How Salmonella forms evil twins to evade the body's defenses

An unusual regulatory mechanism that controls the swimmer/non-swimmer option in genetically identical Salmonella also impacts the bacteria's ability to cause infection. University of Washington scientists reported the discovery this week in the Proceedings of the National Academy of Sciences.
As Salmonella divides into genetically identical clones, either of the two forms of the bacteria can emerge. Some individuals sport flagella -- thin, whip-like projections that propel the bacterium. Others do not. When grown in a lab dish, both types appear.
Salmonella is a common food-poisoning bacteria. It can survive and take hold in hostile environments -- like inside of people who are protected by hoards of infection-fighting cells. In immunocompromised individuals, it causes blood stream infections.
"In an unpredictable world," said Dr. Brad Cookson, professor of microbiology and laboratory medicine, and division head of Clinical Microbiology at the UW, "Salmonella have evolved to hedge their bets." Each guise has its own advantages and drawbacks in invading a host and evading defenses, depending on the situation.
Cookson explained that being genetically the same but differing in appearance and function is useful for a population of disease-causing bacteria. Even though the bacteria might be identical clones, varying characteristics of the individuals -- some of whom are mobile and some of whom are stationary -- allows the population to colonize a host and establish an infection.
"Diversity," Cookson noted, "improves the chance that some of the clones will thrive in fluctuating environments." To infect an animal, swallowed Salmonella breaches the protective mucous of the gut, colonizes the lymph tissues, and then builds a niche inside germ-killing cells. These cells are co-opted into ferrying the Salmonella to the spleen and other organ system tissues.
"The ability to swim," Cookson said, "is presumably a critical survival trait." In an intestinal infection, for example, motile Salmonella bacteria grow faster than their non-motile counterparts because they are able to migrate to the nutrient-rich layers of the intestinal lining. Inside of macrophages, however, non-motile Salmonella have the upper hand.
That is because the protein needed to make flagella, called flagellin, provokes the body's defenses. When Salmonella bacteria secrete flagellin, their macrophage ferry interprets this as a danger signal, and kills itself -- and the Salmonella on board -- in a self-destructive, pro-inflammatory response called pyroptosis: to go up in flames.
As a countermeasure, Salmonella restricts the production of flagellin to avoid tripping the macrophage alarm. This helps Salmonella avoid inciting an inflammatory response that would lessen its chances of colonizing its host.
Cookson's team of researchers, led by Dr. Mary Stewart from the UW Department of Microbiology, identified the genetic regulation for the "ON" and "OFF" production of flagellin. This genetic regulation pathway is behind the uncanny ability of genetically identical Salmonella to generate physically distinct subgroups.
They discovered that a protein that is almost in a class by itself --YdiV -- determines whether a Salmonella cell will produce or not produce flagellin. This protein can prevent certain parts of the Salmonella genome from being read to manufacture a substance called a sigma factor. The sigma factor plays a key role in recruiting other biochemical functions that promote the production of flagellin.
The sigma factor is repressed in only some of the genetically identical cells. This results in the two kinds of subpopulations: those cells that produce flagellin and those that don't. In a lab dish, both types maintain a stable presence within the Salmonella clonal population. In an animal or human, anatomical location determines which type will fare better during each stage of the infection,
The researchers also found that Salmonella strains that lack the YdiV protein are unable to fully repress the production of flagellin. These mutant strains are less infectious. Looking at the other side of the host-pathogen struggle, mutant mice that couldn't launch pyroptosis in response to flagellin were more susceptible to serious Salmonella infections.
The research was supported by a University of Washington Cellular and Molecular Biology Training Grant, National Institute of General Medical Sciences Public Health Service National Research Award, and grants from the National Institutes of Health.

*Source: University of Washington

Neuroscientists boost memory using genetics and a new memory-enhancing drug

When the activity of a molecule that is normally elevated during viral infections is inhibited in the brain, mice learn and remember better, researchers at Baylor College of Medicine reported in a recent article in the journal Cell. "The molecule PKR (the double-stranded RNA-activated protein kinase) was originally described as a sensor of viral infections, but its function in the brain was totally unknown," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and senior author of the paper. Since the activity of PKR is altered in a variety of cognitive disorders, Costa-Mattioli and colleagues decided to take a closer look at its role in the mammalian brain.
Super memory
The authors discovered that mice lacking PKR in the brain have a kind of "super" memory. "We found that when we genetically inhibit PKR, we increased the excitability of brain cells and enhanced learning and memory, in a variety of behavioral tests," he said. For instance, when the authors assessed spatial memory (the memory for people, places and events) through a test in which mice use visual cues for finding a hidden platform in a circular pool, they found that normal mice had to repeat the task multiple times over many days in order to remember the platform's location. By contrast, mice lacking PKR learned the task after only one training session.
Costa-Mattioli and colleagues wanted to know how this molecular process actually works. They found that when PKR is inhibited, the increased synaptic activity (that is, the enhanced communication between neurons) is caused by gamma interferon, another molecule involved in immunity.
"These data are totally unexpected, and show that two molecules classically known to play a role in viral infection and the immune response regulate the kind of brain activity that leads to the formation of long-term memory in the adult brain," said Costa-Mattioli.
Drug targets PKR
Another key finding made by Costa-Mattioli and his team of researchers was the fact that this process could be mimicked by a PKR inhibitor -- a small molecule that blocks PKR activity and thus acts as a "memory-enhancing drug."
"It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR." Definitely then, the next step is to use what we have learned in mice and to try to improve brain function in people suffering from memory loss, said Costa-Mattioli.
Although Costa-Mattioli's memory pill may be years away from approval by the U.S. Food and Drug Administration, its impact on society and medicine could be very profound. There are roughly 6 million Americans and 35 million people world-wide with Alzheimer's disease and more than 70 million Americans over the age of 60 who may suffer from aged-associated impairment of memory.
Costa-Mattioli said, "More investigation is undoubtedly necessary to translate these findings to effective therapies but we would be delighted if our scientific studies were to contribute in some way to this ultimate goal."
"Our identity and uniqueness is made up of our memories," Costa-Mattioli said. "This molecule could hold the key to how we can keep our memories longer, but also how we create new ones."

*Source: Baylor College of Medicine

Obama impide la venta de la píldora del día después sin receta

Por primera vez el Gobierno norteamericano ha desoído las recomendaciones de su propia Agencia del Medicamento, que le aconsejaba vender la píldora del día después en las farmacias y en los supermercados, sin receta médica y sin comprobaciones por parte del farmacéutico. Hasta ahora, la píldora, conocida como Plan B, se vende con receta médica a los menores de 17 años y sin receta a todos los demás. Todos los que quieran adquirirla deben presentarle al farmacéutico una prueba de su edad, como un pasaporte o carné de conducir.
La comunidad científica y la Agencia del Medicamento le habían recomendado a Barack Obama eliminar esos filtros, para venderla libremente a todos los que la desearan, algo que el presidente ha ignorado. Por decisión del presidente, se seguirá pidiendo receta a los menores de 17 y prueba de edad a todos los que quieran adquirirla. La píldora Plan B se vende por unos 50 dólares (unos 37 euros al cambio actual) y contiene altas dosis de la hormona conocida como progestágeno sintético. Si la mujer la ingiere hasta 72 horas después del encuentro sexual puede evitar la ovulación y prevenir un embarazo no deseado. Esa píldora no tiene efecto sobre una mujer que ya esté embarazada.
El gobierno de George W. Bush se opuso a venderla sin receta. Finalmente lo permitió, reticentemente, en 2006, y sólo para mayores de 18 años. Entonces, sin embargo, el asunto ya estaba en los tribunales. Una orden judicial obligó a Obama a rebajar esa edad a los 17 años en julio de 2009. Entonces, comenzó un nuevo proceso de investigación por el cual la Agencia del Medicamento trató de averiguar si sería seguro vender el tratamiento sin restricciones en farmacias y supermercados. "Según la información que se envió a la agencia, [ésta] determinó que el producto es seguro y efectivo en mujeres adolescentes, y que las mujeres adolescentes entienden que el producto no es para uso rutinario, y que no las protege contra enfermedades de transmisión sexual", dijo el miércoles la jefa de la agencia, Margaret Hamburg.
Hamburg le pidió formalmente al gobierno que permitiera la venta libre de Plan B, junto a los preservativos y los espermicidas. Las evidencias científicas, sin embargo, no sirvieron para convencer a la Casa Blanca, a sólo un año de una campaña de reelección del presidente Obama, en la que éste deberá apelar no sólo a sus bases, sino también a los votantes más conservadores y religiosos. La Secretaria de Sanidad, Kathleen Sebelius, se justificó en un comunicado.
"La edad media de comienzo de la menstruación femenina en EE UU es de 12,4 años", dijo Sebelius. "Sin embargo, el 10% de las niñas pueden tener hijos a los 11,1 años. Es sabido que hay diferencias cognitivas y de comportamiento entre niñas adolescentes que son más mayores y las niñas más jóvenes que ya están en edad reproductiva. Si hubiera aprobado esa recomendación, ese producto hubiera estado al alcance de todas las niñas, en todas las edades reproductivas, sin receta médica".
El presidente Obama apoyó la decisión de su ministra de Sanidad en una rueda de prensa, este jueves. "Yo, que tengo dos hijas [de 13 y 10 años] estoy convencido de que debemos asegurarnos de que este asunto se gestiona con el necesario sentido común", dijo. "Es lógico que no se quiera vender la píldora a niñas de 10 o de 11 años que acudan a un supermercado y quieran comprarla, junto a chicles y pilas, porque es permitirles comprar un medicamento que, si no se usa de forma adecuada, puede tener efectos adversos".
En un cambio de tornas, los grupos conservadores han alabado al presidente Obama y la base demócrata en el Congreso le ha acusado de ignorar la ciencia y dejarse llevar por argumentos religiosos. "El proceso de investigación de la Agencia del Medicamento fue exhaustivo y concienzudo", dijo la representante demócrata Diana DeGette. "La información que se envió al Departamento de Sanidad dejaba claro que Plan B es segura y efectiva para los usos para los que se la ha destinado. El acceso a métodos anticonceptivos seguros y fiables es una parte esencial de la sanidad".

**Publicado en "EL PAIS"

Combination of everolimus and exemestane improves survival for women with metastatic breast cancer

In an international Phase III randomized study, everolimus, when combined with the hormonal therapy exemestane, has been shown to dramatically improve progression-free survival, according to research from The University of Texas MD Anderson Cancer Center. The study, known as Breast Cancer Trials of Oral Everolimus (BOLERO-2), was presented Dec. 7 at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium by Gabriel Hortobagyi, M.D., professor and chair of MD Anderson's Department of Breast Medical Oncology. Earlier findings were simultaneously reported in the New England Journal of Medicine.
Everolimus, an immunosuppressant agent first used to prevent rejection of organ transplants, also has anti-angiogenic properties. It inhibits the mammalian target of rapamycin (mTOR) protein, a central regulator of tumor cell division and blood vessel growth in cancer cells; the mTOR pathway is activated in hormone-resistant breast cancer, explained Hortobagyi. Currently, the oral agent is approved for both the treatment of kidney cancer and pancreatic neuro-endocrine tumors, with MD Anderson's research leading the way for the latter's usage approval by the FDA.
Preliminary BOLERO-2 data were first presented at ESMO and showed a significant progression-free survival benefit; these updated findings represent six additional months of patient follow-up, Hortobagyi explained.
"This study is based on the concept that we now know more about the resistance mechanisms to endocrine therapy and the experimental arm of BOLERO-2 uses a dual-attack on treatment refractory hormone receptor-positive breast cancer: it simultaneously inhibits the estrogen-signaling pathway with the aromatase inhibitor, exemestane, and the PI3-kinase/AKT/mTOR pathway with the use of everolimus," Hortobagyi said. "For the first time in a large Phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy."
The international Phase III trial enrolled 724 metastatic breast cancer patients, all of whom were post-menopausal, had hormone receptor-positive disease and evidence of progressive disease. In a two-to-one ratio, 485 women were randomized to receive the combination of everolimus (10 mg daily), and exemestane, an aromatase inhibitor, and compared to 239 women who received exemestane and placebo. All were previously treated with and progressed on letrozole and anastrozole, with the majority of women extensively treated with prior therapies. The median age of the women enrolled was 62 years; the study's primary endpoint was progression-free survival.
In patients receiving the everolimus combination, researchers found a progression-free survival of 7.4 months, compared to 3.2 months in those who took exemestane alone, a finding Hortobagyi describes as "highly significant." The clinical benefit rate -- complete responses, partial responses and stability exceeding six months -- was 50.5 percent in those in the combination arm, compared to 25.5 percent in those who received the hormonal therapy alone. Adverse effects, such as shortness of breath, hyperglycemia, mouth sores and fatigue, were all higher in the combination group, but were manageable and did not disrupt patients' quality of life, the researchers found. Survival data are still being analyzed.
Because aromatase inhibitors are associated with bone loss and fractures, as a safety measure, Hortobagyi and the researchers assessed patients for bone-turnover markers. The addition of everolimus was found to significantly reduce the level of such markers -- an interesting area for future study, noted Hortobagyi.
"Over the years, our treatment approach for such women with metastatic breast cancer has been sequential use of as many hormone therapies as possible, keeping metastatic disease under control for as long as possible. These findings may allow us to change our approach. In this group of heavily pre-treated patients, all of whom progressed on prior endocrine therapy, the addition of this mTOR inhibitor resulted in significant prolongation of progression-free survival and an improved response rate, with only a modest addition of toxicity," said Hortobagyi.
Hortobagyi believes that these findings may be practice-changing for women who meet the criteria for BOLERO-2. Additional studies are planned with everolimus in breast cancer, including in combination with an aromatase inhibitor in the adjuvant setting, as well as additional clinical trials in the metastatic setting.
In addition to Hortobagyi, authors on the international study include: Jorge Baselga, M.D., Massachusetts General Hospital Cancer Center and Harvard Medical School, and the NEJM study's corresponding author; Martine Piccart, M.D., Jules Bordet Institute; Hope S. Rugo, M.D., University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Howard Burris, M.D., Sarah Cannon Research Institute; Mario Campone, M.D., Institut de Cancérologie de l'Ouest; Shinzaburo Noguchi, M.D., Osaka University; Michael Gnant, M.D., Comprehensive Cancer Center, Medical University of Vienna; Kathleen Pritchard, M.D., Sunnybrook Odette Cancer Centre; Luc Vittori, Zhiying Xu, Ph.D., Pabak Mukhopadhyay, Ph.D., Tarek Sahmoud, M.D., Ph.D. and David Lebwohl, M.D., the last five of Novartis Pharmaceuticals.
The trial was funded, in part, by Novartis. Hortobagyi reports receiving research funds from, as well as having served as a consultant for, Novartis.

**Source: University of Texas M. D. Anderson Cancer Center

Premature babies harbor fewer, but more dangerous microbe types

One of the most comprehensive studies to date of the microbes that are found in extremely low-birthweight infants found that hard-to-treat Candida fungus is often present, as well as some harmful bacteria and parasites. Researchers at the Duke University Medical Center and Nicholas School of the Environment looked at the microbes in 11 premature infants and found much less diversity than in full-term infants.
"The babies' guts were taken over by microbes we know are dangerous if they get into the blood," said senior author Patrick Seed, MD, PhD, assistant professor of pediatrics at Duke. "Even after the babies were no longer on antibiotics, healthier bacteria didn't appear in the babies very quickly. This may be one reason why premature babies are so vulnerable to infections."
All of the premature children were placed on antibiotic treatments after birth, which would wipe out some types of bacteria and yeast, but once they were off the antibiotics and taking food, the researchers expected to see more diversity of bacteria in the babies' developing digestive systems than they found.
The findings were published in PLoS One open-access journal on December 8, 2011.
Five infants had blood infections while three had necrotizing enterocolitis, an infection-related death of bowel tissue, said Seed, who is also with the Jean and George Brumley Jr. Neonatal-Perinatal Research Institute and the Duke Center for Microbial Pathogenesis.
Seed said that while the study babies were colonized mainly by organisms that were found in stool specimens, in some cases they also had infections with Staphylococcus epidermidis, a form of staph infection, that was abundant in many of the babies' digestive tracts.
The bacteria and yeast in the premature babies' digestive tracts are known causes of devastating infections in these babies. The gut seems to be a reservoir for some organisms that form infections, Seed said. Previous to this work, "we only knew the tip of the iceberg," he said.
The researchers used genomic (DNA) typing of the bacteria, fungi, and parasites to determine which types were present.
It's not clear if the newborns are picking up these early infections from their mother's milk, blood, or in other ways, or if the pathogens are from the environment surrounding the infants.
"It's important to know where these pathogens come from so that doctors can possibly manipulate the babies' environment or their digestive systems," Seed said. He noted that other studies had shown value for giving babies probiotic substances to tip the internal balance toward more favorable bacteria, necessary for immunity and better health.
Seed stressed that certain bacteria and other microbes are helpful for growing babies and their immune systems, so it is important not to do any damage by creating an antiseptic environment.
"It's a question of balance," Seed said. "As vulnerable as these babies are, we still wouldn't want to wipe out all of the bacteria, even all of the potentially harmful bacteria."

*Source: Duke University Medical Center

El pescado reduce el riesgo cardiaco en las mujeres jóvenes

Las mujeres jóvenes podrían reducir significativamente su riesgo de contraer enfermedades cardiovasculares mediante un hábito tan sencillo como comer más pescado rico en ácidos grasos omega 3, según una nueva investigación danesa centrada en este grupo de población.
En comparación con las mujeres que siguen una dieta rica en estos ácidos grasos, aquellas que no comen nunca o casi nunca pescado pueden presentar un riesgo hasta un 90% mayor, de acuerco con los resultados presentados en la revista 'Hypertension: Journal of the American Heart Association'.
Los investigadores, del Instituto Statens Serum en Copenhague (Dinamarca), usaron los datos de una encuesta sobre embarazos, en la que se recogieron datos de 49.000 mujeres danesas de entre 15 y 49 años y se indagó en sus hábitos alimenticios, estilo de vida e historial familiar. Las participantes tuvieron un seguimiento medio de ocho años, a partir de 1996. En este tiempo se registraron cinco muertes debidas a causas cardiovasculares sin ningún diagnóstico previo.
Además, se produjeron 328 episodios provocados por la hipertensión, 146 cerebrovasculares y 103 infartos cardiacos. Todos estos problemas resultaron ser mucho más frecuentes entre las mujeres que comían poco pescado.
"Por lo que sabemos, este ha sido el primer estudio de este tamaño que se ha centrado exclusivamente en mujeres en edad de tener hijos", señala la doctora Marin Strøm, del Centro de Programación Fetal de la citada institución danesa. "El pescado es la única fuente de la que podemos obtener cantidades importantes de los ácidos grasos omega 3", explica Strøm a ELMUNDO.es.
Hay que tener en cuenta que las mujeres con dietas pobres en pescado también presentaban , en general, mayores tasas de otros factores de riesgo, como obesidad, tabaquismo o consumo de alcohol. Aunque también eran, como media, más jóvenes y más físicamente activas.

-Beneficios a corto y largo plazo
"El mayor desafío de hacer llegar esta clase de mensajes sobre salud a las poblaciones más jóvenes radica en que se cree que los beneficios se producen a muy largo plazo, quizás en 30 o 40 años. Pero nuestro estudio muestra que este no es el caso. Hemos visto una fuerte asociación con la enfermedad cardiovascular en las mujeres que estaban aún en sus treintena tardía", explica la doctora Strøm.
El estudio específico de las mujeres es importante porque, aunque su sistema cardiovascular es parecido al de los hombres, existen también algunas diferencias, según los autores del trabajo. "Por ejemplo, la inflamación, el colesterol y los niveles de triglicéridos pueden tener un mayor influjo negativo entre mujeres", señala Strøm, quien, sin embargo, reconoce: "Pensamos que estos ácidos grasos pueden ser también beneficiosos para otros grupos".
Las mujeres que tomaban suplementos de omega 3 fueron excluidas del estudio, con el fin de observar el efecto beneficioso de tomar estos ácidos grasos únicamente en su forma natural, a través del pescado. Algunos de los productos ricos en omega 3 son el atún, la caballa, el bacalao, el salmón, el mero o el arenque.

**Publicado en "EL MUNDO"

Women advised to avoid ZEN bust-enhancing supplements because of possible cancer risk

Women who use bust-enhancing dietary supplements containing the mycoestrogen zearalenone (ZEN), a naturally occurring toxin that widely contaminates agricultural products, could be increasing their risk of breast cancer. That is the warning from breast health experts in a paper published online ahead of print publication in the January issue of IJCP, the International Journal of Clinical Practice. "No clinical trials have been published on the use of potent oestrogens like ZEN in bust-enhancing products and their use should be discouraged because of the lack of evidence of their long-term safety" says Professor Ian Fentiman, consultant breast surgeon at Guy's and St Thomas' NHS Foundation Trust, London.
The use of ZEN to increase bust size is just one of the key concerns raised by the review focussing on the affects of ZEN and its derivatives on the human reproductive system and breast cancer. It also included the use of ZEN to fatten up livestock, its use in hormone replacement therapy and oral contraceptives, its links with premature puberty and its possible effects on breast cancer.
"ZEN is a toxic non-steroidal mycoestrogen produced by fungi that widely contaminates agricultural products, such as crops, eliciting oestrogenic responses by mimicking the female sex hormones" explains Professor Fentiman.
Using ZEN in animal feed has been associated with a wide range of reproductive anomalies in livestock, including diminished fertility and infertility, reduced litter size and smaller offspring and negative effects on the reproductive organs.
International studies have suggested links between consumption of ZEN-fed animals and products and precocious (early) puberty in young females.
These include an epidemic of premature breast development and early puberty in Puerto Rico, linked to dairy and meat products, and studies from Hungary and Italy where female children with precocious puberty had increased ZEN levels in their serum.
"In fact the European Union has banned using ZEN to fatten up cattle, a technique used in the USA since 1969, because of its links with precocious puberty" says Professor Fentiman.
"Recently it has been suggested that some ZEN derivatives can increase the growth of hormone-dependent breast tumours. It has also been reported that, depending on the dose, ZEN can either promote or prevent breast cancer. So the jury on whether its links with breast cancer are positive or negative is well and truly out at this stage."

-The authors drew a number of conclusions from their review:
There is a lack of information on the human metabolism of ZEN and disagreement on the mechanisms of ZEN oestrogenic action in human tissue.
The presence of this mycoestrogen in cereals, milk, and meat, and the possibility of ZEN involvement in the development of new breast tumours, warrant further investigation.
Future studies should investigate the effects of ZEN on the growth stimulation of hormone-dependent cancers and identify the key genes that promote hormone-dependent cancers.
ZEN promotes programmed cell death and reduces the proliferation of cancer cells when administered at certain doses.
Although ZEN is a common diet toxic mycoestrogen, the potential risk to human health appears to only occur when it is absorbed in concrete concentrations or over a long period of time.
A molecular biomarker of dietary exposure to ZEN and its derivatives will allow the detection and control of harmful food intake.
The interaction of ZEN with anti-oestrogens and anticancer agents and antioxidants requires further investigation.

**Source: Wiley-Blackwell