Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized ¹³C magnetic resonance.

The mammalian brain relies primarily on glucose as a fuel to meet its high metabolic demand. Among the various techniques used to study cerebral metabolism, <sup>13</sup> C magnetic resonance spectroscopy (MRS) allows following the fate of <sup>13</sup> C-enriched substrates through metabolic pathways. We herein demonstrate that it is possible to measure cerebral glucose metabolism in vivo with sub-second time resolution using hyperpolarized <sup>13</sup> C MRS. In particular, the dynamic <sup>13</sup> C-labeling of pyruvate and lactate formed from <sup>13</sup> C-glucose was observed in real time. An ad-hoc synthesis to produce [2,3,4,6,6- <sup>2</sup> H <sub>5</sub> , 3,4- <sup>13</sup> C <sub>2</sub> ]-D-glucose was developed to improve the <sup>13</sup> C signal-to-noise ratio as compared to experiments performed following [U- <sup>2</sup> H <sub>7</sub> , U- <sup>13</sup> C]-D-glucose injections. The main advantage of only labeling C3 and C4 positions is the absence of <sup>13</sup> C- <sup>13</sup> C coupling in all downstream metabolic products after glucose is split into 3-carbon intermediates by aldolase. This unique method allows direct detection of glycolysis in vivo in the healthy brain in a noninvasive manner

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

Supplementary Material for: The E280A Presenilin Mutation Reduces Voltage-Gated Sodium Channel Levels in Neuronal Cells

<strong><em>Background:</em></strong> Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β₂-subunits (Na_vβ₂), releases the intracellular domain of Na_vβ₂ (β₂-ICD), and thereby, increases intracellular sodium channel α-subunit Na_v1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Na_vβ₂ cleavages and Na_v1.1 levels. <b><i>Objective:</i></b> It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Na_vβ₂ processing and Na_v1.1 levels in neuronal cells. <b><i>Methods:</i></b> We first generated B104 rat neuroblastoma cells stably expressing Na_vβ₂ and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Na_vβ₂ processing and Na_v1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively. <b><i>Results:</i></b> The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Na_vβ₂ as compared to wtPS1 controls, both in cells and in a cell-free system. Na_v1.1 mRNA and protein levels, as well as the surface levels of Na_v channel α-subunits, were also significantly reduced in PS1(E280A) cells. <b><i>Conclusion:</i></b> Our data indicate that the FAD-linked PS1(E280A) mutation decreases Na_v channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Na_vβ₂ in neuronal cells