Pregnancy and Fetal Outcomes After Exposure to Mefloquine in the Pre- and Periconception Period and During Pregnancy

Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively-monitored cases were comparable to background rate

Combined biological and chemical assessment of estrogenic activities in wastewater treatment plant effluents

Five wastewater treatment plant effluents were analyzed for known endocrine disrupters and estrogenicity. Estrogenicity was determined by using the yeast estrogen screen (YES) and by measuring the blood plasma vitellogenin (VTG) concentrations in exposed male rainbow trout (Oncorhynchus mykiss). While all wastewater treatment plant effluents contained measurable concentrations of estrogens and gave a positive response with the YES, only at two sites did the male fish have significantly increased VTG blood plasma concentrations after the exposure, compared to pre-exposure concentrations. Estrone (E1) concentrations ranged up to 51ngL−1, estradiol (E2) up to 6ngL−1, and ethinylestradiol (EE2) up to 2ngL−1 in the 90samples analyzed. Alkylphenols, alkylphenolmonoethoxylates and alkylphenoldiethoxylates, even though found at µgL−1 concentrations in effluents from wastewater treatment plants with a significant industrial content, did not contribute much to the overall estrogenicity of the samples taken due to their low relative potency. Expected estrogenicities were calculated from the chemical data for each sample by using the principle of concentration additivity and relative potencies of the various chemicals as determined with the yeast estrogen screen. Measured and calculated estradiol equivalents gave the same order of magnitude and correlated rather well (R 2=0.6

Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells

Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathie

Entanglement in a Solid State Spin Ensemble

Entanglement is the quintessential quantum phenomenon and a necessary ingredient in most emerging quantum technologies, including quantum repeaters, quantum information processing (QIP) and the strongest forms of quantum cryptography. Spin ensembles, such as those in liquid state nuclear magnetic resonance, have been powerful in the development of quantum control methods, however, these demonstrations contained no entanglement and ultimately constitute classical simulations of quantum algorithms. Here we report the on-demand generation of entanglement between an ensemble of electron and nuclear spins in isotopically engineered phosphorus-doped silicon. We combined high field/low temperature electron spin resonance (3.4 T, 2.9 K) with hyperpolarisation of the 31P nuclear spin to obtain an initial state of sufficient purity to create a non-classical, inseparable state. The state was verified using density matrix tomography based on geometric phase gates, and had a fidelity of 98% compared with the ideal state at this field and temperature. The entanglement operation was performed simultaneously, with high fidelity, to 10^10 spin pairs, and represents an essential requirement of a silicon-based quantum information processor.Comment: 4 pages, 3 figures plus supporting information of 4 pages, 1 figure v2: Updated reference

The Reduction of Visceral Adipose Tissue after Roux-en-Y Gastric Bypass Is more Pronounced in Patients with Impaired Glucose Metabolism.

Visceral adipose tissue (VAT) is associated with cardiometabolic risk factors and insulin resistance. The physiological mechanisms underlying the benefits of Roux-en-Y gastric bypass surgery (RYGB) on glucose metabolism remain incompletely understood. The impact of RYGB on VAT was assessed among three groups of patients stratified by their glucose tolerance before surgery. Forty-four obese women were categorized into normoglycemia (n = 21), impaired glucose tolerance (IGT, n = 18) and diabetes (n = 5) before surgery. Body composition measured by dual-energy X-ray absorptiometry (DXA) was performed before surgery, 6 months and 12 months after. The three groups had comparable mean age (mean 38.6 ± SD 9.9) and BMI at baseline (41.9 ± 4.3 kg/m <sup>2</sup> ). After 12 months, total weight loss (mean 35.1% ± 7.5) and excess weight loss (91.1% ± 25.1) were similar between groups. Pre-surgery mean VAT was significantly higher in diabetes (mean 2495 ± 616 g) than in normoglycemia (1750 ± 617 g, p = 0.02). The percentage of VAT to total body fat was significantly higher in diabetes (mean 4.4% ± 0.9) compared to normoglycemia (2.9% ± 0.8, p = 0.003). Twelve months after surgery, VAT loss was significantly greater among patients with diabetes (mean 1927 ± 413 g) compared to normoglycemia (1202 ± 450, p = 0.009). RYGB leads to important VAT loss, and this loss is greater in patients with diabetes prior to surgery. As VAT is associated with insulin resistance, this reduction may account for the profound impact of this surgery on glucose metabolism

The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease

Mutations in the mitochondrial fission factor GDAP1 are associated with severe peripheral neuropathies, but why the CNS remains unaffected is unclear. Using a Gdap1−/− mouse, Niemann et al. demonstrate that a CNS-expressed Gdap1 paralogue changes its subcellular localisation under oxidative stress conditions to also act as a mitochondrial fission facto

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Novel concept to guide systolic heart failure medication by repeated biomarker testing-results from TIME-CHF in context of predictive, preventive, and personalized medicine

Background It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF. Methods This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged >= 60 years, LVEF = II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, beta-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient. Results One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P = 0.013 and P = 0.001), whereas the opposite was the case with low hsCRP (interaction, P = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P = 0.006 and P = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P = 0.021). beta-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P = 0.021). No treatment biomarker interactions were found for RAS inhibition. Conclusion The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted