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Aquaporins are a family of ubiquitously expressed transmembrane water channels implicated in a broad range of physiological functions. We have previously reported that aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. Using either genetic deletion or small molecule inhibitor, we show that AQP4 supports T cell receptor mediated activation of both mouse and human T cells. Intact AQP4 is required for optimal T cell receptor (TCR)-related signaling events, including nuclear translocation of transcription factors and phosphorylation of proximal TCR signaling molecules. AQP4 deficiency or inhibition impairs actin cytoskeleton rearrangements following TCR crosslinking, causing inferior TCR polarization and a loss of TCR signaling. Our findings reveal a novel function of AQP4 in T lymphocytes and identify AQP4 as a potential therapeutic target for preventing TCR-mediated T cell activation.

Despite well recognized improvements in obesity-related comorbidities, increasing evidence implicates bariatric surgery in the onset of adverse skeletal health outcomes. The purpose of this review is to provide a focused update in three critical areas: (i) emergent data on sleeve gastrectomy and bone loss, (ii) evidence linking bariatric surgery to incident fracture, and (iii) intervention strategies designed to mitigate surgical bone loss. Better understanding of these issues will inform our treatment of skeletal health for patients planning bariatric surgery.

Background Individuals are often counseled to use behavioral weight loss strategies to reduce risk for cardiovascular disease (CVD). We examined whether any benefits for CVD risk from weight loss intervention extend uniformly to individuals across a range of underlying health states. Methods The time until first occurrence of a composite of fatal and nonfatal myocardial infarction and stroke, hospitalized angina, or CVD death was analyzed from 8 to 11 years of follow-up of 4,859 adults who were overweight or obese, aged 45–76 years with Type 2 diabetes. Individuals had been randomly assigned to either an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Participants were grouped by intervention assignment and a frailty index (FI) based on deficit accumulation, ordered from fewer (first tertile) to more (third tertile) deficits. Results Baseline FI scores were unrelated to intervention-induced weight losses and increased physical activity. The relative effectiveness of ILI on CVD incidence was inversely related to baseline FI in a graded fashion (p = .01), with relative benefit (hazard ratio = 0.73 [95% CI 0.55,0.98]) for individuals in the first FI tertile to no benefit (hazard ratio = 1.15 [0.94,1.42]) among those in the third FI tertile. This graded relationship was not seen for individuals ordered by age tertile (p = .52), and was stronger among participants aged 45–59 years (three-way interaction p = .04). Conclusions In overweight/obese adults with diabetes, multidomain lifestyle interventions may be most effective in reducing CVD if administered before individuals have accrued many age-related health deficits. However, these exploratory analyses require confirmation by other studies. Clinical Trial Registration NCT00017953

Previous studies have examined the relationship between cortical bone properties and fracture risk in older populations, but they have yet to examine how these properties change within the femur. Most hip fractures are classified by their location: femoral neck, intertrochanteric, or subtrochanteric fractures. Since cortical thickness can vary throughout the femur, a quantitative method of examining thickness by region was developed using a cortical mapping approach applied to computed tomography (CT) scans. Subject-specific finite element (FE) models of proximal femurs were created from baseline CT scans of 107 older adults (ages 60 – 85; 70% White; 72% Female) with obesity as classified by BMI (33.8 ± 4 kg/m2). An existing FE model was morphed to the segmented geometry of each subject’s proximal femur. A nearest neighbor search assigned cortical thickness values to the nearest finite element model node. Cortical thickness was grouped into four femoral compartments: femoral head, femoral neck, intertrochanteric and subtrochanteric regions. Pairwise paired t-tests indicated that cortical thickness differed between femoral compartments (p < 0.05). Multivariate regression models showed greater cortical thicknesses in femoral head, neck, and intertrochanteric regions in African Americans compared to Whites (p < 0.05). Additionally, these models suggest an association between cortical thickness and physical function assessments, such as the timed up-and-go test and leg muscle strength test. Since cortical thickness is not constant throughout the femur, future studies can use the framework developed here to assess each compartment individually and investigate the relationships between cortical thickness, demographics, and functional assessments.

Understanding how trajectories of positive and negative affect relate to dementia risk and underlying structural brain variables is important for dementia prevention. We examined associations between annually assessed Positive and Negative Affect Scale subscales and dementia risk (2000-18) among cognitively-intact community-dwelling women (N=948; aged 72.9±3.7) from the Women’s Health Initiative Study of Cognitive Aging (years 2000-2010) and Magnetic Resonance Imaging Study (2005-2006). Joint latent class mixture models were constructed to identify latent classes of women with similar trajectories of affect and dementia risk over time. Multinomial and logistic regressions examined whether structural MRI measures predicted latent class membership (adjusted for sociodemographic, lifestyle, clinical characteristics, and intracranial volume). Two latent classes of positive affect (high stable:88% and decreasing:12%) and four classes of negative affect (Minimal stable:75%; high stable:4%; emerging:12%; moderate decreasing:9%) were identified. With the high stable trajectory as referent, women with decreasing positive affect were more likely to develop dementia (HR=4.33;p

A mechanistic understanding of the biological basis for sarcopenia could lead to novel biomarkers and intervention targets. We recently reported a novel role of autoimmunity in sarcopenia, which is potentially mediated through cardiac troponin T (cTnT) and its autoantibody. Given the known role of obesity in both autoimmunity and sarcopenia, we further explored the association between circulating cTnT or skeletal muscle IgG and obesity in older adults. We found that, in 37 older adults (NCT01049698, BMI: 30.8 ± 2.3 kg/m²; Age: 69 ± 3.5 yrs) without any cardiac abnormality, serum cTnT was negatively correlated with skeletal muscle volume (r = -0.37, p = 0.02) and leg extension strength (r = -0.38, p = 0.02), but positively correlated with body fat/muscle volume ratio (r = 0.37, p = 0.03). In two other studies including older adults (n = 11 & 12) from a subset of subjects (NCT01049698 & NCT01298817), skeletal muscle IgG1 (GAPDH normalized level by immunoblot) was found to be positively associated with BMI or dual-energy X-ray absorptiometry derived regional fat measurements, including fat mass, abdominal subcutaneous fat, abdominal fat, or thigh fat. We also found that subjects with higher skeletal muscle IgG1 protein levels have significantly higher BMI but lower knee extensor strength. Our finding suggests that obesity may underlie increased circulating cTnT and skeletal muscle IgG infiltration. It also warrants additional investigation into its role in skeletal muscle autoimmunity in older adults.

Lung cancer screening by helical low-dose computed tomography detects nonsolid nodules that may be lung adenocarcinoma precursors. Aspirin’s anti-inflammatory properties make it an attractive target for prevention of multiple cancers, including lung cancer. Therefore, we conducted a phase IIb trial (NCT02169271) to study the efficacy of low-dose aspirin to reduce the size of subsolid lung nodules (SSNs). A total of 98 current or former smokers (67.3% current) undergoing annual low-dose computed tomography screening with persistent SSNs were randomly assigned to receive aspirin 100 mg/day or placebo for 1 year. There was no difference in change in the sum of the longest diameters of target nodules in the placebo and aspirin arm after 12 months of treatment (-0.12 mm [SD = 1.55 mm] and +0.30 mm [SD= 2.54 mm], respectively; 2-sided P = .33 primary endpoint). There were no changes observed in subgroup analyses by individual characteristics or nodule type. One year of low-dose aspirin did not show any effect on lung SSNs. SSNs regression may not be the proper target for aspirin, and/or longer duration may be needed to see SSNs modifications.

Background Increasing protein content of the diet might be an effective strategy to preserve muscle mass in older adults undergoing caloric restriction, thereby preserving muscle function. Methods Ninety-six older adults (70.3 ± 3.7 years, 74% women, 27% African American) with obesity (35.4 ± 3.3 kg/m2; 47% total body fat) were randomized to a 6-month higher protein (providing 1.2-1.5 g/kg/d) weight loss (WL) program, utilizing the Medifast 4&2&1 Plan, or to weight stability (WS). Dual-energy x-ray absorptiometry-acquired total body mass and composition, and fast gait speed over 400 m was assessed at baseline, 3, and 6 months. Results At baseline, dual-energy x-ray absorptiometry-acquired total body, fat, and lean masses were 95.9 ± 14.6, 44.6 ± 7.6, and 48.7 ± 9.5 kg, respectively, and 400-m gait speed was 1.17 ± 0.20 m/s. Total body mass was significantly reduced in the WL group (-8.17 [-9.56, -6.77] kg) compared with the WS group (-1.16 [-2.59, 0.27] kg), with 87% of total mass lost as fat (WL: -7.1 [-8.1, -6.1] kg; -15.9% change from baseline). A differential treatment effect was not observed for change in lean mass (WL: -0.81 [-1.40, -0.23] kg vs WS: -0.24 [-0.85, 0.36] kg). Four-hundred-meter gait speed was also unchanged from baseline although trends suggest slightly increased gait speed in the WL group [0.01 (-0.02, 0.04) m/s] compared with the WS group [-0.02 (-0.05, 0.01) m/s]. Conclusion Intentional weight loss using a high-protein diet is effective in producing significant total body mass and fat mass loss, while helping preserve lean body mass and mobility, in relatively high-functioning older adults with obesity.

Background Low-grade chronic inflammation, characterized by elevations in plasma Interleukin-6 (IL-6), is an independent risk factor of impaired mobility in older persons. Angiotensin receptor blockers and omega-3 polyunsaturated fatty acids (ω-3) may reduce IL-6 and may potentially improve physical function. To assess the main effects of the angiotensin receptor blocker losartan and ω-3 as fish oil on IL-6 and 400 m walking speed, we conducted the ENRGISE Pilot multicenter randomized clinical trial. Methods The ENRGISE Pilot enrolled participants between April 2016 and June 2017, who participated for 12 months. Participants were aged ≥70 years with mobility impairment, had IL-6 between 2.5 and 30 pg/mL, and were able to walk 400 m at baseline. Participants were randomized in three strata 2 × 2 factorial to: (i) losartan 50–100 mg/d or placebo (n = 43), (ii) fish oil 1,400–2,800 mg/d or placebo (n = 180), and (iii) with both (n = 66). Results Two hundred eighty-nine participants were randomized (mean age 78.3 years, 47.4% women, 17.0% black). There was no effect of losartan (difference of means = −0.065 ± 0.116 [SE], 95% confidence interval [CI]: −0.293–0.163, p = .58) or fish oil (−0.020 ± 0.077, 95% CI: −0.171–0.132, p = .80) on the log of IL-6. Similarly, there was no effect of losartan (−0.025 ± 0.026, 95% CI: −0.076–0.026, p = .34) or fish oil (0.010 ± 0.017, 95% CI: −0.025–0.044, p = .58) on walking speed (m/s). Conclusions These results do not support the use of these interventions to prevent mobility loss in older adults at risk of disability with low-grade chronic inflammation. Registration Clinicaltrials.gov NCT02676466.

Exposure to air pollution may accelerate brain aging and increase risk of late-life depressive symptoms (DS). Brain structures underlying these associations are unknown. Longitudinal data from 829 community-dwelling women without dementia (baseline age 81.6 ± 3.6 years old) who participated in both the Women’s Health Initiative Memory Study Magnetic Resonance Imaging study (WHIMS-MRI; 2005-06) and the WHIMS-Epidemiology of Cognitive Health Outcomes (2008-16) were analyzed to examine whether volumetric measures of brain structures mediated associations between long-term exposure to ambient air pollutants and annual increases in DS (as measured by annually assessed 15-item Geriatric Depression Scale). Annual PM2.5 (fine particulate matter of aerodynamic diameter

BACKGROUND: Obesity compounds aging-related declines in cardiorespiratory fitness, with accompanying fatigue and disability. This study determined the effects of two different levels of caloric restriction (CR) during aerobic training on cardiorespiratory fitness, fatigue, physical function, and cardiometabolic risk. METHODS: The INFINITE study was a 20-week randomized trial in 180 older (65–79 years) men and women with obesity (body mass index = 30–45 kg/m2). Participants were randomly assigned to (i) aerobic training (EX; treadmill 4 days/wk for 30 minutes at 65%–70% of heart rate reserve), (ii) EX with moderate (−250 kcal/d) CR (EX + Mod-CR), or (iii) EX with more intensive (−600 kcal/d) CR (EX + High-CR). Cardiorespiratory fitness (peak aerobic capacity, VO(2) peak, primary outcome) was determined during a graded exercise test. RESULTS: One hundred and fifty-five participants returned for 20-week data collection (87% retention). VO(2) peak increased by 7.7% with EX, by 13.8% with EX + Mod-CR, and by 16.0% with EX + High-CR, and there was a significant treatment effect (EX + High-CR = 21.5 mL/kg/min, 95% confidence interval = 19.8–23.2; EX + Mod-CR = 21.2 mL/kg/min, 95% confidence interval = 19.4–23.0; EX = 20.1 mL/kg/min, 95% confidence interval = 18.4–21.9). Both CR groups exhibited significantly greater improvement in self-reported fatigue and disability and in glucose control, compared with EX. CONCLUSION: Combining aerobic exercise with even moderate CR is more efficacious for improving cardiorespiratory fitness, fatigue and disability, and glucose control than exercise alone and is as effective as higher-dose CR.

Introduction Vibrators and dildos are commonly used by women and men in the United States, and are increasingly recommended by clinicians. In addition, sex toys and various household objects are sometimes used for sexual stimulation in ways that pose health risks to their users. Data about the dimensions of such products may inform clinicians' recommendations. Aim The purpose of the present study was to assess the sizes (length and circumference) of vibrators and dildos marketed for vaginal or anal insertion on websites that sell sexual enhancement products. Methods Eight websites that sell sexual enhancement products were identified for inclusion in the study. The dimensions of vaginal vibrators and dildos listed for sale on each website were noted, and descriptive data were calculated for each website. Main Outcome Measures Product length and circumference (mean, median, and range). Results Popular sex toy distributers offer a variety of product sizes. The length of many vibrators and dildos was sized between 4 and 6 in, and circumference was between 4 and 5 in. However, some companies featured products of a considerably larger size than others. Conclusion Length and circumference of vibrators and dildos varied, but on average approximated mean penile dimensions. Clinicians' recommendations for use of vaginal or anal products can be enhanced by familiarity and offering additional information about product sizes and retailers.

OVERWEIGHT and obesity are significant public health problems, with recent estimates suggesting that 72.3% and 64.1% of adult men and women, respectively, have a body mass index (BMI) greater than or equal to 25kg/m2 (1). In women, postmenopausal status is associated with higher prevalence of overweight and obesity (2). Excessive body weight often predisposes to chronic disease, and accordingly, overweight and obese postmenopausal women are at increased risk of developing several cardiometabolic conditions (3–7). Treatments for overweight and obesity, which result in significant weight loss, frequently yield immediate improvement in the cardiometabolic risk profile (8). For most, however, long-term weight loss maintenance remains elusive (9). Data show that about one third of individuals who lose weight will regain all of their lost weight within 1 year, and almost all individuals regress to their baseline weight within 5 years (10,11). Although nearly 60% of overweight women report trying to lose weight ([12] and previous data suggest that most will be unable to maintain their weight loss), the effect of a cycle of intentional weight loss followed by weight regain on cardiometabolic risk in overweight and obese postmenopausal women is not known. Such data are necessary to assess the long-term benefits and risks of intentional weight loss in this population. Observational studies in younger adults show that weight cycling is not associated with increased cardiometabolic risk (13–15). Further, weight regain in this population is not associated with adverse effects on body composition or fat distribution (16,17). However, recent data from our group suggest that, for postmenopausal women, body composition is negatively impacted by weight regain following intentional weight loss (18). Specifically, after a 13% weight reduction, women who regained at least 2kg of lost weight within a year experienced a greater accretion of fat mass, relative to lean mass. Due to the known association between elevated body fat and cardiovascular disease risk, preferential regain of fat suggests that cardiometabolic risk factors may be worse in older adults who regain weight after intentional weight loss, although further investigation is warranted. Therefore, the purpose of this study was to determine how cardiometabolic risk factors change in the year following significant intentional weight loss in postmenopausal women and if observed, changes are affected by weight and fat regain. We also assessed whether these risk factors were worse 1 year after intentional weight loss compared with baseline values in women who experienced weight regain.

Objective To provide an overview of a novel anti-hepatitis C agent, sofosbuvir. Key findings Sofosbuvir is a novel nucleotide analogue inhibitor of hepatitis C virus (HCV) NS5B polymerase that has recently been approved by the Federal Drug Administration for the treatment of HCV genotypes 1, 2, 3 or 4 in a variety of patients. The emergence of such a novel treatment provides benefit to previously untreated genotypes and patient populations, with little chance of promoting significant viral resistance. Excellent sustained virologic response rates 12 weeks after the end of treatment (SVR12) were seen in phase II and III clinical trials when sofosbuvir was used with ribavirin. Even more promising are the results from phase II and III clinical trials that evaluated sofosbuvir in combination with other oral direct acting antivirals (DAAs). Data with sofosbuvir in the hepatitis C virus (HCV)/HIV coinfected and in the pre- and post-transplantation populations are still emerging. The drug was very well tolerated in clinical studies, with the most common adverse events of headache, nausea and fatigue. Summary Overall, sofosbuvir presents a new and effective treatment option for HCV-infected patients.

In this article I examine ditransitive verbs that can describe caused possession (e.g. give, throw, send) by looking at their lexical aspectual properties, a methodology that has proved fruitful for the exploration of (in)transitive verbs. I show that as a whole these ditransitives share a number of aspectual properties in common with (in)transitive verbs of change of state and motion, suggesting a single shared underlying analysis, which I outline in terms of the scalar analysis of change of Beavers (forthcoming b). However, a difficulty of such an analysis is that for many ditransitives, the putative result state (caused possession) is cancellable, which complicates how factors such as telicity are calculated on most models of aspect. To account for this, I show that all ditransitives nonetheless entail at least some non-cancellable result, though there is considerable micro-variation in what that result is. The result is an aspectually based classification of ditransitives quite similar to previously proposed classes of (in)transitives. I also show that the analysis I develop may shed some light on why certain classes of ditransitives only rarely participate in the dative alternation.

Drs. Schwartz, Winograd, and Schauben express concern that our case presented HIE therapy as dangerous. Our aim was not to cast doubt on the possible benefits this therapy option may provide. In fact, the HIE therapy used in this case assisted in stabilizing the patient’s hemodynamics and remains

Three almond field trials were conducted during 2003 and 2004 at two locations in central (Fresno County) and northern (Yolo County) California to evaluate the potential effects of commercial applications of Captan on honey bees, Apis mellifera L. Captan was applied at 5.0 kg (AI)/ha during bloom. Hives were evaluated for hive health and brood development parameters for ∼2 mo after application. This study showed that the application of Captan was not harmful to foraging honey bees or their brood. No treatment-related effects were noted on hive weights, dead bee deformity, number of dead bees, survival of individual larvae, weight of individual emerging adults, and other hive health parameters.