Obesity may also impact flu transmission, not just severity of illness

Obesity increases a person’s risk for severe complications from influenza, including hospitalization and even death. It may also play a role in how flu spreads, according to a new study published in The Journal of Infectious Diseases. The findings suggest that obese adults infected with flu shed the virus for a longer time than adults who are not obese, potentially increasing the opportunity for the infection to spread to others.

“This is the first real evidence that obesity might impact more than just disease severity,” said senior study author Aubree Gordon, MPH, PhD, of the University of Michigan School of Public Health. “It might directly impact transmission as well.”

Analyzing data collected from approximately 1,800 people in 320 households in Managua, Nicaragua, researchers investigated the effect of obesity on the duration of viral shedding over three influenza seasons from 2015 to 2017. Obese adults with flu symptoms and laboratory-confirmed influenza shed influenza A virus for 42 percent longer than adults with flu who were not obese. Among obese individuals infected with flu who were only mildly ill or had no symptoms, the difference was even greater: These obese adults shed influenza A virus for 104 percent longer than non-obese adults with flu.

The duration of viral shedding was determined by tests of nose and throat samples, which detected the presence of influenza virus RNA but did not indicate whether the viruses were infectious. Additional research, now underway, will help determine if the flu virus shed for longer periods by obese individuals is indeed infectious and can spread the illness to others, Dr. Gordon said.

In addition, the differences seen in the duration of viral shedding were limited to influenza A viruses, one of two types of flu viruses that can cause epidemics in humans. Researchers found no association with obesity and the duration of shedding of influenza B virus, which typically causes less serious illness in adults and does not cause pandemics. Obesity also did not appear to impact the duration of viral shedding among children included in the study.

Obesity can alter the body’s immune response and lead to chronic inflammation, which increases with age, in addition to making breathing more difficult and increasing the need for oxygen. These factors may help explain how obesity could affect influenza risk, severity, and transmission potential, the study authors noted.

With rates of obesity rising around the world, the new findings, if supported by future studies, suggest that obesity may play an increasingly important role in flu transmission. In a related editorial commentary that appears with the new study in The Journal of Infectious Diseases, Stacey Schultz-Cherry, PhD, of St. Jude Children’s Research Hospital, noted several potential public health implications, including increased opportunities for influenza to spread in some populations.

“It is therefore even more important to develop effective strategies to prevent and control influenza, especially in the overweight and obese population, which could be challenging because of the poor vaccine responses in this population,” wrote Dr. Schultz-Cherry, who was not involved with the study. “With increasing focus on the development of a universal influenza vaccine, improved protection from influenza is on the horizon. The question remains whether these approaches will not only protect this target population, but also reduce viral shedding duration.”

Fast Facts

• Researchers investigated the effect of obesity on length of time individuals infected with influenza shed the virus.
• Obese adults with flu symptoms shed influenza A virus for 42 percent longer than adults with flu who were not obese. Infected obese adults with mild or no symptoms shed the virus 104 percent longer.
• The findings suggest that obesity may play an important role in the transmission of influenza, in addition to obesity’s known impact on flu severity.

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Story Source:

Materials provided by Infectious Diseases Society of America. Note: Content may be edited for style and length.

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Journal Reference:

1. Hannah E Maier, Roger Lopez, Nery Sanchez, Sophia Ng, Lionel Gresh, Sergio Ojeda, Raquel Burger-Calderon, Guillermina Kuan, Eva Harris, Angel Balmaseda, Aubree Gordon. Obesity Increases the Duration of Influenza A Virus Shedding in Adults. The Journal of Infectious Diseases, 2018; DOI: 10.1093/infdis/jiy370

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Regeneron Pharma (REGN) PT Raised to $440 at Oppenheimer on Q2 Report

‘Eylea Static Decreasing, 2H18 Product Launches’. Oppenheimer raised its price target on Regeneron Pharma (NASDAQ: REGN) to $440.00 (from $410.00).

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Medifast ups FY18 EPS view to $4.35-$4.45 from $3.55-$3.65, consensus $3.83

Raises FY18 revenue view to $460M-$470M from $385M-$395M, consensus $411.6M.

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Insulet lowers FY18 revenue view to $547M-$562M from $565M-$580M

Consensus $577.75M.

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Antihypertensive Therapy Reduces Alzheimer’s, Dementia Risk

Antihypertensive therapy to lower elevated blood pressure (BP) decreases the risk for dementia and Alzheimer’s disease (AD) in older adults, and the benefits may be gained by several different drug classes, new research shows.

Debate continues about whether treating elevated BP or using a specific antihypertensive medication in late life will reduce the risk for dementia, said study investigator Jie Ding, PhD, from the National Institute on Aging, Bethesda, Maryland.

The findings were presented here at the Alzheimer’s Association International Conference (AAIC) 2018.

To investigate, the researchers conducted a meta-analysis of individual patient data from six long-term prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study; Atherosclerosis Risk in Communities Study; Framingham Heart Study; Honolulu-Asia Aging Study; Rotterdam Study; and 3-C study.

They assessed associations of different classes of BP-lowering drugs to incident dementia and Alzheimer’s disease in 31,090 dementia-free community-dwelling participants aged 55 years and older with baseline data on BP and use of BP-lowering drugs who were followed for up to 22 years.

They examined five major drug classes: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers, and diuretics.

Within-study Cox proportional hazards analyses were adjusted for propensity scores to control for risk factors. Analyses were stratified by high baseline BP (systolic BP ≥140 mm Hg or diastolic BP ≥ 90 mm Hg) and normal baseline BP irrespective of medication use, and APOE ԑ4 carrier status.

During follow-up, 3728 study participants developed dementia and 1741 developed AD.

In adults with high baseline BP, those using any BP-lowering drug, regardless of drug class, had a reduced risk for developing all-cause dementia (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.79 – 0.98) and Alzheimer’s disease (HR, 0.85; 95% CI, 0.74 – 0.99) compared with those not using BP medication, Ding reported.

HRs for incident dementia were similarly reduced among APOE ԑ4 carriers (HR, 0.77; 95% CI, 0.64 – 0.93), which mainly reflected the associations with ACEIs (HR, 0.75; 95% CI, 0.57 – 0.98), ARBs (HR, 0.65; 95% CI, 0.47 – 0.91), BBs (HR, 0.74; 95% CI, 0.58 – 0.95), and diuretics (HR, 0.75; 95% CI, 0.59 – 0.94).

No significant associations were noted among APOE ԑ4 noncarriers or in participants with normal baseline BP.

Growing Evidence

Keith Fargo, PhD, director of scientific programs and outreach for the Alzheimer’s Association, told Medscape Medical News that this analysis is“interesting, especially comparing it to the SPRINT MIND study,” which was also reported here at AAIC 2018.

As reported by Medscape Medical News, SPRINT MIND showed that aggressive lowering of systolic blood pressure to 120 mm Hg significantly reduces the risk for mild cognitive impairment (MCI).

“What’s nice about this meta-analysis,” said Fargo, “is the size, 31,000 people, and that it looked at dementia and found a statistical difference for those who were treated vs those who were not in terms of the number of people who developed dementia. So this analysis adds to the overall story especially given that SPRINT MIND is a little bit incomplete at this point,” said Fargo.

It’s also interesting, he noted, that this meta-analysis looked not only at dementia but also Alzheimer’s disease specifically and found a benefit of BP lowering. “This is intriguing,” said Fargo, “and suggests that the onset of Alzheimer’s disease may be slowed through treatment of high blood pressure, which I think is good news.”

The study had no commercial funding. The authors have disclosed no relevant financial relationships. 

Alzheimer’s Association International Conference (AAIC) 2018. Abstract 25142. Presented July 24, 2018.

https://wb.md/2O2seaK

Health Insurance Innovations target raised to $62 from $55 at Canaccord

Canaccord analyst Richard Close maintained a Buy rating on Health Insurance Innovations and raised his price target to $62 from $55, saying revenue and adjusted EBITDA growth is likely to accelerate in 2019. Close said he has taken a conservative stance with the firm’s estimates as not to get too far ahead of the company, but overall he is encouraged with the growth opportunity and bias that estimates move higher as 2018 progresses.

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pH imbalance in brain cells may contribute to Alzheimer’s disease

This is an illustration of how pH imbalance inside endosomes may contribute to Alzheimer’s disease.

Credit: Hari Prasad

Johns Hopkins Medicine scientists say they have found new evidence in lab-grown mouse brain cells, called astrocytes, that one root of Alzheimer’s disease may be a simple imbalance in acid-alkaline — or pH — chemistry inside endosomes, the nutrient and chemical cargo shuttles in cells.

Astrocytes work to clear so-called amyloid beta proteins from the spaces between neurons, but decades of evidence has shown that if the clearing process goes awry, amyloid proteins pile up around neurons, leading to the characteristic amyloid plaques and nerve cell degeneration that are the hallmarks of memory-destroying Alzheimer’s disease.

The new study, described online June 26 in Proceedings of the National Academy of Sciences, also reports that the scientists gave drugs called histone deacetylase (HDAC) inhibitors to pH-imbalanced mice cells engineered with a common Alzheimer’s gene variant. The experiment successfully reversed the pH problem and improved the capacity for amyloid beta clearance.

HDAC inhibitors are approved by the U.S. Food and Drug Administration for use in people with certain types of blood cancers, but not in people with Alzheimer’s. They cautioned that most HDAC inhibitors cannot cross the blood-brain barrier, a significant challenge to the direct use of the drugs for brain disorders. The scientists say they are planning additional experiments to see if HDAC inhibitors have a similar effect in lab-grown astrocytes from Alzheimer’s patients, and that there is the potential to design HDAC inhibitors that can cross the barrier.

However, the scientists caution that even before those experiments can happen, far more research is needed to verify and explain the precise relationship between amyloid proteins and Alzheimer’s disease, which affects an estimated 50 million people worldwide. To date, there is no cure and no drugs that can predictably or demonstrably prevent or reverse Alzheimer’s disease symptoms.

“By the time Alzheimer’s disease is diagnosed, most of the neurological damage is done, and it’s likely too late to reverse the disease’s progression,” says Rajini Rao, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. “That’s why we need to focus on the earliest pathological symptoms or markers of Alzheimer’s disease, and we know that the biology and chemistry of endosomes is an important factor long before cognitive decline sets in.”

Nearly 20 years ago, scientists at Johns Hopkins and New York University discovered that endosomes, circular compartments that ferry cargo within cells, are larger and far more abundant in brain cells of people destined to develop Alzheimer’s disease. This hinted at an underlying problem with endosomes that could lead to an accumulation of amyloid protein in spaces around neurons, says Rao.

To shuttle their cargo from place to place, endosomes use chaperones — proteins that bind to specific cargo and bring them back and forth from the cell’s surface. Whether and how well this binding occurs depends on the proper pH level inside the endosome, a delicate balance of acidity and alkalinity, or acid and base, that makes endosomes float to the surface and slip back down into the cell.

Embedded in the endosome membrane are proteins that shuttle charged hydrogen atoms, known as protons, in and out of endosomes. The amount of protons inside the endosome determines its pH.

When fluids in the endosome become too acidic, the cargo is trapped within the endosome deep inside the cell. When the endosome contents are more alkaline, the cargo lingers at the cell’s surface for too long.

To help determine whether such pH imbalances occur in Alzheimer’s disease, Johns Hopkins graduate student Hari Prasad scoured scientific studies of Alzheimer’s disease looking for genes that were dialed down in diseased brains compared with normal ones. Comparing a dataset of 15 brains of Alzheimer’s disease patients with 12 normal ones, he found that 10 of the 100 most frequently down-regulated genes were related to the proton flow in the cell.

In another set of brain tissue samples from 96 people with Alzheimer’s disease and 82 without it, gene expression of the proton shuttle in endosomes, known as NHE6, was approximately 50 percent lower in people with Alzheimer’s disease compared with those with normal brains. In cells grown from people with Alzheimer’s disease and in mouse astrocytes engineered to carry a human Alzheimer’s disease gene variant, the amount of NHE6 was about half the amount found in normal cells.

To measure the pH balance within endosomes without breaking open the astrocyte, Prasad and Rao used pH sensitive probes that are absorbed by endosomes and emit light based on pH levels. They found that mouse cell lines containing the Alzheimer’s disease gene variant had more acidic endosomes (average of 5.37 pH) than cell lines without the gene variant (average of 6.21 pH).

“Without properly functioning NHE6, endosomes become too acidic and linger inside astrocytes, avoiding their duties to clear amyloid beta proteins,” says Rao.

While it’s likely that changes in NHE6 happen over time in people who develop sporadic Alzheimer’s disease, people who have inherited mutations in NHE6 develop what’s known as Christianson syndrome in infancy and have rapid brain degeneration.

Prasad and Rao also found that a protein called LRP1, which picks up amyloid beta proteins outside the astrocyte and delivers them to endosomes, was half as abundant on the surface of lab grown mouse astrocytes engineered with a human gene variant called APOE4, commonly linked to Alzheimer’s disease.

Looking for ways to restore the function of NHE6, Prasad searched databases of yeast studies to find that HDAC inhibitors tend to increase expression of the NHE6 gene in yeast. This gene is very similar across species, including flies, mice and humans.

Prasad and Rao tested nine types of HDAC inhibitors on cell cultures of mouse astrocytes engineered with the APOE4 gene variant. Broad-spectrum HDAC inhibitors increased NHE6 expression to levels associated with mouse astrocytes that did not have the Alzheimer’s gene variant. They also found that HDAC inhibitors corrected the pH imbalance inside endosomes and restored LRP1 to the astrocyte surface, resulting in efficient clearance of amyloid beta protein.

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Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Hari Prasad, Rajini Rao. Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH. Proceedings of the National Academy of Sciences, 2018; 115 (28): E6640 DOI: 10.1073/pnas.1801612115

https://bit.ly/2vvKFNw