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The Regional Gallery of Fine Arts in Zlín prepared an exhibition of the painter Jan Merta (*1952), one of the most significant Czech painters from the breakthrough generation of the 1980s. Merta, based on the reflection of contemporary postmodern tendencies and, on the basis of his own situational self-reflection, has brought radical changes to Czech fine art. He projects issues from the real-world through his own memory into unique visualizations of his own experiences. As a narrator, he transforms all types of childhood memories, people, and events into a concrete form. By placing them in other contexts and processing them freely, he is able to assign them with a new content. Merta’s first solo exhibition at the KGVU in Zlín aims to present a cross-section of his work from the past 20 years, focusing on the paintings from his “personal vault”. The author then speaks to Jan Merta and discusses the exhibition, his work, life, and family [ABSTRACT FROM AUTHOR]

18 Participants were randomized to receive 30 ml/kg bodyweight Ringer's Lactate at 37° or 15 °C over 30 min. In a second session, participants were crossed over. Over a 120 min period after starting the fluid bolus we measured mean arterial pressure (MAP), cardiac output, systemic vascular resistance, and catecholamine levels. After infusion with cold fluids, the absolute increase in MAP at 45 min was significantly higher at + 6.5 mmHg (95% CI 4.8-8.2) compared with warm fluids (+ 0.6 mmHg, 95% CI, - 1.6 to 2.8; p < 0.001). This increase in MAP was longer-lasting after cold fluids (81.7 min, 95% CI 62.5-100.9) than after warm fluids (19.2, 95% CI 3.4-35; p < 0.001). While cardiac output was similar, systemic vascular resistance increase was greater after cold fluids (159 dyn s/cm 5 , 95% CI 9.5-309) compared to warm fluids (- 66 dyn s/cm 5 , 95% CI - 191 to 57; p = 0.012). Moreover, noradrenaline increased by up to 246% during cold fluids, and decreased with warm fluids (p < 0.001). Fluid bolus given at 15 °C, compared to 37 °C, leads to a greater and more prolonged increase in MAP accompanied by release of intrinsic noradrenaline and vasoconstriction. These results suggest that fluid temperature rather than volume is predominantly responsible for any increase in MAP.Trial Registration: EudraCT-nummer 2022-002137-34 and clinicaltrials.gov NCT05610254 (first registration 09/11/2022)., (© 2024. The Author(s).)

Ultrafine particles (UFPs) are airborne particles with a diameter of less than 100 nm. They are emitted from various sources, such as traffic, combustion, and industrial processes, and can have adverse effects on human health. Long-term mean ambient average particle size (APS) in the UFP range varies over space within cities, with locations near UFP sources having typically smaller APS. Spatial models for lung deposited surface area (LDSA) within urban areas are limited and currently there is no model for APS in any European city. We collected particle number concentration (PNC), LDSA, and APS data over one-year monitoring campaign from May 2021 to May 2022 across 27 locations and estimated annual mean in Copenhagen, Denmark, and obtained additionally annual mean PNC data from 6 state-owned continuous monitors. We developed 94 predictor variables, and machine learning models (random forest and bagged tree) were developed for PNC, LDSA, and APS. The annual mean PNC, LDSA, and APS were, respectively, 5523 pt/cm 3 , 12.0 μm 2 /cm 3 , and 46.1 nm. The final R 2 values by random forest (RF) model were 0.93 for PNC, 0.88 for LDSA, and 0.85 for APS. The 10-fold, repeated 10-times cross-validation R 2 values were 0.65, 0.67, and 0.60 for PNC, LDSA, and APS, respectively. The root mean square error for final RF models were 296 pt/cm 3 , 0.48 μm 2 /cm 3 , and 1.60 nm for PNC, LDSA, and APS, respectively. Traffic-related variables, such as length of major roads within buffers 100-150 m and distance to streets with various speed limits were amongst the highly-ranked predictors for our models. Overall, our ML models achieved high R 2 values and low errors, providing insights into UFP exposure in a European city where average PNC is quite low. These hyperlocal predictions can be used to study health effects of UFPs in the Danish Capital., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cisplatin is a potent cytotoxic agent used in the treatment of various malignancies and exerts its antitumor effect through malignant cell DNA damage and apoptosis induction. Evaluation of systemic delivery of cisplatin is important in optimization of cisplatin treatment. However, accurate quantification of systemic cisplatin is challenging due to its various forms in circulation. This study aimed to develop a sensitive (LOQ < 0.1 µg/mL) and precise Ultra Performance Liquid Chromatography (UPLC) - Tandem Mass Spectrometry (MS/MS) method for quantifying free cisplatin in microdialysates and plasma. Furthermore the aim was to compare free cisplatin concentrations measured in standard plasma samples with those obtained from intravenous microdialysis catheters in a porcine model. The method developed utilizes dichloro(ethylenediamine)platinum(II) as an internal standard that co-elutes with cisplatin, ensuring precise correction for ion suppression/enhancement effects. The method was validated, demonstrating linearity up to 100 µg/mL and good intermediate precision (CV% < 6 %) in the range of 1.0-100 µg/mL, with an LOQ of 0.03 µg/mL. The pharmacokinetic parameters (AUC 0-last , C max , T 1/2 , and T max ) showed no significant differences between the two sampling methods. This validated LC-MS/MS method provides a reliable tool for quantifying systemic free cisplatin concentrations, facilitating future systemic and local pharmacokinetic evaluations for optimization of cisplatin-based cancer treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Ultrafine particles (UFP; particulate matter <0.1 μm in diameter) may be more harmful to human health than larger particles, but epidemiological evidence on their health effects is still limited. In this study, we examined the association between short-term exposure to UFP and mortality and hospital admissions in Copenhagen, Denmark. Daily concentrations of UFP (measured as particle number concentration in a size range 11-700 nm) and meteorological variables were monitored at an urban background station in central Copenhagen during 2002-2018. Daily counts of deaths from all non-accidental causes, as well as deaths and hospital admissions from cardiovascular and respiratory diseases were obtained from Danish registers. Mortality and hospital admissions associated with an interquartile range (IQR) increase in UFP exposure on a concurrent day and up to six preceding days prior to the death or admission were examined in a case-crossover study design. Odds ratios (OR) with 95% confidence intervals (CI) per one IQR increase in UFP were estimated after adjusting for temperature and relative humidity. We observed 140,079 deaths in total, 236,003 respiratory and 342,074 cardiovascular hospital admissions between 2002 and 2018. Hospital admissions due to respiratory and cardiovascular diseases were significantly positively associated with one IQR increase in UFP (OR: 1.04 [95% CI: 1.01, 1.07], lag 0-4, and 1.02 [1.00, 1.04], lag 0-1, respectively). Among the specific causes, the strongest associations were found for chronic obstructive pulmonary disease (COPD) mortality and asthma hospital admissions and two-day means (lag 0-1) of UFP (OR: 1.13 [1.01, 1.26] and 1.08 [1.00, 1.16], respectively, per one IQR increase in UFP). Based on 17 years of UFP monitoring data, we present novel findings showing that short-term exposure to UFP can trigger respiratory and cardiovascular diseases mortality and morbidity in Copenhagen, Denmark. The strongest associations with UFP were observed with COPD mortality and asthma hospital admissions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

Background and Aim: Primary Raynaud's phenomenon (pRP) is characterized by an exaggerated response to cold, resulting in the whitening typically of the fingers and toes. The patients are generally perceived as healthy individuals with a benign condition. However, the condition has been associated with increased cardiovascular mortality and changes in autonomic nervous system activity. This study aimed to investigate whether pRP is associated with pervasive changes in autonomic nervous activity. The hypothesis was that patients with pRP have increased sympathetic nervous activity., Methods: The autonomic nervous activity of 22 patients with pRP was investigated by means of heart rate variability (HRV) and the plasma catecholamine response to head-up tilt and compared with 22 age- and gender-matched controls. In addition, the patients were examined with a [ 123 I]metaiodobenzylguanidine heart scintigraphy and compared with an external control group., Results: The plasma norepinephrine response to head-up tilt was significantly lower in the patient group than in the control group. Similarly, the heart scintigraphy revealed a lower heart-to-mediastinum ratio in the patient group than in the control group. HRV analysis did not reveal significant differences between the groups., Conclusion: The findings of the study showed that the autonomic nervous activity of patients with pRP was altered compared with the activity of healthy individuals. This was observed both during rest and after positional stress, but the findings did not uniformly concur with our initial hypothesis., (© 2021 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Ultrafine particles (UFP), harmful to human health, are emitted at high levels from motorized traffic. Bicycle commuting is increasingly encouraged to reduce traffic emissions and increase physical activity, but higher breathing rates increase inhaled UFP concentrations while in traffic. We assessed exposure to UFP while cycling along a fixed 8.5 km inner-city route in Copenhagen, on weekdays over six weeks (from September to October 2020), during morning and afternoon rush-hour, as well as morning non-rush-hour, traffic time periods starting from 07:45, 15:45, and 09:45 h, respectively. Continuous measurements were made (each second) of particle number concentration (PNC) and location. PNC levels were summarized and compared across time periods. We used generalized additive models to adjust for meteorological factors, weekdays and trends. A total of 61 laps were completed, during 28 days (∼20 per time period). Overall mean PNC was 18,149 pt/cm 3 (range 256-999,560 pt/cm 3 ) with no significant difference between morning rush-hour (18003 pt/cm 3 ), afternoon rush-hour (17560 pt/cm 3 ) and late morning commute (17560 pt/cm 3 ) [p = 0.85]. There was substantial spatial variation of UFP exposure along the route with highest PNC levels measured at traffic intersections (∼38,000-42000 pt/cm 3 ), multiple lane roads (∼38,000-40000 pt/cm 3 ) and construction sites (∼44,000-51000 pt/cm 3 ), while lowest levels were measured at smaller streets, areas with open built environment (∼12,000 pt/cm 3 ), as well as at a bus-only zone (∼15,000 pt/cm 3 ). UFP exposure in inner-city Copenhagen did not differ substantially when bicycling in either rush-hour or non-rush-hour, or morning or afternoon, traffic time periods. UFP exposure varied substantially spatially, with highest concentrations around intersections, multiple lane roads, and construction sites. This suggests that exposure to UFP is not necessarily reduced by avoiding rush-hours, but by avoiding sources of pollution along the bicycling route., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ultrafine particles (UFP; particulate matter <0.1 μm diameter) emitted from motorized traffic may be highly detrimental to health. Active mobility (walking, bicycling) is increasingly encouraged as a way to reduce traffic congestion and increase physical activity levels. However, it has raised concerns of increased exposure to UFP, due to increased breathing rates in traffic microenvironments, immediately close to their source. The recent Coronavirus Disease 2019 (COVID-19) societal closures reduced commuting needs, allowing a natural experiment to estimate contributions from motorized traffic to UFP exposure while walking or bicycling. From late-March to mid-July 2020, UFP was repeatedly measured while walking or bicycling, capturing local COVID-19 closure ('Phase 0') and subsequent phased re-opening ('Phase 1', '2', '2.1' & '3'). A DiSCmini continuously measured particle number concentration (PNC) in the walker/bicyclist's breathing zone. PNC while walking or bicycling was compared across phased re-openings, and the effect of ambient temperature, wind speed and direction was determined using regression models. Approximately 40 repeated 20-minute walking and bicycling laps were made over 4 months during societal re-opening phases related to the COVID-19 pandemic (late-March to mid-July 2020) in Copenhagen. Highest median PNC exposure of both walking (13,170 pt/cm 3 , standard deviation (SD): 3560 pt/cm 3 ) and bicycling (21,477 pt/cm 3 , SD: 8964) was seen during societal closures (Phase 0) and decreased to 5367 pt/cm 3 (SD: 2949) and 8714 pt/cm 3 (SD: 4309) in Phase 3 of re-opening. These reductions in PNC were mainly explained by meteorological conditions, with most of the deviation explained by wind speed (14-22%) and temperature (10-13%). Highest PNC was observed along major roads and intersections. In conclusion, we observed decreases in UFP exposure while walking and bicycling during societal re-opening phases related to the COVID-19 pandemic, due largely to meteorological factors (e.g., wind speed and temperature) and seasonal variations in UFP levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000 mg GSH per day or placebo for 3 weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H 2 O 2 ) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (∼19%) in the GSH group; no change was seen in GSH to glutathione disulfide ratio. Skeletal muscle mitochondrial H 2 O 2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine or the DNA oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty: Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without T2DM. H 2 O 2 emission rate from skeletal muscle mitochondria was not affected by GSH supplementation.

Background: Postbariatric hypoglycemia (PBH) is a potentially serious complication after Roux-en-Y gastric bypass (RYGB), and impaired counterregulatory hormone responses have been suggested to contribute to the condition., Objectives: We evaluated counterregulatory responses during postprandial hypoglycemia in individuals with PBH who underwent RYGB., Setting: University hospital., Methods: Eleven women with documented PBH who had RYGB underwent a baseline liquid mixed meal test (MMT) followed by 5 MMTs preceded by treatment with (1) acarbose 50 mg, (2) sitagliptin 100 mg, (3) verapamil 120 mg, (4) liraglutide 1.2 mg, and (5) pasireotide 300 μg. Blood was collected at fixed time intervals. Plasma and serum were analyzed for glucose, insulin, glucagon, epinephrine, norepinephrine, pancreatic polypeptide (PP), and cortisol., Results: During the baseline MMT, participants had nadir blood glucose concentrations of 3.3 ± .2 mmol/L. At the time of nadir glucose, there was a small but significant increase in plasma glucagon. Plasma epinephrine concentrations were not increased at nadir glucose but were significantly elevated by the end of the MMT. There were no changes in norepinephrine, PP, and cortisol concentrations in response to hypoglycemia. After treatment with sitagliptin, 8 individuals had glucose nadirs <3.2 mmol/L (versus 4 individuals at baseline), and significant increases in glucagon, PP, and cortisol responses were observed., Conclusions: In response to postprandial hypoglycemia, individuals with PBH who underwent RYGB only had minor increases in counterregulatory hormones, while larger hormone responses occurred when glucose levels were lowered during treatment with sitagliptin. The glycemic threshold for counterregulatory activation could be altered in individuals with PBH, possibly explained by recurrent hypoglycemia., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The catecholamines, epinephrine (E) and norepinephrine (NE) are important both as neurotransmitters and hormones, and measurement of E and NE in plasma is therefore of great interest in medical research. However, the low concentrations of E and NE in plasma require an analysis method that is both specific and sensitive. Plasma sample E and NE were extracted using solid phase extraction, and analyzed by an in-sample ion-pairing chromatography (IPC) LC-MS/MS method, that enables the ion-pairing reagent to be diverted to waste without entering the ion source of the mass spectrometer. The method was validated with good performance characteristics and the limit of quantification (LOQ) was found to be 0.20 and 0.02 nmol/L for NE and E, respectively. In conclusion, this work presents development and validation of a method for determining E and NE in plasma with a measuring range covering the entire reference interval for human plasma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Previous studies have demonstrated a relationship between cognitive impairment and hypoglycaemia (<3 mmol/l). This study hypothesised that non-severe insulin-induced hypoglycaemia reduces cognitive function in individuals with type 2 diabetes., Methods: In this randomised crossover study, 25 participants with type 2 diabetes attended two experimental visits with hyperinsulinaemic glucose clamping: one hypoglycaemic clamp (plasma glucose 3.0 ± 0.2 mmol/l) and one euglycaemic clamp (plasma glucose 6.0 ± 0.2 mmol/l). Participants were eligible if their diabetes was treated with diet or glucose-lowering medications (except sulfonylureas or insulin), age was 35-70 years, BMI was 23-35 kg/m 2 and HbA 1c was below 75 mmol/mol (9%). Cognitive function was assessed with a neurocognitive test battery measuring verbal memory, executive function, sustained attention and psychomotor speed. From the examined cognitive domains, a global cognition score was constructed estimating global cognition. A measurement for psychomotor speed was selected as the primary outcome. Participants and people assessing the outcomes were blinded to group assignment., Results: Cognitive performance was impaired during hypoglycaemia with a mean score in the primary outcome test, Symbol Digit Modalities Test measuring psychomotor speed, of 48.7 ± 9.8 (hypoglycaemia) vs 56.6 ± 12.0 (euglycaemia); i.e. a change of -7.9 points (95% CI -10.9, -4.9; p < 0.0001). In addition, hypoglycaemia reduced global cognitive score by -0.7 (95% CI -0.9, -0.6; p < 0.0001). A stable glucose plateau was achieved during both experimental visits. For the hypoglycaemic clamp, mean plasma glucose concentration (± SD) during neurocognitive testing was 3.1 (± 0.3) mmol/l. Age, sex, fasting C-peptide, counter-regulatory hormones and the severity of hypoglycaemic symptoms did not influence cognitive function., Conclusions/interpretation: Acute non-severe hypoglycaemia (mean plasma glucose 3.1 mmol/l) has a substantial negative impact on cognitive function in individuals with type 2 diabetes., Trial Registration: ClinicalTrials.gov NCT03014011., Funding: The study was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (MSD-MA-NORD-007-01). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Funding was also received from Skibsreder Per Henriksen, R. og hustrus Foundation, The Danish Alzheimer Foundation and Savværksejer Jeppe Juhl og hustrus Foundation.

Cathepsin K (CatK) inhibition allows reducing bone resorption with specific advantages compared to the existing anti-osteoporosis drugs. Its clinical use appears even more promising with the recent development of ectosteric inhibitors. A confusing observation, however, is that a low dose of the active site CatK inhibitor odanacatib (ODN) was reported to decrease bone mineral density and increase serum levels of the bone resorption marker carboxy-terminal collagen crosslinks (CTX). The present study provides a possible explanation for this paradox. The resorptive activity of human osteoclasts seeded on bone slices was inhibited when subjected to ODN at doses of 20 nM, but about 100-fold lower doses induced a significant increase in CTX levels and in eroded surface (12 repeats). This low-dose-induced stimulation was prevented by inhibition of non-CatK cysteine proteinases, thereby indicating that the stimulation results from an interplay between CatK and other cysteine proteinases. Effective interplay between these proteinases was also shown in enzymatic assays where the CatK-mediated degradation of collagen was enhanced upon addition of cathepsins B or L. Furthermore, extracts of osteoclasts subjected to a low dose of ODN showed higher levels of cathepsin B compared with extracts of control osteoclasts. In conclusion, the low-dose-induced stimulation of resorption observed in the clinical study can be reproduced in osteoclasts cultured in the absence of any other cell. Our data support an osteoclast-intrinsic mechanism where a mild inhibition of CatK results in increased levels of other proteinases contributing to the collagen degradation process.

The catecholamines, epinephrine (E) and norepinephrine (NE) are small polar, hydrophilic molecules, posing significant challenges to liquid chromatography - tandem mass spectrometry (LC-MS/MS) method development. Specifically, these compounds show little retention on conventional reversed-phase liquid chromatography columns. This work presents development and validation of an LC-MS/MS method for determining catecholamines in urine, based on a new approach to ion-pairing chromatography (IPC), in which the ion-pairing reagent (IPR), 1-Heptane Sulfonic Acid (HSA), is added to the extracted samples instead of the mobile phases. A Hamilton STARlet workstation carried out the solid phase extraction of urine samples. The extracted samples were diluted with 60mmol/L HSA and injected on a Kinetex core-shell biphenyl column with conventional LC-MS/MS suitable mobile phases. Chromatographic separation of E and NE was achieved successfully with very stable retention times (RT). In 484 injections, the RTs were steady with a CV of less than ±4%. Furthermore, HSA was separated from E and NE, allowing HSA to be diverted to waste instead of entering the mass spectrometer ion chamber. The method was validated with good analytical performance, and even though the analysis for urinary catecholamines is increasingly being replaced by plasma free metanephrines in diagnosing pheochromocytomas, this work represents the application of a new analytical technique that can be transferred to other small polar molecules, that are difficult to chromatograph on traditional reversed phase columns., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To identify the prevalence of nonspecific lumbar pain and associated factors among adolescents in Uruguaiana, state of Rio Grande do Sul., Methods: This was a cross-sectional school-based study conducted among adolescents aged 10-17 years who were enrolled in the day shift of the municipal and state educational systems of Uruguaiana. This study evaluated 1455 adolescents. The data-gathering procedures involved two stages. Firstly, a questionnaire on sociodemographic indicators, behavioral patterns and habits of the daily routine and history of nonspecific lumbar pain was applied. Subsequently, height, body mass, flexibility and abdominal strength/resistance measurements were evaluated. To analyze the data, univariate, bivariate and multivariable methods were used and the significance level was taken to be 5% for all the tests., Results: The prevalence of lumbar pain among the adolescents evaluated was 16.1%. Grouped according to sex, the prevalence among males was 10.5% and among females, 21.6%. The variables of sex, body mass index, abdominal strength/resistance and physical activity level presented statistically significant associations with nonspecific lumbar pain. In the adjusted analysis, sex (OR = 2.36; p < 0.001), age (OR = 1.14; p < 0.001) and body mass index (OR = 1.44; p = 0.029) maintained significance in the final model., Conclusions: Female adolescents of older age and who presented overweight or obesity had higher chances of developing nonspecific lumbar pain.

Background: The purpose of this study was to examine the independent and combined influence of cardiorespiratory fitness (CRF), body mass index (BMI) and percentage of fat (% fat) on total cholesterol (TC) and blood pressure (BP) in male and female youth., Methods: 1442 (721 girls) children and adolescents aged 7-12 years were randomly selected. CRF, BMI, % fat (predictor variables), TC, systolic (SBP) and diastolic blood pressure (DBP; outcome variables) were measured. Using standardized cut-off points, we created categories for each variable. Bivariate and multivariable analyses were used to test the independent influence of predictors on outcomes., Results: The prevalence of increased TC, SBP, and DBP were 34.4% (95% CI 31.9-37.0), 9.1% (95% CI 7.5-10.6), and 15.5% (95% CI 13.5-17.4), respectively. In multivariable analyses, CRF was a significant predictor of all outcome variables (P < .05). BMI was associated with SBP and DBP (P < .05) and % fat was associated only with SBP (P < .05). CRF had stronger associations with TC than BMI, whereas the opposite was observed for SBP and DBP., Conclusions: CRF and BMI are independently associated to TC and BP in male and female youth, and individuals unfit/overweight have greater likelihood of presenting these risk factors.

This study aimed to identify the prevalence of physical inactivity and associated factors in adolescents, using a cross-sectional design with a sample of 1,455 adolescents (741 females). Data were collected using a questionnaire consisting of socio-demographic, perceptual, and behavioral variables. Physical activity was estimated with the Physical Activity Questionnaire for Older Children and Adolescents. Prevalence of physical inactivity was 68% (95%CI: 65.6%-70.4%). The following variables remained associated with physical inactivity in the adjusted analysis (p < 0.05): living in an apartment, female gender, older adolescents, lower self-rated physical activity compared to peers, low perception of maternal physical activity, passive commuting to school, non-participation in physical education at school, non-enjoyment of physical education classes, and limited involvement in other types of physical exercise besides physical education at school. There were a high proportion of inactive adolescents. Strategies to prevent physical inactivity in adolescents should be elaborated with a central role for the school and family.

Background and Purpose: Explorations into the heterogeneous population of native GABA type A receptors (GABAA Rs) and the physiological functions governed by the multiple GABAA R subtypes have for decades been hampered by the lack of subtype-selective ligands., Experimental Approach: The functional properties of the orthosteric GABAA receptor ligand 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) have been investigated in vitro, ex vivo and in vivo., Key Results: Thio-4-PIOL displayed substantial partial agonist activity at the human extrasynaptic GABAA R subtypes expressed in Xenopus oocytes, eliciting maximal responses of up to ∼30% of that of GABA at α5 β3 γ2S , α4 β3 δ and α6 β3 δ and somewhat lower efficacies at the corresponding α5 β2 γ2S , α4 β2 δ and α6 β2 δ subtypes (maximal responses of 4-12%). In contrast, it was an extremely low efficacious agonist at the α1 β3 γ2S , α1 β2 γ2S , α2 β2 γ2S , α2 β3 γ2S , α3 β2 γ2S and α3 β3 γ2S GABAA Rs (maximal responses of 0-4%). In concordance with its agonism at extrasynaptic GABAA Rs and its de facto antagonism at the synaptic receptors, Thio-4-PIOL elicited robust tonic currents in electrophysiological recordings on slices from rat CA1 hippocampus and ventrobasal thalamus and antagonized phasic currents in hippocampal neurons. Finally, the observed effects of Thio-4-PIOL in rat tests of anxiety, locomotion, nociception and spatial memory were overall in good agreement with its in vitro and ex vivo properties., Conclusion and Implications: The diverse signalling characteristics of Thio-4-PIOL at GABAA Rs represent one of the few examples of a functionally subtype-selective orthosteric GABAA R ligand reported to date. We propose that Thio-4-PIOL could be a useful pharmacological tool in future studies exploring the physiological roles of native synaptic and extrasynaptic GABAA Rs., (© 2013 The British Pharmacological Society.)

Background: Evidence has suggested that a significant proportion of children and adolescents has high levels of total cholesterol., Objective: To estimate the prevalence of hypercholesterolemia and associated factors in 07-12 year-old school children., Methods: School based cross sectional study of a random sample of 1,294 07-12 year-old school children from Caxias do Sul/RS, Brazil. The students answered an interview with information on socioeconomic status, food habits, and physical and leisure activities. Total cholesterol, cardiorespiratory fitness, body mass and height were measured to calculate body mass index. For the data treatment, univariate, bivariate, and multivariate analyzes were used., Results: The multivariate analysis identified that individuals from high socioeconomic level (OR: 1.70; CI: 1.05-2.75), of female gender (OR: 1.32; CI: 1.03-1.67), and overweight (OR: 1.40; IC: 1.10-1.77) had increased chances of having increased total cholesterol (> 3rd tercile)., Conclusion: High total cholesterol levels on 07-12 year-old school children are associated with high socioeconomic level, female gender, and overweight. Encouraging an active life style and appropriate dietary habits can help control cholesterol levels and reduce risk factors.

Objective: To purpose news body mass index (BMI) cut offs to 7 to 12 years old scholars., Subjects and Methods: 1.413 scholars of 7 to 12 years old selected of aleatory way. Were measured the BMI, total cholesterol (TC), and systolic (SBP) and diastolic blood pressure (DBP). To the date analyze were used the receiver operating characteristic curve (ROC curve) and the bivariate analyze., Results: The BMI cut offs proposed at this study show adequate capacity to identify true positive and negative to the cardiovascular diseases (CVD) risk factors presence. Besides, these cut offs show higher and more balanced sensibility and specificity values than other cut offs proposals., Conclusions: The BMI proposed at this study configure with as the more adequate alternative to the screening for the scholars with increased chances to carry DCV risk factors.

Objective: To propose cutoff points for waist circumference of schoolchildren for the identification of cardiovascular disease risk factors., Methods: This school-based cross-sectional study surveyed 1,413 schoolchildren aged 7 to 12 years old, selected by random cluster sampling. Waist circumference, total cholesterol and systolic and diastolic pressures were measured. Reference values for cardiovascular disease risk factors were developed from measures of total cholesterol and systolic and diastolic blood pressures. The receiver operating characteristic (ROC) curve and bivariate analysis, followed by calculation of sensitivity, specificity and odds ratio, were used in data analysis., Results: The cutoff points had area values under the ROC curve ranging between 0.603 and 0.949, while sensitivity and specificity ranged between 0.500 and 1.00. Among all proposals analyzed, the one presented by this study best balanced sensitivity and specificity values. Bivariate analysis followed by odds ratios calculation indicated that subjects with waist circumference above the proposed cutoff points have increased chances of presenting cardiovascular disease risk factors., Conclusions: The cutoff points proposed in the present study seem to be a valid alternative and better balance sensibility and specificity than other proposals for screening students with increased chances of presenting cardiovascular disease risk factors.

A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.

The novel ginkgolide analog ginkgolide X was characterized functionally at human glycine and gamma-aminobutyric acid type A receptors (GlyRs and GABA(A)Rs, respectively) in the fluorescence-based FLIPR(TM) Membrane Potential assay. The compound inhibited the signaling of all GABA(A)R subtypes included in the study with high nanomolar/low micromolar IC(50) values, except the rho 1 receptor at which it was a significantly weaker antagonist. Ginkgolide X also displayed high nanomolar/low micromolar IC(50) values at the homomeric alpha1 and alpha2 GlyRs, whereas it was inactive at the heteromeric alpha 1 beta and alpha 2 beta subtypes at concentrations up to 300 microm. Thus, the functional properties of the compound were significantly different from those of the naturally occurring ginkgolides A, B, C, J, and M but similar to those of picrotoxin. In a mutagenesis study the 6' M2 residues in the GlyR ion channel were identified as the primary molecular determinant of the selectivity profile of ginkgolide X, and a 6' M2 ring consisting of five Thr residues was found to be of key importance for its activity at the GABA(A)R. Conformational analysis and docking of low-energy conformations of the native ginkgolide A and ginkgolide X into a alpha1 GlyR homology model revealed two distinct putative binding sites formed by the 6' M2 residues together with the 2' residues and the 10' and 13' residues, respectively. Thus, we propose that the distinct functionalities of ginkgolide X compared with the other ginkgolides could arise from different flexibility and thus different binding modes to the ion channel of the anionic Cys-loop receptor.

Objective: To establish the prevalence of high blood pressure and associated factors among schoolchildren from Caxias do Sul, state of Rio Grande do Sul, Brazil., Methods: This school-based cross-sectional study assessed boys and girls aged 7 to 12 years from private and public schools. Three measurements of the children's blood pressure were taken during one visit to the schools. Weight, height, and waist circumference were measured. We also assessed the children's aerobic capacity (9-minute running test) and socioeconomic status. Statistical analysis was carried out using the chi-square test and logistic regression in order to control for confounding factors., Results: The sample included 1,413 children. Prevalence of schoolchildren with high blood pressure was 13.8% (systolic, diastolic, systolic/diastolic), and the proportion was higher (double) for obese and/or overweight children in comparison to normal-weight children. Children with increased waist circumference had 2.8 times greater chance of having high blood pressure levels than those with appropriate waist circumference (95% confidence interval 2.513-3.186 and p = 0.000). Individuals belonging to a high social class, defined according to the Brazilian National Economic Index, had 2.6 times greater chance of having high blood pressure., Conclusions: In the present study, schoolchildren aged 7 to 12 years from Caxias do Sul had high prevalence of high blood pressure levels; increased waist circumference, high socioeconomic status, and low physical capacity were associated with this condition. We suggest that measures be taken to promote the practice of physical activity and dietary control to improve blood pressure levels and thus reduce risk factors.

Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.