Abstract Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short-acting calcium-sensing ...receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur. Chronic administration of SB-423557 did not increase parathyroid cell proliferation in rats. In healthy human volunteers, single doses of intravenous SB-423562 and oral SB-423557 elicited transient elevations of endogenous PTH concentrations in a profile similar to that observed with subcutaneously administered PTH. Both agents were well tolerated in humans. Transient increases in serum calcium, an expected effect of increased parathyroid hormone concentrations, were observed post-dose at the higher doses of SB-423557 studied. These data constitute an early proof of principle in humans and provide the basis for further development of this class of compound as a novel, orally administered bone-forming treatment for osteoporosis.
GlycA is a new composite measure of systemic inflammation and a predictor of many inflammatory diseases. GlycA is the nuclear magnetic resonance spectroscopy-derived signal arising from glucosamine ...residues on acute-phase proteins. This study aimed to evaluate how exercise-based lifestyle interventions modulate GlycA in persons at risk for type 2 diabetes. GlycA, fitness, and body habitus were measured in 169 sedentary adults (45–75 years) with prediabetes randomly assigned to one of four six-month exercise-based lifestyle interventions. Interventions included exercise prescription based on the amount (energy expenditure (kcal/kg weight/week (KKW)) and intensity (%VO2peak). The groups were (1) low-amount/moderate-intensity (10KKW/50%) exercise; (2) high-amount/moderate-intensity (16KKW/50%) exercise; (3) high-amount/vigorous-intensity (16KKW/75%) exercise; and (4) a Clinical Lifestyle (combined diet plus low-amount/moderate-intensity exercise) intervention. Six months of exercise training and/or diet-reduced GlycA (mean Δ: −6.8 ± 29.2 μmol/L; p=0.006) and increased VO2peak (mean Δ: 1.98 ± 2.6 mL/kg/min; p<0.001). Further, visceral (mean Δ: −21.1 ± 36.6 cm2) and subcutaneous fat (mean Δ: −24.3 ± 41.0 cm2) were reduced, while liver density (mean Δ: +2.3 ± 6.5HU) increased, all p<0.001. When including individuals in all four interventions, GlycA reductions were associated with reductions in visceral adiposity (p<0.03). Exercise-based lifestyle interventions reduced GlycA concentrations through mechanisms related to exercise-induced modulations of visceral adiposity. This trial is registered with Clinical Trial Registration Number NCT00962962.
A series of titanium complexes containing a terminal neopentylidene functionality have been prepared by a one electron oxidatively induced α-hydrogen abstraction from the corresponding bis-neopentyl ...precursor (Nacnac)Ti(CH2 tBu)2 (Nacnac- = ArNC(CH3)CHC(CH3)NAr, Ar = 2,6-(CHMe2)2C6H3), among them (Nacnac)TiCHtBu(OTf) and (Nacnac)TiCHtBu(I). It was determined that bulky alkyl groups bound to titanium as well as a bulky coordinating anion from the oxidant are needed to promote α-hydrogen abstraction. Complex (Nacnac)TiCHtBu(OTf) serves as a template for other four-coordinate titanium neopentylidene complexes such as (Nacnac)TiCHtBu(X) (X- = Cl, Br, and BH4). Complexes (Nacnac)TiCHtBu(X) undergo cross-metathesis reactivity with the imine functionality of the Nacnac- ligand forming the imido complexes (HtBuCC(Me)CHC(Me)NAr)TiNAr(X) (X- = OTf, Cl, Br, I, BH4). In addition, C−H activation of two tertiary carbons also takes place to afford the titanacycles Ti2,6-(CMe2)(CHMe2)C6H3NC(Me)CHC(Me)N2,6-(CMe2)(CHMe2)C6H3(X) (X- = OTf, Cl, Br and η2-BH4). Kinetic studies in C6D6 reveal the formation of (HtBuCC(Me)CHC(Me)NAr)TiNAr(I) from (Nacnac)TiCHtBu(I) to be independent of solvent (C6D6, Et2O−d10, THF-d8) and the reaction to be first order in titanium (k = 8.06 × 10-4 s-1 at 57 °C, with activation parameters ΔH ⧧ = 21.3(2) kcal/mol, ΔS ⧧ = −8(3) cal/mol K). Compound (Nacnac)TiCHtBu(OTf) reacts with various substrates to afford products in which the alkylidene functionality has been significantly transformed. When the alkylidene derivatives (NacnactBu)TiCHtBu(X) (X- = OTf, I; NacnactBu - = ArNC(tBu)CHC(tBu)NAr) were prepared, the intramolecular cross-metathesis transformation observed with (Nacnac)TiCHtBu(X) was inhibited completely.
We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk.
We evaluated genetic correlations between a previous genetic study of AF and AF in ...the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.
We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with
< 4.4 × 10
in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio OR per SD = 1.40,
= 1.45 × 10
), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,
= 0.004), but no other primary stroke subtypes (all
> 0.1).
Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
An efficient stereoselective synthesis of the orally active NK1 receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a ...2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired α-(fluorophenyl)morpholine derivative. Interesting and unexpected 1,2-Wittig and 1,3-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have ...potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics.
A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients.
Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10
per year 95% CI, -6.49×10
to -3.14×10
;
=1.82×10
), and location of IA at the internal carotid artery (odds ratio=0.92 95% CI, 0.86-0.98;
=0.0041).
The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Many adults receive inadequate sleep, which elevates obesity and type 2 diabetes risk and may hinder benefits of calorie restriction (CR). We hypothesized that short sleepers would experience less ...weight loss and diminished glycemic benefits compared to adequate sleepers during CR.
We performed secondary analyses in participants randomized to 25% CR in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy- Phase 2 (CALERIE 2) trial. Body weight, dual-energy x-ray absorptiometry-measured body composition, fasting glucose, insulin, and HOMA-IR were assessed at baseline, 12, and 24 months. Self-reported sleep duration identified participants with stable sleep as short (≤7 hrs, n=45) or adequate sleepers (>7 hrs, n=65). Sex, BMI, weight, and race-adjusted linear mixed models identified differences over time and between sleepers.
Short and adequate sleepers had similar body weight and composition values at all timepoints and experienced equivalent CR-induced reductions over time. Baseline HOMA-IR (1.2 vs. 1.0; P=0.047) was higher in short sleepers, with trends noted for glucose (81.7 vs. 83.5 mg/dL; P=0.093) and insulin (5.7 vs. 4.9 µU/mL; P=0.077). Both phenotypes demonstrated enhanced glycemic control relative to baseline at 12 and 24 months. While there were no 12-month differences in absolute glycemic values between sleepers, initial differences re-emerged at 24 months, with higher HOMA-IR (0.9 vs. 0.7; P=0.01) and insulin concentrations (4.3 vs. 3.4 µU/mL; P<0.01) in short vs. adequate sleepers. Short sleepers had worse baseline glycemic control than adequate sleepers. This difference dissipated during active weight loss but returned during weight maintenance. While short sleepers responded to CR in the present analysis, subsequent work must examine the likely synergy of extending sleep in short sleepers during CR to sustain improvements in glycemic control long-term. Importantly, these data also point to CR as a potential metabolic countermeasure to short sleep.
Disclosure
K. K. Hoddy: None. P. Singh: None. J. L. Dorling: None. R. A. Beyl: None. J. P. Kirwan: None. K. Huffman: None. S. B. Racette: None. S. Das: None. C. K. Martin: Advisory Panel; Self; EHE Health, Board Member; Self; NaturallySlim, Other Relationship; Self; ABGIL, Academy of Nutrition and Dietetics, Research Support; Self; American Society for Nutrition, Leona M. and Harry B. Helmsley Charitable Trust, Lilly, National Institutes of Health, Patient-Centered Outcomes Research Institute, U. S. Department of Agriculture, WW.
Funding
National Institute on Aging (U01AG022132, U01AG020478, U01AG020487, U01AG020480, R01AG060499, U24AG047121, U24AG047121); Agricultural Research Service (1950-51000-071-01S); American Heart Association (20POST35210907); National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK07247615); National Institute of General Medical Sciences (U54GM104940)
For persons with osteoarthritis (OA), nutrition education may facilitate weight and OA symptom management.
The primary aim of this study was to determine preferred OA-related nutritional and weight ...management topics and their preferred delivery modality. The secondary aim was to determine whether there is a disconnect between what patients want to know about nutrition and OA management and what information health-care professionals (HCPs) are providing to patients.
The Osteoarthritis Action Alliance surveyed individuals with OA to identify their preferences, categorized in 4 domains: 1) strategies for weight management and a healthy lifestyle; 2) vitamins, minerals, and other supplements; 3) foods or nutrients that may reduce inflammation; and 4) diets for weight loss. HCPs were provided these domains and asked which topics they discussed with patients with OA. Both groups were asked to select currently utilized or preferred formats of nutritional resources.
Survey responses from 338 individuals with OA and 104 HCPs were included. The highest preference rankings in each domain were: 1) foods that make OA symptoms worse (65%), foods and nutrients to reduce inflammation (57%), and healthy weight loss (42%); 2) glucosamine (53%), vitamin D (49%), and omega-3 fatty acids (45%); 3) spices and herbs (65%), fruits and vegetables (58%), and nuts (40%); and 4) Mediterranean diet (21%), low-carbohydrate diet (18%), and fasting or intermittent fasting (15%). There was greater than 20% discrepancy between interests reported by individuals with OA and discussions reported by HCPs on: weight loss strategies, general information on vitamins and minerals, special dietary considerations for other conditions, mindful eating, controlling caloric intake or portion sizes, and what foods worsen OA symptoms. Most respondents preferred to receive nutrition information in a passive format and did not want information from social media messaging.
There is disparity between the nutrition education content preferred by individuals with OA (which often lacks empirical support) and evidence-based topics being discussed by HCPs. HCPs must communicate evidence-based management of joint health and OA symptoms in patient-preferred formats. This study explored the information gap between what individuals with OA want to know and what HCPs believe they need to know.
Greater improvement in insulin sensitivity with weight loss during calorie restriction and exercise interventions may be related to improved coupling of β-oxidation and tricarboxylic acid cycle flux.
...Objectives:
The objective of the study was to evaluate whether serum concentrations of metabolic intermediates are related to adiposity and insulin sensitivity (Si) in overweight healthy subjects and compare changes in metabolic intermediates with similar weight loss achieved by diet only or diet plus exercise.
Design:
This was a randomized controlled trial.
Participants and Intervention:
The cross-sectional study included 46 (aged 36.8 ± 1.0 yr) overweight (body mass index 27.8 ± 0.7 kg/m2) subjects enrolled in a 6-month study of calorie restriction. To determine the effect of diet only or diet plus exercise on metabolic intermediates, 35 subjects were randomized to control (energy intake at 100% of energy requirements); CR (25% calorie restriction), or CR+EX: (12.5% CR plus 12.5% increase in energy expenditure by exercise).
Main Outcome Measures:
Serum concentrations of eight fatty acids, 15 amino acids, and 45 acylcarnitines (ACs) measured by targeted mass spectrometry.
Results:
In overweight subjects, the concentrations of C2 AC and long-chain ACs were positively associated with percent fat (R2 = 0.75, P = 0.0001) and Si (R2 = 0.12, P = 0.05). The percent fat (R2 = 0.77, P < 0.0001), abdominal visceral fat (R2 = 0.64, P < 0.0001), and intrahepatic fat (R2 = 0.30, P = 0.0002) were positively associated with fatty acid concentrations. There was a significant increase in an AC factor (comprised of C2 and several medium chain ACs) in the CR group (P = 0.01).
Conclusion:
In nonobese subjects, fasted serum ACs are associated with Si and fat mass. Despite similar weight loss, serum ACs increase with CR alone but not CR+EX. A greater improvement in Si with weight loss during CR+EX interventions may be related to improved coupling of β-oxidation and tricarboxylic acid cycle flux induced by exercise.
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