Diffuse large B-cell lymphoma is an aggressive form of non-Hodgkin lymphoma that represents 30% of newly diagnosed cases. DLBCL consists of different subtypes that vary biologically and differ significantly in their survival rates following chemotherapy. Among the subtypes, the germinal center B cell-like (GCB) subtype is more responsive to treatment than the activated B cell-like (ABC) subtype. The current standard of care for DLBCL, a combination chemotherapy including four drugs collectively known as CHOP, is able to cure 50% to 60% of patients. Gene activity, or expression, is a measure of the biological activity of a gene. According to an article published in the New England Journal of Medicine (2008;359:2313-2323), patterns of gene activity in a type of non-Hodgkin lymphoma has provided a better understanding of factors that contribute to the survival of patients treated for the disease. Determining the activity levels of all genes in lymphoma patients’ genomes allowed the research team to identify sets of genes in diffuse large B-cell lymphoma (DLBCL) that influenced the effectiveness of treatment. For the study, after thousands of genes in DLBCL tumors were analyzed. One signature, termed the germinal center B-cell signature, was expressed by malignant cells in the tumors and reflected whether the tumors were of the GCB or ABC DLBCL subtype. In contrast, the other two gene expression signatures reflected different activities of the non-malignant cells within the tumor microenvironment. One signature, termed stromal-1, was found in tumors that expressed genes involved in forming or modifying the extracellular matrix, the fibrous network of molecules between cells that regulates the structure and function of tissues. These tumors also contained many macrophages, a type of white blood cell. High expression of this signature was associated with good prognosis. Another signature, termed stromal-2, was present in DLBCL tumors that had abundant angiogenesis, the process whereby new blood vessels are formed. The stromal-2 signature was associated with poor prognosis. The authors used the data from these three gene expression signatures to create a mathematical formula. Using this formula, they found that it was possible to divide patients who had been treated with R-CHOP or CHOP chemotherapy alone into subgroups that had better or poorer survival. The International Prognostic Index (IPI), a predictive index used by physicians to evaluate patients with DLBCL, is based on clinical factors including age, stage of the tumor, and whether cancer has spread to other parts of the body. Combining the gene signature model with the IPI improved the predictive power of both models. According to the authors, the ability of a patient with DLBCL to be cured by current therapy can be predicted by looking at the pattern of gene activity in the tumor biopsy sample taken at diagnosis. The authors also suggested that in the near term, there is a need to incorporate gene expression profiling in clinical trials to allow researchers to standardize results according to the variety of DLBCL tumors included in the trial. In the longer term, new therapies will emerge that are tailored to the particular gene expression profile of a patient’s lymphoma.

Sir Paul M. Nurse, MD, PhD

Paul Nurse is a British biochemist. He was awarded the 2001 Nobel Prize in Physiology or Medicine with Leland H. Hartwell and R. Timothy Hunt for their discoveries regarding cell cycle regulation by cyclin and cyclin dependent kinases.

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Sir Paul M. Nurse receiving his Nobel Prize from His Majesty the King at the Stockholm Concert Hall.
Copyright © Nobel Web AB 2001
Photo: Hans Mehlin

Nurse’s parents came from Norfolk. He was born and raised in Wembley, in north-west London. and was educated at Harrow County Grammar School for Boys. He received his undergraduate degree in 1970 from the University of Birmingham and his PhD in 1973 from the University of East Anglia. Beginning in 1976, Nurse identified the gene cdc2 in yeast (Schizosaccharomyces pombe). This gene controls the progression of the cell cycle from G1 phase to S phase and the transition from G2 phase to mitosis. In 1987, Nurse identified the homologous gene in human, CDK1, which codes for a cyclin dependent kinase.

In 1984, Nurse joined the Imperial Cancer Research Fund. (ICRF, now named the Cancer Research UK London Research Institute. He left in 1988 to chair the department of microbiology at the University of Oxford. He then returned to the ICRF as Director of Research in 1993, and in 1996 was named Director General of the ICRF, which became the Cancer Research UK London Research Institute in 2002. In 2003, he became president of Rockefeller University in New York City where he continues to work on the cell cycle of fission yeast.

In addition to the Nobel Prize, Nurse has received numerous awards and honours. In 1989, he became a fellow of the Royal Society and in 1995 he received a Royal Medal and became a foreign associate of the U.S. National Academy of Sciences. He received the Albert Lasker Award for Basic Medical Research in 1998. Nurse was knighted in 1999. He was awarded the French Legion d’Honneur in 2002. He was also awarded the Copley Medal in 2005. He was elected a Foreign Honorary Member of the American Academy of Arts and Sciences one of the top honours in April 2006.
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Sir Paul Nurse, president of The Rockefeller University, is a Trustee of the Howard Hughes Medical Institute. He is one of 11 Trustees of the Institute, a medical research organization dedicated to the discovery and dissemination of new knowledge in the life sciences.

Nurse, 56, is a distinguished scientist who shared the 2001 Nobel Prize in Physiology or Medicine with Leland Hartwell and R. Timothy Hunt for fundamental discoveries concerning control of the cell cycle. A geneticist who uses fission yeast as a model system, he continues an active research program that focuses on the cell cycle and how the cell organizes its internal structures to prepare for cell division.

A native of England, Nurse became Rockefeller’s ninth president in 2003. He had been chief executive of Cancer Research UK, the world’s largest cancer research organization outside the U.S.

Nurse graduated from the University of Birmingham in 1970 and received his Ph.D. from the University of East Anglia in 1973. Nurse headed laboratories at the University of Sussex, the Imperial Cancer Research Fund (ICRF), and Oxford University before rejoining the ICRF in 1996 as its Director General. He presided over its merger with the Cancer Research Council.

In addition to the Nobel Prize, Nurse’s work has been recognized around the world. He is a Fellow of the Royal Society and, in 1995, became a foreign associate of the National Academy of Sciences. He has received the Gairdner Foundation International Award (1992), the Alfred P. Sloan Jr. Prize from the General Motors Cancer Research Foundation (1997), and the Albert Lasker Award for Basic Medical Research (1998).

***

The Howard Hughes Medical Institute is dedicated to discovering and disseminating new knowledge in the basic life sciences. HHMI grounds its research programs on the conviction that scientists of exceptional talent and imagination will make fundamental contributions of lasting scientific value and benefit to humanity when given the resources, time, and freedom to pursue challenging questions. The Institute prizes intellectual daring and seeks to preserve the autonomy of its scientists as they pursue their research.

A nonprofit medical research organization, HHMI was established in 1953 by the aviator-industrialist. The Institute, headquartered in Chevy Chase, Maryland, is one of the largest philanthropies in the world with an endowment of $14.8 billion at the close of its 2005 fiscal year. HHMI invested $637 million in support of biomedical research and $80 million for support of a variety of science education and other grants programs in fiscal 2005.

The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, and physics. Founded by John D. Rockefeller in 1901, the university has been the site of many important scientific breakthroughs. Rockefeller scientists, for example, established that DNA is the chemical basis of heredity, discovered blood groups, showed that viruses can cause cancer, founded the modern field of cell biology, worked out the structure of antibodies, developed methadone maintenance for people addicted to heroin, devised the AIDS “cocktail” drug therapy, and identified the weight-regulating hormone leptin. Twenty-three Nobel Prize winners have been associated with the university.

The Biology of Algae – A tiny world we may not think about very often, but which is extremely important to the planet, especially algae in the oceans. Take a look at this NASA article, that shows how algae and climate change are connected.

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HIV-1 contains a conical capsid built from ~1,500 copies of the viral CA protein, which pack together on a hexagonal lattice and enclose the RNA genome (left). Electron cryocrystallography was used to produce the first unambiguous pseudoatomic model of the hexamers from which the lattice is assembled (right). The hexamers are stabilized by close interactions between the two CA domains of adjacent subunits (shown in different colors). This newly visualized intermolecular interaction is a novel drug target to disrupt capsid assembly, which may prevent the formation of infectious particles.

by Jason Socrates Bardi, The Scripps Research Institute – Scientists at The Scripps Research Institute have published a detailed molecular model of the full-length HIV CA protein—a viral protein that forms a cone-shaped shell around the genome of HIV. This structure reveals a never-before-seen molecular interaction that may be a weakness at the core of the virus.

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Cell biologists Mark Yeager and Barbie Ganser-Pornillos show a model of the HIV capsid, in which the CA protein forms a cone-shaped shell around the genome of HIV.

CA plays a crucial role in the lifecycle of HIV because it forms a protein shell inside infectious particles, providing a scaffold that organizes important components of the virus. The new CA structure, published in the October 5 issue of the journal Cell, has clinical implications and may help scientists develop new drugs for treating HIV.

“AIDS is a bona fide pandemic,” says study author Mark Yeager. “There are several effective drugs and methods for treating and preventing HIV infections, but there is an ongoing need for new therapy due to the shear enormity of the disease and the emergence of drug resistance.”

Yeager is a professor in the Department of Cell Biology at The Scripps Research Institute and staff cardiologist and director of cardiovascular research at Scripps Clinic. He also has a joint appointment as Andrew P. Somlyo Professor and Chair of the Department of Molecular Physiology and Biological Physics at the University of Virginia. Yeager supervised the research, which was conducted by his postdoctoral fellow Barbie Ganser-Pornillos.

Since it was first reported more than 25 years ago, HIV has spread to every corner of the world. Globally, according to the latest figures available from the World Health Organization, some 40 million people were living with HIV in 2006. The Centers for Disease Control and Prevention (CDC) estimates that 40,000 people become infected with HIV every year in the United States.

HIV infections can be successfully managed for years with a variety of existing drugs known as antiretrovirals, which interfere with critical parts of the viral lifecycle. Interfering with some of these stages can prevent the virus from replicating, integrating its genome into the cell’s DNA, or processing new infectious viral particles.

Doctors often prescribe a regimen of several antiretrovirals from different classes for people living with HIV because AIDS drugs with different mechanisms of action are more effective in combination than when taken alone. Finding new drugs with new mechanisms of action is important because HIV constantly mutates and may become resistant to existing drugs.

In general, the capsid (the protein coat that covers the core of a virion) is an attractive target because it plays a crucial role in the viral lifecycle. It packages and organizes the HIV genome, and this is necessary for the virus to transmit and replicate efficiently. If chemical compounds could target the CA protein, scientists might be able to prevent the protein’s assembly into capsid shells and thereby block infectivity of HIV. Capsid inhibitors would be a novel class of drugs that would complement existing pharmaceuticals.

So Ganser-Pornillos and Yeager set out to find the complete structure of the HIV-1 CA.

But this was no easy task. Assembled capsid shells are large enough to be seen under the most powerful electron microscopes, but are too small and asymmetric to be studied in detail. For years, structural biologists attempted to solve the structure of the CA protein using other methods, but the protein is flexible, and the structure proved elusive. The problem was that CA has two rigid pieces or domains held together by a flexible linker. Think of them like two water balloons tied together with a short string. Scientists had successfully chopped the protein into pieces and solved the structures of the two domains, but despite many years of trying, nobody had visualized how the two domains fit together and how hundreds of copies of CA pack within the lattice of the capsid shell.

Ganser-Pornillos solved the problem by finding exact conditions that fixed assemblies of the full-length CA molecules into well-ordered, two-dimensional (2D) arrays. Normally, recombinant CA molecules form cylindrical shells in vitro, but a few years ago, a single mutation was identified that allowed the formation of alternative shapes—cylinders, cones, and spheres. By creating conditions in which CA formed large hollow spheres, Ganser-Pornillos was able to generate extended 2D crystalline sheets by flattening the spheres onto a thin layer of carbon. Ganser-Pornillos, assisted by Scripps Research Staff Scientist Anchi Cheng, solved the three-dimensional structure of the CA molecules in the sheets by computational analysis of images of tilted 2D crystals recorded in the electron microscope.

Even though the 2D crystals of CA were generated artificially, they were thought to recapitulate the lattice in the HIV capsid because the packing of the CA molecules had a hexagonal, honeycomb like pattern, similar to that seen in authentic viral particles. However, the hexagonal packing of the molecules in the 2D crystals was much more regular, so that a detailed structure could be determined. The clarity of the three-dimensional electron microscopy map was sufficient so that existing high-resolution structures of the two domains of CA could be “docked” into place. The resulting atomic model of the capsid lattice revealed three types of interactions that stabilize this inner core of HIV.

In particular, an interaction between the two pieces of CA had not been visualized previously. Interfering with this interaction could disrupt assembly of the capsid shell and block formation of infectious particles.

“The structure allows us to visualize the interface between the two domains of CA, which we think is the target for a set of experimental drugs,” says Ganser-Pornillos. She and Yeager are now working to improve the structure. They hope to find novel compounds that bind to CA to test if they interfere with the virus’s infectivity.

The article is entitled “Structure of Full-Length HIV-1 CA: A Model for the Mature Capsid Lattice,” and appears in the October 5, 2007 issue of the journal Cell.

Support for this work was provided by grants from the National Institutes of Health and through a postdoctoral fellowship from the George E. Hewitt Foundation for Medical Research.

Science Daily — One of the largest studies to investigate the relationship between blood pressure and type 2 diabetes has found that women who have high blood pressure levels are three times more likely to develop diabetes than women with low blood pressure levels. This effect was independent of body mass index and other conditions that are known to predispose people to cardiovascular disease and diabetes.

Writing in the European Heart Journal today [1], the authors say that clinicians should be aware of the relationships between blood pressure and type 2 diabetes to optimise the management of patients at increased risk for cardiovascular disease.

The researchers from the Brigham and Women’s Hospital, Harvard Medical School and the Harvard School of Public Health, USA, followed over 38,000 female health professionals for ten years. At the start of the study in 1993, all the women were free of diabetes and cardiovascular disease. Follow-up continued to the end of March 2004, at which point data were nearly 100% complete (97.2% for morbidity and 99.4% for mortality).

The lead author, Dr David Conen, a cardiologist and research fellow, explained: “Despite several studies finding a close relationship between hypertension and type 2 diabetes, little information exists on the relationship between blood pressure levels and the subsequent development of type 2 diabetes. Data for women are particularly limited. Finding an independent association between blood pressure and new-onset diabetes is important, because it suggests that women with increasing blood pressure levels should have their blood glucose levels monitored. Individuals at high risk for cardiovascular disease may benefit from early intervention.”

The researchers divided the women into four groups: those with optimal blood pressure (BP), below 120 mmHg systolic, 75 mmHg diastolic; those with normal BP (120-129 mmHg systolic, 75-84 mmHg diastolic); those with high normal BP (130-139 mmHg systolic, 85-89 diastolic); and those with established hypertension (at least 140 mmHg systolic, 90 mmHg diastolic, and/or self-reported history of hypertension or treatment for the condition).

After 10 years of follow-up 1.4, 2.9, 5.7 and 9.4% of women in the four categories respectively had developed type 2 diabetes. After adjusting for various factors such as age, ethnicity, smoking, alcohol intake, body mass index (BMI), exercise, family history of diabetes etc, the researchers found that women with hypertension had a three-fold risk of developing diabetes compared with women with optimal BP.

Dr Conen said: “We found that obesity was also a strong and independent risk factor for the development of type 2 diabetes. However, statistical analyses showed that the relationship between blood pressure and the onset of type 2 diabetes was similar among women who were normal weight, overweight or obese. There was a three-fold increase in risk from the lowest to the highest BP category within all three weight categories. This analysis showed that the association between blood pressure and diabetes was not explained by weight alone.”

Women who had an increase in BP during the study also had an increased risk of developing diabetes. Those whose BP rose but who remained within the range of normal BP had an increased risk of 26% compared to women who had stable or decreasing BP. Women who progressed to hypertension had a 64% increased risk.

Dr Conen said: “Compared with an overall rate of 4.5 events per 1,000 person-years, the incidence rates in the optimal BP category was 1.5 events per 1,000 person-years, showing that these women have a very low risk of developing diabetes. On the other hand, women with high normal BP had a much higher risk compared with women with normal BP, and the risk among those with established hypertension was substantial: after ten years almost 10% of these women had diabetes, a rate of ten events per 1,000 person-years. Taken together, our study demonstrates that BP and BP progression are strong predictors of incident type 2 diabetes, an effect independent of BMI and other components of the metabolic syndrome.” [2]

The authors suggest a possible mechanism for the relation between BP and diabetes may be endothelial dysfunction — a dysfunction of the normal biochemical processes carried out by the layer of cells that line the inner surfaces of blood vessels. “It may be a precursor of both hypertension and diabetes,” said Dr

Conen. “Thus, the progression of endothelial dysfunction may cause worsening of both BP and blood glucose. This is in line with the fact that both BP and blood glucose occur together as part of the metabolic syndrome.”

He concluded: “Our findings provide strong evidence that BP and progression of BP are associated with an increased risk of diabetes. They highlight the fact that cardiovascular risk factors are interrelated and occur in clusters. Thus, an important message for physicians and future guidelines is that none of the cardiovascular risk factors should be looked at individually. The combination of all risk factors should be used to make treatment decisions.”

Notes

[1] Blood pressure and risk of developing type 2 diabetes mellitus: The Women’s Health Study. European Heart Journal, doi:10.1093/eurheartj/ehm400

[2] Metabolic syndrome is a combination of medical disorders that increase the risk of cardiovascular disease and diabetes. Components include central obesity, elevated fasting glucose levels, decreased HDL cholesterol, elevated triglycerides and elevated blood pressure.

Note: This story has been adapted from material provided by Oxford University Press.

(Before Present)

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Two hypotheses of evolution of the smallpox-causing virus are compared in the research paper; variola (VARV) is believed to have diverged from a virus carried by rodents. One of the most similar sequences is found in the Taterapox virus (TATV) that infects the West African naked-soled gerbil. The maps show human migration patterns and the emergence of different strains of smallpox variola. To the right are clusters of the various strains, arranged according to patterns of single-point mutations in the viral DNA.
Click here for a high-resolution PDF

News Release: Lawrence Livermore National Laboratory, September 24, 2007

LIVERMORE, Calif. –Smallpox is older than thought, according to results of a new technique reported in the Sept. 24 issue of the Proceedings of the National Academy of Sciences by researchers from Lawrence Livermore National Laboratory and the Centers for Disease Control (CDC).

The researchers created a molecular clock by looking at the rate of random mutations in the smallpox-causing virus collected in 47 locations around the world, from 1946 – 1977. The variation between the strains was compared to sequences from the most similar animal poxes.

The results indicated that a mild and more severe strain diverged either 16,000 or 68,000 years before present, depending on whether accounts from East Asia or Africa are used to calibrate the molecular clock. In either case, this divergence stretches further back in time than previously believed.

The authors compare hypotheses about where and when strains of the virus evolved. No one hypotheses is ruled out, but an ancient origin seems most plausible since the slowly evolving virus now exclusively infects humans, implying that any intermediate link to an animal host has long since died out.

Collaboration between LLNL’s Pathogen Bioinformatics group and the CDC’s Sequencing and Poxvirus groups took place under a Memorandum of Understanding between the Laboratory and the CDC initiated in early 2003.

The initial research focused on determining viral signatures by looking at unique genetic characteristics. The CDC had recently sequenced the genomes of the various smallpox strains, based on the repository it holds for the World Health Organization (the world’s only other declared smallpox storehouse is in Russia).

The disease was considered eradicated in 1980, three years after the last naturally occurring case in 1977. Vaccinations had been stopped in 1972, following an intensive worldwide effort to wipe out the virus. Smallpox, in its most severe form, was deadly in up to 30 percent of cases.

The researchers said the correlation of historical record and a molecular clock provides a framework that could be applied to studying the natural history of other diseases. Although no particular hypotheses of its evolution is supported or disproved, said corresponding author Inger Damon, M.D., Ph.D., acting chief of the CDC’s Poxvirus and Rabies Branch. “It shows the delineation of tantalizing potential connections between different isolates.”

Analysis of isolates from geographically dispersed areas indicated that local pools of old, and perhaps ancient, strains existed. The human disease may have originated from a rodent-borne virus in Africa. The evolutionary analysis suggests that smallpox disease slowly spread westward from East Asia, which would agree with the oldest smallpox-like descriptions from ancient China as far back as 1122 BC. It is unclear when it first reached the New World – some evidence suggests an ancestral virus arrived with early humans and diversified into a mild version there.

The slow spread out of Asia could explain why smallpox descriptions are missing from ancient Greece or Rome as well as the Old and New Testaments.

The Laboratory’s Shea Gardner and CDC’s Yu Li devised a way to concentrate point mutations in the viral DNA, single nucleotide polymorphisms, or “SNPs.” Four nucleotide bases, arranged in varying sequences, spell out the hereditary information encoded in DNA, the genetic material.

As cells multiply and divide, occasional errors creep in to new copies of the genetic instructions. Some errors are more critical than others. The variation allows some individuals among the offspring to be better-adapted to changing conditions, providing an evolutionary advantage that is passed down to their progeny. Over time, some lines flourish and others die out.

For a reliable molecular clock, it would be nice to see the steady rate of mutation in a general sense without a marked effect of change, pro or con, in any particular gene or subset. So the researchers created a simplified approach for looking across the nearly 200,000 DNA base pairs of the virus genome. They concentrated the mutations for comparing sequences by excerpting stretches in which a single change at one point was flanked by seven unchanged bases at each side.

“We assumed there was a molecular clock ticking,” Gardner said. “The question was what was the rate?”
The Laboratory’s intensive computing capabilities complemented the CDC contribution of calibrating the information with historical accounts, Li said.

“It was a valuable opportunity to be able to compare the genomes,” added Lab scientist Beth Vitalis, who helped analyze the data. She added that additional, related studies of virulence factors are in process.

Founded in 1952, Lawrence Livermore National Laboratory is a national security laboratory, with a mission to ensure national security and apply science and technology to the important issues of our time. Lawrence Livermore National Laboratory is managed by the University of California for the U.S. Department of Energy’s National Nuclear Security Administration.

R. H. Belmaker, M.D.
Editorial, Am J Psychiatry

Modafinil is a novel compound first approved as a wakefulness-promoting agent in narcolepsy and later found safe and effective in several controlled studies of attention deficit hyperactivity disorder (ADHD). The biochemical mechanism of modafinil is different from that of the usual pharmacological treatments of ADHD, such as amphetamine, which release dopamine. While there are no studies showing modafinil superior to amphetamine or methylphenidate in ADHD or narcolepsy, modafinil seems to have low abuse potential in animal and human studies and is thus more convenient both for the individual clinician and for the health care delivery system. Additional uses for modafinil based on its stimulant properties have been explored in several additional diagnoses.

Bipolar depression is a high-priority research area because of data showing that bipolar patients spend a large portion of their lives in clinically significant depressions and that current treatments are inadequate for the management of these bipolar depressions. A recent study by Sachs et al. (1) in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that treatment with sertraline or bupropion as an add-on to a mood stabilizer had no benefit in the treatment of bipolar depression. In this issue of the Journal, Frye et al. now report on a multicenter study of modafinil in bipolar depression. The study randomly assigned 85 patients with bipolar disorder and clinically significant depression despite ongoing treatment with mood stabilizers. Forty-four percent of the patients who were designated to receive modafinil add-on responded within the 6 weeks of the study, and only 23% of those receiving placebo add-on responded, a significant difference.

Previous studies have not found modafinil effective in unipolar depression (2). It is tempting to think that this may reflect a higher prevalence of psychomotor retardation in bipolar depression, which is therefore more responsive to modafinil. However, measures of fatigue and sleepiness did not differ after modafinil and placebo treatment in the study by Frye and associates.

Manic switch was not more common with modafinil than with placebo. However, the mean daily dose of modafinil was only 174 mg (maximum, 200 mg), and studies in narcolepsy and ADHD have sometimes used much higher doses. Patients with past histories of stimulant-induced mania were excluded from the Frye et al. study. The risk of mania in clinical use of modafinil for bipolar depression should be evaluated on the basis of the patient’s past history, especially if dose titration above 200 mg is necessary.

Over one-half of the patients in the study were also taking an antidepressant. While the Sachs et al. study suggested that some antidepressants do little to help bipolar depression (1), other antidepressants not included in the Sachs et al. study have been shown to be effective in bipolar depression, especially antidepressants with more noradrenaline-reuptake-inhibiting properties (3). Therapeutic effects of antidepressants in bipolar depression develop over time, and it is unclear in the article by Frye et al. how many patients receiving antidepressants had been taking these drugs for a long period of time or if they started taking them only 2 weeks before the study.

The response rate of patients in the present study on modafinil was 44%, which the authors point out is similar to response rates in several previous studies of antidepressant treatment of bipolar depression (4). More than half of the patients of Frye et al. were already taking antidepressants and a mood stabilizer. The response rate of about 23% was not different for those receiving antidepressants plus placebo and those receiving placebo only. This could suggest that the present patient group represented antidepressant failures, but the rate is similar to the response rate of about 23% in the study by Sachs et al. (1) for bipolar depressed patients treated with placebo or bupropion or paroxetine. Clearly, there are many differences between patient groups meeting criteria for the diagnosis of bipolar depression.

The present study was double-blind, but all participants, both doctors and patients, knew that it was a study of a new medicine with stimulant-like properties. It is likely that appropriate patients referred to this study were felt by themselves and their physicians to need a stimulant-like compound, perhaps because of fatigue, listlessness, or psychomotor retardation. Patients with prominent agitation or insomnia would be less likely to be referred to or consent to participate in a study where they might receive a stimulant. This could be partially responsible for the positive results.

Often small investigator-initiated studies of new compounds find positive results but larger studies fail to confirm them. It is fairly standard to comment after a small positive study that it should be confirmed in a much larger study. This may not be a universal rule, because in a larger study the investigators might lose the motivation to choose an appropriate subgroup that could be responsive to the compound being tested. It is biologically plausible that modafinil might be useful in some cases of bipolar depression, and the present results in 85 patients support this possibility. A study of perhaps 300 patients might stress the recruitment capacities of the participating centers and lead them to be less discriminating in their choice of patients. This strategy might not lead to definitive further knowledge on the usefulness of modafinil for some bipolar depressed patients.

Does the present study mean that modafinil is the treatment of choice for all bipolar patients with depression? We should avoid assuming that a statistical benefit of one treatment for bipolar depression as a diagnostic entity is relevant for every patient with this heterogeneous condition. The patients in the present study were all taking mood stabilizers. Starting a mood stabilizer would be the first choice for any patient not being so treated. Many of the patients of Frye et al. were taking one mood stabilizer, and Young et al. (5) have shown that adding a second mood stabilizer can often be effective in patients who are having a depressive relapse of bipolar disorder while taking one mood stabilizer. Given that modafinil is an expensive treatment, there well may be bipolar depressed patients for whom appropriate treatment would be a reuptake inhibitor that is also effective on noradrenaline, such as venlafaxine (3).

There have been some preclinical studies of potential wakefulness-inducing treatments that work biochemically by inhibiting the histamine H3 receptor in the brain. However, modafinil has behavioral effects even in mice whose H3 receptor is genetically knocked out (6). It is possible that modafinil is working on the hypocretin system (7), a unique peptide neurotransmitter system that is abnormal in narcolepsy but is unlikely to be a key player in the biochemical mechanism of bipolar depression. Therefore, one could think of modafinil as a nonspecific or symptomatic treatment of bipolar depression. Recent studies have found treatments as diverse as ketamine (8), an anesthetic that antagonizes N-methyl-D-aspartic acid receptors, on the one hand, and exercise (9), on the other hand, to be useful in depression. It may be that a symptomatic rather than a hypothesis-bound mode of thinking is the best way for a clinician to help a patient with bipolar depression. Am J Psychiatry 164:1143-1145, August 2007, doi: 10.1176/appi.ajp.2007.07050749
© 2007 American Psychiatric Association

Science Daily — Researchers report that fasting or eating half as much as usual every other day may shrink your fat cells and boost mechanisms that break down fats.

Consuming less calories and increasing physical activity is usually what people do to lose weight and stay healthy. But some people prefer to adopt a diet which consists of eating as much as they want one day while fasting the next. On each fasting day, these people consume energy-free beverages, tea, coffee, and sugar-free gum and they drink as much water as they need.

Although many people claim that this diet, called alternate-day fasting (ADF), help them lose weight and improved their health, the effects on health and disease risk of ADF are not clear.

Krista Varady and colleagues studied the effects of alternate-day fasting on 24 male mice for four weeks. To assess the impact of ADF on the health of the mice, the scientists not only tested mice that followed and didn’t follow an ADF diet, but they also studied mice that followed the diet only partially: a group of mice consumed 50 percent of their regular diet every other day (ADF-50%) and another consumed 75 percent of their regular diet every other day (ADF-25%).

The scientists noticed that the ADF-100% mice lost weight and the fat cells of both the ADF-100% and ADF-50% groups shrunk by more than half and by 35 percent, respectively. Also, in these two groups of mice, fat under the skin — but not abdominal fat — was broken down more than in mice that did not follow the diet.

These results suggest that complete and modified ADF regimens seem to protect against obesity and type 2 diabetes but do not result in fat or weight loss. More studies will be needed to confirm whether the long-term effects of ADF regimens are beneficial for health and reduce disease risk, the scientists conclude.

Article: “Effects of modified alternate-day fasting regimens on adipocyte size, triglyceride metabolism and plasma adiponectin levels in mice,” by Krista A. Varady, D. J. Roohk, Y. C. Loe, B. K. McEvoy-Hein, and M. K. Hellerstein

Note: This story has been adapted from a news release issued by American Society for Biochemistry and Molecular Biology.

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