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Objective: To estimate the burden of osteoarthritis (OA) among noninstitutionalized adults (≥18 years of age) in the US.Design: Weighted nationally representative data from the 2015 Medical Expenditure Panel Survey were used to estimate OA prevalence in noninstitutionalized adults and compare adults with OA to those without OA for clinical (pain interference with activities [PIA], functional limitations), humanistic (health-related quality-of-life [HRQoL]) and economic outcomes (healthcare costs, wage loss). Productivity/wage loss was estimated among employed working-age adults (18-64 years). Multivariable regression analyses examined the associations between OA and outcomes.Results: In 2015, 10.5% (25.6 million) of noninstitutionalized US adults reported having any OA. Regression analyses indicated that adults with OA were significantly more likely than those without OA to report moderate (adjusted odds ratios [AOR] 1.99; 95% confidence interval [CI] 1.65-2.40] or severe PIA (AOR 2.59; 95% CI 2.21-3.04), any functional limitation (AOR 2.51; 95% CI 2.21-2.85), and poorer HRQoL on the SF-12 version 2 Physical Component Summary score (adjusted beta [standard error] -3.88 [0.357]; P < 0.001). Adjusted incremental annual total healthcare costs and lost wages among adults with OA relative to those without OA were $1778 and $189 per person, respectively, resulting in estimated national excess costs of $45 billion and $1.7 billion, respectively.Conclusions: OA affects approximately 10% of noninstitutionalized adults in the US, resulting in substantial clinical, humanistic, and economic burdens. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) were measured in environmental samples (sponges, fish and sediment) collected in 2014 and 2016 from the Faroe-Shetland Channel and Rosemary Bank Seamount. These data could be used to provide a baseline against which any changes can be assessed in the event of an oil spill and contribute to any environmental impact assessment. Concentrations in all samples were low, often below the detection limits, and were typical of reference sites. Sponges can be used as an alternative indicator species to mussels for monitoring PAHs in the marine environment as they can accumulate PAHs from both the dissolved and particulate phase. PAH concentrations in marine sponges from Scottish waters have not previously been reported. Concentrations were low, but contained a higher proportion of heavier 4- to 6-ring PAHs compared to the fish samples. [ABSTRACT FROM AUTHOR]

Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver. Male db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR. Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis. BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease. • Mitochondrial uncoupling and calorie restriction (CR) cause negative energy balance. • This study is first to compare uncoupling and CR in a metabolic disease model. • Both treatments markedly improved metabolic disease phenotypes in db/db mice. • Despite similar weight loss, uncoupling had superior effects on glucose control. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is frequently co-morbid with anxiety disorders. The co-morbid state has poorer functional outcomes and greater resistance to first line treatments, highlighting the need for novel treatment targets. This systematic review examined differences in resting-state brain connectivity associated with anxiety comorbidity in young- and middle-aged adults with MDD, with the aim of identifying novel targets for neuromodulation treatments, as these treatments are thought to work partly by altering dysfunctional connectivity pathways. Twenty-one studies met inclusion criteria, including a total of 1292 people with MDD. Only two studies included people with MDD and formally diagnosed co-morbid anxiety disorders; the remainder included people with MDD with dimensional anxiety measurement. The quality of most studies was judged as fair. Results were heterogeneous, partly due to a focus on a small set of connectivity relationships within individual studies. There was evidence for dysconnectivity between the amygdala and other brain networks in co-morbid anxiety, and an indication that abnormalities of default mode network connectivity may play an underappreciated role in this condition. • Systematic review of brain connectivity correlates of anxiety in major depression. • Includes twenty-one studies of fMRI functional or effective connectivity. • Findings suggest amygdala dysconnectivity with increasing anxiety. • Reduced amygdala regulation from executive control and default mode networks. • Default mode network areas may represent novel targets for neuromodulation. [ABSTRACT FROM AUTHOR]

Herpes simplex virus DNA polymerase is a heterodimer composed of UL30, a catalytic subunit, and UL42, a processivity subunit. Mutations that decrease DNA binding by UL42 decrease long chain DNA synthesis by the polymerase. The crystal structure of UL42 bound to the C terminus of UL30 revealed an extensive positively charged surface ("back face"). We tested two hypotheses, 1) the C terminus of UL30 affects DNA binding and 2) the positively charged back face mediates DNA binding. Addressing the first hypothesis, we found that the presence of a peptide corresponding to the UL30 C terminus did not result in altered binding of UL42 to DNA. Addressing the second hypothesis, previous work showed that substitution of four conserved arginine residues on the basic face with alanines resulted in decreased DNA affinity. We tested the affinities for DNA and the stimulation of long chain DNA synthesis of mutants in which the four conserved arginine residues were substituted individually or together with lysines and also a mutant in which a conserved glutamine residue was substituted with an arginine to increase positive charge on the back face. We also engineered cysteines onto this surface to permit disulfide cross-linking studies. Last, we assayed the effects of ionic strength on DNA binding by UL42 to estimate the number of ions released upon binding. Our results taken together strongly suggest that the basic back face of UL42 contacts DNA and that positive charge on this surface is important for this interaction. [ABSTRACT FROM AUTHOR]

Abstract: Due to the potentially accumulative nature of the Fladen Ground, an area of intense oil activity in the North Sea, a survey was carried out in 1989 to map the distribution of contamination in relation to these oil activities. All the sediments collected were screened by ultraviolet fluorescence (UVF) for polycyclic aromatic hydrocarbons (PAHs) and selected samples were analysed for n-alkanes (by GC-FID), PAHs and biomarkers (by GC-MSD). This survey was repeated in 2001, with all the 1989 sites being resampled. All of these sediments were analysed for UVF oil equivalents, PAHs, n-alkanes and biomarkers. The concentrations of these parameters decreased between 1989 and 2001, with average decreases ranging from 43% to 88%. In addition, no significant difference was found, for all the parameters, between near field (&#60;5km from an oil installation) and far field (>5km from an oil installation) sites in 2001 indicating that the Fladen Ground is approaching a ‘steady state’ or background concentration for contamination. [Copyright &y& Elsevier]

Using an N-oleoyl ethanolamide scaffold, a series of phosphate polar head group analogues of LPA comprised of various α-substituted phosphonates and thiophosphates was prepared. In a broken cell GTP[γ35S] binding assay, agonist activity was evaluated at the three LPA receptors of the endothelial differentiation gene (Edg) family. This study has resulted in the discovery of a nonhydrolyzable LPA1-selective agonist (11). Additionally, thiophosphate 19 bears an isosteric phosphate mimetic that confers agonism at the LPA1 receptor but not LPA2. [Copyright &y& Elsevier]

Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity. SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry. SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w /w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes. SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics. • The mitochondrial uncoupler SHC517 prevents and reverses diet-induced obesity and glucose intolerance in mice. • SHC517 did not alter body temperature, food intake or fat-free lean mass. • SHC517 is a leading candidate for translational development in the field of mitochondrial uncoupler therapeutics for obesity and related diseases. [ABSTRACT FROM AUTHOR]

Desmetramadol (INN) is an investigational analgesic consisting of the (+) and (-) enantiomers of the tramadol active M1 metabolite. Tramadol is schedule IV with better safety than schedule II opioids. Tramadol is racemic and exerts analgesia by a monoaminergic effect mediated by (-)-tramadol and (-)-M1, and an opioid effect mediated by (+)-M1. CYP2D6 metabolizes (+)-tramadol to (+)-M1. CYP2D6 ultra-metabolizers can produce dangerous (+)-M1 levels and respiratory depression, whereas poor metabolizers produce insufficient (+)-M1 for analgesia. The objectives of this study were to test the hypotheses that (i) desmetramadol and tramadol doses giving equal plasma (+)-M1 yield equal hypoalgesia in metabolically normal subjects, but that (ii) the same doses in metabolically deficient subjects result in desmetramadol having greater plasma (+)-M1 and greater hypoalgesia than tramadol. Consecutive double-blind, randomized, placebo-controlled, three segment cross-over trials 'A' and 'B' investigated steady-state pharmacokinetics and hypoalgesia of 20 mg desmetramadol and 50 mg tramadol in healthy subjects without (N=43) and with (N=60) cotreatment with the potent CYP2D6 inhibitor paroxetine (20 mg daily). In the absence of CYP2D6 inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed q6 hours gave bioequivalent plasma (+)-M1: Css min , 26 + 6 vs. 28 + 7 ng/mL (90% CI, 0.85-1.08); Css max , 36 + 10 vs. 37 + 10 ng/mL (90 CI, 0.88-1.13). Hypoalgesia (cold pressor) of desmetramadol and tramadol were significantly greater than placebo, but equal to each other. In trial B, CYP2D6 inhibition significantly depressed tramadol (+)-M1 Css min (-58%) and Css max (-60%), but increased desmetramadol (+)-M1 Css min (46%) and Css max (41%). In trial B desmetramadol produced significant hypoalgesia as it did in trial A, whereas in trial B tramadol hypoalgesia was insignificant and comparable to placebo. Desmetramadol offers tramadol analgesia without metabolic liabilities. Supported by grant R44 DA027304 from the National Institute on Drug Abuse (NIDA) of NIH. [ABSTRACT FROM AUTHOR]