New diagnostic method could help prevent osteoarthritis

A new method is set to help doctors diagnose osteoarthritis at such an early stage that it will be possible to delay the progression of the disease by many years, or maybe even stop it entirely.

The joint disease osteoarthritis is one of our most common chronic diseases and one of the primary causes of disability for people around the world.

“Osteoarthritis often attacks the knee and hip joints and breaks down the impact absorbing cartilage found there. For those affected, the progression of the disease usually takes many years, with gradually increasing pain which often leads to disability,” says Carl Siversson, who has just defended his thesis in Medical Radiation Physics at Lund University in Sweden.

One of the problems with osteoarthritis has been diagnosing and monitoring the disease before symptoms become evident. It has therefore been difficult to change or delay the course of the disease. A few years ago, researchers from Lund University and Harvard Medical School developed a method to measure the degree of osteoarthritis using an MRI scanner, even at a very early stage. The method is called dGEMRIC (delayed gadolinium-enhanced MRI of cartilage).

“This was major progress, but one problem was that the measurements could only be performed in a limited part of the cartilage. We have now improved the method so that we can study all the cartilage in the joint at once. We have achieved this by solving the problem of how to correct all the irregularities in the MRI images,” says Siversson.

The improved method has now been tested both on healthy individuals and on individuals with osteoarthritis, and the results show that the disease can now be monitored in ways that were not previously possible, according to Siversson.

“Now we are continuing our work to make the method easy for doctors to use in their practice. Our hope is that the method will also be significant for future drug development,” says Siversson, who after completing his PhD will continue his research at Harvard Medical School in Boston, USA.

- The new method is described in Carl Siversson’s thesis: Three-dimensional T1 quantification techniques for assessment of cartilage quality using dGEMRIC:

Alternative to high-voltage shock to correct arrhythmia

Each year hundreds of thousands of people around the world have a cardiac defibrillator implanted in their chest to deliver a high-voltage shock to prevent sudden cardiac death from a life-threatening arrhythmia. While it’s a necessary and effective preventive therapy, those who’ve experienced a defibrillator shock say it’s painful, and some studies suggest that the shock can damage heart muscle.

Scientists at Johns Hopkins believe they have found a kinder and gentler way to halt the rapid and potentially fatal irregular heart beat known as ventricular fibrillation. In a study published in the 28 September issue of Science Translational Medicine, they report success using lower amplitude, high-frequency alternating current at 100-200 Hz to stop the arrhythmia in the laboratory. They say this approach also may prove to be less painful for patients because of the lower amplitude and different frequency range than what is used for standard defibrillator shocks.

“We believe we have found a way to stop a life-threatening arrhythmia by applying a high-frequency alternating current for about one-third of a second,” says Ronald Berger, MD, PhD, a cardiac electrophysiologist at the Johns Hopkins Heart and Vascular Institute and a professor of medicine and biomedical engineering at the Johns Hopkins University School of Medicine. “The alternating current puts the disorganized, rapidly moving heart cells in a refractory state, like suspended animation. When we turn off the current, the cells immediately return to a normal state. If further research confirms what we have learned so far, this could be less painful for a patient while achieving the same result,” says Dr Berger, who is the senior author of the study.

Graduate student Seth Weinberg, a colead author of the study, says the way heart cells behave during ventricular fibrillation is like having a football stadium full of fans, all of whom are doing “the wave” in an uncoordinated, disorganized fashion. “Applying the alternating current,” he says, “is like freezing all of the fans in a position halfway between sitting and standing. When the current is turned off, the fans sit down in an orderly way, ready to be instructed to do the wave in a coordinated way.”

Berger says he and his colleagues, a team of Johns Hopkins cardiologists and biomedical engineers, have shown a proof of principle and a novel scientific finding: It’s the first time heart cells have been put in a suspended state to interrupt ventricular fibrillation.

“The idea to put heart cells in a brief state of suspended animation came from studies showing that alternating current could be used to put nerve cells in a similar state to block the signals that cause pain,” says Harikrishna Tandri, MD, assistant professor of medicine and the other colead author of the study.

To ensure that they were correctly assessing the response of the heart cells to the high frequency current, and, at the same time, distinguishing the response from the cells’ native electrical activity, the researchers used a technique called optical mapping. Unlike other electrical recording techniques, optical mapping measurements are not affected by applied electrical stimuli, according to co-author Leslie Tung, PhD, professor of biomedical engineering, who led the optical mapping aspect of the research.

In order to allow the team to explore the response of individual heart cells to the high-frequency electrical current, co-author Natalia Trayanova, PhD, professor of biomedical engineering, produced a multiscale computational model of the heart.

While more testing is needed in animal models, the researchers are optimistic that their work may lead to a new approach to shock the human heart back to a normal rhythm.

Colorectal cancer drug appears to cause nerve damage

Oxaliplatin, a platinum-based anticancer drug that’s made enormous headway in recent years against colorectal cancer, appears to cause nerve damage that may be permanent and worsens even months after treatment ends. The chemotherapy side effect, described by Johns Hopkins researchers in the September issue of Neurology, was discovered in what is believed to be the first effort to track oxaliplatin- based nerve damage through relatively cheap and easy punch skin biopsies.

The investigators emphasise that the drug therapy clearly improves length of survival in advanced cancer by months to years, and that the goal of their new study is to find ways of preventing or slowing the damage through nerveprotective therapies identified through simple skin testing.

Many patients who take oxaliplatin report bothersome neurological side effects, including pain in the hands and feet and a numbness or tingling in the throat that affects swallowing, according to study leader Michael Polydefkis, MD, MHS, associate professor of neurology at the Johns Hopkins University School of Medicine and director of the EMG Laboratory and Cutaneous Nerve Laboratory at Johns Hopkins Bayview Medical Center. Though these symptoms develop over time in the majority of patients, some report neuropathies as early as when the drug is first infused.

Test results from a study of eight cancer patients showed that each of the patients’ nerve function and neuropathy symptoms worsened over time and that results from the punch skin biopsies neatly mirrored the side effect arc. Using a microscope, the researchers saw that nerve cells’ axons degenerated over the course of oxaliplatin therapy. This progression persisted after treatment stopped. Even 180 days after their last doses, seven out of the eight patients’ axons continued to wither.

“This drug has rapidly become the standard of care for people with advanced colon cancer, but we really knew little about how oxaliplatin affects nerves over time,” he says. “With people living longer lives on oxaliplatin, it’s important to know more about these neurological side effects so patients and their physicians can make educated choices on how this drug is used, and perhaps suggest ways to limit the damage.” doi: 10.1212/WNL.0b013e31822cf

Scientists 'disarm' HIV in step towards vaccine

Researchers have found a way to prevent HIV from damaging the immune system, in a new lab-based study published in the journal Blood. The research, led by scientists at Imperial College London and Johns Hopkins University, could have important implications for the development of HIV vaccines.

HIV/AIDS is the third biggest cause of death in low income countries, killing around 1.8 million people a year worldwide. An estimated 2.6 million people became infected with HIV in 2009.

The research shows that HIV is unable to damage the immune system if cholesterol is removed from the virus’s membrane. Usually, when a person becomes infected, the body’s innate immune response provides an immediate defence. However, some researchers believe that HIV causes the innate immune system to overreact and that this weakens the immune system’s next line of defence, known as the adaptive immune response.

In the new study, the researchers removed cholesterol from the membrane surrounding the virus and found that this stopped HIV from triggering the innate immune response. This led to a stronger adaptive response, orchestrated by immune cells called T cells. These results support the idea that HIV overstimulates the innate response and that this weakens the immune system.

Dr Adriano Boasso, first author of the study, from Imperial College London, said: “HIV is very sneaky. It evades the host’s defences by triggering overblown responses that damage the immune system. It’s like revving your car in first gear for too long. Eventually the engine blows out.

“This may be one reason why developing a vaccine has proven so difficult. Most vaccines prime the adaptive response to recognise the invader, but it’s hard for this to work if the virus triggers other mechanisms that weaken the adaptive response.”

HIV takes its membrane from the cell that it infects. This membrane contains cholesterol, which helps to keep it fluid. The fluidity of the membrane enables the virus to interact with particular types of cell. Cholesterol in the cell membrane is not connected to cholesterol in the blood, which is a risk factor for heart disease but is not linked to HIV.

Normally, a subset of immune cells called plasmacytoid dendritic cells (pDCs) recognise HIV quickly and react by producing signalling molecules called interferons. These signals activate various processes which are initially helpful, but which damage the immune system if switched on for too long.

In collaboration with researchers at Johns Hopkins University, the University of Milan and Innsbruck University, Dr Boasso’s group at Imperial have discovered that if cholesterol is removed from HIV’s envelope, it can no longer activate pDCs. As a consequence, T cells, which orchestrate the adaptive response, can fight the virus more effectively.

The researchers removed cholesterol using varying concentrations of betacyclodextrin (bCD), a derivative of starch that binds cholesterol. Using high levels of bCD they produced a virus with a large hole in its envelope. This permeabilised virus was not infectious and could not activate pDCs, but was still recognised by T cells. Dr Boasso and his colleagues are now looking to investigate whether this inactivated virus could be developed into a vaccine.

“It’s like an army that has lost its weapons but still has flags, so another army can recognise it and attack it,” he said.

Ref: A. Boasso et al. ‘Over-activation of plasmacytoid dendritic cell inhibits antiviral T cell responses: a model for HIV immunopathogenesis.’ Blood, 19 September 2011.

Two doses of HPV vaccine may be as effective as three

Two doses of the human papillomavirus (HPV) vaccine Cervarix were as effective as the current standard three-dose regimen after four years of follow-up, according to researchers from the US National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues. The results of the study, based on data from a community-based clinical trial of Cervarix in Costa Rica, appeared online 9 September 2011, in the Journal of the National Cancer Institute.

Worldwide, approximately 500,000 new cases of cervical cancer are diagnosed every year, and about 250,000 women die from the disease. An overwhelming majority of these new cases and deaths occur in low-resource countries. Virtually all cases of cervical cancer are caused by persistent infection with HPV. Cervarix is one of two vaccines to protect against persistent infection with two carcinogenic HPV types, 16 and 18, which together account for 70% of all cervical cancer cases. The vaccine is intended to be administered in three doses given over the course of six months. To date, investigators have observed up to eight years of protection from persistent HPV infection with the vaccine. Studies are ongoing to determine the maximum length of protection.

The cost of the vaccine as well as the logistical difficulties of administering three doses to an adolescent population in resource-poor countries is greater than administering two doses. Even in wealthier countries such as the United States, few adolescent females complete the entire course of three vaccinations.

The investigators found that, after four years of follow up, two doses of the vaccine conferred the same strong protection against persistent infection with HPV 16 and 18 as did the full three-dose regimen. From just a single dose, they also observed a high level of protection, but they are cautious about the long-term efficacy of a single dose because other vaccines of this type usually require a booster dose. Additional studies are needed to evaluate the efficacy of a single dose, as well as the duration of protection for both one and two doses.

“Our study provides evidence that an HPV vaccine program using two doses will work. It may be that vaccinating more women, with fewer doses for each, will reduce cervical cancer incidence more than a standard three-dose programme that vaccinates fewer women,” said Aimée R. Kreimer, PhD, lead author and investigator in NCI’s Division of Cancer Epidemiology and Genetics. “The main question will be whether the duration of protection from fewer doses is adequate.”

“Further studies are needed to confirm our findings in other populations as well as to quantify the duration of protection for fewer than three doses,” said Kreimer.

Good results from phase III trial for oral MS medication

Sanofi and its subsidiary Genzyme announced early October the publication of the pivotal Phase III TEMSO study with investigational once-daily oral medication teriflunomide in The New England Journal of Medicine (NEJM). Results showed that teriflunomide at the 14mg dosage significantly reduced the annual relapse rate, reduced disability progressions and improved several magnetic resonance imaging (MRI) measures of disease activity, including new or worsening brain lesions. Teriflunomide has a well-characterized safety profile, with a similar proportion of trial participants reporting adverse events compared to placebo.

“The TEMSO data demonstrate the effect of teriflunomide in terms of reducing relapse rates, disability progression and Magnetic Resonance Imaging (MRI) lesions,” said Dr Paul O’Connor, director of the MS Clinic at St Michael's Hospital, Toronto, Canada and principal investigator in the TEMSO study. “These results, sustained over two years, provide clinically meaningful data for teriflunomide.”

The two-year TEMSO (TEriflunomide Multiple Sclerosis Oral) trial involved 1,088 people with relapsing forms of MS from 126 centres across 21 countries. TEMSO is the first study from a broad clinical development programme that includes more than 4,000 trial participants in 36 countries and is one of the largest and broadest clinical programs of any oral MS agent under development, with five Phase III clinical trials either completed or underway.

“The publication of the teriflunomide results in the New England Journal of Medicine is an exciting milestone as we continue the development of our product,” said Dr Elias Zerhouni, President, Global Research & Development, Sanofi.

Similar adverse events, serious adverse events, and adverse events leading to treatment discontinuation were observed with teriflunomide compared to placebo. No serious or opportunistic infections and no deaths occurred in trial participants treated with teriflunomide.

Teriflunomide has been filed with the US FDA in August of 2011 and the EMA filing is expected in the first quarter of 2012.

Obesity Staging System better than BMI

Two new studies show that the Edmonton Obesity Staging System (EOSS), a 5-point system that ranks obese patients by presence of physical, mental and functional health (Stage 0: no health problems to Stage 4: irreversible (end-stage) health problems), is superior to anthropometric measures in predicting mortality in overweight and obese individuals.

The independent studies examined large populations from the US-NHANES and the Aerobics Centre Longitudinal Study, respectively. Lower EOSS scores were associated with healthier eating and greater physical fitness, while higher EOSS scores were associated with history of weight cycling.

Importantly, EOSS 0/1 individuals with Class III obesity had no increased risk of mortality over the almost 20 year observation periods, while overweight and Class I obese individuals with higher EOSS scores had a mortality risk comparable to individuals with higher EOSS scores at higher BMIs. Dr Arya Sharma, who first developed the Staging System, says: “While BMI tells me how 'big' my patient is, EOSS tells me how 'sick' my patient is - this is a better way to make decisions about treatment plans including weight loss than BMI alone.”

The articles were published in the Canadian Medical Association Journal [PMID: 21844111] and Applied Physiology, Nutrition, and Metabolism [PMID: 21838602].

A video of Dr Sharma explaining EOSS can be seen

New study increases potential for personalised medicine

The applicability of personalised medicine has moved one step closer thanks to a research study undertaken by Karsten Suhre, PhD, Professor of Physiology and Biophysics, Weill Cornell Medical College in Qatar (WCMC-Q). In the most comprehensive investigation of its kind, the genetic variance in human metabolism was analysed and new insights into a range of common diseases were discovered.

The study, recently published in the prestigious journal Nature and titled, ‘Human metabolic individuality in biomedical and pharmaceutical research’, establishes metabolomics as an intermediate to providing a biological link that contributes to the understanding of the genetic effects and more effectively impacts discovery and development of individualized biomarkers and therapies.

Prof Suhre led the study, which was a collaboration between European research centres, prior to taking up his position as Director of the Bioinformatics Core at WCMC-Q. Prof Suhre says: “This study suggests that testing biochemical levels, not withstanding inborn errors of metabolism, is an excellent way of understanding individual uniqueness and can potentially increase the development of personalised medicine.”

The research project searched for genetic influences on levels of more than 250 compounds in blood, including lipids, sugars, vitamins, amino acids and others. They discovered variants that have a significant effect on the levels of these compounds, and therefore on the underlying biological and disease processes. The findings provide new insights for many disease-related associations that have been reported in previous studies, including cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, thrombosis and Crohn’s disease.

“Often the effects of variants discovered in genome wide association analyses are modest and we then have a poor understanding of the biological mechanisms behind the associations. However, this approach can overcome these problems and possibly inform individualised therapy or treatment. Previous studies have focused on the levels of one or a few metabolites such as cholesterol levels or sugar in the blood, these are investigated by a general practitioner to help diagnose disease. The new approach in this work analysed a much wider range of small biochemical compounds, to give as complete a picture as possible of the molecules that are symptoms of disease and those that might contribute to disease,” says Prof Suhre. “These remarkable findings enable researchers to identify new and potentially relevant metabolic processes and pathways. We have, therefore, identified new molecules of interest that could be clinically significant.”

Prof Suhre says he is very excited to be part of the visionary and dedicated team of researchers at WCMC-Q and is looking forward to participating in the drive to alleviate health issues that are impacting the region, such as diabetes and heart disease.

Trial shows promise for new prostate cancer treatment

Scientists at Queen’s University have pioneered a new combination treatment for prostate cancer. The treatment, which has been successful in phase one of trials, will now be tested for efficacy in a second phase.

The treatment, aimed at men with an advanced and aggressive form of prostate cancer which has spread to the bone, is the first of its kind to be developed. It combines traditional chemotherapy treatments with two doses of a radioactive chemical which can target areas of the bone affected by prostate cancer.

Chemotherapy is often used to treat the disease; however, benefits of this treatment are usually short-lived. An ability to combine two different types of drugs against prostate cancer may help improve outcomes including survival for these men.

The results of the first phase of the trial, which are published in the European Journal of Nuclear Medicine and Molecular Imaging, demonstrate that it is safe and feasible to combine multiple injections of the radioactive chemical (Rhenium-186 HEDP) along with standard chemotherapy in men with an aggressive form of prostate cancer.

Dr Joe O’Sullivan, Consultant and Senior Lecturer in Clinical Oncology at the Centre for Cancer Research and Cell Biology at Queen’s University, and leader of the study, said: “This is a significant development in the fight against prostate cancer. While this combination treatment still has to go to phase two of trials, to know that this combination is safe and feasible as a treatment is a huge step forward.

“Traditional chemotherapy treatments aren’t always effective in treating aggressive and advanced forms of prostate cancer, so we needed to develop a new treatment which will provide better outcomes for patients with this type of cancer. The combination of chemotherapy with the radioactive chemical Rhenium-186 HEDP has the potential to improve outcomes, including survival, for men with this form of cancer.

“The second phase of the trial has already commenced in The Netherlands and will start in the UK within six months. The trial will involve up to 100 patients from Northern Ireland and the Netherlands and it is hoped that results should be known within two years.”

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