Target for Obesity Drugs Comes Into Focus

      Researchers at the University of Michigan have determined how the hormone leptin, an important regulator of metabolism and body weight, interacts with a key receptor in the brain.

Leptin is a hormone secreted by fat tissue that has been of interest for researchers in obesity and Type 2 diabetes since it was discovered in 1995. Like insulin, leptin is part of a regulatory network that controls intake and expenditure of energy in the body, and a lack of leptin or resistance to it has been linked to obesity in people.

Although there can be several complex reasons behind leptin resistance, in some cases the underlying cause is malfunction of the leptin receptor in the brain. An understanding of how leptin and its receptor interact could lead to new treatments for obesity and metabolic disorders, but the structure of this signaling complex has evaded researchers for years.

Georgios Skiniotis, a faculty member at the Life Sciences Institute and assistant professor in biological chemistry at the U-M Medical School, employed electron microscopy to obtain the first picture of the interaction between leptin and its receptor.

Skiniotis also traced similarities between the leptin receptor and other receptors of the same family, which may provide insight into new targets for treatment of other hormone-related diseases.

"It is exciting not only because it might help with developing new drugs," Skiniotis said. "We now better understand the design and mechanisms of signaling through this class of receptors, which brings us to a whole new set of intriguing questions."

In the paper "Ligand-Induced Architecture of the Leptin Receptor Signaling Complex," published electronically ahead of print on Oct. 11 in Molecular Cell, Skiniotis and his co-authors explain how the receptor is formed by two hinged legs that can swivel until they encounter leptin, which binds to the legs and makes them rigid.

Once the two legs of a receptor become rigid by binding to leptin, they signal to an enzyme called the Janus kinase. A number of drugs have been studied for treatments related to the Janus kinases; inhibiting it may lead to improvement of conditions like rheumatoid arthritis, psoriasis and metabolic disorders that are linked to inflammation.

Alan Saltiel, director of the Life Sciences Institute and a widely cited researcher who works on diabetes, obesity and metabolic disorders, sees a range of possibilities in the work of Skiniotis.

"This study may help solve an important issue we've been struggling with for some time," he said. "Since leptin is a master regulator of appetite, understanding why resistance to its effects develops in obesity has been a major obstacle to discovering new drugs for obesity and diabetes. Developing a clear picture of how leptin can bind to its receptor may be the first step in overcoming leptin resistance."

Tomado de: University of Michigan. "Target for obesity drugs comes into focus." ScienceDaily, 11 Oct. 2012. Web. 28 Nov. 2012.

New Antibiotic Cures Disease by Disarming Pathogens, Not Killing Them

 A new type of antibiotic can effectively treat an antibiotic-resistant infection by disarming instead of killing the bacteria that cause it. Researchers report their findings in the October 2 issue of mBio®, the online open-access journal of the American Society for Microbiology.

"Traditionally, people have tried to find antibiotics that rapidly kill bacteria. But we found a new class of antibiotics which has no ability to kill Acinetobacter that can still protect, not by killing the bug, but by completely preventing it from turning on host inflammation," says Brad Spellberg of the UCLA Medical Center and David Geffen School of Medicine, a researcher on the study.

New drugs are badly needed for treating infections with the bacteriumAcinetobacter baumannii, a pathogen that most often strikes hospital patients and immune- compromised individuals through open wounds, breathing tubes, or catheters. The bacterium can cause potentially lethal bloodstream infections. Strains of A. baumannii have acquired resistance to a wide range of antibiotics, and some are resistant to every FDA-approved antibiotic, making them untreatable.

Spelling and his colleagues found that in laboratory mice it was possible to mitigate the potentially lethal effects of the bacterium by blocking one of its toxic products rather than killing it.

"We found that strains that caused the rapidly lethal infections shed lipopolysaccharide [also called LPS or endotoxin] while growing. The more endotoxin shed, the more virulent the strain was," says Spellberg. This pinpointed a new therapy target for the researchers: the endotoxin these bacteria shed in the body.

Blocking the synthesis of the endotoxin with a small molecule called LpxC-1 prevented infected mice from getting sick. Unlike traditional antibiotics, Spellberg says, LpxC-1 doesn't kill the bacteria, it just shuts down the manufacture of the endotoxin and stops the body from mounting the inflammatory immune response to it that is the actual cause of death in seriously ill patients.

Spellberg says this is a direction few researchers have taken when exploring ways to treat infections but that it could make the difference in finding an effective drug. The results also highlight how important it is to find new, physiologically relevant ways of screening potential antibiotics for pathogens with a high degree of resistance, write the authors. Molecules like LpxC-1 that inhibit rather than kill bacteria wouldn't pass muster with traditional antibiotic screens that are based on killing effectiveness.

Liise-anne Pirofski of the Albert Einstein College of Medicine and a reviewer of the study for mBio® says neutralizing virulence factors is showing a lot of promise as an alternative route for treating infections. "There's a growing movement in infectious disease therapy to control the host inflammation response in treatment rather than just 'murdering' the organism," says Pirofski. "This is a very elegant and important validation that this approach can work -- at least in mice."

American Society for Microbiology. "New antibiotic cures disease by disarming pathogens, not killing them." ScienceDaily, 2 Oct. 2012. Web. 8 Nov. 2012.

Exercise Does a Body -- And a Mind -- Good

We've heard it time and time again: exercise is good for us. And it's not just good for physical health -- research shows that daily physical activity can also boost our mental health. But what actually accounts for the association between exercise and mental health?

A new article in Clinical Psychological Science, a journal of the Association for Psychological Science, explores whether certain psychosocial factors may help to explain the benefits of daily physical activity for adolescents' mental health.

Karin Monshouwer of the Trimbos Institute in the Netherlands and colleagues at Trimbos and VU University Medical Center specifically wanted to examine two existing explanations for the link between exercise and mental health. The self-image hypothesis suggests that physical activity has positive effects on body weight and body structure, leading to positive feedback from peers and improved self-image, and ultimately improving mental health. The social interaction hypothesis, on the other hand, holds that it's the social aspects of physical activity -- such as social relationships and mutual support among team members -- that contribute to the positive effects of exercise on mental health.

Monshouwer and her colleagues surveyed over 7000 Dutch students, ages 11 to 16. The adolescents completed validated surveys aimed at assessing their physical activity, mental health problems, body weight perception, and participation in organized sports. The researchers also gathered data on the adolescents' age, gender, and socioeconomic status; whether they lived at home with their parents; and whether they lived in an urban area.

The researchers found that adolescents who were physically inactive or who perceived their bodies as either "too fat" or "too thin" were at greater risk for both internalizing problems (e.g., depression, anxiety) and externalizing problems (e.g., aggression, substance abuse). Adolescents who participated in organized sports, on the other hand, were at lower risk for mental health problems.

Confirming both the self-image hypothesis and the social interaction hypothesis, adolescents' body weight perception (i.e., "too heavy," "good," or "too thin") and sports club membership each partially accounted for the relationship between physical activity and mental health, even after taking adolescents' backgrounds into account.

These results suggest that certain psychosocial factors -- body image and social interaction -- may help to explain at least part of the connection between physical activity and mental health. The researchers acknowledge, however, that other factors, such as the physiological effects of exercise, are probably also at work.

"We think that these findings are important for policymakers and anyone who works in healthcare or prevention. Our findings indicate that physical activity may be one effective tool for the prevention of mental health problems in adolescence," says Monshouwer.

Monshouwer and her colleagues hope that future studies will be able to examine similar questions while following participants over time. Such longitudinal studies could help researchers to understand how physical activity type and context might influence the relationship between exercise and mental health.

Association for Psychological Science. "Exercise does a body -- and a mind -- good."ScienceDaily, 25 Sep. 2012. Web. 5 Nov. 2012

Estatinas y riesgo de diabetes: más datos

      La utilización de estatinas se relacionó con un leve incremento de las concentraciones de glucosa en ayunas de pacientes con más riesgo de diabetes de tipo 2 en un nuevo estudio de observación [1].

     El estudio, publicado en la versión en línea de BMJ el 13 de septiembre de 2012, fue realizado por la Dra. Nina Rautio (Pirkanmaa Hospital, Tampere, Finlandia) y sus colaboradores. Llegaron a la conclusión de que sus hallazgos indican que la utilización de estatinas «podría tener efectos desfavorables en el metabolismo de la glucosa y… obstaculizar los efectos útiles de la intervención en el estilo de vida de personas con gran riesgo de diabetes de tipo 2».

La intervención intensiva en el estilo de vida es clave

Rautio dijo a heartwire que los resultados no se debieran interpretar como un motivo para desalentar el empleo de estatinas en las personas con más riesgo de ECV o con ECV establecida. Sin embargo, hizo hincapié en que los pacientes con alto riesgo de diabetes se beneficiarían de una intervención más intensiva en el estilo de vida. «Los profesionales sanitarios debieran invertir más de su tiempo en cambiar el estilo de vida, sobre todo de los usuarios de estatinas, en una dirección más saludable — es decir, dieta sana, no tabaquismo y actividad física.

Añadió: «Se ha demostrado que la diabetes de tipo 2 es evitable en personas con muy alto riesgo si se modifican los estilos de vida. Si un paciente se preocupa por los posibles efectos nocivos del tratamiento con estatinas, debe consultar a un médico en torno a esta cuestión y no suspender el tratamiento por sí mismos».

Al comentar sobre el estudio a heartwire, el experto en lípidos, Dr. Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) dijo: «Este estudio muy interesante realizado por Rautio et al está basado en datos de observación y esta es su principal limitación. Termina diciendo que las ventajas del tratamiento con estatinas para la prevención de las enfermedades cardiovasculares en las personas con un incremento del riesgo de diabetes de tipo 2 son de todas formas indudables. Estoy de acuerdo con esta última afirmación».

Ventajas netas

     Sin embargo, Blumenthal admitió que las estatinas pueden acompañarse de un incremento moderado de la glucemia en pacientes con múltiples componentes del síndrome metabólico. No obstante, citó el análisis reciente del estudioJUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin, el cual demostró una ventaja global neta indudable a una media de seguimiento de dos años.

Terminó diciendo: «El mensaje para los médicos es que los pacientes que tienen múltiples componentes del síndrome metabólico deben intentar mejorar más sus hábitos de estilo de vida para combatir el posible incremento de la glucosa cuando se inicia una estatina. Este estudio señala que las estatinas pueden tener efectos desfavorables sobre el metabolismo de la glucosa en determinadas personas, de manera que el cumplimiento de las mejoras en el estilo de vida será muy importante. Esperamos que en el futuro se lleven a cabo más estudios prospectivos sobre este tema».

En el estudio actual los investigadores realizaron un seguimiento a 2798 pacientes con alto riesgo de diabetes durante un año. Se les dio asesoría para modificar el estilo de vida; se determinó la glucemia en ayunas al inicio y a un año.

Los resultados demostraron que 484 individuos (17,3%) utilizaban estatinas al inicio. De estos pacientes, 7,5% presentaron diabetes de tipo 2 durante el seguimiento en comparación con 6,5% de los que no tomaron estatinas, una diferencia no importante.

Incremento de la glucemia en ayunas

     Sin embargo, la glucemia en ayunas se incrementó 0,08 mmol/l en los usuarios de estatinas pero se mantuvo sin cambio en los no usuarios. Esta fue una diferencia importante y persistió así después del ajuste con respecto a edad, género sexual, glucemia en ayunas inicial, presentación de ECV, uso de antihipertensivos o de coronariopatía, peso corporal y modificación del peso a un año.

Los investigadores señalan: «A nuestro entender, este es el primer estudio en el que se analiza la relación de la modificación del estilo de vida sobre el riesgo de diabetes de tipo 2 según el empleo de estatinas. Esta cuestión tiene suma importancia clínica, ya que ahora sabemos que la diabetes de tipo 2 es evitable mediante cambios en el estilo de vida».

Señalaron que un incremento de la glucemia en ayunas en usuarios de estatinas indica el agravamiento de la capacidad de secreción de insulina, pero añadió que los valores de glucosa a dos horas, que reflejan sensibilidad a la insulina, tuvieron una reducción similar en usuarios y no usuarios de estatinas.

Rautio señaló que este estudio se basó en la autonotificación por los pacientes y tuvo un periodo de seguimiento relativamente breve, añadiendo: «Se debe investigar la utilidad de la intervención en el estilo de vida con más detalle en usuarios y en no usuarios de estatinas mediante un estudio concebido en forma apropiada

Tomado de:theheart.org

Original en  heartwire; 21 sep. 2012

Rapid and point-of-care tests accurate, convenient for hepatitis C screening

Rapid and point-of-care screening tests for hepatitis C have a high accuracy and quick turnaround time, suggest results of a systematic review and meta-analysis.

The researchers say that these tests "could play a substantial role in expanded global screening initiatives, which would eventually impact the control of hepatitis C virus(HCV) infection at the population level."

Writing in the Annals of Internal Medicine, Nitika Pant Pai (McGill University Health Centre, Montreal, Quebec, Canada) and colleagues explain that many people infected with hepatitis C remain undiagnosed. It has been suggested that rapid diagnostic tests (RDTs) and point-of-care tests (POCTs) are a time- and cost-saving alternative to conventional laboratory tests. However, their global uptake depends on their performance.

To investigate further, Pant Pai and team performed a meta-analysis of 19 studies assessing the diagnostic accuracy of POCTs and RDTs to screen for hepatitis C in adults.

They found that POCTs of blood (serum, plasma, or whole) had the highest accuracy, followed by RDTs of serum or plasma and POCTs of oral fluids. Indeed, the sensitivity of POCTs of blood was around 99%, followed by 98% for RDTs of serum or plasma, and 98% for POCTs of oral fluid.

Specificity of POCTs of blood was also high, at more than 99%, followed by 98.6% for RDTs of serum or plasma and 98.2% for POCTs of oral fluid.

"First generation point-of-care tests are convenient, effective and informative for clinical decision making," say Pant Pai et al. "These tests don't usually require specialized equipment, they can provide results within 30 minutes, or maximally within one patient visit or one working day, and many do not require electricity."

They add that, in light of the tests' accuracy and an "urgent need to increase hepatitis C screening in marginalized and at-risk populations and in endemic HCV settings," these tests may be useful in expanding first-line screening for hepatitis C.

Por Nikki Withers medwireNews

Tomado de:news-medical.net