Month: December 2010

Gardasil Approved for Anal Cancer Prevention

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The FDA today approved Merck’s Gardasil HPV vaccine for prevention of anal cancer in both males and females ages 9 through 26 years.

HPV — human papillomavirus — is a sexually transmitted infection. It most commonly causes genital warts, but it also causes several cancers and precancerous lesions.

Gardasil already is approved for preventing cervical, vulvar, and vaginal cancer in females, and for preventing genital warts in both males and females.

However, the vaccine is routinely recommended only for girls. It remains optional for boys. Another HPV vaccine, Cervarix, is approved only for cancer prevention in girls.

Anal cancer is relatively rare in the U.S. — about 5,300 cases a year. However, cases have been steadily increasing.

While men who have sex with men are at highest risk, anal cancer is more common in women than in men.

“Treatment for anal cancer is challenging: The use of Gardasil as a method of prevention is important as it may result in fewer diagnoses and the subsequent surgery, radiation, or chemotherapy that individuals need to endure,” Karen Midthun, MD, director of the FDA center for biologics evaluation and research, says in a news release.

In November 2010, an FDA expert advisory panel recommended that the agency approve Gardasil for anal cancer.

HPV vaccines cannot prevent cancer in women or men already infected with the strains of HPV included in the vaccines. That’s why the vaccine is most commonly given to girls and boys before they become sexually active.

The CDC’s Advisory Committee on Immunization Practices, which advises the U.S. Department of Health and Human Services on vaccination policy, likely will discuss extending routine Gardasil vaccination at its February 2011 meeting.

Imaging of Gastrointestinal Bleeding

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Radiological techniques are important in evaluating patients with gastrointestinal bleeding. Scintigraphic, computed tomographic angiographic, and enterographic techniques are sensitive tools in identifying the source of bleeding and may be useful in identifying patients likely to have a benign course and in selecting patients for therapeutic intervention. Angiography plays a key role in bleeding localization, and modern embolization techniques make this a viable therapeutic option. With the refining developments in body imaging and related reconstructive techniques, it is likely that radiological interventions will play an expanding and critical role in evaluating patients with gastrointestinal hemorrhage in the future.

twice daily insulin injection

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Adding twice-daily exenatide injections improves glycemic control in patients with long-standing type 2 diabetes who have poor control with insulin glargine, finds a randomized controlled trial. However, the tradeoff was higher rates of adverse effects.

Researchers enrolled in the trial 261 adults with type 2 diabetes who had a hemoglobin A1c (Hb1c) level of 7.1% to 10.5% and were taking insulin glargine (alone or in combination with metformin, pioglitazone, or both). On average, they had had diabetes for more than 10 years.

The patients were stratified by HbA1c level (≤8.0% or >8.0%) and assigned to double-blind treatment with injections of exenatide (10 μg twice daily) or placebo for 30 weeks. The patients continued taking any oral antihyperglycemic agents. Their basal insulin glargine therapy was titrated as needed.

Trial results, reported on an early-release basis in the Annals of Internal Medicine, showed that patients in the exenatide group had a significantly greater reduction in HbA1c level when compared with their counterparts in the placebo group (1.74% vs 1.04%, P < .001).

The exenatide-treated patients lost weight, whereas the placebo-treated patients gained weight (–1.8 vs +1.0 kg). The former also had a smaller mean increase in insulin dosage (13 vs 20 U/d).

The two groups were similar in terms of the estimated rate of minor hypoglycemia and the rate of serious adverse events.

But the rate of study discontinuation because of adverse effects was higher with exenatide (9% vs 1%), as were rates of nausea (41% vs 8%), diarrhea (18% vs 8%), vomiting (18% vs 4%), headache (14% vs 4%), and constipation (10% vs 2%).

The investigators acknowledge that the study was short, the treatment groups differed somewhat at baseline in factors that could potentially affect outcome, and trial discontinuation was higher in the exenatide group.

“Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment,” albeit with higher rates of adverse effects, they write.

“Long-term studies using regimens associated with weight loss, low risk for hypoglycemia, and improved glycemic control will be required to further examine the potential clinical benefits of the treatment strategies used in this study,” they add.

Ann Intern Med. 2010.

thanks Dr Manish prasad

Prostacyclin Infusion May Prevent Secondary Damage in Pericontusional Brain Tissue

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Reinstrup P et al. – Prostacyclin is a potent vasodilator, inhibitor of leukocyte adhesion, and platelet aggregation, and has been suggested as therapy for cerebral ischemia. A case of focal traumatic brain lesion that was monitored using intracerebral microdialysis, and bedside analysis and display is reported here. When biochemical signs of cerebral ischemia progressed, i.v. infusion of prostacyclin was started. The above case supports the view that new therapies directed toward protection of the sensitive biochemical penumbra zones surrounding focal brain lesions may be evaluated by intracerebral microdialysis.

Development of the NBT assay as a marker of sperm oxidative stress

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Oxidative stress is a well-established cause of male infertility, with reactive oxygen species (ROS) causing infertility principally by impairing sperm motility and DNA integrity. Currently, most clinics do not test their infertile patients for the presence of oxidative stress because the available tests are expensive or difficult to perform. As antioxidant therapy may improve sperm DNA integrity and pregnancy outcomes, it has become apparent that there is an unmet clinical need for an inexpensive and easy-to-perform assay to identify sperm oxidative stress. The aim of this study was to develop a standardized protocol for performing a photometric nitro blue tetrazolium (NBT) assay for the measurement of seminal ROS production via production of coloured formazan, whilst correlating these results with impaired sperm function (motility and DNA integrity). Semen samples from 21 fertile and 36 male aetiology infertile men were assessed for ROS production (NBT assay), sperm DNA integrity (TUNEL), apoptosis (Annexin V) and sperm motility. Infertile men’s semen contained on average fourfold higher levels of ROS than fertile men. The production of ROS by sperm was positively correlated with sperm DNA fragmentation and apoptosis, whilst being negatively correlated with sperm motility. Receiver-operating characteristic plot analysis established a cut-off point of 24 μg formazan/107 sperm having a sensitivity of 91.7% and a specificity of 81% for determining the fertility status of an individual. This study has been successful in establishing a standardized protocol for performing a photometric seminal NBT assay that has significant clinical utility in identifying men with impaired fertility because of oxidative stress.

tuberculosis in prison

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The scourge of tuberculosis (TB) in prisons remains a persistent problem; rates among inmates remain much higher—from 5 to up to 50 times—than those of national averages across both the developed and the developing world [1]–[5], and the situation may be worsening in some regions. In Europe and Central Asian countries, recent research has shown a clear relationship between the rate of growth of prison populations and the increased incidence of TB and multidrug-resistant TB [6]. And at a recent meeting on TB/HIV in the WHO European Region that focused on integrating treatment of these diseases [7], Diane Havlir, chair of the Stop TB Partnership’s TB/HIV Working Group, opened proceedings by asking “What about prisons? Mandatory hospitalization for drug-susceptible TB? We need a debate about these things and to make improvements.”

Some important gaps in our understanding of TB in prisons exist: it’s still unclear how much TB there is within prisons and what fraction of TB in the general population is contributed by disease in incarcerated groups. An article in this week’s PLoS Medicine helps bridge that gap. Iacapo Baussano and colleagues systematically reviewed all the available published evidence on incident latent tuberculosis infection (LTBI) and TB in prisons worldwide, and by doing so were able to estimate the proportion of TB in national populations that is due to TB in prisons. The most striking finding is that, although it is clear that the rate of TB is higher in prisons than in the community, even after a thorough search and rigorous analysis of the evidence, it is not possible to give accurate estimates of the increased incidence of TB in prisons over community rates [8].

The paucity of reliable research evidence on TB in prisons found in this review should spur a renewed research effort. Such research is desperately needed to better inform policies to protect not only the health of people that are incarcerated, but also the health of the community outside.

Prisons provide ideal conditions for TB transmission. The bacterium causing TB is distributed in tiny liquid droplets that are produced when someone with active TB coughs, sneezes, spits, or speaks, enabling one person to infect many others. Therefore, the risk of TB being transmitted in settings in which people are in close contact—as in prisons and hospitals—is particularly high. Numerous other factors, such as poor health services frequently encountered in prisons, poor nutrition, drug addiction, and the presence of other diseases, such as HIV infection, are risk factors that predispose imprisoned people to a high risk of TB incidence.

Obstacles to tackling TB in prisons include inadequate infection control measures, conflicts between infection control measures and prisoner segregation (according to crime and length of sentence), lack of adequate medical facilities, lack of resources (including prison staff), and the low priority that policymakers give to health care within the prison system. Roberts and colleagues outlined how 20 jails in the US implemented measures to control TB and prevent new infections [9]. Even in this high-income setting, only four of the 20 prisons had conducted risk assessments for TB transmission, 11 had monitored tuberculin skin test conversions of inmates and staff, and only nine of the 20 prisons had policies to offer HIV counseling and testing to those with TB—an alarming situation given that HIV infection is the single largest cofactor for development of TB infection.

The new systematic review published in PLoS Medicine provides much-needed evidence for policymakers, including WHO, to renew their efforts to tackle TB in prisons. There is ample guidance available on how best to control and prevent TB in prisons [10],[11] and many academics, health workers, and campaigners have called for the intensive screening of high-risk populations, including prisoners, to be introduced [12] as part of an integrated strategy to reduce global incidence of TB. Future research areas uncovered by this systematic review include measuring the impact of conditions in prisons on TB transmission and assessing the population attributable risk of prison-to-community spread.

On 13 October 2010, the Global Plan to Stop TB 2011–2015 was launched by the Stop Tuberculosis Partnership (a coalition of more than 400 organizations worldwide) with the aim of halving TB mortality and prevalence rates by 2015 compared with a 1990 baseline [13]. One objective to achieving this aim is to “Ensure early diagnosis of all TB cases,” including vulnerable populations such as prisoners. The publication of this systematic review marks a shift from considering the incidence of TB in each prison population to considering the massive global impact of tuberculosis in prisons.

source:PLOS medicine

esophageal carcinoma incidence

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The incidence of oesophageal cancer is increasing. While the incidence of squamous cell carcinoma of the oesophagus has recently been stable or declined in Western societies, the incidence of oesophageal adenocarcinoma has risen more rapidly than that of any other cancer in many countries since the 1970s, particularly among white men. 1 The UK has the highest reported incidence worldwide, for reasons yet unknown. 2 Overall, the prognosis for patients diagnosed with oesophageal cancer is poor, but those whose tumours are detected at an early stage have a good chance of survival. We outline strategies for prevention and describe presenting features of oesophageal cancer to assist generalists in diagnosing and referring patients early. Treatment is often highly invasive and alters patients’ quality of life. We review the evidence from large randomised clinical trials, meta-analyses, and large cohort and case-control studies (preferably those of population based design, since they carry a lower risk of selection bias).

source:BMJ

Mutation-prediction software rewarded

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California contest looks to boost software that can analyse genetic data.


DNA helix
Genetic data from patients will soon be flooding doctor’s offices.

A computer program that predicts the effects of gene mutations has earned its author a doctorate, a stack of journal publications — and now a dancing wind-up toy named Molly.

Yana Bromberg, a bioinformatician at Rutgers University in New Brunswick, New Jersey, won the toy for her program, SNAP, in an experimental contest that culminated on 10 December in Berkeley, California. The competition, called the Critical Assessment of Genome Interpretation (CAGI), asks researchers to predict the biological effects of different mutations, and compares their results against unpublished experimental data.

The contest was conceived by Steven Brenner, a computational genomicist at the University of California, Berkeley, and John Moult, a computational biologist at the University of Maryland in Rockville. Their goal is to accelerate the development of software that can quickly interpret large amounts of genetic data — for example, the whole genome sequence of a tumour from a biopsy.

Data mountain

Such data is already flooding labs and will soon be hitting doctors’ offices. “We’ve already got an enormous amount of data to contend with and we’re struggling to make sense of it,” says Moult. “I see CAGI as one mechanism to help with that process.”

He helped to start a similar competition in 1994, to improve scientists’ ability to determine the shapes of proteins from their amino-acid sequences. That effort, named the Critical Assessment of protein Structure Prediction (CASP), challenges scientists to predict protein structures that have been determined experimentally, but not yet published. The results are revealed at a biannual meeting in Pacific Grove, California.

CAGI works in a similar way. Instead of proteins, Brenner, Moult and coordinator Susanna Repo, a postdoc in Brenner’s lab, provided several challenges that typically involved determining the biological effect of mutations in particular genes and the proteins they encode.

For instance, one challenge provided entrants with different variations in the cancer-associated gene CHEK2 that had been uncovered by a study of the gene in patients with cancer and healthy people, but not yet published. CAGI participants were asked to determine whether given mutations belonged to a patient or a control.

“We’ve got an enormous amount of genetic data to contend with and we’re struggling to make sense of it.”

John Moult
University of Maryland, Rockville

Each team tackled these challenges differently. But their entries generally involved either predicting how a certain mutation changes the shape and function of a protein, or scouring genetic databases to determine the effects of similar mutations. “The ones that did best combined a large number of methods together,” says Brenner.

Despite being hastily organized — some of the challenges were posted just a couple of weeks before their deadlines — CAGI drew more than 100 entries. About 40 people made the trip to Berkeley to learn the results and to collect prizes, which Brenner awarded to anyone who gave a talk on their approach.

Although the organizers were apprehensive about how the contest would work, “it went as well as it possibly could have”, says Brenner. He and his team are still analysing the entries, and hope to reveal the official results in a peer-reviewed publication. On the basis of the success of the Berkeley workshop, they plan to hold the contest again within 2 years.

A challenge too far

There were a few hitches, however. One challenge proved so difficult to tackle at short notice that it generated no entries. In another, to predict the consequence of mutations in the tumour-suppressor gene P53, the relevant experiments became contaminated with mould, so the entries could not be compared against real data in time for the 10 December meeting.

Joost Schymkowitz and Frederic Rousseau’s team at the Free University of Brussels worked on two of the problems. They fared better on one challenge than on the other, but Schymkowitz points out that failures can be as illuminating as successes because they highlight the shortcomings of particular approaches. “It makes you acutely aware of things you cannot do,” he says.

Scott Kahn, chief information officer at the gene-analysis company Illumina in San Diego, California, who attended CAGI as an observer, says that the contest should help to speed up advances in genome prediction. “This does really focus effort in the community,” he says.

Brenner, meanwhile, points out that protein-structure predictions improved greatly after CASP started. “Our hope is that same thing will happen here.

source:Nature

New WHO Guidelines for Preventing TB Among HIV-Infected People

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The new guidelines recommend isoniazid prophylaxis for at least 6 months in HIV-infected individuals in resource-constrained settings who do not have active TB.

For the first time in more than a decade, the WHO has issued new guidelines for preventing tuberculosis (TB) in HIV-infected individuals in resource-constrained settings. To date, the WHO has focused its HIV/TB efforts in such settings on intensified TB case-finding (ICF), isoniazid preventive therapy (IPT), and infection control. These new guidelines update the recommendations for ICF and IPT specifically. Each recommendation is graded as strong or conditional, and the supporting evidence is categorized as high, moderate, low, or very low.

Major recommendations are as follows:

  • All HIV-infected adults and adolescents should be screened for TB with a simple algorithm that relies on four clinical symptoms — cough, fever, weight loss, and night sweats. Individuals without any of these symptoms are unlikely to have active TB and are thus eligible for IPT. (Strong recommendation; moderate quality of evidence)
  • Performance of a tuberculin skin test (PPD) is no longer necessary before initiating IPT. (Strong recommendation; moderate quality of evidence)
  • Eligible HIV-infected individuals should receive IPT for at least 6 months, regardless of whether they are receiving antiretroviral therapy or have successfully completed TB treatment. (Strong recommendation; high quality of evidence)
  • The minimum duration of IPT should be extended to 36 months in settings where TB prevalence and transmission rates are high among HIV-infected people. (Conditional recommendation; moderate quality of evidence)

Comment: TB is the leading cause of morbidity and mortality for HIV-infected individuals worldwide, yet most countries with raging HIV/TB epidemics have not implemented TB screening, and rates of IPT use are abysmal. For example, in 2009, <1% of all HIV-infected individuals received isoniazid chemoprophylaxis. Unfortunately, the guidelines fail to explicitly recommend integrated screening programs for HIV and TB in areas that have a high prevalence of both infections. Despite this shortcoming, the guidelines are a welcome addition. One of the major reasons why IPT has not been prescribed routinely is that many healthcare providers lack access to PPD or chest x-rays in their clinics to rule out active TB disease. Having a simple algorithm for identifying patients with possible TB disease — and removing the need for PPD or a chest x-ray before starting IPT — is a giant step forward that may help reduce the burden of TB disease among HIV-infected people.

— Ashraf Mohammed, PhD, MSc (Med Sci), and Carlos del Rio, MD

Dr. Mohammed is a Humphrey Fellow in the Hubert Department of Global Health at Emory University in Atlanta and is Head of the HIV/AIDS Unit of the Cape Peninsula University of Technology in Cape Town, South Africa. He reports no conflicts of interest.

Published in Journal Watch HIV/AIDS Clinical Care December 20, 2010

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Common Treatments for Gastric Acid May Contribute to Bacterial Overgrowth and Infection,

Dec. 20, 2010 — New research suggests that one out of every 200 patients being treated with gastric acid-suppressive drugs for heartburn and other conditions may develop pneumonia.

Researchers led by Chun-Sick Eom, MD, MPH, from Seoul National University Hospital in South Korea, conducted a review of studies published between 1985 and 2009, looking at the use of gastric acid-suppressive drugs and the risk of developing pneumonia.

Acid Suppressives Strongly Linked to Pneumonia

The researchers found a significant association between the use of one class of gastric acid suppressive, called proton pump inhibitors, and pneumonia.  Eom and his colleagues also found a dose-response relationship between proton pump inhibitors and risk of pneumonia, meaning the more acid suppressive a patient took, the higher the risk of developing pneumonia. Examples of proton pump inhibitors include Aciphex, Nexium, Prevacid, Prilosec, Protonix, and Zegerid.

The researchers also found a strong association between the use of another class, histamine 2-receptor antagonists, and pneumonia. Examples of histamine 2 receptor antagonists include Axid,  Pepcid, Tagamet, and Zantac.

The results are published in the Dec. 20 issue of the Canadian Medical Association Journal.

Forty percent to 70% of hospitalized patients receive acid suppressive medication. The researchers say frequent use of these drugs may be contributing to hospital-acquired pneumonia illnesses and deaths.  The findings suggest that doctors should exercise caution when prescribing these acid suppressives, particularly among patients at high risk for developing pneumonia.

Biological Explanations

There may be several reasons as to why acid suppressives may have this association with pneumonia, Eom and his team report. Acid-suppressive drugs may increase the risk for pneumonia by blocking gastric acid, which could lead to bacteria overgrowth in the upper gastrointestinal tract that may travel to the lungs. It’s also possible the acid-suppressive medication inhibits immune cells, reducing their ability to fight off bacteria and infection.

Acid-suppressive drugs are the second most commonly sold and used medication worldwide, totaling more than $26 billion in sales in 2005 in the U.S. They are prescribed to treat conditions such as heartburn, gastroesophageal reflux disease, and ulcers.   Previous studies have examined a possible link between these drugs and pneumonia in the past, but the results have been mixed.

“Several previous studies have shown that treatment with acid-suppressive drugs might be associated with an increased risk of respiratory tract infections and community-acquired pneumonia in adults and children,” Eom and his colleagues wrote. “Given the widespread use of proton pump inhibitors and histamine 2-receptor antagonists, clarifying the potential impact of acid-suppressive therapy on the risk of pneumonia is of great importance to public health.”v