Medicine Man

Preliminary research culled from a national medical insurance records database in Taiwan suggests that sudden loss of hearing might be an early sign of vulnerability to stroke, foreshadowing an actual cerebrovascular event by as much as two years, according to a study reported in Stroke: Journal of the American Heart Association.

Five-year follow-up data on 1,423 patients hospitalized for an acute episode of sudden sensorineural hearing loss (SSNHL) showed they were more than one-and-a-half times more likely to suffer a stroke than a control group of 5,692 patients who had been hospitalized for an appendectomy.

Because the insurance records may not have contained reliable information, such as correct diagnostic codes or confounding factors, the findings should be considered tentative, said lead investigator Herng-Ching Lin, Ph.D., a professor at Taipei Medical University School of Health Care Administration.

"To the best of our knowledge, no study has investigated the incidence or risk of cerebrovascular diseases developing following the onset of sudden sensorineural hearing loss," Lin said. "But because this is the first time any association has been suggested, and because there were many limitations in the data, the results need to be interpreted cautiously until additional independent studies are performed."

The findings are limited because there is not a clear universal definition for SSNHL in the database that was reviewed. "Secondly, the database did not contain information regarding severity of hearing loss, extent of hearing recovery, tobacco use, body mass index and the medical history of cardiovascular disease and atrial fibrillation - all of which can contribute to stroke risk," Lin explained.

Nonetheless, the researchers recommend that all SSNHL patients undergo a comprehensive neurological exam and blood testing to gauge their risk profile for stroke.

http://www.americanheart.org/

Scientists at Dana-Farber Cancer Institute report they have blocked the development of prostate tumors in cancer-prone mice by knocking out a molecular unit they describe as a "powerhouse" that drives runaway cell growth.

In an article that is being published today as an advanced online publication by the journal Nature, the researchers say the growth-stimulating molecule called p110beta -- part of a cellular signaling network disrupted in several common cancers -- is a promising target for novel cancer therapies designed to shut it down. The report's lead authors are Shidong Jia, MD, PhD, Zhenning Liu, PhD, Sen Zhang PhD, and Pixu Liu, MD, PhD.

The p110beta molecule and a counterpart, p110alpha, are "isoforms" -- slightly different forms - of an enzyme called PI(3)K that is an intense focus of cancer research and drug development. PI(3)K is the linchpin of a cell-signal pathway that responds to growth factor signals from outside the cell.

When activated by growth factor receptors, PI(3)K turns on a cascade of genes and proteins that drives cells to divide and grow. The molecular accelerator is normally kept under control by a tumor-suppressor protein, PTEN, which acts like a brake to curb excess cell growth that could lead to cancer.

Mutations that inactivate PTEN -- in effect releasing the brake on growth signals -- are found in a significant proportion of prostate, breast and brain tumors. The senior authors of the new report, Jean Zhao, PhD, and Thomas Roberts, PhD, previously showed that blocking p110alpha protein inhibits cancerous growth induced by various cancer-causing proteins, such as Her2 and EGFR. With that knowledge in hand, the researchers, in collaboration with pharmaceutical companies, are developing p110alpha blockers.

P110beta, by contrast, was thought to be a relatively insignificant player in tumors. However, "the surprise in this paper is that p110beta has been found to be a bigger player than p110alpha in tumors that result from PTEN loss," noted Zhao. "Now the drug companies, which have been focusing on p110alpha, will have to think about making p110beta inhibitors as well."

Both forms of the p110 molecule have dual tasks: they are involved in responding to insulin signals -- a metabolic function -- as well as relaying growth signals from outside the cell. But the importance of 110beta had been vastly underestimated, the researchers said, for reasons they don't entirely understand.

"We knew that when cells are stimulated with growth factor signals, the activity of p110alpha, but not p110beta, rises rapidly and sharply in triggering excess cell growth," Zhao said. "We speculate that 110beta may be providing a low-level but steady growth stimulus and when PTEN is lost, it becomes an important source of cell proliferation signals."

The new findings stem from experiments in which the scientists disabled the p110beta protein in mice as a way of exploring its normal functions. In one of the experiments, the researchers "knocked out" p110beta in mice that also lacked the PTEN tumor suppressor protein and were therefore highly prone to prostate cancer. Mice that lacked PTEN but had functioning p110beta proteins all developed early prostate cancers by 12 weeks of age. In contrast, the "knockout" mice with no p110beta function remained free of prostate cancer even though the PTEN "brake" had been disabled.

The scientists concluded, as a result, that p110beta becomes a "powerhouse" to drive cancerous cell growth when PTEN function is missing.

In light of the new findings, there is likely to be great interest in finding drugs or other tools to block the p110beta protein in cancers where mutations in PTEN have unleashed the overactive growth signals, said Zhao, who is also an assistant professor of surgery at Harvard Medical School.

The task is made somewhat easier, said Roberts, by the fact that "we know what the inhibitor should look like because of our work on p110alpha inhibitors."

Roberts, who is also a professor of pathology at Harvard Medical School, said that drugs designed to block the p110alpha form are on their way to clinical testing, but he could not predict when p110beta inhibitors might become available for clinical testing.

http://www.dfci.harvard.edu/

Like the masterless samurai for whom it is named, the protein Ronin chooses an independent path, maintaining embryonic stem cells in their undifferentiated state and playing essential roles in genesis of embryos and their development, said Baylor College of Medicine researchers who reported on this novel cellular regulator in the current issue of the journal Cell.

Three proteins - Oct4, Sox2 and Nanog -- had previously been considered the "master" regulators of embryonic stem cells, but "Ronin could be as important as these three," said Dr. Thomas Zwaka, assistant professor in the Stem Cells and Regenerative Medicine (STaR) Center at BCM. In fact, he said, if the action of Oct4, considered the most important, is reduced in embryonic stem cells, Ronin can compensate for the loss.

Embryonic stem cells are pluripotent, meaning they have the potential for becoming all other kinds of cells in the body. They are also capable of self-renewal. Oct4, Sox2 and Nanog were previously thought the major method by which embryonic stem cells remained in their pristine state. Now, Ronin represents a different and parallel pathway to achieve the same result.

Ronin is also expressed in early embryonic development of mice. If it is not present, the embryos die, said Zwaka. It is also found in mature oocytes or egg cells.

"Ronin is a potent transcription repressor," he said. In fact, it prevents the action of genes that promote the differentiation of cells into the various tissues and organs of the body.

"It does it more effectively than the other three factors together," he said. It silences the differentiation genes epigenetically through specific chemical mechanisms that modify histones, the chief packaging proteins for DNA.

He and his colleagues found Ronin as a follow-up to an earlier study that showed a component of the cell death system called caspase-3 actually cleaved and reduced the amount of Nanog protein. This caused the embryonic stem cells to stop self-renewal and begin differentiation into other kinds of cells.

Zwaka and his colleagues searched for other proteins affected by the caspase and found Ronin, which was previously unknown.

The finding prompts other questions. Can Ronin be used to reprogram differentiated cells into those that more closely resemble embryonic stem cells? What is the significance of the portion of Ronin that resembles a "jumping gene" or transponson called P element transposase, usually found in the genomes of fruit flies?

Ronin is also found in areas of the brain such as the hippocampus and the Purkinje cells of the cerebellum.

"What role does it play in the brain?" asked Zwaka.

http://www.bcm.edu/

Pregnant women who receive treatment for substance abuse early in their pregnancy can achieve the same health outcomes as pregnant women with no substance abuse, according to a Kaiser Permanente study published online in the Journal of Perinatology.

The study, which is the largest to date, examined 49,985 women in Kaiser Permanente's prenatal care program and found that integrating substance abuse screening and treatment into routine prenatal care helped pregnant women achieve similar health outcomes as women who were not using cigarettes, alcohol or other drugs. This is also the largest study to examine multiple substances: cigarettes, alcohol, marijuana, methamphetamines, cocaine and heroin.

"This program can happen everywhere and should become the gold standard for women who are pregnant and using cigarettes, alcohol or other drugs," said study lead author Nancy C. Goler, M.D., an OB/GYN and Kaiser Permanente regional medical director of the Early Start Program for the organization's Northern California operations. "The study's big finding was that study participants treated in the Early Start program had outcomes similar to our control group, women who had no evidence of substance abuse."

The study compared 2,073 pregnant women who were screened, assessed and received ongoing intervention during pregnancy through the Early Start program at 21 Kaiser Permanente Northern California outpatient obstetric clinics from 1999 to 2003 to women in three other groups: 156 women who were screened but did not accept assessment or treatment; 1,203 women were screened, assessed and received brief intervention only; and a control group of 46,553 women who showed no evidence of substance abuse.

The study found the risk of stillborn, placental abruption (when the placental lining separates from the mother's uterus), pre-term delivery, low birth weight and neonatal ventilation were dramatically higher for the 156 untreated substance abusers than the 2,073 women in the Early Start program:

• Risk of stillbirth was 16.2 times higher for women who were screened but did not accept assessment or treatment than those who received Early Start treatment

• Risk of placental abruption was 6.8 times higher for women who were screened but did not accept assessment or treatment than those who received treatment

• Risk of pre-term delivery was 2.1 times higher for women who were screened but did not accept assessment or treatment than those who received treatment

• Risk of low birth weight (under 5.5 pounds) was 1.8 times higher for women who were screened but did not accept assessment or treatment than those who received treatment

• Risk of neonatal ventilation was 2.2 times higher for women who were screened but did not accept assessment or treatment than those who received treatment.

The women who went through the Early Start program had the same statistical risks of stillborn, preterm delivery, placental abruption as the control group of women who did not use any cigarettes, alcohol or drugs during their pregnancy.

"The key message here to women who are currently smoking, drinking or using other drugs, or who recently tried to stop, is that it is not too late to seek help when you find out you are pregnant," said Dr. Goler. "The sooner women ask for help, the better the health outcomes will be for themselves, and their babies. My message to all pregnant women, as well as women who are trying to conceive, is to stop all alcohol, cigarette and drug use."

Launched in 1990, Kaiser Permanente's Early Start program integrates obstetric care with substance abuse treatment for pregnant women in three ways: all women are screened by questionnaire for drug, cigarette and alcohol use, and by urine toxicology testing with signed consent; a licensed substance abuse expert works in the OB/GYN department and sees the patients at the same time as their prenatal care appointments; and all providers and patients are educated about the effects of drugs, alcohol and cigarette use during pregnancy.

The program, which is in place in 40 Kaiser Permanente outpatient obstetric clinics in Northern California and being rolled out in other Kaiser Permanente facilities nationwide, screens nearly 40,000 women annually. By providing a licensed professional with expertise in substance abuse and pregnancy in the OB/GYN department - so women have barrier-free access to care in a safe, supportive environment - Early Start exceeds the American College of Obstetricians and Gynecologists Committee on Ethics Opinion recommendations to use universal screening questions, brief intervention, and referral to treatment programs for substance abuse

"This study is a superb example of how effective the Kaiser Permanente's Early Start approach and methodology is in treating chemical dependency and substance abuse in pregnant women," said Margaret Merritt, Executive Director of the American College of Obstetrics and Gynecology, District IX (California). "Early Start exceeds the guidelines set forth by ACOG and is a fantastic example of a program that can be incorporated in a variety of settings to reach this very important group of women."

http://www.kaiser.org/

More than 80 years have passed since the German scientist Hans Spemann conducted his famous experiment that laid the foundations for the field of embryonic development. After dividing a salamander embryo in half, Spemann noticed that one half - specifically, the half that gives rise to the salamander's 'belly' (ventral) starts to wither away.

However, the other 'back' (dorsal) half that develops into its head, brain and spinal cord, continues to grow, regenerating the missing belly half and develops into a complete, though be it smaller, fully functional embryo. Spemann then conducted another experiment, where this time, he removed a few cells from the back half of one embryo and transplanted them into the belly half of a different embryo. To his surprise, this gave rise to a Siamese twin embryo where an extra head was generated from the transplanted cells. Moreover, although the resulting embryo was smaller than normal, all its tissues and organs developed in the right proportions irrespective of its size, and functioned properly. For this work, Spemann received the Nobel Prize in Physiology or Medicine in 1935.

But how does this happen? How exactly is the half embryo able to maintain its tissues and organs in the correct proportions despite being smaller than a normal sized embryo?

Despite many years of research, this question has remained unanswered - until now. More than 80 years since Spemann's classic experiment, Profs. Naama Barkai, Benny Shilo and research student Danny Ben-Zvi of the Weizmann Institute of Science's Molecular Genetics Department, together with Prof. Abraham Fainsod of the Hebrew University-Hadassah School of Medicine, Jerusalem, have finally discovered the mechanisms involved.

Previous studies have shown that the growth and development of cells and organs within the embryo is somehow linked to a special group of substances called morphogens. These morphogens are produced in one particular area within the embryo and then spread throughout the entire embryo in varying concentrations. Scientists then began to realize that the fate of embryo cells, that is to say, the type of tissue and organ they are eventually going to develop into, is determined by the concentration of morphogen that they come into contact with. But this information does not answer the specific question as to how proportion is maintained between organs?

The idea for the present research came about when Weizmann Institute scientist Prof. Naama Barkai and her colleagues developed a mathematical model to describe interactions that occur within genetic networks of an embryo.

The data ascertained from this model suggest that the way morphogens spread throughout the embryo in different concentrations is different than previously thought. The team predicts that an inhibitor molecule, which is secreted from a localized source at one side of the embryo and can bind the morphogen, acts as a type of ferry that 'shuttles' the morphogen to the other side. Therefore, the mathematical model suggests that it is the interactions between the two substances that enable the embryo to keep the relative proportion between organs constant, irrespective of its size. Indeed, these predictions have been validated by experiments conducted on frog embryos by the research team.

The importance of the role of these morphogenic substances, as well as their mechanism of action, is evident by the fact that they have been conserved throughout evolution, where different variants can be found to exist in species ranging from worms to fruit flies and up to higher species including humans. Therefore, understanding the processes that govern embryonic cell development could have many implications. For example, it may lead, in the future, to scientists being able to repair injured tissues.

http://www.weizmann.ac.il/