Alzheimer’s gene risk triggers blood-brain barrier damage

Scientists have known for some time that the APOE4 gene is a risk factor for Alzheimer’s disease. A new study helps to explain why, by showing that the variant has an association with damage to the blood-brain barrier.

APOE4 is the leading genetic risk factor for Alzheimer’s disease. Almost one-quarter of people have one copy of the gene, which increases the risk of developing Alzheimer’s disease by up to four times.

In rarer cases, approximately 2–3% of the population, people carry two copies of the gene, which increases the risk of developing the disease by up to 15 times.

People who carry the variant, whether they have one copy or both, also develop the disease earlier than those who do not.

Although APOE4 is clearly important in the onset of many cases of Alzheimer’s disease, precisely how the genetic variant increases risk has been unclear.

Scientists from the University of Southern California (USC) have now shown a link between APOE4 and damage to the blood-brain barrier, the key structure that protects the brain from toxic substances.

The findings, which could aid the development of personalized treatment strategies for Alzheimer’s disease, appear in Nature.

APOE4 and the blood-brain barrier
This latest study focused on the blood-brain barrier, the protective border of cells separating the blood from the brain. Previous research from the group had shown that people who develop problems with their memory early on also had damage to this structure.

Their research has also shown that people with the APOE4 variant who go on to develop Alzheimer’s disease have a leaky blood-brain barrier, even before doctors can see any changes to cognition.

To investigate the connection between APOE4 and the blood-brain barrier in more detail, the team behind this study used a specialized form of MRI. They looked at the blood-brain barrier of people with mild cognitive impairment — which can be a precursor to Alzheimer’s disease — and those with normal cognitive function, both with and without APOE4.

They found that people who carried the APOE4 variant had a leaky blood-brain barrier in parts of the brain that are critical for memory function, including the hippocampus, even if they were cognitively healthy at the time of the scan.

Those who were experiencing cognitive decline had even worse damage to their blood-brain barrier.

Changes link with cognitive decline
To understand what was causing the leakage in the blood-brain barrier, the researchers looked for damage to a particular cell type — the pericytes — which wrap around blood vessels in the brain to form the critical barrier.

Using a biomarker of pericyte injury, they found higher levels of damage in APOE4 carriers. What is more, the researchers associated levels of the biomarker with both blood-brain barrier damage and cognitive decline.

“Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers,” explains senior author Prof. Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at USC.

Further experiments showed that the damage also correlated with levels of a protein that causes inflammation called cyclophilin A, which is known to be an early sign of Alzheimer’s disease.

Thus, the team was able to put together a hypothesis for how APOE4 causes damage to the blood-brain barrier, potentially leading to the onset of Alzheimer’s disease.

“APOE4 seems to speed up the breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury,” says Prof. Zlokovic.

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Treating the damage
Some parts of the theory need fleshing out, for example, how damage to the blood-brain barrier causes the symptoms of Alzheimer’s disease. Nevertheless, these findings are a step forward in our understanding of how APOE4 shapes Alzheimer’s disease risk.

Future work will be necessary to better understand the genetic risk factors for the disease and, potentially, developing personalized treatments.

Experiments in mice have already shown that blocking the inflammatory process that APOE4 triggers can restore the blood-brain barrier and improve neuronal function, raising hope that doctors could use similar treatments for Alzheimer’s.

First 72 Hours After Acute Kidney Injury Matter

Acute kidney injury (AKI) — even when it resolved quickly — was tied to poorer long-term renal outcomes in a prospective cohort study.
People who experienced non-resolving AKI saw more than a two-fold higher risk for a major adverse kidney event (MAKE) compared with those who didn’t have AKI (adjusted hazard ratio 2.30, 95% CI 1.52-3.48, P<0.001), reported Pavan Bhatraju, MD, MSc, of the University of Washington in Seattle, and colleagues. Even those whose kidney function resolved within 72 hours after a diagnosis of AKI also had a 52% higher risk for a long-term MAKE compared with those with AKI (aHR 1.52, 95% CI 1.01-2.29, P=0.04), according to the study online in JAMA Network Open. However, when the researchers compared cases of AKI, those whose AKI did not resolve saw a significantly higher rate of a MAKE -- a composite of progressive kidney disease, need for long-term dialysis, or all-cause mortality (aHR 1.51, 95% CI 1.22-1.88, P<0.001) compared with those whose AKI resolved. These associations were adjusted for demographic factors like age, sex, and race, as well as for clinical factors including diabetes status, chronic kidney disease status, cardiovascular disease, and sepsis. The associations were also still significant after the group controlled for the magnitude of increased serum creatinine concentrations -- or the AKI stage -- in those who recovered from their AKI. Nearly three-quarters of those with AKI had injury classified as stage 1. "The use of AKI recovery subgroups to risk stratify patients with AKI we believe is clinically intuitive," Bhatraju's group wrote. The observational study included 1,538 hospital patients: half of whom did not experience AKI, 31% of whom had resolving AKI, and 19% who had non-resolving AKI within 3 months of admission. AKI was defined according to standard diagnostic criteria: an increase in serum creatinine concentration of 50% or more or 0.3 mg/dL or more above an outpatient, non-emergency department baseline value within 7 to 365 days prior to the initial hospital admission. AKI that resolved was considered to be a decrease in serum creatinine concentration of 0.3 mg/dL or more or at least 25% from maximum within the initial 72 hours following an AKI diagnosis. During median follow-up of 4.7 years, 36% of the entire cohort had a MAKE. "[These findings] provide evidence for considering the timing of functional recovery from AKI as a factor associated with future adverse events," Ravindra Mehta, MBBS, MD, DM, of the University of California San Diego, said in an accompanying commentary. He also noted that while these findings highlight the value of using AKI recovery pattern to predict long-term kidney outcomes, the study simultaneously underscores how current AKI staging criteria was not helpful in predicting these outcomes "as the severity stage by itself did not differentiate among which patients would develop MAKE." "It is ... clear that clinicians managing patients with AKI should consider the severity of the disease and the ensuing course and tailor their diagnostic and therapeutic interventions to facilitate rapid and complete recovery of kidney function," he concluded.

Shop Smart for Groceries for Diabetes

The grocery store looks different when you have type 2 diabetes. Aisles of menu ideas and possibilities become well-lit lanes of decisions and pitfalls. Instead of, “What’s for dinner?” you wonder, “What will this do to my blood sugar?”

“Before my diagnosis, I went to the store and bought everything on my list and anything that caught my fancy,” says Linda Leitaker, a retired elected city clerk in Lake Almanor, CA. “What I thought I knew about nutrition was woefully inadequate. I had to read, research, and repeat.”

But if you manage your food, it’s a powerful way to control your type 2 diabetes. You don’t need to follow a special diet. Just eat the way it’s recommended for most people. Studies show that healthy, balanced meals are one of the best ways to control your blood sugar and manage your diabetes.

Picture Your Plate

There’s no magic list of foods you can and can’t eat with diabetes.

“You can really eat anything,” says Shamera Robinson, MPH, a registered dietitian and associate director of nutrition for the American Diabetes Association. “Your favorite foods can be part of an individualized eating plan. The best way to go about eating is by finding a balance of nutrients that work for you.”

One way to do that is with the Diabetes Plate Method. Imagine a 9-inch plate split evenly in two. Fill one side with non-starchy vegetables like asparagus, Brussels sprouts, broccoli, cauliflower, greens, squash, or tomatoes.

Split the other half into quarters horizontally. Fill one quarter with carbs, like brown rice, tortillas, beans, fruit, milk, or yogurt. Fill the last quarter with protein, such as eggs, tofu, and lean meats like chicken and fish.

“Carbs will always digest the fastest, then protein, then fat. When you eat all three together, you feel full and don’t crave as much between meals,” Says Lori Zanini, an author, nutritionist, and dietitian in Los Angeles.

Read more…

Ankle Injuries: Causes and Treatments

Ankle injuries are often thought of as sports injuries. But you don’t have to be an athlete or even a “weekend warrior” to turn your ankle and hurt it. Something as simple as walking on an uneven surface can cause a painful, debilitating sprain.

Ankle injuries can happen to anyone at any age. However, men between 15 and 24 years old have higher rates of ankle sprain, compared to women older than age 30 who have higher rates than men. Half of all ankle sprains occur during an athletic activity. Every day in the U.S., 25,000 people sprain their ankle. And more than 1 million people visit emergency rooms each year because of ankle injuries. The most common ankle injuries are sprains and fractures, which involve ligaments and bones in the ankle. But you can also tear or strain a tendon.

What Kinds of Ankle Injuries Are There?

Sprains, Strains, and Fractures

Ankle injuries are defined by the kind of tissue — bone, ligament, or tendon — that’s damaged. The ankle is where three bones meet — the tibia and fibula of your lower leg with the talus of your foot. These bones are held together at the ankle joint by ligaments, which are strong elastic bands of connective tissue that keep the bones in place while allowing normal ankle motion. Tendons attach muscles to the bones to do the work of making the ankle and foot move, and help keep the joints stable.

A fracture describes a break in one or more of the bones. A sprain is the term that describes damage to ligaments when they are stretched beyond their normal range of motion. A ligament sprain can range from many microscopic tears in the fibers that comprise the ligament to a complete tear or rupture. A strain refers to damage to muscles and tendons as a result of being pulled or stretched too far.

Muscle and tendon strains are more common in the legs and lower back. In the ankle, there are two tendons that are often strained. These are the peroneal tendons, and they stabilize and protect the ankle. They can become inflamed as a result of overuse or trauma. Acute tendon tears result from a sudden trauma or force. The inflammation of a tendon is called tendinitis. Microscopic tendon tears that accumulate over time, because of being repeatedly over stretched, and don’t heal properly lead to a condition called tendinosis. Tendons can also rupture. Subluxation refers to a tendon that slips out of place.

Read more…

Tick-borne encephalitis

The size of the problem

Encephalitis is an acute inflammation of the brain, which can cause serious illness and death. The prevalence of encephalitis has proven difficult to ascertain, due to diagnostic and coding challenges, but recent estimates suggest 5.23 cases per 100,000 population per year. Viral causes predominate, with herpes simplex being the commonest aetiology. However, in up to 60% of all cases of encephalitis in the UK, there is no specific cause delineated.

Tick-borne encephalitis (TBE)

The tick-borne encephalitis virus is an RNA flavivirus, which can cause a potentially fatal and untreatable neurological infection across Europe and Asia. The diagnosis of TBE in this area has increased by over 400% since the 1970s. It is thought that some of this increase is as a result of increased vigilance and suspicion of the disease, but also as result of an increase in the tick population and in changing patterns of human behaviour, resulting in greater exposure to ticks. These behaviours include hiking and fishing in affected areas.

A rising prevalence

The question which inevitably arises from this increased prevalence is ‘why has the tick population risen?’

The answer appears to be one comprising elements of changes in land use, increased transportation of animals, and increased co-feeding by nymphs and larvae on the same rodent host. The extent to which this co-feeding occurs depends upon the patterns of seasonal host activity, which is influenced by ambient environmental temperature.

Influence of global warming

The apparent increase in incidence of TBE over the last five decades has therefore been attributed to climate change, which affects both tick and host rodent and other mammalian population dynamics.

New evidence of zoonotic pool of disease

Recent evidence of an increase in the potential TBE viral pool in the UK has emerged in the Thetford Forest area. In summer 2019, a single case of TBE was acquired in the New Forest area. As a result, a study was undertaken by Public Health England and the Emerging and Zoonotic Infections National Institute for Health Research, University of Liverpool to look at the prevalence of tick-borne encephalitis virus in the likely host organisms in this area.

Their results included a finding that almost 48% of deer in the Thetford Forest area were seropositive for TBE virus. They concluded that “this detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis”.

What could happen next?

Although most TBE infections in the UK are imported, the finding of a high incidence of TBE seropositivity in deer and a case of UK acquired TBE is cause for concern. A similar pattern of disease expansion occurred in South Korea some years ago with the consequence of increasing TBE prevalence and the fact that it is now a notifiable disease.

With the further advance of global warming it is therefore possible that tick-borne encephalitis could become a more common pathogen in the UK and should be considered by clinicians in areas of risk.

How Well Are You Aging? A Blood Test Might Tell

Imagine a blood test that could spot whether you are aging too quickly.

New research suggests it’s not the stuff of science fiction anymore.

The scientists analyzed plasma — the cell-free, fluid part of blood — from more than 4,200 people between the ages of 18 and 95, and found a link between 373 proteins and aging.

“We’ve known for a long time that measuring certain proteins in the blood can give you information about a person’s health status — lipoproteins for cardiovascular health, for example,” said study senior author Tony Wyss-Coray. He’s co-director of the Alzheimer’s Disease Research Center at Stanford University in California.

“But it hasn’t been appreciated that so many different proteins’ levels — roughly a third of all the ones we looked at — change markedly with advancing age,” he added in a university news release.

The study was published Dec. 5 in the journal Nature Medicine.

“Proteins are the workhorses of the body’s constituent cells, and when their relative levels undergo substantial changes, it means you’ve changed, too,” Wyss-Coray explained. “Looking at thousands of them in plasma gives you a snapshot of what’s going on throughout the body.”

The findings suggest that physical aging doesn’t occur at a steady pace, but is uneven and has three distinct surges — ages 34, 60 and 78.

At those ages, there are spikes in levels of specific proteins in the blood with noticeable changes, according to the researchers.

Eventually, a blood test for these proteins might be able to identify people who are aging more rapidly than normal and at increased risk for age-related conditions such as Alzheimer’s disease or heart disease.

Such a test might also help identify drugs or other factors that slow or speed aging, the study authors said.

However, any clinical use of such a blood test is at least five to 10 years away, the researchers noted.

“Ideally, you’d want to know how virtually anything you took or did affects your physiological age,” Wyss-Coray said.

Gastric Bypass Surgery

Gastric bypass surgery shrinks the size of your stomach, so you can’t eat as much as you used to. The surgeon will also re-route, or bypass, part of your digestive system so you don’t absorb as much food.

There are several types of gastric bypass surgery:

Roux-en-Y gastric bypass: This is the most common gastric bypass surgery done in the U.S. Surgeons can do it through a small cut, which has a quicker recovery time than more complicated surgery. First, the surgeon makes a small stomach pouch by stapling part of the stomach together or by vertical banding. This limits how much food you can eat.

Next, the surgeon attaches a Y-shaped section of the small intestine to the pouch. That creates a bypass for food, so it skips part of your digestive system. As a result, you absorb fewer calories and nutrients.

Extensive gastric bypass (biliopancreatic diversion):

This is a more complicated type of gastric bypass. The surgeon removes the lower part of the stomach. He then connects the small pouch that remains directly to the last part of the small intestine, completely bypassing the first two parts. It works for weight loss, but it’s not widely used because it has a high complication rate and can leave you short on nutrients.

Risks of Gastric Bypass Surgery

People who have gastric bypass surgery are at risk for:

Pouch stretching. The stomach gets bigger over time, stretching back to its original size.

Breakdown of staple lines. The staples fall apart.

Nutritional, vitamin, and mineral deficiencies. Your body will be less able to get nutrients from food.

Stomal stenosis. A narrowing forms at the connection of the stomach and small intestine causing nausea, vomiting, reflux, and then an inability to eat. This will need to be dilated.

Gastric bypass surgery also may cause “dumping syndrome.” When that happens, food moves too quickly from the stomach to the small intestine. Symptoms include nausea, weakness, sweating, fainting, and, occasionally, diarrhea after eating, as well as becoming extremely weak after eating sweets.

You can get gallstones when you lose weight quickly. If that happens, your doctor can give you medicine to dissolve them.

Because these surgeries change how your body handles food, you should talk with your doctor about making sure you get all the nutrients you need.

Contraception must not be ignored in climate change debates

Wider distribution of contraceptives through investment in family planning programmes would have a profound effect on the climate and the environment, as well as on human welfare, experts have argued. They said population growth is fuelling greenhouse gas emissions and the environmental crisis and almost half of pregnancies globally are unintended, yet the climate debate has so far largely ignored the importance of improving access to effective contraception.

In their commentary* in today’s BMJ Sexual & Reproductive Health, Dr John Bongaarts and Dr Regine Sitruk-Ware of the Population Council in New York point out that contentious ongoing policy debate about potential interventions against global climate change focuses on switching to renewable energy sources and increasing energy use efficiency, but they say we must prioritise other approaches to limit greenhouse gas emissions given the urgency of the problem and the lack of political will. They recommend improving global access to effective contraception as one such policy, because: population growth is a key driver of climate change; higher and more effective use of contraception reduces unplanned pregnancies and hence population growth; and many more women and men would freely choose to use contraception if only it were available and acceptable.

They cite research that has found that women who want to avoid pregnancy might still not use contraceptives for a mixture of social, economic, health and service-related reasons. These include lack of access and high cost for women in poor areas, as well as myths about hormones, traditional social norms (particularly in traditional and/or patriarchal societies) and disapproval of husbands, noting: “Fear of side effects and dissatisfaction with available methods are often the dominant reasons women are reluctant to use (or continue to use) contraception.”

They call for culturally sensitive media campaigns developed in collaboration with community leaders, investment in men’s and women’s education and careful counselling, to change norms around women’s roles in society and expectations around their ability to exercise their reproductive preferences, and to address concerns and incorrect rumours about contraceptive methods and side effects. They add: “Access to a wide range of options is essential to maximise the chances that clients’ needs and concerns are satisfied at different times of their reproductive lives.”

They discuss methods still under development for both male and female contraception, noting that these will offer more choices to women and men, thus reducing unplanned births and abortions – but insisted we need not and must not wait for these innovations.

They conclude: “Wider distribution of contraceptives already on the market through greater investment in voluntary but underfunded family planning programmes is sufficient to raise contraceptive use substantially. This in turn would have a profound positive impact on human welfare, the climate and the environment.”

Patients, doctors may not share priorities for chronic diseases

Carolyn Crist

Patients and doctors often have different views about which chronic health conditions are their top priorities, suggests a study in France.

After separate surveys of patients and their physicians, researchers found that priorities matched up for some conditions, such as diabetes and hypothyroidism, but diverged on others, like anxiety and sleeping disorders.

“An increasing number of patients live with multiple chronic conditions, especially among younger cohorts,” said Dr. Stephanie Sidorkiewicz, a general practitioner in Paris and a researcher at Paris Descartes University, who led the study.

“Against this backdrop, physicians increasingly have difficulties understanding patient expectations and responding appropriately to their individual situations, especially given they at the same time face increased pressure on their time,” she told Reuters Health by email. “However, understanding patients’ perspectives is necessary to set realistic and shared treatment goals.”

As reported online September 9 in Annals of Family Medicine, Sidorkiewicz and colleagues surveyed 233 patients from 16 general practices in Paris in 2017. All patients had been seeing their doctor for at least a year. Patients and doctors checked off all of the patient’s current chronic conditions based on a list of 124 conditions and ranked the three top-priority conditions.

About 8 in 10 patients reported two or more chronic health conditions. The three most common were high blood pressure, osteoarthritis and chronic anxiety disorder.

Agreement between doctors and patients on the number of conditions a patient had was moderate, but agreement on specific chronic conditions ranged from poor to very good.

Among 153 patient-doctor pairs where each made a priority list, about 88% had at least one matching priority. However, 29% of patients’ first priorities didn’t appear anywhere on their doctors’ lists. In addition, 19 pairs, or about 12%, had no matching priorities.

Doctors and patients agreed the most on high blood pressure, hypothyroidism and diabetes, potentially because these have more concrete measurements and guidelines, the study team notes. They also agreed somewhat on asthma, obesity, osteoarthritis and eczema. However, patients tended to rate their chronic anxiety, sleeping and low-back pain conditions as higher priorities, likely due to the impact on their daily lives.
“We were somewhat expecting to find some discrepancies between patients’ and physicians’ priorities, but the extent of these discrepancies was much more severe than we had expected,” Sidorkiewicz said. “Patients and doctors even disagreed on the presence of certain diseases in patients.”

The results align with similar studies in other countries, including Switzerland, where doctors are unaware of patients’ priorities for about 1 in 4 patients, said Dr. Stefan Neuner-Jehle of the University of Zurich, who wasn’t involved in the current study.

“The patient has a role in this procedure as well, in terms of actively thinking about priorities of care before the encounter and openly talking during the encounter,” he told Reuters Health by email. “Standardized patient-centered approaches and tools may be helpful for both physicians and patients.”

Examples of such tools that are available online include the Mayo Clinic’s ICAN Discussion Aid ( and Patient Revolution’s Plan Your Conversation Cards (

“Clinicians have expertise in the guidelines, evidence and healthcare knowledge, and patients have expertise in their lived experience. We need both,” said Kasey Boehmer of the Mayo Clinic’s Knowledge and Evaluation Research Unit in Rochester, Minnesota, who also wasn’t involved in the study.

These two-way conversations can help especially with chronic conditions that are difficult to diagnose and treat and don’t fit under a traditional medical paradigm, such as chronic low back pain, fibromyalgia and autoimmune diseases, she said.
“That background knowledge that we may or may not be on the same page is helpful,” she told Reuters Health by phone. “Give yourself permission to share those experiences in your life and how your health and your healthcare is intertwined with your life.”

Omega-3 supplements ‘no benefit’ to type 2 diabetics

Mark Gould

Thursday, 22 August 2019

People with type 2 diabetes “should not be encouraged” to take omega-3 fish oil supplements, researchers from the University of East Anglia say.

Writing in the BMJ* the authors say they carried out the most extensive systematic review of trials to date to assess effects of polyunsaturated fats on newly diagnosed diabetes and glucose metabolism, including previously unpublished data. They reviewed 83 studies and found no evidence of that supplements were either harmful or beneficial.

They found that long chain omega-3 had little or no effect on likelihood of diagnosis of diabetes or measures of glucose metabolism such as HbA1c, plasma glucose or fasting insulin, or homoeostatic model assessment for insulin resistance.

Dr Lee Hooper, who led the research, told the BBC there had been concerns omega-3 supplements might make glucose control more difficult. However, people with diabetes or who are at risk of developing it, can also have high levels of triglycerides – a type of blood fat – which omega-3 has been shown to reduce.

She said: “We found neither harm nor benefit.”

She described fish oil supplements as “really expensive stuff”.

“If somebody’s at risk of diabetes, there are much better things to spend money on, like a physical activity – or oily fish,” she added.

Douglas Twenefour, deputy head of care at Diabetes UK, said: “Eating a healthy, varied diet is incredibly important, and we know that certain foods – including fruits, vegetables, wholegrains, yoghurt and cheese – can help to lower your risk of type 2 diabetes.

“While omega-3 fatty acids are crucial for our overall health, it’s generally better for people with type 2 diabetes to get their intake by eating at least two portions of oily fish a week, than by taking supplements.”

But Dr Carrie Ruxton, from the industry-funded Health and Food Supplements Information Service, said: “While I would prefer people to follow the government’s advice and eat more fish, this isn’t the reality and a daily omega-3 supplement – whether from fish oil or algae – can bridge the gap.”