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The aim of the present study was to provide support for the validation of the Teammate Burnout Questionnaire (TBQ). Athletes from a variety of team sports ( N = 290) completed the TBQ and the Athlete Burnout Questionnaire (ABQ). Confirmatory factor analysis revealed acceptable fit indexes for the three-dimensional models (i.e., physical and emotional exhaustion, sport devaluation, reduced accomplishment) of the TBQ and the ABQ. Multi-trait multi-method analysis revealed that the TBQ and ABQ showed acceptable convergent and discriminant validity. The preliminary validation of the TBQ indicates the utility of the scale to reflect athletes' perceptions of their teammates' burnout and offers researchers the opportunity to quantitatively assess an important aspect of the social environment in the development of athlete burnout., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Appleby, Davis, Davis, Stenling and Vickery.)

Protection and decontamination of surfaces after exposure to chemical warfare agents (CWAs) are of considerable interest to the homeland defense and battlespace operation communities. In this work, polyurethane was spin-coated onto aluminum oxide quartz crystal microbalance (QCM) sensors. Polyurethane film thickness was varied by altering the concentration of the polymer/chloroform solution used for spin-coating. Atomic force microscopy confirmed the formation of smooth, homogeneous films on the QCM sensor surface. Aluminum oxide QCM sensors coated with polyurethane were exposed to saturated vapors of dichloropentane (DCP), a mustard gas (HD) simulant, and dimethyl methylphosphonate (DMMP), a sarin gas (GB) simulant, and the mass uptake, diffusion coefficient, volume fraction, and partition coefficient of the simulant in the film were determined from QCM data. Results showed that both DCP and DMMP readily sorbed into the films although the mass uptake of DCP was greater than that of DMMP owing to DCP's higher vapor pressure. Additionally, the CWA simulant uptake increased with polyurethane film thickness. Sorption diffusion coefficients were 1 × 10 -13 cm 2 /s and 1 × 10 -12 cm 2 /s for DCP and DMMP vapor, respectively. Simulant desorption was also measured and showed that some DMMP remained in the film/substrate system, while DCP sorption was fully reversible. Reversible desorption for both CWA simulants was relatively quick and independent over the range of film thicknesses studied, with average desorption diffusion coefficients of 2 × 10 -9 cm 2 /s and 1 × 10 -11 cm 2 /s for DCP and DMMP, respectively. Collectively, this study is expected to inform protection and decontamination strategies of equipment and structures upon exposure to CWAs., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

This study examined the influence of 7 high school esports developmental programs on student self-regulation, growth mindset, positive youth development (PYD), perceived general health and physical activity (PA), and sport behaviour. A total of 188 students (male n = 120; female n = 68) originally participated (89 enrolled in an esports program in their school and 99 acted as aged-matched controls), with 58 participants ( n = 19 esports group; n = 39 controls) completing both pre- and post-program information. At baseline, no significant differences were found between youth e-athletes and their aged-matched controls. The analysis for the observation period showed a significant interaction effect for the PYD confidence scale, with post-hoc comparisons showing a significant decrease in the control group from pre- to post assessment whereas the esports group remained the same. Time main effects showed a decrease in the self-regulation motivation factor, PYD connection factor and PA for all participants. Overall, this study showed that students enrolled in their respective school esports program did not differ from those who did not in self-regulation, growth mindset, PYD, perceived health and PA, and sport behaviour. It was likely that all participants showed a decrease in motivation, connection, and PA due to COVID19 lockdown during the study period. This study is the first to investigate the longitudinal impact of student involvement in high school esports and showed that esports participation did not have a negative impact on any health or psychological factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Trotter, Coulter, Davis, Poulus and Polman.)

The aims of the present study were twofold. First, to investigate self-reported social support, self-regulation, and psychological skill use in esports athletes (e-athletes) compared to traditional athletes. Second, to determine if self-reported social support, self-regulation, and psychological skill use influenced e-athlete in-game rank. An online survey was used to collect data from an international sample of e-athletes ( n = 1,444). The e-athletes reported less social support, self-regulation, and psychological skill use than reported by traditional athletes in previous studies. E-athletes with higher scores in social support, self-regulation, and psychological skill use was associated with higher in-game rank. The lack of an organisational structure in esports may be a contributing factor as to why e-athletes score lower than traditional athletes on social support, self-regulation, and psychological skill use. Future research is warranted to explore the development of esports programs aiming to promote athletes' social support, self-regulation, and use of psychological skills to enhance in-game performance and well-being., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trotter, Coulter, Davis, Poulus and Polman.)

COVID-19 is spreading globally with the angiotensin converting enzyme (ACE)-2 serving as the entry point of SARS-CoV-2 virus. This raised concerns how ACE2 and the Renin-Angiotensin (Ang)-System (RAS) are to be dealt with given their roles in hypertension and their involvement in COVID-19's morbidity and mortality. Specifically, increased ACE2 expression in response to treatment with ACE inhibitors (ACEi) and Ang II receptor blockers (ARBs) might theoretically increase COVID-19 risk by increasing SARS-CoV-2 binding sites. However, ACE2 is part of the protective counter-regulatory ACE2-Ang1-7-MasR axis, which opposes the classical ACE-AngII-AT1R regulatory axis. We used Gitelman's and Bartter's syndromes (GS/BS) patients, rare genetic tubulopathies that have endogenously increased levels of ACE2, to explore these issues. Specifically, 128 genetically confirmed GS/BS patients, living in Lombardia, Emilia Romagna and Veneto, the Northern Italy hot spots for COVID-19, were surveyed via telephone survey regarding COVID-19. The survey found no COVID-19 infection and absence of COVID-19 symptoms in any patient. Comparison analysis with the prevalence of COVID-19 in those regions showed statistical significance ( p < 0.01). The results of the study strongly suggest that increased ACE2 does not increase risk of COVID-19 and that ACEi and ARBs by blocking excessive AT1R-mediated Ang II activation might favor the increase of ACE2-derived Ang 1-7. GS/BS patients' increased ACE2 and Ang 1-7 levels and their characteristic chronic metabolic alkalosis suggest a mechanism similar to that of chloroquine/hydroxychloroquine effect on ACE2 glycosylation alteration with resulting SARS-COV-2 binding inhibition and blockage/inhibition of viral entry. Studies from our laboratory are ongoing to explore GS/BS ACE2 glycosylation and other potential beneficial effects of BS/GS. Importantly, the absence of frank COVID-19 or of COVID-19 symptoms in the BS/GS patients cohort, given no direct ascertainment of COVID-19 status, suggest that elevated ACE2 levels as found in GS/BS patients at a minimum render COVID-19 infection asymptomatic and thus that COVID-19 symptoms are driven by ACE2 levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Calò, Rigato, Sgarabotto, Gianesello, Bertoldi, Ravarotto and Davis.)

The isolation of Salmonella from feed is challenging and adjustments need to be made in order to accurately isolate the pathogen from feed. This is due to the complex nature of the feed matrix, which is both porous and fibrous. The outlined method below contains the essential components of a successful Salmonella methodology for the analysis of feed that overcomes the limitations of currently available methods.

The widespread effects of the coronavirus disease 2019 (COVID-19) pandemic have negatively impacted upon many athletes' mental health and increased reports of depression as well as symptoms of anxiety. Disruptions to training and competition schedules can induce athletes' emotional distress, while concomitant government-imposed restrictions (e.g., social isolation, quarantines) reduce the availability of athletes' social and emotional support. Written Emotional Disclosure (WED) has been used extensively in a variety of settings with diverse populations as a means to promote emotional processing. The expressive writing protocol has been used to a limited extent in the context of sport and predominantly in support of athletes' emotional processing during injury rehabilitation. We propose that WED offers an evidence-based treatment that can promote athletes' mental health and support their return to competition. Research exploring the efficacy of the expressive writing protocol highlights a number of theoretical models underpinning the positive effects of WED; we outline how each of these potential mechanisms can address the multidimensional complexity of the challenging circumstances arising from the COVID-19 pandemic (e.g., loss of earnings, returning to training and competition). Considerations and strategies for using WED to support athletes during the COVID-19 pandemic are presented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Davis, Gustafsson, Callow and Woodman.)

Affective responses to exercise are noted to be dynamic and frequently vacillate between positive and negative valence during physical activity. Recalled affect following exercise can influence anticipated affective responses to exercise and guide future behaviors. Research examining affective memory processes indicates that the recall of an experience can substantially differ from the actual experience and change over time. Grounded in the dual mode model (Ekkekakis, 2003), this study examines individuals' recall of exercise-related affect over a period of 2 weeks. Forty-two adults (26 women, 16 men; M age = 29.64, SD = 5.69) completed two 20-min treadmill exercise trials in a randomized control crossover design; the trials were set either at a low or high exercise intensity based upon individuals' ventilatory threshold. Data analyses indicate that the affective responses to the low-intensity condition were evaluated more positively than in the high-intensity condition. Recalled affect fluctuated over a 2-week time period following both the low- and high-intensity exercise trials. A significant reduction at the 24-h recall measurement point was observed in both exercise intensity conditions. Implications for future research and health promotion interventions aiming to optimize affective responses to exercise are presented., (Copyright © 2020 Slawinska and Davis.)

Background and Purpose: Yoga has shown promise as a treatment for depression and anxiety. The present pilot study investigated the feasibility of an eight-week grouptreatment integrating emotion-focused psychoeducation, compassion-focused therapy, and Virya yoga for depression and anxiety in primary healthcare., Materials and Methods: Patients seeking treatment for depression and anxiety in a primary healthcare centre completed either an integrative group-treatment (N = 14) or treatment as usual (TAU, N = 17). Outcome measures were analysed pre- and posttreatment. Correlations in the intervention group were investigated between treatment outcomes and amount of yoga practice between sessions., Results: Large within-group effect sizes on all outcome measures were found at posttreatment. Symptom reduction did not differ between groups (p = 0.155). Improvement in alexithymia correlated significantly (p < 0.05) with amount of yoga practice between sessions., Conclusion: Integrating yoga with a psychological group-treatment is a somewhat feasible approach to treatment for depression and anxiety in primary healthcare., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We investigated the association between obesity, self-reported physical activity, cigarette smoking, alcohol consumption, and perceived health in esports players, and the influence of player in-game rank. Data was collected with an online survey with an international participant sample of esports players representing five esports and all skill levels ( n = 1772). Esports players were more likely to be categorized as normal weight, or obesity class 2 and 3 and as non-smokers (92%) and non-drinkers (65.1%) compared to international reference data. Esports players met international physical activity guidelines less than global general population. Esports players ranked in the top 10% were more physically active compared to the remaining esports players. As esports player in-game rank increased, so did the amount of time spent playing esports. Although esports players appear generally healthy, a small group was significantly obese and most esports players did not meet physical activity guidelines, indicating potential future health risks.

Athletes' affective states can vary dramatically before, during, and after competition. Further, intense affect is associated with physiological responses that may amplify biological reactions manifested from the execution of physical tasks underlying performance. Fluctuations in perceptual cues (eg, perceived exertion) and physiological responses (eg, blood lactate, heart rate) can influence performance and vary dramatically in relation to competition. However, the pattern of these fluctuations and potential associations between perceptual cues and biological responses may also diverge during task execution with differential implications for performance. Data collected from highly trained athletes (N = 25; M age  = 25.4) during a competition (ie, maximum total distance) comprised of three 7-minute cycling time trials and were analyzed with longitudinal multilevel modeling. Results showed that affective states were negatively associated with perceived exertion at the within-person level and negatively associated with heart rate at the between-person level within each trial. Blood lactate and heart rate were positively associated at the between-person level, whereas heart rate was positively associated with perceived exertion at the within-person level. The anticipation of more pleasurable affective states predicted less decline in affective states, but not physiological responses, during each trial. Anticipated affective states prior to each trial were also associated with affective states upon its completion. These findings suggest associations among perceptual cues and physiological responses may differ depending on the level of analysis (between- vs. within-person level associations), and anticipated affective states prior to performance may influence affective states during and after task execution., (© 2020 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Gitelman's syndrome (GS) and Bartter's syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature's experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine's ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.

Evidence on cellular/molecular mechanisms leading to atrial fibrillation (AF) are scanty. Increased expression of Rho kinase (ROCK) and myosin-phosphatase-target subunit-1 (MYPT-1), ROCK activity's marker, were shown in AF patients, which correlated with connexin 40 (Cx40) expression, membrane protein of heart gap junctions, key for rapid action potential's cell-cell transfer. AF is the most frequent arrhythmia in dialysis patients who present increased MYPT-1 phosphorylation, which correlates with left ventricular (LV) mass. Given ROCK's established role in cardiovascular-renal remodeling, induction of impaired cell-to-cell coupling/potential conduction promoting AF initiation/perpetuation, we evaluated in dialysis patients with AF, MYPT-1 phosphorylation, Cx40 expression, and their relationships to support their involvement in AF. Mononuclear cells' MYPT-1 phosphorylation, Cx40 expression, and the ROCK inhibitor fasudil's effect were assessed in dialysis patients with AF (DPAFs), dialysis patients with sinus rhythm (DPs), and healthy subjects (C) (western blot). M-mode echocardiography assessed LV mass and left atrial systolic volume. DPAF's phospho-MYPT-1 was increased vs. that of DPs and C (1.57 ± 0.17 d.u. vs. 0.69 ± 0.04 vs. 0.51 ± 0.05 respectively, p < 0.0001). DP's phospho-MYPT-1 was higher vs. that of C, p = 0.009. DPAF's Cx40 was higher vs. that of DPs and C (1.23 ± 0.12 vs. 0.74 ± 0.03 vs. 0.69 ± 0.03, p < 0.0001). DPAF's phospho-MYPT-1 correlated with Cx40 ( p < 0.001), left atrial systolic volume ( p = 0.013), and LV mass ( p = 0.014). In DPAFs, fasudil reduced MYPT-1 phosphorylation ( p < 0.01) and Cx40 expression ( p = 0.03). These data point toward ROCK and Cx40's role in the mechanism(s) leading to AF in dialysis patients. Exploration of the ROCK pathway in AF could contribute to AF generation's mechanistic explanations and likely identify potential pharmacologic targets for translation into treatment., Competing Interests: The authors declare no conflict of interest.

Background: Despite a sustained focus by policymakers and researchers on improving the standard of clinical care in public mental health services, the use of evidence-based practice remains low. Among other challenges, this reflects the difficulty of translating clinical research into useable policy that can be feasibly funded and monitored by state or large healthcare systems., Case Presentation: In this paper we present a case study of Washington State's strategy for monitoring the use of clinical elements at the session level for all Medicaid-funded children's mental health services. The implementation of this strategy reflects policy actions to promote effective practice while also actively influencing multiple other levels of the implementation ecology. The approach is informed by the Policy Ecology Framework, the Consolidated Framework for Implementation Research, the evidence-based policymaking literature, and common ontology and clinical elements models., Conclusions: We found the strategy developed in Washington State to be a feasible method of collecting session level information about the use of effective clinical mental health practices. In addition, the approach appears to be having influence on multiple layers of the implementation ecology that could be explored through further study., Competing Interests: The authors declare that they have no competing interests.

Chronic kidney disease patient's progression to end-stage renal disease as well as their high mortality are linked to cardiovascular disease. However, the high incidence rate of cardiovascular morbidity and mortality in these patients is not fully accounted for by traditional cardiovascular risk factors such as diabetes, hypertension and obesity. Renal disease and CVD are associated with endothelial dysfunction, inflammation and oxidative stress and in this review we will examine what is known regarding their similar roles in both CVD and chronic kidney disease, specifically focusing on the interconnections between oxidative stress, inflammation and endothelial dysfunction. These interconnections are best visualized as a vicious circle wherein these entities coexist and communicate with each other, thereby exacerbating the processes underpinning these different entities with the end result of the high morbidity and mortality that characterize CKD patients. By exploring this vicious circle i.e. the mode and extent of the interrelationships as well as some of the underlying mechanisms involved, this review aims at outlining our current understanding as well as highlighting future avenues for research and potential targets for therapeutic intervention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Fabry disease is characterized by deficient expression/activity of α-GalA with consequent lysosomal accumulation in various organs of its substrate Gb3. Despite enzyme replacement therapy, Fabry disease progresses with serious myocardial, cerebral and renal manifestations. Gb3 accumulation may induce oxidative stress (OxSt), production of inflammatory cytokines and reduction of nitric oxide, which may impact on Fabry disease's clinical manifestations., Methods: OxSt status was characterized in 10 patients compared with 10 healthy subjects via protein expression of p22phox, subunit of NADH/NADPH oxidase, (Western blot), Heme oxygenase (HO)-1 levels (ELISA), antioxidant/anti-inflammatory, lipid peroxidation as malondialdehyde (MDA) production (colorimetric assay), phosphorylation state of Extracellular Signal Regulated Kinase (ERK)1/2 and Myosin Phosphatase Target Protein (MYPT)-1 (Western blot), marker of Rho kinase activation, both involved in OxSt signaling. Cardiac left ventricular (LV) mass was also evaluated (M-mode echocardiography)., Results: LV mass was higher in Fabry's males (123.72±2.03SEM g/m2) and females (132.09±6.72g/m2). p22phox expression was also higher in patients (1.04±0.09 d.u. vs 0.54±0.05 d.u. p<0.01) as well as MDA levels (54.51±3.97 vs 30.05±7.11 nmol/mL p = 0.01) while HO-1 was reduced (8.84±0.79 vs 14.03±1.23 ng/mL, p<0.02). MYPT-1's phosphorylation was increased in patients (0.52±0.11 d.u. vs 0.03±0.08 d.u., p<0.01) while phosphorylation of ERK1/2 was reduced (0.91±0.08 d.u. vs 1.53±0.17 d.u., p = 0.004)., Conclusions: This study documents OxSt activation and the altered reaction to it in Fabry patients. Cardiac remodeling, Rho kinase signaling activation and reduction of protective HO-1 might suggest that, in addition to enzyme replacement therapy, OxSt inhibition by either pharmacological or nutritional measures, is likely to prove useful for the prevention/treatment of Fabry patients' cardiovascular-renal remodeling., Competing Interests: This study was supported by an unrestricted grant from Sanofi- Genzyme. Linda Landini is employed by Sanofi-Genzyme. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Purpose: Gitelman's syndrome (GS) presents normo-hypotension and absence of cardiovascular-renal remodeling despite high angiotensin II (Ang II), activation of renin-angiotensin-aldosterone system and is a human model of endogenous antagonism of Ang II signaling, opposite to hypertension. GS's clinical presentation leads to questions regarding what features might be responsible. One area of investigation involves Ang II signaling. In hypertensive patients, RhoA/Rho kinase (RhoA/ROCK) pathway activation by Ang II is involved in hypertension development/maintenance and induction of long-term consequences (cardiovascular-renal remodeling), while GS has reduced p63RhoGEF gene and protein levels and ROCK activity. Ang II signaling is mediated by Gαq, which interacts with p63RhoGEF via the α6-αN linker connecting p63RhoGEF's DH and PH domains acting as a conformational switch to activate RhoA/ROCK signaling., Methods: We have investigated in GS patients, the presence of mutations in either p63RhoGEF's α6-αN linker domain and in Gαq's Ala253, Trp263, and Tyr356 residues, crucial for p63RhoGEF-Gαq interplay., Results: No mutations have been found in specific aminoacids of p63RhoGEF α6-αN linker and Gαq, key for p63RhoGEF/Gαq interplay., Conclusions: Gitelman's syndrome normo/hypotension and lack of cardiovascular-renal remodeling are not due to mutations of p63RhoGEF α6-αN linker and Gαq interactions. This opens the way for investigations on different coding and no-coding regions (p63RhoGEF and Gαq promoters) and on altered transcriptional/post-transcriptional regulation. Clarification of how these biochemical/molecular mechanisms work/interact would provide insights into mechanisms involved in the GS's Ang II signaling fine tuning, in human physiology/pathophysiology in general and could also identify significant targets for intervention in the treatments of hypertension.

Burnout is a construct that has garnered considerable attention in sport psychology within recent years. Several hypothesized models regarding how the three dimensions (exhaustion, devaluation, and reduced sense of accomplishment) temporally relate to each other have been advanced. One proposal outlined by Maslach and Leiter suggests that exhaustion predicts devaluation which predicts reduced sense of accomplishment. However, there is no consensus among researchers as it has been argued that exhaustion predicts devaluation and reduced accomplishment separately. The aim of this study was to test multiple alternative hypotheses regarding the relationships of the burnout dimensions in athletes. Two samples of Swedish youth elite athletes with differing time spans between measurements were used. Specifically, one sample involved time-intensive measures collected every week over an eight-week period, and the other sample included four measurement points across an 18-month period. Results showed that none of the previously proposed models outlining the temporal relations of burnout dimensions were supported. Statistical analysis of the models including the cross-lagged predictions of dimensions did not have any statistically significant impact except when exhaustion negatively predicted devaluation between time 1 (month 0) and time 2 (month 6) in the 18-month sample; this relation faded in the following time points. Further, issues regarding the stability of devaluation and reduced sense of accomplishment emerged as their autocorrelation were very weak in the time-intensive sample. These findings raise a number of points for further theoretical and practical discussions about the athlete burnout construct., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: Cardiovascular disease (CVD) is the leading cause of excess mortality in chronic kidney disease (CKD) and dialysis patients (DP) who have higher prevalence of left ventricular hypertrophy (LVH), the strongest predictor of CV events. Rho kinase (ROCK) activation is linked in hypertensive patients to cardiac remodeling while ROCK inhibition suppresses cardiomyocyte hypertrophy and, in a human clinical condition opposite to hypertension, its downregulation associates with lack of CV remodeling. Information on ROCK activation-LVH link in CKD and DP is lacking., Materials and Methods: Mononuclear cells (PBMCs) MYPT-1 phosphorylation, a marker of ROCK activity, and the effect of fasudil, a ROCK inhibitor, on MYPT-1 phosphorylation were assessed in 23 DPs, 13 stage 3-4 CKD and 36 healthy subjects (HS) by Western blot. LV mass was assessed by M-mode echocardiography., Key Findings: DP and CKD had higher MYPT-1 phosphorylation compared to HS (p<0.001 and p=0.003). Fasudil (500 and 1000μM) dose dependently reduced MYPT-1 phosphorylation in DP (p<0.01). DP had higher LV mass than CKD (p<0.001). MYPT-1 phosphorylation was higher in patients with LVH (p=0.009) and correlated with LV mass both in DP and CKD with LVH (p<0.001 and p=0.006)., Significance: In DP and CKD, ROCK activity tracks with LVH. This ROCK activation-LVH link provided in these CVD high-risk patients along with similar findings in hypertensive patients and added to opposite findings in a human model opposite to hypertension and in type 2 diabetic patients, identify ROCK activation as a potential LVH marker and provide further rationale for ROCK activation inhibition as target of therapy in CVD high-risk patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Wearable technology is readily available for continuous assessment due to a growing number of commercial devices with increased data capture capabilities. However, many commercial devices fail to support suitable parameters (cut points) derived from the literature to help quantify physical activity (PA) due to differences in manufacturing. A simple metric to estimate cut points for new wearables is needed to aid data analysis., Objective: The purpose of this pilot study was to investigate a simple methodology to determine cut points based on ratios between sedentary behaviour (SB) and PA intensities for a new wrist worn device (PRO-Diary™) by comparing its output to a validated and well characterised 'gold standard' (ActiGraph™)., Study Design: Twelve participants completed a semi-structured (four-phase) treadmill protocol encompassing SB and three PA intensity levels (light, moderate, vigorous). The outputs of the devices were compared accounting for relative intensity., Results: Count ratios (6.31, 7.68, 4.63, 3.96) were calculated to successfully determine cut-points for the new wrist worn wearable technology during SB (0-426) as well as light (427-803), moderate (804-2085) and vigorous (≥ 2086) activities, respectively., Conclusion: Our findings should be utilised as a primary reference for investigations seeking to use new (wrist worn) wearable technology similar to that used here (i.e., PRO-Diary™) for the purposes of quantifying SB and PA intensities. The utility of count ratios may be useful in comparing devices or SB/PA values estimated across different studies. However, a more robust examination is required for different devices, attachment locations and on larger/diverse cohorts., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Hypothesis/introduction: Angiotensin II (Ang II) has been shown to control erythropoietin (EPO) synthesis as Ang II type 1 receptor (AT1R) blockers block Ang-II-induced EPO oversecretion. To further explore the involvement of AT1R in processes controlling EPO levels, plasma EPO and mononuclear cell NADPH oxidase 4 (NOX4) - a NOX family member involved in oxygen sensing, which is a process central to controlling EPO levels - were assessed in Bartter's/Gitelman's syndrome (BS/GS) patients, a human model of endogenous AT1R antagonism and healthy subjects. Heme oxygenase (HO)-1, antioxidant and anti-inflammatory factor related to NOX4 activation, and the relationship of EPO and NOX4 to HO-1 were also assessed., Materials and Methods: EPO was measured by chemiluminescent immunoassay, HO-1 by sandwich immunoassay and NOX4 protein expression by Western blot., Results: EPO was increased in BS/GS patients compared to healthy subjects (7.64 ± 2.47 vs. 5.23 ± 1.07 U/l; p = 0.025), whereas NOX4 did not differ between BS/GS and healthy subjects (1.76 ± 0.61 vs. 1.65 ± 0.54 densitometric units; p = n.s.), and HO-1 was increased in BS/GS patients compared to healthy subjects (9.58 ± 3.07 vs. 5.49 ± 1.04 ng/ml; p = 0.003). NOX4 positively correlated with HO-1 only in BS/GS patients; no correlation was found between EPO and either NOX4 or HO-1 in those two groups., Conclusions: The effect of the renin-angiotensin system on EPO cannot be solely mediated by Ang II via AT1R signaling, but rather, EPO levels are also determined by a complex interrelated set of signals that involve AT2R, nitric oxide levels, NOX4 and HO-1 activity.

Reactive oxygen species (ROS) are intermediates in reduction-oxidation reactions that begin with the addition of one electron to molecular oxygen, generating the primary ROS superoxide, which in turn interacts with other molecules to produce secondary ROS, such as hydrogen peroxide, hydroxyl radical, and peroxynitrite. ROS are continuously produced during metabolic processes and are deemed to play an important role in cardiovascular diseases, namely, myocardial hypertrophy and fibrosis and atherosclerosis, via oxidative damage of lipids, proteins, and deoxyribonucleic acid. Angiotensin II (Ang II) is a potent vasoactive agent that also exerts mitogenic, proinflammatory, and profibrotic effects through several signaling pathways, in part involving ROS, particularly superoxide and hydrogen peroxide. Moreover, Ang II stimulates NADPH oxidases, leading to higher ROS generation and oxidative stress. Bartter/Gitelman syndrome patients, despite elevated plasma renin activity, Ang II, and aldosterone levels, exhibit reduced peripheral resistance, normal/low blood pressure, and blunted pressor effect of vasoconstrictors. In addition, notwithstanding the activation of the renin-angiotensin system and the increased plasma levels of Ang II, these patients display decreased production of ROS, reduced oxidative stress, and increased antioxidant defenses. In fact, Bartter/Gitelman syndrome patients are characterized by reduced levels of p22(phox) gene expression and undetectable plasma peroxynitrite levels, while showing increased plasma antioxidant power and expression of antioxidant enzymes, such as heme oxygenase-1. In conclusion, multifarious data suggest that Bartter and Gitelman syndrome patients are a model of low oxidative stress and high antioxidant defenses. The contribution offered by the study of these syndromes in elucidating the molecular mechanisms underlying this favorable status could offer chances for new therapeutic targets in disease characterized by high levels of reactive oxygen species., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Early identification of autism spectrum disorder (ASD) is essential to ensure that children can access specialized evidence-based interventions that can help to optimize long-term outcomes. Early identification also helps shorten the stressful "diagnostic odyssey" that many families experience before diagnosis. There have been important advances in research into the early development of ASDs, incorporating prospective designs and new technologies aimed at more precisely delineating the early emergence of ASD. Thus, an updated review of the state of the science of early identification of ASD was needed to inform best practice. These issues were the focus of a multidisciplinary panel of clinical practitioners and researchers who completed a literature review and reached consensus on current evidence addressing the question "What are the earliest signs and symptoms of ASD in children aged ≤24 months that can be used for early identification?" Summary statements address current knowledge on early signs of ASD, potential contributions and limitations of prospective research with high-risk infants, and priorities for promoting the incorporation of this knowledge into clinical practice and future research., (Copyright © 2015 by the American Academy of Pediatrics.)

This article reviews current evidence for autism spectrum disorder (ASD) interventions for children aged <3 years, based on peer-reviewed articles published up to December 2013. Several groups have adapted treatments initially designed for older, preschool-aged children with ASD, integrating best practice in behavioral teaching methods into a developmental framework based on current scientific understanding of how infants and toddlers learn. The central role of parents has been emphasized, and interventions are designed to incorporate learning opportunities into everyday activities, capitalize on "teachable moments," and facilitate the generalization of skills beyond the familiar home setting. Our review identified several comprehensive and targeted treatment models with evidence of clear benefits. Although some trials were limited to 8- to 12-week outcome data, enhanced outcomes associated with some interventions were evaluated over periods as long as 2 years. Based on this review, recommendations are proposed for clinical practice and future research., (Copyright © 2015 by the American Academy of Pediatrics.)

This article reviews current evidence for autism spectrum disorder (ASD) screening based on peer-reviewed articles published to December 2013. Screening provides a standardized process to ensure that children are systematically monitored for early signs of ASD to promote earlier diagnosis. The current review indicates that screening in children aged 18 to 24 months can assist in early detection, consistent with current American Academy of Pediatrics' recommendations. We identify ASD-specific and broadband screening tools that have been evaluated in large community samples which show particular promise in terms of accurate classification and clinical utility. We also suggest strategies to help overcome challenges to implementing ASD screening in community practice, as well as priorities for future research., (Copyright © 2015 by the American Academy of Pediatrics.)

Recent evidence showed that endogenous nicotinamide adenine dinucleotide phosphate-oxidase 4 (NOX4) may exert a protective role on the cardiovascular system inducing vasodilation, reduction of blood pressure, and anti-proliferative actions. However, the functional significance of NOX4 in the cardiovascular system in humans remains elusive. Mononuclear cell levels of NOX4 were assessed by immunoblotting in 14 Gitelman's patients (GS), a unique human model of endogenous Ang II signaling antagonism and activation of anti-atherosclerotic and anti-remodeling defenses, and compared to 11 untreated essential hypertensive patients as well as to 11 healthy normotensive subjects. The association between NOX4 and its effector heme oxygenase (HO-1) (sandwich immunoassay) was also evaluated. NOX4 protein levels were decreased in hypertensive patients as compared to both GS and healthy subjects (1.06±0.31 AU vs. 1.76±0.54, P=0.002 and vs. 1.61±0.54, P=0.018, respectively). NOX4 protein level did not differ between GS and healthy subjects. HO-1 levels were increased in GS patients as compared to both hypertensive patients and healthy subjects (8.65±3.08 ng/ml vs 3.70±1.19, P<0.0001, and vs 5.49±1.04, P=0.008, respectively. NOX4 levels correlate with HO-1 levels only in GS (r(2)=0.63; P=0.001), (r(2)=0.088; P=ns, in hypertensive patients and r(2)=0.082; P=ns, in healthy subjects). Our findings show that NOX4 and its effector HO-1 are reduced in hypertensive patients compared to GS patients, a human model opposite to hypertension. Although the functional significance of NOX4 needs further clarification, our preliminary data in a unique human model of anti-atherosclerotic and anti-remodeling defenses activation, highlight the potentially protective role of NOX4 in the human cardiovascular system.

Cinnamon ( ròu guì) has in vitro insulin potentiating activity, and proanthocyanidins from cinnamon prevent in vitro formation of advanced glycation end products. Some human studies were equivocal, but several have shown beneficial effects of cinnamon supplementation on circulating glucose, lipids, and/or insulin. This placebo-controlled double-blind trial tested the effects of a dried water extract of cinnamon ( Cinnamomum cassia ) on circulating glucose, lipids, insulin, and insulin resistance. Men and women from Beijing and Dalian, China, were invited to participate if they had fasting serum glucose >6.1 mmol/L or 2-h glucose >7.8 mmol/L. Participants, (173 were enrolled and 137 completed the study) were randomly assigned to receive either a spray-dried, water extract of cinnamon (CinSulin ® ), 250 mg/capsule, or a placebo, twice a day for two months. Mean ± SEM age of participants was 61.3 ± 0.8 years, BMI was 25.3 ± 0.3 and M/F ratio was 65/72. After 2 mo, fasting glucose decreased (p < 0.001) in the cinnamon extract-supplemented group (8.85 ± 0.36 to 8.19 ± 0.29 mmol/L) compared with the placebo group (8.57 ± 0.32 to 8.44 ± 0.34 mmol/L, p = 0.45). Glucose 2 h after a 75 g carbohydrate load, fasting insulin, and HOMA-IR also decreased with cinnamon extract compared with placebo. Total and LDL-cholesterol decreased with cinnamon extract and HDL-cholesterol decreased in both the cinnamon-extract and placebo groups. In conclusion, supplementation with 500 mg of water-extract of cinnamon for two months reduced fasting insulin, glucose, total cholesterol, and LDL cholesterol and enhanced insulin sensitivity of subjects with elevated blood glucose.

Dietary changes could potentially reduce prostate cancer morbidity and mortality. Transgenic adenocarcinoma of the mouse prostate (TRAMP) prostate tumor responses to a 100 g of fat/kg diet (whole walnuts, walnut oil, and other oils; balanced for macronutrients, tocopherols [α-and γ]) for 18 weeks ad libitum were assessed. TRAMP mice (n=17 per group) were fed diets with 100 g fat from either whole walnuts (diet group WW), walnut-like fat (diet group WLF, oils blended to match walnut's fatty acid profile), or as walnut oil (diet group WO, pressed from the same walnuts as WW). Fasted plasma glucose was from tail vein blood, blood was obtained by cardiac puncture, and plasma stored frozen until analysis. Prostate (genitourinary intact [GUI]) was weighed and stored frozen at -80°C. Plasma triglyceride, lipoprotein cholesterol, plasma multianalyte levels (Myriad RBM Rat Metabolic MAP), prostate (GUI), tissue metabolites (Metabolon, Inc., Durham, NC, USA), and mRNA (by Illumina NGS) were determined. The prostate tumor size, plasma insulin-like growth factor-1 (IGF-1), high density lipoprotein, and total cholesterol all decreased significantly (P<.05) in both WW and WO compared to WLF. Both WW and WO versus WLF showed increased insulin sensitivity (Homeostasis Model Assessment [HOMA]), and tissue metabolomics found reduced glucose-6-phosphate, succinylcarnitine, and 4-hydroxybutyrate in these groups suggesting effects on cellular energy status. Tissue mRNA levels also showed changes suggestive of altered glucose metabolism with WW and WO diet groups having increased PCK1 and CIDEC mRNA expression, known for their roles in gluconeogenesis and increased insulin sensitivity, respectively. WW and WO group tissues also had increased MSMB mRNa a tumor suppressor and decreased COX-2 mRNA, both reported to inhibit prostate tumor growth. Walnuts reduced prostate tumor growth by affecting energy metabolism along with decreased plasma IGF-1 and cholesterol. These effects are not due to the walnut's N-3 fatty acids, but due to component(s) found in the walnut's fat component.

Angiotensin II (Ang II) plays a key role in hypertension, renal and cardiovascular pathophysiology via intracellular pathways that involve the activation of a multiplicity of signaling mechanisms. Although experimental and genetic animal models have been developed and used to explore Ang II signaling's role in hypertension, a complete understanding of the processes mediating Ang II signaling in hypertension in humans remains elusive. One impediment is that these animal models do not exhibit all the traits of human hypertension, making it impossible to extrapolate from them to humans. To overcome this issue, we have used patients with Bartter's and Gitelman's syndromes, a human model of endogenously blunted and blocked Ang II signaling that presents a constellation of clinical findings which manifest themselves as the opposite of hypertension. This article reviews the aspects of the pathophysiology of human hypertension and its short and long term sequelae, and uses the results of our studies in Bartter's and Gitelman's syndromes along with those of others to gain better insight and understanding of the role of Ang II signaling in these processes.

The plant hormone abscisic acid (ABA) controls many aspects of plant growth and development, including seed development, germination and responses to water-deficit stress. A complex ABA signaling network integrates environmental signals including water availability and light intensity and quality to fine-tune the response to a changing environment. To further define the regulatory pathways that control water-deficit and ABA responses, we carried out a gene-trap tagging screen for water-deficit-regulated genes in Arabidopsis thaliana. This screen identified PLASTID MOVEMENT IMPAIRED1 (PMI1), a gene involved in blue-light-induced chloroplast movement, as functioning in ABA-response pathways. We provide evidence that PMI1 is involved in the regulation of seed germination by ABA, acting upstream of the intersection between ABA and low-glucose signaling pathways. Furthermore, PMI1 participates in the regulation of ABA accumulation during periods of water deficit at the seedling stage. The combined phenotypes of pmi1 mutants in chloroplast movement and ABA responses indicate that ABA signaling may modulate chloroplast motility. This result was further supported by the detection of altered chloroplast movements in the ABA mutants aba1-6, aba2-1 and abi1-1., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background & Aims: Cardiovascular disease, the most common cause for morbidity and mortality in end-stage renal disease (ESRD), has prompted the exploration of multiple approaches to improve outcomes. Cardiovascular risk factors such as oxidative stress (OxSt) and cardiac remodelling are common in ESRD and dialysis patients. Green tea (GT) is well recognized as reducing OxSt. This 6 months study evaluated in 20 ESRD patients under chronic dialysis, the effect of GT treatment (1 g/day as commercially available capsule) on cellular and plasma OxSt and proliferation related markers using a molecular biology approach., Methods: Mononuclear cell p22(phox), Haeme Oxygenase (HO)-1 protein expression, and phosphorylated ERK1/2 status were evaluated in dialysis patients at baseline, after 3 and 6 months of GT treatment by Western blot analysis and plasma oxLDL by ELISA. Cardiac remodelling was assessed by echocardiographic left ventricular (LV) mass determination at baseline and at the end of the study., Results: GT treatment reduced p22(phox) and pERK1/2 from baseline while HO-1 increased. At baseline, LV mass correlated with both p22(phox) and oxLDL. GT treatment decreased LV mass from baseline, which correlated with oxLDL. 9 patients had LV hypertrophy at baseline, which, at 6 months, was normalized in 5 and reduced in 3, showing a parallel decrease of p22(phox), pERK1/2, oxLDL and increase of HO-1., Conclusions: Treatment with GT decreased the expression of OxSt-related proteins tightly associated with cardiovascular disease and decreased LV mass. It appears highly likely that the addition of GT can provide a benefit in terms of cardiovascular protection in dialysis patients., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Natural selection on photosynthetic performance is a primary factor determining leaf phenotypes. The complex CO2 diffusion path from substomatal cavities to the chloroplasts - the mesophyll conductance (g(m)) - limits photosynthetic rate in many species and hence shapes variation in leaf morphology and anatomy. Among sclerophyllous and succulent taxa, structural investment in leaves, measured as the leaf dry mass per area (LMA), has been implicated in decreased gm . However, in herbaceous taxa with high g(m), it is less certain how LMA impacts CO2 diffusion and whether it significantly affects photosynthetic performance. We addressed these questions in the context of understanding the ecophysiological significance of leaf trait variation in wild tomatoes, a closely related group of herbaceous perennials. Although g(m) was high in wild tomatoes, variation in g(m) significantly affected photosynthesis. Even in these tender-leaved herbaceous species, greater LMA led to reduced g(m). This relationship between g(m) and LMA is partially mediated by cell packing and leaf thickness, although amphistomy (equal distribution of stomata on both sides of the leaf) mitigates the effect of leaf thickness. Understanding the costs of increased LMA will inform future work on the adaptive significance of leaf trait variation across ecological gradients in wild tomatoes and other systems., (© 2013 John Wiley & Sons Ltd.)

Background: Both increased and decreased levels of the adipokine retinol-binding protein 4 (RBP4) have been reported in cardiovascular disease, and levels of RBP4 have been related to diabetes, metabolic syndrome and cardiovascular risk. Recently, clear in vitro and ex vivo vasodilatory and inhibitory of platelet activation effects of RBP4 has been shown and a reduced RBP4 level was found in high cardiovascular risk patients, suggesting a potential cardiovascular protective role for increased levels of RBP4., Patients and Methods: Plasma level of RBP4 (ELISA) was determined in a cohort of Bartter's and Gitelman's syndrome (BS/GS) patients, a human model of endogenous Ang II signalling antagonism and activation of anti-atherosclerotic and antiremodelling defenses, the opposite of cardiovascular risk patients, and in healthy normotensive subjects. Haem Oxygenase (OH)-1 protein level (sandwich immunoassay) as a potential mediator of RBP4 stimulation of PI3K/Akt pathway and flow-mediated dilation (FMD) as a measure of endothelium (NO)-dependent response have also been measured., Results: RBP4 in BS/GS patients (40·59 ± 15·32 μg/mL vs. 25·05 ± 5·56, P = 0·011) along with HO-1 protein levels (9·44 ± 3·09 ng/mL vs. 5·49 ± 1·04, P = 0·003) and FMD (10·52% ± 2·22 vs. 7·99 ± 1·13 P = 0·006) were significantly increased compared with healthy normotensive subjects., Conclusions: The increase of RBP4 in BS/GS, a human model of endogenous Ang II signalling antagonism and activation of anti-atherosclerotic and antiremodelling defenses, the opposite of cardiovascular risk patient, found in concert with an increased NO-mediated vasodilation and HO-1 levels supports a protective role for this adipokine in vascular protection/cardiovascular risk., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

The mean expected value of the OBT/HTO ratio (i.e. generic ratio) is derived in this study on the joint basis of a long-term study conducted at Atomic Energy of Canada Limited (AECL)'s Chalk River Laboratories (CRL), model simulations targeted at filling gaps in a yet incomplete timeline of CRL measurements and a reference dataset comprised of numerous experiments reported in the literature. Cultivar variability and disparity in site-specific settings are covered by the reference dataset. Dynamical variability caused by meteorology has been a specific target of the long-term experimental campaign at CRL, where the former two types of variability were eliminated. The distribution of OBT/HTO ratios observed at CRL appears to be a fairly good match to the distribution of OBT/HTO ratios from the literature. This implies that dynamical variability appears important in both cases. Dynamics of atmospheric HTO at CRL is comprised of a sequence of episodes of atmospheric HTO uptake and re-emission of plant HTO. The OBT/HTO ratio appears sensitive to the proportion of the duration of these two episodes: the lesser the frequency (and duration) of plume arrivals, the higher the expected mean OBT/HTO ratio. With the plume arrival frequency defined by the typical wind rose, one would encounter a mean OBT/HTO ratio close to 2. It is important to note that this number is seen both in the reference dataset, and in the continuous timeline of HTO and OBT reconstructed from CRL observations by dynamical interpolation (modelling). Many datasets (including that of CRL) targeted at the OBT/HTO ratio are biased high compared to the suggested number. This could be explained by scarce measurements of the low OBT/HTO ratios in the short phase of uptake of atmospheric HTO by the plant., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Objective: p63RhoGEF, a guanine nucleotide exchange factor, has been reported 'in vitro' as key mediator of the angiotensin II-induced RhoA/Rho kinase activation leading to vasoconstriction and cardiovascular remodeling. We assessed p63RhoGEF gene and protein expression and RhoA/Rho kinase activity in essential hypertensive and Bartter's and Gitelman's syndrome patients, a human model opposite to hypertension; the latter have, in fact, increased plasma angiotensin II, activation of the renin-angiotensin system, yet normotension/hypotension, reduced peripheral resistance and lack of cardiovascular remodeling due to an endogenously blunted angiotensin II type 1 receptor signaling., Methods: Mononuclear cell p63RhoGEF gene and protein expression and the phosphorylation status of the myosin phosphatase target protein-1 (MYPT-1), marker of Rho kinase activity, were assessed in essential hypertensive patients, Bartter's/Gitelman's patients and healthy individuals by quantitative real-time PCR and western blot., Results: p63RhoGEF mRNA and protein level and MYPT-1 phosphorylation status were higher in hypertensive patients and lower in Bartter's/Gitelman's patients compared with healthy individuals: p63RhoGEF mRNA level: 0.59 ± 0.17 ΔΔCt vs. 0.37 ± 0.17 vs. 0.20 ± 0.19, analysis of variance (ANOVA): P <0.016; p63RhoGEF protein level 1.35 ± 0.14 vs. 1.09 ± 0.05 vs. 0.90 ± 0.09 densitometric units, ANOVA: P <0.0001; MYPT-1: 1.39 ± 0.34 vs. 1.01 ± 0.12 vs. 0.81 ± 0.06, ANOVA: P < 0.0001. p63RhoGEF mRNA was significantly correlated with both SBP and DBP in both hypertensive patients (R = 0.79, P < 0.02 and R = 0.78, P < 0.02) and in Bartter's syndrome/Gitelman's syndrome patients (R = 0.87, P < 0.001 and R = 0.86, P < 0.001), respectively., Conclusion: Increased p63RhoGEF mRNA and protein level and Rho kinase activity are shown for the first time in essential hypertensive patients, whereas the opposite was found in Bartter's/Gitelman's patients, a human model opposite to hypertension. These results combined with other 'in-vitro' studies strongly support the crucial importance of p63RhoGEF in Ang II-mediated signaling involved in the regulation of blood pressure and its long-term complications in humans.

It has become increasingly recognized that organically bound tritium (OBT) is the more significant tritium fraction with respect to understanding tritium behaviour in the environment. There are many different terms associated with OBT; such as total OBT, exchangeable OBT, non-exchangeable OBT, soluble OBT, insoluble OBT, tritiated organics, and buried tritium, etc. A simple classification is required to clarify understanding within the tritium research community. Unlike for tritiated water (HTO), the environmental quantification and behaviour of OBT are not well known. Tritiated water cannot bio-accumulate in the environment. However, it is not clear whether or not this is the case for OBT. Even though OBT can be detected in terrestrial biological materials, aquatic biological materials and soil samples, its behaviour is still in question. In order to evaluate the radiation dose from OBT accurately, further study will be required to understand OBT measurements and determine OBT fate in the environment. The relationship between OBT speciation and the OBT/HTO ratio in environmental samples will be useful in this regard, providing information on the previous tritium exposure conditions in the environment and the current tritium dynamics., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Premise of the Study: Within plastids, geranylgeranyl diphosphate synthase is a key enzyme in the isoprenoid biosynthetic pathway that catalyzes the formation of geranylgeranyl diphosphate, a precursor molecule to several biochemical pathways including those that lead into the biosynthesis of carotenoids and abscisic acid, prenyllipids such as the chlorophylls, and diterpenes such as gibberellic acid. •, Methods: We have identified mutants in the GERANYLGERANYL DIPHOSPHATE SYNTHASE 1 (GGPS1) gene, which encodes the major plastid-localized enzyme geranylgeranyl diphosphate synthase in Arabidopsis thaliana. •, Key Results: Two T-DNA insertion mutant alleles (ggps1-2 and ggps1-3) were found to result in seedling-lethal albino and embryo-lethal phenotypes, respectively, indicating that GGPS1 is an essential gene. We also identified a temperature-sensitive leaf variegation mutant (ggps1-1) in A. thaliana that is caused by a point mutation. Total chlorophyll and carotenoid levels were reduced in ggps1-1 white tissues as compared with green tissues. Phenotypes typically associated with a reduction in gibberellic acid were not seen, suggesting that gibberellic acid biosynthesis is not noticeably altered in the mutant. In contrast to other variegated mutants, the ggps1-1 green sector photosynthetic rate was not elevated relative to wild-type tissues. Chloroplast development in green sectors of variegated leaves appeared normal, whereas cells in white sectors contained abnormal plastids with numerous electron translucent bodies and poorly developed internal membranes. •, Conclusions: Our results indicate that GGPS1 is a key gene in the chlorophyll biosynthetic pathway.

Reduced NO availability is associated with endothelial dysfunction, hypertension, insulin resistance and cardiovascular remodeling. SIRT1 upregulates eNOS activity and inhibits endothelial cell senescence, and reduced SIRT1 is related to oxidative stress and reduced NO-dependent dilation. Bartter's/Gitelman's syndromes (BS/GS) are rare diseases that feature a picture opposite to that of hypertension in that they present with normo/hypotension, reduced oxidative stress and a lack of cardiovascular remodeling, notwithstanding high levels of angiotensin II and other vasopressors, upregulation of NO system, and increased NO-dependent vasodilation (FMD), as well as increase in both endothelial progenitor cells and insulin sensitivity. To our knowledge, in BS/GS patients SIRT1 has never been evaluated. BS/GS patients' mononuclear cell SIRT1 (western blot), FMD (B-mode scan of the right brachial artery) and heme oxygenase (HO)-1 (sandwich immunoassay), a potent antioxidant protein, were compared with the levels in untreated stage 1 essential hypertensive patients (HPs) and in healthy subjects (C). SIRT1 (1.86 ± 0.29 vs. 1.18 ± 0.18 (HP) vs. 1.45 ± 0.18 (C) densitometric units, P<0.0001) and HO-1 protein (9.44 ± 3.09 vs. 3.70 ± 1.19 (HP) vs. 5.49 ± 1.04 (C) ng ml⁻¹, P<0.0001) levels were higher in BS/GS patients than in the other groups. FMD was also higher in BS/GS patients: 10.52 ± 2.22% vs. 5.99 ± 1 .68% (HP) vs. 7.99 ± 1.13% (C) (ANOVA: P<0.0001). A strong and significant correlation between SIRT1 and FMD was found only in BS/GS patients (r(2)=0.63, P=0.0026). Increased SIRT1 and its direct relationship with increased FMD in BS/GS patients, while strengthening the relationship among SIRT1, NO and vascular function in humans, point toward a role for reduced SIRT1 in the endothelial dysfunction of hypertension.