New clues to sepsis may speed diagnosis

Sepsis is an infection that kills as many Americans each year as stroke and Alzheimer’s combined-about 250,000-but very little has changed in the treatment of this age-old scourge.

Now researchers at Columbia University Irving Medical Center have found a clue in understanding how an infection can spiral into sepsis by blunting the body’s immune response. This research may also help doctors identify the patients who may need immediate intensive treatment to save their lives.

From Infection to Organ Failure

Sepsis can start with a simple infected cut. When the immune system fails to fight off the infection, sepsis occurs when inflammation spreads throughout the body, leaving patients vulnerable to organ damage, severe secondary infections, and death. While time is of the essence, doctors lack quick, efficient ways to diagnose this deadly condition.

“The best treatment for sepsis starts with rapid detection. Our results suggest that specific molecules called microRNAs may be potential biomarkers of poor prognosis, indicating the need for more aggressive treatment options,” explains the study’s senior leader Sankar Ghosh, Ph.D., the Silverstein and Hutt Family Professor of Microbiology & Immunology and chair of the Department of Microbiology & Immunology at Columbia University Vagelos College of Physicians and Surgeons (VP&S).

The immune system initially launches a vigorous attack against sepsis, but then the innate immune response shuts down. In a search to understand the underlying mechanism, Ghosh’s team identified two microRNAs (miR-221 and miR-222) that are produced in immune cells during prolonged inflammation. These microRNAs silence inflammatory gene expression and in a mouse model of sepsis suppress the immune system at a time when the body desperately needs a full immune response.

Identifying Patients in Danger of Sepsis

Patients with suspected sepsis had a similar reaction. Among 30 hospitalized patients, those with evidence of organ failureexhibit higher levels of miR-221 and miR-222 in their blood samples. In septic patients, those with elevated miR-221 and miR-222 also exhibited evidence of immunosuppression.

The two microRNAs could be the basis of a test to help physicians classify patients into those with organ failure who are at high risk of sepsis and death and those patients with milder infections. With faster diagnosis, doctors could start antibiotics and fluids to control the infection more quickly before patients succumb to organ failure and secondary infections.

“When doctors face sepsis in the hospital, it is usually a mystery as to what is causing the infection, but they must act quickly. They can choose to use the broadest spectrum of antibiotics for an aggressive approach to cover every bacterial cause of infection, but this may later cause antibiotic resistance, a growing problem,” says study co-author Daniel Freedberg, MD, assistant professor of medicine at CUIMC. “Any test that can identify the cause of sepsis to guide treatment options is invaluable.”

Clinical trials will be needed to validate the usefulness of testing patients for these microRNAs as a quick guide to prognosis and treatment. The research comes at a time when the number of sepsis cases per year has been on the rise in the United States, according to the National Institutes of Health. Creating better diagnostics may be able to help reverse this trend and save lives.

 Explore further: Putting the brakes on sepsis

More information: John J. Seeley et al. Induction of innate immune memory via microRNA targeting of chromatin remodelling factors, Nature (2018). DOI: 10.1038/s41586-018-0253-5

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New tools for brain mapping should boost research into depression, dementia

Researchers at Florida Institute of Technology have developed the fastest method to date for creating a key molecule used by neuroscientists at Columbia University in mapping brain activity. They also discovered ways to create two new versions of that molecule – a neurotransmitter called glutamate – that can further advance this critical field of study.

This work, funded by the National Institutes of Health, was published in the American Chemical Society journal, ACS Chemical Neuroscience 2018.

“Our molecules to the neuroscientists are as valuable as cameras are to Google Maps,” said Nasri Nesnas, a professor of chemistry at Florida Tech who is the principal investigator and corresponding author of the paper. “We now have the fastest method to make the best cameras.”

Glutamate, or Glu, plays a critical role in brain activities related to emotion, cognition and memory. Therefore, neuroscientists are working to decode the brain to understand neurological disorders including depression and dementia, in part by studying “glutamatergic receptors,” where Glu is the molecule of interest.

The human brain is the most complex organ in the human body and is composed of over 85 billion neurons. Each of these neurons can be linked through up to 10,000 connections, known as synapses. Synaptic connections act like brain “switches” and release small molecules called neurotransmitters that pass along electrical signals.

The UV lamps in this photo reactor will activate the neurotransmitter glutamate, thus enabling it to serve as a powerful tool to map the brain. Credit: Florida Institute of Technology

Glu is the most common neurotransmitter. To aid neuroscientists in mapping the enormously complex brain circuitry, researchers have used light to activate inactive, or “caged,” neurotransmitters in live brain tissue, including glutamate.

The work reported on in ACS Chemical Neuroscience will make the process of making caged Glu more effective, Nesnas said, by cutting the number of steps in half and overall time by 80 percent, while doubling the yields of previous methods.

“There were challenges that many scientists had with making these photo-responsive Glu tools. We have made this process more facile and efficient, and we also made two other variations of these tools that have the potential to perform better since they may not pose the same interference problems that the previous one had with other receptors on neurons,” Nesnas said.

Graduate student Charitha Guruge, the lead author of the paper and one of four Florida Tech Ph.D. students involved in the research – Yannick Ouedraogo, Richard Comitz and Jingxuan Ma are the other collaborators – said he is excited about developing tools that should lead to better understanding of – and thus possible cures for – some of the most perplexing and damaging ailments of our time.

“I find working in this area to be truly rewarding, since there are too many neurological disorders, especially those relating to depression, dementia and bipolar, far from being understood,” he said. “I would like to be able to use chemistry to develop these tools to help the neuroscience community reach answers quickly.”

 Explore further: Remake, refill, reuse: recycling at the synapse revealed

More information: Charitha Guruge et al. Improved Synthesis of Caged Glutamate and Caging Each Functional Group, ACS Chemical Neuroscience (2018). DOI: 10.1021/acschemneuro.8b00152

https://bit.ly/2KM4GJo

Staying safe in the sun — a dermatologist helps separate facts from hype

Skin cancer is the number-one cancer diagnosis in the United States – it’s more common than breast, prostate, and lung cancers combined. Skin cancers can be divided into two types – nonmelanoma (basal and squamous cell carcinomas) and melanoma, with melanoma being the least common but most life-threatening. Each year, some 90,000 people are diagnosed with melanoma. Sarah Arron, MD, Ph.D., shares her thoughts on skin cancer prevention and helps separate the facts from the hype.

Which SPF?

The sun protection factor (SPF) number indicates the time it will take for UVB rays to redden your skin. I tell my patients to choose SPF 30 or higher because most people do not apply sunscreen as directed.

SPF moisturizer?

These are a great idea! It’s important that you like wearing the sunscreen enough to make it a part of your daily routine.

Eyes and lips?

Wear lip balm with SPF 15 and sunglasses with UV blockers in the lenses.

If being in the sun makes me happy, why should I protect myself from it?

Sun exposure can boost mood, and that makes sunshine addictive for some people. We like to rationalize that addiction by saying it must be healthy if it makes us feel or look good. But it’s not.

There is no such thing as a healthy tan, even though the tanning bed industry promotes its products that way. Until we dismiss the idea of a “healthy” tan, we’ll continue to see an epidemic of skin cancer in this country.

Are there other ways to prevent skin cancers?

Seek the shade and avoid outdoor activities during the peak sun hours of 10 a.m. to 2 p.m. Sports enthusiasts can go out in the early morning, take a break, and go out again later in the afternoon.

Carina Woodruff, MD, examines a patient during a free skin cancer screening at UCSF. Credit: Barbara Ries

You can also buy UV protective clothing, including hats (in many styles), swim tights, swim shirts, sleeves for tennis players, and more.

What about my vitamin D levels?

It’s true that one of the ways our skin makes vitamin D is through UV radiation. But there are many other ways to get vitamin D, such as leafy greens, fortified milk, and supplements. Moreover, it’s rare that individuals are so scrupulous about avoiding sun exposure that it causes vitamin D deficiency.

What does broad-spectrum mean?

It means the sunscreen provides protection from both types of damaging ultraviolet (UV) radiation – UVA and UVB. Both contribute to skin aging and skin cancers. UVB is the dominant sunburn and suntanning ray, whether the ultraviolet rays come from the sun or a tanning salon, while UVA penetrates deeper into the skin, causing premature aging and wrinkling. The SPF number measures only UVB protection, so you need to make sure your sunscreen specifies UVA protection as well.

Chemical vs. mineral?

Each has its pros and cons. Mineral sunscreens contain titanium and zinc oxide. People with sensitive skin may have less reaction to a mineral sunscreen. Some of my patients prefer minerals due to concern about chemical safety and a preference for a natural approach. The downside is that these may feel thicker and heavier and can leave a ghost-like sheen on the face. Chemical sunscreens include avobenzone and oxybenzone in their ingredients and are usually formulated to feel lighter and appear more elegant. Neither is more protective than the other.

Do people with dark skin need to wear sunscreen?

Yes. When the sun affects our skin, there are two levels of damage. One is immediate, which we recognize as sunburn and which mostly affects lighter-skinned individuals. Patients with darker skin who don’t get sunburned may think their skin is protected, but there’s a second kind of damage that leads to loss of elasticity and premature aging of skin, as well as DNA mutations in the cells that may ultimately cause skin cancer.

What are the warning signs of cancer?

In general, with skin cancer we’ll see a persistent lesion that is growing and changing in shape and appearance and that bleeds without ever healing. It’s very important that people get to know their own skin and their own spots, so that when new things appear they can point them out to their primary care doctor or dermatologist. I recommend a head-to-toe screening with a dermatologist to establish a baseline for the future.

Which skin-protection websites are trustworthy?

For our organ transplant recipients (who have a 60- to 100-fold higher risk of skin cancer), we produced a downloadable booklet – and the information in it is relevant to all patients: skincancer.ucsf.edu.

https://bit.ly/2lTGAy3

How to start exercising when you’re out of shape

Though you may face challenges if you’re carrying excess weight or haven’t been active in a long time, you can still get fit and gain all the benefits that exercise has to offer.

The easiest way to get started is with walking because it’s low-impact and low-risk, and all you need is a pair of supportive walking or running shoes. Begin by scheduling one dedicated walk each day, and then find opportunities to take additional steps, like going window-shopping at lunch or walking in place instead of sitting while watching TV. You might like the impetus of a home treadmill, which you can set at a slow speed to start.

Another simple way to exercise at home is to get more dynamic with everyday activities. For example, pick up the pace as you do household chores, and work in sessions that are at least 10 minutes long.

You can also dive into exercise by working out in water, whether you swim or take a water fitness class. Water makes you feel lighter and more agile, so many people find it easier to move in a pool than on dry land.

Riding a stationary bike is also less strenuous on your body than weight-bearing exercises, even walking. Try a recumbent bike; its seat is lower to the ground and your legs will be extended, which may feel more comfortable to you.

Just don’t let enthusiasm put you at risk of burnout by doing too much too soon. Increase the length and the intensity of your workouts at a slow, steady pace as you progress.

 Explore further: A 3×10 exercise plan that’ll work for you

More information: The U.S. National Institute of Diabetes and Digestive and Kidney Diseases has tips on how to stay active at any weight, as well as why fitness is so important.

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‘Mind over matter’ key to a healthy lifestyle?

People who want to increase their participation in regular exercise and adopt a healthier lifestyle may be best to mentally visualise it, new research by Curtin University has found.

The research, published in the leading journal Health Psychology, found that ‘mental imagery interventions’, or visualising an activity or task, may be effective in helping people change their behaviours, including moderating alcohol consumption and participating in regular physical activity.

Lead Australian author John Curtin Distinguished Professor Martin Hagger, from the School of Psychology at Curtin University, said the research aimed to explore the link between visualisation and increasing healthy behaviour.

“There are strong links between chronic illnesses like heart disease and diabetes and behaviour, and imagery-based interventions offer an inexpensive, effective way of promoting healthy behaviours such as physical activity and healthy eating,” Professor Hagger said.

“We found that people who simply visualised the steps necessary to do the healthy behaviour on a regular basis were more likely to be motivated, and actually do, the healthy behaviour.”

Mental imagery was also more effective in promoting healthy behaviours when the visualisation lasted longer, when people were reminded to do their imagery by text message, and when the person was given detailed instructions on how to conduct the imagery exercise.

Professor Hagger explained that the research could have important implications for health professionals and the broader community around the world.

“Previous studies have shown that imagery interventions have been used in various contexts including enhancing athletes’ performance, flight simulation training for aircraft pilots and for symptom relief in hospital settings. Our research shows that imagery is also effective for promoting participation in healthy behaviours,” Professor Hagger said.

“Our findings may not only be of interest to health professionals around the world, but could be of interest and potentially implemented within other industries.”

 Explore further: Research finds counting your drinks reduces alcohol consumption

More information: Dominic Conroy et al. Imagery interventions in health behavior: A meta-analysis., Health Psychology(2018). DOI: 10.1037/hea0000625

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Brain study paves way for therapy for common cause of dementia

The authors discovered more proliferating dysfunctional endothelial cells (red arrows) in diseased human brains compared to controls. Credit: R.M. Rajani et al., Science Translational Medicine (2018)

Scientists have uncovered a potential approach to treat one of the commonest causes of dementia and stroke in older people.

Studies with rats found the treatment can reverse changes in blood vessels in the brain associated with the condition, called cerebral small vessel disease.

Treatment also prevents damage to brain cells caused by these blood vessel changes, raising hope that it could offer a therapy for dementia.

Small vessel disease, or SVD, is a major cause of dementia and can also worsen the symptoms of Alzheimer’s disease. It is responsible for almost half of all dementia cases in the UK and is a major cause of stroke, accounting for around one in five cases.

Patients with SVD are diagnosed from brain scans, which detect damage to white matter—a key component of the brain’s wiring.

Until now, it was not known how changes in small blood vessels in the brain associated with SVD can cause damage to brain cells.

A team led by the University of Edinburgh found that SVD occurs when cells that line the small blood vessels in the brain become dysfunctional. This causes them to secrete a molecule into the brain.

The molecule stops production of the protective layer that surrounds brain cells—called myelin—which leads to brain damage.

Treating rats with drugs that stop blood vessel cells from becoming dysfunctional reversed the symptoms of SVD and prevented brain damage, tests found.

Researchers say that further studies will need to test whether the treatment also works when the disease is firmly established. They will also need to check if the treatment can reverse the symptoms of dementia.

Dementia is one of the biggest problems facing society, as people live longer and the population ages. Estimates indicate there are almost 47 million people living with dementia worldwide and the numbers affected are expected to double every 20 years, rising to more than 115 million by 2050.

The research, published in Science Translational Medicine, was carried out at the Medical Research Council Centre for Regenerative Medicine and the UK Dementia Research Institute at the University of Edinburgh. It was funded by the MRC, Alzheimer’s Research UK and Fondation Leducq.

Professor Anna Williams, Group Leader at the University of Edinburgh’s MRC Centre for Regenerative Medicine, said: “This important research helps us understand why small vessel disease happens, providing a direct link between small blood vessels and changes in the brain that are linked to dementia. It also shows that these changes may be reversible, which paves the way for potential treatments.”

Dr. Sara Imarisio, Head of Research at Alzheimer’s Research UK said: “Changes to the blood supply in the brain play an important role in Alzheimer’s disease as well as being a direct cause of vascular dementia. This pioneering research highlights a molecular link between changes to small blood vessels in the brain and damage to the insulating ‘white matter’ that helps nerve cells to send signals around the brain.

“The findings highlight a promising direction for research into treatments that could limit the damaging effects of blood vessel changes and help keep nerve cells functioning for longer. There are currently no drugs that slow down or stop Alzheimer’s disease and no treatments to help people living with vascular dementia. Alzheimer’s Research UK is very pleased to have helped fund this innovative research, which is only possible thanks to the work of our dedicated supporters.”

Dr. Nathan Richardson, the MRC’s Head of Molecular and Cellular Medicine, commented: “This study is a great example of how innovative discovery science into regenerative mechanisms can be applied to improve our understanding of how vascular changes contribute to dementia. This research in rats opens up new possibilities for developing therapies for cerebral small vessel disease.”

 Explore further: Vascular dementia trial of Viagra-type drug nears closing stages

More information: R.M. Rajani el al., “Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats,” Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aam9507

https://bit.ly/2z8KMnl

Abivax Phase 2a HIV med data ‘mixed’

• Paris-based Abivax announced topline results from the second cohort of its Phase 2a study of ABX464 in patients with HIV, with mixed findings.
• Twelve patients were given a dose of 50 mg per day of ABX464 for three months. From the available data at 12 weeks, eight patients had completed the study.
• Four patients showed a reduction in total HIV DNA in peripheral blood CD4+ T cells, ranging from 2% to 85%, while the other four patients experienced an increase in HIV DNA, ranging from 5% to 36%.

The treatment aims to reduce the reservoirs of infected immune cells that can lay dormant in a patient’s blood, brain, gut and lymph nodes even after viral load has been reduced to undetectable levels by other regimens.

In the first cohort of the study, which included nine patients given 150 mg per day of ABX 464 for 28 days, eight patients showed a decrease in HIV DNA in peripheral blood CD4+ T cells up to 52%.

The second cohort was designed to see if a lower dose of the drug could also decrease levels — so far the results are mixed — and to see if the drug could be tolerated for a longer period of time. Abivax did not release any safety data, but said the drug was well-tolerated.

Rectal tissue biopsies were also conducted, with four patients showing a reduction in HIV DNA ranging from 16% to 71%, and four patients showing an increase in HIV DNA from 14% to 123%.

Abivax intends to present the full data at an upcoming medical meeting.

“The study results demonstrate that some HIV-infected patients receiving 50mg of ABX464 had a relevant drop in the HIV DNA reservoir. Further studies will identify the characteristics of the patients most likely to benefit from ABX464 in different dosing regimens, alone or in combination with other HIV cure strategies,” said Ian McGowan, a professor at the University of Pittsburgh School of Medicine and chair of Abivax’s Scientific Advisory Board, in a statement.

Shares of Abivax were up nearly 7% on the news in trading on the Euronext Paris stock exchange.

https://bit.ly/2KwnrkC