Circadian clock may impact organ transplant success

Health care providers assess blood and tissue type as well as organ size and health to enhance transplant success. New research indicates that checklist might also need to include the circadian clock. While some human studies have shown the time of day transplant surgery is performed can influence the outcome, this study of mice with dysfunctional internal clocks is the first correlating circadian clocks with transplant success, said Dr. Daniel Rudic, vascular biologist at Georgia Health Sciences University and corresponding author of the study published in the Proceedings of the National Academy of Sciences.
The GHSU researchers found that arteries of mice with circadian clock dysfunction became thick and diseased within a few weeks of being transplanted to healthy mice. Arteries transplanted from healthy mice to the mutant mice remained healthy.
Blood vessel disease, and resulting blood loss to donated organs, is a key pitfall for transplant patients, potentially leading to organ failure and rejection.
"You take an organ out of a human, you don't think about it having a bad clock," Rudic said. "But the fact is the time at which you do the organ transplant may influence overall success and, if you have a donor who has a sleep disorder or is a night shift worker, it may affect it as well."
Since even healthy clocks produce variability in tissue function across the span of a day, transplantation might be best performed during optimal organ function, he said.
In addition to enabling sleep/wake cycles, circadian clocks are found throughout the body and involved in a lot more than sleep. "The clock is expressed not only in the brain but everywhere in the body and can function autonomously in different areas," Rudic said.
"Our research shows it's the clock within the blood vessel that is key to conferring the disease response in this case," said Dr. Bo Cheng, GHSU postdoctoral fellow and the study's first author.
While the researchers can determine whether clock gene expression is up, down or mutated, there is currently no way to do the tests in humans. Until screening tests are identified, donors could be screened for signs of dysfunction such as a sleep disorder or even aberrant behaviors that can impair healthy clocks, such as shift work, Rudic said. "Ideally this will open up some new research avenues," he said.
Interestingly, when blood vessels from the mutant mouse stay in that mouse, disease progression is much slower. "We believe that bad clock function worsens when it intersects with disease, so if you are eating a high-fat diet or if you undergoing a serious surgery like a transplant, and you have a bad clock, disease may occur and may occur quickly," Rudic said.
In 2009, he reported in the journal Circulation that mice with mutated or missing clock genes were prone to vascular disease similar to smokers and people with high blood pressure and cholesterol. That study showed the blood vessel clocks regulate key signaling that enables blood vessel dilation and remodeling.

**Source: Georgia Health Sciences University

Algunos anticonceptivos inyectables duplican el riesgo de transmitir y contraer VIH

Un estudio realizado en siete países africanos -Botsuana, Kenia, Ruanda, Sudáfrica, Tanzania, Uganda y Zambia- con 3.790 parejas heterosexuales serodiscordantes (aquellas en las que uno de los miembros está infectado por el VIH y el otro no) concluye que las mujeres que toman anticonceptivos inyectables multiplican por dos su riesgo de adquirir la infección por VIH así como de transmitirla a los hombres con los que se acuestan. El por qué no está del todo claro, pero parece, según apuntan los investigadores, que este método provoca ciertos cambios en la estructura de la vagina y en la forma en la que se regulan algunas proteínas que favorecen la entrada del virus.
El hallazgo, publicado en la revista 'The Lancet', plantea un dilema, sobre todo en África: "Por una parte, la promoción de estos anticonceptivos en áreas con una alta incidencia de VIH podría contribuir a propagar aún más la epidemia de sida, con consecuencias trágicas. Por otro lado, limitar el acceso a uno de los métodos anticonceptivos más usados en África subsahariana podría aumentar la mortalidad materna e infantil, con consecuencias igualmente trágicas", escribe en un comentario Charles S. Morrison, de Clinical Sciences en Durham (EEUU).
¿Cómo salir de esta encrucijada? Para Renee Heffron, uno de los autores de la investigación de la Universidad de Washington, se necesitarían con urgencia dos cosas. "Primero es imprescindible realizar un ensayo clínico a gran escala destinado a conocer mejor la relación entre este sistema anticonceptivo y el riesgo de contraer VIH. Y, además, es importante que se lancen programas destinados a promover la importancia de seguir utilizando el preservativo, junto a otros métodos de anticoncepción".
De las 3.790 parejas que participaron en el estudio, en 1.314 era el hombre el que tenía el VIH mientras que en las 2.476 restantes, la seropositiva era la mujer. En el momento de iniciar la investigación, el 15% de las mujeres sin el virus usaba anticoncepción hormonal, al igual que el 17% de quienes sí estaban infectadas. Después, durante el estudio, los porcentajes aumentaron a un 21% y un 33%, respectivamente. Tras 24 meses de seguimiento, los investigadores comprobaron que esta anticoncepción, por sí sola -tras descartar factores como el sexo de riesgo o la edad, por ejemplo- duplicaba el riesgo tanto de contraer la infección como de transmitirla.
Aunque el trabajo tiene limitaciones, como el hecho de fiarse de la palabra de las participantes y no haber medido si utilizaban bien el método anticonceptivo, los autores señalan que "es el primer estudio prospectivo que muestra que esta anticoncepción hormonal aumenta el riesgo de que los hombres, parejas de mujeres infectadas, contraigan el VIH". A la inversa, ya se había comprobado en estudios anteriores.
En cualquier caso, "nuetros datos son lo suficientemente importantes como para tenerlos en cuenta en los programas de planificación familiar y de prevención del VIH", explica Jared Baeten, otro de los investigadores, también de la Universidad de Washington.
En el mundo, más de 140 millones de mujeres utilizan la anticoncepción hormonal. En África subsahariana, donde viven 16 millones de seropositivas, los anticonceptivos hormonales inyectables son de los más extendidos.

**Publicado en "EL MUNDO"

This is your brain on estrogen

It's no secret that women often gain weight as they get older. The sex hormone estrogen has an important, if underappreciated, role to play in those burgeoning waistlines. Now, researchers reporting in the October Cell Metabolism, a Cell Press publication, have traced those hormonal effects on metabolism to different parts of the brain. The findings may lead to the development of highly selective hormone replacement therapies that could be used to combat obesity or infertility in women without the risks for heart disease and breast cancer, the researchers say.
"When women approach menopause, they gain weight in fat and their energy expenditure goes down," says Deborah Clegg of the University of Texas Southwestern Medical Center. Estrogen levels decline and women grow increasingly susceptible to obesity and metabolic syndrome.
Estrogen acts on receptors found throughout the body, in fat, on ovaries and in muscle. But when it comes to the hormone's influence on metabolism, Clegg suspected receptors in the brain.
Others had traced the effects of estrogen on energy balance specifically to estrogen receptor-α (ERα). When her team deleted those receptors from the entire brains of mice, "we got very, very fat mice," Clegg said. The animals consumed more calories and burned less.
The researchers showed female mice lacking ERα in one part of the brain (the hypothalamic steroidogenic factor-1 or SF1 neurons) gained weight without eating any more. Loss of ERα from another brain area (the hypothalamic pro-opiomelanocortin or POMC neurons) had the opposite effect: animals ate more without gaining weight. Loss of ERα receptors in those same neurons also led to various problems in ovulation and fertility.
The findings suggest that drugs developed to specifically target estrogen receptors in the brain might offer a useful alternative to hormone replacement therapies that hit receptors throughout the body. The researchers say they would like to continue to isolate other estrogen-related effects and symptoms, for instance, on hot flashes and cognition.
"The more we know about estrogen's sites of action, the more likely it is we could develop designer hormone replacement therapies targeting tissue X, Y or Z," Clegg said.

**Source: Cell Press

Same-day discharge after elective PCI not associated with increased risk of death, rehospitalization

Among selected low-risk Medicare patients who underwent an elective percutaneous coronary intervention (PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries), same-day discharge was rarely implemented, but was not associated with an increased risk of being rehospitalized or having a higher risk of death at 2 days or at 30 days, than patients who remained in the hospital overnight, according to a study in the October 5 issue of JAMA. "Percutaneous coronary intervention is one of the most commonly performed cardiac procedures with more than 1 million episodes of care annually among Medicare recipients. Risks associated with PCI are highest within the first 24 to 48 hours after the procedure and include periprocedural myocardial infarction [MI; heart attack], acute stent thrombosis [blood clot formation within the stent], bleeding, or renal failure," according to background information in the article. "However, short- and long-term outcomes after PCI have improved because of the evolution in device technology and pharmacotherapy. Despite this improvement, patients are usually observed overnight in the hospital after elective PCI to monitor for PCI-related complications." The safety of same-day discharge among older individuals undergoing this procedure is not known. Same-day discharge would increase bed availability for the hospital and reduce medical expenses.
Sunil V. Rao, M.D., of the Duke Clinical Research Institute, Durham, N.C., and colleagues conducted a study to examine the prevalence of same-day discharge among older individuals following PCI and the rates of death or rehospitalization. The study included data from 107,018 patients 65 years or older undergoing elective PCI procedures at 903 sites participating in the CathPCI Registry between November 2004 and December 2008 and were linked with Medicare Part A claims. Patients were divided into 2 groups based on their length of stay after PCI: same-day discharge or overnight stay. The primary outcomes measured were rehospitalization or death occurring within 2 days and by 30 days after PCI.
The researchers found that prevalence of same-day discharge was 1.25 percent (n = 1,339 patients), with significant variation across facilities. There was no significant difference in the rates of procedural success between the 2 groups. Patient characteristics were similar between the 2 groups, although same-day discharge patients underwent shorter procedures with less multivessel intervention. Patients who were discharged home the same day were more often categorized in the lowest quintile of predicted risk for death or rehospitalization, while there were approximately equal proportions of lower- and higher-risk patients observed overnight.
"There were no significant differences in the rates of death or rehospitalization at 2 days (same-day discharge, 0.37 percent vs. overnight stay, 0.50 percent or at 30 days (same-day discharge, 9.63 percent vs. overnight stay, 9.70 percent). Among patients with adverse outcomes, the median [midpoint] time to death or rehospitalization did not differ significantly between the groups (same-day discharge, 13 days vs. overnight stay, 14 days). After adjustment for patient and procedure characteristics, same-day discharge was not significantly associated with 30-day death or rehospitalization," the authors write.
The researchers note that despite the apparent safety of same-day discharge for selected patients, the present analysis demonstrates that this approach is rarely practiced among sites represented in the National Cardiovascular Data Registry. "This may reflect reluctance on the part of clinicians to discharge patients the same day as the PCI procedure because of concerns over early post-PCI complications. Although these concerns are well founded, the rates of vascular or bleeding complications were extremely low (less than 1 percent) among the patients in our analysis, with no clinically significant differences between groups."
"These data suggest that a proportion of low-risk patients currently observed overnight may be eligible for same-day discharge without an increase in early or intermediate-term adverse events."
The authors add that according to published guidelines, same-day discharge can be considered for patients undergoing PCI who have low-risk clinical features, successful procedures without prolonged post-procedure use of parenteral (by injection) antithrombotic agents, and adequate social support.

**Source: JAMA and Archives Journals

Una nueva combinación de quimioterapia duplica la supervivencia en casos de cáncer de páncreas avanzado

No todo son malas noticias para un cáncer del que se suele hablar en tono trágico. La revista científica «Journal of Clinical Oncology» publica una investigación que avala la utilización de una combinación de fármacos para luchar contra el cáncer de páncreas avanzado. Los resultados demuestran que con ese cóctel de quimioterapia («gemcitabina» más «nab-paclitaxel») se consigue una supervivencia global de 12 meses y una tasa de supervivencia a un año del 48% en el cáncer de páncreas ductal, uno de los tumores de peor pronóstico.
Arañar un año de vida más en esta enfermedad tan compleja no es un resultado menor. «Este tipo de cáncer es una patología letal con una media de supervivencia de seis meses. Y los datos que hemos recogido son muy buenos. Este es el tratamiento con más actividad en páncreas que hemos visto en los últimos 20 años», asegura Manuel Hidalgo, director del Centro Oncológico Clara Campal y uno de los investigadores que ha participado en el estudio.
Manuel Hidalgo: «Es el tratamiento con más actividad frente al cáncer pancreático de los últimos 20 años»Otra buena noticia es que el tratamiento, probado en 67 pacientes de cuatro hospitales estadounidenses, muestra también que los efectos adversos con un dosis eficaz son tolerables por lo que la investigación puede continuar con mayor número de enfermos. La idea es probarlo en medio millar de pacientes en una nueva fase que contará con pacientes españoles.
Los dos fármacos no son ajenos para los oncólogos. La «gemcitabina» se utilizaba ya frente al cáncer de páncreas y con «nab-paclitaxel», el último en llegar, se está tratando ya a personas con melanoma, cáncer de mama y pulmón como uso compasivo. De momento, parece una combinación acertada que suma a la quimioterapia clásica la actividad de un nuevo mecanismo de acción. El tratamiento actúa atacando al estroma, un tejido formado por células no tumorales que se convierte en un escudo protector del tumor. «El fármaco elimina parte del estroma y permite que la quimioterapia se difunda mejor en el tumor», explica Hidalgo.
Con la dosis semanal máxima tolerada, se obtuvo respuesta en asi la mitad de los pacientes ; en 21 de 44 pacientes y dos tercios experimentaron control de la enfermedad. La media de supervivencia libre de progresión se situó en 7,9 meses, la media de supervivencia global 12,2 meses y la tasa de supervivencia a un año fue del 48%.

**Publicado en "ABC"

Natural compound helps reverse diabetes in mice

Researchers at Washington University School of Medicine in St. Louis have restored normal blood sugar metabolism in diabetic mice using a compound the body makes naturally. The finding suggests that it may one day be possible for people to take the compound much like a daily vitamin as a way to treat or even prevent type 2 diabetes. This naturally occurring compound is called nicotinamide mononucleotide, or NMN, and it plays a vital role in how cells use energy.
"After giving NMN, glucose tolerance goes completely back to normal in female diabetic mice," says Shin-ichiro Imai, MD, PhD, associate professor of developmental biology. "In males, we see a milder effect compared to females, but we still see an effect. These are really remarkable results. NMN improves diabetic symptoms, at least in mice."
The research appears online Oct. 4 in Cell Metabolism.
Imai says this discovery holds promise for people because the mechanisms that NMN influences are largely the same in mice and humans.
"But whether this mechanism is equally compromised in human patients with type 2 diabetes is something we have to check," Imai says. "We have plans to do this in the very near future."
All cells in the body make NMN in a chain of reactions leading to production of NAD, a vital molecule that harvests energy from nutrients and puts it into a form cells can use. Among other things, NAD activates a protein called SIRT1 that has been shown to promote healthy metabolism throughout the body, from the pancreas to the liver to muscle and fat tissue.
According to the study, aging and eating a high-fat diet reduce production of NMN, slowing the body's production of NAD and leading to abnormal metabolic conditions such as diabetes. NAD cannot be given to the mice directly because of toxic effects. But after administering NMN, levels of NAD rise and the diabetic mice show dramatically improved responses to glucose. In some cases, they return to normal.
"I'm very excited to see these results because the effect of NMN is much bigger than other known compounds or chemicals," says first author Jun Yoshino, MD, PhD, postdoctoral research associate. "Plus, the fact that the body naturally makes NMN is promising for translating these findings into humans."
Imai and his colleagues found that young, healthy mice on a high-fat diet developed diabetes in six months or less. In these mice, they found that NAD levels were reduced. But after administering NMN, levels of NAD increased and the female mice had normal results in glucose tolerance tests -- a measure of how well the body moves glucose from the blood to the organs and tissues for use. Glucose tolerance was also improved after male diabetic mice received NMN but did not quite return to normal. The researchers are interested in learning more about these differences between male and female mice.
"We don't have a clear answer, but we are speculating that sex hormones, such as estrogen, may be important downstream for NAD synthesis," Yoshino says.
In older mice, they observed that about 15 percent of healthy males fed a normal diet developed diabetes.
"When we injected these older diabetic mice with NMN, they had improved glucose tolerance, even after one injection," says Kathryn F. Mills, research lab supervisor and an equally contributing first author of the study. "We also injected older healthy mice and found that they weren't adversely affected. It's good to know that even if the mice are not diabetic, giving NMN is not going to hurt them."
Imai says few studies have examined normal mice that naturally develop diabetes as a simple result of aging because the experiments take so long. In an interesting twist, few elderly female mice developed diabetes at all. But after switching to a high fat diet, older female mice quickly developed severe diabetes.
"Again, when we injected these females with NMN, we came up with a completely normal glucose tolerance curve," Mills says. "We can also see that the NMN has completely reversed and normalized the levels of cholesterol, triglycerides and free fatty acids."
Though the mice received NMN by injection in this study, Imai's group is now conducting a long-term study of diabetic mice that get NMN dissolved in their drinking water. Imai calls this work a first step toward a possible "nutriceutical" that people could take almost like a vitamin to treat or even prevent type 2 diabetes.
"Once we can get a grade of NMN that humans can take, we would really like to launch a pilot human study," Imai says.

**Source: Washington University School of Medicine

Presentan un vídeo para dar a conocer la realidad de la esclerosis lateral amiotrófica (ELA)