Specific, relatively uncommon variations at a region of human chromosome 8 have recently been linked to fat (lipid) levels in the blood that decrease an individual’s risk of atherosclerosis (a disease of the major arterial blood vessels that is a main cause of heart attack and stroke). The only currently described gene in this region of chromosome 8 is TRIB1, but it has not been previously linked in any way to regulation of lipid levels.

Now, a team of researchers, led by Jan Breslow, at The Rockefeller University, New York, and Daniel Rader, at the University of Pennsylvania School of Medicine, Philadelphia, has identified in mice a role for this gene in regulating lipid production by the liver. Specifically, overexpression of Trib1 in the liver decreased levels of lipids such as cholesterol in the blood, while lack of Trib1 increased levels of the same lipids. These data suggest that TRIB1 is the gene responsible for the associations between chromosome 8 and lipid levels in the blood.

TITLE: Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice

Source:
Karen Honey

Journal of Clinical Investigation

The effects of H1N1 swine flu have been investigated in a group of piglets. Scientists writing in BioMed Central’s open access Virology Journal studied the pathology of the virus, finding that all infected animals showed flu-like symptoms between one and four days after infection and were shedding virus two days after infection.

Roongroje Thanawongnuwech led a team of researchers from Chulalongkorn University, Bangkok, who infected 22-day old pigs with both the H1N1 strain of swine flu and the less dangerous H3N2 subtype. He said, “The results demonstrated that both swine flu subtypes were able to induce flu-like symptoms and lung lesions in weanling pigs. However the severity of the disease with regard to both gross and microscopic lung lesions was greater in the H1N1-infected pigs”.

All infected pigs developed respiratory symptoms such as nasal discharge, coughing, sneezing and conjunctivitis. Upon pathological examination, lung lesions large enough to be seen by the naked eye were observed. According to Thanawongnuwech, “These lesions were characterized by dark plum-colored, consolidated areas on lung lobes and were most severe two days after infection, especially in the H1N1-infected pigs, where approximately a third of the lung was covered”. The course of infection was limited to less than a week and none of the animals died.

Pathogenesis of swine influenza virus (Thai isolates) in weanling pigs: an experimental trial
Donruethai Sreta, Roongtham Kedkovid, Sophon Tuamsang, Pravina Kitikoon and Roongroje Thanawongnuwech
Virology Journal 2009, 6:34 doi:10.1186/1743-422X-6-34
virologyj/content/6/1/34

Source:
Graeme Baldwin

BioMed Central

President Bush in his State of the Union speech on Wednesday pledged to support a “culture of life” in his second term
and called for a ban on creating embryos for experimentation, the… San Diego
Union-Tribune reports (Lewis, San Diego Union-Tribune, 2/3). Bush said he wants to “work with
Congress to ensure that human embryos are not created for experimentation or grown for body parts,” according to the New York Times (Stevenson/Sanger, New York Times, 2/3). However, he
“sidestepped” the issue of federal funding for human embryonic stem cell research by addressing the “much less controversial”
issue of banning the creation of embryos exclusively for scientific research, according to the Boston Globe (Canellos, Boston Globe, 2/3). Bush’s embryonic stem
cell policy — which he announced on Aug. 9, 2001 — limits federally funded embryonic stem cell research to stem cell lines
created on or before that date (Kaiser Daily Reproductive Health Report, 1/27).

A video of Bush’s speech, including an excerpt of his
comments on medical ethics and research, is available online. A video
of the Democratic response and the complete transcript of the State of the Union also are available online.

“Reprinted with permission from kaisernetwork kaisernetwork. You can view the entire Kaiser Daily Reproductive Health Report, search the archives,
or sign up for email delivery at www.kaisernetwork/dailyreports/repro The Kaiser Daily Reproductive Health Report is published for
kaisernetwork, a free service of The Henry J. Kaiser Family
Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

According to a study published in the December 24/31 issue of JAMA,
sleeping an hour longer each night may lead to a lower incidence of
coronary artery calcification – a predictor of future heart disease.

Coronary
artery calcification is characterized by an accumulation of calcium
plaques that detected computed tomography scans of the heart. As a risk
factor for atherosclerotic heart disease, coronary artery calcification
also shares many of the same risk factors for heart disease including:

Being male
Being older
Glucose intolerance
Tobacco use
High cholesterol levels and other disorders of lipoprotein
metabolism (dyslipidemia)
Hypertension (high blood pressure)
Obesity
Raised inflammatory markers
A low educational level

In
some recent studies, sleep quantity and quality has been found to be
related to several of these risk factors. “However, some of
these
correlations have only been documented in studies in which sleep is
measured by self-report, which may be biased or insufficiently
accurate,” write the authors of the study.

To test if an
objectively-measured sleep duration was linked to the development of
calcification over a 5 year period, Christopher Ryan King, B.S.
(University of Chicago) and colleagues conducted a study with 495
individuals. The participants were part of the Coronary Artery Risk
Development in Young Adults [CARDIA] study, a sample of black and white
men and women between the ages of 35 and 47. The study began in
2000-2001, a time in which none of the participants demonstrated
evidence of detectable coronary calcification on computed tomography
scans.

Baseline data and follow-up data were collected on
factors that could potentially make it more difficult for the
researchers to tease out the effect of sleep. These possible
confounders included age, sex, race, education, apnea risk, smoking
status, lipids, blood pressure, body mass index, diabetes, inflammatory
markers, alcohol consumption, depression, hostility, and other
self-reported medical conditions. Measurements of sleep duration, sleep
fragmentation, daytime sleepiness and overall sleep quality were
provided by wrist actigraphy (a tool that monitors rest and activity)
and self-reports. The researchers focused the study on the effect that
these sleep metrics had on new calcification as detected by computed
tomography scans in 2005-2006.

Results indicated that 12.3% (61
participants) developed calcification after 5 years. After
controlling for confounding factors like age, sex, race, education,
smoking and apnea risk, the researchers report that one additional hour
of sleep per night lowered the estimated odds of calcification by 33%.
In addition, the magnitude or significance of sleep was not appreciably
altered by potential mediators. Sleep metrics other than duration did
not appear to be significantly linked to the risk of calcification.

“We
have found a robust and novel association between objectively measured
sleep duration and 5-year incidence of coronary artery calcification,”
write King and colleagues. “This study further demonstrates the utility
of a simple objective measure of sleep that can be used at home. Future
studies will be needed for crucial extensions to these results. First,
these results need confirmation in other cohorts. Second, does sleep
moderate the rate at which calcification accumulates? Third, will
objective sleep tie to coronary disease event outcomes over the long
term? While calcification predicts such outcomes, it is difficult to
know how and if the predictors of calcification themselves will
determine outcomes, or if their impact will be purely mediated by their
effect on calcification. Finally, if this association is born out,
interventional studies will be needed to guide clinical advice.”

Short Sleep Duration and Incident Coronary Artery Calcification
Christopher Ryan King; Kristen L. Knutson; Paul J. Rathouz; Steve
Sidney; Kiang Liu; Diane S. Lauderdale
JAMA (2008). 300[24]:
pp. 2859-2866.
Click
Here to View Abstract

: Peter M Crosta

The Global Alliance for Chronic Diseases has announced its intention to release a Request for Applications (RFA) on Implementation Research on Hypertension in Low and Middle Income Countries

A study led by the Smoking Control Unit of the Catalan Institute of Oncology (ICO) has confirmed that the anti-tobacco laws in Europe have a direct effect on the reduction in consumption and passive exposure to smoke. This conclusion was reached by relating the Tobacco Eurobarometer and the Tobacco Control Scale (TCS).

A new study, published in the magazine Plos One, has confirmed the hypothesis that the greater the restrictions, the lower the consumption and passive exposure to smoke. The study was carried out in the 27 countries of the EU and relates the Eurobarometer survey on tobacco and the Tobacco Control Scale (which takes into account the main measures taken in order to control smoking at international level).

“The countries with the highest score in the TCS apply active control policies and the consumption of tobacco and the proportion of the population exposed to smoke, both at home and in the work place, is more reduced”, explained Esteve FernГЎndez MuГ±oz, co-author of the study and the Head of the Tobacco Control Unit of the ICO to SINC.

In countries such as the United Kingdom, Ireland, Malta and Sweden, which score higher on the TCS (that is to say, they adopt stricter controls on smoking), the consumption is “relatively low” -28.8% lower-, as is exposure to smoke -13.8% lower in the home and 23.4% lower in the work place -.

However in the Czech Republic, Germany, Luxembourg, Greece and Austria, where there are fewer control measures, smoking is “relatively high” – more than 30%-, as well as the exposure to smoke – between 15% and 30% in the home and between 15% and 36% in the work place -.

Progressively more measures in Spain

FernГЎndez MuГ±oz pointed out that the reform of Law 28/2005 on health care measures concerning smoking, which came into force yesterday, “is an example of the very important progress in the control of smoking and means the abolition of the ‘Spanish model’ of supposed tolerance”.

Although Spain scores high on the TCS, there are some aspects in which its score is low, such as the price of tobacco. He assured us that, “It is one of the countries in Europe with the cheapest prices”.

“It has been demonstrated that increasing the price of tobacco is the most effective measure for controlling smoking (30 points out of 100 on the TCS scale) as compared with other action, such as, treatment to quit smoking (10 points on the TCS)”, ponnted out the researcher.

The experts forecast that these measures will reduce the incidence of cardiovascular disease in the short and medium-term, as well as the incidence of cancer, mainly lung cancer, in the long-term. In Spain, passive exposure to smoke leads to between 1,200 and 3,200 deaths per year due to lung cancer and heart attacks.

References:

Jose M. MartГ­nez SГЎnchez, Esteve FernГЎndez, Marcela Fu, Silvano Gallus, Cristina MartГ­nez, Xisca Sureda, Carlo La Vecchia, Luke Clancy. “Smoking Behaviour, Involuntary Smoking, Attitudes towards Smoke-Free Legislations, and Tobacco Control Activities in the European Union”. Plos One 5 (11): e13881, noviembre 2010.

Source:
SINC

FECYT – Spanish Foundation for Science and Technology

An international team of scientists, led by Monash University researchers, has uncovered the workings of a superbug that kills elderly hospital patients worldwide – a discovery that has the potential to save lives and health care systems billions of dollars each year.

The research published in the prestigious scientific journal Nature, unravelled ways to genetically modify the bacterium Clostridium difficile and solved the mystery surrounding its toxicity.

Professor Julian Rood from the Department of Microbiology and lead author, microbiologist Dr Dena Lyras, made a major scientific breakthrough which allowed mutants of the superbug to be made. They then identified which of two suspected toxic proteins was essential for the bacterium to cause severe disease.

“Contrary to previously accepted scientific belief, our results show that toxin B, which was considered the less important toxin is actually the toxin that causes disease,” Professor Rood said.

“This discovery will lead to new methods for the control and prevention of this disease”.

Professor Rood and Dr Lyras have been working toward this result for more than a decade. Dr Lyras said strains of Clostridium difficile are found in almost every hospital in Australia.

“It is the major cause of diarrhoea in hospital patients undergoing antibiotic therapy. The antibiotics destroy the ‘good’ bacteria in the gut, allowing a ‘bad’ bacterium to grow in the colon, where it causes a chronic bowel infection that is very difficult to treat,” Dr Lyras said.

“The disease produces two types of Toxins, known as A and B. Worldwide research has tended to focus on these purified toxins in isolation from the bug. This only resulted in part of the story being told. We took a big picture approach and through genetic modification of the bug, together with infection studies with our US collaborators, we were able to see the whole picture,” Dr Lyras said.

Statistics show that in the US, more people die from Clostridium difficile infections than all other intestinal infections combined, with most deaths involving patients aged 65 years or over. The disease is believed to have contributed to more than 8,000 deaths in the UK in 2007. A less aggressive form of the bacteria is present in Australia but statistics in 1995-dollars show the cost of managing the disease to be around $1.25 million dollars per hospital, per year.

Their research lays the foundation to find better ways to treat the superbug.

“We are now beginning to understand the workings of the superbug, which allows us to work on treatments for it. We are confident our research will pave the way for future drugs to try to wipe out this disease. I can’t put a time frame on how quickly drugs could be developed, but we’re certainly on that road to discovery,” Dr Lyras said.

Source: Dr. Dena Lyras
Monash University

Joe Korner, Director of Communications at The Stroke Association comments:

“This research is of the utmost importance. It clearly shows that thousands of people could be saved from life shattering strokes every year, simply by making sure that everyone who has a transient ischaemic attack (TIA) or minor stroke gets currently available treatment quickly. It is not about a brand new technology, or a costly intervention. It is about organising our services so that a TIA or minor stroke is always treated, and treated urgently.

“Too often people ignore stroke symptoms if they don’t last very long. Yet, a TIA is one of the only warning signs that a major stroke may be on its way and it is vital that anyone with a TIA is referred urgently to specialist services and for those at highest risk to be seen within 24 hours.

“Making desperately needed organisational changes will save the NHS money over the long term as more strokes will be prevented. As part of the Comprehensive Spending review we called upon the Treasury to invest in the reorganisation of stroke and TIA services to ensure that everyone receives the treatment that they need to save lives. It is not often that medical research indicates so strongly the efficiency of treatment supporting the need for urgent and immediate investment.”

1. The Stroke Association is the only UK charity solely concerned with combating stroke in people of all ages. The charity funds research into prevention, treatment, better methods of rehabilitation and helps stroke patients and their families directly through its community services which include communications support, family and carer support, information services, welfare grants, publications and leaflets. The Stroke Association also campaigns, educates and informs to increase knowledge of stroke at all levels of society acting as a voice for everyone affected by stroke.

2. A stroke is a brain attack which causes brain damage. A stroke can be diagnosed by using FAST – Facial weakness, Arm weakness, Speech problems, Test all three. If any of these symptoms are present call an ambulance straight away.

stroke

Nicotine may improve the symptoms of depression in people who do not smoke, Duke University Medical Center scientists have discovered.

The finding does not mean that people with depression should smoke or even start using a nicotine patch, the researchers caution. They say that smoking remains the No. 1 preventable cause of death and disability in the United States, and that the addictive hazards of tobacco far outweigh the potential benefits of nicotine in depression.

But the finding suggests that it may be possible to manipulate nicotine’s effects to safely reap its potential medical benefits, according to the researchers. As an example of the drug’s potential, they said, pharmaceutical companies already are developing compounds for treating other brain disorders by mimicking the beneficial properties of nicotine while avoiding its addictive nature.

“The hope is that our research on nicotine will spur the development of new treatments for depression, which is a huge public health problem,” said lead study investigator Joseph McClernon, Ph.D., an assistant research professor of medical psychiatry and researcher at the Duke Center for Nicotine and Smoking Cessation Research.

“Our study also provides evidence that smokers may indeed smoke, in part, to improve their mood — a notion that has been quite controversial in the field,” he said.

The team’s findings are scheduled to appear the week of Sept. 11, 2006, in the online edition of the journal Psychopharmacology and will be published in print in November.

The research was supported by the National Alliance for Research on Schizophrenia and Depression.

Scientists have established that people prone to depression are twice as likely to be smokers, and are less likely to succeed in quitting smoking after taking up the habit, according to McClernon. The Duke study explored the theories behind the higher smoking rates among people experiencing depression.

“Smokers may be more prone to depression than nonsmokers,” said Edward Levin, Ph.D., a professor of biological psychiatry and researcher at the Duke center, who was senior investigator in the current study. “Or, people with depression may be self-medicating by smoking, albeit in a deadly way.”

In the study, the researchers recruited 11 people who did not smoke but who were experiencing symptoms of depression. Participants were randomly assigned to wear either a nicotine patch or a placebo patch that did not contain any nicotine. The researchers used a standardized method, a 20-item questionnaire called the Center for Epidemiological Studies Depression scale, to measure depression symptoms among the study participants.

“Despite the small number of participants, this is the largest study of its kind,” McClernon said.

The team found that participants who wore the nicotine patch for at least eight days experienced a significant decline in their depression-assessment rating scores. McClernon said this finding indicates that the drug led to an improvement in depression symptoms.

As a possible explanation for how nicotine exerts its beneficial effect, McClernon said: “The same areas of the brain that are stimulated by nicotine appear to be involved in the regulation of mood.”

Nicotine stimulates the release of specific neurotransmitters, including serotonin, dopamine, and norepinephrine, which carry messages between nerves cells. Depression has been linked to chemical imbalances of these neurotransmitters, McClernon said.

Looking ahead to possible therapeutic uses of nicotine for treating depression, the researchers say the nicotine molecule can be manipulated to remove its addictive effect while maintaining its ability to increase levels of the various brain chemicals that can alter mood. Currently, pharmaceutical companies are developing nicotinelike drugs that target chemical imbalances in the brain that are thought to cause anxiety, schizophrenia, attention deficient hyperactivity disorder, Alzheimer’s disease and Parkinson’s disease.

The study also suggests that people prone to depression may need extra help in order to quit smoking, such as nicotine replacement therapy, the scientists said.

Despite the positive effects of nicotine discovered in their study, the researchers emphasize that it is not currently appropriate for treatment of any medical disorder outside of nicotine dependence.

“I certainly recommend that people don’t smoke,” Levin said. “If you do smoke, quit.”

###

Other researchers participating in the study included F. Berry Hiott, Eric C. Westman and Jed E. Rose.

Contact: Marla Vacek Broadfoot

Duke University Medical Center

Bristol-Myers Squibb Company and Otsuka Pharmaceutical Co., Ltd. today announced the launch of ABILIFY® DISCMELT™ (aripiprazole) Orally Disintegrating Tablets, a new oral form of the antipsychotic medication ABILIFY® (aripiprazole) that disintegrates rapidly in the mouth. The U.S. Food and Drug Administration (FDA) approved ABILIFY DISCMELT on June 7, 2006.

ABILIFY DISCMELT provides a convenient alternative for adults with schizophrenia or manic episodes associated with Bipolar I Disorder. Pharmacokinetic studies showed that ABILIFY DISCMELT Orally Disintegrating Tablets are bioequivalent to regular ABILIFY tablets, thereby offering similar efficacy and safety at the same doses as the oral tablets.

“Many adults with schizophrenia or Bipolar I Disorder, both in inpatient and outpatient settings, don’t take their medication as prescribed,” said John Zajecka, M.D., Director, Psychiatry Treatment Research Center and Associate Professor, Department of Psychiatry, Rush University Medical Center in Chicago. “ABILIFY DISCMELT provides healthcare professionals a formulation alternative that may be desirable for some adult patients.”

Some adults with schizophrenia or bipolar mania may have difficulty swallowing tablets or, in institutional settings, may hide pills inside their cheek to later spit them out. ABILIFY DISCMELT tablets are placed on the tongue and disintegrate rapidly upon contact with saliva, providing the convenience of a tablet without the need for liquid.

The vanilla-flavored ABILIFY® DISCMELT™ (aripiprazole) 10 mg and 15 mg Orally Disintegrating Tablets are packaged in blister packs and each dosage form is colored differently with scattered specks. Directions for use of ABILIFY DISCMELT Orally Disintegrating Tablets can be found in the FULL PRESCRIBING INFORMATION and should be shared with patients. Adults with phenylketonuria should be advised that ABILIFY DISCMELT contains phenylalanine.

About ABILIFY

The first and only available dopamine partial agonist,1 ABILIFY® (aripiprazole) is indicated for the treatment of schizophrenia including maintaining stability in adults who had been symptomatically stable on other antipsychotic medications for periods of three months or longer and observed for relapse during a period of up to 26 weeks. ABILIFY is also indicated for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder, and for maintaining efficacy in adults with Bipolar I Disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least six (6) weeks. Physicians who elect to use ABILIFY for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual. Since its initial approval in 2002, more than seven million prescriptions have been written in the United States.2

ABILIFY is available by prescription only. ABILIFY tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. The effective dose range is 10-30 mg/day for schizophrenia patients, and 15 or 30 mg/day for Bipolar I Disorder patients. In addition to administration as a tablet, ABILIFY is available in a 1 mg/mL nonrefrigerated oral solution. The safety of doses of ABILIFY above 30 mg/day has not been evaluated in clinical trials.

ABILIFY is taken once daily with or without food. It is important to talk to a healthcare professional for more information about ABILIFY.

IMPORTANT SAFETY INFORMATION for ABILIFY® (aripiprazole):

Increased Mortality in Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular or infectious in nature. ABILIFY® (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis (see Boxed WARNING).

ABILIFY is contraindicated in patients with a known hypersensitivity to the product.

As with all antipsychotic medications, including ABILIFY, a rare condition referred to as neuroleptic malignant syndrome (NMS) has been reported. As with all antipsychotic medications, prescribing should be consistent with the need to minimize the risk of tardive dyskinesia (TD).

Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, have been reported at an increased incidence in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY, including a significant dose response relationship in a fixed-dose trial. ABILIFY is not approved for the treatment of patients with dementia-related psychosis.

Hyperglycemia, including some serious cases ranging from ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. Patients on ABILIFY should be appropriately tested before and monitored during treatment.

ABILIFY may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

As with other antipsychotic drugs, ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Like other antipsychotics, ABILIFY may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain ABILIFY does not affect them adversely.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.

As antipsychotics have been associated with esophageal dysmotility and aspiration, ABILIFY should be used cautiously in patients at risk for aspiration pneumonia.

As the possibility of a suicide attempt is inherent in psychotic illness and bipolar disorder, close supervision of high-risk patients should accompany drug therapy.

Prescriptions for ABILIFY® (aripiprazole) should be written for the smallest quantity consistent with good patient management to reduce the risk of overdose.

Physicians should determine if a patient is pregnant or intends to become pregnant while taking ABILIFY. Patients should be advised not to breast-feed while taking ABILIFY.

Patients should be advised to avoid alcohol while taking ABILIFY.

Both CYP3A4 and CYP2D6 are responsible for ABILIFY metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in ABILIFY clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit ABILIFY elimination and cause increased blood levels.

Commonly observed adverse events reported with ABILIFY in 3-week bipolar mania trials at a greater than or equal to 5% incidence for ABILIFY and at a rate at least twice the rate of placebo include, respectively, akathisia (15% vs 4%), constipation (13% vs 6%), and accidental injury (6% vs 3%).

Treatment-emergent adverse events reported with ABILIFY in short-term trials at an incidence greater than or equal to 10% and greater than placebo, respectively, include headache (31% vs 26%), agitation (25% vs 24%), anxiety (20% vs 17%), insomnia (20% vs 15%), nausea (16% vs 12%), dyspepsia (15% vs 13%), somnolence (12% vs 8%), akathisia (12% vs 5%), lightheadedness (11% vs 8%), vomiting (11% vs 6%), and constipation (11% vs 7%).

The adverse events reported in a 26-week, double-blind schizophrenia trial comparing ABILIFY and placebo were generally consistent with those reported in the short-term, placebo-controlled schizophrenia trials, except for a higher incidence of tremor: 9% for ABILIFY vs. 1% for placebo.

About Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd.
Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. are collaborative partners in the development and commercialization of ABILIFY in the United States and major European countries.

ABILIFY® (aripiprazole) was discovered by Otsuka Pharmaceutical Co., Ltd. Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a healthcare company with the mission statement: “Otsuka – people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative, original products, focusing its core businesses on pharmaceutical products for the treatment of disease and consumer products for the maintenance of everyday health. The Otsuka Pharmaceutical Group comprises 87 companies and employs approximately 27,000 people in 17 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned US $6.8 billion in consolidated annual revenues in fiscal 2005.

Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.

For more information and FULL PRESCRIBING INFORMATION, including Boxed WARNING, visit: abilify

otsuka-global
bms

View drug information on Abilify.

Having charted the occurrence of a common chemical change that takes place while stem cells decide their fates and progress from precursor to progeny, a Johns Hopkins-led team of scientists has produced the first-ever epigenetic landscape map for tissue differentiation.

The details of this collaborative study between Johns Hopkins, Stanford and Harvard appear in the early online publication of Nature.

The researchers, using blood-forming stem cells from mice, focused their investigation specifically on an epigenetic mark known as methylation. This change is found in one of the building blocks of DNA, is remembered by a cell when it divides, and often is associated with turning off genes.

Employing a customized genome-wide methylation-profiling method dubbed CHARM (comprehensive high-throughput arrays for relative methylation), the team analyzed 4.6 million potentially methylated sites in a variety of blood cells from mice to see where DNA methylation changes occurred during the normal differentiation process. The team chose the blood cell system as its model because it’s well-understood in terms of cellular development.

They looked at eight types of cells in various stages of commitment, including very early blood stem cells that had yet to differentiate into red and white blood cells. They also looked at cells that are more committed to differentiation: the precursors of the two major types of white blood cells, lymphocytes and myeloid cells. Finally, they looked at older cells that were close to their ultimate fates to get more complete pictures of the precursor-progeny relationships – for example, at white blood cells that had gone fairly far in T-cell lymphocyte development. (Lymphoid and myeloid constitute the two major types of progenitor blood cells.)

“It wasn’t a complete tree, but it was large portions of the tree, and different branches,” says Andrew Feinberg, M.D., M.P.H., King Fahd Professor of Molecular Medicine and director of the Center for Epigenetics at Hopkins’ Institute for Basic Biomedical Sciences.

“Genes themselves aren’t going to tell us what’s really responsible for the great diversity in cell types in a complex organism like ourselves,” Feinberg says. “But I think epigenetics – and how it controls genes-can. That’s why we wanted to know what was happening generally to the levels of DNA methylation as cells differentiate.”

One of the surprising finds was how widely DNA methylation patterns vary in cells as they differentiate. “It wasn’t a boring linear process,” Feinberg says. “Instead, we saw these waves of change during the development of these cell types.”

The data shows that when all is said and done, the lymphocytes had many more methylated genes than myeloid cells. However, on the way to becoming highly methylated, lymphocytes experience a huge wave of loss of DNA methylation early in development and then a regain of methylation. The myeloid cells, on the other hand, undergo a wave of increased methylation early in development and then erase that methylation later in development.

Rudimentary as it is, this first epigenetic landscape map has predictive power in the reverse direction, according to Feinberg. The team could tell which types of stem cells the blood cells had come from, because epigenetically those blood cells had not fully let go of their past; they had residual marks that were characteristic of their lineage.

This project involved a repertoire of talents..”None of whom were more integral than Irv Weissman at Stanford,” Feinberg says. “He’s a great stem cell biologist and he lent a whole level of expertise that we didn’t have.”

One apparent application of this work might be to employ these same techniques to assess how completely an induced pluripotent stem cell (iPSC) has been reprogrammed.

“You might want to have an incompletely reprogrammed cell type from blood, for example, that you take just to a certain point because then you want to turn it into a different kind of blood cell,” Feinberg says, cautioning that the various applications are strictly theoretical.

Because the data seem to indicate discreet stages of cell differentiation characterized by waves of changes in one direction and subsequent waves in another, cell types conceivably could be redefined according to epigenetic marks that will provide new insights into both normal development and disease processes.

“Leukemias and lymphomas likely involve disruptions of the epigenetic landscape,” Feinberg says. “As epigenetic maps such as this one begin to get fleshed out by us and others, they will guide our understanding of why those diseases behave the way they do, and pave the way for new therapies.”

The research was supported by the National Institutes of Health and a grant from the Thomas and Stacey Siebel Foundation.

Johns Hopkins authors, in addition to Feinberg, are Hong Ji, Peter Murakami, Akiko Doi, Hwajin Lee, Martin J. Aryee, and Rafael A. Irizarry. Other authors are Lauren I. R. Ehrlich, Jun Seita, Paul Lindau, Derrick J Rossi, Matthew A. Inlay, Thomas Serwold, Holger Karsunky, Lena Ho, and Irving L. Weissman, all of Stanford University; and Kitai Kim and George Q. Daley, both of Harvard University.

Source:
Maryalice Yakutchik
Johns Hopkins Medical Institutions