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Archive - Jul 2015

July 21st

Levels of Two Blood Biomarkers (ADMA and Hcy) Predict Pre-Eclampsia Month Ahead of Disease Onset

Levels of biomarkers in the blood of pregnant women can be used to predict which women are at risk of pre-eclampsia, according the results of a study published online on July 22, 2015 in BJOG: An International Journal of Obstetrics and Gynaecology. ADMA and Hcy, both known to be raised in women with pre-eclampsia, are present in the blood in higher than normal concentrations a month before the onset of the condition. The article is titled “Serial Determinations of Asymmetric Dimethylarginine and Homocysteine during Pregnancy to Predict Pre-Eclampsia: a Longitudinal Study.” Pre-eclampsia is a combination of raised blood pressure (hypertension) and protein in the urine (proteinuria). It is quite common, usually occurring after 20 weeks of pregnancy, and affecting between 2 and 8 in 100 women during pregnancy. In most cases it is mild and has little effect on the pregnancy. However for 1 in 200 women, the effects are more serious. Severe pre-eclampsia can affect the mother by damaging the kidneys, liver, and other organs and, in really severe cases, cause seizures and coma. There is often less fluid than normal around the baby and the placenta can be affected, restricting blood flow and nutrients necessary for the baby's growth. The exact cause of pre-eclampsia is not understood but it is more common in first pregnancies. Once identified, mothers can be monitored and treated. Often the baby will be delivered early by being induced or by caesarean section. The current study addresses the need to find a reliable way of screening women to find those at risk of pre-eclampsia. The research team led by Dr.

July 21st

New Study Directly Links Beta-CTF Protein to Pathology of Alzheimer’s Disease Development; Protein Acts at Earliest Stage of the Disease

A recent study conducted at the Nathan S. Kline Institute for Psychiatric Research (NKI) and the NYU Langone Medical Center implicates a new culprit in Alzheimer's disease (AD) development. The research reveals that C-terminal fragment beta (beta-CTF) -- the precursor of the amyloid beta (Aß) peptide -- acts at the earliest stage of Alzheimer's to initiate a range of abnormalities leading to the loss of groups of neurons critical for memory formation. Results from the study were published online on July 21, 2015 in the journal, Molecular Psychiatry, and the article has been selected for an issue cover. The article is titled “De Novo Deleterious Genetic Variations Target a Biological Network Centered on Aβ Peptide in Early-Onset Alzheimer Disease.” The recent study findings involving beta-CTF have significant implications for treatment strategies and furthering the course of Alzheimer's drug development. Presently, the most common strategy for treating AD is targeting the amyloid beta peptide, which has had modest success in clinical trials. Findings from this new research suggest that drugs that may reduce beta-CTF levels as well as beta-amyloid, such as the class of BACE1 inhibitors currently under development, may help slow or stop the progression of AD. Beta-CTF is formed during endocytosis, the process by which cells absorb nutrients and sample various materials from the outside environment. It has been known for some time that abnormalities of endocytosis develop very early in AD, well before clinical symptoms, and that variant forms of genes controlling endocytosis are frequently implicated as risk factors promoting Alzheimer's.

Elevating cAMP Levels in Nucleus Accumbens Region of Brain Improves Stress Response; Signaling Molecule May Be Therapeutic Target for Depression Treatment

Increasing the levels of a signaling molecule found in the brain can positively alter response to stress, revealing a potential new therapeutic target for treatment of depression, University of Texas (UT) Southwestern Medical Center researchers said. The study, which appears in Nature Neuroscience, determined that elevating levels of the molecule cyclic adenosine monophosphate (cAMP) in brain cells had a positive impact on stress-induced behaviors in mice. Other studies have shown that patients with major depressive disorder often have impaired cAMP signaling and that chronic anti-depressant treatments often turn on this signaling system. The title of the current article is “The Role of Ventral Striatal cAMP Signaling in Stress-Induced Behaviors.” "This is the first step in the development of a treatment for patients with major depressive disorder using this new strategy," said senior author Dr. James Bibb, Professor of Psychiatry, and Neurology and Neurotherapeutics at UT Southwestern. Major depressive disorder (MDD) may be triggered or exacerbated by severe or chronic stress. Depression affects more than 120 million people worldwide. Between 20 percent to 40 percent of people with depression are not helped by existing therapies, highlighting the need for new treatments and approaches. The study was supported by the Center for Depression Research and Clinical Care at UT Southwestern. The Center, established with a $5 million lead gift from the Hersh Foundation earlier this year, combines basic research, translational clinical research in genetics, functional brain imaging, and treatment research across the entire age span, with a special focus on treatment of resistant, chronic, or recurrent depression.

Diabetes Drug Class (Glitazones) May Reduce Risk of Parkinson’s

A type of drug used to treat diabetes may reduce the risk of developing Parkinson's disease, according to a new study published online on July 21, 2015 in the open-acces journal PLOS Medicine. The article is titled “Glitazone Treatment and Incidence of Parkinson’s Disease among People with Diabetes: A Retrospective Cohort Study.” The research, led by the London School of Hygiene & Tropical Medicine, found that diabetes patients taking glitazone anti-diabetes drugs (either rosiglitazone or pioglitazone) had a 28% lower incidence of Parkinson's disease than people taking other treatments for diabetes who had never taken glitazones. Glitazones are a class of drug that activate the peroxisome proliferation-activated gamma (PPAR-gamma) receptor, which is found inside cells in many different body organs. PPAR-gamma receptor activation by glitazones leads to reduced insulin resistance, which has been useful for treating people with diabetes, but the receptor has many other functions that have not been studied as thoroughly in humans. Although the potential effect of glitazones on Parkinson's disease had previously been demonstrated in rodents and in vitro, the authors of the PLOS article believe this is the first study to show the relationship between glitazone use and incidence of Parkinson's disease in humans. The study, which was funded by The Michael J Fox Foundation for Parkinson's Research, looked at more than 160,000 diabetes patients in the UK. Researchers used electronic health records from the UK Clinical Practice Research Datalink to match 44,597 glitazone users with 120,373 people using other anti-diabetic drugs. Glitazone users were matched by age, sex, GP practice, and diabetes treatment stage with up to five users of other diabetic treatments.

Zone in with Zon: RNA Is Present in Normal Genomic DNA and May Play Functional Role; Human Genomic DNA “Misincorporates” Over 1 Million Ribonucleotides Per Replication Cycle

In a stunning discussion in his most recent blog, posted on July 20, 2015, eminent nucleic acid chemist Jerry Zon, Ph.D., describes recent findings that a significant amount of RNA is present in normal DNA. In fact, Dr. Zon said that ribonucleotide "misincorporation" represents the most common type of replication error and occurs quite frequently in normal cells. Even more surprising, Dr. Zon said, there seem to be some positive consequences to having “some Rs among the Ds,” so to speak. Replication fidelity is, of course, hugely important and a key facet of replication fidelity, Dr. Zon noted, is the discrimination of the sugar backbone of the nucleic acid strand [ribose nucleic acid triphosphates (rNTPs) versus deoxyribose dNTPs] so that the correct sugar NTP is chosen. The two classes have very similar structures, differing by the added presence of only a single oxygen in the ribo versus deoxy forms. Hence, polymerases are challenged, Dr. Zon said, with distinguishing between the two types of nucleotides. Otherwise they risk inserting the incorrect substrate into the newly replicated nucleic acid strand. Consequently, sugar discrimination is a very important trait for DNA polymerases in this environment enriched for rNTPs over dNTPs. Recent studies of human polymerase delta found that in reactions containing nucleotide concentrations similar to those estimated to be present in mammalian cells, there was one rNTP incorporated per ∼2000 dNTPs—a result which predicts that human polymerase delta may introduce >1,000,000 rNMPs into the genome per replication cycle. Earlier results in analogous studies using yeast, led investigators to state that “[t]he idea that rNMP incorporation into DNA may be more common than previously appreciated leads one to wonder about possible benefits of rNMP incorporation," Dr. Zon reported.

Successful Treatment of Eczema Using Rheumatoid Arthritis Drug Reported by Yale Physicians; Same Drug (Tofacitinib Citrate) Previously Also Found Useful in Vitiligo and Alopecia Areata

Researchers at Yale School of Medicine have successfully treated patients with moderate to severe eczema using a rheumatoid arthritis drug recently shown to reverse two other disfiguring skin conditions, vitiligo and alopecia areata. The study is evidence of a potential new era in eczema treatment, they report. The research findings were published online on July 17, 2015 in the Journal of the American Academy of Dermatology. The article is titled “Treatment of Recalcitrant Atopic Dermatitis with the Oral Janus Kinase Inhibitor Tofacitinib Citrate.” Eczema (atopic dermatitis) is a chronic condition that causes severe itching and leaves the skin red and thickened. It can adversely affect sleep and quality of life. Standard treatments, such as steroid creams and oral medicines, commonly fail to relieve symptoms in patients with moderate to severe eczema. Based on current scientific models of eczema biology, Yale Assistant Professor of Dermatology Brett King, M.D., Ph.D., hypothesized that a drug already approved for rheumatoid arthritis, tofacitinib citrate, would interrupt the immune response that causes eczema. The drug is an inhibitor of Janus kinase. In the new study, Dr. King and his colleagues report that treatment with the drug led to dramatic improvement in six patients with moderate to severe eczema who had previously tried conventional therapies without success. During treatment, all six patients reported significant reduction in itching, as well as improved sleep. The redness and thickening of the skin diminished, also. "These individuals were not only very happy with the results, they also expressed a tremendous sense of relief at being comfortable in their skin for the first time in many years," Dr. King said. Dr.

July 20th

Fresh-Water Prawns & Simple Biology May Trump Big Pharma in Battle Against Potentially Deadly Schistosomaisis; 800 Million Humans Now at Risk Worldwide

A deadly disease may have met its match: a bug-eyed, pint-sized crustacean. A Stanford-led study in Senegal, West Africa, finds that freshwater prawns can serve as an effective natural solution in the battle against schistosomiasis, a potentially deadly parasitic disease (image shows parasite) that infects approximately 230 million people. The prawns prey on parasite-infected snails, while also providing a source of marketable protein-rich food. Because prawns cannot support schistosomiasis' complex life cycle, they do not transmit the disease themselves. "The results of our study open the pathway to a novel approach for the control of schistosomiasis," said co-author Dr. Giulio De Leo, a biology professor at Stanford's Hopkins Marine Station and a senior fellow at the Stanford Woods Institute for the Environment. The new study, published online on July 20, 2015, tracked parasite-infected snails and people in two villages. In one village, the international research team and Senegalese partner Biomedical Research Center Espoir pour la Santé stocked a river access point with prawns. Over the course of 18 months, the researchers found 80 percent fewer infected snails and a 50 percent lower disease burden (the mean number of parasite eggs in a person's urine) in people living in the village neighboring the prawn-stocked river. The PNAS article is titled “Reduced Transmission of Human Schistosomiasis after Restoration of a Native River Prawn That Preys on the Snail Intermediate Host.” In a mathematical model of the system, stocking prawns, coupled with infrequent mass drug treatment, eliminated schistosomiasis in high-transmission sites. "Where drugs, alone, fail to control schistosomiasis due to rapid reinfection, prawns may offer a complementary strategy" for controlling the disease, the study's authors write.

July 19th

Whole Exome Sequencing Permits “Personalized Medicine” Approach to Thoracic Aortic Aneurysms

Researchers at the Aortic Institute at Yale-New Haven, Yale University School of Medicine have tested the genomes of more than 100 patients with thoracic aortic aneurysms, a potentially lethal condition, and provided genetically personalized care. Their work will also lead to the development of a "dictionary" of genes specific to the disease, according to researchers. The study was published online on July 15, 2015 in The Annals of Thoracic Surgery. The article is titled “Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting.” Experts have known for more than a decade that thoracic aortic aneurysms -- abnormal enlargements of the aorta in the chest area –tend to run in families and be caused by specific genetic mutations. Until recently, comprehensive testing for these mutations has been both expensive and impractical. To streamline testing, the Aortic Institute collaborated with Allen Bale, M.D., of Yale's Department of Genetics to launch a program to test whole genomes of patients with the condition. Over a period of three years, the researchers applied a technology known as whole exome sequencing (WES) to more than 100 individuals with these aneurysms. This technology sequences that part (~1%) of the human genome that codes for proteins. "To our knowledge, it's the first widespread application of this technology to this disease," said lead author and cardiac surgeon John A. Elefteriades, M.D., Director of the Aortic Institute. The researchers detected four mutations already known to cause thoracic aortic aneurysms. "The key findings are that this technology can be applied to this disease and it identifies a lot of patients with genetic mutations," said Dr. Elefteriades.

Co-Administration of High Levels of Resveratrol and Quercetin May Significantly Reduce the Cardiac Toxicity of Doxorubincin, Allowing Increased Use of This Highly Effective Anti-Cancer Drug

Resveratrol (image) and quercetin, two polyphenols that have been widely studied for their health properties, may soon become the basis of an important new advance in cancer treatment, primarily by improving the efficacy and potential use of an existing chemotherapeutic cancer drug. Resveratrol, a powerful antioxidant found in red wine and other foods, has already received much attention as a possible explanation for the "French paradox," a low incidence of cardiovascular disease despite a diet often high in fats. The new research suggests that resveratrol may soon have value far beyond that. In laboratory experiments, researchers at Oregon State University have developed a system to increase the bioavailability of these compounds in the body by using "copolymers" that make the compounds water soluble and allow their injection into the blood stream, creating levels that are far higher than could ever be obtained by diet or oral intake. The resveratrol and quercetin then appear to reduce the cardiac toxicity of a very widely used cancer drug, Adriamycin (doxorubicin). Although highly effective in the treatment of lymphomas, breast, ovarian, and other cancers, Adriamycin can only be used for a limited time in humans because of its cardiotoxicity. The co-administration of these polyphenols might allow much more extensive use of this drug, while at the same time improving its efficacy and demonstrating the polyphenols' own anti-cancer properties, scientists said. This research has been published online by the Journal of Controlled Release and will appear in the September 10, 2015 print issue of this journal. The authors are scientists from the College of Pharmacy at Oregon State University (OSU) and the School of Pharmacy at Pacific University. Both institutions supported the research.

Olfactory, Visual, and Thermal Cues Lead Mosquitoes to Targets; New Information May Result in Better Mosquito Traps, But Offers Little Hope for Reducing Bite Incidence

On summer evenings, we try our best to avoid mosquito bites by dousing our skin with bug repellents and lighting citronella candles. These efforts may keep the mosquitoes at bay for a while, but no solution is perfect because the pests have evolved to use a triple threat of visual, olfactory, and thermal cues to home in on their human targets, a new Caltech study suggests. The study, published by researchers in the laboratory of Dr. Michael Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering, was published online on July 16, 2015 in Current Biology. The article is titled “"Mosquitoes Use Vision to Associate Odor Plumes with Thermal Targets." When an adult female mosquito needs a blood meal to feed her young, she searches for a host--often a human. Many insects, mosquitoes included, are attracted by the odor of the carbon dioxide (CO2) gas that humans and other animals naturally exhale. However, mosquitoes can also pick up other cues that signal a human is nearby. They use their vision to spot a host and thermal sensory information to detect body heat. But how do the mosquitoes combine this information to map out the path to their next meal? To find out how and when the mosquitoes use each type of sensory information, the researchers released hungry, mated female mosquitoes into a wind tunnel in which different sensory cues could be independently controlled. In one set of experiments, a high-concentration CO2 plume was injected into the tunnel, mimicking the signal created by the breath of a human. In control experiments, the researchers introduced a plume consisting of background air with a low concentration of CO2. For each experiment, researchers released 20 mosquitoes into the wind tunnel and used video cameras and 3-D tracking software to follow their paths.