online ahead of print in the Journal of Clinical Oncology. Principal investigator Dr. Eitan Amir, medical oncologist in the PMH Cancer Program, University Health Network, says clinicians involved immediately altered treatment in one of seven patients based on the new biopsy results. "This was a study of specifically undertaking biopsy of areas of breast cancer recurrence and altering treatment therapy based on the findings in real-time." says Dr. Amir. "For clinicians, these findings show it is feasible to biopsy recurrence of breast cancer. For patients with progressive or recurring disease, these findings may encourage them to ask their physician if a second biopsy is needed to confirm their treatment therapy is still correct." The study team analyzed 121 biopsies from patients with progressing or recurring disease to determine any changes in the predictive markers (such as hormone or HER2 "receptors") that influence response to breast cancer treatments. It is the presence, absence and/or combinations of these receptors that help oncologists provide effective personalized medicine to each individual. Dr. Amir says the most important findings were the potential for negative receptors to become positive. "It is significant because this change in receptor status potentially introduces new effective treatment options for patients." This was the case for most of the women whose therapy changed after results of the second biopsy were available compared to basing the treatment plan on initial biopsy at the time of diagnosis. This study was also the first to look at the survival of patients whose treatment was changed post-biopsy. "It's been known for over 30 years that recurring cancer can differ from the primary cancer, but nobody knew if this was important," says Dr. Amir. "More recently we have learned that patients with a change in receptor status may have worse outcomes from breast cancer, possibly due to basing treatment on incorrect predictive markers. However, our study shows that if treatment is modified according to biopsy results from a metastatic site, the survival rates of patients with recurrent disease which is different from the original tumor were similar to those where disease was the same."

Dr. Amir's research results build on the findings of the initial, smaller PMH study of 29 biopsies that first shed light on the importance of a second biopsy in breast cancer recurrence. The earlier findings were reported in the Annals of Oncology, Oxford University Press. "This knowledge provides more insight into why some patients whose disease progresses respond to treatment and others do not." Why receptors change during the course of disease is not yet known, says Dr. Amir, but a priority area for further research. This study was funded by the Canadian Breast Cancer Foundation -- Ontario Region. Dr. Amir's research is also supported by The Princess Margaret Hospital Foundation. Sandra Palmaro, CEO of the Canadian Breast Cancer Foundation -- Ontario Region says: "Dr. Amir's new findings provide more proof that conducting a second biopsy on patients suspected of having recurrent breast cancer can lead to changes in treatment for a significant number of patients. This can help ensure women get the treatment best suited to their individual situations, and avoid unneccessary or ineffective treatments. By finding and funding important research, the Foundation's donors are helping to create a future without breast cancer."

Researchers examine role of inflammatory mechanisms in a healing heart

Published: Wednesday, November 30, 2011 - 15:34 in Health & Medicine Virginia Commonwealth University researchers have found that an inflammatory mechanism known as inflammasome may lead to more damage in the heart following injury such as a heart attack, pointing researchers toward developing more targeted strategies to block the inflammatory mechanisms involved. Following a heart attack, an inflammatory process occurs in the heart due to the lack of oxygen and nutrients. This process helps the heart to heal, but may also promote further damage to the heart. The mechanisms by which the heart responds to injury are not fully understood, so researchers have been examining the cellular pathways involved to gain further insight. In a study published online the week of Nov. 21 in the Proceedings of the National Academy of Sciences, researchers addressed the role of a specific inflammatory mechanism, called inflammasome, during the process of healing in the heart. Using an animal model, the team found that inflammasome amplifies the response by generating the production of a key inflammatory mediator known as Interleukin-1. Further, they described that pharmacologic inhibition of the formation of inflammasome prevents heart enlargement and dysfunction. "Defining the role of the inflammasome in the response to injury in the heart and the possibility to intervene opens a new area of investigation for the prevention and treatment of heart failure following a heart attack," said Antonio Abbate, M.D., assistant professor of medicine in the VCU Department of Internal Medicine and Division of Cardiology. According to Abbate, who serves as the interim director for the cardiac intensive care unit at the VCU Pauley Heart Center, this study supports the team's previous findings that showed that Interleukin-1 affects the heart, and blocking Interleukin-1 benefits patients of heart attack and heart failure. "Based on the findings of the current study we are even more convinced that blocking Interleukin-1 may be safe and beneficial, and we are now exploring novel ways to do so," he said.

Abbate said there are four ongoing clinical trials at the VCU Pauley Heart Center in patients with various heart conditions treated with a drug called anakinra which blocks Interleukin-1. Abbate and his team continue to examine the molecular mechanisms of inflammasome formation and heart injury, and hope to determine new ways to intervene with potentially more targeted strategies in the future.

Cell molecule identified as central player in the formation of new blood vessels
Published: Monday, November 28, 2011 - 22:33 in Health & Medicine Scientists at the University of North Carolina at Chapel Hill School of Medicine have identified a cellular protein that plays a central role in the formation of new blood vessels. The molecule is the protein Shc (pronounced SHIK), and new blood vessel formation, or angiogenesis, is seriously impaired without it. The study, which appeared online Nov. 16, 2011 in the journal Blood, was led by associate professor of cell and molecular physiology at UNC, Ellie Tzima, PhD, who is also a member of the university's Lineberger Comprehensive Cancer Center and the McAllister Heart Institute. "Angiogenesis is the formation of new blood vessels from existing blood vessels and it's a process that's important during embryonic development and in the development of diseases such as cancer," Tzima said. "So understanding the molecular mechanisms of how blood vessels form is important from the basic science perspective and for understanding and treating disease." Vascular networks form and expand by sprouting, similar to the way trees grow new branches. The process allows fresh oxygen and nutrients to be delivered to tissues, whether in a developing embryo or a cancerous tumor. Blood vessel formation is spurred by a variety of chemical signals that zoom along complex pathways. Some are cues that come from growth factors, others from the tissue matrix that the cells sit on. This extracellular matrix (ECM) serves the cell in a number of ways, such as supporting the cell's structure, helping to regulate cell-to-cell communication. The protein Shc, is known to regulate a number of important molecular signaling pathways, but its role in angiogenesis has remained unknown until now, Tzima says. She also points out that Shc is evolutionarily conserved, which indicates its essential importance across species. "We hypothesized that Shc would be the central player that accepts signals from all of the stimuli that have been previously shown to be important for regulating blood vessel formation and would process them and regulate the cell's response," Tzima said. "And that is what we found -- that Shc coordinates signals, those coming from growth factors as well as from the extracellular matrix." Tzima suggests that we imagine the cell as a complex highway network with electronic toll plazas through which cars with a transponder can whiz at highway speeds without slowing down. The system works because the transponder's personalized signal is relayed to a computer system that calculates the toll and charges the car's account in a flash. "Shc is the toll plaza, the checkpoint through which signals crucial to blood vessel formation must pass and get coordinated for proper angiogenesis to occur." In the study, Tzima and her team found that Shc is required for angiogenesis in zebrafish, mouse and human endothelial cell culture models of blood vessel formation. "The animal

studies gave us the broad perspective that Shc may be important to this process," said graduate student and study first-author Daniel T. Sweet. "Zebrafish and mice have previously been used to explore blood vessel formation in vivo. We found that without Shc, blood vessel formation is impaired." "Then for a closer look we used a cell culture model to determine which endothelial cell processes require Shc for angiogenesis. We found it mediates signals from growth factor receptors and extracellular matrix receptors," Sweet said. "Shc is important for the crosstalk between these processes, meaning that they need to "talk" to each other in order to properly form a tube or to sprout and migrate. That's the exciting thing about this paper." Tzima notes that elegant genetic models of mice have been used to understand important cellular processes, including angiogenesis. "But if you want to think about designing therapeutics it becomes much more important to understand the molecular mechanism. And this was the strength of the study. We went all the way down to molecular interactions that allowed us to figure out this new angiogenesis pathway."