Trace elements link to dialysis morbility

A systematic review published in the open access journal BMC Medicine has shown that, compared to healthy controls, dialysis patients have significantly different blood concentrations of trace elements.

Marcello Tonelli, from the University of Alberta, Canada, led a team of researchers who investigated the trace element status of dialysis patients in 128 studies. They found that levels of cadmium, chromium, copper, lead, and vanadium were higher and that levels of selenium, zinc and manganese were lower in the hemodialysis patients, compared with controls. Tonelli said: “Since both deficiency and excess of trace elements are potentially harmful yet amenable to therapy, the hypothesis that trace element status influences the risk of adverse clinical outcomes is worthy of investigation.”

The researchers found that data examining any possible relation between trace element status and clinical outcomes are scarce. However, they point out that the nephrology community’s experience with aluminium toxicity exemplifies the damage that uncontrolled elemental accumulation can cause. “Aluminium accumulation led to serious toxicity in dialysis patients prior to the recognition that aluminium in dialysate and oral medications was responsible. Today, such aluminium-related toxicity is extremely rare. However, the possibility that other trace elements may accumulate in patients with kidney failure and cause unrecognised chronic toxicity has received surprisingly little attention.”

As well as the potentially toxic accumulation of some elements, this research highlights the reduced blood levels of others, including zinc. Tonelli points out that zinc supplementation is routinely used to correct deficiency in people from the general population, significantly reducing the risk of infection and all-cause death. He said: “Our data suggest that future studies should investigate the link between zinc or selenium status and clinical outcomes in dialysis patients, in whom the risk of infection is dramatically elevated compared to people with normal kidney function.”

● Citation: Trace elements in hemodialysis patients: A systematic review and meta-analysis M Tonelli ET AL, BMC Medicine 2009, 7:25doi:10.1186/1741- 7015-7-25



Researchers reveal alcohol’s site of action

People have used alcohol for thousands of years for its pleasant and intoxicating effects. A new study finally provides an explanation for how it produces these effects in the brain. The breakthrough could lead to new treatments for alcohol abuse and dependence.

Despite considerable research, an understanding of how alcohol affects the brain has remained elusive. A decade ago, researchers funded by the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) identified a membrane channel in brain cells that’s activated by ethanol, the type of alcohol found in alcoholic beverages. The channel, called G-protein-coupled inwardly rectifying potassium channel (GIRK), is found on cells throughout the brain and plays a key role in brain function. Studies since then have confirmed that alcohol exerts its effects in living animals, at least in part, through GIRK. However, scientists haven’t known whether alcohol interacts directly with GIRK or affects it some other way.

Dr Paul A. Slesinger and his colleagues at the Salk Institute recently solved the structure of a molecule related to GIRK. They noticed that both it and a protein that allows fruit flies to sense alcohol have alcoholbinding sites similar to an area on GIRK. Funded by NIAAA and the US National Institute of General Medical Sciences (NIGMS), they set out to investigate whether ethanol binds GIRK at the suspected site.

The researchers systematically substituted different amino acids in the protein sequence of GIRK’s potential alcohol binding “pocket”. In the online edition of Nature Neuroscience on 28 June 2009, they reported that amino acids with bulkier side chains reduced or eliminated ethanol’s ability to activate GIRK. In contrast, those with smaller side chains didn’t block the alcohol’s effect on GIRK.

These experiments, combined with structural analyses, led the scientists to propose a model for how alcohol activates GIRK channels. At rest, the channels open and close, but alcohol binding stabilises the open shape, leading to alcohol-activated currents in brain cells. “We believe alcohol hijacks the intrinsic activation mechanism of GIRK channels and stabilises the opening of the channel,” says first author Prafulla Aryal.

Identifying the physical site that ethanol uses to exert its effect is an important step in developing new approaches to treat alcohol abuse and dependence. For example, it might be possible to develop a drug that blocks alcohol from entering GIRK’s binding pocket.



Blankets can take place of drugs

Patients with brain injuries or dangerously high fevers are often cooled to reduce their core body temperature to prevent further damage and aid healing. Unfortunately, cooling induces a natural and familiar response – shivering. This shivering counteracts efforts to keep the patient's temperature low, causes physical stress, and is currently treated with sedatives and other drugs. Now, a study recommended by Andreas Kramer, Clinical Assistant Professor in the Departments of Critical Care Medicine and Clinical Neuroscience at University of Calgary, Canada, a member of Faculty of 1000 Medicine and leading expert in the field of critical care medicine, demonstrates that simply warming the skin can decrease shivering in many patients, without the need for drugs.

Physicians at Columbia University and the New York Presbyterian Hospital found that the intensity of shivering and physiological stress increased when warming blankets were removed from therapeutically cooled patients. Shivering subsided when the blankets were replaced.

Though warming the skin does not reduce shivering in all patients, Kramer concludes that “its simplicity, low cost, widespread availability, lack of adverse effects, and the potential to avoid sedation ... make it an attractive treatment option.”

● Reference: The full text of this article is available at:
http://www.f1000medicine.com/ article/id/1162143



Researchers strengthen obesity–diabetes link

A molecular switch found in the fat tissue of obese mice is a critical factor in the development of insulin resistance, report scientists at the Salk Institute for Biological Studies in the United States.

Previously found to increase glucose production by the liver during fasting, the culprit – a protein known as CREB – is also activated in fat tissue of obese mice where it promotes insulin resistance.

Their findings, published in the March 2009 issue of Cell Metabolism, suggest that CREB activity could provide an early warning for obese people predisposed to develop insulin resistance and may lead to new diabetes treatments that would not require weight loss.

“Obesity is a major risk factor for the development of type II diabetes,” says Marc Montminy, MD, PhD, a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study, “but not everyone who is obese becomes insulin resistant, so identifying the initial events that trigger resistance represents an important goal for diabetes research.”

Maziyar Saberi, PhD, cofirst author a postdoctoral researcher in the Division of Endocrinology and Metabolism at the University of California, San Diego, said: “Given that obesity is now at its highest levels and expected to worsen in the near future, therapies that could potentially halt the genesis of type II diabetes in the face of obesity will be of great value.”



What turns genes on and off?

New research shows that a father’s sperm passes along a previously unrecognised set of instructions that helps guide the early development of his children. The instructions likely tell the developing embryo when specific genes should be turned on or off.

Scientists have found that in sperm, most paternal genes important for embryonic development are flagged with special proteins bearing chemical tags. These proteins and their tags, called modified histones, influence when developmental genes and other key processes are turned on, shut off, or put on hold at critical stages in an embryo’s growth.

The findings by Howard Hughes Medical Institute investigator Bradley R. Cairns were reported in an advance online publication on June 14, 2009, in the journal Nature.

The findings show that sperm genes are packaged along with chemical “guideposts” that help determine which genes should be turned on or off at specific stages of development, says Cairns who collaborated with Douglas Carrell and other colleagues at the University of Utah. Those developmental guideposts are epigenetic – they regulate gene access and utilisation without changing the DNA sequence of a gene.

Epigenetics influences gene expression in several ways: One is through methylation – the addition of a methyl group to a DNA molecule to deactivate a gene. Demethylation – subtraction of a methyl group – activates the gene. Genes can also be silenced or activated by modifying histone proteins that serve as spools on which DNA strands are wrapped.

Previous work in Cairns’ lab, in zebrafish and yeast, had shown that histones can package certain genes so they remain flexible during development. His group showed that genes in the ‘off’ position can also be poised to turn on later. “It’s gene packaging,” he says “that determines the potential for a gene’s activity.” “Those genes are the important decision makers in the embryo,” Cairns says. “You need to make sure those genes from the father turn on for normal development … and they have to turn on at the right



New PET tracer shows promise for Alzheimer's

Bayer Schering Pharma AG, Germany, has presented positive data on a global Phase II study with the novel positron emission tomography (PET) tracer florbetaben at the International Conference on Alzheimer's Disease (ICAD) in Vienna, Austria, in July. This study shows that patients with a clinical diagnosis of Alzheimer´s disease can be differentiated from age-matched healthy volunteers (HVs) on the basis of florbetaben uptake pattern in the brain.

Until now, the clinical diagnosis of Alzheimer´s disease (AD) with current methods such as cognitive tests is still limited. Currently, a definite diagnosis of Alzheimer´s disease is only possible post mortem. The results of this study showed PET images with a high specificity of over 90%: More than 90% of the HVs had a negative florbetaben scan (i.e. no tracer uptake) in the relevant brain regions. The results also show a sensitivity of approximately 80% indicated by the clinical diagnosis, meaning that about 80% of the clinically suspected Alzheimer patients had positive florbetaben scans indicating the presence of beta-Amyloid plaques. This is in line with the results of studies comparing the clinical diagnosis with the definite post mortem histopathological diagnosis.

Additional Phase II and pivotal Phase III global studies are under preparation to validate the potential shown by florbetaben in this Phase II setting. Start of the Phase III program is planned for end of 2009.

Florbetaben is an inlicensed 18F-labeled PET tracer that specifically binds to beta- Amyloid plaques. These plaques consist of proteins that accumulate in the brain and are a pathological hallmark of Alzheimer’s disease. As the aggregation of the beta-Amyloid protein in the brain is also a key target for new therapeutic treatments under development, florbetaben might also be able to support the development of these new treatment approaches.



Students develop sutures embedded with stem cells

Johns Hopkins biomedical engineering students have demonstrated a practical way to embed a patient’s own adult stem cells in the surgical thread that doctors use to repair serious orthopaedic injuries such as ruptured tendons. The goal, the students said, is to enhance healing and reduce the likelihood of re-injury without changing the surgical procedure itself.

The project team – 10 undergraduates sponsored by Bioactive Surgical, a US-based medical technology company – won first place in the recent Design Day 2009 competition conducted by the university’s Department of Biomedical Engineering. In collaboration with orthopaedic physicians, the students have begun testing the stem cell–bearing sutures in an animal model, paving the way for possible human trials within about five years.

The students believe this technology has great promise for the treatment of debilitating tendon, ligament and muscle injuries, often sportsrelated, that affect thousands of young and middle-aged adults annually. “Using sutures that carry stems cells to the injury site would not change the way surgeons repair the injury,” said Matt Rubashkin, the student team leader, “but we believe the stem cells will significantly speed up and improve the healing process. And because the stem cells will come from the patient, there should be no rejection problems.”

Bioactive Surgical developed the patent-pending concept for a new way to embed stem cells in sutures during the surgical process. As envisioned by the company and the students, a doctor would withdraw bone marrow containing stem cells from a patient’s hip while the patient was under anaesthesia. The stem cells would then be embedded in the novel suture through a quick and easily performed proprietary process. The surgeon would then stitch together the ruptured Achilles tendon or other injury in the conventional manner, but using the sutures embedded with stem cells.

At the site of the injury, the stem cells are expected to reduce inflammation and release growth factor proteins that speed up the healing, enhancing the prospects for a full recovery and reducing the likelihood of re-injury.



Transcranial ultrasound surgery shows promise

A team at the University Children’s Hospital Zurich has completed a feasibility study testing the use of noninvasive transcranial MRguided focused ultrasound surgery (MRgFUS) for the treatment of neuropathic pain. Ten adult patients diagnosed with chronic neuropathic pain successfully underwent non-invasive deep brain ablation surgery (central lateral thalamotomy) with transcranial MRgFUS and showed improvement in pain scores and reduction of pain medication with no adverse effects at three months followup. This is the first study in the world to test non-invasive transcranial focused ultrasound as a treatment modality for functional brain disorders.

“This study showed that we can perform successful operations in the depth of the brain without opening the cranium or physically penetrating the brain with medical tools, something that appeared to be unimaginable only a few years ago,” said Daniel Jeanmonod, neurosurgeon at the University of Zurich.

“By eliminating any physical penetration into the brain, we hope to duplicate the therapeutic effects of invasive deep brain ablation without the side effects for a wider group of patients.”

Neurosurgeons currently treat patients with functional neurological disorders, such as neuropathic pain or Parkinson’s disease, by inserting a tiny probe through the cranium and brain to reach and ablate damaged tissue.

“The more traditional invasive treatment works to alleviate pain and other symptoms, however it exposes the patient to complications, including infections, bleeding and damage to surrounding brain tissue,” Dr Jeanmonod explained. “Also, only patients whose target tissue lies in the clear path of the probe are eligible for the invasive procedure.

“We now have early clinical evidence suggesting that transcranial MRgFUS provides a safe and effective way to non-invasively ablate tissue deep within the brain,” said Ernst Martin, MD, Director of the Magnetic Resonance Center at the University Children’s Hospital Zurich. “While we need to monitor these patients further, we are very encouraged by the results to date and look forward to continuing our research.”