Scientists discover how neuroactive steroids dampen inflammatory signaling in cells

For the first time, scientists discovered how neuroactive steroids naturally found in the brain and bloodstream inhibit the activity of a specific kind of protein called Toll-like receptors (TLR4), which have been known to play a role in inflammation in many organs, including the brain.

This UNC School of Medicine-University of Maryland collaboration, published in Nature Scientific Reports, shows how the neurosteroid allopregnanolone prevents the activation of pro-inflammatory proteins important for gene regulation, as well as the creation of cytokines, which are known to be involved in many different inflammatory conditions. Inflammatory cell signaling in the brain is heightened in many neuropsychiatric conditions, including alcohol use disorder, depression, and posttraumatic stress. It is also seen in sepsis, epilepsy, multiple sclerosis, and Alzheimer’s disease.

“It has been very difficult to treat brain disease that involves inflammation, but allopregnanolone’s inhibition of TLR4 signaling activation in macrophages and the brain provides hope that we can develop better therapies to help millions of people suffering with these conditions,” said senior author A. Leslie Morrow, PhD, the John Andrews Distinguished Professor in the Departments of Psychiatry and Pharmacology at the UNC School of Medicine.

Neuroactive steroids, which are naturally occurring steroids in the brain and elsewhere in the body, have many functions critical for life and health. These steroids decline with aging and are deficient in many neuropsychiatric conditions, such as depression. Morrow and her colleagues have proposed that treatment with these compounds may prevent uncontrolled TLR4 signaling in conditions where this signaling contributes to disease.

Recent studies showed that the neurosteroid compounds pregnenolone and allopregnanolone have therapeutic effects in depression, schizophrenia and PTSD. But until now, scientists didn’t understand how. The UNC-Maryland study suggests that inhibition of inflammatory signaling may contribute to these effects, and inhibition of TLR4 signaling may be a new target for these conditions.

In collaboration with Laure Aurelian, PhD, at the University of Maryland, Morrow and colleagues found that allopregnanolone inhibits TLR4 activation in macrophages, which are found in white blood cells and part of the immune system, including in the brain. In particular, the researchers found that allopregnanolone prevents TLR4 binding to MD2 proteins that work together to produce transcription factors that regulate the genes responsible for inflammatory responses in cells and tissues. Allopregnanolone also tamps down chemokines and cytokines, such as NFkB, HMGB1, MCP-1 and TNF-a, all of which are part of the immune system and involved in many different inflammatory diseases.

Morrow and colleagues found that pregnenolone also inhibited TLR4 signaling in macrophage cells. “Pregnenolone’s effects in the brain were less pronounced,” Morrow said. “But inhibition of peripheral inflammation protects the brain as well because systemic inflammation affects organs throughout the body indirectly.”

Now that scientists have identified this inhibitory mechanism that dampens inflammatory signals responsible for brain inflammation, researchers can create new compounds to fill this particular role of neurosteroids without unwanted side effects. In addition, researchers can now plan clinical studies to determine the best doses, formulations, and modes of administration for different conditions.

David Rubinow, MD, chair of the department of psychiatry at UNC-Chapel Hill, who was not involved in the study, said, “This great example of collaborative and translational research provides physiologic insights with great potential for spawning new, more effective primary and adjunctive treatments for the many individuals suffering from brain disorders characterized by so-called neuroinflammation.”

Flu Season Far From Over, CDC Says

By Steven Reinberg

HealthDay Reporter

FRIDAY, Feb. 8, 2019 (HealthDay News) — Though much of the United States is in the grip of the flu, the season hasn’t peaked yet, health officials said Friday.

As of Feb. 2, flu is widespread in 47 states, and 24 states are experiencing high levels of the disease. In addition, hospitalizations are increasing, according to the U.S. Centers for Disease Control and Prevention.

“Flu activity has continued to increase this week,” said Lynnette Brammer, the lead of CDC’s domestic influenza surveillance team.

The most common type of flu around is still the influenza A strain H1N1. But it may be waning, Brammer said, as the level of influenza A H3N2 has increased.

Both of these flu strains are in this year’s vaccine, but while the H1N1 component is up to 65 percent effective, the effectiveness of the H3N2 is far less, according to the CDC.

Even though it is nearly mid-February, the flu season is expected to continue for several more weeks, probably well into March, Brammer said.

“There’s still a lot more flu season to come,” she said. “I expect activity to continue for several more weeks.”

That’s why she’s urging anyone who hasn’t yet been vaccinated to get a flu shot. “It’s not too late,” Brammer said.

An underrated benefit of the vaccine is that even if you get sick, your flu will be milder than if you haven’t been vaccinated. A milder flu can prevent complications like pneumonia that can be deadly, especially to the very young and very old.

Brammer also stressed that getting vaccinated not only protects you, but those around you, as well.

According to the CDC, flu activity is high in New York City, Alabama, Alaska, Arkansas, Colorado, Connecticut, Georgia, Indiana, Kansas, Kentucky, Massachusetts, Mississippi, Nebraska, New Jersey, New Mexico, North Carolina, Oklahoma, Rhode Island, South Carolina, South Dakota, Texas, Utah, Vermont, Virginia and West Virginia.

It’s still too early to tell how severe this season will be, Brammer said. So far, the season has been much less severe than last year when the H3N2 virus predominated. Last year, flu sent nearly 1 million Americans to the hospital and killed about 80,000.

This season is still classified as a less severe season, Brammer said. “But we’re not finished yet,” she said. “We’ll have to see how it plays out.”

The CDC doesn’t track adult deaths from flu, but they do keep tabs on pediatric deaths. This week, four more children died from flu, bringing the total to 28.

The best way to protect yourself and those around you is to get a flu shot, and there’s still time to get vaccinated, Brammer said.

The CDC recommends that everyone aged 6 months and older get vaccinated.

Getting a flu shot should be at the top of the list for those at high risk for flu, including the elderly, people with heart disease or lung disease, and pregnant women.

Brammer added that this year’s vaccine is well matched to the circulating strains of flu, and vaccine is still available. “I haven’t heard of any shortages,” she said.

As long as flu is circulating, it’s not too late to get vaccinated. “And right now, flu is circulating at a pretty high level,” Brammer said.

If you get the flu, antiviral drugs such as Tamiflu and Relenza can make your illness less severe. But if you’re sick, the CDC recommends that you stay home so you don’t infect others.

Brammer wouldn’t be surprised if the flu season doesn’t peak for several more weeks. It also wouldn’t surprise her if the H1N1 virus peaks before the H3N2 virus.

In any case, even when the season peaks, there’s still a long way to go before it’s over, she said.

Sleep Patterns May Offer Clues to Alzheimer’s

HealthDay Reporter

WEDNESDAY, Jan. 9, 2019 (HealthDay News) — Poor sleep is common among Alzheimer’s patients, and researchers say they’re beginning to understand why.

Scientists studied 119 people aged 60 and older. Eighty percent had no thinking or memory problems, while the rest had only mild problems.

The researchers found that participants with less slow-wave sleep — deep sleep that’s needed to preserve memories and to wake up feeling refreshed — had higher levels of the brain protein tau.

Elevated tau levels are a possible sign of Alzheimer’s disease and have been linked to brain damage and mental decline, the scientists said.

The findings suggest that poor sleep among older adults could be a warning sign of declining brain health, according to the researchers at Washington University School of Medicine in St. Louis.

“We saw this inverse relationship between decreased slow-wave sleep and more tau protein in people who were either cognitively normal or very mildly impaired, meaning that reduced slow-wave activity may be a marker for the transition between normal and impaired,” said first author Dr. Brendan Lucey. He’s an assistant professor of neurology and director of the Washington University Sleep Medicine Center.

“Measuring how people sleep may be a noninvasive way to screen for Alzheimer’s disease before or just as people begin to develop problems with memory and thinking,” Lucey said in a university news release.

He noted that the people with increased tau levels “were actually sleeping more at night and napping more in the day, but they weren’t getting as good quality sleep.”

Lucey doesn’t expect sleep monitoring to replace brain scans or cerebrospinal fluid analysis for identifying early signs of Alzheimer’s disease. “But it could supplement them,” he said. The study only found an association between sleep quality and tau levels.

“It’s something that could be easily followed over time, and if someone’s sleep habits start changing, that could be a sign for doctors to take a closer look at what might be going on in their brains,” Lucey said.

About 5.7 million Americans have Alzheimer’s disease. Brain changes associated with the disease can begin up to two decades before symptoms such as memory loss and confusion appear.

The study findings were published Jan. 9 in the journal Science Translational Medicine.

Diabetes: Can we teach the body to heal itself?

In diabetes, the pancreas is unable to produce enough insulin, the hormone that is key to regulating levels of blood sugar. New research now asks if we can teach pancreatic cells to address this problem on their own.

The pancreas contains three different types of cells, each of which produces different hormones that contribute to the regulation of blood sugar levels, one way or another.

These cells are alpha-cells that produce glucagon to boost blood sugar, beta-cells that produce insulin to lower levels of glucagon, and delta-cells that produce somatostatin, a hormone that regulates alpha- and beta-cell activity.

In both type 1 and type 2 diabetes, research has linked the lack of insulin with problems in pancreatic beta-cells.

However, a new study by researchers from the University of Bergen in Norway suggests that, with just a small “push,” we may be able to train the body to start producing adequate levels of insulin once more, on its own.

More specifically, the investigators explain, some alpha-cells could turn into beta-cells and release insulin.

“We are possibly facing the start of a totally new form of treatment for diabetes, where the body can produce its own insulin, with some start-up help,” says study co-author Luiza Ghila from the Raeder Research Lab in the Department of Clinical Science at the University of Bergen.

The researchers explain their findings in detail in a study paper in the journal Nature Cell Biology.

Higher risk of blood clots associated with some HRT tablets

Thursday, 10 January 2019

Some hormone replacement therapy (HRT) tablets appear to be associated with a higher risk of rare but serious venous thromboembolism (VTE), suggests a large study* published today in The BMJ.

However, the study found no increased risk of VTE for HRT skin patches, gels or creams, although the vast majority of women choosing HRT are prescribed oral preparations.

Different treatments of HRT used to relieve menopausal symptoms are available depending on the symptoms, such as tablets containing oestrogen only or a combination of oestrogen and progestogen, as well as ‘transdermal’ treatments, such as patches, gels and creams.

Previous trials have shown increased risks of blood clots in menopausal women using HRT, but there is a lack of information on risks associated with different types of HRT.

Therefore, Yana Vinogradova, a member of an epidemiological team at the University of Nottingham led by Julia Hippisley-Cox, set out to assess the association between VTE risk and all available types of HRT in the UK between 1998 and 2017.

The research team used two UK primary care databases (QResearch and CPRD) and compared HRT prescription records of 80,396 women aged 40-79 years who developed blood clots (cases) with those of over 391,494 women who did not (controls).

Other relevant factors, such as lifestyle, family history of blood clots, and underlying conditions linked to blood clots were taken into account.

Analysis showed that most HRT tablets were found to be associated with increased VTE risk (nine extra cases per 10,000 women per year) compared with no HRT.

Tablets containing equine oestrogen, including single and combined preparations, were consistently associated with higher risks than tablets containing synthetic oestrogen.

In addition, higher doses of oestrogen were also associated with higher VTE risk, but there was no increased VTE risk found for skin patches, gels and creams.

This was an observational study so it could not establish cause and the researchers acknowledged some limitations that may have influenced the results.

Nevertheless, they said: “This study has provided a more detailed picture of the VTE risks for different HRT preparations and can help clinicians and women make treatment choices.”

They suggested clinicians should give greater consideration to transdermal HRT, particularly for women already at an increased VTE risk and in line with recent guidelines.

Royal College of General Practitioners chair Professor Helen Stokes-Lampard said the study was interesting but stressed that it showed association and not causation.

“The menopause is a transition stage for every woman and can cause difficulties for many – and for some specific symptoms, such as hot flushes and night sweats, HRT is the only medical treatment that has good evidence of benefit,” she said.

“While this study is certainly interesting and important, as the authors themselves acknowledge, the findings do not prove that tablets cause more DVTs [Deep vein thrombosis] than patches, just that there is an association. As such, it is essential that more research is conducted in this area and taken into account as new clinical guidelines are updated and developed.

“It’s important that patients don’t panic or stop taking HRT as a result of reading about this study, but instead discuss their concerns at their next routine GP appointment, or seek advice from a reputable website like NHS Choices.”

Flu Cases on Upswing as New Medicine Arrives

Jan. 7, 2019 — As predictable as post-holiday bills and weight loss resolutions, flu activity is on the rise in the U.S., the CDC reports.
Slideshow
Slideshow: Foods for the Flu

For the week ending Dec. 29, 2018, 19 states and New York City reported high flu activity, compared to 9 states and New York City the previous week. More than 1,000 lab-confirmed cases of influenza-related hospitalizations have been reported, and as of Dec. 29, 13 children have died of flu this season.

Experts hesitate to predict how bad a flu season will be, but they say several points are worth noting about year’s flu season:

A new drug to treat flu, Xofluza, is now available to pharmacies nationwide. It joins Tamiflu, the most commonly prescribed treatment.
It’s not too late to get a flu shot.
While symptoms can make you miserable, preventing complications is most important.

New Drug on the Block

Xofluza (baloxavir marboxil) was approved by the FDA in late October and treats flu symptoms, says Andrew Villani, a spokesperson for Genentech, which distributes the prescription medicine. However, when WebMD checked six pharmacies last week, just one had it in stock, although all offered to order it.

Xofluza is a single dose oral medication, and like other medicines for flu, needs to be taken quickly after symptoms start. The ideal window, doctors say, is to start it within 48 hours after symptoms begin.

Xofluza is approved for people 12 years old and older, based on results of a study that pitted the drug against a placebo. The study found the median time to symptoms improving was 54 hours on the drug and 80 hours on placebo, Villani says. “Xofluza helps you recover from the symptoms of the flu in just over 2 days,” he says.

Xofluza Availability

In a telephone spot check of major drug chains in Los Angeles, Chicago, New York City, Minneapolis, Atlanta, and Kankakee, Il., only the Minneapolis drug store had it in stock.

Staff at the other stores said they could order it, giving various timelines about how long it would take to get it in.
Old Standbys

Tamiflu has been on the market since 1999. In 2016, a generic version was approved. It comes in pill or liquid form and can be taken by people 14 days old and older.

It is typically taken twice daily for 5 days. (It can also be prescribed to prevent flu; that regimen is once a day for 7 days.) Besides Tamiflu and Xofluza, the FDA has approved zanamivir (Relenza) to treat flu in people 7 years old and older. A powder that is inhaled, it is usually taken twice daily for 5 days.

Another drug, peramivir (Rapivab), is given in a vein by a health care professional. The FDA approved it for people 2 years old and older. The one-time dose usually takes less than 30 minutes to administer.

More on Tamiflu, Xofluza

Advocates of Xofluza mention the convenience of the single dose vs. 5 days’ worth of Tamiflu doses. While the drugs require different doses and work differently, they have the same result, according to William Schaffner, MD, medical director of the National Foundation for Infectious Diseases. Both interfere with the flu virus’ ability to reproduce and multiply, he says.
Facts About the Flu Vaccine

No studies have looked at head-to-head comparisons of Xofluza and Tamiflu, says Villani of Genentech, which also markets Tamiflu.

The CDC does not recommend Xofluza for pregnant women or breastfeeding mothers, and it’s also not recommended for flu prevention or patients in the hospital.

Patients don’t seem to know about the newer drug, says Lisa Dabby, MD, an emergency medicine doctor at the UCLA Medical Center in Santa Monica, CA. “Not one person has asked me to prescribe it,” she says of Xofluza. “People know Tamiflu and they ask for it.”

If someone did request the new drug, she would consider prescribing it, she says, but first would want to be sure local pharmacies are stocking it to save patients frustration in finding it. And she reminds them: “These antivirals are not the be-all, end-alls.” They shorten how long symptoms last, but they don’t make them disappear instantly, she reminds patients.

As for side effects, patients on these antivirals most often complain of diarrhea and nausea, she says. Others report headache and common cold symptoms.

In kids, Tamiflu has been linked with some psychiatric side effects, such as irritability and occasional seizures. Those reports have caused some pediatricians to hesitate to prescribe it, Schaffner says. But those symptoms go away once the drug is stopped.
Tamiflu, Xofluza Costs

On a wholesale level, the cost of Xofluza is about $150 and of Tamiflu about $152, Villani says.

Insurance coverage and copays for these two drugs vary. But those who have commercial insurance that covers Xofluza can use a coupon available on the drug’s website and ”may pay as little as $30,” he says. Those without insurance may reduce their costs for it by about $60, with a net cost of about $90, he says.

The generic version of Tamiflu is sold online, without insurance, for about $50.

More Stats on the Flu Season

Usually, flu activity peaks from December through February, the CDC says, and February has been the most common peak month in the past 36 years.

This year, the circulating viruses are predominantly influenza A (H1N1)pdm09 and H3N2, with influenza B viruses also circulating, the CDC says.

The H1N1 viruses have been most prevalent in the United States, but the influenza A (H3) has been most common in the southeastern U.S., the CDC says.

And some good news: Most of the circulating viruses analyzed are similar to the viruses in this season’s vaccine.

Focusing on Complications, Risks

While patients with the flu are eager to feel better and get back to work or family responsibilities, doctors are focused on more than that, Schaffner says. “The main thing we want to do is prevent the serious complications of influenza.”

These include pneumonia, inflammation of the heart, and organ failure. Those at high risk of flu complications include anyone 65 and older, children younger than 5, pregnant women and women who have delivered a baby within the past 2 weeks, Native Americans, Alaska Natives, and nursing home or long-term care home residents. In addition, anyone with health conditions such as asthma, sickle cell disease, lung or heart disease, diabetes, kidney or liver problems, the very obese (BMI of 40 or more), immune system issues such as HIV, or cancer is at high risk of getting complications.

When his patients come back for a follow-up visit after getting through the flu, griping about time off work or flu misery in general, Schaffner says he often tells them: “I’m glad you are [still] here to complain.”

Things You Should Never Do to Your Skin

The Derm: Heidi Waldorf, M.D., Director of Laser And Cosmetic Dermatology, Mt. Sinai Hospital, New York City

It was Jerry Seinfeld who gave dermatologists the “Pimple Popper M.D.” moniker. The truth is, Mr. Seinfeld, we express, drain, and extract, but, we never, ever pop. The difference lies in the details of semantics and technique. Squeezing a blemish (often with bacteria-laden fingertips), creates a lot of inflammation in the skin, sometimes leaving behind scars and discoloration. If a zit is too big to bear, try to see your dermatologist for an injection of cortisone, or put on a bit of benzoyl peroxide to bring that baby down. Chronic breakouts should be managed with medical regimen tailored specifically to your type of skin and acne.

Pickers, Waldorf and I urge you, find your zen zone. Do not take that anxiety out on the skin (more on this later).

Read More…

Could You Be Eating These Foods Wrong?

Yes, eating healthy means choosing the right foods, but that’s only part of it. For example, the skin of many fruits and veggies (or just under it) is where a lot of the vitamins and minerals are, so when you peel it off, you’re missing out. Find out what you can do to get the most nutritional value out of what you put in your mouth.

Read More…

The Low-Impact Cardio Workout You Need for Lazy Days

Let’s be real for a hot second: Some days, when you start getting ready for the gym, your body (and mind) just isn’t in the mood. It’s those days — when burpees feel 10,000 times harder than they did yesterday — that you need a more chill workout. There’s nothing wrong with doing something low impact. In fact, experts say that it’s crucial to break up those balls-to-the-walls days with more low-key routines to give your body time to recover while still being active. (That said, you can still get your brain in the game. Here’s how.)

That’s where this workout from Ellen Barrett comes in. It’s a cardio-based, fat-burning walking workout, so you can do it pretty much anywhere. And it’s only 20 minutes, so you can even squeeze it in on that lunch break.

Read More…

Scientists design ‘smart’ wound healing technique

New research, published in the journal Advanced Materials, paves the way for “a new generation of materials that actively work with tissues to drive [wound] healing.”

As more and more surgical procedures are performed in the United States, the number of surgical site infections is also on the rise.

Chronic wounds that do not heal — such as those that occur in diabetes — often host a wide range of bacteria in the form of a biofilm.

Such biofilm bacteria are often very resilient to treatment, and antimicrobial resistance only increases the possibility that these wounds become infected.

According to recent estimates, chronic wounds affect approximately 5.7 million people in the U.S. Some chronic wounds can result in amputations, as is the case with diabetic ulcers.

On a global level, researchers approximate that every 30 seconds a chronic, nonhealing diabetic ulcer causes an amputation.

In this context, there is a dire need for innovative, effective wound healing methods. New research shows promise in this regard, as scientists have devised a molecule that helps harness the body’s natural healing powers.

The molecules are called traction force-activated payloads (TrAPs). They are growth factors that help materials such as collagen interact with the body’s tissues more naturally.

Ben Almquist, Ph.D., a lecturer in the department of engineering at Imperial College London in the United Kingdom, led the new research.

TrAP technology and wound healing

Materials such as collagen are often used in wound healing. For instance, collagen sponges can treat burn injuries, and collagen implants can help bones regenerate.

But how does collagen interact with tissue? In so-called scaffold implants, cells move through the collagen structure, pulling the scaffold along with them. This triggers healing proteins, such as growth factors, that help the tissue regenerate.

In the new study, Almquist and the team engineered TrAP molecules to recreate this natural process. The scientists “folded” DNA strands into aptamers, which are three-dimensional shapes that bind to proteins.

Then, they designed a “handle” for cells to grip. They attached cells to one end of the handle and a collagen scaffold to the other end.

Lab tests revealed that the cells dragged the TrAPs along as they moved through the collagen implants. In turn, this activated growth proteins that triggered the healing process within the tissue.

The scientists explain that this technique recreates healing processes that exist throughout the natural world. “Using cell movement to activate healing is found in creatures ranging from sea sponges to humans,” says Almquist.

“Our approach mimics them and actively works with the different varieties of cells that arrive in our damaged tissue over time to promote healing,” he adds.

A ‘new generation’ of healing materials

The research also revealed that tweaking the cellular handle changes the type of cells that can attach and hold on to the TrAPs.

In turn, this enables TrAPs to release personalized regenerative proteins based on the cells that have attached to the handle.

This adaptability to different types of cells means that the technique can be applied to various types of wounds — ranging from bone fractures to scar tissue injuries caused by heart attacks and from nerve damage to diabetic ulcers.

Finally, aptamers are already approved as drugs for human clinical use, which could mean that the TrAP technique may become widely available sooner rather than later.

“The TrAP technology provides a flexible method to create materials that actively communicate with the wound and provide key instructions when and where they are needed,” explains Almquist.

“This sort of intelligent, dynamic healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds,” he adds.

The researcher concludes, “[t]his technology has the potential to serve as a conductor of wound repair, orchestrating different cells over time to work together to heal damaged tissues.”