Publisher Health

Scientists are not yet clear on how the tau protein changes from a benign protein essential for normal function in our brains into the toxic neurofibrillary tangles that are a signature of Alzheimer’s and other neurodegenerative diseases.
But a new method developed by researchers at UC Santa Barbara gives the ability to control and follow in real time the process by which it happens. The technique employs a novel use of low voltage electricity as a surrogate for the natural signals that trigger the protein to fold and assemble, both for its normal function in the brain and in the runaway process leading to often fatal disease.
“This method provides scientists a new means to trigger and simultaneously observe the dynamic changes in the protein as it transitions from good to bad,” said Daniel E. Morse, Distinguished Professor Emeritus of Biochemistry and Molecular Genetics, and senior author of a paper that appears in the Journal of Biological Chemistry.
“The method should be widely useful to identify molecules and conditions that direct different trajectories of assembly in a number of different but related amyloid diseases,” stated Eloise Masqulier, lead author of the interdisciplinary team of students, researchers and faculty from molecular biology, chemistry and engineering including Esther Taxon, Sheng-Ping Liang, Yahya Al Sabeh, Lior Sepunaru and Michael J. Gordon.
Under normal circumstances, tau is a soluble protein that starts out in an open, loose configuration, like a piece of string. In response to a signal, tau proteins fold up and progressively assemble with one another, enabling them to bind to tiny cylindrical structures — microtubules — that support the shape of the neurons and transport nutrients and molecules inside the cells. However, in pathological cases, the signal goes too far, causing the protein to assemble uncontrollably, forming the insoluble amyloid filaments that become neurofibrillary tangles inside neurons, interrupting their function and eventually killing them.
Using their new method with the core portion (a peptide) of tau, the investigators were able to observe and analyze a critical “tipping point” between normal, reversible folding and assembly, and the irreversible, pathological assembly that underlies tauopathic, neurodegenerative diseases. Employing less than a volt of electrical potential to mimic hyperphosphorylation (the disease-promoting signal), the scientists triggered and finely tuned the tau-peptide’s folding in their lab experiments, using spectroscopic methods to reveal details of the folding and progressive assembly to form amyloid-like filaments.
Unlike other modes of examining protein folding and assembly, such as x-ray diffraction or cryo-electron microscopy that provide static snapshots of the processes as they occur in time, the new electrochemical method allows users to continuously witness and analyze details of the progressive, dynamical folding and assembly as they occur in real time, permitting the first direct observations of the critical earliest steps in these processes. Also unlike most techniques previously used for studies of tau and its core peptide, because the electrical trigger closely mimics the natural triggering signal, the method permits direct observation of these processes without the need for additional “helper” molecules.
The authors report that the technology can also be used as a tool to more rapidly test and identify drugs and antibodies potentially useful for prevention or treatment of Alzheimer’s and other amyloid diseases.
“Because we can turn on and fine-tune the process at will,” Morse explained, “we can use this system to see what molecules could interdict or block specific stages of folding and assembly.”

Some doctors say that however reasonable guidelines may seem, their cumulative burden causes “constant frustration” to medical practice.The intent is admirable: Give doctors guidelines so they can be sure to cover what needs to be discussed with patients and help select options. Let’s talk about your diet and any problems you might have sleeping. Are you getting enough exercise? If not, here is some advice. You are due for colon cancer screening. Do you prefer a colonoscopy or a fecal test? Here are the pros and cons of each.But there is a problem. There are just not enough hours in a workday to discuss and act on all the guidelines.Suppose an American doctor wanted a gold star when seeing patients and followed all of the guidelines for preventive, chronic and acute disease care issued by well-known medical groups. That could require nearly 27 hours per day, a team of doctors wrote in a study last year for the Journal of General Internal Medicine.No one could actually do that, so imagine a doctor shrugged off the chronic and acute care, as well as administrative work, and merely followed the preventive care checklist recommended by the U.S. Preventive Services Task Force, an independent panel of health experts. That would be 8.6 of the doctor’s hours each day, according to a study in the American Journal of Public Health.As anyone who has been sped through a 15-minute annual wellness visit knows, doctors cannot be so exacting. That the guidelines are so thorough yet so often glossed over prompts questions about their usefulness. At the same time, doctors’ pay often depends on checking off guideline boxes.“Is this an issue? Absolutely,” said Dr. Michael Pignone, a former member of the Preventive Services Task Force and chairman of the department of internal medicine at the University of Texas at Austin’s Dell Medical School.“Suffice it to say that what has been incentivized isn’t always what delivers the most health or benefit,” Dr. Pignone said.Guidelines have become “a constant frustration,” said Dr. Minna Johansson, a general practitioner in Uddevalla, Sweden, who also directs the Global Center for Sustainable Healthcare at the University of Gothenburg. She worked with doctors in other countries on an analysis of the issue that was published last month in BMJ. “A lot of guidelines may seem reasonable when considered in isolation,” Dr. Johansson said. “But the cumulative burden of all guideline recommendations combined is absurd.”Dr. Johansson was inspired to study the issue working in a small town on Sweden’s west coast.“I have a yearly visit with my patients,” she said. Spending that precious time discussing a lifestyle prescription that, however well meaning, is unlikely to change a patient’s habits, is of dubious value, she said. And, she added, it “crowds out more important discussions.”“Maybe the patient smokes or has suicidal thoughts,” she said.And, she added, many guidelines, like those for extensive discussions about improving exercise habits or diet, have not been shown to result in important health benefits.Dr. Johansson worked with Dr. Gordon Guyatt of McMaster University in Hamilton, Ontario, and Dr. Victor Montori of the Mayo Clinic in Rochester, Minn. They argue that this problem affects medical systems throughout North America and Western Europe.In Norway, for example, guidelines for assessing and treating high blood pressure apply to the nearly three-quarters of adults with pressures above the goal of 120/80. If the guidelines were strictly adhered to, patients would need so many regular follow-up visits that accommodating them would require more general practitioners than are currently working in Norway.And implementing all the British guidelines for improving patients’ lifestyles could require more doctors and nurses than are practicing in the entirety of Britain.The researchers say that guideline makers should consider what the study calls “the time needed to treat” — how much time it takes to implement a guideline.For example, they say, the British guideline on assessing a patient’s physical activity would take 15 percent of a doctor’s visit to implement, but there is no evidence it would improve long-term health. That, they say, might suggest the guideline should be jettisoned.Dr. Carol Mangione, chair of the U.S. Preventive Services Task Force, said the task force considered the time guidelines take. And nowhere is it suggested that doctors try to tick off each guideline recommendation in a single visit.“Clinicians do not — and would never be expected to — implement all of the suggested screenings, counseling services, and preventive medications in a single patient visit,” Dr. Mangione wrote in an email. “When caring for patients, clinicians use both their judgment and the information obtained during conversations with each patient to prioritize which preventive services should be offered during each visit.”Even that is not easy, said Dr. Daniel Jonas, director of the division of general internal medicine at Ohio State University.Guidelines can serve a purpose, Dr. Jonas said. “I think they’re incredibly helpful,” he added. But, he said, “deciding what to prioritize in a busy primary care practice is a big challenge.”Dr. Montori added another complication.“To assume that patients and clinicians can sort and prioritize recommendations over multiple visits,” he said, “wishes away the fundamental problem that many patients cannot get primary care, see the same clinician or have unhurried consultations.”Dr. Pignone said that some of the burden should be shared with other professionals, like nutritionists, who can talk to patients about healthy diets. But, he said, that is only a partial solution. He’d like to see current recommendations prioritized by their impact on health and on their cost effectiveness. As examples, he said, childhood immunizations would rank high but existing guidelines to give tetanus boosters to adults who already had tetanus shots would rank lower.Dr. Guyatt said guidelines should be held to the same standard as new drugs. Before they are implemented, there should be evidence that they are helpful.“Somebody might say, ‘Oh, a new drug has side effects but what harm is there in this guideline?’” he said. “But yes, there is real harm. There is a trade-off between doing things that are actually useful and spending time on things that are useless.”

Published16 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Michelle RobertsDigital health editorAn on-demand, non-hormonal male contraceptive pill may be a real possibility say scientists who have found a cell pathway, or switch, that stops sperm from being able to swim.Tests in mice suggest it keeps sperm stunned for at least a few hours – long enough to stop them reaching the egg.Many more tests are planned and needed, moving to rabbits before people.The idea is users could pop a pill an hour before sex and keep an eye on the clock for when it wears off.How does it work?Unlike the female contraceptive pill, it does not involve any hormones. Scientists say that is one of the advantages of the approach they are exploring – it will not knock out testosterone and cause any male hormone deficiency side effects. Instead, the “sperm-swim” switch they are targeting is a cellular signalling protein called soluble adenylyl cyclase or sAC. The experimental male pill inhibits or blocks sAC. ‘We’re using a male contraceptive gel’Male pill – why are we still waiting?In the early study in mice, funded by the US National Institutes of Health and published in the journal Nature Communications, a single dose of the drug, called TDI-11861, immobilised sperm before, during and after mating. The effect lasted for around three hours. By 24 hours, it appeared to have fully worn off. One of the scientists, Dr Melanie Balbach from Weill Cornell Medicine in New York, said it showed promise as a reversible, easy-to-use contraceptive. If it does ultimately work in humans, men might be able to take it only when, and as often, as needed. They could make day-to-day decisions about their fertility.But it would not protect against sexually transmitted infections, experts warn. Condoms would be needed for that. Prof Allan Pacey, professor of andrology at the University of Sheffield, said: “There is a pressing need for an effective, reversible, oral contraceptive for men and although many different approaches have been tested over the years, none has yet reached the market.”The approach described here, to knock out key enzyme in sperm that is critical for sperm movement, is a really novel idea. The fact that it is able to act, and be reversed, so quickly is really quite exciting.”If the trials on mice can be replicated in humans with the same degree of efficacy, then this could well be the male contraceptive approach we have been looking for.”Meanwhile, other researchers have been looking at a slightly different pathway to halt sperm swimming, by blocking a protein on the surface of sperm. More on this storyMale pill – why are we still waiting?26 March 2019Are we ready for men to take the pill?22 October 2019

A recent study suggested the use of a decades-old medicine taken before imbibing could reduce the amount of alcohol consumed.Ever wake up regretting the last round of drinks from the previous night? There’s a medicine that might help.A recent study adds to the evidence that people who binge-drink may benefit from taking a dose of the medication naltrexone before consuming alcohol, a finding that may be welcomed now that alcohol-related deaths in the United States have surpassed 140,000 a year.Nearly half of American drinkers reported bingeing, defined as more than four drinks in a sitting for men and more than three for women, in the previous month, according to a U.S. government health survey.Some may view binge-drinking as harmless because the habit is widespread and a low percentage of binge drinkers are dependent on alcohol, according to experts.But it is considered a major risk factor for alcohol-related illness and injuries, and it heightens the possibility that an individual will develop an alcohol disorder.In the study, which was published in December in the American Journal of Psychiatry, 120 men who wanted to reduce bingeing but were not severely dependent on alcohol were given naltrexone to take whenever they felt a craving for alcohol or anticipated a period of heavy drinking.Naltrexone, which blocks endorphins and reduces the euphoria of intoxication, was approved in the United States for the treatment of alcohol dependence nearly 30 years ago. But it is typically prescribed for patients with more severe alcohol disorders to take daily to abstain from drinking.The new study’s targeted approach, in which patients were advised to take the pill one hour before they expected to drink, is less common, although studies going back decades have also demonstrated the effectiveness of the as-needed dosing method.The randomized control trial was double-blinded, so half of the men received naltrexone and half received a placebo, and neither the participants nor the scientists knew who had received which. Each week, participants also received counseling on how to reduce their alcohol use.By the end of the 12-week study, those given naltrexone reported bingeing less frequently and consuming less alcohol than those who had been given a placebo, a change that lasted for up to six months. The most commonly reported side effect of naltrexone was nausea, although it was generally mild and resolved itself as people adjusted to taking the drug.Glenn-Milo Santos, a professor at the University of California, San Francisco and the study’s lead author, said patients could discuss the treatment option with their clinicians, even if it was not suitable for all. “Increasing awareness that there are effective medicines that can help people with their alcohol use is important in and of itself,” he said.Taking naltrexone on an as-needed basis rather than as a daily dose may be more tolerable for some people because it allows their dopamine levels to recover in between uses. The approach could also let people feel more in control of their treatment. The practice is more widely embraced in Europe, where regulators in 2013 approved the medication nalmefene for similarly targeted dosing by people trying to drink less alcohol.Dr. Lorenzo Leggio, a physician-scientist at the National Institutes of Health, said the latest study was “very important” because, while alcohol treatments had traditionally been designed for people with severe addictions, far more people, like the study’s participants, had mild or moderate alcohol disorders.Last year, N.I.H. officials proposed rebranding these stages as “preaddiction” to underscore the need for early intervention, much as the diabetes field improved care by identifying and treating prediabetes.“If we attack the medical problem right away and early on, you cannot only treat the problem but prevent the development of the more severe forms of the disease,” Dr. Leggio said.The recent study enrolled exclusively gay and transgender men, groups in which there is a higher prevalence of binge-drinking, so the findings might not be applicable to all binge drinkers. The participants were recruited “via street outreach, recruitment fliers, sexual health clinics, needle exchanges, community organizations, bars, websites and social media,” according to the study, and additional participants in an unrelated study were also invited to join. Nearly everyone involved in the study reported having some college education and a regular health care provider.Dr. Henry Kranzler, a professor of psychiatry at the University of Pennsylvania who led earlier trials of targeted dosage of naltrexone, said the approach provided a “niche opportunity” because not all people found it easy to anticipate their cravings and to self-medicate in advance of them.“It takes a level of awareness that many people don’t have,” he said.Researchers agree that while there is no one-size-fits-all approach to treating alcohol disorders, naltrexone and other approved medications are vastly underused.Katie Witkiewitz, the director of the Center on Alcohol, Substance Use and Addictions at the University of New Mexico, said the drugs’ patents had expired, so cheap generic versions were available — but their original makers no longer advertise them.In a 2019 government health survey on alcohol and drug use, fewer than one in 10 people with an alcohol use disorder reported having received any treatment, and less than 2 percent of those individuals said they had been offered medication. Many physicians do not even know about the drugs.Ms. Witkiewitz said that two months ago she was supervising a patient she thought would benefit from naltrexone. But she said that the patient’s primary care doctor mistakenly believed that prescribing the medication required additional training in addiction medicine and refused to write a prescription.“There’s a real gap in the medical community,” she said.

Most health and teaching unions have called off planned strikes after an improved pay offer from the Welsh government.But some unions still insist the offer is below where they want it to be, and the dispute over better pay and working conditions looks far from over.Union members will vote on whether to accept or reject the offer over the next few weeks, but the Welsh government says a better offer will not be made.”Ultimately it ends with a fair, in-line-with-inflation pay rise,” said one teacher. “That’s the only way it can end.”

The family of a man killed in a hit-and-run crash have said they had no hesitation in offering his organs for donation.Aaron Wilson, 29, had his leg amputated as a result of the crash in Coventry and later died in hospital. The father-of-one’s heart, liver and lungs were among the organs transferred to other patients, his family said.His mum Irene Wilson said she knew it was what her son would have wanted.Four people have been charged in connection with Mr Wilson’s death.

Published1 hour agoShareclose panelShare pageCopy linkAbout sharingImage source, Watson WoodhouseBy Datshiane Navanayagam & Fergus HewisonFile on 4A mental health trust mixed up the names of two teenagers who died in its care in a report seen by one of their families, it has emerged.Christie Harnett, Emily Moore and Nadia Sharif lost their lives in an eight-month period up to February 2020. In a report given to Nadia’s parents, who are from Middlesbrough, the trust mistakenly called her “Christie” at one stage, leaving them “angry and upset”.Tees, Esk and Wear Valleys NHS Trust apologised for the “appalling” error.The trust’s current chief executive, Brent Kilmurray, who was not in post when the teenagers died, also said: “I’m incredibly sorry for what happened in that case.”Given everything that happened, that was a serious mistake, and again, I reiterate my apology to Nadia’s family.”Image source, Family photographAll three teenagers had experienced complex mental health problems.Investigations by the NHS into how they died after harming themselves in the same way found multiple failings in their care and treatment. Christie, from County Durham, and Nadia both died aged 17 in West Lane Hospital, in Middlesbrough. It was found to have been “unstable and overstretched” at the time. Services for children and young people there are now provided by another mental health trust.If you’ve been affected by issues in this article there is help and support at BBC Action LineEmily, also from County Durham, died in February 2020. She had been in West Lane, but then spent time in another hospital run by a neighbouring trust, before being moved to an adult unit run by Tees, Esk, and Wear Valleys after turning 18. This move to adult services was found to have been based “entirely” on age and did not take her clinical needs into consideration.Image source, Family PhotographEmily’s father David Moore said he had tried desperately to stop her being moved.”At the last meeting we had, I was actually down on my hands and knees begging, saying, ‘please do not send her to Tees, Esk and Wear Valley’,” he said.All three young women died after using the same method of self-harm, and the trust was heavily criticised by investigators for failing to properly recognise the danger posed by this to each of them.Image source, MICHAEL HARNETTThe families of all three teenagers now want a public inquiry.The trust is also facing being prosecuted over Christie’s death, with a hearing scheduled at Teesside Magistrates’ Court on 21 February. If found guilty it could face a large fine.The trust has apologised for failings in the three young women’s care and treatment, and said it had invested heavily in patient safety since they died, spending £8m and recruiting an extra 700 members of staff.File on 4: Three Friends is available on BBC Sounds.Follow BBC North East & Cumbria on Twitter, Facebook and Instagram. Send your story ideas to northeastandcumbria@bbc.co.uk.More on this storyStaff concerns ‘ignored’ at teenager deaths hospital3 November 2022Teenagers died after failures at ‘unstable’ hospital2 November 2022Mental health trust prosecuted over girl’s death28 June 2022Grieving families urge public inquiry into NHS trust1 March 2022Bereaved dad cycles to Number 10 in bid for inquiry4 October 2022Health trust must improve amid staffing concerns10 December 2021Teenager ‘let down’ by mental health trust18 February 2020Teen recalls ‘humiliating’ hospital care4 July 2019