Applying Systematic Review To Field Of Nutrition

Posted on 21st May 2013 in Uncategorized

Systematic reviews, also referred to as evidence-based reviews, provide objective assessments with pre-specified questions that can be used to develop clinical and public health practice guidelines, make recommendations, set research agendas, and formulate scientific consensus statements.

"Systematic reviews serve as a means of synthesizing and evaluating evidence from multiple studies in a rigorous and transparent way that minimizes bias," says corresponding author Alice H. Lichtenstein, DSc, director of the Cardiovascular Nutrition Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University. "The systematic review approach is flexible and can accommodate unique challenges posed by questions related to food and nutrition."

Writing in the Journal of Nutrition, the authors provide examples illustrating the flexibility of the approach to a wide range of nutrition-related topics including: effectiveness and safety of vitamin D in relation to bone health, effects of soy on health outcomes, and health effects of (n-3) fatty acids on arrythmogenic mechanisms in animal and isolated organ/cell culture studies.

"When we deal with nutrition-related topics and systematic reviews, we often address issues that are not encountered in other fields of study," says co-author Elizabeth A. Yetley, PhD, a former senior nutrition research scientist with the National Institutes of Health (NIH). "Nutrient intake, whether from food or supplements, tends to be more difficult to accurately quantify than, for example, the daily dosage of a medication. Therefore, when performing a systematic review, it is particularly important to document methods of assessment."

Equally important, the authors write, is the documentation of new data as it emerges, as well as objectivity. Objectivity of a systematic review comes from individuals trained in systematic review methodologies, such as co-author Joseph Lau, MD, director of the Tufts Evidence-based Practice Center at the Institute for Clinical Research and Health Policy Studies at Tufts Medical Center. "To be involved in a systematic review, I must be free of personal biases or vested interest in a particular outcome. I focus on the methodology and look to my colleagues for their nutrition expertise," says Lau, also a professor at Tufts University School of Medicine.

The process of performing a systematic review begins with clearly defining the research question. Lichtenstein, the Stanley N. Gershoff professor at Tufts’ Friedman School of Nutrition Science and Policy, and colleagues advocate the "PICO" approach to formulating research questions. The acronym PICO stands for Population (participants), Intervention (or exposure for observational studies), Comparator and Outcome."

"While systematic reviews cannot replace expert judgment and should not be used as a sole source of information for developing science-based recommendations and policies, they are valuable tools that can be adapted effectively for use in the field of nutrition," says Lichtenstein.

This project was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services.

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Physician Style And HMO Affiliation Impact Lengths Of Patient Visit, Study Finds

Posted on 20th May 2013 in Uncategorized

In a new study, "Primary Care Visit Length, Quality, and Satisfaction for Standardized Patients with Depression" in the December 2007 issue of the Journal of General Internal Medicine, Estella Geraghty and her colleagues found several key determinants for visit length, ranging from individual style and practice volume to whether a physician practiced within a health maintenance organization (HMO) or whether the doctor had any nonprofessional experience with depression.

Identifying the key predictors that drive the length of doctor visits has long remained elusive, despite much effort by researchers. Using what are called "standardized patients" — actors who have been carefully coached to simulate specific patient ailments — Geraghty and her team were able to control patient presentations and more accurately gauge physician practices.

Researchers found that visit length for patients with similar conditions varied more than 10-fold among primary care physicians, with much of the variation attributed to individual physician styles. Doctors working in HMOs and those with the busiest schedules, for example, spent significantly less time with patients. Physicians with personal or vicarious experience with depression, however, spent more time with their patients. They spent as much as 11 percent more time with depressed patients than doctors who did not have that connection with the ailment.

The study found that despite using standardized patients to control for variability in cases, visit times still ranged significantly, from about six minutes to more than 72 minutes, with an average visit lasting approximately 22 minutes.

Geraghty, an assistant professor of clinical internal medicine at UC Davis, pointed out that meeting patients’ desires for longer visits tends to conflict with the pressures faced by most physicians in established practices.

"Physicians who work in HMOs or who have busy practices risk jeopardizing patient satisfaction because, inevitably, their patient visits are shorter," she said. "Patient satisfaction is an important component of care because it influences a patient’s adherence to a physician’s recommended plan for treatment. Consequently, there is a constant tension between practice efficiency and providing a long enough visit to satisfy the patient."

Geraghty noted that it could be important for doctors who can’t easily carve out more time for consultations with their patients to find alternative ways to improve patient satisfaction. She said small steps, such as exhibiting greater empathy, enhancing active listening skills, decreasing waiting-room time, asking more open-ended questions about primary complaints and allowing patients to respond with minimal interruption could help compensate for unavoidably short visit lengths.

The study involved 298 primary care visits by 18 standardized patients to physicians at medical offices in California and New York. Standardized patients are healthy persons trained to portray the personal history, physical symptoms, emotional characteristics and everyday concerns of an actual patient. Using these actor-patients helped Geraghty and her colleagues limit the uncontrolled variability associated with patient differences encountered when using real-life patients.

The researchers concluded that more study is needed to examine the relationship of quality and visit length and to understand how physicians can maximize patient satisfaction within a reasonable amount of time.

Co-authors on the study were Richard L. Kravitz, professor of internal medicine, and Peter Franks, a professor of family and community medicine.

The study was funded by a Health Resources Services Administration training award that Geraghty received, and by National Institutes of Health grants.

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First Diagnostic Test for Hereditary Children’s Disease

Posted on 19th May 2013 in Uncategorized

Idiopathic Infantile Hypercalcemia (IIH) is among the top ten most common inherited diseases. The researchers estimate that one in every 47,000 people — around 600 Canadians and 6,000 Americans — may suffer from IIH, but there was no way until now of confirming the diagnosis.

"Developing a positive diagnostic test for IIH is a major step in understanding this disease," says co-lead researcher Glenville Jones, a professor in the Department of Biomedical and Molecular Sciences. "We hope the test will be made available for the approximately 600 Canadians who may be afflicted with IHH."

The body’s inability to break down vitamin D results in an excess of calcium in the blood. Children with IIH suffer from calcifications and tissue hardening throughout the body, as well as calcification of the kidneys and renal failure.

"This is classic case of research going from the bench to the bedside," explains Dr. Jones. "Our research started in the laboratory but the findings will have a definite impact on the health of Canadians."

This research was conducted in collaboration with pediatricians Martin Konrad and Karl-Peter Schlingmann from the University Children’s Hospital in Munster, Germany, and funded in part by the Canadian Institutes of Health Research. The findings were published June 15 in the New England Journal of Medicine.

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Mutated Gene Causes Death Of Nerves In Brain; Identification Of First Glutamate Receptor Linked With Neurodegeneration

Posted on 18th May 2013 in Uncategorized

The gene carries instructions to make a receptor for chemicals called neurotransmitters, which nerve cells use to communicate. The discovery, from mouse studies, marks the first time scientists have identified and directly linked a mutant gene in the glutamate receptor family to the death of brain cells. Because of the mutation, the resulting faulty receptor acts as if a neurotransmitter always is present–even when none of the chemical is there. This false detection causes the nerve cells to die.

"The mutations in the d2 glutamate receptor gene may play a role in changing the metabolism of the adult nerve cells to reactivate a program of cell death that normally occurs only during natal development. If we can reveal more about this process and understand it, it may be possible to slow the process down or stop it and preserve the neuron," explains Nathaniel Heintz, Ph.D., professor and head of the Laboratory of Molecular Biology at Rockefeller and an investigator at Howard Hughes.

During fetal development, programmed cell death is used to sculpt the final number of cells in the mature brain. About twice as many cells begin the process of developing into brain nerves than are needed in an adult brain. Consequently, many of the cells activate a biochemical program to commit suicide, known as an apoptotic death, because they receive certain chemical signals.

"We think that the surveillance mechanisms that monitor the normal metabolism of neurons are much like those monitoring the cell-division cycle in other types of cells. In neurodegenerative diseases, these mechanisms may activate the apoptotic cell death pathway as a normal response to the severe dysfunction of neurons. Our discovery of the d2 glutamate receptor gene mutation helps us to understand how this gene functions in normal neurons, but the $64,000 question remains: 'How does its altered function trigger cell death?'" says Heintz.

Heintz and his colleagues would like to pursue studies of two possible explanations related to the mutant receptor's function and the initiation of cell death. The glutamate receptor is part of a biochemical relay system that transports signals between cells. When glutamate binds to the receptor, located in the outer membrane of the neuron, the receptor allows charged molecules, usually calcium ions, to enter the cell and pass the signal along.

The first possibility of how the mutation causes cell suicide is simply that death ensues from the direct action of the receptor increasing the amount of ions coming into the cell. Other studies have shown that unusually high levels of calcium ions can enter the cell in response to increased activation of glutamate receptors, as occurs in stroke. These ions are critical in causing cell death. However, no direct pathway linking calcium ions to programmed death has yet been discovered. The second possibility is that the mutation alters the signaling properties of the receptor, and that the resulting aberrant signals are critical in the initiation of cell death.

The receptor mutation occurs because of the substitution of two of the four nucleic acids used to build the gene, located on chromosome 6 of lurcher (Lc) mice. This switch changes the instructions carried by the gene and consequently, the receptor protein it makes. The mutation causes the death of Purkinje neurons in the cerebellum, the brain structure that controls all aspects of coordination and fine motor control in mature animals.

Heintz's coauthors included Jian Zuo, Philip L. De Jager, Weining Jiang, Ph.D., at Rockefeller, and Kanji A. Takahashi and David J. Linden, Ph.D., at Johns Hopkins. The National Institute for General Medical Sciences, part of the federal government's National Institutes of Health, funded the research, with support from the National Institute of Mental Health, the McKnight Foundation, the Derelbiss Fund and the National Alliance for Research on Schizophrenia and Depression.

Rockefeller began in 1901 as the Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. Recently, the university created five centers to foster collaborations among scientists to pursue investigations of Alzheimer's Disease, of biochemistry and structural biology, of human genetics, of sensory neurosciences and of the links between physics and biology.

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Expression of Certain Transporter Proteins May Predict Resistance to Drug Therapy

Posted on 17th May 2013 in Uncategorized

In a Turkish study, researchers analysed specimens of synovium (the soft tissue that lines the surfaces within joints) from patients with RA who had undergone knee or hip replacement surgery. The presence of BCRP was reported in 41% of samples from RA patients, compared with 0% of samples in the healthy control group. The level of BCRP staining (a technique where a stain specific to a particular protein is used) was more prominent, indicating that the protein was being expressed at higher levels in cells actively involved in the immune response (macrophages, endothelial cells and fibroblasts).

Furthermore, of the 40% of RA patients with cells that showed a presence of BCRP, some had a higher concurrent disease activity score (DAS28, an index that rates scores of 28 tender and swollen joints) despite receiving treatment for their condition, when compared with patients without BCRP. Researchers noted that this difference was not statistically significant (4.32±0.32 vs 3.37±1.16, p>0.05).

"The results of our study show that the presence of BRCP was only detected in patients with RA and that arguably it is found more prominently in patients with high disease activity," said Dr. Umut Kalyoncu, Hacettepe University Rheumatology Department, Ankara, Turkey, and lead author of the study. "The BCRP protein is a pump involved in transporting substances across the cellular membrane. What we hypothesise is that, due to the location of the cells showing highest levels of BCRP, the presence of this protein may create a barrier for treatments entering the synovium of RA patients. Testing RA patients for the presence of BCRP may help us determine which patients will respond better to certain treatments."

Researchers screened samples using histochemical methods from seventeen patients (female n=14) with RA for the presence of p-glycoprotein (a protein involved in the transport of various molecules across cellular membranes), BCRP and multidrug resistance protein 1 and compared with samples taken from a control group of healthy controls and other inflammatory (ankylosing spondylitis, juvenile chronic arthritis) and non-inflammatory (osteoarthritis) rheumatic diseases. Prior to surgery, 53% of patients were taking methotrexate, 47% were taking sulphasalazine, 70% hydroxychloroquine, 18% leflunomide and 12% were taking anti-TNF drugs.

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Racial Differences in Breast Cancer Treatment Persist Despite Similar Economics

Posted on 16th May 2013 in Uncategorized

Heather A. Young, Ph.D., an associate professor of epidemiology at The George Washington University, said these findings underscore the difficulties in measuring the impact of race and socioeconomic status on health outcomes.

"There is likely something about race that we are still not capturing, whether it is different patterns of social support, access to transportation, or family burden, something is causing the disparities in care to persist," she said.

The data Young presented at the Third AACR Conference on the Science of Cancer Health Disparities was able to capture socioeconomic status, but only by measuring poverty status from U.S. Census data.

"We have yet to fully capture the variety of variables that encompass socioeconomic status," said Young.

What is clear, from this study and others, is that the time to treatment in Washington, D.C., for African-American women lags behind what is recommended by professional guidelines and is significantly longer than what is seen for white women.

"The situation is likely similar or worse in other urban areas, which may have higher rates of uninsured," said Young.

Using data from the D.C. Cancer Registry, which captured all cancer cases from 1998 to 2006, the researchers found that African-American women were 2.19-fold more likely to wait more than two months longer than white women from the time of diagnosis to treatment.

African-American women had a mean time to diagnosis of 26.1 days compared with 14.1 days for white women. This disparity appeared to increase over time. If these African-American women were diagnosed between 2001 and 2003, they were significantly more likely to wait for treatment than if they had been diagnosed between 1998 and 2000. The gap widened even further between 2004 and 2006.

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How Toxoplasma Gondii Gets Noticed

Posted on 15th May 2013 in Uncategorized

A strong immune response spares T. gondii-infected hosts from deadly infection—an event that may also benefit the parasite, which relies on survival of the host to ensure its own transmission. But how the infected host elicits an immune response isn’t completely understood.

Like many other parasites, T. gondii resides within specialized vesicles inside infected host cells, but the process by which peptides from the trapped bugs are processed by infected cells and presented to killer T cells is mysterious.

In new research, Romina Goldszmid and her colleagues at the National Institutes of Health in Bethesda use T. gondii infections in mice to study how portions of the parasitic proteins escape the vesicle in a process known as cross-presentation.

They find that the parasite gets noticed by the immune system when the membrane of the bug-containing vesicle fuses to the endoplasmic reticulum—an organelle normally involved in presenting pathogens to T cells—allowing a swap of parasitic peptides.

The report will appear online on January 19th in The Journal of Experimental Medicine.

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Novel Virus Entry Mechanism Could Lead To New Drugs Against Poxviruses

Posted on 14th May 2013 in Uncategorized

Many viruses, such as influenza, are surrounded by a single lipid membrane, or envelope, and to enter cells this membrane must be removed. Previously, all enveloped viruses were thought to shed their lipid membrane by fusion with a cell membrane which allows the virus core to be released into the cell.

In contrast, the extracellular form of Vaccinia virus has two lipid membranes, meaning a single fusion event will not release a naked virus core into the cell. The researchers found that interactions between polyanionic or negatively charged molecules on the cell surface and glycoproteins on the virus particle caused a non-fusogenic disruption of the virus outer envelope, allowing the poxvirus to enter the cell.

As well as discovering how the double membrane problem is solved, the researchers demonstrated that polyionic compounds can be used to treat poxvirus infections, even days after infection has started. Disrupting the outer membrane with polyanionic compounds exposes the virus, allowing antiviral antibodies to be more effective. The disruption of the outer membrane also limits the spread of the virus in the body.

Professor Geoffrey L. Smith FRS, from Imperial College London and a Wellcome Trust Principal Research Fellow, said: "This work has uncovered a completely novel biological process. It increases our understanding of how viruses can manipulate biological membranes and will help the development of new drugs against poxviruses, such as variola virus, the cause of smallpox."

The research team included Mansun Law, Gemma C. Carter, Kim L. Roberts, Michael Hollinshead and Geoffrey L. Smith.

The researchers have filed a patent for this discovery with Imperial Innovations, the College’s spin out arm.

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Elderly Can Blame Fractures and Falls on Low Sodium

Posted on 13th May 2013 in Uncategorized

"Screening for a low sodium concentration in the blood, and treating it when present, may be a new strategy to prevent fractures," comments Ewout J. Hoorn, MD, PhD (Erasmus Medical Center, Rotterdam, the Netherlands). However, hyponatremia does not appear to affect the risk of osteoporosis, as defined by low bone mineral testing, so more research is needed to understand the link between sodium levels and fracture risk.

The study included more than 5,200 Dutch adults over age 55, all with initial information on sodium levels and six-year follow-up data on fractures and falls. "A number of recent studies suggested a relationship between hyponatremia, falls, osteoporosis, and fractures," Hoorn explains. The authors’ goal was to confirm these possible associations using prospective, long-term follow-up data.

About eight percent of the study participants, all community dwelling adults, had hyponatremia. This group of older participants had a higher rate of diabetes and was more likely to use diuretics (water pills) than those with normal sodium levels. Subjects with hyponatremia had a higher rate of falls during follow-up: 24 versus 16 percent. However, there was no difference in bone mineral density between groups, so hyponatremia was not related to underlying osteoporosis.

Nevertheless, the group with low sodium levels had a higher rate of fractures. With adjustment for other risk factors, the risk of vertebral / vertebral compression fractures was 61 percent higher in the older adults with hyponatremia. The risk of non-spinal fractures, such as hip fractures, was also significantly increased: a 39 percent difference.

The relationship between hyponatremia and fracture risk was independent of the increased rate of falls in the low-sodium group. Subjects with hyponatremia also had a 21 percent increase in the risk of death during follow-up.

Hyponatremia is the most common electrolyte disorder, usually developing because the kidneys retain too much water. "Although the complications of hyponatremia are well-recognized in hospitalized patients, this is one of the first studies to show that mild hyponatremia also has important complications in the general population," says Hoorn.

Further study will be needed to clarify the mechanism by which low sodium levels increase fracture risk. In the meantime, "Screening older adults for and treatment of hyponatremia in older adults may be an important new strategy to prevent fractures," adds Hoorn.

Study co-authors are Fernando Rivadeneira, MD, PhD, Joyce B.J. van Meurs, PhD, Gijsbertus Ziere, MD, PhD, Bruno H. Ch. Stricker, MB, PhD, Albert Hofman MD, PhD, Huibert A.P. Pols MD, PhD, Robert Zietse MD, PhD, André G. Uitterlinden PhD, M. Carola Zillikens MD, PhD (Erasmus Medical Center).

The study abstract, "Mild Hyponatremia as a Risk Factor for Fractures: The Rotterdam Study," [F-FC232] was presented as an oral presentation on November 19 at the Colorado Convention Center in Denver, CO.

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University of Iowa Researcher Studies Deafness In Fruit Flies, Humans

Posted on 12th May 2013 in Uncategorized

Eberl says their recent work — showing that loss of function in the Myosin VIIA gene leads to complete deafness in fruit flies — has brought scientists one step closer to understanding how such mutations result in inner-ear abnormalities and deafness in humans.

"Myosin VIIA was one of the first human hereditary deafness genes to be identified. But it is not clear exactly how this molecule works in the human ear," he says.

Previous evidence suggested that fruit flies and humans rely on the same genes to develop their auditory organs, which in the fruit fly is in the antenna. Eberl’s research shows that at least one molecular component specialized for hearing function, myosin VIIA, is conserved in these ears.

In looking for clues to inherited deafness in humans, Eberl begins with the "love song" of the fruit fly. Although they may seem an odd choice, the fruit fly and its love song are very effective tools for learning about the molecular and cellular mechanisms involved in hearing in insects and animals, including humans, says Eberl, who is trying to identify the genes responsible for hearing in fruit flies.

Whether or not mutant fruit flies can hear the fruit fly love song (actually a vibrating wing) enables Eberl to evaluate the function of genes responsible for hearing. He and his graduate student, Sokol Todi, implant electrodes into the antennas of the flies, and record the voltages the receptor cells generate as the flies listen to the love song. By comparing the electrical impulses generated by the normal flies to those generated by myosin VIIA mutant flies, they showed that the myosin VIIA gene is essential for hearing in flies, as it is in humans.

Now that they know the same molecule is used, scientists will be able to design experiments to test specific mechanisms that have been hypothesized. Eberl says, "These experiments are next to impossible in humans, but quite feasible in the fruit fly."

"Understanding how this protein works and examining its functional role in hearing will provide new insights into auditory mechanisms, not only in fruit flies, but in humans, as well," he says.

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The American Heart Association and the National Institutes of Health provided support for the research.

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