Dengue vaccine enters Phase 3 trial in Brazil

A large-scale clinical trial to evaluate whether a candidate vaccine can prevent the mosquito-borne illness dengue fever has been launched in Brazil. The vaccine, TV003, was developed by scientists in the laboratory of Stephen Whitehead, Ph.D., at the USNIH’s National Institute of Allergy and Infectious Diseases (NIAID). The Butantan Institute, a non-profit producer of immunobiologic products for Brazil, licensed the NIAID dengue vaccine technology and is sponsoring the placebocontrolled, multi-centre Phase 3 trial using test vaccine produced in Sao Paulo.

Dengue fever is common in many parts of the tropics and subtropics and about half the world’s population is at risk of infection. The World Health Organization estimates that up to 400 million dengue infections occur annually, resulting in 500,000 hospitalizations. More than 1.5 million cases of dengue were reported in Brazil in 2015.

Dengue is caused by any of four related viruses, termed serotypes DEN-1, DEN-2, DEN-3 and DEN-4, which are transmitted to people by Aedes aegypti mosquitoes. A person exposed to one dengue virus type gains immunity to that type, but not to the other three. In fact, a second infection with a virus type that differs from the first can lead to a more severe course of disease.

“Researchers in NIAID’s Laboratory of Infectious Diseases spent many years developing and testing dengue vaccine candidates designed to elicit antibodies against all four dengue virus serotypes,” said NIAID Director Anthony S. Fauci, M.D.

“Earlier clinical trials of this candidate conducted in the United States by NIAID showed that it could elicit a robust antibody and cellular immune response after just one dose,” he added. “Because the impact of dengue fever in Brazil is especially large and the country has an excellent health infrastructure, it is an ideal location to test the vaccine candidate.”

The new trial aims to enrol almost 17,000 healthy people aged 2 to 59 years in 13 cities, beginning in Sao Paulo. Two-thirds of the volunteers will receive a single dose of the candidate vaccine, while one-third will receive an inactive placebo injection. Neither participants nor study staff will know which of the two groups a volunteer is in. All volunteers will be monitored for five years through a combination of in-person visits to the health clinic and telephone or text communications from the investigators. The goal of the trial is determine if the candidate vaccine prevents dengue fever and to provide additional information about its safety. Although the trial is scheduled to last five years, the investigators hope to have early indications of the potential efficacy of the vaccine in less than two years.



Freezing nerves prior to knee replacement improves outcomes

The first study of its kind has found that freezing nerves before knee replacement surgery combined with traditional pain management approaches significantly improves patient outcomes. The results of the preliminary retrospective study led by Vinod Dasa, MD, Associate Professor of Clinical Orthopaedics at LSU Health New Orleans School of Medicine, were published online 10 February 2016 in the journal, The Knee.

The study investigated the cases of 100 patients with advanced osteoarthritis requiring total knee replacement in Dr Dasa’s LSU Health New Orleans orthopaedic practice. Half of them were treated with standard multiple pain management options, before cryoneurolysis (nerve freezing) was introduced to the practice. The first 50 patients to undergo cryneurolysis in addition to multimodal pain management comprised the treatment group, which was compared to the control group who had standard therapy alone. The treatment and control groups were similar in terms of gender, age and body mass index. The only difference is that the treatment group received cryoneurolysis via an FDAapproved handheld device five days prior to surgery. The KOOS (Knee Injury and Osteoarthritis Outcome Score), PROMS (Patient-reported Outcomes Measurement Information System), WOMAC (Western Ontario and McMaster Universities Arthritis Index) and Oxford Knee Score were used to measure outcomes.

“Patients in the treatment group had significantly shorter hospital stays, were prescribed significantly fewer opioids during the first 12 weeks post-operatively and had significantly fewer knee symptoms,” notes Dr Vinod Dasa, Associate Professor of Clinical Orthopaedics at LSU Health New Orleans School of Medicine.

The ability to decrease hospital length of stay following total knee replacement should substantially reduce costs for hospitals and payers. In the present study, only 6% of patients treated with cryoneurolysis prior to surgery stayed in the hospital for two or more days compared to 67% of patients who did not receive this treatment. Similarly, almost half of patients treated with cryoneurolysis were discharged on the same day of surgery compared with only 14% in the control group. The shorter length of stay of the patients in the treatment group may be due to better local control of pain and a reduced need for nerve blocks that can impair motor function, as well as reduced use of opioids for pain control, which allows patients to walk and function well enough to go home sooner.

doi: 10.1016/j.knee.2016.01.011



Height influences risk of cardiovascular disease, diabetes, cancer

Height is largely genetically determined, but in recent decades the height of children and adults has steadily increased throughout the world: In adulthood the children are almost always significantly taller than their parents. The largest increase in height in recent decades is found in the Netherlands. Dutch men are now 20 cm taller than they were 150 years ago. Interestingly, in the Netherlands the per capita consumption of milk and dairy products is the highest in the world.

These observations led the German Center for Diabetes Research (DZD) scientists Professor Norbert Stefan and Professor Hans-Ulrich Häring of the Department of Internal Medicine IV in Tübingen and the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Zentrum München at the University of Tübingen (IDM). Also part of the research collaboration was Professor Matthias Schulze of the German Institute of Human Nutrition in Potsdam (DIfE) and Professor Frank Hu of the Harvard School of Public Health and Medical School in Boston, US. Their research? – To analyse the causes and medical effects of an increase in height.

Their study shows that height has an important impact on mortality from certain common diseases, irrespective of body fat mass and other modulating factors. Previous studies have shown clearly that tall people, in comparison to short people, have a lower risk of cardiovascular disease and type 2 diabetes, but have a higher cancer risk.

“Epidemiological data show that per 6.5cm in height the risk of cardiovascular mortality decreases by six percent, but cancer mortality, by contrast, increases by four percent,” Professor Schulze said. The authors suspect that the increase in body height is a marker of overnutrition of high-calorie food rich in animal protein during different stages of growth. Thus, already in utero, lifelong programming might take place that until now has mainly been established for the insulin-like growth factor 1 and 2 and the IGF-1/2 system.

Among other consequences, activation of this system causes the body to become more sensitive to insulin action, thus positively influencing the lipid metabolism.

“Accordingly, our new data show that tall people are more sensitive to insulin and have lower fat content in the liver, which may explain their lower risk for cardiovascular disease and type 2 diabetes,” Professor Stefan added. These findings fit in with published data that suggest that tall people have relative protection against disorders of the lipid metabolism. However, this activation of the IGF-1/2 system and other signalling pathways may be related to an increased risk of certain cancers, especially breast cancer, colon cancer, and melanoma because cell growth is permanently activated, the authors suspect. The result is an inverse association with the risk of cardiovascular disease and type 2 diabetes, but a positive association with the risk of cancer.

The scientists advocate considering the factor growth and adult height more than hitherto in the prevention of the above abovementioned major diseases. In particular, physicians should be made more aware of the fact that tall people – although less often affected by cardiovascular disease or type 2 diabetes – have an increased risk of cancer. Hitherto, the importance of diet has been underestimated, especially during pregnancy and in children and adolescents.

doi: 10.1016/S2213-8587(15)00474-X



New study highlights effectiveness of herpesvirus vaccine against Ebola

As the latest in a series of studies, researchers at Plymouth University, National Institutes of Health and University of California, Riverside, have shown the ability of a vaccine vector based on a common herpesvirus called cytomegalovirus (CMV) expressing Ebola virus glycoprotein (GP), to provide protection against Ebola virus in the experimental rhesus macaque, non-human primate (NHP) model. Demonstration of protection in the NHP model is regarded as a critical step before translation of Ebola virus vaccines into humans and other great apes.

The study is published online 15 February 2016 in Scientific Reports.

In addition to establishing the potential for CMV-based vaccines against Ebola virus, these results are exciting from the potential insight they give into the mechanism of protection. Herpesvirusbased vaccines can theoretically be made to produce their targeted protein (in this case, Ebola virus GP) at different times following vaccination. The current CMV vaccine was designed to make the Ebola virus GP at later times. This resulted in the surprising production of high levels of antibodies against Ebola virus with no detectable Ebola-specific T cells. This immunological shift towards antibodies has never been seen before for such primate herpesvirus-based vaccines, where responses are always associated with large T cell responses and poor to no antibodies.

“This finding was complete serendipity,” says Dr Michael Jarvis who is leading the project at Plymouth University. “Although we will definitely need to explore this finding further, it suggests that we may be able to bias immunity towards either antibodies or T cells based on the time of target antigen production. This is exciting not just for Ebola, but for vaccination against other infectious as well as non-infectious diseases”.

A largely untold story is the devastating effect Ebola virus is having on wild great ape populations in Africa. Although the present study administered the vaccine by direct inoculation, a CMV-based vaccine that can spread from animal to animal may be one approach to protect such inaccessible wild animal populations that are not amenable to vaccination by conventional approaches. The current study is a step forward, not only for conventional Ebola virus vaccines for use in humans, but also in the development of such ‘self-disseminating vaccines’ to target Ebola in great apes, and other emerging infectious diseases in their wild animal host before they fully establish themselves in humans.

doi: 10.1038/srep21674


New MRI technique offers faster diagnosis of multiple sclerosis

A new way of using MRI scanners to look for evidence of multiple sclerosis in the brain has been successfully tested by researchers at The University of Nottingham and Nottingham University Hospitals NHS Trust.

Multiple sclerosis (MS) is a neurological condition which is notoriously difficult to diagnose as it has many symptoms. Not all sufferers experience all of them and the disease can progress at different rates. MRI scans have been used as a diagnostic tool to detect white matter lesions in the brain but these are not always an indicator of the disease.

Now a research team at Nottingham has found a way to use clinical MRI to distinguish between MS lesions and other brain white spots which are found in MS. The study is published in the Multiple Sclerosis Journal.

They have used a clinical MRI scanner of the type all neuroscience centres have to carry out a special type of scan called a T2-weighted imaging process which is able to reveal lesions in the brain’s white matter that are centred on a vein – a known indicator of MS.

Leading the work, Dr Nikos Evangelou, said: “We already knew that large research MRI scanners could detect the proportion of lesions with a vein in the brain’s white matter, but these scanners are not clinically available. So we wanted to find out whether a single brain scan in an NHS hospital scanner could also be effective in distinguishing between patients known to have MS and patients known to have non-MS brain lesions. We are excited to reveal that our results show that clinical application of this technique could supplement existing diagnostic methods for MS.”

A total of 40 patients were recruited from the neurology outpatients’ department of Nottingham University Hospitals NHS Trust. Initially a test cohort of 10 patients with MS and 10 patients with non-MS white brain matter lesions were scanned. Anonymised scans were analysed blinded to clinical data and simple diagnostic rules were devised. The same rules were applied to a validation cohort of 20 patients (13 with MS and 7 with other lesions) by a blinded observer.

Within the test cohort, all patients with MS had central veins in more than 45% of brain lesions, while the rest had central veins visible in less than 45% of lesions. Then, by applying the same diagnostic rules to the second cohort, all the remaining patients were correctly categorised into MS or non-MS, by the blinded observer, taking less than two minutes per scan.

The new study is significant because currently among patients referred to MS treatment centres with suspected MS, fewer than 50% are found to have it. This shows that diagnosing MS in a significant minority of cases can be challenging.

The Nottingham University team has now started a new study examining patients with real uncertainty about the diagnosis and aim to extend the study in other UK towns so more patients can participate in this important research.



Migraines worsen as women approach menopause

Migraine headaches heat up as women approach menopause, according to a new study from researchers at the University of Cincinnati (UC), Montefiore Headache Center, Albert Einstein College of Medicine and Vedanta Research.

The findings were published online this week in Headache: The Journal of Head and Face Pain, a publication of the American Headache Society.

“Women have been telling doctors that their migraine headaches worsen around menopause and now we have proof they were right,” said Vincent Martin, M.D., professor of internal medicine in UC’s Division of General Internal Medicine and co-director of the Headache and Facial Pain Program at the UC Neuroscience Institute.

The risk of high frequency headaches, with 10 days of headache per month, increased by 60% in middle-aged women with migraine during the perimenopause – the transitional period into menopause marked by irregular menstrual cycles – as compared to normally cycling women, said Dr Martin, the study’s lead author.

Dr Martin and his teamed studied 3,664 women who experienced migraine before and during their menopausal years.

The menopausal years include both the perimenopause and menopause. Menopause begins when women have not had a menstrual period for one year. Symptoms such as hot flashes, irritability, depression and insomnia are common during both.

“Changes in female hormones such as oestrogen and progesterone that occur during the perimenopause might trigger increased headaches during this time,” said Richard Lipton, M.D., director, Montefiore Headache Center and professor and vice chair of neurology, and the Edwin S. Lowe Chair in Neurology, Albert Einstein College of Medicine.

The risk of headache was most apparent during the later stage of the perimenopause, which is a time during which women first begin skipping menstrual periods and experience low levels of oestrogen.

Dr Martin said women who participated in the study also reported that high frequency headaches increased by 76% during menopause. However, researchers think that it may not necessarily be the direct result of hormonal changes, but rather due to medication overuse that occurs commonly during this time.

“Women as they get older develop lots of aches and pains, joints and back pain and it is possible their overuse of pain medications for headache and other conditions might actually drive an increase in headaches for the menopause group,” said Dr Martin.

                                  
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