Researchers induce Alzheimer's neurons from pluripotent stem cells

Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder. "Creating highly purified and functional human Alzheimer's neurons in a dish -- this has never been done before," said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. "It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it."
The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.
"We're dealing with the human brain. You can't just do a biopsy on living patients," said Goldstein. "Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory."
Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.
The iPSC-derived neurons from the Alzheimer's patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.
With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.
"The differences between a healthy neuron and an Alzheimer's neuron are subtle," said Goldstein. "It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results."
The researchers have already produced some surprising findings. "In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant," Goldstein said, adding that they discovered a different early event plays a bigger role.
The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.
Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer's neurons present a huge opportunity in a desperate fight. "At the end of the day, we need to use cells like these to better understand Alzheimer's and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us -- emotionally and financially."
Funding for this research came, in part, from the California Institute for Regenerative Medicine, the Weatherstone Foundation, the National Institutes of Health, the Hartwell Foundation, the Lookout Fund and the McDonnell Foundation.
A patent application has been filed on this technology by the University of California, San Diego. For more information, go to: techtransfer.universityofcalifornia.edu/NCD/22199.html

**Source: University of California, San Diego Health Sciences

High animal fat diet increases gestational diabetes risk

Women who consumed a diet high in animal fat and cholesterol before pregnancy were at higher risk for gestational diabetes than women whose diets were lower in animal fat and cholesterol, according to researchers at the National Institutes of Health and Harvard University. Gestational diabetes is a form of diabetes seen during pregnancy. Gestational diabetes increases the risk for certain pregnancy complications and health problems in the newborn.
Women whose diets were high in total fat or other kinds of fats -- but not in animal fat or cholesterol -- did not have an increased risk.
Moreover, the increased risk for gestational diabetes seen with animal fat and cholesterol appeared to be independent of other, dietary and non-dietary, risk factors for gestational diabetes. For example, exercise is known to reduce the risk of gestational diabetes. Among women who exercised, however, those who consumed higher amounts of animal fat and cholesterol had a higher risk than those whose diets were lower in these types of fat.
"Our findings indicate that women who reduce the proportion of animal fat and cholesterol in their diets before pregnancy may lower their risk for gestational diabetes during pregnancy," said senior author Cuilin Zhang, M.D., M.P.H., Ph.D., of the Epidemiology Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), one of three NIH institutes supporting the study.
The researchers concluded that changing the source of 5 percent of dietary calories from animal fat to plant-derived sources could decrease a woman's risk for gestational diabetes by 7 percent.
The U.S. Department of Agriculture website, ChooseMyPlate.gov, contains information on healthy eating for children and adults, as well as health and nutrition information for pregnant and breast feeding women.
First author Katherine Bowers, Ph.D., conducted the research with NICHD colleagues Dr. Zhang and Edwina Yeung, Ph.D., and with Deirdre K. Tobias and Frank B. Hu, M.D., M.P.H., Ph.D., of Harvard University, in Boston.
Their findings appear online in the American Journal of Clinical Nutrition.
The research was also funded by the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases.
The researchers utilized information from more than 13,000 women participating in the Nurses' Health Study II. The women were 22 to 45 years old when they enrolled in the study. Every two years they responded to questions on their general health, pregnancy status, and lifestyle habits, such as consuming alcohol or smoking. In addition, every four years they completed a comprehensive survey about the kinds of food and drink they consumed.
About 6 percent of the participants reported having been diagnosed with gestational diabetes. The researchers calculated the amount of animal fat in participants' diets as a percentage of total calories and divided participants into five groups, or quintiles, based on those percentages. Then the researchers compared the risk for developing gestational diabetes for each group. Women in the highest quintile of intake had almost double the risk for gestational diabetes compared to women in the lowest quintile.
They also observed that women in the highest quintile for cholesterol consumption were 45 percent more likely to develop gestational diabetes than were women in the lowest quintile.
"This is the largest study to date of the effects of a pre-pregnancy diet on gestational diabetes," Dr. Bowers said. "Additional research may lead to increased understanding of how a mother's diet before and during pregnancy influences her metabolism during pregnancy, which may have important implications for the baby's health at birth and later in life."

**Source: NIH/National Institute of Child Health and Human Development

El deporte y las bajas temperaturas activan el tejido adiposo que adelgaza

Una de las líneas de trabajo más prometedoras e interesantes en la investigación contra la obesidad se centra en la grasa. Pero no en la responsable del sobrepeso, de color blanquecino y amarillento, sino en la parda o marrón, que, curiosamente, quema calorías y adelgaza.
El gran reto en el que trabajan distintos laboratorios consiste en saber activar su funcionamiento, es decir, descubrir el interruptor que permita adelgazar a voluntad. Dos relevantes artículos recién publicados apuntan en dos direcciones: pasar frío y hacer ejercicio.
Estas dos pistas son más importantes de lo que pueden parecer a simple vista (es conocida la relación del frío y el ejercicio en el adelgazamiento).
En el caso del frío, nunca se había demostrado en humanos (sí en ratones) que una exposición a bajas temperaturas sirviera para activar la grasa parda. Hasta 2009 tampoco se había descrito la presencia y actividad de este nuevo tejido en adultos humanos. Se creía que solo estaba presente en ratas y bebés, que lo usan para mantener su temperatura corporal.

-Hasta 2009 no se describió la presencia de grasa parda en adultos
Un artículo publicado en el Journal of clinical investigation, coordinado por André Carpentier, de la Universidad de Sherbrooke, en Quebec, ha dado este paso en un ensayo en el que participaron seis hombres de entre 23 y 42 años a los que se sometió a frío moderado durante fracciones de dos horas (su temperatura en la piel cayó entre 3,8 y 0,4 grados).
“El trabajo tiene una gran importancia clínica”, apunta Francesc Villarroya, miembro del Centro de Investigación Biomédica en Red (Ciber) de Fisiopatología de la Obesidad y Nutrición. “Un estímulo tan simple como un ambiente frío genera un impacto y pone en marcha el funcionamiento de esta grasa buena que consume calorías”, indica. Además, va más lejos: “Se podría inducir una relación entre la obesidad y temperaturas excesivamente altas en las casas”.
El deporte también activa el tejido adiposo marrón —en sus células abundan las mitocondrias, de ahí su tonalidad—, según un trabajo publicado en Nature entre cuyos autores figura Bruce Spiegelman, profesor de Biología y Medicina en el Dana-Faber Cancer Institute de la Universidad de Harvard.
Este equipo de investigadores ha descubierto (esta vez sí, en ratones) una hormona nueva (que han bautizado como irisina) que genera el músculo cuando se ejercita y que se dirige a la grasa parda con la misión de despertar su funcionamiento.
De esta forma, al hacer deporte, “no solo se queman calorías por el movimiento, sino que además existe un consumo extra por la activación de este tejido” que, también, pero de forma paralela, consume las reservas de lípidos, comenta Francesc Villarroya. Este investigador promete nuevos hallazgos: “Esta área del metabolismo está estallando.

**Publicado en "EL PAIS"

Brachytherapy reduced death rates in high-risk prostate cancer patients, study finds

Brachytherapy for high-risk prostate cancers patients has historically been considered a less effective modality, but a new study from radiation oncologists at the Kimmel Cancer Center at Jefferson suggests otherwise. A population-based analysis looking at almost 13,000 cases revealed that men who received brachytherapy alone or in combination with external beam radiation therapy (EBRT) had significantly reduced mortality rates. Their findings are reported online January 23 in the International Journal of Radiation Oncology*Biology*Physics.
Brachytherapy involves the precise placement of radiation sources directly at the site of a tumor and is typically used to treat low and intermediate risk prostate cancers. However, brachytherapy treatment for high-risk patients is less common and controversial, given in part to early retrospective studies that found it to be associated with lower cure rates compared to EBRT.
Many experts believe that these early series were limited by poor brachytherapy technique, and that high-quality contemporary brachytherapy may be an effective tool against high-risk prostate cancer.
"The study contradicts traditional policies of using brachytherapy in just low and intermediate risk patients by suggesting there may instead be an improvement in prostate cancer survival for high-risk patients," said co-author Timothy Showalter, M.D., assistant professor in the Department of Radiation Oncology at Thomas Jefferson University Hospital, and associate research member of Jefferson's Kimmel Cancer Center. "Although studies like this cannot prove an advantage for brachytherapy, our report does suggest that brachytherapy is no less effective than EBRT and should be considered for some men with high-risk prostate cancer."
Researchers identified 12,745 Surveillance, Epidemiology and End Results database patients diagnosed from 1988 to 2002 with high-grade prostate cancer of poorly differentiated grade and treated with brachytherapy (7.1 percent), EBRT alone (73.5 percent) or brachytherapy plus EBRT (19.1 percent). The team used multivariate models to examine patient and tumor characteristics associated with the likelihood of treatment with each radiation modality and the effect of radiation modality on prostate cancer-specific mortality.
Treatment with brachytherapy alone or brachytherapy in combination with EBRT, the researchers found, was associated with significant reduction in prostate cancer-specific mortality rates compared to EBRT alone.
Significant predictors of use of brachytherapy or brachytherapy plus EBRT were younger age, later year of diagnosis, urban residence and earlier T-stage.
According to the researchers, including lead author Xinglei Shen, M.D., a resident in Jefferson's Department of Radiation Oncology and a part-time master's degree student in the Jefferson School of Population Health, the study's findings provide ample evidence to further study brachytherapy as part of an effective treatment strategy for men with high-grade prostate cancer.
"Today, for the most part, brachytherapy is not being used for these high-risk patients or even recommended," Dr. Shen said. "But if you look at the biology and theory behind it, it makes sense: you can really give a lot more dose with brachytherapy than with EBRT alone to the prostate. And this presents an opportunity for high-risk patients."

**Source: Thomas Jefferson University

Un estudio dice que trabajar más de 11 horas diarias causa depresión

El refranero popular muestra una vez más su sabiduría: 'Lo bueno, si breve, dos veces bueno'. Nuevos datos muestran que las jornadas laborales demasiado largas se relacionan con un riesgo mayor de sufrir episodios depresivos.
A las conclusiones de estudios anteriores que relacionaban los horarios de trabajo con trastornos psicológicos y del sueño, la disminución de las funciones cognitivas o los problemas depresivos y de ansiedad, los datos del último artículo publicado en la revista 'PLoS ONE' añaden también la depresión.
Tras analizar las condiciones laborales y la situación personal de 2.000 funcionarios británicos con edades comprendidas entre los 35 a los 55 años, los autores concluyen cómo trabajar 11 horas o más aumenta en más del doble la posibilidad de sufrir cuadros depresivos. El estudio está dirigido por Marianna Virtanen, miembro del Instituto Finlandés de Salud Ocupacional en el University College de Londres.
"Seguimos la evolución de estos trabajadores a través de entrevistas durante cerca de seis años y los datos son claros. Aquellos que contaban con jornadas de 11 horas o más o que hacían horas extra (en total, un 16% de las personas analizadas), tenían entre un 2,3 a un 2,5 más de posibilidades de desarrollar episodios depresivos y ansiedad si lo comparamos con aquellos cuya jornada se limitaba a siete u ocho horas (54%)", dice Virtanen.
El trabajo tuvo en cuenta datos como el estatus socioeconómico o el estilo de vida de los participantes para que no 'contaminaran' los resultados. Así, el estudio arroja un 'retrato robot' de aquellas personas con más riesgo de caer en la depresión: varones casados o viviendo con su pareja,que ocupa un puesto de alta responsabilidad y activo o empleos donde hay una carga importante de presión, y que consumen alcohol de forma moderada.
"Los datos son importantes y preocupantes", afirma Virtanen. "Hay que tener en cuenta que la Organización Mundial de la Salud (OMS) considera que los trastornos depresivos serán la principal causa de enfermedad en el año 2030 y que, en la actualidad, además de las condiciones de vida personales, este tipo de episodios mentales acarrean un deterioro sustancial de la productividad en el trabajo, por no hablar de los días laborales perdidos", señala la autora.

Middle-age risk factors drive greater lifetime risk for heart disease

A new study in the New England Journal of Medicine reports that while an individual's risk of heart disease may be low in the next five or 10 years, the lifetime risk could still be very high, findings that could have implications for both clinical practice and public health policy. "The current approach to heart disease prevention focuses on only short-term risks, which can give a false sense of security, particularly to individuals in their 40s and 50s," said Dr. Jarett Berry, assistant professor of internal medicine at UT Southwestern Medical Center who was lead author of the study. "Early life decisions we make can have a significant impact on the rest of our lives -- and heart healthy choices are no different. The risk factors we develop in younger and middle ages are going to determine our heart disease risk across our lifetime."
Although medical experts have long known that the presence of risk factors was a predictor of heart disease across time, gender and race, Dr. Berry noted that the concept of lifetime risk represents an important change in how individuals and their physicians will approach heart disease risk and prevention. "If we want to reduce cardiovascular disease, we need to prevent the development of risk factors in the first place," he said. "What determines your heart disease risk when you are 70 or 80 is what your risk factors are when you're 40."
Examining the results of longitudinal studies over the past 50 years, investigators found that people with two or more major risk factors in middle-age had dramatically higher lifetime risks for cardiovascular death, myocardial infarction and stroke across the lifespan. Similar trends were observed across all race and age groups.
The scientists used data collected in the Cardiovascular Lifetime Risk Pooling Project, measuring risk factors of more than 254,000 participants -- including black and white men and women -- at ages 45, 55, 65 and 75 years. Individuals with multiple risk factors had substantially higher lifetime risks for heart disease -- as much as 10 times the rates of those without risk factors in some cardiovascular disease categories.
Most previous studies on heart disease risk estimates have focused on short-term risk over a five- or 10-year period, said Dr. Berry, who took part in the investigation while at Northwestern University Feinberg School of Medicine. Heart disease is much more common in older age, and therefore, nearly all individuals younger than 50 are considered low-risk. "But most adults in the U.S. considered low-risk in the short term are actually at high risk across their remaining life span," he said.
This latest study also showed that the decline in cardiovascular disease rates over the past several decades reflects changes in the prevalence of the risk factors rather than access to and effects of better treatment, Dr. Berry said. Smoking and cholesterol levels have fallen in recent decades, for instance, due to behavioral changes in the general population.
Nevertheless, researchers found that the long-term risk for cardiovascular disease within each risk factor group has remained similar. "Regardless of where you were born or when you were born, the effects of risk factors on lifetime risk for heart disease are about the same," Dr. Berry said.
Therefore, preventing the development of risk factors in the first place will be more effective than treating the effects of these risk factors once they develop, researchers concluded. The study was funded by the National Heart, Lung and Blood Institute.

**Source: UT Southwestern Medical Center

CDC reports that unexplained skin condition is non-infectious, not linked to environmental cause

The US Centers for Disease Control and Prevention has completed a comprehensive study of an unexplained skin condition commonly referred to as Morgellons and found no infectious agent and no evidence to suggest an environmental link. The full results are reported in the Jan. 25 issue of the online journal PLoS ONE.
In this study, investigators took an in-depth look at a skin condition characterized by unexplained lesions that contain fibers, threads, or other foreign material, accompanied by sensations of crawling, biting, or stinging. The condition is not currently recognized as a distinct clinical disorder with established diagnostic criteria. However, increasing inquiries to the CDC in 2006-2009 regarding the condition prompted the study in Northern California, where many of the persons who reported these symptoms lived.
The researchers found and enrolled 109 persons with symptoms of this condition by searching through the electronic medical record database of a large HMO. They conducted extensive testing to rule out infectious causes, and found no indication that the condition was attributed an infection. The researchers also determined that the fibers associated with the lesions were apparently fragments of cloth or other debris. The investigators showed that the condition is uncommon, estimating that it results in fewer than four out of 100,000 people seeking medical attention. About half of the study participants had evidence of other medical, most commonly psychiatric, illnesses.
The CDC suggests that people suffering with symptoms similar to those reported in the study should see their health care provider for a complete physical to ensure proper diagnosis of all illnesses, including psychiatric, and follow the recommended treatments.
"We found no evidence that this condition is contagious, or that suggests the need for additional testing for an infectious disease as a potential cause," says Dr. Mark Eberhard, Director of CDC's Division of Parasitic Diseases and Malaria and a lead study investigator. "This alleviates concerns about the condition being contagious between family members and others."

**Source: Public Library of Science