“Our observations may help to explain the increased acquisition of HIV-1 infection and the reduced magnitude of HIV-specific CD8 T-cell responses observed in the STEP trial among the Ad5 seropositive vaccine recipients,” senior investigator Dr. Eric J. Kremer told Reuters Health.

Dr. Kremer of Centre National de la Recherche Scientifique Montpellier, France and colleagues studied the effect of Ad5 vector alone or Ad5 immune complexes on dendritic cells.

The team found that the treated cells induced significantly higher stimulation of Ad5-specific CD8 T cells. Co-cultures of HIV and dendritic T cells showed that Ad5 immune complex caused significantly enhanced HIV infection.

“Our data suggest that the delivery/formulation of antigens through immune complexes may result in a powerful immunization strategy to stimulate T cells either in vivo or ex vivo,” Dr. Kremer noted.

However, co-investigator Dr. Guiuseppe Pantaleo of the University of Lausanne, Switzerland added that “because Ad5 does not infect non-human primates it will be very difficult to develop an animal model to test this hypothesis.”

Furthermore, he concluded, “it is going to be important to have access to sera from individuals enrolled in the STEP trial in order to also confirm our results in the vaccinated individuals.”

Source:

1. Ad5 Immune Complexes May Improve HIV Replication

“Research on the mental health of doctors has led to a call for preventive interventions to lower the risk of burnout and mental distress,” write Karin E. Isaksson Rø, MDr, from the Research Institute, Modum Bad, in Vikersund, Norway, and colleagues. “Early intervention programmes could ensure that practising doctors in trouble get help in time, before their problems interfere with care of patients and give rise to medical errors, but such programmes have been poorly investigated.”

At a Norwegian resource center, 227 physicians participated in a counseling intervention during 2003 to 2005 and completed a self-reported assessment at 1 year. The intervention consisted of individual counseling lasting 1 day or group-based counseling lasting 1 week, aimed at motivating reflection on and acknowledgement of the physicians’ situation and personal needs. Primary endpoints were levels of burnout, measured with the Maslach burnout inventory, and predictors of reduced emotional exhaustion, based on linear regression.

Of 185 physicians (81%) who completed 1-year follow-up, 88 were men and 97 were women. On a scale of 1 to 5, the mean level of emotional exhaustion significantly decreased from 3.00 ± 0.94 to 2.53 ± 0.76 (t = 6.76; P < .001), which was similar to the level found in a representative sample of 390 Norwegian physicians. In addition, participants had decreased their working hours by 1.6 ± 11.4 hours/week.

The proportion of physicians on full-time sick leave decreased from 35% (63 of 182 physicians) at baseline to 6% (10 of 182 physicians) at follow-up, and the proportion that had undergone psychotherapy increased from 20% (36 of 182 physicians) to 53% (97 of 182 physicians). After adjustment for sex, age, and personality dimensions, reduction in emotional exhaustion in the overall cohort was independently associated with reduced number of work hours per week (β = 0.17; P = .03). Among men, “satisfaction with the intervention” was an independent predictor of reduced emotional exhaustion (β = 0.25; P = .04).

“A short term counselling intervention could contribute to reduction in emotional exhaustion in doctors,” the study authors write. “This was associated with reduced working hours for the whole cohort and, in men, was predicted by satisfaction with the intervention.”

Study limitations include an inability to determine causality, lack of further analyses of subgroups possibly causing a false negative finding (type 2 error), regression analyses for each sex also subject to possible type 2 errors, and possible recall bias.

“Considering doctors’ reluctance to seek help, despite high levels of distress, it is important to offer interventions that facilitate access and that can enhance motivation to reconsider personal and professional priorities when necessary,” the study authors write. “The indications of factors possibly contributing to reduction in emotional exhaustion need to be further investigated with a more controlled design.”

Source:

1. Counseling May Reduce Clinician Burnout and Stress

PRO 140 blocks CCR5, the predominant coreceptor used by HIV for cell entry during transmission and the initial stages of disease. In vitro, it inhibits CCR5-tropic virus at concentrations “that do not antagonize the natural activity of CCR5,” the researchers explain.

“The magnitude of the reduction in viral load was surprising. To our knowledge, these represented the largest reductions in HIV-1 RNA reported after just one dose of any HIV drug,” lead author Dr. Jeffrey M. Jacobson told Reuters Health. “The findings may be related to the long serum half-life of the drug and the efficiency with which it blocks HIV in humans.”

Dr. Jacobson, from Drexel University College of Medicine, Philadelphia, and colleagues tested PRO 140 in 39 subjects with HIV-1 RNA levels of at least 5000 copies/mL and CD4+ cell counts of 250 cells/microliter or higher. In addition, the subjects had received no antiretroviral therapy for 3 months and only R5 HIV-1 was detectable.

The subjects were randomized to receive a single IV infusion of PRO 140, at doses of 0.5, 2, or 5 mg/kg, or placebo. The subjects were followed for 58 days to assess the safety, efficacy, and serum levels of PRO 140.

PRO 140 appeared to be safe and well tolerated and was associated a rapid, marked, and prolonged drop in viral load.

The anti-HIV effect was also dose dependent. The average reduction in HIV-1 RNA levels ranged from 0.58 log10 to 1.83 log10 with the 0.5- and 5-mg/kg doses, respectively. A greater than 10-fold reduction in mean viral load was seen within just 4 days of treatment and persisted for up to 3 weeks.

“PRO 140 has the potential to provide a potent, well-tolerated and long-acting drug,” Dr. Jacobson emphasized. “Whereas all HIV drugs currently are administered at least once daily, PRO 140 potentially could be administered on a weekly or less frequent basis, and thereby provide a novel approach to HIV therapy.”

He added that “studies are underway to examine both higher IV doses (of PRO 140) and a subcutaneous dosage form.”

Source:

1. Anti-CCR5 Monoclonal Antibody Has Strong Anti-HIV Activity

Triamcinolone Acetonide Nasal Spray (Nasacort AQ) Warnings Strengthened

On September 19, the FDA approved safety labeling revisions for triamcinolone acetonide nasal spray (Nasacort AQ; sanofi-aventis US) to strengthen warnings and precautions related to its newly approved use in children aged 2 to 5 years.

Because of the rare risk for local Candida albicans infection of the mouth and pharynx, the FDA advises that children receiving triamcinolone therapy for several months or longer be periodically examined for evidence of Candida infection or other signs of adverse events on the nasal mucosa. Other rare local nasal effects may include epistaxis and nasal septal perforation.

Patient using immunosuppressants are more susceptible to infections vs healthy individuals, the FDA reminded clinicians, emphasizing that varicella zoster (chickenpox) and measles have been reported with increased severity and with some fatalities in susceptible individuals.

Particular care should be taken to avoid exposure in children and adults who have not had these diseases or have been properly immunized. Prophylaxis with varicella zoster immune globulin or pooled intramuscular immune globulin prophylaxis should be considered for patients exposed to disease.

Corticosteroids such as triamcinolone should be used with caution, if at all, in patients with active or quiescent tuberculosis infection; untreated fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex, the FDA warned, noting the potential for clinical worsening.

The FDA also warned of the risk for hypercorticism and adrenal suppression in patients receiving nasal steroids at higher-than-recommended doses and susceptible patients receiving usual doses. If these changes occur, triamcinolone should be slowly tapered and patients carefully observed for symptoms of withdrawal such as joint and/or muscular pain, lassitude, and depression. Rapid decreases in systemic corticosteroid dosage can cause severe exacerbation of symptoms in patients with asthma or other clinical conditions requiring long-term therapy.

Orally inhaled corticosteroids, such as triamcinolone, may also cause a reduction in pediatric growth velocity. Pediatric growth should be monitored routinely via methods such as stadiometry, and treatment should be titrated to the lowest effective dose.

Triamcinolone nasal spray is indicated for the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in patients 2 years and older.

Atazanavir Sulfate Capsules (Reyataz) Linked to Risk for Rash

On September 30, the FDA approved safety labeling revisions for atazanavir sulfate capsules (Reyataz; Bristol-Myers Squibb Co) to warn of the risk for rash associated with their use.

The incidence of rash (all grades, regardless of causality) across controlled clinical studies was approximately 20% in atazanavir-treated patients; median time to onset was 7.1 weeks and median duration, 1.3 weeks.

Most rashes consisted of mild-to-moderate maculopapular skin eruptions not requiring interruption of therapy, and the discontinuation rate for rash was less than 1% overall.

However, atazanavir should be discontinued in patients in whom a severe rash develops because cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have also been reported.

Atazanavir is a protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Rocuronium Bromide Injection (Zemuron) May Cause Residual Paralysis

On August 28, the FDA approved safety labeling revisions for rocuronium bromide intravenous injection (Zemuron; Organon USA, Inc) to advise of warnings and precautions associated with its use.

Rocuronium should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with the drug’s actions and potential complications, the FDA advised. Clinicians administering this and other neuromuscular-blocking agents are advised to use a peripheral nerve stimulator to monitor drug effect, the need for additional doses, and the adequacy of spontaneous recovery or antagonism and to decrease the complications of overdosage if additional doses are administered.

To prevent complications resulting from residual paralysis, patients should only be extubated after they have sufficiently recovered from the neuromuscular block. Other factors that can affect residual paralysis should also be considered, such as drug interactions or patient condition; use of a reversal agent may be indicated in some cases.

The FDA also warned of reported myopathy after long-term administration of other nondepolarizing neuromuscular-blocking agents alone or in combination with corticosteroid therapy in patients receiving care in the intensive care unit. For patients receiving both types of drugs, use of the neuromuscular-blocking agent should be limited in duration and reserved for settings in which the specific benefits of the drug outweigh the risk.

Rocuronium injection is indicated for inpatients and outpatients as an adjunct to general anesthesia to facilitate both rapid sequence and routine tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

Source:

1. FDA Safety Changes: Nasacort AQ, Reyataz, Zemuron

“Antiretroviral therapy for treatment of human immunodeficiency virus type 1 (HIV-1) infection has improved steadily since the advent of potent combination therapy in 1996,” write DHHS Panel Co-Chairs John G. Bartlett, from Johns Hopkins University in Baltimore, Maryland, and H. Clifford Lane, from the National Institutes of Health in Bethesda, Maryland, and colleagues. “New drugs have been approved that offer new mechanisms of action, improvements in potency and activity even against multidrug-resistant viruses, dosing convenience, and tolerability….The primary goal of the Panel is to provide recommendations for HIV practitioners based on current knowledge of antiretroviral drugs used to treat adults and adolescents with HIV infection in the United States.”

When needed, the DHHS panel reviews new clinical data, the availability of new agents, and other evidence and updates treatment recommendations for management of HIV-1 infection. These guidelines have focused on baseline evaluation, treatment objectives, indications for starting antiretroviral therapy, choosing the initial regimen in treatment-naive patients, drugs or combination regimens to be avoided, managing adverse effects and drug interactions, managing treatment failure, and special considerations regarding specific patient subgroups.

This latest revision includes guidelines for adults and adolescents and special populations. However, other guidelines are available with detailed recommendations for pregnant women, children, and individuals with occupational or nonoccupational HIV exposure.

Even with frequent revisions, these guidelines cannot always stay abreast of the rapidly evolving science in this field, and they may not apply equally to all patients. Clinicians should therefore exercise good judgment in management decisions suited to unique patient situations.

Overall treatment objectives reinforced in this latest revision are to decrease morbidity and mortality rates, improve quality of life and immunologic function, decrease viral load, and prevent vertical transmission. The guidelines reiterate that antiretroviral drugs cannot eradicate HIV.

Before treatment, genotypic drug resistance testing, as well as evaluation of drug interactions and comorbid conditions, is recommended to allow individual tailoring of the treatment regimen. Factors associated with treatment success include high potency of antiretroviral therapy, good treatment adherence, low viremia and high CD4 count at baseline, and rapid reduction of viremia.

Clinicians should consider the potential harms and benefits of beginning antiretroviral treatment early. Antiretroviral treatment should be started in patients who have had an AIDS-defining illness or who have a CD4 count less than 350 cells/mm³. Other indications for therapy initiation, independent of CD4 count, include pregnancy, HIV nephropathy, or hepatitis B virus coinfection.

Preferred antiretroviral regimens should include at least 2, and preferably 3, active drugs from multiple classes. In treatment-naive patients, viral load should decrease to less than detection limits within 12 to 24 weeks, although 6% to 16% of treatment-naive patients may have antiretroviral drug resistance.

Specific changes in content from the January 2008 guidelines are as follows:

• A new table suggests laboratory tests to perform at baseline and during antiretroviral treatment to monitor for efficacy and safety issues.
• In patients with viral loads 500 to 1000 copies/mL, resistance testing should be considered, although it may not always be reliable at these levels (level of evidence, BII).

Specific changes regarding what to prescribe for antiretroviral-naive patients are as follows:

• For protease inhibitor–based regimens:
  • Ritonavir-boosted darunavir has been added as a preferred protease inhibitor component (level of evidence, AI).
  • Except for pregnant women, once-daily ritonavir-boosted lopinavir has been moved from an alternative to a preferred protease inhibitor component (level of evidence, AI).
• For dual-nucleoside reverse transcriptase inhibitor (NRTI) options:
  • Abacavir plus lamivudine have been moved from a preferred to an alternative dual-NRTI component. This decision results from large observational cohort studies suggesting an increased risk for myocardial infarction in patients with high cardiac risk factors, and concerns regarding virologic potency in patients with baseline viral loads 100,000 copies/mL (level of evidence, BI).
• Combinations no longer indicated or that should be used only with caution are as follows:
  • Because of efficacy concerns, a combination of unboosted atazanavir plus didanosine plus emtricitabine (or lamivudine) is not recommended (level of evidence, BI).
  • Because several small studies suggested early virologic failure, the combination of nevirapine plus tenofovir plus emtricitabine (or lamivudine) should be used only with caution and with close monitoring of virologic responses (level of evidence, CII).

For treatment-experienced patients, the revised guidelines offer a new section on regimen simplification for virologically suppressed patients.

“HIV care requires, as always, partnerships and open communication,” the DHHS panel concludes. “The provider can make recommendations most likely to lead to positive outcomes only if the patient’s own point of view and social context are well known. Guidelines are only a starting point for medical decision making [that] can identify some of the boundaries of high-quality care, but cannot substitute for sound judgment.”

Source:

1. Revised Antiretroviral Therapy Guidelines Issued for Teens and Adults With HIV-1

The study was conducted by researchers from Imperial College London, the German Institute of Human Nutrition, and other research institutions across Europe and was published on 13 November in the New England Journal of Medicine.

The researchers wrote that previous studies relied heavily on BMI (body mass index, a person’s weight in kilos divided by the square of their height in metres) to assess the link between body fat (adiposity) and risk of death, but not many had looked into the effect of how the body fat is distributed.

For the study the researchers used data from 359,387 participants from 9 countries that were taking part in the European Prospective Investigation into Cancer and Nutrition (EPIC), one of the largest long-term prospective studies in the world. The average age of the participants when data were first collected was 51.5 years, and 65.4 per cent were women.

Using a statistical tool called Cox regression analysis the investigators looked for links between BMI, waist circumference, and waist-to-hip ratio with risk of death, while taking into account other factors like age, location, education, smoking, alcohol, exercise and height.

Source:

1. Large Waist Nearly Doubles Death Risk

Speaking today at the American Academy of Dermatology’s SKIN academy (Academy), dermatologist Ellen S. Marmur, MD, FAAD, chief of the division of dermatologic and cosmetic surgery at The Mount Sinai Medical Center in New York, presented the latest advances in diagnosing skin cancer and the Academy’s new detection strategies that emphasize the importance of patient involvement.

“There are some exciting innovations in diagnosing skin cancer that can help us detect skin cancer early, when it is most treatable,” said Dr. Marmur. “Even simple detection tools designed by the Academy that patients can use in their own homes can save thousands of lives.”

New Technologies for Diagnosing Skin Cancer

Dermatologists traditionally diagnose skin cancer by evaluating the skin using a clinical examination and, if necessary, a magnifying device and then biopsying any suspicious lesions. Now, technological advances in computers, lasers and other polarizing light sources are providing dermatologists with tools to enhance the evaluation of suspicious lesions and, in some cases, decreasing the number of biopsies needed for an accurate diagnosis. The idea is to hone in on suspicious lesions earlier and with more specificity.

One of the newest technological developments in the fight against skin cancer is the use of sophisticated imaging to scan and enhance certain features of suspected lesions. Similar to how a computerized tomography (CT) scan highlights areas of the brain for abnormalities, imaging devices can now work on the skin to help detect cancerous tissue.

Another exciting technology dermatologists are using to evaluate suspected skin cancers is a hand-held light device known as dermascopy that can look at the pigment of the skin through specialized filters that magnify and polarize lesions. For example, similar to how filters are used on cameras to create certain backgrounds, filters are used on this device to enhance certain features of lesions such as brown or red background colors that could indicate a melanoma (the deadliest form of skin cancer).

Dr. Marmur noted that one of the main benefits of dermascopy is the ability to immediately evaluate a potential melanoma based on its magnified characteristics, which could help decrease the number of biopsies needed to make an accurate diagnosis, or can push the physician to biopsy a borderline lesion that appears more suspicious with the assistance of the dermatoscope.

In addition, newer computer systems are being used in conjunction with hand-held photography devices to more accurately diagnose melanomas. For example, the photo device takes a digital picture of the suspicious lesion, which is then magnified on the computer screen for closer examination. The computer system also contains a database of characteristics of approximately 100,000 evolving melanomas, which the lesions are then graded against to see if certain features score high enough on the scale to warrant having a biopsy.

“With the improvement of early detection methods, we are finding an increasing number of smaller skin cancers,” said Dr. Marmur. “We know from experience that detecting skin cancer in its earliest stage means better cure rates and survival rates. Prognosis plummets as the depth of melanoma increases even by the smallest increment of one millimeter.”

Source:

1. Stop Skin Cancer On The Spot: New Tools Aid In Diagnosing And Detecting Skin Cancer In Earliest Stages

Varki, UC San Diego School of Medicine distinguished professor of medicine and cellular and molecular medicine, and co-director of the UCSD Glycobiology Research and Training Center, and colleagues studied a non-human cellular molecule called N-glycolylneuraminic acid (Neu5Gc). Neu5Gc is a type of glycan, or sugar molecule, that humans don’t naturally produce, but that can be incorporated into human tissues as a result of eating red meat. The body then develops anti-Neu5Gc antibodies - an immune response that could potentially lead to chronic inflammation, as first suggested in a 2003 PNAS paper by Varki.

“We’ve shown that tumor tissues contain much more Neu5Gc than is usually found in normal human tissues,” said Varki. “We therefore surmised that Neu5Gc must somehow benefit tumors.”

It has been recognized by scientists for some time that chronic inflammation can actually stimulate cancer, Varki explained. So the researchers wondered if this was why tumors containing the non-human molecule grew even in the presence of Neu5Gc antibodies.

“The paradox of Neu5Gc accumulating in human tumors in the face of circulating antibodies suggested that a low-grade, chronic inflammation actually facilitated the tumor growth, so we set out to study that hypothesis,” said co-author Nissi M.Varki, M.D., UCSD professor of pathology.

Using specially bred mouse models that lacked the Neu5Gc molecule - mimicking humans before the molecule is absorbed into the body through ingesting red meat - the researchers induced tumors containing Neu5Gc, and then administered anti-Neu5Gc antibodies to half of the mice. In mice that were given antibodies inflammation was induced, and the tumors grew faster. In the control mice that were not treated with antibodies, the tumors were less aggressive

Others have previously shown that humans who take non-steroidal anti-inflammatory drugs (commonly known as NSAIDs) have a reduced risk of cancer. Therefore, the mice with cancerous tumors facilitated by anti-Neu5Gc antibodies were treated with an NSAID. In these animals, the anti-inflammatory treatment blocked the effect of the Neu5Gc antibodies and the tumors were reduced in size.

“Taken together, our data indicate that chronic inflammation results from interaction of Neu5Gc accumulated in our bodies from eating red meat with the antibodies that circulate as an immune response to this non-human molecule - and this may contribute to cancer risk,” said Varki.

Source:

1. How Cancer Progression Can Be Spurred By Eating Red Meat

Ms Kvaskoff, from St Lucia, is one of only 10 academics to win a 2008 L’Oreal France-UNESCO For Women in Science Award, with the prizes presented in Paris next week.

The awards are worth 10,000 Euros each and are given to French women completing PhDs in the life sciences to enable greater recognition for their work and to build a career in their chosen fields.

“Women are statistically underrepresented in the sciences, especially in research and more specifically at the upper professional levels,” Ms Kvaskoff said.

“Young women may see research as an unreachable world; this is indeed the vision I had of it myself as a young girl. However, women have specific resources of their own and I believe they have a lot to bring to research.”

Ms Kvaskoff’s PhD focuses on cutaneous melanoma, and whether its occurrence can be linked to hormonal, nutritional and genetic causes.

Central to her research is a large French database, the E3N cohort, which lists approximately 100,000 women born between 1925 and 1950 and includes their responses to bi-yearly health surveys.

The questionnaires carry information about the group’s exposure to certain factors (including hormonal treatments, diet, tobacco and alcohol consumption) and could help explain why certain conditions, including melanoma, develop over time.

“During my studies, I have always had an interest in studying cancer, and have generally directed my internships towards cancer research,” Ms Kvaskoff said.

“I started to study the epidemiology of cutaneous melanoma in 2005 during an internship at the Cancer Council Queensland, where I worked on sunburn and solarium use in Queenslanders.”

She then completed her masters in France, before deciding to undertake her doctoral studies as part of a “Cotutelle” program which allows her to pursue research jointly at the Queensland Institute for Medical Research and a French research laboratory (Inserm at the Institut Gustave Roussy in Paris).

Ms Kvaskoff said her studies stemmed from a desire to promote disease education and prevention, and named Nobel laureate Marie Curie as a research idol.

“She was an admirable person who imposed herself as a woman in a mainly-male scientific world, and whose discoveries left their mark in history,” Ms Kvaskoff said.

The L’Oreal France-UNESCO For Women in Science Award ceremony will take place on November 17 at the Palais de la Découverte in Paris.

Source:

1. Melanoma Research Claims French Science Prize

“Our study also looked at possible medications that can reverse or halt bone loss,” says Dr. Fred Saad, lead author and director of urologic oncology at the Université de Montréal’s Faculty of Medicine and the Centre Hospitalier de l’Université de Montréal (CHUM), who completed the exhaustive study with colleagues from McMaster University, the Université Laval, the University of Toronto and the University of British Columbia.

“Bone is a dynamic tissue which undergoes a cyclic process of breaking down and rebuilding,” adds Dr. Saad. “Medications called bisphosphonates help with the rebuilding process and have been successfully used to combat osteoporosis, which is good news for cancer patients.”

Evaluating the studies

Dr. Saad and colleagues evaluated data from more than 3,500 breast and prostate cancer studies. They concluded that breast cancer patients treated with aromatase inhibitors were more likely to have bone loss and fractures compared to patients who didn’t receive the therapy. Similarly, men who received androgen deprivation therapy to treat their prostate cancer had an increased risk of bone disorders. Although the numbers vary from one study to the next (from five to 45 percent), an elevated risk is consistently observed.

“Awareness of the incidence of cancer-associated bone loss raises issues for clinicians who should identify those patients who are most at risk for fractures and prescribe treatment strategies,” says Dr. Saad. “This information is not only a concern for the specialists, but also for the general practitioners who frequently encounter these patients.”

Bisphosphonate treatment reduces bone loss

Dr. Saad’s group also evaluated data that included bisphosphonate treatment for cancer patients receiving chemotherapy. Prostate cancer patients who received bisphosphonate treatment and androgen deprivation therapy did show an increase in bone loss. In the same vane, there was a protective effect on bone loss for breast cancer patients who were treated with bisphosphonates.

“It is clear that the use of bisphosphonates attenuates bone loss,” concludes Dr. Saad. “However, the optimal dosing and long-term impact is unclear and needs to be determined. Other measures to combat the bone loss, such as exercise, vitamin D intake, avoidance of cigarettes, may also be beneficial

Source:

1. Cancer Treatment May Result In Bone Loss - New Cross Canada Study