Friday, July 31, 2009
Similarities in brain activity during lucid dreaming and psychosis suggest that dream therapy may be useful in psychiatric treatment, a European Science Foundation (ESF) workshop has found. This is strengthened by the potential evolutionary relationship between dreams and psychosis.
Lucid dreaming – when you are aware you are dreaming – is a hybrid state between sleeping and being awake. It creates distinct patterns of electrical activity in the brain that have similarities to the patterns made by psychotic conditions such as schizophrenia. Confirming links between lucid dreaming and psychotic conditions offers potential for new therapeutic routes based on how healthy dreaming differs from the unstable states associated with neurological and psychiatric disorders.
New data affirms the connection by showing that while dreaming lucidly the brain is in a dissociated state, according to Ursula Voss from the University of Frankfurt in Germany. Dissociation involves losing conscious control over mental processes, such as logical thinking or emotional reaction. In some psychiatric conditions this state is also known to occur while people are awake.
"In the field of psychiatry, the interest in patients' dreams has progressively fallen out of both clinical practice and research. But this new work seems to show that we may be able to make comparisons between lucid dreaming and some psychiatric conditions that involve an abnormal dissociation of consciousness while awake, such as psychosis, depersonalisation and pseudoseizures." said the workshop's convener Silvio Scarone, from the Università degli Studi di Milano in Milan, Italy.
Meanwhile, the previously discredited idea of treating some conditions with dream therapy has attracted interest from clinicians. An example is people suffering from nightmares can sometimes be treated by training them to dream lucidly so they can consciously wake up.
"On the one hand, basic dream researchers could now apply their knowledge to psychiatric patients with the aim of building a useful tool for psychiatry, reviving interest in patients' dreams," continues Scarone. "On the other hand, neuroscience investigators could explore how to extend their work to psychiatric conditions, using approaches from sleep research to interpret data from acute psychotic and dissociated states of the brain-mind."
The existence of such psychotic conditions may be rooted in the evolutionary role of dreams, where dreaming is thought to have emerged to enable early humans to rehearse responses to the many dangerous events they faced in real life. Developed by Antti Revonsuo at University of Turku in Finland, if this threat simulation theory is correct it may have origins even further back in evolution, given that other mammals such as dogs also exhibit the characteristic electrical activity of dreaming.
Researchers also looked at the idea that paranoid delusions and other hallucinatory phenomena occur when the dissociative dreaming state involving replay of threatening situations is carried through into wakefulness.
"Exposure to real threatening events supposedly activates the dream system, so that it produces simulations that are realistic rehearsals of threatening events in terms of perception and behavior," said Scarone. "This theory works on the basis that the environment in which the human brain evolved included frequent dangerous events that posed threats to human reproduction. These would have been a serious selection pressure on ancestral human populations and would have fully activated the threat simulation mechanisms."
However, dreaming is unlikely to have evolved purely to recreate threats. It may also have a role in the learning process, according to Allan Hobson, a psychiatrist and dream researcher recently retired from Harvard University in the US. Contents are added while you are awake and integrated with the automatic program of dream consciousness during sleep. This works with observations that daytime learning is consolidated by night-time sleeping, leading to the phenomenon where people remember facts better the day after they have learnt them than at the time.
Around one in five young people in the U.S. have a current mental, emotional, or behavioral disorder. About half of all adults with mental disorders recalled that their disorders began by their mid-teens and three-quarters by their mid-20s. Early onset of mental health problems have been associated with poor outcomes such as failure to complete high school, increased risk for psychiatric and substance problems, and teen pregnancy.
A new article by Mary E. Evans, RN, PhD, FAAN, published in the Journal of Child and Adolescent Psychiatric Nursing assesses the recently released government report on preventing these disorders among young people. Dr. Evans' paper concludes that using certain interventional programs in schools, communities and health care settings, risk for mental illness can be better identified and treated.
The article highlights the fact that specific risk and protective factors have been identified for many disorders. For example, certain thinking and behavioral patterns are risks for the development of depression. Nonspecific factors that increase risk for developing disorders also include poverty, marital conflict, poor peer relations, and community violence. Also, certain neurobiological factors contribute to the development of disorders in youth, but this is also influenced by environmental factors.
A key risk factor for externalizing disorders is aggressive social behavior that begins in early childhood. A number of interventions have been developed to provide training in parenting skills to prevent the development of aggressive and antisocial behavior. In addition, some preventive interventions have targeted specific disorders such as depression and schizophrenia. Cognitive behavioral treatment for high-risk adolescents has lowered the rate of major depressive symptoms. Also, a number of community-based programs have been shown to be effective in promoting healthy behaviors.
Prevention of Mental, Emotional, and Behavioral Disorders in Youth: The Institute of Medicine Report and Implications for Nursing
Mary E. Evans
Journal of Child and Adolescent Psychiatric Nursing Early View, Date: August 2009
Link to JCAPN abstract
A lack of sunlight is associated with reduced cognitive function among depressed people. Researchers writing in BioMed Central's open access journal Environmental Health used weather data from NASA satellites to measure sunlight exposure across the United States and linked this information to the prevalence of cognitive impairment in depressed people.
Shia Kent, from the University of Alabama at Birmingham, led a team of US researchers who used cross-sectional data from 14,474 people in the NIH-NINDS-funded REGARDS study, a longitudinal study investigating stroke incidence and risk factors, to study associations between depression, cognitive function and sunlight.
He said: "We found that among participants with depression, low exposure to sunlight was associated with a significantly higher predicted probability of cognitive impairment. This relationship remained significant after adjustment for season. This new finding that weather may not only affect mood, but also cognition, has significant implications for the treatment of depression, particularly seasonal affective disorder."
Kent and his colleagues speculate that the physiological mechanisms that give rise to seasonal depression may also be involved in sunlight's effect on cognitive function in the context of depressive symptoms. Cognitive function was assessed by measurement of short-term recall and temporal orientation. As well as regulating the hormones serotonin and melatonin, light has been shown to also affect brain blood flow, which has in turn been linked with cognitive functions.
The researchers write: "Discovering the environment's impact on cognitive functioning within the context of seasonal disorders may lead not only to better understanding of the disorders, but also to the development of targeted interventions to enhance everyday functioning and quality of life."
Effect of sunlight exposure on cognitive function among depressed and non-depressed participants: a REGARDS cross-sectional study.
Shia T Kent et al
Environmental Health, 2009; 2009, 8:34doi:10.1186/1476-069X-8-34
Link to EH abstract
Science Daily (July 31, 2009)
A team of researchers from Case Western Reserve University School of Medicine have solved the mystery of why some children are more susceptible to malaria infection and anemia. These novel findings suggest that some children who are exposed to Plasmodium falciparum malaria before birth become tolerant to the malaria parasites, or their soluble products. This tolerance, which persists into childhood, reduces the ability of the immune system to attack and destroy parasites and increases the susceptibility of these children to develop a malaria infection. It also increases their risk for anemia.
The study is led by Indu Malhotra, Ph.D., and Christopher King, M.D., Ph.D., professor of international health, medicine, and pathology, with their colleagues at the Center for Global Health and Diseases at the Case Western Reserve University School of Medicine and their Kenyan colleagues at the Kenya Medical Research Institute and Division of Vector Borne Diseases.
The Case Western Reserve study investigated how prenatal malaria exposure affects anti-malaria immunity in young children and their susceptibility to subsequent malaria infections. Little is known about how immunity to malaria develops in infants, a process which researchers must understand in order to design effective vaccines for children. In particular, it is unclear how a mother's malaria infection affects a child's acquisition of anti-malaria immunity.
"These findings could have important implications for the design of malaria vaccines for use in areas where children are often exposed to malaria before birth and for the design of strategies for the prevention of malaria during pregnancy," says Dr. Christopher King.
The babies were classified into three groups: "sensitized" – those babies whose cord blood cells produce activating cytokines in response to the malaria antigens; "exposed, not-sensitized'' – babies whose bodies did not produce activating cytokines but made an inhibitory cytokine; and "not-exposed''– babies born to mothers with no P. falciparum malaria infection at delivery.
In their first three years of life, the "exposed, not-sensitized" group had a 60 percent greater risk of malaria infection than the "not-exposed" group and a slightly higher risk of malaria infection than the "sensitized" group. They also had lower hemoglobulin levels, a sign of anemia, than the other babies. The T cells of "exposed, not-sensitized" children were less likely to make activating cytokines in response to malaria antigens.
Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya.
Indu Malhotra et al
PLoS Medicine, 6(7): e1000116 DOI: 10.1371/journal.pmed.1000116
Link to PLoS Med abstract
— The typical dose of a medication considered pivotal in treating tuberculosis effectively is much too low to account for modern-day physiques, UT Southwestern Medical Center researchers said.
The finding, reported online and in the August edition of Antimicrobial Agents and Chemotherapy, is particularly important for those living in societies plagued by obesity, said Dr. Tawanda Gumbo, associate professor of internal medicine at UT Southwestern and the study's lead author.
"What really drives the variability of this particular drug is patient weight and gender, so in our simulations we took that into account," Dr. Gumbo said. "What we found is that we're really using doses for very skinny people – 105 to 110 pounds. I haven't met many adults who are at that weight."
About one-third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes TB, and as many as 2 million people die from the disease each year. TB, which is the leading cause of death among people infected with HIV/AIDS, kills more people than any other disease caused by a single infectious agent, according to the National Institutes of Health. Treatment usually lasts six to 12 months and includes a combination of antibiotics such as Pyrazinamide, the drug examined in this study.
Because treatment typically includes multiple drugs, introducing new ones to existing regimens has made it harder to identify which, if any, of the drugs are working at the current dosage levels. Researchers also have struggled to identify the needed dosage as well as exactly where in the body these drugs work to combat the bacterium.
The new model developed at UT Southwestern uses cultured cells to gauge the effectiveness and proper dosage of anti-tuberculosis drugs.
Pharmacokinetics-Pharmacodynamics of Pyrazinamide in a Novel In Vitro Model of Tuberculosis for Sterilizing Effect: a Paradigm for Faster Assessment of New Antituberculosis Drugs
Tawanda Gumbo et al
Antimicrobial Agents and Chemotherapy August 2009, p. 3197-3204, Vol. 53, No. 8 doi:10.1128/AAC.01681-08
Link to AAC abstract
A U.S. plan to rely on swine flu vaccines without ingredients to stretch the supply would reduce the number of available shots just when other countries need them most, the British journal Lancet said in an editorial.
The ingredients, called adjuvants, have never been approved for flu vaccines in the U.S. and are controversial because some studies show they cause immune disorders in mice. The World Health Organization recommended on July 7 that adjuvants be used to boost global amounts of vaccine, and the Lancet criticized the U.S. for plans to rely exclusively on standard formulations.
The U.S. Health and Human Services Department declared a public health emergency over swine flu in April, giving the Food and Drug Administration the power to allow the use of unapproved medical products including adjuvants. The health department agreed to purchase more than $415 million of the vaccine additives, while saying it may not use them if enough shots are available for U.S. residents.
“The USA must support the use of dose-sparing strategies to avoid depletion of an already short vaccine supply,” said the authors of the Lancet editorial. “All countries will require the vaccine, but current manufacturing capacity will not be able to meet this demand.”
Adjuvants are mixes of oil and water that trigger a stronger response in the body to antigen, the substance that induces immunity. The additives, whose effectiveness vary by flu strain, may boost the strength of the antigen as much as 10- fold, as was the case with a bird flu vaccine approved in Europe, said John Treanor, a professor of medicine, microbiology and immunology at the University of Rochester, in an interview.
MF59, an oil-and-water adjuvant made by Novartis AG and approved in Europe, has been safely given to more than 40 million people, mostly adults, to prevent seasonal flu, according to the company.
The U.S. plans human tests to determine safety and effectiveness of flu adjuvants and will “review all clinical data to inform our decision on their potential use,” said Bill Hall, a spokesman for the Health and Human Services Department, in an e-mail.
“We have provided significant support to the World Health Organization’s vaccine programs, and we will continue to work to support our international partners and developing nations around the world,” Hall said.
Editorial: Supply and safety issues surrounding an H1N1 vaccine
The Lancet, Volume 374, Issue 9687, Page 358, 1 August 2009 doi:10.1016/S0140-6736(09)61395-7
Link to The Lancet editorial
University of Missouri news bureau (July 28, 2009)
Vaccines to protect against sexually transmitted diseases, including HIV and herpes, are being developed and may soon be available to college students. However, limited research has been conducted to determine if students will accept the vaccines once they are available. In a new study, a University of Missouri researcher has found that students who feel invulnerable, or invincible, to physical harm are unlikely to get an HIV vaccine.
Alternately, students who feel invulnerable to psychological harm are more likely to get the vaccine.
"Previous researchers have used invulnerability measures to predict health-endangering behaviors in students, but this study is unique in that it considers the role of invulnerability in students' health-protective or preventative behaviors," said Russell Ravert, assistant professor in the MU College of Human Environmental Sciences.
In the study, Ravert measured two invulnerability factors: danger and psychological. Students with increased danger invulnerability, those who viewed themselves as physically invincible, were more likely to decline the vaccine. One explanation is that strong feelings of danger invulnerability may be associated with decreased threat, which can diminish protective behaviors, Ravert said.
Students who felt psychological invulnerability, those who didn't care what others thought, were more likely to accept a vaccine. Students' psychological invulnerability may protect against the possible stigma associated with getting vaccinated for HIV, or other sexually transmitted diseases, Ravert said.
"It is important to determine what factors are associated with vaccine acceptance because not all students will be willing to take vaccines," Ravert said. "Efforts to promote vaccines should consider that students who aren't worried about being harmed are less likely to get the vaccine, even when it's warranted by their sexual behavior."
In the study, the strongest predictor of vaccine acceptance was students' perceived susceptibility to contracting HIV, followed by their number of sexual partners. Students' decisions also were influenced by the cost of the vaccine.
In future studies, Ravert will examine college students' invulnerability beliefs as they relate to risk-taking behaviors and other preventative health behaviors, as well as how invulnerability beliefs vary across age groups.
College Student Invulnerability Beliefs and HIV Vaccine Acceptability.
Russell D. Ravert, PhD and Gregory D. Zimet, PhD
American Journal of Health Behavior, Vol 33 Issue: 4 Cover date: July/August 2009 Page(s): 391-399
Link to AJHB abstract
Thursday, July 30, 2009
A new urine test developed with funding from the Wellcome Trust will allow doctors to diagnose Chlamydia infection in men within the hour, improving the ability to successfully treat the infection on the spot and prevent re-transmission.
Chlamydia, caused by the bacterium Chlamydia trachomatis, is the most common sexually-transmitted bacterial infection in the UK, particularly amongst sexually active men and women aged 16-24 years.
In the majority of cases, the disease is asymptomatic in both men and women. If symptoms show, they may include discharge or pain when passing urine for men. Recent research suggests that, if untreated – even when no symptoms show – it may be a cause of reduced fertility. In women, it can lead to even more serious complications, such as pelvic inflammatory disease, chronic pelvic pain and ectopic pregnancy.
Once diagnosed, Chlamydia can be treated easily with a one-off antibiotic pill. However, until now, male rapid tests for Chlamydia have been relatively inaccurate and involved urethral swabs, which can cause discomfort.
"Horror stories about painful swabs have put men off getting tested for Chlamydia, and other non-invasive tests are expensive, technically complex and take days to obtain the result," explains Dr Helen Lee from the University of Cambridge. "This has led to many cases of infection in men going undiagnosed and being transmitted to their female partners, with potentially more serious complications."
The Chlamydia Rapid Test, a urine test developed by Dr Lee and colleagues at Diagnostics for the Real World (DRW) and the University of Cambridge, can be used with minimal training. It is designed to be used in conjunction with FirstBurst, a device for collecting the first voided urine from men. FirstBurst collects six times the amount of Chlamydia bacteria compared to a standard urine sample. The test then uses a unique signal amplification system developed by DRW to boost the test's sensitivity and gives the results in less than an hour.
The British Medical Journal publishes an evaluation† of the test, which shows that it is significantly more accurate than existing urine-based rapid tests. The researchers took samples from over 1,200 men at two clinical sites. They found that the test correctly identified Chlamydia infection in 84.1% of samples, more accurate than the nearest competitor rapid tests for men.
"Without an effective and rapid testing programme for men, we are unlikely to succeed in efforts to control Chlamydia infection," says Dr Lee. "This new test is both accurate and swift, allowing men attending the clinics to be tested and treated on site in one visit."
The researchers also questioned participants about their willingness to wait for the test result. The vast majority – 96% - said they were willing to wait an hour or more.
The Chlamydia Rapid Test has received regulatory approval and is on the market in France, where it is used in clinics, and will shortly come onto the market in Spain, Portugal, Italy and a number of other European countries.
"If we are to stem the tide in the spread of Chlamydia, we have to step up a gear in our ability to diagnose and treat this infection," says Dr Ted Bianco, Director of the Wellcome Trust's Technology Transfer Division, which funded the development of the test. "Right now, our tests are too slow to permit on the spot treatment or too insensitive to detect an adequate proportion of cases. The new assay offers a way forward. Health authorities everywhere that are serious about tackling Chlamydia need to put this 'test to the test' in the context of their national programs of control."
It is hoped that the new test will also be of particular use in the developing world, where management of Chlamydia in men is often based on self-diagnosis and specific diagnostic tests are rarely available. A high prevalence of Chlamydia infection amongst sex workers in these countries means that male customers are likely to transmit infection to other sexual partners. The Chlamydia Rapid Test requires minimum instrumentation and does not need to be carried out by a medically-trained professional.
Performance evaluation of a new rapid urine test for chlamydia in men: prospective cohort study
Elpidio-Cesar Nadala et al
British Medical Journal 2009;339:b2655 doi:10.1136/bmj.b2655
Link to BMJ abstract
Simeon Bennett for Bloomberg News (July 30, 2009)
Malaria is becoming resistant to the most powerful drugs available in Southeast Asia, as the World Health Organization races to stop the spread of the strain that could be “disastrous” for global malaria control.
Treatments derived from artemisinin, the basis of the most effective anti-malaria drugs, took almost twice as long to clear the parasites that cause the disease in patients in western Cambodia as in patients in northwestern Thailand, according to a study published in the New England Journal of Medicine.
The delay in parasite clearance times shows the drugs are losing their power against the disease in Cambodia, the study said. The failure of artemisinin-based treatments would be “disastrous” for global efforts aimed at curbing the death and disease wrought by the malady, said Arjen Dondorp, who led the study at the Mahidol Oxford Research Unit in Bangkok.
“There is no question that this is resistance to artemisinin,” Carlos Campbell, a malaria expert with the Seattle-based Program for Appropriate Technology in Health, or PATH, wrote in an editorial accompanying the study. “History warns us that it will intensify and spread unless containment steps are taken.”
Scientists have known for decades that Pailin, near Cambodia’s border with Thailand, is a breeding ground for drug- resistant malaria. Chloroquine and Roche Holding AG’s Fansidar started to fail there in the 1950s and 1960s, before becoming ineffective elsewhere, according to the study. The WHO, with $23 million from the Bill & Melinda Gates Foundation, is coordinating efforts to prevent artemisinin-resistant malaria from spreading to Africa, which has 90 percent of the world’s cases of the disease.
Campbell noted that there isn’t an alternative class of malaria drugs to replace artemisinin derivatives. Artemisinin- based medications work by giving malaria a short, sharp shock, clearing most of the parasites from the blood within hours. The drawback is they don’t remain in the body. The WHO’s guidelines recommend combining the drug with one of several less-powerful, longer-lasting medicines that eradicate stragglers.
Those other drugs, such as mefloquine, may cause adverse effects including nausea, vomiting and nightmares. When the two drugs are sold side by side, rather than combined in a single pill, some patients take only the artemisinin to avoid unpleasant symptoms, paving the way for relapses and drug resistance.
Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp, M.D.,
The New England Journal of Medicine, 361: 445-467,No 5 July 30, 2009
Link toNEJM abstract
Editorial: Malaria Control — Addressing Challenges to Ambitious Goals
Carlos C. Campbell, M.D., M.P.H.
The New England Journal of Medicine, 361: 522-523, No 5 July 30, 2009
Link to NEJM editorial extract/361/5/522
Scientists in Singapore, The Netherlands and France report that they have developed a novel immunization method that will induce fast and effective protection in humans against the life-threatening malaria parasite, Plasmodium falciparum, which infects 350 to 500 million people world-wide and kills over one million people each year.
"It is not practical to apply the experimental method used in our study as a means of vaccination," said Laurent Renia, Ph.D., principal investigator at the Singapore Immunology Network (SIgN).
"But, this method of immunization could be applied successfully to similar investigations to find biological markers which would indicate the extent of protection against malaria. It would thus advance the currently limited knowledge of what constitutes protective anti-malaria immunity in humans," added Dr. Renia, who played a pivotal role in the research project by conceptualizing the experimental protocol and designing and conducting the follow-up experiments.
The scientists' experimental approach involved exposing two groups of healthy human subjects to mosquitoes once a month over a three-month period at the Radboud University Nijmegen Medical Centre in The Netherlands. One group (vaccine group) was exposed to mosquitoes infected with the malaria parasite, P. falciparum, and the second group (control group) to uninfected mosquitoes.
During the period of exposure, the study participants were treated with chloroquine, an anti-malaria drug that prevented P. falciparum from multiplying in the blood. Eight weeks after the last round of immunization and four weeks after the discontinuation of chloroquine administration, the participants in both groups were re-exposed to infected mosquitoes and tested for protection against P. falciparum. The four-week period was considered to be sufficient for chloroquine levels to drop below that which might inhibit parasite multiplication and malaria development.
The scientists found that all individuals in the vaccine group had acquired complete protection against the parasite, while those in the control group who did not receive immunization developed parasites in their blood.
This unique method of immunization allowed the human immune system to direct its response to eliminating the P. falciparum parasite at the earlier, liver stage of its life cycle. (Chloroquine kills the parasite at the later blood stage.) To induce an immune response, the scientists used malaria parasites that were whole and intact. Other methods have used genetically inactivated parasites or parasites that had been weakened by radiation to induce anti-malaria immunity.
The unique immunization method demonstrated a significant improvement over other experimental malaria vaccines that are currently used in clinical trials and that could induce up to only 50% protection in humans.
Using their novel approach, the scientists examined and gained important insight into the protective anti-malaria immune response in humans, which is difficult to acquire, whether through previous exposure or vaccination. (Naturally acquired immunity to malaria develops over a period of 10 to 20 years and with repeated exposure to malaria parasites.)
By studying the antibodies, biological substances and cells present in the human subjects from the time of pre- to post-immunization, the scientists identified a specialized group of parasite-specific immune cells that indicated protection against P. falciparum in humans.
These immune cells, known as pluripotent effector memory T cells, which can mediate the removal of pathogens from the body, were found in the blood samples of subjects who had been immunized and re-exposed to P. falciparum. The control group did not have these specialized cells. These results indicate that these cells could serve as a biological indicator to check for malaria protection in humans during the stages of vaccine development.
"This is an elegant study which uses nature itself to tell us the answer to some basic questions regarding what can induce protective immunity against malaria," said Raymond Lin, M.D., senior consultant and Head of Microbiology at the Department of Laboratory Medicine of Singapore's National University Hospital.
"It shows that exposure to whole unmodified malarial parasites can protect against subsequent infection, while minimizing adverse events through the use of anti-malarial drugs," he added. "This provides hope for future vaccines and offers prospects of alternatives to conventional vaccine approaches. Also, the remarkable experiment studies infection in humans, using real parasites and real mosquitoes yet in a controlled and safe clinical trial setting. Future vaccine researchers will doubtless refer to this paper for guidance. Malaria is a major health threat in this region which Singaporeans are vulnerable to, so having world-class malaria expertise here is important to us."
Protection against a Malaria Challenge by Sporozoite Inoculation.
Meta Roestenburg, M.D.et al,
The New England Journal of Medicine, 361: 468-477,No 5 July 30, 2009
Link to NEJM abstract
UCSF researchers have identified a new potential drug target for the herpes virus that causes Kaposi’s sarcoma, re-opening the possibility of using the class of drugs called protease inhibitors against the full herpes family of viruses, which for 20 years has been deemed too difficult to attain.
The new drug target, which is known as a protease dimer, could serve as a model for developing new therapeutics for diseases ranging from cancer to Alzheimer’s, the researchers say. Findings are reported in the Advance Online Publication section of Nature Chemical Biology.
Most current antiviral drugs target the active sites of viral proteins, where enzymes and receptors work in a lock-and-key approach to either activate or deactivate that particular protein, the researchers explained. Traditionally, drug development has focused on inhibiting that lock-and-key action to prevent the enzyme, or receptor from being effective.
Some viral enzymes known as proteases, however, including those for HIV and the herpes virus family, take the form of a dimer, or two identical halves – much like a fully opened clamshell – in their most stable state. Those proteases play an essential role in making the virus infectious, but require the two clamshell halves to bind together to be activated, according to the paper.
The HIV protease was successfully targeted for drug development in the 1980s, by blocking the active site on the surface of the dimer, but the herpes virus protease dimer has consistently eluded efforts to disrupt it at its active site, the researchers said.
The UCSF team set out to find ways to instead prevent the two halves of the dimer from connecting at that clamshell joint, to prevent it from activating. What they found was a new target on the unstable, monomer form of the protease, which responded well to a chemical inhibitor.
“If you disrupt the protein-protein interactions, you don’t need the key to a specific lock,” said Charles S. Craik, PhD, senior author on the paper and a professor of pharmaceutical chemistry in the UCSF School of Pharmacy. “Instead, we’re essentially preventing the lock from being made in the first place.”
Craik, who also led a team that identified HIV protease inhibitors in the late 1980s, said the Nature Chemical Biology paper validates this new site as a viable option for small-molecule drugs to treat Kaposi’s, as well as other members of this viral family.
“All known herpes virus proteases are structurally similar,” Craik explained. “The inhibitor we found knocks out not only KS, but also the cytomegalovirus protease, so the site we’ve identified here could be a target for a broad-acting inhibitor against the entire viral family.”
To their knowledge, the researchers said, this is the first small-molecule inhibitor of a herpes virus protease to not only act outside the active site, but also to select for the partially unfolded protein to keep it from forming the dimer interface.
Herpes viruses make up one of the most prevalent viral families, including eight human viruses that cause a variety of devastating illnesses, the researchers said. Those include mononucleosis (Epstein-Barr virus), shingles (Varicella zoster virus), genital herpes (herpes simplex), retinitis (cytomegalovirus) and cancer (Kaposi’s sarcoma). While therapies exist for these viruses, they often have negative side effects and are facing rising viral resistance.
In addition to validating herpes virus proteases as suitable targets, Craik said this research was also among the first to use computational design to identify and create a potential drug to target that protease interface.
Using high-throughput screening, the team screened a library of 182 compounds that it had specifically and rationally designed to mimic the protease interface. The work identified six molecules that inhibited the Kaposi’s sarcoma virus protease activity by at least 50 percent, including one that was highly potent.
Inhibition of a viral enzyme by a small-molecule dimer disruptor
Tina Shahian et al
Nature Chemical Biology Published online: 26 July 2009 | doi:10.1038/nchembio.192
Link to NCB abstract
A meta-analysis of more than 50,000 patients has shown that general practitioners (GPs) have great difficulty separating those with and without depression, with substantial numbers of missed and misidentified.
GPs looking for depression make more misidentifications (false positives of depression) than the number of depressions they correctly spot following an initial consultation but accuracy could improved by re-assessment of people suspected of having depression.
These are the conclusions of an article published Online First and in an upcoming edition of The Lancet, written by Dr Alex Mitchell of University of Leicester together with Dr Amol Vaze, and Dr Sanajay Rao of Leicester Partnership Trust. The study pooled 41 trials from nine countries that used robust outcome standard of a semi-structured interview to assess depression. The researchers found that GPs were able to recognize about half of people who had clinical depression and correctly reassured 80% of healthy people.
Dr Alex Mitchell said "Imagine a typical GP who is trying to spot depression in a rural practice. He or she might see 100 people over five days. If all the people with depression came to see the GP at once, they would fill the surgery for at least half a day. However the hard pressed GP would actually only spot half of these cases and half would be missed. On four days the GP would see people with other complaints but he or she would mistakenly diagnose up to one in five as depressed, equivalent to almost one full day of contacts. In the worst case scenario false diagnoses could outnumber true diagnoses three to one."
Writing in the journal, the researchers said: "Our results should not be interpreted as a criticism of GPs for failing to diagnose depression but rather a call for better understanding of the problems that non-specialists face."
Dr Mitchell commented further that "research also suggests equivalent errors in the diagnosis of depression from allied health professionals and hospital specialists. Health professionals may be reluctant to give a label of depression, particularly in the medical notes. Further not all diagnostic errors are converted into therapeutic mistakes. Clinicians appear to treat those in whom they are most confident of the diagnosis and not those in whom a diagnosis is uncertain. Clinicians may also revise their diagnosis with subsequent assessments and we recommend that GPs give such people two appointments rather than one before coming to a decision, if the diagnosis is not initially clear."
Clinical diagnosis of depression in primary care: a meta-analysis
Dr Alex J Mitchell MRCPsych, Amol Vaze MRCPsych, Sanjay Rao MRCPsych
The Lancet Early Online Publication, 28 July 2009 doi:10.1016/S0140-6736(09)60879-5
Link to The Lancet article
A year ago, a study by Rhode Island Hospital and Brown University researchers reported that fewer than half the patients previously diagnosed with bipolar disorder received an actual diagnosis of bipolar disorder after using a comprehensive, psychiatric diagnostic interview tool --the Structured Clinical Interview for DSM-IV (SCID). In this follow-up study, the researchers have determined the actual diagnoses of those patients.
Their study is published in the July 28 ahead of print online edition of The Journal of Clinical Psychiatry.
Under the direction of lead author Mark Zimmerman, MD, director of outpatient psychiatry at Rhode Island Hospital, the researchers' findings indicate that patients who received a previous diagnosis of bipolar disorder that was not confirmed by a SCID, they were significantly more likely to be diagnosed with borderline personality disorder as well as impulse control disorders.
Zimmerman, who is also an associate professor of psychiatry and human behavior at The Warren Alpert Medical School of Brown University, says, "In our study, one quarter of the patients over-diagnosed with bipolar disorder met DSM-IV criteria for borderline personality disorder. Looking at these results another way, nearly 40 percent (20 of 52) of patients diagnosed with DSM-IV borderline personality disorder had been over-diagnosed with bipolar disorder."
The results of the study also indicate that patients who had been over-diagnosed with bipolar disorder were more frequently diagnosed with major depressive disorder, antisocial personality disorder, posttraumatic stress disorder and eating and impulse disorders.
Zimmerman and colleagues note that "we hypothesize that in patients with mood instability, physicians are inclined to diagnose a potentially medication-responsive disorder such as bipolar disorder rather than a disorder such as borderline personality disorder that is less medication-responsive."
In their previously published study that concluded bipolar disorder was over-diagnosed, they state that the over-diagnosis of bipolar disorder can have serious consequences, because while bipolar disorder is treated with mood stabilizers, no medications have been approved for the treatment of borderline personality disorder. As a result, over-diagnosing bipolar disorder can unnecessarily expose patients to serious medication side effects, including possible impact to renal, endocrine, hepatic, immunologic and metabolic functions.
Zimmerman concludes, "Because evidence continues to emerge establishing the efficacy of certain forms of psychotherapy for borderline personality disorder, over-diagnosing bipolar disorder in patients with borderline personality disorder can result in the failure to recommend the most appropriate forms of treatment."
Psychiatric Diagnoses in Patients Previously Overdiagnosed With Bipolar Disorder
Mark Zimmerman, MD; Camilo J. Ruggero, PhD; Iwona Chelminski, PhD; and Diane Young, PhD
The Journal of Clinical Psychiatry. Online ahead of print: July 28, 2009 (doi:10.4088/JCP.08m04633)
Link to JCP abstract
Wednesday, July 29, 2009
Science Daily (July 29, 2009)
The American Academy of Cosmetic Surgery announces the results of its 2009 Less Common Cosmetic Procedures consumer survey saying the media has coined these cosmetic procedures as 'fringe' and made it seem that they are in high demand but it is important to clarify the facts. The results reveal that less common cosmetic procedures are generally over-hyped and over-analyzed.
According to survey results, procedures such as bicep or tricep implants, calf implants, buttock implants, lip implants, penile enlargement and vaginal rejuvenation are performed significantly less than other cosmetic procedures. Only 1.6% of respondents reported ever having a less common cosmetic procedure. That number is significantly small and lacks the evidence of a growing trend. When respondents were asked to report what kind of less common cosmetic surgery procedure they had performed, the most common response was eyelash restoration (42.9%) and bicep or tricep implants (28.6%).
"This survey highlights that even though there has been increased attention on these procedures, the numbers prove that the trend is minimal at this point in time," said Dr. Patrick McMenamin, MD, President of the AACS. Although 'fringe' procedures are underperformed, safety still needs to be a priority.
When asked about concerns regarding less common cosmetic procedures, the majority of respondents indicated they were most concerned about safety (88.8%) and cost (81.8%).
There is no doubt using a sunbed or sunlamp will raise the risk of skin cancer. Previously, the International Agency for Research on Cancer (IARC) assessed sunbeds and sunlamps as "probably carcinogenic to humans".
But it now says their use is definitively "carcinogenic to humans".
Campaigners believe the move, announced in the journal Lancet Oncology, will increase pressure for tighter industry regulation of sunbed use.
The new assessment puts sunbed use on a par with smoking or exposure to asbestos.
The IARC is an expert committee that makes recommendations to the World Health Organization. It made its decision following a review of research which concluded that the risk of melanoma - the most deadly form of skin cancer - was increased by 75% in people who started using sunbeds regularly before the age of 30.
In addition, several studies have linked sunbed use to a raised risk of melanoma of the eye. The charity Cancer Research UK warned earlier this year that heavy use of sunbeds was largely responsible for the number of Britons being diagnosed with melanoma topping 10,000 a year for the first time.
A review of human carcinogens—Part D: radiation
Fatiha El Ghissassi et al n behalf of the WHO International Agency for Research on Cancer Monograph Working Group
The Lancet Oncology, Volume 10, Issue 8, Pages 751 - 752, August 2009 doi:10.1016/S1470-2045(09)70213-X
Link to The Lancet Oncology abstract
Systematic review of literature over 50 years finds no evidence that organically produced foods are nutritionally superior to conventionally produced foodstuffs, according to a study published July 29 in The American Journal of Clinical Nutrition.
Consumers appear willing to pay higher prices for organic foods based on their perceived health and nutrition benefits, and the global organic food market was estimated in 2007 to be worth £29 billion (£2 billion in the UK alone). Some previous reviews have concluded that organically produced food has a superior nutrient composition to conventional food, but there has to-date been no systematic review of the available published literature.
Researchers from the London School of Hygiene & Tropical Medicine have now completed the most extensive systematic review of the available published literature on nutrient content of organic food ever conducted. The review focused on nutritional content and did not include a review of the content of contaminants or chemical residues in foods from different agricultural production regimens.
Alan Dangour, of the London School of Hygiene & Tropical Medicine's Nutrition and Public Health Intervention Research Unit, and one of the report's authors, comments: 'A small number of differences in nutrient content were found to exist between organically and conventionally produced foodstuffs, but these are unlikely to be of any public health relevance. Our review indicates that there is currently no evidence to support the selection of organically over conventionally produced foods on the basis of nutritional superiority. Research in this area would benefit from greater scientific rigor and a better understanding of the various factors that determine the nutrient content of foodstuffs'.
Nutritional quality of organic foods: a systematic review.
Alan D Dangour et al
The American Journal of Clinical Nutrition, July 29, 2009 DOI: 10.3945/ajcn.2009.28041
Link to AJCN abstract
Researchers in Israel and Kenya have shown that the contribution of variable degrees of immune suppression, either due to existing chronic infections such as parasitemias and/or nutrition, in different populations may influence and prolong the serological-diagnostic window period of HIV. However, the immunosuppression can be overcome, by in-vitro enhancement of antibody production (termed- Stimmunology).
The results, which appear in the August 2009 issue of Experimental Biology and Medicine, show that pre-treating the whole blood sample in the SMARTube™ containing immune potentiating agents promoted the synthesis and release of antibodies against HIV-1 prior to their detection in corresponding plasma samples in a group of donors who would otherwise be classified as HIV-1 seronegative blood donors.
The identification of techniques that can lead to detection of HIV infection during this window period is of obvious public health importance especially in resource poor settings highlighting the importance of these findings. Overcoming the suppression, in-vitro, led to the production of detectable levels of anti-HIV antibodies in the whole blood sample and to the detection of potentially infectious blood units which were missed by regular HIV serology. Interestingly, the ratio of missed infections among the total HIV infected blood donors was higher among the younger (high-school) donors versus adult donors.
Dr. Jehuda-Cohen noted that "this study, offers one of the keys to making the blood supply safer, by overcoming the problem of this protracted window period perhaps unique to certain field study sites with a high incidence/prevalence of HIV-1. This is true not only for HIV but also for other infections such as HCV, which has even a longer window period than HIV"
In-vitro enhancement of antibody production, made simple by the SMARTube™, has been shown to enable the earlier detection of HIV infection. This is critical for saving lives not only via a safer blood supply but also by detection of HIV infection among pregnant women who seem to have a very long window period. "A pregnant women testing false negative for HIV will not be offered ART which could have saved her baby" said Dr. Jehuda-Cohen (a mother of seven).
Detecting Seronegative-Early HIV Infections Among Adult Versus Student Kenyan Blood Donors, by Using Stimmunology
Jasper Mumo, Ami Vansover, and Tamar Jehuda-Cohen
Experimental Biology and Medicine 234: 931-939; published online before print doi: 10.3181/0812-RM-372
Link to EBM abstract
Tuesday, July 28, 2009
A chimp's attention is captured by faces more effectively than by bananas. A series of experiments suggests that the apes are wired to respond to faces in a similar manner to humans.
Masaki Tomonaga and Tomoko Imura from the Primate Research Institute at Kyoto University, Japan, tested the effects of a series of different images on chimps' reaction times. Tomonaga said, "It is well known that faces are processed in a different manner from other types of complex visual stimuli. Recent studies of face perception in humans clarified that faces represent special stimuli with regard to visuospatial attention as well. That is, they are able to capture our attention. We've shown that chimps share this tendency to notice and pay attention to faces in preference to other objects."
The researchers gave chimps the option of playing a game for food. If the chimps chose to, they could approach a computer screen where an image would be displayed, followed by a target. If the chimps pressed the target, they would receive a reward. In one set of experiments, the image was displayed on one side of the screen followed by the target either on the same side or the previously blank side. Reaction times were shown to improve when the target appeared behind the image. The chimps were then presented with two images side by side, one of which was a chimpanzee face. When the target appeared behind the face, reaction times were better than when it appeared behind the other object – showing that attention had indeed been drawn to the face-side of the screen.
Chimpanzee faces were shown to attract attention more effectively than bananas and other objects such as flowers, houses or trains. This effect was reduced when the faces were inverted, suggesting that it is the specific configuration of an upright face that catches the eye. According to Tomonaga, "This attentional capture was also observed when upright human faces were presented, indicating that this effect is not limited to their own species".
Faces capture the visuospatial attention of chimpanzees (Pan troglodytes): evidence from a cueing experiment.
Masaki Tomonaga and Tomoko Imura.
Frontiers in Zoology 2009, 6:14 (23 July 2009) doi:10.1186/1742-9994-6-14
Link to Frontiers abstract
HIV-positive patients who are co-infected with hepatitis C virus are twice as likely to develop an AIDS-defining illness than individuals who are only infected with HIV, Italian investigators report in the August 15th edition of Clinical Infectious Diseases. Moreover, co-infected patients with cirrhosis had an even more marked increase in their risk of developing an AIDS-defining condition.
The author of an accompanying editorial described the research findings as “important”, adding that they “may affect the clinical management of hepatitis C virus-HIV coinfection.”
Liver disease, often due to hepatitis C, is now an important cause of illness and death in people with HIV. Hepatitis C infection has been independently associated with an increased risk of non-Hodgkin’s lymphoma, which is an AIDS-defining illness. However, the association between the infection and the development of other AIDS-defining illnesses in co-infected patients has not been established.
Therefore Italian investigators from the ICONA Foundation Study Group designed a study involving 5397 HIV-positive patients, approximately half of whom were co-infected with hepatitis C. They compared the risk of developing AIDS-defining illnesses between these two groups. These illnesses were divided into broad categories: non-Hodgkin’s lymphoma; viral (such as Kaposi’s sarcoma); bacterial infections; HIV-related illnesses (for example, wasting); protozoal infections (like toxoplasmosis); and fungal infections (including pneumocystis).
“To our knowledge, this is the first study to investigate whether the risk associated with hepatitis C virus infection may be different according to specific AIDS-defining events and whether it is exacerbated in patients with liver cirrhosis”, write the investigators. They add, “our results have important implications because hepatitis C coinfection is frequent among HIV-infected individuals.”
The investigators suggest that the findings of their study should be taken into account by doctors treating co-infected patients, “in particular when deciding when to start antiretroviral therapy”.
This recommendation is endorsed by the editor of the accompanying editorial, who suggests the study “highlights and strengthens the need for careful follow-up of hepatitis C-HIV-coinfected patients, including preventative methods (screening, prophylaxis, and vaccination of preventable diseases), effective management of co-morbidities…and early and effective therapies against HIV and hepatitis C virus.”
Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with and without liver cirrhosis.
Antonella d’Arminio Monforte et al.
Clinical Infectious Diseases 49: 612-622, 2009.
Link to CID abstract
Editorial: Coinfection with hepatitis C virus and HIV: more than double trouble.
Lionel Piroth et al.
Clinical Infectious Diseases 49: 623-625, 2009.
Link to CID editorial
Monday, July 27, 2009
The Archbishop of Canterbury today reiterated his opposition to ordaining gay clergy and authorizing same-sex blessings, warning liberal churches that such practices would lead to isolation and relegation in the Anglican communion.
Rowan Williams was responding in a statement to developments in the US Episcopal church which earlier this month voted to open the ordination process to gay people and to consider developing blessings for same-sex couples.
In typically lengthy and nuanced prose, the archbishop said that the church's stance on these matters was unlikely to "repair the broken bridges in the life of the other Anglican provinces" and that "very serious anxieties had already been expressed" in the communion.
Same-sex blessings were "at the very least analogous" to Christian marriage and people living in such unions could not "without serious incongruity" have a representative function in a church whose public teaching was "at odds with their lifestyle", he said.
This disparity in theology and practice between conservatives and liberals – exacerbated by the consecration of Gene Robinson in 2003 as the communion's first bishop in a relationship with another man – would lead to a "twofold ecclesial reality", he added.
"Perhaps we are faced with the possibility of a two-track model, two ways of witnessing Anglican heritage, one of which had decided that local autonomy had to be the prevailing value."
Those Anglican provinces accepting the covenant – a good behavior guide for churches – would be able to participate fully in communion matters and in ecumenical and interfaith dialogue. Those who thought it more important to adhere to local pressures would have a lesser, unofficial, role in the life of the communion because there had to be clarity "about who has the authority to speak for whom".
Williams has been pushing the covenant as the only way to heal the rift between warring factions, but it has found little favor with the Episcopal Church, which sees the document as disproportionately punitive towards churches that are more inclusive and liberal.
Neither Williams nor the covenant does enough to tackle the issue of African churches interfering in US parishes, say Episcopalians, interventions that have seen conservative churches flock to African archbishops and bishops for spiritual leadership. In an act of rebellion, some Episcopalians broke away earlier this year to form their own church.