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Testosterone key to disease transmission

High levels of testosterone may be a key factor in spreading disease among mice, according to biologists. The findings could help explain why males in a population are often more likely to get infected, and transmit disease. Previous research has linked testosterone, the male sex hormone, to immune system suppression. Studies have shown that males, compared to females, experience more bouts of disease, and account for a larger share of disease transmission. However, it is not fully clear what makes males such super-spreaders of disease. “We know that testosterone makes males more susceptible to disease,” said Daniel Grear, Penn State doctoral student in ecology. “We wanted to find out if it impacts their behavior as well and how that increases their ability to transmit disease.” Grear and his Penn State colleagues Sarah E. Perkins, postdoctoral fellow, and Peter J. Hudson, the Verne M. Willaman chair in biology and director of the Huck Institutes of Life Sciences at Penn State, investigated the effects of increased testosterone on mice behavior. Our plan was to raise the testosterone levels in wild mice and measure the disease risk they posed to the population,” said Grear, who presented the team’s findings at the annual meeting of the Ecological Society of America in Milwaukee, Wis., (Aug. 8).
The researchers randomly treated 24 male mice trapped at five sites in Huntingdon County, Pa., with testosterone implants. Twenty-five other male mice received sham implants, while mice at three separate sites received neither treatment. All sites were trapped twice a week for six weeks before and after treatment. The trapping sites were innovatively positioned to represent a large grid and mice were electronically tagged so researchers could keep precise track of where the animals were being recaptured. Such a social network, Grear explained, could help provide a clear picture of how the treated and untreated mice mix on the grids over time. Tests on recaptured mice indicated that the average number of contacts made between both males and females by mice that received the treatment — sham and testosterone — increased significantly increased after treatment. In other words, all mice were mixing more when testosterone treated mice were present.
Researchers also found that all mice at the separate untreated sites made significantly less contacts with other mice during the same time that the testosterone treatment significantly increased contacts. “These findings suggest that even if some individuals in a population have high levels of testosterone, they can impact the behavior of those around, and drive the transmission of diseases transmitted by close contact such as the respiratory pathogen Bordetella,” explained Grear, whose work is funded by the National Science Foundation.

EurekAlert! Medicine
September 2, 2008

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Steroids in female mouse urine light up nose nerves of male mice

A group of steroids found in female mouse urine goes straight to the male mouse’s head, according to researchers at Washington University School of Medicine in St. Louis. They found the compounds activate nerve cells in the male mouse’s nose with unprecedented effectiveness. “These particular steroids, known as glucocorticoids (GCCs), are involved in energy metabolism, stress and immune function,” says senior author Timothy E. Holy, Ph.D., assistant professor of neurobiology and anatomy. “They control many important aspects of the mouse’s physiology and theoretically could give any mouse that sniffs them a detailed insider’s view of the health of the animal they came from.” Holy plans further research to see if activating the nerves in the male mouse’s nose leads to particular behavioral responses. He probes the male mouse’s reaction to chemical signals from female mice to advance understanding of pattern recognition and learning in the much more complex human brain. In 2005, he found that female mice or their odors cause male mice to sing. He doesn’t know yet if the GCC steroids’ effects on the male mouse nose help to trigger this behavior.

Science has long recognized that urine, sweat and other bodily fluids contain chemical communication signals called pheromones that can influence the biology or behavior of others. Most mammals use the information in these signals for social purposes, such as establishing territory or dominance, or in courtship and mating. In many cases, though, the specific chemical identities of the signals are unknown. The new study, published in The Journal of Neuroscience and led by graduate student Francesco Nodari, identified compounds that are unusually potent stimulators of the mouse nose. The pheromones activate nerve cells 30 times as often as all the other pheromones previously identified in female mouse urine combined. In addition, several of the new signals activate specific nerve cells. This may mean the male mouse’s brain can assess different aspects of female mouse health by selectively analyzing individual pheromones. Stressing female mice led to a threefold increase in the levels of GCCs in their urine, directly linking the female mouse’s health and the GCC pheromones.

The GCC pheromones that Nodari identified were sulfated, which means they had a chemical attachment comprised of sulfur and oxygen atoms. This attachment is added to deactivate the steroids prior to excretion in the urine. When Nodari used an enzyme to remove these attachments, the GCCs lost their ability to activate nerves, further suggesting that the link between the sulfated GCCs and the nerve cells is a channel fine-tuned by evolution to carry information from female mice to male mice. The nerves researchers studied in the male mouse nose are located in an area known as the accessory olfactory system. Humans and many closely related apes don’t have an accessory olfactory system, but most other mammals and some reptiles do. The system, found in a structure called the vomeronasal organ, sends its outputs to a different part of the brain than the main olfactory system. Like the main olfactory system, it’s dedicated to detecting airborne particles. But researchers believe the accessory olfactory system focuses on compounds from sources that are physically very close to or touching the animal. According to Holy, this focus on scents from nearby sources makes the accessory olfactory system “halfway between a taste system and a sense of smell.” He believes the GCC pheromones account for approximately 75 percent of the signals detected in female urine by the male accessory olfactory system. “Because these new pheromones are so good at activating the accessory olfactory system, they will be very helpful in efforts to better understand what this system does,” he says. “That high degree of activation likely also means they have much potential for advancing the general study of pheromones.”

EurekAlert! Medicine
July 8, 2008

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Hunger hormone increases during stress, may have antidepressant effect

While levels of the so-called “hunger hormone” ghrelin are known to increase when a person doesn’t eat, findings by University Texas Southwestern scientists suggest that the hormone might also help defend against symptoms of stress-induced depression and anxiety. “Our findings in mice suggest that chronic stress causes ghrelin levels to go up and that behaviors associated with depression and anxiety decrease when ghrelin levels rise. An unfortunate side effect, however, is increased food intake and body weight,” said Dr. Jeffrey Zigman, assistant professor of internal medicine and psychiatry at UT Southwestern and senior author of a study appearing online today and in a future print edition of Nature Neuroscience.

Dr. Michael Lutter, instructor of psychiatry at UT Southwestern and lead author of the study, said, “Our findings support the idea that these hunger hormones don’t do just one thing; rather, they coordinate an entire behavioral response to stress and probably affect mood, stress and energy levels.” It is known that fasting causes ghrelin to be produced in the gastrointestinal tract, and that the hormone then plays a role in sending hunger signals to the brain. Research groups including Dr. Zigman’s have suggested that blocking the body’s response to ghrelin signals might be one way to help control weight by decreasing food intake and increasing energy expenditure. “However, this new research suggests that if you block ghrelin signaling, you might actually increase anxiety and depression, which would be bad,” Dr. Zigman said. To determine how ghrelin affects mood, Dr. Zigman and his colleagues restricted the food intake of laboratory mice for 10 days. This caused their ghrelin levels to quadruple. As compared to the control mice, which were allowed free access to food, the calorie-restricted mice displayed decreased levels of anxiety and depression when subjected to mazes and other standard behavior tests for depression and anxiety.

In addition, mice genetically engineered to be unable to respond to ghrelin were also fed a restricted-calorie diet. Unlike their calorie-restricted wild-type counterparts, these mice did not experience the antidepressant-like or anti-anxiety-like effects. To test whether ghrelin could regulate depressive symptoms brought on by chronic stress, the researchers subjected mice to daily bouts of social stress, using a standard laboratory technique that induces stress by exposing normal mice to very aggressive “bully” mice. Such animals have been shown to be good models for studying depression in humans. The researchers stressed both wild-type mice and altered mice that were unable to respond to ghrelin. They found that after experiencing stress, both types of mice had significantly elevated levels of ghrelin that persisted at least four weeks after their last defeat encounter. The altered mice, however, displayed significantly greater social avoidance than their wild-type counterparts, indicating an exacerbation of depression-like symptoms. They also ate less than the wild-type mice.

Dr. Zigman said the findings make sense when considered from an evolutionary standpoint. Until modern times, the one common human experience was securing enough food to prevent starvation. Our hunter-gatherer ancestors needed to be as calm and collected as possible when it was time to venture out in search of food, or risk becoming dinner themselves, Dr. Zigman said, adding that the anti-anxiety effects of hunger-induced ghrelin may have provided a survival advantage. Dr. Lutter said the findings might be relevant in understanding conditions such as anorexia nervosa. “We’re very interested to see whether ghrelin treatment could help people with anorexia nervosa, with the idea being that in a certain population, calorie restriction and weight loss could have an antidepressant effect and could be reinforcing for this illness,” Dr. Lutter said.

EurekAlert! Medicine
June 24, 2008

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Testosterone turns birds into bad parents

The spotless starlings of the western Mediterranean compete ruthlessly for nesting sites, and can be killed or seriously injured as a result. When Jose Veiga and Vicente Polo at Spain’s National Museum of Natural Sciences in Madrid placed testosterone implants in 30 female starlings they found that these birds tended to be better at acquiring and holding onto their nests, but took less care of their young. High levels of testosterone may work to a female’s advantage where competition for nesting sites is fierce, the authors suggest, but reduce reproductive success elsewhere. The research will be published in a forthcoming issue of The American Naturalist.

New Scientist
May 13, 2008

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Why synthetic estrogens wreak havoc on reproductive system

Researchers at Yale School of Medicine now have a clearer understanding of why synthetic estrogens such as those found in many widely-used plastics have a detrimental effect on a developing fetus, cause fertility problems, as well as vaginal and breast cancers. The study was led by Hugh S. Taylor, M.D., professor in the Department of Obstetrics, Gynecology & Reproductive Science and section chief of Reproductive Endocrinology and Infertility at Yale School of Medicine. Past research shows that exposure to the synthetic estrogen diethylstilbestrol (DES) alters the expression of HOXA10, a gene necessary for uterine development, and increases the risk of cancer and pregnancy complications in female offspring. The team sought to understand why a developing female fetus exposed to DES might develop uterine cancer and other problems years after exposure. Even though DES is no longer on the market, the authors chose to study its effects to gain insight into how similar synthetic estrogens might work.

The team studied DNA from the offspring of 30 pregnant mice injected with DES. They found changes in certain regions of the HOXA10 gene. These alterations continued beyond the time of development and persisted into adulthood, indicating that exposure to DES and similar substances results in lasting genetic memory, known as “imprinting.” “We found that HOXA 10 protein expression was shifted to the bottom portion of the uterus in the female offspring,” said Taylor. “We also found increased amounts of the enzyme responsible for changes in the DNA. Rather than just changing how much of the protein is there, DES is actually changing the structure of the HOXA 10 gene. “These findings bring us closer to understanding the way in which DES interacts with the developing reproductive system,” said Taylor. Pregnant women are frequently exposed to other similar substances with estrogen-like properties, such as Bisphenol-A (BPA). BPA is found in common household plastics and has recently been linked to long-term fertility problems. Like DES, these other substances may also impact female reproductive tract development and the future fertility of female fetuses.

Science Daily
April 15, 2008

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Fish devastated by sex-changing chemicals in municipal wastewater

While most people understand the dangers of flushing toxic chemicals into the ecosystem through municipal sewer systems, one potentially devastating threat to wild fish populations comes from an unlikely source: estrogen. After an exhaustive seven-year research effort, Canadian biologists found that miniscule amounts of estrogen present in municipal wastewater discharges can decimate wild fish populations living downstream. The research, led by Dr. Karen Kidd, an NSERC-funded biology professor at the University of New Brunswick (Saint John) and the Canadian Rivers Institute, confirms that synthetic estrogen used in birth control pills can wreak havoc on the sex lives of fish. Small amounts of estrogen are excreted naturally by women whether or not they are taking birth control pills.

Male fish exposed to estrogen become feminized, producing egg protein normally synthesized by females. In female fish, estrogen often retards normal sexual maturation, including egg production. “We’ve known for some time that estrogen can adversely affect the reproductive health of fish, but ours was the first study to show the long-term impact on the sustainability of wild fish populations,” explains Kidd. “What we demonstrated is that estrogen can wipe out entire populations of small fish — a key food source for larger fish whose survival could in turn be threatened over the longer term.” Kidd and her colleagues reported the findings last year in the Proceedings of the National Academy of Sciences of the United States of America. She is also presenting the research at the prestigious 2008 American Association for the Advancement of Science (AAAS) Conference during a session entitled, From Kitchen Sinks to Ocean Basins: Emerging Chemical Contaminants and Human Health.

Estrogen is part of a broader class of sex-changing chemical compounds known as endocrine disrupting substances. These contaminants, also present in pulp mill effluents, can seriously interfere with normal hormonal processes, notes Kidd, the Canada Research Chair in Chemical Contamination of Food Webs. To better understand the impacts of estrogen on fish, the researchers conducted a seven-year, whole-lake study at the Experimental Lakes Area in northwestern Ontario. Over three summers, they added tiny amounts — low parts per trillion — of the synthetic estrogen used in birth control pills to the lake to recreate concentrations measured in municipal wastewater. During that period, they observed that chronic exposure to estrogen led to the near extinction of the lake’s fathead minnow population as well significant declines in larger fish, such as pearl dace and lake trout.

“Generally, the smaller the fish, the more vulnerable they are to estrogen,” remarks Kidd. Part of the reason, she adds, is that smaller fish have a shorter lifespan and will often die after reproducing only once. The researchers used synthetic estrogen because it tends to persist longer in the environment than natural estrogens. Yet the problem with estrogen is not its environmental persistence but rather its persistent discharge in municipal wastewater into surface waters. Kidd says the risk is greatest for aquatic ecosystems downstream from municipalities that either discharge untreated wastewater or maintain only primary treatment facilities. On the flipside, the problem is of less concern near cities that remove a wide range of chemical contaminants, including estrogens, from wastewater using secondary and tertiary treatment processes. It is now understood, she says, that removing estrogen through wastewater treatment can reverse the adverse impact of this substance/hormone on wild fish. In fact, three years after halting additions of synthetic estrogen to the experimental lake, the researchers discovered that the fathead minnow population was on the rebound.

Science Daily
March 4, 2008

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Hurt an organ, help a disease?

Researchers report that by injuring an animal’s pancreas, they have found a population of cells that naturally become insulin-producers. It’s not clear whether the find will impact diabetes patients, but researchers are intrigued by the discovery and what it might reveal about the transformative ability of pancreatic cells. In people with diabetes, insulin-producing cells in the pancreas, called beta cells, have been destroyed or may behave sluggishly. This leaves the body unable to regulate its blood sugar. Coaxing the pancreas to make new beta cells is one of the great goals of diabetes research. Scientists debated for years whether the pancreas holds stem cells that could replenish beta cells, but in 2004, biologists led by Douglas Melton at Harvard looked for these stem cells in the pancreas of mice and failed to find them. His team instead reported that existing beta cells could multiply to form new ones (ScienceNOW, 5 May 2004). Harry Heimberg of Vrije Universiteit in Brussels, Belgium, wondered whether there were additional sources of new beta cells. Earlier experiments in rats had found that clamping a pancreatic duct and stopping digestive enzymes from entering the small intestine roughly doubles the mass of beta cells in the pancreas. But which cells in the pancreas were generating these extra beta cells?

Heimberg and his colleagues caused the same severe injury in mice. Then they searched for pancreatic cells that might somehow turn into beta cells. To do this, they focused on the genetic marker neurogenin 3, which appears in cells slated to become beta cells when they’re just beginning to develop in an embryo. Within 3 days of injury, the scientists found cells with this gene. Furthermore, preventing the gene’s expression reduced beta-cell proliferation, the group reports in the 25 January issue of Cell. When these neurogenin 3 cells were taken from an adult mouse and injected into a pancreas removed from a mouse embryo, they developed into beta cells and produced insulin, suggesting that the cells were developing into new beta cells in the injured animal. Further studies found that the neurogenin 3 cells weren’t making insulin before the injury. That means beta cells hadn’t bolstered the beta-cell supply by themselves, as Melton had shown was possible in normal animals.

Many questions remain. Where do the cells come from, for example? The cells sit along the ducts of the organ, so they could originate as mature ductal cells that revert to an embryonic state after the injury and then become beta cells. Or, says Heimberg, they could be progenitor cells, which unlike stem cells cannot self-replenish. Other big questions are whether the neurogenin 3 cells can be coaxed to come forward in the normal human pancreas without damaging the organ, and whether they can be turned into insulin producers. Melton suspects the cells began as mature pancreatic cells, likely from the ducts, as they don’t have many characteristics of stem cells. The study, he says, shows that there’s another mechanism to keep beta cells coming, which might offer a new cell source to consider in the hunt for ways to replenish beta cells.

ScienceNow
February 5, 2008

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Understanding role of stress in just about everything

Stress, to put it bluntly, is bad for you. It can kill you, in fact. A study now reveals that stress causes deterioration in everything from your gums to your heart and can make you more susceptible to everything from the common cold to cancer. Thanks to new research crossing the disciplines of psychology, medicine, neuroscience, and genetics, the mechanisms underlying the connection are rapidly becoming understood. The first clues to the link between stress and health were provided in the 1930s by Hans Selye, the first scientist to apply the word “stress”– then simply an engineering term– to the strains experienced by living organisms in their struggles to adapt and cope with changing environments. One of Selye’s major discoveries was that the stress hormone cortisol had a long-term effect on the health of rats.

Cortisol has been considered one of the main culprits in the stress-illness connection, although it plays a necessary role in helping us cope with threats. When an animal perceives danger, a system kicks into gear: A chain reaction of signals releases various hormones — most notably epinephrine (“adrenaline”), norepinephrine, and cortisol — from the adrenal glands above each kidney. These hormones boost heart rate, increase respiration, and increase the availability of glucose (cellular fuel) in the blood, thereby enabling the famous “fight or flight” reaction. Because these responses take a lot of energy, cortisol simultaneously tells other costly physical processes — including digestion, reproduction, physical growth, and some aspects of the immune system — to shut or slow down. When occasions to fight or flee are infrequent and threats pass quickly, the body’s stress thermostat adjusts accordingly: Cortisol levels return to baseline (it takes 40-60 minutes), the intestines resume digesting food, the sex organs kick back into gear, and the immune system resumes fighting infections. But problems occur when stresses don’t let up –or when, for various reasons, the brain continually perceives stress even if it isn’t really there.

Stress begins with the perception of danger by the brain, and it appears that continued stress can actually bias the brain to perceive more danger by altering brain structures such as those which govern the perception of and response to threat. Prolonged exposure to cortisol inhibits the growth of new neurons, and can cause increased growth of the amygdala, the portion of the brain that controls fear and other emotional responses.The end result is heightened expectation of and attention to threats in the environment. Stress hormones also inhibit neuron growth in parts of the hippocampus, a brain area essential in forming new memories. In this way, stress results in memory impairments and impairs the brain’s ability to put emotional memories in context.

These brain changes are thought by some researchers to be at the heart of the link between stress and depression — one of stress’s most devastating health consequences — as well as posttraumatic stress disorder (PTSD). Although when we think of stressors we might think of big things like abuse, illness, divorce, grieving, or getting fired, it is now known that the little things — traffic, workplace politics, noisy neighbors, a long line at the bank — can add up and have a similar impact on our well-being and our health. People who report more minor irritants in their lives also have more mental and physical health problems than those who encounter fewer hassles. And recent research shows that PTSD may be the result of stressors adding up like building blocks, remodeling the plastic brain in a cumulative rather than a once-and-for-all fashion. The idea that stress directly causes coronary heart disease has been around since the 1950s; although once controversial, the direct stress-cardiac link is now well-documented by many studies. For instance, men who faced chronic stresses at work or at home ran a 30 percent higher likelihood of dying over the course of a nine-year study; in another study, individuals reporting neglect, abuse, or other stressors in childhood were over three times as likely as nonstressed individuals to develop heart disease in adulthood. Adding insult to injury, stress may even have a selfperpetuating effect. Depression and heart disease, for example, are not only the results of stress, but also causes of (more) stress. Consequently, the chronically stressed body can appear less like a thermostat than like a wailing speaker placed too close to a microphone — a feedback loop in which the stress response goes out of control, hastening physical decline with age.

Growing evidence shows that our sensitivity to stress as adults is already “tuned,” so to speak, in infancy. Specifically, the amount of stress encountered in early life sensitizes an organism to a certain level of adversity; high levels of early life stress may result in hypersensitivity to stress later, as well as to adult depression. A history of various stressors such as abuse and neglect in early life are a common feature of those with chronic depression in adulthood, for example. At McGill University in Montreal, Michael J. Meaney and his colleagues have studied mother and infant rats, using rat maternal behavior as a model of early life stress and its later ramifications in humans. The key variable in the world of rat nurturance is licking and grooming. Offspring of rat mothers who naturally lick and groom their pups a lot are less easily startled as adults and show less fear of novel or threatening situations — in other words, less sensitivity to stress — than offspring of less nurturant mothers.

Science Daily
January 22, 2008

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New gene therapy heals growth deficiency disorder in live animal

A team of Vanderbilt researchers have demonstrated for the first time that a new type of gene therapy, called RNA interference, can heal a genetic disorder in a live animal. The study shows that RNA interference can “rescue” a strain of mouse that has been genetically engineered to express a defective human hormone that interferes with normal growth. When the gene that produces the defective human growth hormone is inserted into the mouse’s genome, it also stunts the mouse’s growth. But when a small snippet of RNA that interferes with the hormone’s production is also added, the mouse is restored to normal. “It has been very satisfying to figure out the underlying cause of this genetic disorder and then identify a way to prevent it,” says John Phillips, the David T. Karzon Professor of Pediatrics at the Vanderbilt University Medical Center, who has been studying human growth deficiency disorders since 1978. He collaborated on the research with graduate students Nikki Shariat and Robin Ryther, who are directed by Professor of Biological Sciences James G. Patton.

Growth hormone deficiency has been estimated to occur in between one in 4,000 to 10,000 children. It has a number of different causes, but one that is genetically inherited is called Isolated Growth Hormone Deficiency type II, and this is the subject of the study. Children with IGHD-II appear fairly normal at birth but do not gain weight or grow as fast as they should, and their bones do not mature properly. The current treatment consists of daily injections of growth hormone for years until the patients reach their adult height. Not only is this treatment extremely expensive, it also fails to correct the underlying source of the problem: deterioration and death of cells in the pituitary gland that produce growth hormone. As a result, this single hormone deficiency can develop into multi-hormonal deficiency over time. IGHD-II is what geneticists call a dominant negative disorder. It is caused by a defective form of human growth hormone that not only can’t stimulate growth itself but also blocks the action of normal growth hormone. “It acts like Aesop’s dog in the manger … which has no use for the hay but keeps the cows from eating,” says Phillips. Some other common dominant negative diseases include forms of colon cancer, deafness, muscular dystrophy, brittle bone disease, kidney disease and retinitis pigmentosa.

The blueprint for a protein like growth hormone is genetically encoded in a series of special segments called exons. The instructions in the exons are first copied onto a length of special RNA, called messenger-RNA. The messenger-RNA is moved to a structure in the cell called a ribosome, which links amino acids together in the order specified by the RNA sequence to create the protein. Normal growth hormone is produced by a series of five exons. The defective hormone is the result of a splicing error: It is made by combining the segments coded by the first two exons and the last two exons, mistakenly skipping the third exon. “A normal person has a very small amount of this defective hormone — about 1 percent — but people in families with IGHD-II produce 10 to 20 to 50 percent. And the more they make the slower they grow,” says Patton.

In 2003, co-author Iain Robinson at the National Institute for Medical Research in London created a transgenic mouse with the human growth hormone gene that duplicated growth hormone deficiency. Although the altered mice still contained the mouse growth hormone genes, he found that high levels of the defective human growth hormone not only stunted their growth but actually killed the cells in the pituitary that produce growth hormone. “This came as a real surprise: We never thought that a splicing error would lead to cell death,” says Patton. Meanwhile, progress in RNA interference research gave Patton and Phillips an idea for a way to correct this disorder. In the last 15 years, scientists have realized that short pieces of double-stranded RNA, called silencing-RNA, use a pathway that is normally used by cells to regulate genes. This has created an opportunity for developing highly targeted therapies for a number of genetic diseases including macular degeneration in the eye and to block viruses such as herpes and RSV respiratory viruses. “To the best of our knowledge, this is the first time it has been used to correct a dominant negative disorder in a living animal,” says Patton.

The researchers realized that the messenger-RNA that produced the defective hormone had a unique signature created by skipping the third exon. This allowed the Patton lab to create a specific silencing-RNA, designed to bind uniquely with the defective messenger-RNA. “You might call this the ‘if you don’t like the message, kill the messenger’ approach,” Phillips quips. Having created the special silencing-RNA, the next problem was how to deliver it to the pituitary gland which, in the case of the mouse, is the size of a grain of uncooked rice and is located at the base of the brain. As a proof of concept, the researchers decided to create a second strain of mouse which carried the special silencing-RNA and mate them with the growth deficiency strain. Their offspring should have both the genetic defect that produces the defective growth hormone and the silencing-RNA that should inhibit its production, allowing the mouse growth hormone to act. The experiment was successful. The offspring grew normally and showed no defects in their pituitaries.

Now the researchers are investigating ways to deliver their silencing-RNA to the pituitary gland that would be suitable for treating humans. The cells that produce growth hormone have special receptors that signal the cells to release their stocks of growth hormone. If they can figure out a way to attach the silencing-RNAs to a compound that binds to this receptor, they should be able to deliver them to the cells where they can interfere with the activity of the defective growth hormone.
Source: Endocrinology.

Science Daily
January 8, 2008

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Even mild thyroid problems double risk of heart condition

Individuals with subclinical hypothyroidism—a mildly underactive thyroid only detectable by a blood test—are twice as likely to develop heart failure, compared to those with normal thyroid levels, according to a new study. Heart failure, also called congestive heart failure, is when the heart can’t pump enough blood to the body’s other organs, which can cause fatigue, ankle swelling and shortness of breath. Although previous studies have shown that hyperthyroidism—an overactive thyroid—and hypothyroidism can cause heart problems, this is the first time that a large study found a negative effect on heart function when the thyroid was only mildly under-active. If other studies confirm these findings, then physicians might want to consider treating mild thyroid problems to prevent potential cardiac problems or to avoid increasing the severity of an existing heart condition,” said Doug Bauer, M.D., an author of the study and a Professor of Medicine, Epidemiology and Biostatistics at the University of California at San Francisco School of Medicine in San Francisco.

Subclinical thyroid disorders are detected by a blood test that evaluates the levels of thyroid-stimulating hormone (TSH). Subclinical hypothyroidism is defined by TSH levels greater than 4.5 mU/L and normal free thyroxine levels. Individuals with subclinical hypothyroidism can evolve into overt hypothyroidism, where the free thyroxine levels fall below normal, which always requires thyroid hormone therapy. The Cardiovascular Health Study involved over 3,000 adults 65 years and older, who were evaluated to determine if those individuals who had subclinical hypothyroidism had an increased risk of developing heart failure over a twelve-year period. The study shows that individuals who had a TSH level equal or greater than 10 mU/L had a two-fold risk of developing heart failure, compared to those who had normal thyroid levels.

Science Daily
October 30, 2007

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Better Type 2 diabetes treatment closer as scientists solve critical part of insulin puzzle

Scientists are now one step closer to improved treatment of Type 2 diabetes following significant findings made by scientists at Australia’s Garvan Institute of Medical Research. World-wide, more than 200 million people suffer from this disease, resulting in disability and reduced life expectancy. In Australia it affects around 7% of the population. People with Type 2 diabetes do not produce enough insulin, a hormone made in the pancreas that helps convert the sugar in our blood into energy in our muscles. Current therapies force our bodies to make more insulin, make better use of the insulin that already exists or mimic the action of insulin. But none of these therapies specifically address the reasons why insulin production fails in the first place. The team from Garvan’s Diabetes Signalling Unit, led by Associate Professor Trevor Biden and Dr Carsten Schmitz-Peiffer, has identified an enzyme known as “PKCepsilon” (PKCe) that is active during diabetes and blocks the availability of insulin. Their findings are published in the journal Cell Metabolism.

“In PKCe, we believe we’ve identified a very important biological target that will enable us to address one of the major underlying causes of diabetes,” said Biden. “The next step is to develop a targeted pharmaceutical that will inhibit PKCe and allow the insulin producing cells of the pancreas to do their job.” “While current therapies can force the body to produce more insulin, no existing drug does what a PKCe inhibitor would do, and that is to act only on the diabetic pancreas, allowing it to produce insulin when most needed, just as glucose levels rise after a meal. In other words, we’d be restoring normal function.” Biden and Schmitz-Peiffer have been studying the relationship between fat oversupply and Type 2 diabetes for many years. Far from being an inert substance, fat contains molecules that bring about complex changes in the way our bodies produce and use insulin. Specifically, fat molecules reduce the ability of muscle cells to respond to insulin, a phenomenon known as ‘insulin resistance’. Most of us cope with this by producing more insulin, but people who develop diabetes can’t, probably because fat molecules also disrupt the glucose-sensitive, insulin-producing (‘beta’) cells in their pancreas.

“Our recent research shows that absence of PKCe restores the capacity of the pancreas to produce insulin, a result we were not expecting,” said Schmitz-Peiffer. “Genetically modified mice, without PKCe, were fed high fat diets and became fat and insulin resistant but failed to develop diabetes. Instead, they produced extra insulin.” “What this tells us is that we will be able to protect people at high risk of developing diabetes from losing the ability to produce insulin. Blocking PKCe won’t stop them from becoming insulin resistant, but it will restore their capacity to compensate. Fine-tuning insulin production in this way is a big advance on current drugs targeting the pancreas, which can overstimulate beta cells and so reduce the effectiveness of insulin.” “In the world of diabetes research, this is a ground-breaking discovery. It’s like slotting in a critical part of a jigsaw puzzle, a part that suddenly makes the whole picture much clearer.” The work of Trevor Biden and Carsten Schmitz-Peiffer forms part of a large Diabetes and Obesity research program at Garvan, in which clinicians and scientists work together to investigate the complexities of a disease that is affecting increasingly larger proportions of the world’s population.

Science Daily
October 16, 2007

Original web page at Science Daily

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Accuracy of thyroid hormone testing improved with state-of-the-art test

Researchers at Georgetown University Medical Center have developed a fast and accurate way to measure a major hormone released by the thyroid gland — an advance they say may help in the treatment of many women who have overactive or underactive thyroid glands. According to the American Association of Clinical Endocrinologists, approximately 27 million Americans have thyroid glands that produce too little of the hormone, thyroxine, a condition known as hypothyroidism, or else the gland produces too much, known as hyperthyroidism. Thyroxine regulates the body’s metabolism, and hypothyroidism, associated with fatigue and weight gain, is much more common than hyperthyroidism, characterized by weight loss. More than eight out of 10 patients with thyroid disease are women, and nearly one out of 50 women in the United States is diagnosed with hypothyroidism during pregnancy.

In order to treat these conditions, physicians need to know how much synthetic thyroxine to either give patients or how much natural hormone should be blocked, and there have long been concerns that the common “immunoassay” test now in use worldwide is neither specific nor very accurate. To date, the immunoassay test has been used to measure those levels in women known to have abnormal levels of thyroid function based on a screening test. In this study, published in the April issue of the journal Thyroid, the researchers tested the method they had developed and found that it was far superior to the immunoassay, and just as good as a very expensive, time-consuming, but very accurate laboratory analysis that is less commonly used. “This is a very specific test and is not plagued by the false readings that make the currently used immunoassay test notoriously inaccurate,” said one of the study’s investigators, Jacqueline Jonklaas, M.D., Ph.D., assistant professor in the Department of Medicine. “After further confirming studies, we believe this new assay will become the test of choice in most clinical situations.”

The test to measure thyroid hormones, which uses tandem mass spectrometry, was developed by Steven Soldin, Ph.D. FACB, a professor at Georgetown University Medical Center in the Departments of Medicine, Pharmacology and Oncology and Director of both the Georgetown Bioanalytical Core Laboratory and Children’s National Medical Center Chemistry Laboratory. Soldin came to GUMC in 2002 to design such state-of-the-art tests, and now, versions of the same tandem mass spectrometry technology that can measure free thyroxine (FT4) levels in blood are already in use at a number of medical centers, says Dr. Soldin, a co-author. In this study, researchers tested the ability of their new test to measure thyroxine in blood by enrolling 98 pregnant women as well as 29 women who were not pregnant. Measuring the hormone in pregnant women can be tricky, the researchers say, because some conditions that may be present (high levels of binding proteins and certain antibodies) can affect immunoassay performance.

Thyroxine output dramatically changes during pregnancy in order to support development of the fetus. Thyroxine helps control metabolism and physical development, and because a fetus does not develop its own supply until the second trimester, it is crucial that pregnant women have adequate supplies in the first trimester, investigators say. The investigators used three different tests — immunoassay, the Georgetown tandem mass spectrometry, and the “gold standard” laboratory test known as equilibrium dialysis — to measure the hormone in blood samples donated by the volunteers. They found that, across all stages of pregnancy, there was almost total agreement between mass spectrometry and equilibrium dialysis, but immunoassay results differed significantly. “Pregnancy is the most difficult situation in which to measure thyroxine, and if this test can perform so well in these conditions, it can likely be used for all other clinical needs,” Jonklaas said.

One major use of such a test would be to help guide treatment of people with hypothyroidism or hyperthyroidism, Jonklaas said. Physicians diagnose these conditions using a test that measures thyroid-stimulating hormone (TSH), a hormone released by the pituitary gland which stimulates the thyroid gland to secrete thyroxine. When TSH is high, levels of thyroxine are low, and vice versa. But after the condition is diagnosed, doctors have used the immunoassay to determine what level of thyroxine should be supplemented or repressed. “We think our treatment of hyperthyroidism and hypothyroidism would be much more accurate if we combined TSH testing with tandem mass spectrometry instead of with the immunoassay,” Jonklaas said. The reason the mass spectrometry test is so accurate is because it measures the thyroxine molecule specifically and uses a filtering system to separate out the “free” thyroxine –the form that is active–from deactivated thyroxine that is bound to proteins, Soldin said. The direct/analogue immunoassay test, on the other hand, doesn’t separate the two forms, but uses a mathematical formula to come up with a result, he said. “It is so cheap and quick to use, but it provides a number that can be wrong almost half the time.”

Science Daily Health & Medicine
September 4, 2007

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Dog contraceptive signals end to castration

Male dogs can breathe a sigh of relief. The days of removing their testicles to stop them breeding or to curb aggressive behaviour may be numbered. A contraceptive implant that halts testosterone and sperm production for months at a time is expected to gain European approval within weeks, while steps are being taken to enable the drug to be sold in the US. Both egg and sperm production are controlled by the release of sex hormones from the pituitary gland, which is in turn controlled by gonadotrophin releasing hormone (GnRH). The implant, developed by Peptech in Macquarie Park, Australia, contains a drug called deslorelin or Suprelorin, which binds to GnRH receptors and overstimulates them so that they become desensitised to the hormone. As well as making the dogs temporarily infertile, deslorelin blocks testosterone production, curtailing aggressive behaviour. “It’s reversible,” says Katie Yeates of Peptech. “It gives you the option of breeding later.”

A six-month implant was launched in Australia in late 2004, where it costs between AUS$60 and AU$90 a dose ($52 to $77). Peptech recently launched a 12-month implant and is now developing similar implants for cats and female dogs. David McDowell, veterinary consultant for the UK’s Royal Society for the Prevention of Cruelty to Animals, says while oral contraceptives have been used in female cats for years, long-term use may stimulate breast tumours or uterus infections. Although the new implants work through a different mechanism, he fears similar side effects may be associated with long-term use in dogs. “Provided owners use them within the manufacturers’ guidelines, we would welcome the new drug,” he says. “However, if dog owners don’t want to use their pet for breeding, we believe neutering is the best option.”

New Scientist
August 21, 2007

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Estrogen therapy gives aging brain cells a boost

Cyclical, long-term estrogen injections protected brain cells from age-related deterioration, according to a new study conducted at Mount Sinai School of Medicine. The study suggests that age is a factor in estrogen treatment and sheds light on the intricate relationship between mind, age, and hormones. In a multi-center study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. Working with colleagues from the University of Toronto and the University of California-Davis, Drs. Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovarectomized, which induced menopause: old monkeys that received estrogen, old monkeys that did not receive estrogen, young monkeys that received estrogen, and young monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.

Cognitive performance tests showed the older treated animals performed almost as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause–before the onset of full menopause–and began treatment within months of ovariectomy. Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex–a region of the brain associated with cognitive tasks that Dr. Rapp used to test the monkeys–the older estrogen-treated animals showed a greater density of synaptic spines–tentacle-like structures that link brain cells to one another and aid in brain cell communication–while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.

The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Dr. Morrison. “There’s been a great deal of confusion as to whether estrogen helps or harms post-menopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful.” Dr. Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline. “We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline,” Dr. Morrison explains. “Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything.” “The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity, says Dr. Morrison. “Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories.”

The younger animals retain neural plasticity in the absence of estrogen, Dr. Morrison explains, “but what’s happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit.” Rhesus monkeys undergo menstrual cycles and a menopause that closely mimics those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to very old monkeys would result in less benefit. “It’s possible a middle-aged brain reacts differently to estrogen than a young brain, and that a very old brain might not react to estrogen at all,” Dr. Morrison explains, “so this window of opportunity may be fairly narrow–we just don’t know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it’s too late, we may possibly prevent memory loss.” What is also unclear, Dr. Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment. Drs. Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovarectomized, so that the aging process is more natural and not acutely induced.

Science Daily
July 24, 2007

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Estrogen feminized male fathead minnows (above) and caused a population crash

All across the world, people are polluting waterways with estrogen. Excreted in urine, the hormone passes through most wastewater plants and ends up in streams and lakes, where some studies suggest it is feminizing male fish. Now a large experiment has shown that even a very low level of estrogen in a lake can cause enough reproductive harm to wipe out an entire population of minnows in 2 years. Extra estrogen isn’t good for male fish. Laboratory studies have shown that chronic exposure to low doses causes males to produce eggs in their testes and takes away their secondary sex characteristics, such as darker coloration and tubercules on their noses. The big question was what those levels mean for populations in the wild. To find out, researchers led by Karen Kidd of the University of New Brunswick, Canada, performed an experiment in a lake in western Ontario. Each summer for 3 years, they spiked the lake with a few parts per trillion of 17α-ethynylestradiol–the active ingredient in birth-control pills–in concentrations like those found in streams and lakes elsewhere. The experiment took place in a remote area set aside for research.

Within weeks of the first doses, male minnows started making vitellogenin, a protein that helps eggs mature in females. They wound up with levels 8000 to 10,000 times normal. (Females increased production to 8 to 80 times their usual levels, and the estrogen somehow slowed egg development.) Sexual development was delayed in the males, and fewer and fewer fish were found; apparently, the fish had stopped reproducing. After the second year, the researchers couldn’t find any fathead minnow nests. “We didn’t expect to see such a dramatic and quick response,” Kidd says. It took more than 2 years after researchers stopped adding estrogen for the population to begin to recover. Other male fish in the lake, such as suckers and trout, also produced vitellogenin, but their populations were not as hard hit, presumably because these larger species have longer natural life spans. However, chronic exposure might cause similar effects, the researchers speculate.

“These are dire consequences,” says Dave Epel of Stanford University in Palo Alto, California. “This is a red flag.” But it is difficult to gauge the impact of estrogen on populations of fathead minnows across North America, Kidd notes. The fish are still found in rivers receiving treated sewage, so apparently some populations survive the hormonal onslaught. And without baseline data, it’s impossible to know whether populations have fallen. Still, given the wide range of fish affected by estrogen, Kidd says it would be prudent for cities to adopt modern treatment systems that remove up to 95% of the estrogen.

ScienceNow
June 12, 2007

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Androgen responsive intronic non-coding RNAs

Transcription of large numbers of non-coding RNAs originating from intronic regions of human genes has been recently reported, but mechanisms governing their biosynthesis and biological functions are largely unknown. In this work, we evaluated the existence of a common mechanism of transcription regulation shared by protein-coding mRNAs and intronic RNAs by measuring the effect of androgen on the transcriptional profile of a prostate cancer cell line.

Using a custom-built cDNA microarray enriched in intronic transcribed sequences, we found 39 intronic non-coding RNAs for which levels were significantly regulated by androgen exposure. Orientation-specific reverse transcription-PCR indicated that 10 of the 13 were transcribed in the antisense direction. These transcripts are long (0.5–5 kb), unspliced and apparently do not code for proteins. Interestingly, we found that the relative levels of androgen-regulated intronic transcripts could be correlated with the levels of the corresponding protein-coding gene (asGAS6 and asDNAJC3) or with the alternative usage of exons (asKDELR2 and asITGA6) in the corresponding protein-coding transcripts. Binding of the androgen receptor to a putative regulatory region upstream from asMYO5A, an androgen-regulated antisense intronic transcript, was confirmed by chromatin immunoprecipitation.

Altogether, these results indicate that at least a fraction of naturally transcribed intronic non-coding RNAs may be regulated by common physiological signals such as hormones, and further corroborate the notion that the intronic complement of the transcriptome play functional roles in the human gene-expression program.

BioMed Central
March 6, 2007

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More cloned puppies born

More cloned puppies have been born to the lab formerly associated with South Korean cloner Woo Suk Hwang. Hwang left his job at Seoul National University this year after an investigation found that he had faked data in papers on cloning human embryos for the derivation of stem cells. Those papers were retracted, and Hwang is facing criminal charges associated with his work. But many of his former colleagues are continuing with cloning research. One team of researchers at Seoul National University, which only partially overlaps with those named on Hwang’s human cloning papers, previously succeeded in producing the world’s first cloned dog: Snuppy, an Afghan hound born from an adult skin cell. Now that same group — minus Hwang and with a few other changes to the team — has produced three more dog clones, they report in the veterinary journal Theriogenology. The puppies, named Bona, Peace and Hope, were born this June and July, the team said in a news conference. Like Snuppy, the dogs are also Afghan hounds, but unlike Snuppy they are female. The achievement confirms that it is just as possible to clone female pups as male ones, notes the team, and shows that the efficiency of canine cloning can be improved.

At the time that Snuppy was announced to the world, researchers were impressed by the technical achievement in cloning a dog — a task known to be technically possible but notoriously difficult. If the efficiency of the process could be radically improved and a kennel of cloned dogs produced then it could one day be used to help study models of human disease. Lead researcher Byeong Chun Lee says that the team has improved the efficiency of the cloning technique. In the current work, the team transplanted 167 cloned embryos into 12 carrier females to produce 3 live pups. Previously, the team transplanted 1,095 cloned embryos into 123 carrier females and produced two pups: Snuppy and another dog that died soon after birth. A leap in efficiency was similarly claimed between Hwang’s two human embryo cloning papers, with the first published in 2004 and the second in 2005.

“Both are huge improvements in a short time frame,” says Christopher Scott, executive director of the Program on Stem Cells and Society at the Stanford Center for Biomedical Ethics in Palo Alto, California. He says he will remain unconvinced by the claimed efficiency boost until there is independent confirmation of the technique. Other scientists say the achievement is plausible, because this is where the team’s expertise lies. “They’re very good at producing animal clones,” said Arthur Kriegstein, director of the Program in Developmental and Stem Cell Biology at the University of California, San Francisco.

Nature
January 9, 2007

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Testosterone gives male birds their color

New research suggests that as testosterone in male birds increases, so does the level of carotenoids, the chemicals that create the bright coloring on birds’ feathers, beaks, and legs. The brilliant reds, yellows, and oranges serve as indicators of sexual competitiveness, signaling to females that the bearer is healthy and a potentially good mate. Scientists already knew that testosterone in male birds brings out their macho best, making them sing more sweetly and court with added vigor—other key indicators of males’ health and sexual appeal. But until now the relationship between bird coloring and testosterone had eluded biologists. Researcher Julio Blas, a biologist at the University of Saskatchewan in Saskatoon, Canada, and colleagues decided to tackle the issue through experiments in Spain with native red-legged partridges.

Blas’s team increased the testosterone of male partridges during the mating season and saw a 20 percent rise in carotenoids—which birds get from food such as berries and insects—in their blood and livers. “A bird in good shape should be colorful and also should sing more,” said Blas, whose research appears this week in the journal Proceedings of the National Academy of Sciences. “Until now these lines of evidence have been researched independently of each other. What we did is connect these two lines of research.” The finding could solve another outstanding puzzle. High levels of testosterone come with a price, as the hormone usually depresses the immune system, increasing birds’ susceptibility to disease. But recent studies have shown that birds manipulated in the lab to have high testosterone could still have robust immune systems. The link between testosterone and carotenoids may be the answer, Blas says. Carotenoids help build vitamins and are strong antioxidants—chemicals that help animals detoxify harmful molecules called free radicals. In short, carotenoids appear to compensate for the effect of testosterone by keeping the immune system strong.

Sick male birds have dull coloring. This is probably because the carotenoids are being used by the struggling bird’s immune system in an effort to fight off disease, Blas says. “When a chicken becomes sick, its yellow legs become paler,” he said. “Why? Because it is using its carotenoids to fight illness.” But birds that are in good shape can have it all—elevated testosterone, a healthy immune system, and large deposits of color-carrying carotenoids in their legs, beaks, and feathers. “It may be that only the really high-quality individuals can withstand the immunosuppressive effect of testosterone,” said Lynn Siefferman, a biologist at Indiana University in Bloomington who studies bluebirds, feather color, and testosterone. “The idea is that they will put health before reproduction” and not mate, she said.

National Geographic
December 19, 2006

Original web page at National Geographic

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Hormone resistance of pituitary tumors and Cushing disease explained

Montréal scientists led by Dr Jacques Drouin, researcher at the Institut de recherches cliniques de Montréal (IRCM), and collaborators from around the world (Canada, France, the Netherlands and United States) unravel mechanism of hormone resistance in pituitary tumors of Cushing disease patients. Cushing disease is caused by pituitary tumors that produce excessive amounts of hormone because the tumor cells have become resistant to negative feedback control by a class of steroid hormones, glucocorticoids. In Cushing disease, this excessive hormone production can lead to hypertension, obesity, diabetes and osteoporosis.

Through detailed molecular investigation of the mechanism of this negative feedback, a Montréal research group has identified two essential components (proteins) of this feedback mechanism. Extrapolating from these basic studies, they have shown that about half of the pituitary tumors from Cushing disease patients are deficient in expression of either of these proteins, thus providing a molecular explanation for the hormone resistance that is the hallmark, and likely first event, in the formation of these tumors. The novel insight provided by knowledge of the basic mechanism of hormone resistance will lead to the rational design of therapeutic approaches for the better management of Cushing disease patients. This insight will also help understand other forms of hormone resistant cancers.

Science Daily
November 6, 2006

Original web page at Science Daily

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Progesterone shows promise as treatment for traumatic brain injuries

Emory University researchers have found that giving progesterone to trauma victims shortly following brain injury appears to be safe and may reduce the risk of death and the degree of disability. The results of this study–the first clinical trial of its kind in the world–will be available online in the journal Annals of Emergency Medicine. Researchers say the next step will be to confirm their findings in a much larger group of traumatic brain injury (TBI) patients. “Progesterone treatment for TBI has been extensively studied in laboratory animals for more than 15 years, but this is the world’s first use of progesterone to treat brain injury in humans,” says Arthur Kellermann, MD, MPH, professor and chair of the Department of Emergency Medicine, Emory University School of Medicine and a co-author of the study. “Emory scientist Donald Stein was the first to discover that progesterone has neuroprotective effects, and much of the foundational work on progesterone for TBI was from his laboratory. Their results were so impressive, that we felt it was time to take this treatment to the bedside for testing in patients who had suffered a serious brain injury. We are grateful to the National Institute of Neurological Disorders and Stroke (a division of the National Institutes of Health) for their support of this work,” says Kellermann.

Approximately 1.5 to 2 million people in the U.S. sustain a TBI each year, leading to 50,000 deaths and 80,000 new cases of long-term disability. It is also a major cause of death and disability among children and military personnel. Despite the enormity of the problem, scientists have failed to identify effective medications to improve outcomes following a TBI. In fact, no new medical therapies have been developed for traumatic brain injuries in over 30 years. Emory’s researchers designed a clinical trial to assess the promise of progesterone for treatment of TBI. Their three-year pilot study, called ProTECT (which stands for “Progesterone for Traumatic brain injury–Experimental Clinical Treatment”), enrolled 100 participants. Their phase II study was primarily designed to evaluate whether progesterone can be administered intravenously in a reliable way, and whether the treatment is safe to use in humans with TBI. The researchers also hoped to find preliminary evidence that the treatment might be effective.

Although it is widely considered a “sex steroid,” progesterone is also a neurosteroid that exerts protective effects on human tissue. It is naturally present in small but measurable amounts in the brains of males and females. Laboratory studies suggest that progesterone is critical for the normal development of neurons in the brain and exerts protective effects on damaged brain tissue. Study participants were enrolled at Grady Memorial Hospital (the site of the study because it is Atlanta’s only Level 1 Trauma Center). To be a candidate for the study, patients had to reach the hospital within 11 hours of injury. People enrolled in the study had a “blunt” traumatic brain injury, which typically occurs from a car accident, motorcycle crash or a fall. Enrolled patients had an initial Glasgow Coma Scale (GCS) score ranging between 4 and 12. The GCS is a widely used scale that quantifies the initial level of impairment from a TBI. A score of 4-8 signals severe TBI, usually accompanied by coma, while a score of 8-12 signals a moderate TBI.

Because study candidates were cognitively impaired, their family members or other legal representatives were asked to give proxy consent for enrollment in the study. Four out of every five patients (80 percent) enrolled received intravenous progesterone, and one of every five (20 percent) received placebo. Patients, family members, doctors nor study staff knew which participants received progesterone or placebo until the study was completed. Thirty days after injury, objective rating scales were used to assess each participant’s neurological function and level of disability.

In an earlier paper, the researchers reported that progesterone can be reliably given intravenously and achieve predictable levels in the bloodstream. The new paper reports the team’s findings about drug safety and effectiveness. “We found encouraging evidence that progesterone is safe in the setting of TBI, with no evidence of side effects or serious harmful events,” says David Wright, MD, assistant professor in the Department of Emergency Medicine at Emory and lead author of the study. “In addition, we found a 50 percent reduction in the rate of death in the progesterone-treated group. Furthermore, we found a significant improvement in the functional outcome and level of disability among patients who were enrolled with a moderate brain injury.” The researchers evaluated disability using the Disability Rating Scale, an objective measurement tool, and assessed functional outcome using the highly validated Glasgow Outcome Scale.

The researchers found no significant differences in the rate of adverse events among patients who received progesterone compared to those who received placebo. About 30 percent of patients given placebo died within 30 days of head injury, compared to only 13 percent of those given progesterone. Most patients who died had a severe TBI. Because more severe TBI patients in the progesterone group survived, it is not surprising that they had a higher average level of disability at 30 days than survivors in the placebo group. One-year outcomes will be reported at a later date. Progesterone is a promising treatment because it is inexpensive, widely available and has a long track record of safe use in humans to treat other diseases. The team previously reported that IV progesterone can be easily administered in an arm or hand vein rather than through a central IV line in the neck, chest or groin.

The research team is now planning a large, multi-center, phase III clinical trial designed to test the effectiveness of progesterone in 1000 patients with TBI and hopes to secure funding from the NIH for this project. They also hope to study the effects of progesterone treatment in animal models of blast-related brain injury, a major cause of death among combat personnel. They plan to implement a study of progesterone to treat pediatric brain injury as well, because brain injury is a leading cause of death and disability in children.

Science Daily Health & Medicine
October 24, 2006

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Low testosterone levels associated with increased risk of death in men

Men who have a low testosterone level after age 40 may have a higher risk of death over a four-year period than those with normal levels of the hormone, according to a report in the August 14/28 issue of Archives of Internal Medicine, one of the JAMA/Archives journals. Unlike women undergoing menopause, middle-aged men generally do not experience a dramatic decrease in the production of sex hormones, according to background information in the article. Testosterone levels gradually decline as a man ages, decreasing approximately 1.5 percent per year after age 30. The effects of low testosterone levels include decreased muscle mass and bone density, insulin resistance, decreased sex drive, less energy, irritability and feelings of depression.

Molly M. Shores, M.D., and colleagues at the VA Puget Sound Health Care System and University of Washington, Seattle, studied the relationship between hormone levels and death in a total of 858 male veterans older than age 40 years. All participants received care in the VA Puget Sound Health Care System and had their testosterone levels checked at least twice between 1994 and 1999, with at least one week and no more than two years elapsing between tests. The men were followed for an average of 4.3 years and a maximum of eight years, through 2002. About 19 percent (166) of the men had a low testosterone level; 28 percent (240) had an equivocal testosterone level, meaning that their tests revealed an equal number of low and normal levels; and 53 percent (452) had normal testosterone levels. One-fifth (20.1 percent) of the men with normal testosterone levels died during the course of the study, compared with 24.6 percent of men with equivocal levels and 34.9 percent of those with low levels. Men with low testosterone levels had an 88 percent increase in risk of death compared with those who had normal levels. When the researchers considered other variables that may influence risk of death, such as age, other illnesses and body mass index, the association between low testosterone levels and death persisted.

Previous studies have found that testosterone levels may dramatically decrease one to two days after surgery, trauma or critical illness–all factors that can increase the risk of death. To eliminate these effects, the authors reanalyzed the data excluding men who had died within the first year of follow-up. Men with low testosterone levels were still 68 percent more likely to have died. “The persistence of elevated mortality risk after excluding early deaths suggests that the association between low testosterone and mortality is not simply due to acute illness,” they write. “Large prospective studies are needed to clarify the association between low testosterone levels and mortality.” (Arch Intern Med. 2006;166:1660-1665).

Science Daily
August 29, 2006

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Fat-generated hormone drives energetic capacity of muscle

The fat-generated hormone adiponectin plays an important role in the energetic capacity of skeletal muscle, according to a new study in the July, 2006, Cell Metabolism, published by Cell Press. Adiponectin is unusual among fat hormones in that its levels generally decline in those who are obese. The researchers report evidence in people and mice, linking low adiponectin levels to insulin resistance and reductions in the number of “cellular power plants” called mitochondria in skeletal muscle. The findings suggest that therapies designed to boost the adiponectin signal might prove beneficial for the treatment of insulin resistance and diabetes, they said.

“We have discovered a skeletal muscle pathway by which adiponectin increases mitochondrial number and function and exerts antidiabetic effects,” said lead author Anthony Civitarese from Pennington Biomedical Research Center in Baton Rouge, Louisiana. Mitochondria utilize nutrient components, including fats and carbohydrates, to generate usable energy. The number of mitochondria therefore influences the way that muscles function. For example, people who exercise regularly have more mitochondria in their muscles than do those who are sedentary. Earlier studies found that obese individuals and those with type 2 diabetes have reduced adiponectin concentrations, the researchers said. The new study examined the effects of that reduced adiponectin on skeletal muscle. The researchers first examined children whose parents had type 2 diabetes and those with no family history of the disease. Muscle taken from individuals prone to diabetes was insulin resistant and had lower than normal concentrations of mitochondrial enzymes, suggesting some dysfunction, they found. The level of adiponectin also correlated with the estimated number of mitochondria in the muscle samples.

Further study of adiponectin-deficient mice similarly found that the animals were resistant to insulin and exhibited deficits in mitochondria in their skeletal muscles. Finally, the researchers showed that adiponectin treatment of human muscle tissue in culture sparked the production of mitochondria. The treatment also limited the production of harmful free radicals, or reactive oxygen species, a sign that the mitochondria were operating more efficiently. The current findings, together with earlier studies that showed that adiponectin increases glucose uptake from the blood stream, suggest that the hormone might have therapeutic potential for those with insulin resistance or type 2 diabetes, Civitarese said. However, adiponectin itself is difficult to produce in the quantities that would be required for a drug, he added. “It may be that a mimetic drug that acts like adiponectin might prove beneficial,” he said.

Science Daily
August 1, 2006

Original web page at Science Daily

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Primate center research suggests multiple ‘body clocks’

Research conducted at Oregon Health & Science University suggests that contrary to popular belief, the body has more than one “body clock.” The previously known master body clock resides in a part of the brain called the suprachiasmatic nucleus (SCN). Researchers at OHSU’s Oregon National Primate Research Center (ONPRC) have now revealed the existence of a secondary clock-like mechanism associated with the adrenal gland. The research also suggests a high likelihood that additional clocks exist in the body. The study results are printed in the current edition of the journal Molecular Endocrinology.

“We’re all familiar with the idea that the body has a master clock that controls sleep-wake cycles. In fact, most of us have witnessed the impacts of this clock in the form of jet lag where it takes the body a number of days to adjust to a new time schedule following a long flight,” explained Henryk Urbanski, Ph.D., senior author of the study and a senior scientist at ONPRC. “Our latest research suggests that a separate but likely related clock resides in the adrenal gland. The adrenal gland is involved in several important body functions, such as body temperature regulation, metabolism, mood, stress response and reproduction. The research also suggests that other peripheral clocks reside throughout the body and that these clocks are perhaps interconnected.”

To conduct the research, scientists studied adrenal gland function in rhesus macaque monkeys which is very similar to human adrenal gland function. Specifically, researchers measured gene expression in the adrenal gland of monkeys during a 24-hour period (six times a day, four-hour intervals). In analyzing this information, researchers identified 322 genes in the adrenal gland with functions that varied rhythmically over a 24-hour period, meaning that each gene’s function peaked and diminished at the same time each day. Interestingly, the scientists also noted that a subgroup of these 322 genes also exist in the SCN — the home of the body’s master body clock. This suggests that the adrenal gland has its own timing mechanism that is related to, but separate from, the SCN body clock.

“Of course, different genes peaked in function at different times of the day,” explained Dario Lemos, an OHSU graduate student in the Urbanski lab and first author of the study. “For instance, genes controlling catecholamine secretion were more active in the day with function greatly decreasing at night. Catecholamines are involved in many important body functions, such as stress and mood.” This research provides important new information regarding the complex, rhythmic, 24-hour functions of the body. The research may also impact current therapies for a variety of diseases. For instance, data gathered in this study and future studies may suggest that certain therapies be delivered at certain times to synchronize with normal body functions controlled by body clocks.

“One example is testosterone replacement, a common treatment for certain disorders in males such as sexual dysfunction and depression,” explained Urbanski. “Patients receiving testosterone late in the day often complain of sleep loss. This is likely due to the fact that in healthy people, testosterone levels are lower in the afternoon and evening. As more data is gathered about body clock functions in our lab and others, we will likely learn of a specific window of time during the day where testosterone therapy is effective, but less disruptive for patients.”

Science Daily
June 6, 2006

Original web page at Science Daily

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Males with elevated levels of testosterone lead shorter lives but have more success siring offspring

Comparative studies have studied testosterone levels and related them to mating systems and aggression, but very few studies have attempted to relate testosterone to fitness, that is, the combination of lifetime reproductive success and survival, in the wild or experimentally. Over nine breeding seasons, Wendy Reed (North Dakota State University) and her colleagues followed a group of dark-eyed juncos, small mountain songbirds found throughout North America. They injected males with elevated levels of testosterone and found that they had shorter lives but that they were very successful at siring more offspring — even with females who were mated with other males. “The surprising result was that testosterone-treated males had a higher overall fitness than control males,” write the authors in a study in the May issue of American Naturalist.

This led to the question of why don’t juncos naturally have higher levels of testosterone? Testosterone-treated males produced more offspring, but they were smaller, and smaller offspring had lower postfledging survival. Older, more experienced females preferred to mate with older males and realized higher reproductive success when they did so. While young males treated with testosterone increased their ability to attract older females, it resulted in poor reproductive performance. “Although testosterone increased male fitness, as measured by lifespan and number of offspring, the extended effects on offspring and female mates were generally negative and may ultimately constrain the evolution of higher testosterone levels in males,” conclude the authors.

Science Daily
May 9, 2006

Original web page at Science Daily

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Hormone treatment could help people to overcome phobias

Does the prospect of public speaking make you panic? Do you run for the hills at the mere mention of spiders? Help could be at hand: researchers have come up with a way to ease the crippling symptoms of phobia. The treatment, developed by a Swiss-led research team, could one day help sufferers to face their fear simply by popping a pill before facing a stressful situation. The researchers hope that it may even have permanent effects, by helping phobics deal with the daunting prospect of undergoing therapy in which they come face to face with their fears.

The remedy contains a human hormone called cortisol, which the body produces naturally in times of stress or fear to help subdue the panic response. Previous studies have shown that increased levels of cortisol help us to blank out painful memories and emotions, allowing us to deal more effectively with stressful situations. This will never be a daily pill. But it could be used in combination with behavioural therapy. Researchers led by Dominique de Quervain of the University of Zurich studied whether artificially increasing levels of cortisol can help phobics overcome the paralysing fear that they feel when faced with the source of their anxiety. They tested 40 people with social phobia and 20 with a fear of spiders. They gave half of them cortisol and then, an hour later, forced the volunteers to give a presentation and undergo an impromptu maths test, or to view a picture of a large spider.
Participants who took cortisol reported significantly less fear, on a scale of 0 to 10, than those given a placebo. The results appear in Proceedings of the National Academy of Sciences. The next step will be to repeat the trial using a larger group of people, says de Quervain, and to combine it with behavioural techniques.

Psychologists do not know exactly what causes severe phobias, de Quervain says. Phobics may have naturally low cortisol levels, which means that the first time they encounter a spider, or have to stand in front of an audience, they develop an intense fear that then preys on their mind. And if natural cortisol defences are low, this could prevent someone forming non-panicked reactions on subsequent exposure. Traditionally, severe phobias are treated using behavioural therapy, in which a patient gradually embraces their fear. An arachnophobe, for example, might begin by looking at pictures of spiders, before graduating to seeing or handling the real thing. Cortisol might help people to overcome their initial fears when embarking on such treatment and increase the proportion of patients who stay with the course, the researchers suggest. “Perhaps they will learn faster that the stimulus is not fearful,” says de Quervain.

The hormone, which has a wide range of effects on both brain and body, is already used to treat chronic conditions such as arthritis. Side effects of daily use include changes in blood pressure and metabolism, and the risk of diabetes. There are also fears that extended exposure to increased cortisol levels can affect long-term memory. The cortisol dose needed to set someone on the road to beating their phobia will hopefully be small and infrequent; a kick-start for therapy rather than a long-term medication, says de Quervain. “This will never be a daily pill,” he says. “But it could be used in combination with behavioural therapy.”

Nature
April 11, 2006

Original web page at Nature

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Growth hormone is made in the brain, report scientists

Scientists have found that growth hormone, a substance that is used for body growth, is produced in the brain, according to an article published in this week’s Proceedings of the National Academy of Sciences. The researchers — from three institutions — found that growth hormone is produced within the hippocampus, a structure deep inside the brain that is involved in memory and emotion. The scientists also found that more growth hormone is produced in females than in males, and more in adults. More growth hormone was also produced in response to estrogen. The study has implications for menopausal women using estrogen replacement therapy and for athletes taking growth hormone and anabolic steroids to increase muscle mass.

The scientists suspect that reasoning and mood may also be affected by these differences in the amount of growth hormone in the brain. “Growth hormone has been associated with growth of muscles and bones, and the production of it was believed to lie mainly in the pituitary gland,” said co-author Ken S. Kosik, co-director of the Neuroscience Research Center at the University of California, Santa Barbara. “No one had thought too much about what growth hormone might be doing in the brain. Hormones in the brain may not be obvious compared to what they are doing in the rest of the body.” The authors previously found that hippocampal growth hormone increases with learning. The current study shows that the hormone is very different in males versus females.

“Males and females look different, we act different, so of course our brains are different,” said Tracey J. Shors, co-author and a professor of psychology at the Center for Collaborative Neuroscience at Rutgers: the State University of New Jersey. “There are remarkable differences. People used to think of females as a male with hormones. That’s just not the case.” The authors found that growth hormone in the brain is increased with stress, especially in males. The effect in females depended on how much estrogen they had at the time. “One interesting interpretation of these results is that exposure to a stressful event increases growth hormone expression in males — but the increase in females may be dependent on their levels of estrogen at the time,” said first author Christine P. Donahue. Donahue, formerly a postdoctoral fellow of Ken Kosik, is an instructor in the Department of Neurology at Harvard Medical School.

The authors suggest that because growth hormone in the body is associated with growth of the body, it may also cause growth in the brain. Females have more dendritic spines (parts of neurons) in the hippocampus than do males. This is especially true when estrogen levels are high and when growth hormone levels are high. They also produce more new neurons in the hippocampus during this time. ‘ “Sex differences in the brain is an area of research that has exploded in recent years,” said Shors. “Sex hormones, like estrogen, have a tremendous effect on the growth and architecture of the brain. Several studies in our lab and in others have shown that males learn differently than females. It is possible that sex differences in these hormones are somehow involved.”

Science Daily Health & Medicine
April 11, 2006

Original web page at Science Daily Health & Medicine

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Human beta-cell line offers hope for type 1 diabetes breakthrough

Transplantation of insulin-producing pancreatic beta-cells shows great promise as a treatment for type 1 diabetes, but development of this therapy has been hampered by a severe shortage of donor beta-cells, which are obtained from decreased human donors. In research published in the October issue of Nature Biotechnology, Ji-Won Yoon, PhD, Professor of Pathology and Director of the Rosalind Franklin Comprehensive Diabetes Center at Rosalind Franklin University of Medicine and Science, Dr. Naoya Kobayashi (Okayama University Graduate School of Medicine and Dentistry), and their international colleagues describe a “reversibly immortalized” cell line that can supply large amounts of insulin-producing human beta-cells. Ultimately, a cell line of this sort may provide an abundant source of beta-cells for transplantation and an alternative to beta-cells from cadavers.

Type 1 diabetes results from the loss of insulin-producing beta-cells in the pancreas. Because the supply of beta-cells from cadavers is insufficient to meet the needs of 99% of diabetic patients, alternative sources of beta-cells would be highly desirable. Previous efforts to coax mature human beta-cells to survive and replicate in the laboratory have not succeeded, however, because the cells died or lost their ability to produce insulin in response to sugar stimulation. Dr. Yoon, Dr. Kobayashi and colleagues got around this problem by manipulating and analyzing large numbers of human beta-cells. First, they added genes that extend cell lifespan to human beta-cells and looked for the rare cells that did not form tumors and that expressed insulin or other beta-cell proteins. Out of more than 250 cells lines screened, only one passed this test. This cell line was allowed to replicate to produce large numbers of cells. Then, the genes that extend cell lifespan were removed to ensure that the cells would not form tumors and to promote beta-cell behavior. The resulting cells produced about 40% as much insulin as normal beta-cells and successfully controlled blood sugar levels in diabetic mice for more than 30 weeks.

While further research is needed before these cells can be considered for testing in humans, plans to develop a “universal beta-cell line” are well underway, and Dr. Yoon anticipates that human clinical trials might begin as soon as three to five years from now. The discovery of this technique to create a reversibly immortalized beta-cell line represents a significant leap in the quest to develop an effective and universal treatment for type 1 diabetes; it is estimated that 18.2 million Americans suffer from diabetes. The long-term impact of this discovery, and those that will follow, will undoubtedly be profound and far-reaching.

Science Daily
November 8, 2005

Original web page at Science Daily

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Hormone jab naturally reduces appetite

A hormone jab may offer burger lovers and the obese a way of reducing their appetites like the turn of a dial. A team at Imperial College London, UK, have found a natural hormone that boosts the stomach’s “full” signal. The hormone is oxyntomodulin, a peptide produced by the small intestine after a meal. In a trial, a group of 14 obese and overweight subjects self-administered doses of the hormone 30 minutes before breakfast, lunch and dinner. After four weeks they had lost an average 2.3 kilograms compared with a control group. The loss amounted to on average 2.4% of body weight.

“By giving the overweight subject oxyntomodulin we are fooling the brain, in a very natural way, into thinking it has just eaten a meal and is no longer hungry,” says Steve Bloom, who led the trials. The researchers also found that the daily energy-intake by the test group was reduced by an average of 170 kilocalories after the first injection, to 250 kcal per day at the end of four weeks. The average recommended intake is 2500 kcal per day for men and 1940 kcal for women. The test subjects’ leptin levels – a hormone responsible for regulating the body’s energy expenditure – were also reduced. The researchers also found a reduction in the levels of adipose hormones. These hormones normally encourage the build up of adipose tissues – where fat cells are stored.

Now a spin-off company is developing an analogue of the hormone and a “patient friendly” oral preparation, thus avoiding the need for self-injecting. It will be some years before anything is widely available, however. Any treatment can hardly come soon enough, says Bloom. The health effects of obesity kill over 1000 people every week in the UK alone. In the US, over 65% of adults are overweight. Bloom says that there were no significant side effects to the hormone injection during the trial and that patients did not develop tolerance to the effects of the hormone. Drugs currently being developed to combat obesity have broad effects on the brain so are more likely to have unwanted side effects, he adds.

“The big thing is that you have had an oxyntomodulin administration from your own gut switching off your hunger after a meal every day of life,” says Bloom. “This is the way you normally lose your appetite after a meal.”

Journal reference: Diabetes

New Scientist
August 16, 2005

Original web page at New Scientist

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Mother-to-daughter transplant reverses diabetes

A woman in Japan has had her diabetes reversed by a transplant of insulin-producing cells from her mother. The procedure has given strikingly fast results and marks a departure from previous operations, which relied on cadaver organs as a source of the cells. The first successful transplantation of such cells, called islet cells, from the pancreas of a non-living donor to a diabetic patient was performed in 2000. Since then, about 100 people have had their diabetic condition reversed by the procedure. But waiting for a suitable donor can be a problem, particularly in countries such as Japan, where traditional beliefs against removal of organs from the deceased means that donors are in short supply.

For this reason, a team led by Shinichi Matsumoto of Kyoto University Hospital decided to investigate the possibility of extracting islet cells from a live donor. Their first patient was a 27-year-old woman who had become dependent on daily insulin shots after suffering inflammation of the pancreas at a young age. Her 56-year-old mother was the donor. In a day-long operation, the team transplanted about 10mL of tissue from the pancreas of the mother to the daughter. The procedure was a tricky one, since islet cells are notoriously delicate. “It’s difficult to extract them and keep them healthy,” explains islet transplantation expert Stephanie Amiel of King’s College London, UK. She adds that the cells sometimes form clots after the operation.

Matsumoto says that transplants taken from live donors make for healthier cells. Both mother and daughter fared well, he says, and 22 days after the surgery, the young woman no longer needed insulin injections to regulate her blood sugar. “From our experience, this patient has more than double the blood insulin level compared with patients who received one cadaveric islet transplantation,” says Matsumoto. The researchers say that people who receive cells from non-living donors tend to become insulin independent only after two or three such procedures.

Amiel says that the daughter’s speedy recovery from the recent operation is remarkable given that she only received islets from a portion of the pancreatic tissue; most procedures involve transplanting cells from the entire organ. But Amiel also adds that because the surgery took place in January, the long-term benefits are unclear. “These are quite early days,” he says. Matsumoto says he plans to conduct a further 10 such operations this year.

Nature
May 10, 2005

Original web page at Nature