The bacterium responsible for tuberculosis (TB), mycobacterium tuberculosis (Mtb), is notoriously difficult to kill. The most commonly used antibiotics, rifampicin and isoniazid, need to be used for extended periods of time (typically 6-24 months) to effectively eliminate infection. In addition, emergence of antibiotic-resistant strains is an increasing problem.

Researchers at Albert Einstein College of Medicine of Yeshiva University have now identified a new biochemical pathway in Mtb and two novel ways to kill the bacterium. The pathway involves four enzymatic steps in the conversion of the disaccharide, trehalose, to α-glucan mediated by TreS, Pep2, GlgE (which has been identified as a maltosyltransferase that uses maltose 1-phosphate) and GlgB. Focusing on GlgE, the researchers found that blocking the enzyme induced toxic accumulation of maltose-1-phosphate, killing the bacteria in vitro and in a mouse model of infection. Inhibition of another enzyme in the pathway was non-lethal until combined with inactivation of Rv3032, a glucosyltransferase involved in a distinct α-glucan pathway. Inhibition of Rv3032 alone was also non-lethal to the bacteria.

The research validates inhibition of GlgE as therapy for TB but also highlights the potential for targeting two α-glucan pathways – a strategy that potentially leads to reduced incidence of resistance. Both approaches are also distinct from the mechanisms of currently used antibiotics.

The study is published in Nature Chemical Biology.

Extreme accumulation of fat in muscle tissue is associated with cardiovascular disease and is a contributory factor in insulin resistance and type II diabetes. It is therefore important to understand the mechanisms by which fat is taken up from the bloodstream and metabolised by tissues. Surprisingly, the role of blood vessels themselves in the transport of lipids has not been clearly established. Researchers at the Karolinska Institutet have now identified a role for vascular endothelial growth factor-B (VEGF-B) in endothelial targeting of lipids to peripheral tissues.

The VEGFs and their receptors are major regulators of angiogenesis and pharmacological intervention, for example with bevacizumab (a monoclonal antibody specific for VEGF-A), has been successfully exploited in oncology. This latest study has shown that VEGF-B, in mice, controls endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. Mice that were deficient in VEGF-B (Vegfb^-/-) showed reduced uptake and accumulation of lipids in muscle, heart and brown adipose tissue. Instead, the Vegfb^-/- mice preferentially transported lipids to white adipose tissue, resulting in a small weight increase. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium.

The authors of the study, published in Nature, propose that this new role for VEGF-B could potentially lead to novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.

Fatty acids can be stored as triacylglycerol in lipid droplets, typically within adipose tissue, and then later released by the action of triacylglycerol hydrolase (TGH, also known as carboxylesterase-3, Ces3). Under normal circumstances, the released fatty acids provide an energy source, but excessive accumulation of triacylglycerol in peripheral tissues is associated with obesity and is a risk factor for type II diabetes and cardiovascular disease.

Researchers at the University of Alberta, Canada, reasoned that blocking the action of TGH would lead to better blood lipid profiles, but might also result in accumulation of triacylglycerol in the liver. However, they have found that mice lacking TGH (tgh^-/-) display global metabolic benefits with no obvious down-side. In both fasted- and fed-states, the animals had reduced plasma triacylglycerol, apolipoprotein B, and fatty acid levels. Despite the attenuation of very low-density lipoprotein (VLDL) secretion, TGH deficiency did not increase hepatic triacylglycerol levels. The tgh^-/- mice exhibited increased food intake and energy expenditure without change in body weight, and these metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance.

The authors of the study, published in Cell Metabolism, suggest that pharmacological inhibition of TGH could be a useful therapeutic target, although cautioning that further work is required. It may be desirable to target TGH in specific tissues (e.g. hepatic versus adipose) but those subtleties have yet to be established.

Cerebral cavernous malformations (CCM) are irregular clusters of dilated, leaky capillaries found in the central nervous system in around 0.5% of the general population. Although many of those with the condition will never be aware of the fact, for others the symptoms can be severe. Depending on the specific location of the CCM in the brain or spinal cord, patients may experience seizures, headaches, paralysis, hearing or vision changes, and cerebral haemorrhage. Current treatment options rely on management of the symptoms (e.g. control of seizures with anti-epileptic drugs) or surgical resection.

Researchers at University of North Carolina School of Medicine, Chapel Hill have now identified a potential target for therapeutic intervention in CCM. The disease is associated with mutations in any of three genes, ccm1, ccm2 or ccm3, which encode the corresponding CCM-1, -2 and -3 proteins. These proteins form a common complex and act co-ordinately in regulation of the cytoskeleton. It had previously been shown that loss of CCM-2 resulted in overexpression of the GTPase, RhoA, but this latest study demonstrates that CCM-1 and CCM-3 are also required for regulation of RhoA.

The team were able to restore normal function to endothelial cells lacking CCM-1, -2 or -3 by inhibition of the RhoA-activated Rho Kinase (ROCK), either using an inhibitor, Y-27632, or shRNA knockdown of ROCK2. The results suggest that inhibition of ROCK may represent a target for pharmacological intervention in this disease.

The study is published in the Journal of Biological Chemistry.

Although the disorder is not very well known, narcolepsy is thought to affect 1 in 2000 individuals and this figure may be higher as a consequence of under-reporting and under-diagnosis. The most common symptom is excessive daytime sleepiness (EDS), which may be accompanied by sudden loss of muscular control (cataplexy) triggered by strong emotions. Narcoleptics may also experience sleep paralysis (short periods of paralysis when waking or falling asleep), hypnagogic or hypnopompic hallucinations (vivid images or sounds, respectively, when waking or falling asleep) or automatic behaviour (when routine activities are continued during a sleep episode).

For the last ten years it has been known that narcoleptics have a deficiency in hypocretin (orexin), a neurotransmitter involved in control of sleep/wakefulness. In parallel with the neurotransmitter deficiency there is a massive loss of hypothalamic neurons that produce hypocretin and it has been hypothesised that this results from an autoimmune response.

Swiss scientists have now identified autoantibodies to Tribbles homolog 2 (Trib2), an autoantigen previously identified in autoimmune uveitis, in narcolepsy patients. The team developed a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Having identified enrichment of Trib2 in the mouse hypocretin neurons, the team went on to analyse sera from narcoleptics. Narcolepsy patients with cataplexy had higher Trib2-specific antibody titres compared with either normal controls or patients with other inflammatory neurological disorders. Trib2-specific antibody titres were highest early after narcolepsy onset, sharply decreased within 2–3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. Additionally, high Trib2-specific antibody titres correlated with the severity of cataplexy.

The study, published in the Journal of Clinical Investigation, provides the first evidence that narcolepsy is an autoimmune disorder.

Cystic fibrosis (CF) results from a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) that results in impaired transport of chloride and bicarbonate ions. Patients with CF have thickened mucus, accompanied by inflammation, which affects the lungs and organs of the intestinal tract. Although the disease has received much scientific attention, current treatments only manage the symptoms and affected individuals continue to suffer from reduced life expectancy.

A new study from researchers at University of California, San Diego School of Medicine, has now identified defects in signalling mediated by peroxisome proliferator-activated receptor-γ (PPAR-γ) that contribute to disease symptoms. Examining colonic epithelial cells and whole lung tissue from CFTR-deficient mice, the team found reduced expression of genes that are normally activated by PPAR-γ. Lipidomic analysis of the colonic epithelial cells suggested that the defect resulted in part from reduced amounts of the endogenous PPAR-γ ligand, 15-keto-prostaglandin E₂ (15-keto-PGE₂). The researchers were able to partially restore gene expression by treating the mice with rosiglitazone, a PPAR-γ agonist used in the treatment of diabetes, reducing the severity of disease.

Rosiglitazone had no effect on chloride secretion in the colon, but increased expression of carbonic anhydrases 2 and 4 (Car2 and Car4) resulting in increased bicarbonate secretion and reduced mucus retention.

The study, published in Nature Medicine, suggests that levels of 15-keto-PGE₂ could provide a marker for patients who might benefit from treatment with a PPAR-γ agonist.

Results from a phase II trial of the experimental drug Dimebon (latrepirdine) in people with Huntington’s disease have provided indications that it may improve cognition. The drug, being developed by Medivation, Inc., is also in Phase III trials for Alzheimer’s disease. In July 2009, Medivation and Pfizer, Inc. launched a Phase III clinical trial (HORIZON) of the drug for Huntington’s disease.

Huntington’s disease is a progressive neurodegenerative disorder that impacts movement, behaviour and cognition, generally resulting in death within 20 years of the disease’s onset. The disease steadily erodes memory and ability to think and learn. Over time, this cognitive impairment contributes to the loss of the ability to work and perform the activities of daily life. There are no treatments current available that effectively alter the course of the disease or improve cognition.

We have previously reported on the potential for Dimebon in Alzheimer’s disease (July 2008, July 2009), where the ability of the drug to stabilise and/or enhance mitochondrial function is believed to be of benefit. Mitochondria are also thought to play a role in the development of Huntington’s disease, suggesting that Dimebon could also have utility in this condition.

Karl Kieburtz, M.D., University of Rochester Medical Center neurologist and lead investigator on the Horizon trial, said:

“This is the first clinical trial that has focused on what is perhaps the most disabling aspect of the disease. While more investigation needs to be done, these results are encouraging and show, for the first time, a statistically significant benefit in terms of improved cognitive function in patients with Huntington’s disease.”

In the phase II study, the impact of the drug on 91 patients over a 90 day period was assessed. Half were given the drug and the other half a placebo. The patients were then evaluated using a cognitive tool called the Mini-Mental State Examination. This test – which is used by clinicians to evaluate the stage and severity of dementia and Alzheimer’s disease – consists of questions used to evaluate an individual’s orientation, memory, and ability to follow commands. The researchers found that the drug on average improved the scores of people taking the drug compared to those who received the placebo. Although the treatment had no significant impact on the Unified Huntington’s Disease Rating Scale (UHDRS) or the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog), the results support further investigation in Huntington’s disease.

Results of the study are published in the Archives of Neurology.

Launched in 2009, the Medpedia Project aims to evolve a model for sharing and advancing knowledge in health and medicine. It provides a free online collaborative platform, allowing healthcare professionals to contribute to the growing knowledge base. As well as building a medical encyclopedia, professionals and non-professionals can share information about conditions, treatments, lifestyle choices, etc. Other parts of the Medpedia platform include Medpedia Answers for asking and answering medical and health questions; Medpedia Alerts for displaying real-time medical and health news alerts; and Medpedia News & Analysis for sharing medical news and analysis. The latter includes syndicated articles from blogs such as this one.

Now Medpedia has announced the launch of their clinical trial platform, which updates every 24 hours from data at ClinicalTrials.gov. Search results provide details on a trial’s purpose, who may participate, locations, and contact information from a database of around 80,000 registered trials. Whilst these data are accessible via other sources, including ClinicalTrials.gov itself, the new platform allows content to be “pushed” or fed automatically to appropriate contexts. Trial information can show up alongside a Medpedia article covering the same condition, in a personalized feed of someone interested in that condition, or in a patient community related to that condition.

Dr. David L. Katz MD, MPH, Director of the Prevention Research Center at Yale University School of Medicine, said:

“Clinical trials are among the most important of tools for advancing biomedical knowledge, and improving the human condition. But for this to happen, the trials must successfully recruit their participants, and awareness of the trials must be effectively disseminated. All too often, these requirements are rate limiting. In its customarily user-friendly manner, Medpedia is helping to resolve this problem with its clinical trial finder. This tool should serve doctors and patients alike, helping to get important trials done, and helping to spread the word about important findings as they come in.”

This free resource is available now on Medpedia at www.medpedia.com/clinical-trials. All we need now is an easy way to find trial results!

Stroke continues to be a major health issue and is a significant cause of death and disability. The recent introduction of clot-dissolving therapies has had a significant impact on survival, although the narrow window of opportunity for successful treatment remains a challenge. For those surviving stroke, the period immediately following is critical for recovery of physical and cognitive abilities. There has therefore been much interest in treatments that will aid the spontaneous recovery of function observed in the first few months following a stroke.

Researchers at Carver College of Medicine and College of Public Health (Ms Acion), University of Iowa, Iowa City, have now reported results from a clinical trial with escitalopram, a selective serotonin-reuptake inhibitor (SSRI) antidepressant. The team hypothesised that treatment with antidepressants may be beneficial because of their ability to stimulate production of compounds essential for nerve growth.

In the randomised trial, 43 patients were assigned to take 5 to 10 milligrams of escitalopram daily, 45 to take placebo daily and 41 to participate in a problem-solving therapy program developed for patients with depression. After 12 weeks of treatment, patients taking escitalopram had higher scores on neuropsychological tests assessing overall cognitive function, specifically on those measuring verbal and visual memory. The beneficial effect of escitalopram on cognitive recovery was independent of its effect on depressive symptoms and was not influenced by stroke type or mechanism of ischemic stroke. In addition, escitalopram was well tolerated and the frequency of adverse effects similar to those of patients receiving placebo.

The authors of the study, published in the February issue of Archives of General Psychiatry, suggest that the utility of antidepressant therapy in post-stroke recovery warrants further investigation.

An aortic aneurysm is a bulge in the aorta, the largest blood vessel in the body, which results from weakening of the artery wall. The majority of these occur in the portion of the aorta that passes through the abdomen and are referred to as abdominal aortic aneurysms (AAA). AAA is something of a stealth disease, since it is generally asymptomatic and may only be diagnosed at a routine physical examination or following X-ray. Over time the aneurysm may expand, with an increased risk of rupturing. Unfortunately, the rapid blood loss following aneurysm rupture is frequently fatal and accounts for at least 15,000 deaths in the US annually.

The only treatment for AAA currently available is surgical intervention. Early diagnosis is followed by monitoring the size of the aneurysm until the risk of rupture exceeds the risk of surgery. However, scientists at Providence Heart + Lung Institute at St. Paul’s Hospital and the University of British Columbia (UBC) have now raised the possibility of pharmacological intervention. Using experimental models of AAA, the team have found a role for the protein-degrading enzyme Granzyme B (GMZB).

GMZB is a serine protease expressed by a variety of immune cells and is responsible for destroying unwanted tissue, such as virally-infected cells. This role is supported by the pore-forming protein, perforin, which delivers GMZB to the intracellular compartment. The UBC research has shown that GMZB, which is abundantly expressed in aneurysms from human and animal model AAA, also plays a role in the pathogenesis of AAA. Further, the experimental data suggest that this is a perforin-independent mechanism involving extracellular matrix degradation and subsequent loss of vessel wall integrity. The results suggest that an inhibitor of GMZB may provide a therapeutic option in the treatment of AAA.

The study is published in the American Journal of Pathology.