Needle unnecessary for successful acupuncture

Acupuncture works – but it works equally well with or without needle penetration. This conclusion can be drawn from a treatment study involving cancer patients suffering from nausea during radiotherapy.

Anna Enblom, a physiotherapist and doctoral candidate at the Department of Medicine and Health Sciences at Linköping University and the Vårdal Institute in Sweden, carried out four studies that are now being reported in her doctoral dissertation. The first study involved a group that received ordinary medical treatment for nausea, but not acupuncture. In that group only one quarter of the nauseous patients experienced any relief.

The acupuncture study of 215 patients who were undergoing radiation treatment in the abdomen or pelvic region chose by lot one of these two acupuncture types. Traditional acupuncture was given to 109, with needles penetrating the skin in particular points. According to ancient Chinese tradition, the needle is twisted until a certain 'needle sensation' arises.

The other 106 patients received a simulated acupuncture instead, with a telescopic, blunt placebo needle that merely touches the skin. The acupuncture was performed by physiotherapists two or three times a week throughout the five-week radiation period. Afterwards 95% of the patients in both groups felt that the acupuncture treatment had helped relieve nausea, and 67% had experienced other positive effects such as improved sleep, brighter mood and less pain.

The final study shows that patients that received traditional or simulated acupuncture felt considerably better than the group that had only received care following ordinary routines. The difference, 37% compared with 63% of nauseous patients, is statistically significant. On the other hand, there was no difference between the two acupuncture groups.

The effects therefore seem not be due to the traditional acupuncture method, as was previously thought, but rather a result of the increased care the treatment entails. Patients could converse with the physiotherapists, they were touched and they had extra time for rest and relaxation.



Researchers identify antibody that inhibits HIV infection

A small antibody fragment that is highly effective in neutralizing the human immunodeficiency virus (HIV) by preventing the virus from entering cells has been identified by researchers at the US National Cancer Institute (NCI. This finding may provide insight into the development of new treatments against HIV and other viruses.

Antibodies are large proteins naturally produced by the immune system to help fight disease-causing foreign invaders, such as viruses and bacteria.

Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies, characterised by slightly different tip structures, to exist and bind to different targets, known as antigens.

Previous research has shown that reducing antibodies to the smallest independently functional fragment, known as a variable domain, can extend their utility as therapeutic agents. These fragments, called domain antibodies (dAbs), retain the variable tip structure and, therefore, the antigenbinding specificity of the parent antibody.

Because of their small size, they are able to access targets that cannot be reached by much larger, whole antibodies. In an earlier study, the researchers identified a unique antibody, called m0, while screening a large library of antibodies directed against the HIV protein, Env (also known as gp120). The library contained the variable portions of antibodies that can bind to Env antigens.

“We found an antibody fragment that exhibited the ability to neutralize HIV and had properties that allowed us to construct a novel library containing dAbs directed against HIV,” said Dimiter S. Dimitrov, PhD, of NCI’s Center for Cancer Research.

Based on m0’s framework, the leading author of the study, Weizao Chen, PhD, constructed a very large library of dAbs (25 billion different dAbs), screened it against Env proteins from two different strains of HIV, and identified a dAb, m36, that bound strongly to different Env proteins and blocked the infectivity of a broad range of HIV strains. The researchers believe that m36 represents the first human dAb against HIV reported. “The antibody fragment that we identified, m36, could have potential in the development of a therapeutic drug that inhibits HIV,” said Dimitrov.

“Further research with this molecule also could offer insight about how the virus infects cells and how it evades neutralization by the immune system.” The research team is working to test various combinations of m36 with other inhibitors that may be effective against HIV. The team is also attempting to construct more potent versions of m36.

Partnership with industry could speed the ability to evaluate m36 as a potential treatment for HIV. Dimitrov’s team is also using this approach to identify dAbs against cancer and other disease-related antigens.

● For more information on Dr Dimitrov’s research, visit <http://ccr.cancer.gov/staff/staff. asp?profileid=5749>.



Newborn neurons can settle in wrong part of brain

In a study that could have significant consequences for neural tissue transplantation strategies, researchers at the Salk Institute for Biological Studies report that inactivating a specific gene in adult neural stem cells makes nerve cells emerging from those precursors form connections in the wrong part of the adult brain. In a paper published in the 11 November 2008 issue of PLoS Biology, the team, led by Fred H. Gage, PhD, professor in the Laboratory of Genetics, discovered that a protein called cdk5 is necessary for both correct elaboration of highly branched and complex antennae, known as dendrites, which are extended by neurons, and the proper migration of cells bearing those antennae.

Previously described functions of cdk5 are manifold, among them neuronal migration and dendritic pathfinding of neurons born during embryonic development. “The surprising element was that the dendrites of newborn granule cells in the adult hippocampus lacking cdk5 stretched in the wrong direction and actually formed synapses with the wrong cells,” explains Prof Gage. These findings offer extremely valuable, although unanticipated, input for investigators whose goal is to develop transplantation strategies to treat brain injuries or neurodegeneration.

“Our data shows that cells that fail to find their ‘right spot’ might actually become integrated into the brain and possibly interfere with normal information processing,” says the study’s lead author Sebastian Jessberger, MD, assistant professor at the Swiss Federal Institute of Technology in Zurich, Switzerland.



Inhaled corticosteroids raise pneumonia risk

Lung disease experts at Johns Hopkins are calling for physicians to show greater caution in prescribing inhaled corticosteroid drugs for people with chronic obstructive pulmonary disease after finding evidence that the widely used antiinflammatory medications increase the risk of pneumonia by a full third.

The call for caution is based on the Johns Hopkins team's review and analysis of adverse events recorded in 11 clinical studies that in total involved more than 14,000 men and women with COPD.

The team’s review, believed to be the largest and most comprehensive performed in the last decade among COPD sufferers, compared adverse events among those who took inhaled corticosteroids and others who did not. In their report in the Journal of the American Medical Association, researchers found that the increased risk mostly occurred in people taking the highest possible doses, such as 500 micrograms of fluticasone twice daily for a relatively short time (less than two years), whose lung function was 40% or lower than expected and who also combined their steroid therapy with bronchodilators, used to keep the airways open.

Researchers say it remains unclear why the treatment increases risk of lung infection, but they suspect that the drugs suppress the immune system. Despite the increased pneumonia risk, the team found no clear evidence that the drug therapy also pushes up rates for other steroid-related problems, such as bone fractures, nor was there an increase in deaths.

Senior study investigator and critical care specialist Eddy Fan, MD, says the results should spur physicians to screen and monitor their patients to find the lowest possible steroid dose that works. The merged analysis from seven studies that kept track of infections from pneumonia revealed a 34% higher rate among those who underwent steroid therapy (777 infections in 5,405 people), compared to those who did not during the same time frame (561 infections in 5,371).

In five studies that recorded death rates and three that counted bone fractures, no significant differences emerged between the group using steroid therapy and those who did not. In breaking down the overall rise in risk, the researchers found that in people taking the highest possible dose of each inhaled corticosteroid, there was a 46% increase in risk for pneumonia.

Infection risk nearly doubled in those who had less than 40% normal lung function, as opposed to those whose lungs were stronger. Pulmonologist M. Brad Drummond, MD, MHS, who led the study, says the absence of an overall difference in death rates between users and non-users of corticosteroids was likely due to the shortterm follow-up of three years or less across all of the studies. ● For more information, visit: www.hopkinsmedicine.org/pulmonary/clinics/interstitial_lung_disease.html



Age-related eye disease study data released

The US National Eye Institute (NEI), has released more than 10 years of data collected during the Age- Related Eye Disease Study (AREDS), which looked at the progression of age-related macular degeneration and age-related cataract in 4,757 adults aged 55 to 80.

Researchers around the world can apply for access to this complete set of medical history records and clinical trial results as well as select genetic information to gain a better understanding of two complicated vision conditions that affect aging adults.

“This vast pool of data is now at the fingertips of scientists, which is an unprecedented occurrence in the field of ophthalmology,” said Frederick L. Ferris III, MD, clinical director of the NEI. “Now that the entire AREDS database is available to the global research community, we hope that researchers will be inspired to delve more deeply into analysing the genetic and environmental factors involved in the onset and progression of age-related macular degeneration and age-related cataract.”

The AREDS data are accessible through the online database of Genotypes and Phenotypes, known as dbGaP, which archives and distributes data from studies that explore the relationships between genetic variations (genotypes) and observable traits (phenotypes). The first version of controlled-access AREDS data became available through dbGaP in June 2007.

The updated version now incorporates the complete information obtained from all participants during trial enrollment and follow-up visits, including data from photographs of the patients’ eyes and information regarding their nutritional intake, quality of life, and rates of illness and death.

AREDS began in 1992 as a long-term, multi-center, prospective study designed to evaluate the progression of age-related macular degeneration and age-related cataract. Participants were also enrolled in a clinical trial of high-dose vitamin and mineral supplements. They were followed for a median of 6.5 years during the trial and an additional five years after the trial’s conclusion.

In addition, DNA was isolated from blood samples taken from more than 3,700 AREDS participants beginning in 1998. DNA from many of these participants is currently being stored in the NEI-AREDS Genetic Repository.

Access to these DNA samples for research purposes is available for a fee through the Coriell Institute for Medical Research at <http://ccr.coriell.org/Sections/ Collections/AREDS/?SsId=68>. The public, open-access AREDS data can be viewed on the dbGaP website at <http://www.ncbi.nlm.nih.gov/p rojects/gap/cgi-bin/study.cgi? study_id=phs000001.v2.p1>.



Fibromyalgia related to brain abnormalities

Using molecular imaging researchers have uncovered evidence that supports the idea that fibromyalgia is related to functional brain abnormalities. Fibromyalgia syndrome is a common and chronic disorder characterised by widespread muscle pain, fatigue and multiple tender points.

Using single photon emission computed tomography (SPECT), researchers in France were able to detect functional abnormalities in certain regions in the brains of patients diagnosed with fibromyalgia, reinforcing the idea that symptoms of the disorder are related to a dysfunction in those parts of the brain where pain is processed.

“Fibromyalgia is frequently considered an ‘invisible syndrome’ since musculoskeletal imaging is negative,” said Eric Guedj, MD, and lead author of the study. “Past imaging studies of patients with the syndrome, however, have shown above-normal cerebral blood flow (brain perfusion) in some areas of the brain and below-normal in other areas. After performing whole-brain scans on the participants, we used a statistical analysis to study the relationship between functional activity in even the smallest area of the brain and various parameters related to pain, disability and anxiety/ depression.”

In the study, which was reported in the November 2008 issue of The Journal of Nuclear Medicine, 20 women diagnosed with fibromyalgia and 10 healthy women as a control group responded to questionnaires to determine levels of pain, disability, anxiety and depression. SPECT was then performed, and positive and negative correlations were determined. The researchers confirmed that patients with the syndrome exhibited brain perfusion abnormalities in comparison to the healthy subjects.

Further, these abnormalities were found to be directly correlated with the severity of the disease. An increase in perfusion (hyperperfusion) was found in that region of the brain known to discriminate pain intensity, and a decrease (hypoperfusion) was found within those areas thought to be involved in emotional responses to pain. In the past, some researchers have thought that the pain reported by fibromyalgia patients was the result of depression rather than symptoms of a disorder. “Interestingly, we found that these functional abnormalities were independent of anxiety and depression status,”

Dr Guedj said. According to Dr Guedj, disability is frequently used in controlled clinical trials to evaluate response to treatment. Because molecular imaging techniques such as SPECT can help predict a patient’s response to a specific treatment and evaluate brain-processing recovery during follow-up, it could prove useful when integrated into future pharmacological controlled trials. “Fibromyalgia may be related to a global dysfunction of cerebral pain-processing,” Dr Guedj added.

“This study demonstrates that these patients exhibit modifications of brain perfusion not found in healthy subjects and reinforces the idea that fibromyalgia is a ‘real disease/disorder’.’’ Although fibromyalgia is often considered an arthritisrelated condition, it does not cause inflammation or damage to the joints, muscles or other tissues. Like arthritis, however, the significant pain and fatigue caused by fibromyalgia can interfere with a person’s ability to carry out daily activities.



Hairspray linked to hypospadias

Women who are exposed to hairspray in the workplace during pregnancy have more than double the risk of having a son with the genital birth defect hypospadias, according to a new study published 21 November 2008 in the journal Environmental Health Perspectives.

The study is the first to show a significant link between hairspray and hypospadias, one of the most common birth defects of the male genitalia, where the urinary opening is displaced to the underside of the penis.

The causes of the condition are poorly understood. Women have a two to threefold increased risk of having a son with hypospadias if they are exposed to hairspray in the workplace in their first trimester of pregnancy, according to the new study, by researchers from Imperial College London, University College Cork and the Centre for Research in Environmental Epidemiology in Barcelona.

The study suggests that hairspray and hypospadias may be linked because of chemicals in hairspray known as phthalates. Previous studies have proposed that phthalates may disrupt the hormonal systems in the body and affect reproductive development. Usually, hypospadias can be successfully treated with corrective surgery after a boy reaches his first birthday, but more severe cases can lead to problems with urinating, sexual relations and fertility.



Scientists identify new leprosy bacterium species

A new species of bacterium that causes leprosy has been identified through intensive genetic analysis of a pair of lethal infections, a research team reports in the December 2008 issue of the American Journal of Clinical Pathology.

All cases of leprosy, an ancient disease that still maims and kills in the developing world, previously had been thought to be caused by a single species of bacterium, said lead author Xiang-Yang Han, MD, PhD, associate professor in Laboratory Medicine at The University of Texas MD Anderson Cancer Center. R. Geetha Nair, MD, a physician with Maricopa Integrated Health System in Phoenix, Arizona, US, contacted Dr Han in 2007 for help confirming a possible leprosy diagnosis in a patient who died that February. Analysis of autopsied tissue at the Phoenix hospital suggested a diagnosis of diffuse lepromatous leprosy (DLL).

Dr Han said DLL uniquely attacks a patient’s skin vasculature, blocking or impeding blood flow. This leads to extensive skin death at late stage and may cause secondary infection and fatal shock.

The DLL bacterium had never been studied. Dr Han developed in 2002 a way to identify unusual bacteria by analysing small but significant differences in the 16S ribosomal RNA gene. “This is like a fingerprint analysis to solve crimes,” Dr Han said. Across a group of bacteria called mycobacteria, the 16S rRNA gene is 93 to 100% identical.

There are 110 species of mycobacteria, with those causing tuberculosis and leprosy the best known. Sequencing the 16S rRNA gene is a fast and accurate way to identify mycobacteria, which usually grow slowly, Dr Han noted.

Dr Han and colleagues compared the lethal bacterium’s 16S rRNA gene and five other genes to other mycobacteria. They found that the bacterium had the most in common with Mycobacterium leprae, previously thought to be the sole cause of leprosy.

Yet there were also significant differences with M. leprae. The lethal bacterium’s 16S rRNA gene sequence differed by 2.1%. In all previously studied M. leprae strains, no variation in the 16S rRNA gene had been noted at all. Analysis of the other five genes turned up more differences. The researchers named the new species Mycobacterium lepromatosis. They have since confirmed M. lepromatosis as the cause of two lethal cases of DLL in Singapore.

The team is working to better understand the bacterium and how it causes DLL. They are attempting to sequence the entire M. lepromatosis genome and looking for ways to grow the organism in the lab. Neither leprosy mycobacteria can be cultured because over millions of years they lost genes necessary to survive outside their hosts, a process called reductive evolution.

One of the puzzles of leprosy is that M. leprae strains collected worldwide are virtually identical, while the clinical features of the disease and its severity vary greatly both geographically and from person to person. Evidence suggests that individual host immune factors play the key role in determining how the disease progresses.

The authors conclude that the new species M. lepromatosis could account for some of this geographical and individual variation.



Atrial fibrillation common in patients with atherothrombosis

A significant portion of patients with atherothrombosis also have atrial fibrillation (AF), greatly increasing their risk for cardiovascular death, heart attack and stroke, according to new findings from the large, international REACH registry published 7 November 2008 in the American Heart Journal.

The findings also showed that standard treatments including anticoagulant and antiplatelet therapies are underused in AF patients. The new findings from the REACH (REduction of Atherothrombosis for Continued Health) registry showed that AF was present in approximately 12% of patients who had atherothrombotic disease, which includes coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CVD).

The findings also showed that, among patients with or at risk for atherothrombotic disease, the risk for death and non-fatal cardiovascular outcomes was greater for AF vs. non-AF patients, including more than twice as high for CV death (3.2% vs 1.4%; p<0.0001), 87% higher for death from all causes (4.3% vs. 2.3%, p<0.0001), 50% higher for non-fatal stroke (2.4% vs 1.6%, p<0.0001), and nearly 50% higher for the combined endpoint of CV death/heart attack/stroke and/or hospitalisation for atherothrombotic events (17.9% vs 12.1%, p<0.0001). Despite these higher risks in AF patients, only a little more than half received anticoagulant therapy, only 60% received antiplatelet therapy, and less than one in five received both.

“We've known that AF is a major risk factor for ischemic stroke, but its prevalence and impact in the broader population of patients with atherothrombosis was previously unclear,” said, lead author Shinya Goto, MD, PhD, FACC, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan. “Our findings help fill that gap, and show across all atherothrombotic disease categories, AF consistently increases the risk of death and non-fatal CV outcomes.

For example, the combined endpoint of CV death, heart attack and stroke and/or hospitalization for atherothrombotic events was higher in AF patients no matter what form of atherothrombotic disease they initially had, and was highest in patients initially recruited with PAD. Further, our analysis underscores the need to determine the optimal management of AF patients with or at risk for atherothrombosis.”

● The REACH registry is a large, contemporary, representative and geographically diverse cohort of stable outpatients with or at high risk ofatherothrombosis. A total of 68,236 patients with either established atherothrombotic disease (CAD, PAD, or CVD, n=55,814) or at least three risk factors for atherothrombosis (n=12,422) were enrolled from 5,587 physician practices in 44 countries (in Europe, North and South America and Asia) in 2003-2004.



New obesity drug shows promise

According to trials, a new obesity drug, Tesofensine, which may be launched on the world market in a few years, can produce weight loss twice that of currently approved obesity drugs.

The Danish company Neurosearch and a number of researchers at the Faculty of Life Sciences at University of Copenhagen are behind the promising findings. Tesofensine can produce weight loss twice that of currently approved obesity drugs, and should be studied in phase III trials.

These are the conclusions of an article, to be published in The Lancet, written by Professor Arne Astrup, Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Denmark, and colleagues.

Tesofensine – which inhibits the presynaptic uptake of the neurotransmitters noradrenaline, dopamine and serotonin in the brain – has been shown to be safe and effective in animal models. It also caused unintended weight loss when it was given to obese patients with Parkinson’s or Alzheimer’s disease when it was researched for those conditions. The drug works by suppressing hunger, leading to an energy deficit which burns off excess body fat.



Experimental TB drug explodes bacteria from the inside out

An international team of biochemists has discovered how an experimental drug unleashes its destructive force inside the bacteria that cause tuberculosis (TB). The finding could help scientists develop ways to treat dormant TB infections, and suggests a strategy for drug development against other bacteria as well.

A report describing the research, led by Clifton E. Barry, III, PhD, of the US National Institute of Allergy and Infectious Diseases (NIAID) is published in the 28 November issue of Science. Dr Barry’s collaborators included scientists from NIAID and from the Novartis Institute for Tropical Diseases in Singapore.

One-third of the world’s population is infected with Mycobacterium tuberculosis (M. tb), the bacteria that cause TB. “Currently, there are no drugs available that specifically target latent tuberculosis infections in which bacteria are present but are not actively dividing,” notes NIAID Director Anthony S. Fauci, MD. “Dr Barry and his colleagues have now given us a detailed picture of how the candidate TB drug PA-824 is metabolised inside Mycobacterium tuberculosis.

Their discovery is a promising step towards developing effective drugs against latent TB as well as other bacteria.” Previously, Dr Barry and his collaborators found that M. tb mutants lacking a specific bacterial enzyme were resistant to PA-824, but at that time, they did not know the function of the enzyme.

“It took several years, but at last we were able to recreate in the test tube what happens inside mycobacterial cells when the bacterial enzyme, which we named Ddn, and a second bacterial component called a cofactor, interact with PA-824,” says Dr Barry. The key event in PA-824 metabolism, they found, is the production of nitric oxide (NO) gas. “This highly reactive molecule,” he adds, “is akin to a bomb blast that kills the bacteria from within.” NO gas is produced naturally by certain immune system cells after they engulf M. tb or other bacteria.

This is one way that people with healthy immune systems can contain M. tb infection. However, this natural immune response is not always enough to completely rid the body of TB bacteria. In essence, PA-824 performs similarly to the NO-producing immune cells – but the drug’s effect is more specific and triggered only after it enters the bacteria. The non-dividing M. tb bacteria characteristic of latent TB infections are walled off by immune cells that aggregate around the bacteria to form a body called a granuloma.

Oxygen levels are low inside granulomas. In their latest research, the scientists observed that NO-generation during PA-824 metabolism is greatest when oxygen levels are low. This observation suggests how PA-824 may work against non-dividing M. tb. PA-824 was originally designed to work best under aerobic, or oxygenated, conditions.

With this new understanding of how the bacterial enzyme and cofactor act on PA-824 under low-oxygen conditions, Dr Barry says, scientists can design drugs with a chemical structure similar to PA-824 but optimise them from the start to behave best under low-oxygen conditions. Because humans have neither the bacterial cofactor nor any enzymes equivalent to Ddn, PA- 824 has no effect on human cells.

Conversely, many bacteria have enzymes in the same family as Ddn. Thus, says Dr Barry, it is possible to envision new kinds of NO-generating drugs designed to interact with enzymes associated with other disease-causing bacteria as well.

● R Singh et al. Bicyclic nitroimidazoles are intracellular NO donors and kill non-replicating Mycobacterium tuberculosis. Science DOI: 10.1126/ science.1164571 (2008).

                                  
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