HƯỚNG DẪN SƠ CỨU (FIRST AID)
KHI BỊ CÔN TRÙNG, ĐỘNG VẬT VÀ NGƯỜI CẮN TRONG LÚC SINH HOẠT NGOÀI TRỜI Lynn Ly phỏng dịch theo "The Everything First Aid"
Những hoạt động ngoài trời như làm việc, vui chơi, giải trí, du ngoạn ở trong một số hoàn cảnh , khí hậu , và thời tiết . Khí hậu nóng và lạnh đều có thể gây ra những hệ quả đối lập (adverse consequences), và những sinh vật (critters) sống bên ngoài thỉnh thoảng gây dị ứng (ngứa ngáy khó chịu) hoặc tổn thương . Cơ thể bị thiếu nước hoặc ở cao độ (thí dụ lên đỉnh núi) và ở trong một số điều kiện ngoài trời khác cũng có thể làm bạn cảm thấy suy yếu đi .
Cho dù không có vấn đề ǵ khi bạn hoạt động ngoài trời, nhưng thật quan trọng bạn biết làm ǵ để chăm sóc hoặc trợ giúp những người bị chấn thương, bị bệnh tật bất ngờ .
I) BỊ CÔN TRÙNG, LOÀI VẬT VÀ NGƯỜI CẮN
Nhiều loại côn trùng và các sinh vật khác, bao gồm cả con người, gây ra các vết cắn và vết châm chích có thể cho cảm giác không thoải mái hoặc đe dọa tính mạng từ nhẹ nhẹ đến trung b́nh. Điều quan trọng là biết làm ǵ, làm thế nào để trị liệu, và khi nào th́ cần t́m kiếm đến trợ giúp từ chuyên gia y tế để trị liệu bất kỳ thương tổn tàng ẩn bên trong.
1) B̉ CẠP CẮN (SCORPION BITES)
Ḅ cạp là loại côn trùng nhiều chân có h́nh dạng giống tôm hùm (lobster-like arthoropods) nằm trong xếp loại côn trùng có nọc độc (arcahnid class, cùng loài nhền nhện = spider class), có một ng̣i / kim xoăn ở phần cuối nơi đuôi, và chúng thường được t́m thấy ở vùng sa mạc phía Tây Nam của Mexico (nước Mễ Tây Cơ). Những vết chích / đốt của bọ cạp dường như không có khả năng gây tử vong và dễ dàng điều trị, nhưng lại nguy hiểm cho trẻ nhỏ và người già hơn . Những triệu chứng bao gồm đau nhức ngay lập tức (immediate pain), nóng rát (burning), sưng tấy chút chút (minor swelling) và cảm giác tê (numb) hoặc ngứa ran (tingling sensation).
Những buớc sau đây cần nên thực hiện để trị liệu vết ḅ cạp cắn:
1. Rửa vùng bị ḅ cạp cắn bằng xà pḥng / xà bông và nước
2. Dùng túi trườm lạnh đặt lên vùng bị ḅ cạp cắn trong ṿng 10 phút , nếu cần thiết th́ lập đi lập lại việc trườm lạnh vùng bị cắn với khoảng cách giữa các lần trườm lạnh là 10 phút .
3. Gọi điện thoại đến trung tâm kiểm soát chất độc (the Poison Control Center), hay đi bệnh viện khi có bất kỳ triệu chứng nghiêm trọng ǵ
2) BỌ VE CẮN (TICK BITES)
Những người sống vùng rừng cây hay đồng cỏ, hay những người dành thời gian vui chơi giải trí ở những khu vực này th́ dễ bị bọ ve cắn . Loài côn trùng nho nhỏ này sống bằng cách hút máu các loài động vật có vú (mammals) thí dụ như hươu nai (deer), loài gậm nhấm (rodents), thỏ (rabbits) và có thể truyền bệnh từ động vật sang người .
Việc sơ cứu (first aid) những vết bọ ve cắn bao gồm loại bỏ con bọ ve đang bu bám ngay lập tức để tránh những phản ứng từ vết cắn và giảm thiểu tối đa các loại bệnh nhiễm trùng do bọ ve gây ra thí dụ bệnh Lyme, bệnh nóng sốt Colorado bọ ve (Colorado tick fever), bệnh nóng sốt được phát hiện ở núi đá (Rocky Mountain Spotted fever)
Để tháo bỏ con bọ ve bu bám trên người , hăy làm như sau:
1. Dùng cây nhíp (tweezers) hay cây kẹp nhỏ nhỏ cong cong hay thẳng thẳng (small curl or flat forcepts) kẹp lấy đầu con bọ ve và càng cận sát nơi da đang bị con bọ ve cắn càng tốt, rồi nhẹ nhàng kéo ra, đừng bóp nát hay xoay vặn con bọ ve
2. Rửa vùng bị bọ ve cắn bằng xà pḥng / xà bông và nước.
3. Bôi thuốc Antihistamine hoặc loại 1% hydrocortisone cream (loại kem chứa 1% chất hydrocortisone)
Cần phải có sự chăm sóc y tế chuyên nghiệp , nếu con bọ ve cắn quá sâu và bạn không thể tháo gỡ nó ra được, hoặc bạn đang ở trong khu vực được thông báo là có nhiều nguy cơ bị bệnh lyme, hoặc bạn có triệu chứng nóng sốt hay triệu chứng cảm cúm , hoặc bạn có trải nghiệm bắp thịt trở lên suy nhược, tê liệt (paralysis) , hoặc nổi vết tṛn đỏ trên da gọi là "phát ban mắt ḅ" (the bull's eye rash) là đặc chưng của bệnh Lyme .
CẢNH BÁO !!!
Đừng bao giờ bôi petroleum jelly (vaseline), rượu cồn ( alcohol ) ahy ammonia lên con bọ ve - chúng sẽ cắn chặt sâu vào da hơn. Nếu bạn đang ở trong vùng cảnh báo có nhiều nguy cơ bệnh Lyme mà bị bọ ve cắn, bạn nhất định phải phone báo bác sĩ để được tư vấn và ngay lập tức được chăm sóc và điều tri bao gồm việc sử dụng thuốc kháng sinh
Current vaccination policies may not be enough to prevent measles resurgence
BioMed Central
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Current vaccination policies may not be sufficient to achieve and maintain measles elimination and prevent future resurgence in Australia, Ireland, Italy, the UK and the US, according to a study published in the open access journal BMC Medicine.
To successfully achieve and maintain measles elimination in these countries in the medium to long term, further country-specific immunisation efforts may be needed in addition to current strategies. Measles elimination has been defined as the absence of endemic measles transmission in a region or other defined geographic area for twelve months or longer.
A team of researchers at the Bruno Kessler Foundation and Bocconi University, Italy used a computer model to simulate the evolution of measles immunity between 2018 and 2050 in seven countries; Australia, Ireland, Italy, Singapore, South Korea, the UK and the US. The authors focused their analysis on countries with a routine two-dose measles vaccination programme and a high primary school involvement rate, but with different demographics and vaccination histories. The aim was to evaluate the effect of possible adjustments to existing immunisation strategies, and to estimate the proportion of people who may remain susceptible to measles in high-income countries over time.
The authors' projections up until 2050 suggest that if current vaccination policies remain unchanged, the proportion of the population susceptible to measles would only remain below 7.5% in Singapore and South Korea, two countries which had high vaccination coverage in the past. Previous research estimated that the proportion of the population that does not have immunity (maximum susceptibility) needs to be 7.5% or less for measles to be eliminated.
In 2018, the proportion of the population susceptible to measles infection in the countries under study ranged from 3.7% in the UK to 9.3% in Italy (the only country where the proportion was found to be higher than 7.5%). In Australia, Ireland, the UK and the US, vaccination from routine programmes would need to continuously cover more than 95% of the population to keep the proportion of susceptible individuals below 7.5% until 2050.
Dr. Filippo Trentini, the first author said: "In recent years, we've witnessed a resurgence of measles cases even in countries where, according to World Health Organisation guidelines, elimination should already have been achieved. This resurgence is due to suboptimal vaccination coverage levels. In Italy, where measles incidents rates were among the highest, the government has made measles vaccination compulsory for children before they enter primary school. We investigated the potential of this and other policies to reinforce immunisation rates in seven high-income countries."
Co-author Dr. Stefano Merler added: "Our results suggest that most of the countries we have studied would strongly benefit from the introduction of compulsory vaccination at school entry in addition to current immunisation programmes. In particular, we found that this strategy would allow the UK, Ireland and the US to reach stable herd immunity levels in the next decades, which means that a sufficiently high proportion of individuals are immune to the disease to avoid future outbreaks. To be effective, mandatory vaccination at school entry would need to cover more than 40% of the population."
In Italy, the fraction of susceptible individuals by 2050 is projected to be 10%, even if coverage for routine vaccination reaches 100%, and additional vaccination strategies targeting both children at school entry and adults may be needed to achieve elimination.
Scientists capture first-ever video of body's safety test for t-cells
University of Texas at Austin
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VIDEO: For the first time ever, UT Austin researchers captured the process in which developing killer T-cells (purple and white) are tested by dendritic cells (yellow), and others, to see if... view more
Credit: University of Texas at Austin
For the first time, immunologists from The University of Texas at Austin have captured on video what happens when T-cells - the contract killers of the immune system, responsible for wiping out bacteria and viruses - undergo a type of assassin-training program before they get unleashed in the body. A new imaging technique that allowed for the videos, described today in the journal Nature Communications, holds promise for the fight against autoimmune disorders such as Type 1 diabetes.
One of the human body's most potent weapons against many diseases is the T-cell, but in people with autoimmune disorders, T-cells also wreak havoc by mistaking normal cells for invaders and attacking healthy parts of the body.
"T-cells have the daunting task of recognizing and fighting off all of the diverse pathogens that we encounter throughout our lives, while avoiding attacking our own healthy tissue," said associate professor Lauren Ehrlich, one of the authors of the study. "These cells mature in the thymus, an organ just above the heart, where they 'get educated' to not attack the body."
Ehrlich and postdoctoral researcher Jessica Lancaster captured video of this educational process in a mouse thymus. Using a pair of powerful lasers that fire in short pulses and scan through a slice of live tissue every 15 seconds to reconstruct the positions, movements and intracellular signaling of cells, they observed that as T-cells develop, other cells in the thymus help them to encounter all sorts of ordinary human proteins that, later on, the T-cells will need to ignore in order to avoid attacking other parts of the body. The researchers learned more about how different types of cells work together in the thymus to perform the safety tests and, in the event a T-cell fails, trigger it to self-destruct.
Ehrlich says studying T-cells with this new imaging technique holds promise for improvements for human health that will depend on a better understanding of what's happening in the thymus. For example, patients who received bone-marrow transplants endure weeks or months with suppressed immune systems and a higher risk for developing autoimmune disorders, and people with Type 1 diabetes have T-cells that often attack the cells in the pancreas that produce insulin.
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This work was supported by the National Institute of Allergy and Infectious Diseases and the Cancer Prevention and Research Institute of Texas; Ehrlich is a CPRIT scholar
Tobacco and e-cig promotions spark teens' use of nicotine products, Stanford study finds
Stanford Medicine
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Owning items that promote e-cigarettes and other alternative tobacco products doubles the likelihood that a young person will try these products, a new study led by the Stanford University School of Medicine has found. The finding illustrates the influence of such marketing on teenagers.
The study, which will be published online May 17 in JAMA Network Open, followed 757 California teens for a year. At the beginning of the year, participants had never used alternative tobacco products, including e-cigarettes, chewing tobacco, cigars, cigarillos, pipes and hookahs.
But some participants owned marketing materials for these products, such as coupons, samples and branded hats or T-shirts.
"We wanted to see how owning promotional materials would affect young people's use later on," said the study's lead author, Hoda Magid, PhD, a postdoctoral scholar in health research and policy. Among teens, cigarette smoking rates have dropped in recent decades, but their use of e-cigarettes and other tobacco products has risen sharply. "The increase in use of alternative tobacco products poses a threat to the decades of hard work that public health experts have done to reduce tobacco use," Magid said.
"We need to know trajectories of use of alternative tobacco products," said the study's senior author, Bonnie Halpern-Felsher, PhD, professor of pediatrics. Understanding when and why youth start using such products is important for stemming the tide of addiction to them, she said.
Restrictions on conventional smokes
While marketing to minors and providing samples is illegal for all tobacco products, providing coupons and branded promotional items such as T-shirts and hats is not illegal for most alternative tobacco products, except smokeless tobacco. Enforcement of all policies is lacking, Halpern-Felsher said.
"The problem is that the FDA has been very slow to enact new or enforce existing laws and regulations for e-cigarettes," Halpern-Felsher said. "Right now, the FDA is not going after manufacturers who have not put in an application to market e-cigarettes." The Family Smoking Prevention and Tobacco Control Act requires all tobacco companies to submit premarket applications to FDA and receive agency authorization before putting a product on the market, but the compliance dates have been extended to 2021 or 2022, depending on the product. This means thousands of e-cigarettes and other alternative tobacco products are being marketed without any FDA review.
When the study began, participants were 13 to 19 years old and attended California high schools. They completed questionnaires asking whether they had ever used traditional cigarettes or any alternative tobacco products, and whether they or their friends owned promotional items -- such as coupons, free samples, T-shirts, posters and hats -- for any type of nicotine product. The researchers asked similar questions about the use of cigarettes and alternative tobacco products a year later and analyzed changes in the teens' use of e-cigarettes and other tobacco products as a function of owning or receiving promotional materials.
At the start of the study, 81 of the 757 participants owned items that promoted tobacco products, including 52 who owned promotional items for e-cigarettes. Over the course of the study, 129 participants, or 17 percent, began using alternative tobacco products but not traditional cigarettes. Twelve participants began using traditional cigarettes alone or in combination with alternative tobacco products. Before adjusting for confounding factors, teens who owned promotional items were found to be 2.23 times as likely to try alternative tobacco products as those who did not own such items. After adjusting for age, gender, race/ethnicity, maternal education level and baseline alcohol and cigarette use, the teens who owned promotional materials were 2.13 times as likely as their peers to begin using alternative tobacco products. When teens who had tried both alternative tobacco products and cigarettes during the year were included in the analysis, the influence of owning promotional materials did not reach statistical significance.
The findings provide evidence that ownership of marketing materials is strongly associated with more young people using e-cigarettes and other alternative tobacco products, the researchers said. The findings clearly show that no tobacco company, including any e-cigarette company, should be allowed to provide coupons, free samples or other marketing materials to teens, and suggest that the FDA should further restrict and enforce such marketing techniques, Halpern-Felsher said.
"Manufacturers say they're not marketing to teens, but teens are reporting owning these promotional items, and they're reporting use of alternative tobacco products," Magid said. Current restrictions and laws that make marketing cigarettes and other tobacco products to minors should be enforced for all nicotine-containing products, she added.
For many HIV+ women, daily survival takes precedence over viral suppression
Georgetown University Medical Center
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WASHINGTON -- According to scientists who study women infected with HIV, statistics often paint an impressionist view of the lives of these women that misses the granular detail that tells the real story. The imprecise big picture is that most of this population is doing a good job at suppressing the virus, but facts gathered on the ground show that many struggle with issues of daily living that can make taking a pill to keep HIV at bay difficult.
In JAMA Network Open, researchers say that while a majority of the 1,989 HIV+ women they have been studying since 1994 have been able to control their virus -- often on and off -- challenges such as mental health, unstable housing, and lack of social support constitute ongoing barriers to effective and sustained viral suppression.
"Survival is a priority over putting a pill in your mouth for a number of our participants, and that is the public health challenge we must address," says the study's first author Seble G. Kassaye, MD, MS, associate professor of medicine at Georgetown University Medical Center.
"The truth of their lives is a lot less rosy than a few lines of statistics in a summary report can reveal," she adds.
Kassaye, an infectious diseases clinician and epidemiology expert, is the principal investigator of the Washington Metropolitan site of the NIH-funded longitudinal cohort, the Women's Interagency HIV study (WIHS), which has tracked many of the participants since it first opened in 1994. Four other WIHS sites (two in New York, Chicago and San Francisco) sites contributed data to this work.
WIHS was launched because of the recognition that HIV is almost as common in women as in men, in some populations, and that the biology and route of infection can differ. For example, in Washington DC, 1.9 percent of African American women are HIV+, compared to 4.4 percent of African American men. And 30 percent of HIV+ women who have been studied have no explanation as to how they became infected -- "It was likely from heterosexual sex, perhaps with a man who may not have been aware of his status or did not disclose infection," Kassaye says. "About a quarter of the women acquired HIV infection related to injection drug use, but that has become an increasingly less common cause of HIV transmission in the current era."
In this study, the researchers took a longitudinal look at how well each participant kept their virus in check, and if they had trouble doing so, why? Each person was interviewed and had a blood draw every six months to establish viral levels. Specific levels indicated the virus was well controlled, or uncontrolled -- a condition called viremia.
The researchers found that over 23 years of viral levels, 3 patterns or 'trajectories' were present: 29 percent were at a low probability for viremia, 39 percent were at intermediate probability, and 32 percent were at high probability. These superseded the usual cross-sectional or short term analyses that are often provided to capture viremia outcomes at the population level. More recently between 2015-2017, 71 percent of women achieved sustained viral suppression, including 35 percent of the high probability of viremia group.
"So, the rosy picture is that 71 percent of the women achieved viral suppression, but the granular detail tells us that some women are doing very well with 89.6 percent of the women in the low probability of viremia consistently suppressed in the recent years, but others are still struggling to get to viral suppression," says Kassaye.
"Despite this struggle, I believe these women continue to resource their personal resiliencies to take their HIV medications as prescribed," adds the study's senior author, Michael Plankey, PhD, clinical infectious disease epidemiologist and professor of medicine at Georgetown University Medical Center.
While today's HIV treatment is much less toxic than it used to be, and drug therapy is now suggested for anyone who is infected -- and are therefore in much greater use -- the barriers to daily therapy are real, she says. The researchers found that women in the high viremia group were more likely to report depressive symptoms (54 percent), have higher levels of current illicit drug (41 percent) and alcohol use (14 percent), be less likely to have stable housing (66 percent) and were more likely to die prematurely (39 percent).
"Just in DC, we see that the public health issues and stigma surrounding HIV remain endemic. My colleagues have treated generations of HIV+ women: grandmothers, their daughters, and their granddaughters. I have seen women with HIV who do not have any support, but if that person develops cancer, there will be a roomful of people coming to the clinic with her," Kassaye says.
An answer to reaching universal treatment and viral suppression will require "wrap-around" services that can effectively address social and mental health issues," she says.
Cancer drug could be repurposed to provide treatment for brain aneurysms
Research uncovers a new genetic basis of a form of brain aneurysm, and suggests that it could be treated by an existing drug currently used to tackle cancer
University of Sussex
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IMAGE: A 3D reconstruction of an angiogram showing the aneurysm circled in red. view more
Credit: Taken directly from paper published in American Journal of Human Genetics, May 2019
•Brain aneurysms are relatively common, affecting around 2% of the general population
•Carrying a high risk of death, they can only be treated with difficult surgical procedures
•New research, which identifies a new genetic basis of a specific type of brain aneurysm, found that this abnormality could be countered by an existing family of anti-cancer drugs
An important class of drug used to treat cancer patients could be used to treat brain aneurysms, according to new research published this week.
Brain aneurysms are a bulge in a blood vessel caused by a weakness in the blood vessel wall. As blood passes through the weakened blood vessel, blood pressure causes a small area to bulge outwards.
They can develop anywhere in the body but are most common in the abdominal aorta (the artery that carries blood away from the heart) and the brain.
It's difficult to estimate exactly how many people are affected by brain aneurysms as they usually cause no symptoms until they rupture, but experts believe it could be anywhere from 1 in 100 to as many as 1 in 20 people.
Treatment is difficult, involving complex surgery which is currently only attempted in select cases. In a notable example, Game of Thrones actress Emilia Clarke suffered from two aneurysms while filming the series, undergoing surgery as a result.
Working in collaboration with colleagues at University of Washington School of Medicine in Seattle, USA, scientists at the University of Sussex may now have found a safer and more efficient possible treatment involving 'Receptor tyrosine kinase inhibitors'; a class of drug currently used to treat cancer.
Using sophisticated 'next generation' DNA sequencing technologies, teams in Washington lead by Manuel Ferreira, Associated Professor of Neurological Surgery, identified a new genetic basis of a form of brain aneurysm (mutations PDGFRB). This was unexpected, as mutations in this gene have been previously identified in completely different human developmental disorders.
Mark O'Driscoll, Professor of Human Molecular Genetics at the Genome Damage and Stability Centre at the University of Sussex, then found that multiple disease-associated mutations in PDGFRB caused a specific abnormality in its encoded protein. This abnormality causes its activity to remain locked in a hyper-active form, referred to as 'gain-of-function variants' - in effect, causing the protein to always be 'turned-on'.
Publishing their findings in this months' edition of the American Journal of Human Genetics, the Sussex team also demonstrated that this abnormal form of the protein can, in some cases, be countered by a drug which is currently used in cancer treatments.
Professor O'Driscoll said: "This is an extremely exciting discovery which shows how basic lab-derived observations on a genetic level can move into a clinical setting and start making big changes to public healthcare and treatments.
"Our research focused primarily on understanding the genetic and cellular mechanisms underlying a particular type of aneurysm.
"By finding a new genetic basis in some patients, we were also able to demonstrate that a known cancer drug could counter this genetic basis in most instances.
"Understanding the genetics behind diseases like this is crucial in identifying possible treatments and next steps - and that is exactly what our part in this new research has shown.
"The lead authors and our collaborators on this paper based in the US, are now working on the next stages to test this drug further."
Drug repurposing is not unheard of, and there are already some success stories including the use of thalidomide as a treatment for leprosy as well as a blood cancer called multiple myeloma.
Dr Manuel Ferreira, lead author of the report from the University Of Washington School Of Medicine, said: "We are now very close to treating these aneurysm patients with PDGFRB variants with specific receptor tyrosine kinase inhibitors
Mining 25 years of data uncovers a new predictor of age of onset for Huntington disease
University of British Columbia
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Investigators at the University of British Columbia (UBC)/Centre for Molecular Medicine & Therapeutics (CMMT) and BC Children's Hospital have examined more than 25 years of data to reveal new insights into predicting the age of onset for Huntington disease.
"This discovery may enable us to provide families with additional information," said lead author Galen Wright, a research associate in the UBC faculty of medicine, CMMT and BC Children's. "It could also potentially improve disease management by providing genetic counsellors with valuable data in the future."
Huntington disease is an inherited disorder that affects one in approximately 7,000 Canadians. For every affected person, there are four to five individuals that carry the gene mutation that causes the disease, but are not yet ill. The disease often begins around age 40. Symptoms include motor, cognitive and psychiatric changes.
Huntington disease is caused by a single mutation in the huntingtin gene, where patients carry an expanded stretch of repetitive DNA. While the length of this mutation has long been regarded as the greatest indicator of when (and whether) an individual will exhibit symptoms of the disease, researchers at UBC have uncovered a genetic variant that also significantly influences age of onset in patients.
"Our study reveals that age of onset in Huntington disease is influenced not only by the length of the expansion mutation, but also by the DNA sequence directly adjacent to this repetitive sequence," said senior author Dr. Michael Hayden, a Killam professor of medical genetics and director emeritus for the CMMT, which is part of the faculty of medicine at UBC and located at BC Children's.
This is the key finding in a new study published today in the American Journal of Human Genetics. While previous studies of the huntingtin gene have focused on the length of the string of glutamine building blocks in the DNA of the gene, this study examined variants in the DNA sequence encoding for these glutamine building blocks and the relationship between these variants and the age of onset of the disease.
The DNA sequence that causes Huntington disease is primarily made up of repeats of three letters of DNA, CAG, which encode the protein building block, glutamine. But UBC researchers have shown that the presence of another glutamine building block, CAA, significantly impacts the disease. In individuals where the CAA sequence is replaced with a CAG sequence, patients were found to present with the disorder decades earlier than expected, despite carrying an identical number of glutamine amino acids.
"Now we know that the age of onset in Huntington disease is significantly impacted by the length of uninterrupted CAG sequence," said Hayden.
The length of uninterrupted CAG sequence also appears to contribute to somatic instability.
The researchers screened samples from patients in the UBC Huntington disease biobank for the variant in the huntingtin gene, to examine age of onset and whether the mutation was more likely to expand to longer repeat lengths in the blood. Hayden established this bank -- which now contains approximately 8,000 specimens -- in 1986 in an effort to conduct such studies.
Hayden's team hopes to screen additional DNA samples to further refine age of onset prediction models for people from families with Huntington disease with this variant, and to look at how these variants express themselves in brain tissue.
Percutaneous edge-to-edge repair in patients with heart failure and secondary mitral regurgitation
PCR
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Paris, France, 21 May 2019. Heart failure is a common cardiovascular disorder with ominous prognosis despite significant therapeutic advances. Mitral regurgitation (MR, leaking of the mitral valve within the heart) affects at least 50% of patients with heart failure and is independently associated with worse prognosis. Timely diagnosis is essential, and management is complex, requiring an expert approach. These patients should be referred for assessment and management by a multidisciplinary Heart Team.
Detailed imaging assessment is essential to confirm the diagnosis and severity of MR and provide further insights into cardiac anatomy and function that will guide the choice of management.
The first essential step in management is the institution of optimised pharmacological therapy and use of cardiac resynchronisation devices according to guideline recommendations. Recent evidence supports the use of transcatheter mitral edge-to-edge repair using the MitraClip device in carefully selected patients with heart failure-associated MR who remain symptomatic despite these measures.
Surgical treatment of heart failure-associated MR should be considered in patients with coronary artery disease undergoing surgical revascularisation. Circulatory support devices and cardiac transplantation are an alternative in patients with extreme left and/or right ventricular failure and no accompanying severe comorbidity.
Expensive, high-risk and ultimately futile procedures should be avoided in patients who will derive little or no symptomatic benefit or quality of life improvement. Specialist palliative care should be available for these patients.
This summary is based upon a published Viewpoint article [1] and underpins a more extensive joint position statement in preparation by a collaborative working group derived from the European Association of Percutaneous Cardiovascular Intervention (EAPCI), European Heart Rhythm Association (EHRA), European Association of Cardiovascular Imaging (EACVI) and Heart Failure Association (HFA) of the European Society of Cardiology.
Metals influence C-peptide hormone related to insulin
New field of metalloendocrinology explores subtle effects of metals in body
University of California - Davis
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Metals such as zinc, copper and chromium bind to and influence a peptide involved in insulin production, according to new work from chemists at the University of California, Davis. The research is part of a new field of "metalloendocrinology" that takes a detailed look at the role of metals in biological processes in the body.
"We're asking questions people didn't realize we don't have the answers to," said Marie Heffern, assistant professor of chemistry at UC Davis and senior author on the paper, to be published in the journal ChemBioChem.
Metals play a role in many biochemical processes. Hemoglobin contains iron and carries oxygen in the blood; zinc and copper are involved in a third to a half of all body functions. But while scientists know the overall amount of an element in a given component of the body, such as blood, they generally don't know the exact location of these metals, the state they are in or their biological role in the body.
"A metal is an ingredient - what you do with it is what makes the difference," Heffern said. Her laboratory at UC Davis is using new techniques to understand how metals are distributed inside and outside cells, how they bind to proteins and other molecules and the subtle influences they have on those molecules.
The new study looked at C-peptide, or connecting peptide, a short chain of amino acids. C-peptide is being investigated for potential in treating kidney disease and nerve damage in diabetes, so any better understanding of how it behaves in different conditions could be useful in drug development.
Influencing shape and uptake by cells
When the pancreas makes insulin, C-peptide connects two chains of insulin in a preliminary step. C-peptide is then cut out, stored along with insulin and released at the same time. C-peptide used to be considered a byproduct of insulin production but now scientists know that it acts as a hormone in its own right.
The researchers measured how readily zinc, copper and chromium bound to C-peptide in test tubes, and how the metals affected the ability of cells to take up C-peptide.
The metals had subtle effects on the structure of C-peptide, notably on its ability to curl into a helix in some conditions. Copper and chromium prevented cells from taking up the hormone, but other metals such as zinc, cobalt and manganese did not have such an effect.
The results show that metals can potentially "tune" the activity of hormones such as C-peptide by altering their structure or affecting uptake into cells, Heffern said. Additional authors on the paper are postdoctoral researcher Michael Stevenson, research specialist Kylie Uyeda, graduate student Jessica San Juan and Ian Farran, undergraduate majoring in biochemistry and molecular biology.
University of Virginia chemist IDs possible addiction-free pain reliever
An estimated 1.7 million Americans suffer from substance abuse disorders related to opioid use for pain relief, according to the National Institute on Drug Abuse. This causes an economic burden of more than $78 billion per year in health care and addiction treatment costs, as well as loss of worker productivity and increased criminal activity. In 2017, more than 47,000 people died as a result of drug abuse involving opioids and related drugs.
As the problem amplifies, researchers are seeking non-addictive chronic pain treatment options that produce few or no negative side effects.
Ken Hsu, a chemistry professor at the University of Virginia, and his graduate student, Myungsun Shin, has identified an enzyme that "chews up fat" molecules to produce chemical signals that control inflammation.
The naturally occurring enzyme, called diacylglycerol lipase-beta, or DAGL?, is a possible new drug target for reducing pain. Hsu developed, during his postdoctoral training, selective molecules that inhibit DAGL? and reduce inflammation, similarly to aspirin and other non-steroidal anti-inflammatory drugs, or NSAIDS. However, unlike NSAIDs, DAGL? inhibitors can provide pain relief without gastrointestinal toxicity in preclinical models when used over a long term. And unlike opioids, DAGL? inhibitors do not exhibit addictive properties.
"This could be a new route to treating long-term inflammation and pain without the side effects of toxicity and risk of addiction observed with current treatment options," Hsu said. "Generally, if we block inflammation, we also affect the immune response. But we're suggesting a different approach, one where we can stop inflammation without impacting the normal immune response."
Hsu's findings were published today in the online edition of the journal Cell Chemical Biology.
According to Hsu, studies at UVA in collaboration with Virginia Commonwealth University demonstrate that DAGL? inhibitors are highly effective at reducing different pain states, including neuropathic pain and chemotherapy-induced peripheral neuropathy.
In the new study, the Hsu lab uncovered a new role for DAGL? in dendritic cells, a specialized type of innate immune cell that not only controls inflammation, but can also activate our body's ability to fight infections by stimulating T cells, which produce an immune response.
"We found that by blocking DAGL?, we can stop inflammation without affecting immunity," Hsu said. "This supports the idea that DAGL? is a viable target for long-term blockade of inflammation and pain without potentially compromising our immune system."
Hsu's research program is focused on using chemistry to find new ways to modulate the immune system, whether for fighting cancer, or, in this case, a better understanding of molecular pathways that can be targeted to reduce chronic inflammation and pain.
Tobacco and e-cig promotions spark teens' use of nicotine products, Stanford study finds
Stanford Medicine
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Owning items that promote e-cigarettes and other alternative tobacco products doubles the likelihood that a young person will try these products, a new study led by the Stanford University School of Medicine has found. The finding illustrates the influence of such marketing on teenagers.
The study, which will be published online May 17 in JAMA Network Open, followed 757 California teens for a year. At the beginning of the year, participants had never used alternative tobacco products, including e-cigarettes, chewing tobacco, cigars, cigarillos, pipes and hookahs.
But some participants owned marketing materials for these products, such as coupons, samples and branded hats or T-shirts.
"We wanted to see how owning promotional materials would affect young people's use later on," said the study's lead author, Hoda Magid, PhD, a postdoctoral scholar in health research and policy. Among teens, cigarette smoking rates have dropped in recent decades, but their use of e-cigarettes and other tobacco products has risen sharply. "The increase in use of alternative tobacco products poses a threat to the decades of hard work that public health experts have done to reduce tobacco use," Magid said.
"We need to know trajectories of use of alternative tobacco products," said the study's senior author, Bonnie Halpern-Felsher, PhD, professor of pediatrics. Understanding when and why youth start using such products is important for stemming the tide of addiction to them, she said.
Restrictions on conventional smokes
While marketing to minors and providing samples is illegal for all tobacco products, providing coupons and branded promotional items such as T-shirts and hats is not illegal for most alternative tobacco products, except smokeless tobacco. Enforcement of all policies is lacking, Halpern-Felsher said.
"The problem is that the FDA has been very slow to enact new or enforce existing laws and regulations for e-cigarettes," Halpern-Felsher said. "Right now, the FDA is not going after manufacturers who have not put in an application to market e-cigarettes." The Family Smoking Prevention and Tobacco Control Act requires all tobacco companies to submit premarket applications to FDA and receive agency authorization before putting a product on the market, but the compliance dates have been extended to 2021 or 2022, depending on the product. This means thousands of e-cigarettes and other alternative tobacco products are being marketed without any FDA review.
When the study began, participants were 13 to 19 years old and attended California high schools. They completed questionnaires asking whether they had ever used traditional cigarettes or any alternative tobacco products, and whether they or their friends owned promotional items -- such as coupons, free samples, T-shirts, posters and hats -- for any type of nicotine product. The researchers asked similar questions about the use of cigarettes and alternative tobacco products a year later and analyzed changes in the teens' use of e-cigarettes and other tobacco products as a function of owning or receiving promotional materials.
At the start of the study, 81 of the 757 participants owned items that promoted tobacco products, including 52 who owned promotional items for e-cigarettes. Over the course of the study, 129 participants, or 17 percent, began using alternative tobacco products but not traditional cigarettes. Twelve participants began using traditional cigarettes alone or in combination with alternative tobacco products. Before adjusting for confounding factors, teens who owned promotional items were found to be 2.23 times as likely to try alternative tobacco products as those who did not own such items. After adjusting for age, gender, race/ethnicity, maternal education level and baseline alcohol and cigarette use, the teens who owned promotional materials were 2.13 times as likely as their peers to begin using alternative tobacco products. When teens who had tried both alternative tobacco products and cigarettes during the year were included in the analysis, the influence of owning promotional materials did not reach statistical significance.
The findings provide evidence that ownership of marketing materials is strongly associated with more young people using e-cigarettes and other alternative tobacco products, the researchers said. The findings clearly show that no tobacco company, including any e-cigarette company, should be allowed to provide coupons, free samples or other marketing materials to teens, and suggest that the FDA should further restrict and enforce such marketing techniques, Halpern-Felsher said.
"Manufacturers say they're not marketing to teens, but teens are reporting owning these promotional items, and they're reporting use of alternative tobacco products," Magid said. Current restrictions and laws that make marketing cigarettes and other tobacco products to minors should be enforced for all nicotine-containing products, she added.
Metals influence C-peptide hormone related to insulin
New field of metalloendocrinology explores subtle effects of metals in body
University of California - Davis
Metals such as zinc, copper and chromium bind to and influence a peptide involved in insulin production, according to new work from chemists at the University of California, Davis. The research is part of a new field of "metalloendocrinology" that takes a detailed look at the role of metals in biological processes in the body.
"We're asking questions people didn't realize we don't have the answers to," said Marie Heffern, assistant professor of chemistry at UC Davis and senior author on the paper, to be published in the journal ChemBioChem.
Metals play a role in many biochemical processes. Hemoglobin contains iron and carries oxygen in the blood; zinc and copper are involved in a third to a half of all body functions. But while scientists know the overall amount of an element in a given component of the body, such as blood, they generally don't know the exact location of these metals, the state they are in or their biological role in the body.
"A metal is an ingredient - what you do with it is what makes the difference," Heffern said. Her laboratory at UC Davis is using new techniques to understand how metals are distributed inside and outside cells, how they bind to proteins and other molecules and the subtle influences they have on those molecules.
The new study looked at C-peptide, or connecting peptide, a short chain of amino acids. C-peptide is being investigated for potential in treating kidney disease and nerve damage in diabetes, so any better understanding of how it behaves in different conditions could be useful in drug development.
Influencing shape and uptake by cells
When the pancreas makes insulin, C-peptide connects two chains of insulin in a preliminary step. C-peptide is then cut out, stored along with insulin and released at the same time. C-peptide used to be considered a byproduct of insulin production but now scientists know that it acts as a hormone in its own right.
The researchers measured how readily zinc, copper and chromium bound to C-peptide in test tubes, and how the metals affected the ability of cells to take up C-peptide.
The metals had subtle effects on the structure of C-peptide, notably on its ability to curl into a helix in some conditions. Copper and chromium prevented cells from taking up the hormone, but other metals such as zinc, cobalt and manganese did not have such an effect.
The results show that metals can potentially "tune" the activity of hormones such as C-peptide by altering their structure or affecting uptake into cells, Heffern said. Additional authors on the paper are postdoctoral researcher Michael Stevenson, research specialist Kylie Uyeda, graduate student Jessica San Juan and Ian Farran, undergraduate majoring in biochemistry and molecular biology.
Designing biological movement on the nanometer scale
Scientists have designed proteins that move in response to acid, a technology that could help medication enter cells
University of Washington Health Sciences/UW Medicine
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IMAGE: This is molecular art depicting the new proteins that can move in predictable, tunable ways in response to their environment. The proteins were designed from scratch on computers, then produced... view more
Credit: Ian Haydon/Institute for Protein Design
Synthetic proteins have been created that move in response to their environment in predictable and tunable ways. These motile molecules were designed from scratch on computers, then produced inside living cells.
To function, natural proteins often shift their shapes in precise ways. For example, the blood protein hemoglobin must flex as it binds to and releases a molecule of oxygen. Achieving similar molecular movement by design, however, has been a long-standing challenge.
The May 17 issue of Science reports the successful design of molecules that change shape in response to pH changes. (pH is a chemical scale from basic to acidic.)
The Institute for Protein Design at the University of Washington School of Medicine led the multi-institutional research.
The researchers set out to create synthetic proteins that self-assemble into designed configurations at neutral pH and quickly disassemble in the presence of acid.
The results showed that these dynamic proteins move as intended and can use their pH-dependent movement to disrupt lipid membranes, including those on the endosome, an important compartment inside cells.
This membrane-disruptive ability could be useful in improving drug action. Bulky drug molecules delivered to cells often get lodged in endosomes. Stuck there, they can't carry out their intended therapeutic effect.
The acidity of endosomes differs from the rest of the cell. This pH difference acts as a signal that triggers the movement of the design molecules, thereby enabling them to disrupt the endosome membrane.
"The ability to design synthetic proteins that move in predictable ways is going to enable a new wave of molecular medicines," said senior author David Baker, professor of biochemistry at the UW School of Medicine and director of the Institute for Protein Design. "Because these molecules can permeabilize endosomes, they have great promise as new tools for drug delivery."
Scientists have long sought to engineer endosomal escape.
"Disrupting membranes can be toxic, so it's important that these proteins activate only under the right conditions and at the right time, once they're inside the endosome," said Scott Boyken, a recent postdoctoral fellow in the Baker lab and lead author on the recent project.
Boyken achieved molecular motion in his designer proteins by incorporating a chemical called histidine. In neutral (neither basic nor acidic) conditions, histidine carries no electric charge. In the presence of a small amount of acid, it picks up positive charge. This stops it from participating in certain chemical interactions. This chemical property of histidine allowed the team to create protein assemblies that fall apart in the presence of acid.
"Designing new proteins with moving parts has been a long-term goal of my postdoctoral work. Because we designed these proteins from scratch, we were able to control the exact number and location of the histidines," said Boyken. "This let us tune the proteins to fall apart at different levels of acidity."
Other scientists from the UW, The Ohio State University, Lawrence Berkeley National Laboratory, and Howard Hughes Medical Institute's Janelia Research Campus contributed to this research.
Those in Vicki Wysocki's Group at OSU used native mass spectrometry to determine the amount of acid needed to cause disassembly of the proteins. They confirmed the design hypothesis that having more histidines at interfaces between the proteins would cause the assemblies to collapse more suddenly.
Collaborators in the Kelly Lee lab at the UW School of Pharmacy showed that the designer proteins disrupt artificial membranes in a pH-dependent manner that mirrors the behavior of natural membrane fusion proteins.
Follow-up experiments conducted in Jennifer Lippincott-Schwartz's lab at HHMI's Janelia Research Campus showed that the proteins also disrupt endosomal membranes in mammalian cells.
Re-engineered viruses that can escape endosomes are the most commonly used drug delivery vehicles, but viruses have limitations and downsides. The researchers believe a drug delivery system made only of designer proteins could rival the efficiency of viral delivery without the inherent drawbacks
Being sick in the morning can be different from being sick at night
Cell Press
In a review published May 17 in the journal Trends in Immunology, researchers discuss how time of day affects the severity of afflictions ranging from allergies to heart attacks.
Researchers in Switzerland compiled studies, predominantly in mice, that looked at the connection between circadian rhythms and immune responses. For example, studies showed that adaptive immune responses--in which highly specialized, pathogen-fighting cells develop over weeks--are under circadian control. This is "striking," says senior author Christoph Scheiermann, an immunologist at the University of Geneva, "and should have relevance for clinical applications, from transplants to vaccinations."
The body reacts to cues such as light and hormones to anticipate recurring rhythms of sleep, metabolism, and other physiological processes. In both humans and mice, the numbers of white blood cells also oscillate in a circadian manner, raising the question of whether it might be possible one day to optimize immune response through awareness and utilization of the circadian clock.
In separate studies that compared immune cell time-of-day rhythms under normal conditions, inflammation, and disease, researchers found that:
•Heart attacks in humans are known to strike most commonly in the morning, and research suggests that morning heart attacks tend to be more severe than at night. In mice, the numbers of monocytes--a type of white blood cell that fights off bacteria, viruses, and fungi--are elevated in the blood during the day. At night, monocytes are elevated in infarcted heart tissue, resulting in decreased cardiac protection at that time of day relative to morning.
•The ability of immune cells to fight atherosclerotic plaques can depend on CCR2--a chemokine protein linked to immune function and inflammation. CCR2 exhibits a daily rhythm in mice, peaking in the morning, and based on its influence on immune cells, can be followed to understand white blood cell behaviors in mouse models of atherosclerosis.
•Parasite infections are time-of-day dependent. Mice infected with the gastrointestinal parasite Trichuris muris in the morning have been able to kill worms significantly faster than mice infected in the evening.
•A bacterial toxin tied to pneumonia initiates an inflammatory response in the lungs of mice. Recruitment of immune cells during lung inflammation displays a circadian oscillation pattern. Separately, more monocytes can be recruited into the peritoneal cavity, spleen, and liver in the afternoon, thus resulting in enhanced bacterial clearance at that time.
•Allergic symptoms follow a time-of-day dependent rhythmicity, generally worse between midnight and early morning. Hence, the molecular clock can physiologically drive innate immune cell recruitment and the outcomes of asthma in humans, or airway inflammation in mice--the review notes.
"Investigating circadian rhythms in innate and adaptive immunity is a great tool to generally understand the physiological interplay and time-dependent succession of events in generating immune responses," Scheiermann says. "The challenge lies in how to channel our growing mechanistic understanding of circadian immunology into time-tailored therapies for human patients."
Changes in subsistence hunting threaten local food security
Modern weapons, commercial hunting, fragmented landscapes impacting local subsistence hunters in Neotropical rain forests
Wildlife Conservation Society
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IMAGE: Scientists say that subsistence hunting in Neotropical rain forests -- the mainstay of local people as a source of protein and a direct connection to these ecosystems -- is in... view more
Credit: Galo Zapata-Rios/WCS
Scientists with the Universidad San Francisco de Quito and WCS Ecuador Program publishing in the journal BioTropica say that subsistence hunting in Neotropical rain forests - the mainstay of local people as a source of protein and a direct connection to these ecosystems - is in jeopardy from a variety of factors.
The authors say that the relatively small groups that hunted in large and mostly undisturbed forests, using traditional weapons, have been replaced by a growing population using fragmented habitats and modern hunting methods. Meanwhile, increased exploitation from mining, oil exploitation and tourism has fueled a rapidly growing commercial trade in wildlife.
Thus, the authors say that subsistence hunting is less likely to be sustainable, threatening the food security of local people and the persistence of species with critical roles in the functioning of Neotropical rain forests.
Said co-author Galo Zapata?Ríos, Science Director of WCS's Ecuador Program: "No longer can subsistence hunting be seen or managed as a sustainable activity carried out by small, isolated human groups occupying large tracts of natural habitat and using traditional hunting methods. Any approach to the problem must take into account the fundamentally different context in which subsistence hunting occurs in the present day."
Managing subsistence hunting in this changing context will require a more efficient combination of tools. These might include banning the hunting of large and sensitive species, shifting toward smaller species with high reproductive rates, coupled with strengthening protected areas - some of which are already under threat of being downgraded, downsized, or degazetted. One approach to addressing this might be participatory zoning, to designate residential areas and areas where farming, gathering non-timber forest products, forestry and hunting can be practiced sustainably, while allowing for the designation of no-hunting areas that serve as source areas for hunted species. Other tools include diversification of income sources (e.g., ecotourism), production of domestic animals for food, mini-livestock breeding, and payment for ecosystem services alternatives to reduce the role of wildlife protein on local people's subsistence.
Current vaccination policies may not be enough to prevent measles resurgence
BioMed Central
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Current vaccination policies may not be sufficient to achieve and maintain measles elimination and prevent future resurgence in Australia, Ireland, Italy, the UK and the US, according to a study published in the open access journal BMC Medicine.
To successfully achieve and maintain measles elimination in these countries in the medium to long term, further country-specific immunisation efforts may be needed in addition to current strategies. Measles elimination has been defined as the absence of endemic measles transmission in a region or other defined geographic area for twelve months or longer.
A team of researchers at the Bruno Kessler Foundation and Bocconi University, Italy used a computer model to simulate the evolution of measles immunity between 2018 and 2050 in seven countries; Australia, Ireland, Italy, Singapore, South Korea, the UK and the US. The authors focused their analysis on countries with a routine two-dose measles vaccination programme and a high primary school involvement rate, but with different demographics and vaccination histories. The aim was to evaluate the effect of possible adjustments to existing immunisation strategies, and to estimate the proportion of people who may remain susceptible to measles in high-income countries over time.
The authors' projections up until 2050 suggest that if current vaccination policies remain unchanged, the proportion of the population susceptible to measles would only remain below 7.5% in Singapore and South Korea, two countries which had high vaccination coverage in the past. Previous research estimated that the proportion of the population that does not have immunity (maximum susceptibility) needs to be 7.5% or less for measles to be eliminated.
In 2018, the proportion of the population susceptible to measles infection in the countries under study ranged from 3.7% in the UK to 9.3% in Italy (the only country where the proportion was found to be higher than 7.5%). In Australia, Ireland, the UK and the US, vaccination from routine programmes would need to continuously cover more than 95% of the population to keep the proportion of susceptible individuals below 7.5% until 2050.
Dr. Filippo Trentini, the first author said: "In recent years, we've witnessed a resurgence of measles cases even in countries where, according to World Health Organisation guidelines, elimination should already have been achieved. This resurgence is due to suboptimal vaccination coverage levels. In Italy, where measles incidents rates were among the highest, the government has made measles vaccination compulsory for children before they enter primary school. We investigated the potential of this and other policies to reinforce immunisation rates in seven high-income countries."
Co-author Dr. Stefano Merler added: "Our results suggest that most of the countries we have studied would strongly benefit from the introduction of compulsory vaccination at school entry in addition to current immunisation programmes. In particular, we found that this strategy would allow the UK, Ireland and the US to reach stable herd immunity levels in the next decades, which means that a sufficiently high proportion of individuals are immune to the disease to avoid future outbreaks. To be effective, mandatory vaccination at school entry would need to cover more than 40% of the population."
In Italy, the fraction of susceptible individuals by 2050 is projected to be 10%, even if coverage for routine vaccination reaches 100%, and additional vaccination strategies targeting both children at school entry and adults may be needed to achieve elimination.
UC Riverside researchers develop new drugs that target therapeutically relevant protein surfaces
University of California - Riverside
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IMAGE: The Pellecchia lab at UC Riverside is working on an approach in which effective drugs can be obtained by appropriately designing molecules to contain an aryl-fluoro sulfate (the chemical group... view more
Credit: Pellecchia lab, UC Riverside.
RIVERSIDE, Calif. -- A University of California, Riverside, research team has come up with a new approach to targeting cancer cells that circumvents a challenge faced by currently available cancer drugs.
A cancer target is often a rogue protein that signals cancer cells to proliferate uncontrollably and invade organs. Modern cancer drugs have emerged that work by striking a tight bond between the drug and a particular amino acid called cysteine, one of the 20 natural amino acids that constitute our proteins. Cysteine is unique in that it can react with specific organic functional groups to form a strong molecular bond.
Only a few new cancer drugs that target cysteine have been recently approved by the Food and Drug Administration, or FDA. A challenge cancer researchers face is that cysteine is rarely found within binding sites of cancer targets, limiting the application of this approach to only a few drug targets.
The UC Riverside research team has now met this challenge by exploring the development of drugs that target other potentially reactive amino acids, such as lysine, tyrosine, or histidine, which occur more often within the binding site of the target.
The researchers also addressed another challenge: The target they used for proof of concept was a protein-protein interaction, or PPI, target. PPIs represent a large class of possible therapeutic targets for which designing effective drugs is particularly difficult. This is because PPIs lack a well-defined and deep-binding pocket onto which drugs can de designed to bind tightly.
"To date, there is only one drug approved by the FDA that was designed to antagonize -- or block -- a PPI target," said Maurizio Pellecchia, a professor of biomedical sciences in the School of Medicine, who led the research. "Only a few others have entered clinical trials. Our approach provides novel and effective avenues to derive potent and selective PPI antagonists by designing drugs that can react with lysine, tyrosine, or histidine residues that are ubiquitously present at binding interfaces of PPIs."
Study results appear in the Journal of Medicinal Chemistry.
Pellecchia, who holds the Daniel Hays Chair in Cancer Research at UCR, explained that academic researchers, the biotechnology industry, and pharmaceutical companies are heavily pursuing the design of "covalent drugs" that bind irreversibly with their targets. Those that target cancer cells most often target cysteine because it is more reactive than all other amino acids in a protein target. Oncology drugs such as Osimertinib, Ibrutinib, Neratinib, and Afatinib have all been approved in very recent years by the FDA, he said, and all target a cysteine that is present on the binding site of their respective targets.
"Our work widens the available target space beyond cysteine," he added. "Such covalent agents could represent significant stepping stones in the development of novel drug candidates against PPIs, which represent an untapped large class of therapeutic targets not only in oncology, but also in other conditions including neurodegenerative and inflammatory diseases."
VIDEO: For the first time ever, UT Austin researchers captured the process in which developing killer T-cells (purple and white) are tested by dendritic cells (yellow), and others, to see if... view more
Credit: University of Texas at Austin
For the first time, immunologists from The University of Texas at Austin have captured on video what happens when T-cells - the contract killers of the immune system, responsible for wiping out bacteria and viruses - undergo a type of assassin-training program before they get unleashed in the body. A new imaging technique that allowed for the videos, described today in the journal Nature Communications, holds promise for the fight against autoimmune disorders such as Type 1 diabetes.
One of the human body's most potent weapons against many diseases is the T-cell, but in people with autoimmune disorders, T-cells also wreak havoc by mistaking normal cells for invaders and attacking healthy parts of the body.
"T-cells have the daunting task of recognizing and fighting off all of the diverse pathogens that we encounter throughout our lives, while avoiding attacking our own healthy tissue," said associate professor Lauren Ehrlich, one of the authors of the study. "These cells mature in the thymus, an organ just above the heart, where they 'get educated' to not attack the body."
Ehrlich and postdoctoral researcher Jessica Lancaster captured video of this educational process in a mouse thymus. Using a pair of powerful lasers that fire in short pulses and scan through a slice of live tissue every 15 seconds to reconstruct the positions, movements and intracellular signaling of cells, they observed that as T-cells develop, other cells in the thymus help them to encounter all sorts of ordinary human proteins that, later on, the T-cells will need to ignore in order to avoid attacking other parts of the body. The researchers learned more about how different types of cells work together in the thymus to perform the safety tests and, in the event a T-cell fails, trigger it to self-destruct.
Ehrlich says studying T-cells with this new imaging technique holds promise for improvements for human health that will depend on a better understanding of what's happening in the thymus. For example, patients who received bone-marrow transplants endure weeks or months with suppressed immune systems and a higher risk for developing autoimmune disorders, and people with Type 1 diabetes have T-cells that often attack the cells in the pancreas that produce insulin.
Blister packaging for drugs in nursing homes: Much discussed, but hardly investigated
Robust study data are lacking for arguments on the pros and cons/IQWiG proposes a study design
Institute for Quality and Efficiency in Health Care
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In blister packaging, a pharmacy (or a service provider commissioned by it) portions and packs the prescribed drugs of a patient according to weekdays and times of day, sorted into individual transparent packages (blisters). In this way, one can see at a glance when tablets should be taken and whether all tablets have been taken as planned.
For some years now, there has been a broad and controversial debate in Germany as to whether increased blister packaging for nursing home residents is suitable for relieving the burden on the long-term care system and sustainably improving the care of nursing home residents. The German Federal Ministry of Health therefore commissioned the Institute for Quality and Efficiency in Health Care (IQWiG) to examine, among other things, findings from studies. The report is now available.
According to IQWiG's search for evidence, studies on patient-specific blister packaging have so far been predominantly conducted for the outpatient sector, also internationally. However, as far as blister packaging for nursing homes is concerned, hardly any robust data from studies are available. Even the common arguments put forward by various stakeholders and interest groups for or against more blister packaging in nursing homes are not scientifically proven. This also applies to the aspect of cost-effectiveness.
Possible advantages and disadvantages
In the opinion of its advocates, the fact that medication errors will occur less frequently with blister packaging supports the introduction of this method. Because the more illnesses a resident suffers from, the more complex drug therapy becomes. In addition, if nursing staff were relieved of the burden of organizing the administration of drugs, they would have more time to care for the individual patient. And this in turn could increase job satisfaction in nursing and make the profession more attractive for young people.
Critics, however, fear a loss of competence if tasks are increasingly shifted from nurses to other professional groups. Moreover, patients might also lose some of their autonomy because they would be even less able to recognize and decide which drugs to take and which not. Critics also point out that not all drugs are "blisterable". This could even complicate the administration of drugs for nursing staff in nursing homes, as they would have to remember a second distribution of drugs in addition to the tablets in the blisters.
Initially, blister packaging causes additional costs. However, these should at least in part be compensated if wastage is reduced. The fact that not every patient receives a full package, but only individual tablets in the blister, means that overall, fewer tablets are thrown away.
Studies examine blister packaging in the outpatient sector
The IQWiG researchers found a number of studies that investigated aspects of the benefit of blister packaging, but they all referred to an outpatient setting; however, such studies can hardly be transferred to residential settings. This holds especially because people who live at home should still be able to handle their medication themselves. No study investigated residential geriatric long-term care.
The studies originating from Germany are mainly before-and-after comparisons without a control group, which were evaluated in model projects by health insurance funds. However, the results of such studies are not very meaningful from a scientific point of view - both with regard to the benefit for nursing home residents (symptoms, state of health, side effects of medication, etc.) and for the nursing staff (professional competence, work-related quality of life, etc.). IQWiG concludes that the benefit and harm of blister packaging in nursing homes therefore remain unclear.
Statements on cost-effectiveness can only be made by means of estimation
The evidence on the cost-effectiveness of blister packaging for nursing homes is also insufficient, but the Institute was able to estimate possible effects based on various sources. IQWiG assumed that a weekly blister costs about €3 and that drug expenditure will decrease by 4.1% due to less waste. If at least €73.17 of costs for blistered drugs are incurred per week and resident, blister packaging would be cost-neutral. This, however, refers only to drug costs. Due to a lack of data, it is not possible to consider other monetary effects (e.g. due to fewer hospital referrals).
Statements on non-monetary effects are also uncertain: Assuming that about half to two thirds of the approximately 818,000 people needing full residential nursing care in Germany receive blister-packed drugs, the time savings for nursing staff would amount to about 22 to 51 minutes per month and resident.
Great need for research: IQWiG proposes a design for a new study
The Institute has identified a great need for research on blister packaging in nursing homes. Thomas Kaiser, Head of the IQWiG's Drug Assessment Department, notes: "The discrepancy between the broad and sometimes vehement debate about blister packaging on the one hand and the lack of evidence on the other surprised us. Individual stakeholders and interest groups passionately argue for or against blister packaging, without being able to scientifically support their pros or cons. It is good that the commission from the Ministry of Health has now disclosed this." Against this background, IQWiG developed the design for a future study and integrated it into the report. Thomas Kaiser affirms: "Our research has shown that high-quality studies are indeed available on other research questions in residential long-term care and that such studies are evidently feasible."
Process of report production
In June 2018 the German Ministry of Health commissioned IQWiG to prepare the report as a rapid report in an accelerated procedure. Interim products were thus not published and did not undergo a hearing. The present rapid report was sent to the Ministry on 29 March 2019.
An English-language extract of the report will be available soon; if you would like to be informed when it is published, please send an email to info@iqwig.de
Nivolumab with ipilimumab: Combination has added benefit in advanced renal cell carcinoma
Advantages in overall survival are not offset by serious disadvantages
Institute for Quality and Efficiency in Health Care
Renal cell carcinoma is one of the cancer diseases for which the range of promising treatment options has become considerably wider in recent years. In several early benefit assessments since 2013, the German Institute for Quality and Efficiency in Health Care (IQWiG) has already been able to determine an added benefit of a new drug in comparison with the respective appropriate comparator therapy (ACT).
The Institute has also come to a positive conclusion in its current assessment of nivolumab with ipilimumab: The drug combination has considerable added benefit in comparison with the ACT (sunitinib) for patients with advanced renal cell carcinoma and an intermediate risk score, and even major added benefit for patients with at least three risk factors and a corresponding unfavourable prognosis.
Antibodies as multipurpose weapons
In recent years, both monoclonal antibodies have already been subject of several early benefit assessments because, alone or in combination, they are also used against other types of cancer, e.g. melanoma, squamous cell carcinoma of the lung and non-small cell lung cancer. As so-called checkpoint inhibitors, they block different molecules on the outside of immune cells.
Nivolumab binds to the PD-1 receptors on T lymphocytes and thus prevents their defence-inhibiting effect. Ipilimumab, in contrast, weakens the inhibitory effect of the CTLA-4 molecules on the T lymphocytes. Both increase proliferation and activity of the immune cells, so that they can fight the tumour cells more vigorously.
Premature end of study after interim analysis
The data for both corresponding dossier assessments - in each case of one of the drugs in combination with the other - are from the randomized controlled trial CheckMate 214. The study was ended prematurely after the first interim analysis because the results on overall survival were clearly in favour of the combination.
For patients with an intermediate risk score, the study data showed statistically significant and clinically relevant advantages in overall survival, symptoms and health-related quality of life. With both positive and negative effects of approximately the same magnitude regarding side effects, the conclusion for this outcome category was: Greater or lesser harm is not proven. Overall, there was an indication of a considerable added benefit.
The survival advantage was even more pronounced in patients with higher risk scores. In addition, there were hints of lesser harm of different extent for a number of side effects. This was offset by hints of greater harm in three side effects. However, these did not outweigh the advantages, so that the Institute sees an overall indication of a major added benefit.
G-BA decides on the extent of added benefit
Both dossier assessments are part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After their publication, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.
More English-language information will be available soon (extracts of the dossier assessments as well as easily understandable information on informedhealth.org). The website http://www.gesundheitsinformation.de, published by IQWiG, provides easily understandable German-language information.
Button batteries can rapidly damage stomach lining before symptoms appear
Experts recommend changing current practice of watchful waiting
Digestive Disease Week
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San Diego, CA (May 18, 2019) -- Damage to the lining of the stomach can occur quickly when children swallow button batteries; therefore, clinicians should consider prompt endoscopic removal, even when the child is symptom free and the battery has passed safely through the narrow esophagus, according to research presented at Digestive Disease Week® (DDW) 2019. The recommendations represent a change from current practice of watching and waiting.
"We know there can be injury even when there are no symptoms," said Racha Khalaf, MD, lead researcher and pediatric gastroenterology, hepatology and nutrition fellow at the Digestive Health Institute at Children's Hospital Colorado, Aurora. "Batteries in the stomach cause damage, including perforation of the gastric wall, so physicians should consider removing the batteries as soon as possible and not let them pass through the digestive tract."
Researchers from pediatric hospitals in Colorado, Florida, Texas and Ohio collected data regarding 68 button battery ingestions from January 2014 to May 2018. Previous research has been conducted on button batteries lodged in the esophagus, but little is known about the effect in the stomach.
"We have been seeing more injuries from button batteries," Dr. Khalaf said. "The batteries come in toys, remote controls, key fobs, singing greeting cards and watches. They are everywhere."
Erosive injuries to the mucous lining of the stomach were found in 60 percent of cases reviewed, with no apparent relationship between damage and symptoms, or with the amount of time passed since ingestion. This suggests that clinicians and parents should not wait for symptoms or passage of time to act, Dr. Khalaf said, adding that removing the battery earlier avoids repeated trips to the emergency room or pediatrician's office and reduces repetitive x-rays or other imaging.
The authors' recommendations are more aggressive than those of two national organizations that have issued recommendations about button battery ingestion. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommends observation when it's been less than two hours since ingestion, the battery is 20 mm or smaller, and the child is at least 5 years old. The National Capital Poison Center, which runs the National Battery Ingestion Hotline, currently recommends observation alone for asymptomatic gastric button batteries to allow them to pass through the digestive system
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