A look at the latest research

BPA’S IMPACTS on Brain and Behavior

Bisphenol A (BPA), the oft-criticized chemical found in many plastic consumer items, has been linked to brain and behavior alterations, including increased hyperactivity and stress, according to a recent rodent study, with the results published in Endocrinology.

Researchers led by Heather B. Patisaul, PhD, of North Carolina State University in Raleigh, pointed out that there have already been links between prenatal BPA exposure and altered aff ective behaviors in children based on epidemiological data, “but the mechanisms are unclear.” In order to determine these mechanisms, the scientists studied prairie voles, “a novel animal model for neuroendocrine toxicology,” since the prairie vole is more “prosocial than lab rats or mice.” “It’s compelling to see them in a species that shares many social characteristics with humans,” Patisaul says.

Patisaul and her team exposed male and female prairie vole pups orally to 5 ug/kg bw/day, 50 ug/kg bw/day, or 50 mg/kg bw/day BPA or vehicle over postnatal days (PNDs) 8-14. Th e subjects were then tested as juveniles in “open fi eld and novel social tests and for partner preference as adults.” Afterward, their brains were collected and assessed for immunoreactive (-ir) tyrosine hydroxylase (TH; a dopamine marker) neurons in the principal nucleus of the bed nucleus of the stria terminalis (pBNST) and TH-ir, OT-ir, and AVP-ir neurons in the paraventricular nucleus (PVN) of the hypothalamus.

The authors wrote, “Female open field activity indicated hyperactivity at the lowest dose and anxiety at the highest dose. Eff ects on social interactions were also observed, and partner preference formation was inhibited at all dose levels. BPA masculinized pBNST TH-ir neuron numbers in females. Additionally, 50 mg/kg bw BPA exposed females had more AVP-ir neurons in the anterior PVN and fewer OT-ir neurons in the posterior PVN.” Even at the lowest doses of BPA, the chemical eliminated sex diff erences in the PVN TH-ir neuron numbers, and sex reversed it at the highest dose. However, “minimal behavioral eff ects were observed in BPA-exposed males.”

The authors concluded that exposure to BPA altered the social behavior of the prairie voles, as well as the associated limbic system, especially in the females. The behavioral changes were accompanied by altered OT- and AVP-ir cell numbers in subregions of the PVN, and TH-ir cell numbers in the pBNST. They wrote, “These data support the hypothesis that BPA alters affective behaviors, potentially via disruption of OT/AVP pathways.”

VITAMIN D Shows Promise in ICU Patients

Researchers in Austria have determined that vitamin D may have eff ects on critically ill patients, according to a study recently published in the Journal of the American Medical Association.

The scientists, led by Karin Amrein, MD, MSc, of the Medical University of Graz, noted that vitamin D status has historically been linked to increased mortality and morbidity in patients who are critically ill but while that association is clear, a causal association has never been proven.

Amrein and colleagues conducted the VITdAL-ICU trial, a randomized double-blind, placebo-controlled, single-center trial from May 2010 through September 2012 at five ICUs that included a medical and surgical population of 475 critically ill adult white patients with vitamin D defi ciency (≤20 ng/mL) who received either vitamin D3 (n = 237) or a placebo (n = 238). Vitamin D3 or a placebo was given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for five months.

The primary outcome was the length of stay at the hospital, while length of ICU stay, the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day seven, hospital mortality, and six-month mortality were also measured. Neither the primary outcome nor the secondary outcomes were statistically significantly different for either group. In the predefined subgroup of patients with severe vitamin D deficiency (≤12 ng/mL; n=200 or 42% of the total population), hospital mortality was significantly lower with 28.6% for vitamin D3 compared with 46.1% in the placebo group.

“Although the primary endpoint, length of hospital stay, was negative,” Amrein says, “this is the first study that shows a significant hospital survival benefit in severely vitamin D deficient ICU patients (absolute difference 17.5%, number needed to treat six). As evident in the Kaplan Meier curves, a numerical difference became apparent at two weeks after study inclusion. This may be highly relevant also to other, less severely ill patients, but the high event rate in this patient population possibly enabled us to generate the hypothesis that vitamin D3 indeed is crucial for survival in severe acute illness. If future studies confirm the benefit of vitamin D treatment for hospital survival in ICU patients, this would be spectacular as vitamin D has few side effects and is inexpensive. Currently, however, only small doses (up to 200 IU daily) of vitamin D are given in the ICU. There are also not too many interventions that have ever reduced hospital mortality in critically ill patients. Until we have further data, it may be worthwhile testing for vitamin D deficiency in severely ill patients and consider giving the currently by the Endocrine Society recommended doses of 1500 to 2000 IU of cholecalciferol per day to this vulnerable patient group. If future studies confirm the benefit of vitamin D treatment for hospital survival in ICU patients, this would be spectacular as vitamin D has few side effects and is inexpensive. Currently, however, only small doses (up to 200 IU daily) of vitamin D are given in the ICU. It may be worthwhile testing for vitamin D deficiency in severely ill patients and consider giving the currently by the Endocrine Society recommended doses of 1500 to 2000 IU of cholecalciferol per day to this vulnerable patient group.”

Metabolic Determinants of T2D Non-Remission Status after Bariatric Surgery

Research recently published in Diabetes, Obesity and Metabolism may provide insights into why some patients achieve diabetes remission after bariatric surgery while others don’t.

Sangeeta R. Kashyap, MD, of the Cleveland Clinic, and her team noticed that while bariatric surgery “can produce complete and persistent type 2 diabetes remission,” around 30% – 70% of patients do not achieve remission, “despite marked weight loss.”

The team analyzed in total 40 adults [mean body mass index 36 ± 3 kg/m2 , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] enrolled in the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. They defined T2D remission as “HbA1c <6.5% and fasting glucose <126mg/dl (i.e. <7mmol/l) without antidiabetic medication.” They then studied a number of factors in the participants: “Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed.” Kashyap and colleagues looked at the 37 patients who had complete follow-up data after 24 months and found that bariatric surgery induced T2D remission rates at 40% and 27% at 12 and 24 months, respectively. The thing that stuck out the most was the fact that baseline adiponectin levels predicted lower HbA1c levels at 12 and 24 months, while elevated adiponectin levels “correlated with enhanced beta-cell function, lower triglyceride levels, and fat loss.” The authors concluded that smaller rises in adiponectin, which mediates insulin action and adipose mass, may be why some patients do not achieve T2D remission up to two years after bariatric surgery. They wrote, “Elevated adiponectin was linked to improved glycaemic control and paralleled by higher pancreatic beta-cell function and multi-organ insulin sensitivity, irrespective of gut hormone responses. Together with reductions in hs-CRP, our adiponectin data extend previous clinical work and show that bariatric surgery effectively promotes diabetes remission by lowering adiposopathy.” However, they note that future work must be done to determine whether targeting adiposopathy by decreasing body fat and/or increasing adiponectin after bariatric surgery leads to better diabetes remission rates in obese adults, as adipose tissue appears intimately involved in the cross-talk between skeletal muscle, liver, and pancreatic glucose homeostasis.

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