Innovative approach successfully maps susceptibility to type 2 diabetes

Research carried out at the Hebrew University of Jerusalem has provided the first proof of molecular risk factors leading to type 2 diabetes, providing an “early warning” sign that could lead to new approaches to treating this and other human disease conditions.
Despite extensive research on the molecular basis for the variance in susceptibility between individuals to common diseases, the subject is still poorly understood. A prime example of this is type 2 diabetes (T2D), a very widespread human disorder.
What is it that characterizes the susceptibility to this disease? Epigenetic variations – which are small molecular marks superimposed on the DNA structure – have been frequently hypothesized to modify predisposition, but direct evidence was missing.
Now, a research team led by Dr. Asaf Hellman of the Hebrew University’s Institute of Medical Research Israel Canada has developed a novel, multistep, study design involving the analysis of disease-contributing epigenetic variations among hundreds of patients and control individuals. The research was presented in a scientific conference at the Cambridge University Genomic Center and was recently published in the scientific journal Human Molecular Genetics.
Taking an innovative research direction, the Hebrew University research team decided to map DNA methylation variations rather than DNA sequence variations, as was traditionally done. The team undertook a proof-of-concept study among 1,169 type 2 diabetes patients and non-diabetic controls. The results demonstrated the unique abilities of this novel research approach by revealing a clear-cut, disease-predisposing DNA methylation signature. This is a first report in the scientific literature of epigenetic risk factor for T2D.
DNA methylation is a naturally occurring mechanism used to regulate genes and protect DNA from some types of cleavage. It is one of the regulatory processes that are referred to as epigenetic, in which an alteration in gene expression occurs without a change in the nucleotide sequence of the DNA. Defects in this process cause several types of disease that afflict humans.
The method used by Hellman was developed during postdoctoral training at the Harvard University Medical School. Later, his research students at the Hebrew University, Gidon Tperoff and Dvir Aran, further developed it into an efficient, genome-wide mapping method.
The mapping was carried out on the methylation sites in cooperation with Prof. Benjamin Glaser, head of the Endocrinology and Metabolism Department at the Hebrew University-Hadassah Medical School and a leading researcher of T2D genetics, and with additional key researchers including Professors Jeremy Kark and Yechiel Friedlander from the Braun Hebrew University-Hadassah School of Public Health and Community Medicine, Prof. Julio Wainstein from the Wolfson Medical Center, and Prof. Ephrat Levy-Lahad from the Shaare Zedek Medical Center.
This analysis not only revealed, for the first time, a clear-cut epigenetic signature in T2D, telltale methylation signature marks were also shown to appear on the DNA of young individuals who latter developed impaired glucose metabolism, even before the appearance of clinical diabetic manifestations.
These findings shed new light on the mechanism of individual predisposition to T2D and pave the way for the elucidating of similar mechanisms in a long list of common human diseases, including many metabolic, autoimmune and psychiatric disorders.
Given that epigenetic marks are sensitive to a wide range of environmental clues, including diets, chemical exposures, intrauterine environments, and also to therapeutic drugs, these finding may open the way for the development of new prevention and/or intervention epigenetic therapies.

More information: Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood, Human Molecular Genetics.

**Provided by Hebrew University of Jerusalem (news : web)

¿Es un riesgo laboral la comida rápida?

Esta semana 'de tardes'. La que viene entra por las noches y, dentro de 15 días, desde las ocho de la mañana hasta la una de la tarde. Quizá usted sea una de esas personas que hagan girar su vida en torno al planning de turnos de trabajo del mes. Si es así, intente cuidarse, pues tiene más posibilidades de sufrir obesidad o diabetes tipo 2.
Así por lo menos lo afirman los autores de la última editorial publicada en 'PLoS Medicine', en que abren una nueva línea de estudio en cuanto a las causas de la obesidad en el mundo. Si hace apenas unos días se alertaba en la misma publicación de que los turnos de noche aumentaban estos riesgos al perturbar los ritmos circadianos, ahora dan un nuevo paso y ponen el acento en aquellos que soportan distintos turnos de trabajo.
"Basándonos en estudios anteriores sobre el trabajo de las enfermeras estadounidenses, observamos cómo hay una asociación entre los turnos laborales y el riesgo de sufrir estas enfermedades debido, principalmente, a que la mayoría seguía patrones alimenticios muy pobres al no tener tiempo de preparar o encontrar nada mejor que poder comer. Creemos que esto afecta no sólo a las enfermeras, sino al resto de profesionales con horarios variados", explican los autores.
Actualmente, se calcula que entre el 15 al 20% de la población activa europea y estadounidense trabaja sin un horario fijo, lo que hace más complicado seguir una dieta sana y variada. "Es un estudio llamativo porque es la primera vez que se asocian ambos conceptos, pero también es muy lógico. Una persona que se pasa semanas trabajando de noche y a las dos de la madrugada tiene un descanso y se va a tomar algo tiene más facilidad de tomar alimentos precocinados o los llamados fast food", analiza para ELMUNDO.es el doctor Felipe Casanueva, director científico de CIBERobn.
"Lo mismo pasa con el resto de horarios y, sobre todo, cuando una persona está sometida a cambios horarios frecuentes y rápidos. Si trabajas por las tardes, pero tienes que entrar muy pronto o por las mañanas pero ya sales tarde no tienes tiempo para preparar nada con un poco de cuidado o, de tenerlo, no sirve de nada comer una semana sano y pasarte tres comiendo cosas precocinadas. Si a esto añadimos que la comida rápida es fácil de encontrar, tiene buen sabor y es barata, acudimos a ella más, por lo que aumentamos nuestras probabilidades de terminar sufriendo diabetes y obesidad", añade.
Precisamente, la facilidad con la que se encuentra esta comida en comparación con menús más variados y sanos, es la perenne queja de los autores de este editorial. "Los gobiernos deben mejorar los hábitos de los consumidores y adoptar medidas concretas para garantizar que sea más fácil y barato comer sano que no", reza en el artículo.

-Riesgo laboral
Para la Organización Mundial de la Salud (OMS) la obesidad ya puede calificarse como pandemia. Con 502 millones de obesos en todo el mundo, muchos especialistas apuntan directamente a los organismos competentes para rebajar estas cifras. Pero ¿qué medidas se podrían tomar? Los autores de este nuevo estudio se atreven a sugerir que la llamada 'comida basura' sea legítimamente considerada como una nueva forma de riesgo laboral en un intento para que en los lugares de trabajo que tengan a empleados con estos turnos se implantasen menús más sanos y baratos.
Una medida que para algunos especialistas quizá peque de "exageración" ya que "en España, el 23% de su población adulta es obesa y una ínfima minoría de ellos se debe a los turnos laborales", explica el doctor Casanueva. "Pero sí es cierto que desde hace tiempo los nutricionistas exigen medidas administrativas que fomenten dietas variadas y ricas en verduras y frutas, haciéndolas más accesibles y baratas porque la obesidad ya no se asocia sólo a la diabetes, sino también a diferentes tipos de cáncer, como el de mama, el de colon o el de páncreas. Es realmente una epidemia a la que hay que buscar medidas", comenta este especialista.

**Publicado en "EL MUNDO"

Avastin can stabilize tumors in ovarian cancer, studies find

Two independent groups working with advanced-stage cases say the drug extended the period before the disease worsened by more than 3.5 months.Avastin can stabilize tumors in women suffering from advanced-stage ovarian cancer, extending the period before the disease worsens by more than 3.5 months, according to the results of two large, international clinical trials conducted by separate research teams.

**Read the whole article on LA Times - Science

Los médicos del Hospital Brigham and Women's cuentan los tres casos de trasplantes de cara

Un hombre sin rostro, la mujer deformada por un chimpancé y el que no salía a la calle por miedo a los comentarios. Podrían ser frases de circo para presentar a personajes cómicos o teatrales, sin embargo corresponden a pacientes que, por un motivo u otro, perdieron su rostro y con él su identidad. Estas tres personas han recuperado su normalidad gracias a los trasplantes de cara realizados en el Hospital Brigham and Women's (BWH), en Boston (EEUU). Los médicos que participaron en estas tres operaciones cuentan ahora en la revista médica 'The New England Journal of Medicine' cuáles son las claves de estos trasplantes y cómo ha sido la evolución de los pacientes.

Dallas Wiens, de 25 años, perdió por completo su rostro tras un aparatoso accidente eléctrico en el año 2008. No podía respirar por la nariz, no tenía ninguna expresión facial... No tenía rostro, en definitiva. Pero tras 17 horas en quirófano, recibir 24 unidades de hematíes y 13 de plasma, es decir, entre tres y cuatro litros de sangre, salió con una nueva cara que le permitió, meses después, aparecer públicamente para dar las gracias a la familia del donante. Detalles de esta operación, y de las otras tres realizadas en el BWH, son ahora publicados para compartir esta experiencia con el resto de médicos que están, o quieren estar, implicados en un trasplante de cara.
"A diferencia que la reconstrucción convencional, el trasplante de cara busca transformar los rostros deformados en otros con una apariencia y funcionamiento casi normal, algo que las convencionales técnicas quirúrgicas de cirugía plástica reconstructiva no pueden lograr", explica el doctor Bohdan Pomahac, principal autor del estudio, director del Programa de Cirugía Plástica de Trasplantes en el BWH y cirujano jefe en las tres intervenciones que ahora publican.
Este cirujano, junto con el resto de su equipo, cuenta cómo utilizaron determinados nervios de los donantes, como los de los brazos, para unirlos a los colgajos de la cara de los receptores. "Nuestra estrategia quirúrgica utiliza todos los grades nervios motores y sensitivos para ofrecer un feedback propioceptivo [señales del injerto al organismo] a medida que el injerto se recupera, facilitando la integración cortical de la nueva cara", señalan los médicos del BWH.
En cuanto a la circulación facial, los cirujanos explican que planificaron la recuperación de los tejidos implantados mediante un suplemento vascular simplificado "guiado por un preciso mapa de los vasos en el receptor", ya que, según explican, implantar vaso por vaso hubiera complicado y prolongado la recuperación del injerto. Con esta técnica consiguieron la recuperación facial de los tres pacientes en menos de cuatro horas.


Charla Nash. Amplíe si quiere ver su cara antes de la operación. BWH
A pesar del espectacular resultado que se pudo ver en cada uno de estos tres pacientes, el postoperatorio no fue un camino de rosas. Charla Nash, la mujer que fue atacada por un chimpancé y que se quedó sin nariz, ojos, labios y maxilar, sufrió un rechazo agudo al mes y medio de ser intervenida, sufrió una trombosis venosa profunda en la pierna izquierda en el tercer mes, y tuvo varias infecciones. No obstante, ha tenido avances en su recuperación. Antes de ser intervenida no podía respirar, hablaba con dificultad, no tenía expresión facial y era incapaz de cerrar la boca. Gracias al trasplante, a los dos meses podía respirar por la nariz y por la boca. También ha ido adquiriendo sensibilidad en diferentes zonas de su cara, aunque por el momento no ha recuperado la función motora.

Por su parte, James Maki, que perdió su nariz, el labio superior, las mejillas, el paladar así como varios músculos y nervios de su cara tras caer sobre un raíl electrificado en el metro de Boston en 2005, sufrió una neumonía al segundo día de ser intervenido. A pesar de este contratiempo, al ser dado de alta de la UCI, cuatro días después de su operación, ya podía comer, beber y ver con su nueva cara. Sin embargo, dos semanas después presentó un rechazo del que se recuperó y fue dado de alta dos meses más tarde. En el momento de la recopilación de datos para este artículo, el paciente ya tenía sensación en su frente y barbilla y movía sus labios burdamente.
"Nuestro objetivo sigue siendo documentar el progreso de los pacientes que han recibido un trasplante de cara, y perfeccionar el uso de los inmunosupresores", afirma Pomahac. De hecho, en el artículo que publican ahora estos cirujanos señalan que esperan inminentes y graduales cambios en la apariencia facial de estos pacientes. "Anticipamos que el esqueleto y el volumen facial podrían moldear la apariencia final, haciendo improbable el parecido con los donantes. Es nuestra opinión subjetiva, al igual que la de las familias de dos donantes, que opinan que los pacientes no se parecen a sus familiares (la otra familia ha elegido permanecer en el anonimato)", explican los médicos.

**Publicado en "EL MUNDO"

Los Angeles Vote to Decide on Condoms in Sex Films

Come June, voters here will have a chance to cast their ballots in the presidential primary. Along with their presidential preferences, they will be asked to decide whether actors in pornographic films should be required to wear condoms.
For several years, the AIDS Healthcare Foundation has been lobbying state, county and city lawmakers to enact legislation that would force adult film performers and makers to use condoms and charge a fee to pay for inspections to make sure that they comply.
Growing frustrated in its efforts, the group moved this summer to get the issue placed on the city ballot.
“All politicians have treated this as a hot potato issue,” said Michael Weinstein, president of the AIDS Healthcare Foundation. “The city punts to the county, the county punts to the state, and the State Legislature has punted. We’ve taken it to the voters as a last resort, and that is testimony to the lack of leadership on the issue.”
Los Angeles County officials have said that it would be too difficult to monitor the pornography industry through the health department and that it is a matter for the State Legislature. But Mr. Weinstein said that the group had not been able to find any state lawmaker willing to introduce the bill.
The group collected more than 70,000 signatures, nearly double the 41,000 needed to get the measure on the ballot. The city clerk certified the signatures this week, but the measure still faces legal challenges. The city attorney, Carmen Trutanich, filed papers in court saying that it appeared that voters in the city did not have the legal authority to adopt the measure and that only the state could mandate such regulations.
Under current regulations issued by the California Division of Occupational Safety and Health, actors are required to use condoms. But the agency can act only after it receives a complaint, and it has issued few fines on the matter.
Officials have said that they believe the city could legally require its own inspections, as the proposal seeks.
“We believe that cities and counties can regulate under their police power unless specifically restricted by something else,” Ellen Widess, the director of the state division, wrote to city attorneys last week.
Mr. Weinstein said that with its limited resources, there was little the agency could do to force filmmakers to comply with the current regulations.
Steven Hirsch, a pornography industry veteran and the founder of Vivid Entertainment, said that even if the measure was passed, it would be nearly impossible to enforce.
“It’s unrealistic to think that a city can regulate how movies are being shot,” Mr. Hirsch said. “People will just film elsewhere and take the jobs with them. And what are they going to do, have condom police out and about patrolling the set?”

**Follow @NYTNational

Tests for biomarker may help determine diagnosis of heart attack within hours

For patients admitted to an emergency department with chest pain, use of a contemporary or highly sensitive test for levels of troponin I (a protein in muscle tissue) may help rule-out a diagnosis of heart attack, while changes in the measured levels of this biomarker at 3 hours after admission may be useful to confirm a diagnosis of heart attack, according to a study in the December 28 issue of JAMA. One of the most common reasons patients seek care in an emergency department is for acute chest pain. "Early identification of individuals at high and intermediate risk for myocardial ischemia [insufficient blood flow to the heart muscle] is crucial because they benefit the most from early and aggressive treatment. According to international consensus and task force definitions of myocardial infarction [(MI; heart attack], the diagnosis of MI is based mainly on an elevated cardiac troponin level exceeding the 99th percentile and demonstrating an increase or decrease over time," the authors write. Highly sensitive troponin assays have been developed recently that reliably assess troponin levels in more than 50 percent of the general population. "The reliable detection of very low troponin concentrations using these new highly sensitive assays in the acute setting might pose a challenge in everyday clinical practice."
Till Keller, M.D., of the University Heart Center Hamburg, Germany, and colleagues evaluated the diagnostic performance of the newly developed highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of heart attack. The study included a total of 1,818 patients with suspected acute coronary syndrome (condition such as heart attack or angina) who were enrolled at chest pain units in Germany from 2007 to 2008. Twelve biomarkers including hsTnI and cTnI were measured on admission and after 3 and 6 hours.
Of the patients in the study, 413 (22.7 percent) had a final discharge diagnosis of acute MI. For discrimination of acute MI, both hsTnI and cTnI were superior to the other evaluated diagnostic biomarkers. Using the 99th percentile cutoff, hsTnI on admission had a sensitivity of 82.3 percent and negative predictive value (NPV) of 94.7 percent; hsTnI determined after 3 hours had a sensitivity of 98.2 percent with NPV of 99.4 percent. Compared with hsTnI, the cTnI assay (using the 99th percentile as cutoff) had comparable sensitivity and NPV: 79.4 percent sensitivity and 94.0 percent NPV on admission, and 98.2 percent sensitivity and 99.4 percent NPV after 3 hours.
"Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1 percent at admission to 95.8 percent after 3 hours, and for cTnl increased from 80.9 percent at admission to 96.1 percent after 3 hours," the authors write.
"The shortcoming of conventional troponin assays with low sensitivity within the first hours after chest pain onset led to the evaluation of various so-called early biomarkers in the diagnosis of MI. In our study, the diagnostic information of hsTnI was superior to all other evaluated biomarkers alone."
"Use of hsTnI and cTnI assays in patients with suspected MI provides useful diagnostic information," the researchers write. "Determination of hsTnI and cTnI values 3 hours after admission to the emergency department with use of the 99th percentile cutoff provides an NPV greater than 99 percent, potentially allowing a safe rule-out of MI. Application of the relative change in hsTnI or cTnI concentration within 3 hours after admission in combination with the 99th percentile diagnostic cutoff value on admission improves specificity and may facilitate an accurate early rule-in of MI."

**Source: JAMA and Archives Journals

UT Southwestern research suggests new way to ensure effectiveness of TB treatment

A UT Southwestern Medical Center study using a sophisticated "glass mouse" research model has found that multidrug-resistant tuberculosis (TB) is more likely caused in patients by speedy drug metabolism rather than inconsistent doses, as is widely believed. If the study published in The Journal of Infectious Diseases is borne out in future investigations, it may lead to better ways to treat one of the world's major infectious diseases. Health workers worldwide currently are required to witness each administration of the combination of drugs during months of therapy.
"Tuberculosis is a common ailment, accounting for up to 3 percent of all deaths in many countries. Although effective therapy exists, there are still cases of treatment failure and drug resistance remains a threat," said Dr. Tawanda Gumbo, associate professor of internal medicine and senior author of the study.
The results seem to challenge the current approach endorsed by the World Health Organization.
Under that method, directly observed therapy-short-course strategy (DOTS), TB that responds to medication is treated with a cocktail of drugs under the supervision of health care workers, who in many countries must travel to isolated villages -- a costly and time-consuming process.
"Every TB patient is supposed to be watched as they swallow their pills in order to increase adherence and decrease emergence of drug resistance. This is the most expensive part of the program, but has been felt to be cost-effective since it improves compliance," said Dr. Gumbo, administrative director of research programs for the Office of Global Health at UT Southwestern.
In this study, UT Southwestern researchers created a sophisticated system of high-tech test tubes, which they called a "glass mouse," that mimicked standard therapy being given daily for 28 to 56 days, with dosing adherence varying between 0 percent and 100 percent. The threshold for defined non-adherence (failure to take a required dose of medication) was reached at 60 percent of the time or more.
"The first main finding in our laboratory model was that in fact non-adherence did not lead to multidrug resistance or emergence of any drug resistance in repeated studies, even when therapy failed. In fact, even when we started with a bacterial population that had been spiked with drug-resistant bacteria, non-adherence still did not lead to drug resistance," he said.
In fact, using computer simulations based on 10,000 TB patients in Cape Town, South Africa, the researchers discovered that approximately 1 percent of all TB patients with perfect adherence still developed drug resistance because they cleared the drugs from their bodies more quickly.
The body sees drugs as foreign chemicals and tries to rid itself of them, Dr. Gumbo said. A population of individuals with a genetic trait that speeds the process has been found in one area of South Africa that has a high rate of multidrug-resistant TB. In that population, patients who receive standard doses of drugs end up with concentrations in their bodies that are too low to kill the TB bacillus and drug resistance develops, he said.
A Journal of Infectious Diseases editorial that accompanies the study suggests that monitoring the levels of TB drugs in a patient's blood could be as important as monitoring compliance with therapy -- in contrast to current WHO guidelines.
"These data, based on our preclinical model, show that non-adherence alone is insufficient for the emergence of multidrug-resistant TB," Dr. Gumbo said. "It might be more cost-effective to measure patients' drug concentrations during treatment and intervene with dosage increases in those who quickly clear the drugs from their systems."

**Source: UT Southwestern Medical Center