Clock Molecule’s Sensitivity To Lithium Sheds Light On Bipolar Disorder

ScienceDaily (Feb. 21, 2006) — Researchers at the University of Pennsylvania School of Medicine discovered that a key receptor protein is a critical component of the internal molecular clock in mammals. What’s more, this molecule — called Rev-erb — is sensitive to lithium and may help shed light on circadian rhythm disorders, including bipolar disorder. The findings, which also provide insight into clock-controlled aspects of metabolism, are reported in this week’s issue of Science.
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Health & Medicine

* Sleep Disorder Research
* Insomnia Research
* Obesity

Mind & Brain

* Insomnia
* Psychiatry
* Depression

Reference

* Circadian rhythm sleep disorder
* Circadian rhythm
* Jet lag
* Appetite

“We’re interested in the internal control of metabolism because feeding behavior is on a daily cycle, and hormonal activities that regulate this are circadian,” says senior author Mitch Lazar, MD, PhD, Director of the Institute for Diabetes, Obesity, and Metabolism at Penn. “Many studies, including those here at Penn, suggest a relationship between the human circadian clock and metabolism. Proteins are the gears of the clock, and not much is known about what regulates protein levels within the cell.”

Rev-erb was known to be a key component of the clock that exists in most cells of the body. Rev-erb inhibits clock genes called bmal and clock, but within a normal 24-hour circadian cycle the Rev-erb protein is destroyed within the cell, allowing bmal and other clock proteins to increase. Among other actions, these clock genes cause Rev-erb to increase, which again inhibits bmal and clock. “The time it takes for that to happen determines the length of the cycle — roughly 24 hours — and keeps the clock going,” explains Lazar.

Penn colleague and coauthor Peter Klein, MD, PhD, Assistant Professor of Medicine, discovered a few years ago that the drug lithium, used to treat biopolar illness, inhibits GSK3, an enzyme known to regulate circadian rhythm in several animal species. In the present study, the researchers showed that the destruction of Rev-erb, a receptor shown previously by Lazar and others to play a role in maintaining normal metabolism, is prevented by GSK3 in mouse and human cells. “It’s like pulling a pin out of the gears of the clock, to allow them to turn in a synchronized manner,” says Lazar.

Lithium blocks this action of GSK3, tagging Rev-erb for destruction, which leads to activation of clock genes such as bmal1. “We suggest that just as our cells in the incubator need to have their internal clocks reset, maybe this is what happens in some people with circadian disorders,” says Lazar. “One effect of lithium may be to reset clocks that become stuck when Rev-erb levels build up.”

These results point to Rev-erb as a lithium-sensitive component of the human clock and therefore a possible target for developing new circadian-disorder drugs. Some patients taking lithium have developed kidney toxicity and other problems. Lazar surmises that new treatments that lead to the destruction of Rev-erb would have the potential of providing another point of entry into the circadian pathway.

Noting that Rev-erb is present in metabolically active tissues, Lazar and his team at the Institute for Diabetes, Obesity, and Metabolism are also interested in the relationship between the control of the circadian clock and metabolic diseases such as obesity and diabetes. “There is a dynamic interplay between circadian rhythms and metabolism,” Lazar says. “You don’t eat while you are sleeping, and the body needs to take this into account.”

Study co-authors are Lei Yin and Jing Wang, both from Penn. The research was funded by the National Institute of Diabetes & Digestive & Kidney Diseases and the National Institute of Mental Health.

Inner Workings Of Molecular Thermostat Point To Pathways To Fight Diabetes, Obesity

ScienceDaily (Sep. 13, 2009) — Best known as the oxygen-carrying component of hemoglobin, the protein that makes blood red, heme also plays a role in chemical detoxification and energy metabolism within the cell. Heme levels are tightly maintained, and with good reason: Too little heme prevents cell growth and division; excessive amounts of heme are toxic.
Researchers at the University of Pennsylvania School of Medicine have discovered a molecular circuit involving heme that helps maintain proper metabolism in the body, providing new insights into metabolic disorders such as obesity and diabetes.

The work builds on 2007 findings from the same team, led by Mitchell Lazar, MD, PhD, Director of Penn’s Institute for Diabetes, Obesity, and Metabolism, showing that a protein called Rev-erbα coordinates the daily cycles of heme. The new research, published online in Genes & Development, makes it clear that Rev-erbα, by controlling the production of heme, also plays a key role in maintaining the body’s correct metabolism. This happens through a molecular pathway that allows the cell to monitor and adjust internal heme levels, creating more when heme levels fall, and slowing it down when levels rise.

The circuit is a negative feedback loop, with Rev-erbα as its central component, explains Lazar. “Rev-erbα is a thermostat for heme.” When heme levels are high, Rev-erbα is activated, reducing heme, which leads the cell back towards a normal state. On the other hand, when heme levels are low, Rev-erbα activity is low, and this permits the cell to make more heme, again leading back toward a normal state. Maintaining this stasis allows energy metabolism to occur but avoids harm to the cell due to excessive levels of heme.

Understanding the control of heme levels is likely to be relevant to several diseases. For example, obesity is a condition where fat tissue builds up due to low energy expenditure relative to energy intake. Proteins such as Rev-erbα that help maintain a cell’s proper metabolism and energy balance point to their role in such metabolic disorders as obesity and diabetes and suggest ways to intervene.

Rev-erbα is a transcription factor, a protein that binds to DNA in front of, or within, genes to alter their expression. Rev-erbα acts as repressor of gene expression, that is, gene expression goes down when it binds to DNA.

Lazar has been studying the protein for nearly 20 years, yet he never really knew how it worked. What he did know was that, as a member of a family of nuclear receptor proteins, Rev-erbα could bind DNA and likely had an intracellular binding partner.

Typical nuclear receptor proteins are like sensors, registering a specific molecular event and responding accordingly, generally by altering gene expression patterns. So, Lazar asked, “What is the purpose of having a system that responds to changes in cellular heme levels?” He hypothesized that the sensor could act to regulate heme itself.

Working with cultured human and mouse cells his team, led by first author, graduate student Nan Wu, monitored heme levels as Rev-erbα abundance changed. What they found confirmed the protein’s role in heme regulation: when overexpressed, heme levels dropped; when suppressed, heme levels rose.

“That was consistent with the hypothesis,” says Lazar. “The question was, how does heme do this?”

To figure that out, the team looked for Rev-erbα binding sites within the sequences of genes known to control heme biosynthesis and found one in PGC-1α, a transcription factor that stimulates the production of heme. Since Rev-erb activity is controlled by heme itself, the net effect is that, as heme levels rise, PGC-1α gets repressed, and heme synthesis drops off.

The team also demonstrated the physiological consequence of disrupting this pathway. “We reasoned, if heme levels get too low, cells won’t like it,” Lazar says, “and they don’t: They stop growing, and they reduce their oxygen consumption in a manner consistent with the role of heme being used to make ATP,” a form of cellular energy.

Lazar states that, “Up until now, no one knew there even was a mechanism for keeping heme levels in this narrow range. We’ve shown that it exists and have defined molecular players that make it work.”

In so doing, he and his team have linked heme biosynthesis with both energy metabolism and the body’s internal clock. Rev-erbα is a negative regulator of genes involved in energy metabolism. It also, along with PGC-1α and heme, rises and falls over a 24-hour period and even regulates some of the cogs within the clock itself.

Now the question is, can this pathway be exploited in the clinic. Lazar’s team showed that downregulating heme stifled cell division and metabolism, while upregulating heme enhanced them. It therefore is possible, Lazar says, that by pharmacologically “tickling” Rev-erbα or its other cellular partners to believe the cell has more or less heme than it actually does, researchers may be able to either boost or suppress metabolism accordingly, opening the door to potential therapies for cancer and obesity.

The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Lei Yin, Elyisha A. Hanniman, and Shree Joshi, all from Penn, are co-authors.

Pityriasis Rosea

What is pityriasis rosea?

Pityriasis rosea is a common rash usually seen in individuals between the ages of 10 to 35 years old. The rash typically lasts six to eight weeks, rarely extending 12 weeks or longer. Once a person has pityriasis rosea, it generally does not recur in their lifetime.

Pityriasis rosea characteristically begins as an asymptomatic single, large pink patch called the “herald patch” or mother patch, measuring 2-10 centimeters. The herald patch is a dry, pink to red patch which appears on the back, chest, or neck and has a well-defined, scaly border.

One to two weeks following the initial appearance of the herald patch, a person will then develop many smaller pink patches across their trunk, arms, and legs. The second stage of pityriasis rosea erupts with a large number of oval spots, ranging in diameter from 0.5 centimeter (size of a pencil eraser) to 1.5 centimeters (size of a peanut). The individual spots form a symmetrical “Christmas tree” pattern following lines of cleavage. This rash is usually limited to the trunk, arms, and legs, rarely occurring on the face and neck. Pityriasis rosea generally spares the face, hands, and feet.

Who gets pityriasis rosea?

Pityriasis rosea is, for the most part, equally common between the two sexes, although there is a slightly higher occurrence reported in women. It generally occurs in children and young adults between 10-35 years of age. Pityriasis rosea has no racial predominance. Most people only get pityriasis once in their lifetime, although it is theoretically possible to have it more than once.

What are signs and symptoms of pityriasis rosea?

Most people do not notice any symptoms with pityriasis rosea except for the appearance of the rash itself. Mild, intermittent itching is reported in about 50% of individuals affected, especially when people become overheated from exercise or hot showers. Itching seems to increase with stress. Sometimes pityriasis is accompanied by flu-like symptoms, such as sore throat, fatigue, nausea, aching, and decreased appetite. Most people are otherwise in very good health and don’t feel any other symptoms.

Researchers find prostate cancer stem cell

WASHINGTON (Reuters) – Researchers have found a stem cell, a kind of master cell, that may cause at least some types of prostate cancer.

Their findings are only experimental — the stem cells were found in mice — but could explain at least some types of prostate cancer and eventually offer new ways to treat it, they reported on Wednesday in the journal Nature.

The findings also show a potential new source for prostate tumors — so-called luminal cells, which secrete various compounds used in the prostate.

“The role of stem cells in the development of prostate cancer has been a focus of speculation for many years,” Dr. Helen Rippon of Britain’s Prostate Cancer Charity said in a statement.

“Importantly, this new stem cell does not rely on androgens — the male sex hormones that control prostate growth — to survive and grow. This may give a clue as to why prostate cancer often becomes resistant to treatments designed to regulate these androgens in the later stages of the disease,” added Rippon, who was not involved in the research.

“This improved knowledge will also be a step forward in learning how we might help to prevent the disease from developing in men in the first place.”

Michael Shen of Columbia University Medical Center and colleagues named the new stem cells CARNs, for castration-resistant Nkx3.1-expressing cells.

They normally regenerate part of the tissue that lines the inside of the gland, which produces semen. But the cells can also form tumors if certain genes meant to stop out-of-control growth get turned off.

Shen said researchers had believed that tumors arise from a different layer of cells in the prostate, called basal cells.

“Previous research suggested that prostate cancer originates from basal stem cells, and that during cancer formation these cells differentiate into luminal cells,” Shen said in a statement. “Instead, CARNs may represent a luminal origin for prostate cancer.”

Prostate cancer is the second most common cancer in men worldwide after lung cancer, killing 254,000 men a year globally.

(Writing by Maggie Fox; Editing by Philip Barbara)

HIV Screening Tests Proposed to Be Added to Medicare’s List of Covered Preventive Services

The Department of Health and Human Services (HHS) today announced a new proposal that would cover Human Immunodeficiency Virus (HIV) infection screening for Medicare beneficiaries who are at increased risk for the infection, including women who are pregnant and Medicare beneficiaries of any age who voluntarily request the service.

“The President has set clear priorities for an improved national response to ending the HIV epidemic,” said HHS Secretary Kathleen Sebelius. “Today’s action by HHS’ Centers for Medicare & Medicaid Services (CMS) sends a strong signal that this Administration takes prevention very seriously, especially when it comes to HIV and AIDS.”

“While younger age groups account for most cases of HIV infection in the United States,  the Centers for Disease Control and Prevention (CDC) estimates that in 2006, approximately 19 percent of all U.S. residents with AIDS were age 50 years or older when the disease was diagnosed, ” she added.  “Knowing about their HIV status can help patients live longer, fuller lives as well as avoid unintentional transmission of the virus to others.”

CMS’ efforts mark the first time that Medicare has proposed to expand its list of covered preventive services under a new authority established by Congress.  The Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) gave CMS the ability to consider whether Medicare should cover “additional preventive services,” if certain requirements are met.

Acquired immunodeficiency syndrome (AIDS) is diagnosed when an HIV-infected person’s immune system becomes severely compromised or a person becomes ill with an HIV-related infection. Of the more than one million Americans estimated to have the HIV infection, the CDC has estimated that about a quarter of them do not realize they are infected.  Without treatment, the HIV infection usually develops into AIDS within 8 to 10 years.  While there is presently no cure for HIV, screening can help identify infected patients so that they can receive medical treatment that could help delay the onset of AIDS for years.

“This proposal to cover HIV screening for our Medicare population has great potential in terms of saving lives and improving the quality of life for many seniors, as well as beneficiaries under age 65,” said Acting CMS Administrator Charlene Frizzera.

The White House’s top HIV/AIDS official saluted the move by HHS, calling it a critical step in helping HIV and AIDS patients to get the treatment they need.

“The President is committed to re-focusing national attention on the domestic HIV epidemic and salutes this decision as an important step in our overall strategy,” said Jeffrey S. Crowley, the Director of the White House Office of National AIDS Policy. “We are working with agencies across the government to achieve the President’s goals of reducing HIV incidence, getting all people living with HIV/AIDS into care and improving health outcomes, and reducing HIV-related health disparities. The actions taken by the HHS today are an important part of our efforts.”

Under MIPPA, CMS can consider whether Medicare should cover preventive services that Congress has not already deemed as covered or non-covered by law, as long as they have been “strongly recommended” or “recommended” by the U.S. Preventive Services Task Force..  For instance, the Task Force graded HIV screening as “strongly recommended.”  More information about the Task Force is available online at http://www.ahrq.gov/clinic.

CMS uses the national coverage determination process to make decisions on these types of preventive services.  This process provides transparency about the evidence that CMS considers when making its decisions and allows opportunity for the public to comment on CMS’ proposals.

“We are pleased to be able to propose an expansion to Medicare’s portfolio of preventive services,” said Barry M. Straube, M.D., CMS Chief Medical Officer and Director of the Agency’s Office of Clinical Standards & Quality.  “Before the MIPPA law, CMS had not been able to expand preventive services without Congressional action.  Now we can take more active steps to evaluate the evidence about CMS Office of Public Affairswhich services are reasonable and necessary to help keep Medicare beneficiaries healthy.”

Health Care Co-Ops Option on Table

With the raging debate over health care reform, which I don’t think anyone debates the fact that we need it, it’s just highly debatable as to which way is the best way to come at this thing, there has been a newer proposal floating around that might catch the ear of some conservative Republicans who are dead set against the idea of government run health care.  The Obama administration keeps getting a lot of pushback on their health care plan, which entails a lot of government intervention, and with good reason. People typically are very leery of most anything that is government run because the government is notorious for being no good at running business.

If you’ve ever lived in a college town, you may know what a co-op is.  When I think of co-op, I think of co-op food places, like an organic produce co op or things like that, where farmers come together to provide a service, selling home grown veggies and fruits and a variety of other organically grown and natural foods, to the public. It’s not really a for-profit venture, because everything that is received by the business is put right back into it, so everyone is contributing, the people that run it, the people that buy stuff there, and so on and so forth.  It takes the cooperation of many parties to make it work, hence the name.

This could present it’s own family of challenges though.  Cooperative ventures are notoriously hard to break into, because they may face greater problems trying to get hospitals, doctors and other providers to provide them services for agreed upon reduced costs.  These co op health providers would be like a mutual insurance company where they provide services to clients for a reduced cost, however, getting everyone to agree to what those lower costs would be is the challenge, and also the fact that these co ops may not gain enough market share to really make a difference in the amount people are paying for their health insurance is another big “if”.

The Wonderful Avocado

I have to admit, until the past few months, the only times I’d really have avocados around the house was when I was making guacamole. But in these past few months, I’ve loved adding them to my brown rice, salads, and most any other dish that I make, or even just eating some slices on the side to help keep me full and satisfied. Once you get the hang of getting them to just the right ripeness, you’ll get hooked on these amazing little “fruits”.  Not to mention, you’ll love the health benefits they give, and the flavor you enjoy when you eat them, although you may not know that eating them gives you these benefits, rest assured that even though they are a relatively high fat piece of produce, they are good for the body when eaten in the right amount.

One of the first nutrients that avocados possess that are mega important is omega 3 monosaturated fat.  It is one of the only things in the produce section that you will get this from. For this reason, avocados are immensely popular with the vegan and vegetarian crowd since the only other real source they can get these from are flax seeds and various types of nuts.  They have about 5 grams of monosaturated fat per serving, which may seem like a lot for produce, and some dieters may shy away from them for this reason, but the benefits far outweigh this minor fact, and actually when eaten in moderation, avocados have properties that may aid someone who is trying to lose weight.

One important thing they do help with is keeping you feeling full and satisfied. This is due to the fiber and omega 3 monosaturated fat content. Because you’re fuller longer, you won’t eat as much.  In fact, high avocado consumption has been shown to lower the blood serum levels of cholesterol, which is excellent for those that suffer high cholesterol and have a hard time keeping it  in check.  They are also an excellent food for those who suffer from hair loss, as they are high in vitamin E, a vitamin that helps regrow healthy hair.  To add to that, they also contain zinc, another important building block for hair growth, vitamin C, and folate, all awesome additions to the diet for hair loss.

Avocados actually contain more potassium than a banana, in fact, over fifty percent more than a banana, which is something I did not know until now. They are also high in the powerful B vitamins, so they are great for giving you energy boosts, and are one of the few produce items that offer you vitamin E AND vitamin K.  They also happen to have the highest fiber content of any other fruit.  Yes, they are considered a fruit, I know, they seem more like a vegetable, kind of like the whole tomato thing, that always throws me off. Only downside is they may make you gassy if you eat too much, but hey, that can always be rectified with a little Beano!

Medicine Wheel Model For Nutrition Shows Promise For Control Of Type 2 Diabetes

American Indian populations experience significant nutrition-related health disparities compared to other racial and ethnic groups within the US. American Indian adults have the highest age-adjusted rates for cardiovascular disease, diabetes and obesity of any racial or ethnic group. Age-adjusted rates of diabetes among Native people vary from 14% to 72%, which are 2.4 to more than 6 times the rate of the general US population.

In a study published in the September 2009 issue of the Journal of the American Dietetic Association, researchers from the South Dakota State University, Brookings, report that a culturally-sensitive educational program based on the Medicine Wheel Model for Nutrition shows promise in changing dietary patterns in an American Indian population and impacting glycemic control.

During a 6-month period from January 2005 through December 2005, participants from the Cheyenne River Sioux Reservation were randomized to an education intervention or to a usual care control group. The education group received six nutrition lessons based on the Medicine Wheel Model for Nutrition, a diet patterned after the traditional consumption of macronutrients for Northern Plains Indians: protein (25% of energy), moderate in carbohydrate (45% to 50% of energy) and low in fat (25% to 30% of energy). The usual care group received the usual dietary education from their personal providers.

The education group experienced a significant weight loss and decrease in body mass index (BMI) from baseline to completion. The usual care group had no change in weight or BMI. There were no between group differences due to intervention in energy, carbohydrate, protein and fat intake and physical activity.

Writing in the article, Kendra K. Kattelmann, PhD, RD, Professor and Director, Didactic Program in Dietetics, Nutrition, Food Science and Hospitality Department, South Dakota State University, Brookings, states, “A diet patterned after the historical hunter-gatherer type diet, or even the early reservation diet (with the higher proportion of energy being supplied from protein), may provide better blood glucose control and lower the circulating insulin levels in Northern Plains Indians with type 2 diabetes. Tribal leaders are interested in preserving the history of their food patterns and embrace the development of educational tools depicting their historical consumption patterns. This trial is one of the first studies reported that attempts to measure the influence of the traditional Northern Plains Indians diet on control of type 2 diabetes.”

In a commentary, Jamie Stang, PhD, MPH, RD, LN, Chair of the Public Health Nutrition Program at the University of Minnesota, School of Public Health, cites some of the dietary challenges faced by the American Indian population. “Limited access to grocery stores that offer low fat, low sugar or whole grain food products and a variety of fruits and vegetables is the most frequently cited barrier to healthy eating…The loss of hunting and fishing rights, unavailability of traditional foods such as wild game, loss of traditional agriculture due to water scarcity and poor soil condition and loss of traditional ways of procuring and preparing foods have also been identified as reasons for poor food choices. Many urban American Indians live in neighborhoods that lack large, well-stocked grocery stores which limits their availability of healthful foods…Even the most culturally competent, evidence-based programs cannot improve eating behaviors among individuals or populations who live and work in an environment that does not support or provide healthy food choices.”

The article is “The Medicine Wheel Nutrition Intervention: A Diabetes Education Study with the Cheyenne River Sioux Tribe” by Kendra K. Kattelmann, PhD, RD; Kibbe Conti, MS, RD; Cuirong Ren, PhD. The commentary is “Improving Health among American Indians through Environmentally-focused Nutrition Interventions” by Jamie Stang, PhD, MPH, RD, LN. Both appear in the Journal of the American Dietetic Association, Volume 109 Issue 9 (September 2009), published by Elsevier.

1. Kendra K. Kattelmann, Kibbe Conti, Cuirong Ren. The Medicine Wheel Nutrition Intervention: A Diabetes Education Study with the Cheyenne River Sioux Tribe. Journal of the American Dietetic Association, 2009; 109 (9): 1532 DOI: 10.1016/j.jada.2009.06.362
2. Jamie Stang. Improving Health among American Indians through Environmentally-Focused Nutrition Interventions. Journal of the American Dietetic Association, 2009; 109 (9): 1528 DOI: 10.1016/j.jada.2009.06.371

Infertility And The Battle Of The Sexes: Evolutionary Explanation For Today’s Fertility Problems?

Aderans Research Institute Inc. (ARI) announced it has launched Phase 2 of its clinical study on cell-based hair regeneration for men and women.

Aderans Research Institute Inc. (ARI) announced it has launched Phase 2 of its clinical study on cell-based hair regeneration for men and women.

Structured around the findings of the recently completed Phase 1 of the study, this second phase will continue to evaluate the impact of its novel cell treatment process on pattern hair loss, also known as androgenetic alopecia. Phase 2 of the study is being conducted in six U.S. cities: Atlanta, Boston, New York, Raleigh, Houston, and Washington DC. Phase 1 was conducted exclusively in the United Kingdom.

“The second phase of this study is another step in our efforts to truly understand the impact of regenerative cell therapy on pattern hair loss. It’s a tremendous opportunity,” says Kurt Stenn, MD, Vice President and Chief Scientific Officer. The company’s research is focused on developing a state-of-the-art tissue engineering solution to the regeneration of hair, taking actual hair cells— fibroblasts and keratinocytes, the two primary cell types within hair follicles—and promoting their growth in controlled laboratory environments. The research teams then recombine them and these “combined hair cells” are then placed in the patient’s skin, where they are expected to elicit hair growth. “This is research the industry has always wanted to do, and ARI has combined the support, the market, and the scientific wherewithal to do it,” says Vern Liebmann, Vice President.

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