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Drugging the undruggable: Treatment path for muscular dystrophy

DMD is the most common form of muscular dystrophy, a disease that leads to progressive weakness and eventual loss of the skeletal and heart muscles. It occurs in 16 of 100,000 male births in the U.S. People with the disease exhibit clumsiness and weakness in early childhood and typically need wheelchairs by the time they reach their teens. The average life expectancy is 26. While earlier research had revealed the crucial role played by an enzyme called MKP5 in the development of DMD, making it a promising target for possible treatment, scientists for decades had been unable to disrupt this family of enzymes, known as protein tyrosine phosphatases, at the enzymes' "active" site where chemical reactions occur. In the new study, Anton Bennett, the Dorys McConnell Duberg Professor of Pharmacology and professor of comparative medicine, and his team screened over 162,000 compounds. They identified one molecular compound that blocked the enzyme's activity by binding to a previously undiscovered allosteric site -- a spot near the enzyme's active site. "There have been many attempts to design inhibitors for this family of enzymes, but those compounds have failed to produce the right properties," Bennett said. "Until now, the family of enzymes has been considered 'undruggable.'" By targeting the allosteric site of MKP5 instead, he said, "We discovered an excellent starting point for drug development that circumvented the earlier problems." The researchers tested their compound in muscle cells and found that it successfully inhibited MKP5 activity, suggesting a promising new therapeutic strategy for treating DMD. The research was supported by a National Institutes of Health grant through the National Institute of Arthritis and Musculoskeletal and Skin Diseases, as well as by the Blavatnik Fund for Innovation at Yale, which annually presents awards to support the most promising life science discoveries from Yale faculty. Bennett said that the Blavatnik funding, which is administered by the Yale Office of Cooperative Research, was critical in moving the research forward. "It resulted in a license with a major pharmaceutical company," he said, "and we hope they will rapidly move forward with the development of the new treatment." The finding has implications well beyond muscular dystrophy, he added. The researchers have demonstrated that the MKP5 enzyme is broadly implicated in fibrosis, or the buildup of scar tissue, a condition that contributes to nearly one-third of natural deaths worldwide. "Fibrosis is involved in the end-stage death of many tissues, including liver, lung, and muscle," Bennett said. "We believe this enzyme could be a target more broadly for fibrotic tissue disease." The research team from Yale included Naftali Kaminski, the Boehringer-Ingelheim Professor of Internal Medicine and chief of pulmonary, critical care and sleep medicine; Jonathan Ellman, the Eugene Higgins Professor of Chemistry and professor of pharmacology; Karen Anderson, professor of pharmacology and of molecular biophysics and biochemistry; Elias Lolis, professor of pharmacology; Zachary Gannam, a graduate student in pharmacology; Kisuk Min, a postdoctoral fellow; Shanelle Shillingford, a graduate student in chemistry; Lei Zhang, a research associate in pharmacology; and the Yale Center for Molecular Discovery. Story Source: Materials provided by Yale University. Original written by Brita Belli. Note: Content may be edited for style and length.

14th September, 2020

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Child specialists aren’t where most of India’s kids are

UP, Bihar, MP and Rajasthan between them account for nearly half of all children born in India each year but have barely one-sixth of the paediatricians in the country. The imbalance between where the need for child specialists is and where they are available is just as pronounced within states with most of them concentrated in the bigger cities while the villages are where most children are. In UP and Bihar, which have the largest child populations, for instance, a large chunk of paediatricians, about 60% and 46% respectively, are concentrated in the top few cities. The skew in distribution within larger states is worst in West Bengal where over 74% of paediatricians in the state are in the Greater Kolkata region. The skew in distribution of paediatricians within larger states is worst in West Bengal where over 74% of paediatricians in the state are in the Greater Kolkata region, followed by Telangana, where almost 69% are in the Greater Hyderabad area. This skew was revealed when the Indian Academy of Pediatrics (IAP), the largest association of paediatricians, did a district-wise mapping of its 31,176 members. The IAP claims its membership covers over 90% of paediatricians in India. While skew in availability of specialists is old hat, the extent of that skew is usually hard to come by as Digital India has no database on district-wise or even state-wise availability of doctors, let alone specialists. There isn’t even a system of unique ID number for the estimated 11 lakh-plus doctors, 20 lakh nurses and other categories of health personnel.Child specialists aren’t where most of India’s kids are The IAP database shows there are several districts without a single paediatrician and 125 with less than five. There are very few paediatricians in the North Eastern states and over 80% of those that are there are to be found in the state capitals. Maharashtra has the highest number of IAP members, 4,674, but almost 60% are in Greater Mumbai, Pune and Nagpur. This is followed by Tamil Nadu, Karnataka and Kerala in that order. However, in Tamil Nadu and Kerala, there appears to be a somewhat better distribution across districts, probably because of higher levels of urbanisation. “We are aware of the skew in distribution of paediatricians. That is why digital IAP, or dIAP a new division of IAP, is working to create webinars and lectures for those working far from the metros where there are fewer opportunities of getting regularly updated in the field. We are also working to put in place a mechanism for teleconsultation so that even non-paediatricians having to treat children can get help from experts,” said IAP president Dr Bakul Parekh. Dr Yogesh Jain, a paediatrician and public health expert working in Chhattisgarh, pointed out that not only is the proportion of sick kids seen by paediatricians small, the need for a specialist or even a doctor is not that high. “We need more well-trained and mentored mid-level health providers who should be supportively supervised if kids in rural areas are to be helped,” he said, adding that tele-teaching has a greater role than tele-consults.

16th September, 2020

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Antibiotics taken late in pregnancy can increase risk for inflammatory bowel diseases in offspring

The antibiotic treatment also caused lasting changes in the gut microbiome of mothers that were passed on to their offspring. While their offspring developed disease, adult mice given antibiotics did not see an increase in IBD. This suggests that the timing of antibiotic exposure is crucial, especially during the early developmental period after birth when the immune system is undergoing maturation. "The newborn mice inherited a very altered, skewed population of microbes," said Eugene B. Chang, MD, Martin Boyer Professor of Medicine at the University of Chicago, Director of the Microbiome Medicine Program of the Microbiome Center, and senior author of the study, published this week in the journal Cell Reports. "None of the mothers developed IBD, but even though they had the same genetic background, the offspring with an altered microbiome during this critical period of immune development became highly susceptible to the development of colitis." Chang cautioned, however, that these results from an animal study should not be taken as a reason for pregnant women or those nursing newborn infants to avoid antibiotics when they are needed to treat dangerous bacterial infections. Instead, he said, it should serve as a reminder that best practices dictate avoiding casual, indiscriminant over usage 'just to be safe', say, for a common cold that is most likely caused by a virus. "Antibiotics should absolutely be used judiciously when they're indicated," Chang said. "But we as physicians should keep in mind the importance of antimicrobial stewardship, because this study suggests that it may have long term consequences that potentially impact health and risk for certain diseases." Lasting changes in the gut microbiome Several epidemiological studies have suggested that exposure to antibiotics during the peripartum period (late pregnancy and the nursing period after birth) increases the risk for IBD in humans. Direct evidence for this association has been lacking, however, because of vast differences in individual gut microbiomes, challenges in controlling for variables, and the limits of conducting clinical experiments in pregnant women and infants. To address these issues, Jun Miyoshi, MD, PhD, a postdoctoral scholar, and Alexandria Bobe, a graduate student in Chang's lab, designed a series of experiments with a standard genetic mouse model for IBD to study the timing of antibiotic treatment during the peripartum period and its impact on gut microbes and immune system development in offspring. The researchers gave cefoperazone, a commonly-used antibiotic, to mouse mothers in the late stages of pregnancy through the period that they nursed their pups, i.e. to mimic a common clinical scenario of early antibiotic exposure in humans. None of the adult mice treated with antibiotics developed colitis, but their pups exhibited a high risk for developing colitis compared to those from mothers that were not treated with antibiotics. Using state-of-the-art, high-throughput sequencing technologies, the team also analyzed the gut microbial population structures of mothers and their offspring. The mothers showed a decrease in diversity of bacteria, and changes in the relative numbers of certain groups of bacteria. For example, there were fewer populations of Bacteroidetes and more from the phyla Firmicutes and Verrucomicrobia. Surprisingly, these changes persisted even four to eight weeks after stopping the antibiotic treatment. The mouse pups also had similar changes in their gut bacteria, with microbial communities matching their mothers at birth. The diversity of microbes in these pups was significantly different from that of mice not treated with antibiotics, and these differences lasted into adulthood. "What this should tell us is, at least as physicians, is that antibiotics are not as innocuous as we think they are, and injudicious, casual use of them can have consequences," Chang said. "When they're used during pregnancy or early childhood, they can disturb the development of a normal gut microbiome which would otherwise be essential for proper immune development. In genetically susceptible hosts, the inability to develop the immune system properly can have negative consequences like inflammatory bowel disease or any other kinds of complex immune disorders." Working toward a definition of health Chang said that understanding more about the microbiome in an unhealthy state can help scientists begin to learn how to promote the development of a microbiome that sets the stage for a healthy immune system. "What this study showed is what an 'unhealthy' microbiome looks like, so presumably whatever is missing may be important to promote health," he said. "What we want to eventually develop is a microbial cocktail we can give to infants that ensures that they develop properly, metabolically and immunologically. That's going to have a significant impact on human health, by reducing risk for many types of diseases and by promoting wellness." Story Source: Materials provided by University of Chicago Medical Center. Note: Content may be edited for style and length.

16th September, 2020

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Asymptomatic Covid+ workers can work: Kerala

THIRUVANANTHAPURAM: Guest workers who are Covid-positive but asymptomatic have been allowed by the Kerala government to work in exclusive areas. The guidelines issued by the general administration department, however, contradict guidelines issued by the health department that restrict asymptomatic positives to strict home care. “Guest workers found positive have to be segregated. If they are asymptomatic positive, then they may work in areas exclusively marked by taking all precautions,’’ say the new guidelines. The new guidelines prohibit such workers from mixing with others. Their stay and food have to be arranged as per first line treatment centre (FLTC) guidelines issued for asymptomatic positives. If one develops symptoms such as fever, cough, sore throat, diarrhoea, loss of smell or breathlessness, they have to be referred to a Covid hospital in the district, and information has to be passed to DISHA 1056. Experts have raised concerns. “For the viral diseases, treatment is supportive care. How can you ask people to work if they are Covid-positive? It is against ICMR directions. Such guidelines should have been issued after consulting the health department,’’ said Dr G S Vijayakrishnan, general secretary, Kerala Government Medical Officers Association. However, the new guidelines also stipulate that guest workers be quarantined for 14 days upon arrival. As per the new norms, the place of quarantine may be decided by the contractor. It must be ensured that the room is safe and hygienic. The workers who arrive without a testing certificate may be subjected to antigen testing on the fifth day, and the contractor must bear the cost. The technical teams, officers, and consultants who reach the state should also be offered a safe place by the contractor. The technical officer can be advised to take rapid antigen or RT-PCR tests in the last 96 hours and follow the protocol for their period of stay at the project site or in the vicinity.

17th September, 2020

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IMA publishes list of 382 docs who died due to Covid-19, demands they be treated as martyrs

New Delhi, Sep 16 : Taking exception to Health Minister Harsh Vardhan not mentioning the death of healthcare workers due to COVID-19 in his statement in Parliament, the IMA on Wednesday published a list of 382 doctors who died due to the viral disease and demanded that they be treated as "martyrs". On MoS Health Ashwini Kumar Choubey's statement that public health and hospitals come under states and so insurance compensation data is not available with the Centre, the doctors' body said that it amounts to "abdication of duty and abandonment of the national heroes who have stood up for our people". "The IMA (Indian Medical Association) finds it strange that after having formulated an unfriendly partial insurance scheme for the bereaved families to struggle with the ignominy of the government disowning them altogether stares at them," it said. According to the IMA COVID-19 data on September 16, as many as 2,238 doctors were infected with the disease and of them 382 lost their lives, a senior official of the doctors' body said. Referring to Vardhan statement, the IMA said the 19th paragraph acknowledges the contribution of healthcare workers during this pandemic, but "conceals" the morbidity and mortality of doctors, nurses and healthcare workers. Terming it "indifference", the doctors' body said, "No nation has lost as many doctors and healthcare workers like India. Doctors suffer four times mortality of ordinary citizens and private practitioners suffer eight times mortality on the same scale." "To feign that this information doesn't merit the attention of the nation is abominable. If the government doesn't maintain the statistics of the total number of doctors and healthcare workers infected by COVID- 19 and the statistics of how many of them sacrificed their life due to the pandemic, it loses the moral authority to administer the Epidemic Act 1897 and the Disaster Management Act." "This also exposes the hypocrisy of calling them corona warriors on one hand and denying them and their families the status and benefits of martyrdom," the IMA stated. Publishing a list of 382 doctors who died in the COVID-19 pandemic, along with their addresses, it said, "We demand they be acknowledged and treated as martyrs." Their families and children deserve solace and solatium from the government, the IMA stressed. "The IMA also commends to the government they seek such data from the representatives of nurses and other healthcare workers," the statement said. The doctors' body said it had shared with the health ministry hundreds of suggestions and feedback during this national health emergency. "The prime minister deemed it fit to invite the national president of IMA to a meeting to share the concerns and seek suggestions and cooperation. The suo moto statement of the health minister preferred to ignore the national dimension of the war against COVID-19," it said in the statement. PLB NSD NSD Courtesy: ET Healthworld

17th September, 2020

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CPAP provides relief from depression

Using data from the Sleep Apnea Cardiovascular Endpoints (SAVE) trial led by Flinders University, the new study has found a significant decrease in cases of depression after patients received CPAP treatment for their sleep apnea. This is by far the largest trial of its type and one of very few studies reporting such an effect, says Professor Doug McEvoy from Flinders University. From detailed analysis of the SAVE data, Flinders University experts and collaborators at the George Institute have found that CPAP for moderate-severe OSA in patients with cardiovascular disease has broader benefits in terms of preventing depression, independent of improved sleepiness. Prior studies investigating the effect of CPAP on mood with various experimental designs and length of follow-up periods have yielded heterogenous results. "Patients who have had a stroke or heart attack are prone to suffer from low mood and are 2 to 3 times more likely to develop clinical depression, which then further elevates their risk of future heart attacks and strokes," says SAVE principal investigator Professor McEvoy, a senior author in the paper just published by The Lancet in EClinicalMedicine. With up to 50% of patients with CV disease likely to have OSA, the study is "welcome news that treatment of OSA substantially relieves cardiovascular patients' depressive symptoms and improves their wellbeing." The paper's first author, Dr Danni Zheng, from the George Institute for Global Health (UNSW), says the 2687 OSA patients enrolled in the SAVE trial were based solely on their history of cardiovascular disease and not on their current mood status. "After following them for an average of 3.7 years, we found that CPAP provided significant reductions in depression symptoms compared with those who were not treated for OSA. The improvement for depression was apparent within six months and was sustained." As expected, those with lower mood scores to start with appeared to get the greatest benefit. "Our additional systematic review which combined the SAVE study findings with previous work provided further support of the treatment effect of CPAP for depression," Dr Zheng says. Story Source: Materials provided by Flinders University. Note: Content may be edited for style and length.

15th September, 2020

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Covid genomes in India have 5.39% mutation similarity with 72 nations: Study

Coronavirus genomes in India have 5.39 per cent mutation similarity with 72 nations, found a study by a group of researchers trying to identify the genetic variability and potential molecular targets in the virus and humans to find the best possible answer for combating COVID-19. Mutations in an organism's genetic material are natural 'errors' in the cell replication process that may give the virus new 'powers' of survival, infectivity, and virulence. It can affect the ability of vaccines and drugs to bind the virus, or to create a specific immune response against it. The study also reveals that the US, the UK and India are the top three nations with a geometric mean of 3.27 per cent, 3.59 per cent, and 5.39 per cent, respectively, of mutation similarity score with other 72 countries. Indrajit Saha, an assistant professor in the Department of Computer Science and Engineering of National Institute of Technical Teachers' Training and Research, Kolkata, and his team have also developed a web-based COVID-Predictor to predict the sequence of viruses online on the basis of machine learning. The scientists are on track to identify the number of virus strains using single nucleotide polymorphism, spot the potential targproteins of the virus and human host based on protein-protein interactions, recognise candidate of synthetic vaccines based on conserved genomic regions that are highly immunogenic and antigenic and detect the virus miRNAs that are also involved in regulating human mRNA. They analysed 566 Indian SARS-CoV-2 genomes separately to find the genetic variability in terms of point mutation and single nucleotide polymorphism. The scientists have mainly found that 57 out of 64 SNPs are present in six coding regions of Indian SARS-CoV-2 genomes, and all are non-synonymous in nature. This work has already been published in Infection, Genetics, and Evolution journal. They have extended this research for more than 10,000 sequences around the globe and found 20,260, 18,997, and 3514 unique mutation points globally, including India, excluding India and only for India, respectively with the similarity score as mentioned above. Courtesy: ET Healthworld

17th September, 2020

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Covid-19 : Testing essentials

The Covid-19 pandemic has so far affected 216 countries. As per reports shared by WHO. Globally, there has been 29, 119,433 confirmed cases, including 9,25,965 deaths. In India, from January to September 2020, there has been 4,846,427 confirmed cases of Covid-19 with 79,722 deaths. The epidemic is growing very rapidly in India with daily record cases of 96,000. The government health adviser fears that the coronavirus crisis will worsen in the upcoming days. The advisory by the Indian Council of Medical Research (ICMR) recommends that TEST, TRACK AND TREAT is the only way to prevent the spread of infection and save lives. Current testing strategies include the following: - Molecular testing by RT-PCR (reverse transcriptase-polymerase chain reaction) to help identify people who are currently infected. - Serologic/antibody testing that detects those who have already had the infection and have developed antibodies. Antibody/serological tests are the ones that can identify presence of IgG/IgM antibodies. These antibodies are specifically related to the COVID-19 antigen. Serological tests determine whether a person has had COVID-19 and then recovered. They differ from diagnostic tests that simply show whether a person is infected at the time of testing. Doing an antibody test may have multiple benefits, as mentioned below: Application in public health: Can determine who is asymptomatic/immune to the virus, and if immunity has been attained. Application in determining vaccine effectiveness: The serological tests are a vital part of vaccine development and monitoring its effectiveness. Application in treatment: Use of the plasma from convalescent/ recovered patients to treat people who are critically ill with COVID-19. Application in designing the return-to-work protocol: In the case of healthcare workers and people on the frontline, the serological test may play a determining role. Sero-surveillance initiated at the right time will help in the following ways: To determine the burden of COVID-19 at the community level and monitor the trends in the transmission of SARS-CoV-2 infection. To delineate the geographical spread of the infection in the general population and hotspot cities. To design and implement appropriate containment measures instead of waiting for the end of the epidemic. Repeated serosurveys carried out at regular intervals can be a useful tool to monitor the epidemic precisely. To determine the socio-demographic risk factors for SARS-CoV-2 infection. We believe that robust testing can go a long way and is critical for the effective management of this pandemic. Hence, ETHealthworld.com along with Association of Healthcare Providers of India (AHPI) has partnered with Cipla to create a much needed awareness through this digital conclave on overall ‘COVID-19 Testing Essentials’ with major emphasis on antibody testing and its usage as a tool for sero-surveillance. Healthcare fraternity from across the country and health domains will get in touch with the panel experts and their peers digitally, enabling all of us to come together to ensure a healthier India. Courtesy: ET Healthworld

17th September, 2020

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