Retinal vascular diameters in relation to physical activity in Danish children - The CHAMPS Eye Study.

Our objective was to determine associations between retinal vascular caliber and physical activity (PA) in a school-based child cohort. In a prospective study, we created a childhood cumulative average PA-index using objectively measured PA (accelerometry) assessed at four periods between 2009 and 2015. Cumulative exposure to PA intensities was estimated. Cross-sectional examinations on biomarkers, anthropometry, and ophthalmological data including retinal fundus photographs were performed in 2015. Semi-automated measurements of retinal vascular diameters were performed and summarized into central retinal arteriolar and venular equivalents (CRAE, CRVE). We included 307 participants. Mean age in 2015 was 15.4 years (0.7). The mean CRAE and CRVE were 156.5 µm (2.8) and 217.6 µm (7.7), respectively. After adjusting for age, gender, and axial length, more time in PA was independently related to thinner retinal venules (ß-coefficient = -1.25 µm/%, 95% confidence interval = -2.20, -0.30, P < .01). Sedentary time was associated with wider venules (P < .01). Furthermore, birthweight (ß-coefficient = 0.56 µm/%, 95% confidence interval = 0.18, 0.95, P < .01) was associated with CRVE. Blood pressure was associated with thinner retinal arterioles (ß-coefficient = -0.19 µm/mmHg, 95% confidence interval = -0.36, -0.01, P = .04). We concluded that children with higher PA in childhood had thinner retinal venular caliber. Our results suggest that PA during childhood positively impacts the retinal microcirculation and that retinal vascular analysis may be a possible assessment to detect microvascular impairments in children with an increased risk of future cardiovascular disease.

Does adiposity mediate the relationship between physical activity and biological risk factors in youth?: a cross-sectional study from the International Children's Accelerometry Database (ICAD).

BACKGROUND/OBJECTIVES: To model the association between accumulating 60 daily minutes of moderate-to-vigorous physical activity and a composite score of biological risk factors into a direct and an indirect effect, using abdominal obesity as the mediator. SUBJECTS/METHODS: Cross-sectional data from the International Children's Accelerometry Database (ICAD) including 6-18-year-old children and adolescents (N=3412) from 4 countries providing at least 3 days of accelerometry-assessed physical activity. A standardized composite risk score was calculated from systolic blood pressure and fasting blood samples of insulin, glucose, triacylglycerol and inverse HDL-cholesterol. Abdominal obesity was assessed by the waist-circumference:height ratio. Two-stage regression analysis, allowing for exposure-mediator interaction, was used for the effect decomposition. RESULTS: Participants achieving 60 daily minutes of moderate-to-vigorous physical activity had a 0.31 (95% CI: -0.39, -0.23) standard deviations lower composite risk score than those achieving less than 60 min. Modelling the associations suggested that 0.24 standard deviations (95% CI: -0.32, -0.16) was attributed to the direct effect and -0.07 (95% CI: -0.11, -0.02) to the indirect effect indicating that 22% of the total effect was mediated by central adiposity. Modelling 30 and 90 min of moderate-to-vigorous physical activity per day resulted in changes in the direct but not the indirect effect. CONCLUSIONS: One hour of daily moderate-to-vigorous physical activity was associated with clinically relevant differences in metabolic control compared to engagement in less than this minimally recommended amount. The majority of the difference was explained by the direct effect of physical activity.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.241.

Motor competence and cardiorespiratory fitness have greater influence on body fatness than physical activity across time.

We investigated the longitudinal associations among physical activity (PA), motor competence (MC), cardiorespiratory fitness (VO2peak ), and body fatness across 7 years, and also analyzed the possible mediation effects of PA, MC, and VO2peak on the relationships with body fatness. This was a seven-year longitudinal study with three measuring points (mean ages [in years] and respective sample size: 6.75±0.37, n=696; 9.59±1.07, n=617; 13.35±0.34, n=513). PA (moderate-to-vigorous PA-MVPA and vigorous PA-VPA) was monitored using accelerometers. MC was assessed by the "Körperkoordinationstest für Kinder-KTK" test battery. VO2peak was evaluated using a continuous running protocol until exhaustion. Body fatness was determined by the sum of four skinfolds. Structural equation modeling was performed to evaluate the longitudinal associations among PA, MC, VO2peak, and body fatness and the potential mediation effects of PA, MC, and VO2peak . All coefficients presented were standardized (z-scores). MC and VO2peak directly influenced the development of body fatness, and VO2peak mediated the associations between MVPA, VPA, MC, and body fatness. MC also mediated the associations between MVPA, VPA, and body fatness. In addition, VO2peak had the largest total association with body fatness (ß=-0.431; P<.05), followed by MC (ß=-0.369; P<.05) and VPA (ß=-0.112; P<.05). As PA, MC, and VO2peak exhibited longitudinal association with body fatness, it seems logical that interventions should strive to promote the development of fitness and MC through developmentally appropriate physical activities, as the synergistic interactions of all three variables impacted body fatness.

Association between sweet drink intake and adiposity in Danish children participating in a long-term intervention study.

BACKGROUND: In some previous studies direct associations between intake of soft drinks, sugar-sweetened beverages and adiposity have been reported. The majority of these studies were, however, conducted in the USA and it is uncertain if the results are applicable to non-US countries. OBJECTIVE: To assess the association between sweet drink intake at age 6 and 9 years and the subsequent 3- to 7-year changes in body mass index (BMI) and sum of four skin-folds (Σ4SF). METHODS: Information on sweet drink intake (7 days food record) and physical activity (accelerometer) was obtained at age 6 years (n = 366) [Correction made here after initial online publication.] and 9 years (n = 269). Weight, height and Σ4SF were measured at age 6, 9 and 13 years. Additional information on socio-economic status, maternal BMI and pubertal status was obtained. RESULTS: No associations were observed between sweet drink intake at age 6 years and change in BMI or logΣ4SF from age 6 to 9 years or 6 to 13 years. Also, no associations were observed between change in sweet drink intake from age 6 to 9 years and subsequent change in BMI or logΣ4SF from age 9 to 13 years. A weak direct association was observed between sweet drink intake at age 9 years and change in logΣ4SF from age 9 to 13 years (per 100 g ∼ 3.38 fl oz) (ß: 0.014, 95% confidence interval [CI]: -0.001 to 0.029, P = 0.06), while no association was seen for BMI. In supplementary analyses a similar association was observed for soft drinks (ß: 0.087, 95% CI: 0.048 to 0.126, P = 0.001) but only in the intervention group. CONCLUSION: We observed associations between intake of sweet drinks and soft drinks and change in skin-fold thickness in a group of Danish children. However, as the associations did not remain significant when multiple testing was considered or was only significant among children from the intervention group, the results do not confirm or refute the direct association reported in previous studies.

Importance of epoch length and registration time on accelerometer measurements in younger children.

AIM: The aim of this study was to investigate the effect of epoch length on accumulation of minutes of physical activity per day over a spectrum of intensities, and the effect that selection of number of hours of acceptable registration required per day had on number of days that were considered acceptable. METHODS: Participants were 696 children (369 boys and 327 girls) aged 6.7±0.4 yrs, from a population-based cohort. Physical activity was assessed by the Actigraph accelerometer for four days. RESULTS: Main findings were that epoch length had a profound impact on accumulation of minutes of physical activity per day for higher intensities, whereas it had no effect on mean counts per minute. The chosen number of hours for an acceptable registration per day heavily influenced the number of days that were considered acceptable. CONCLUSION: The findings in the present investigation should be taken into consideration when planning objective measurements of daily physical activity in younger children, and highlight the need for setting international recommendations for physical activity measurements with accelerometers, if different studies are to be comparable.

Circadian epigenomic remodeling and hepatic lipogenesis: lessons from HDAC3.

Circadian rhythms have evolved to anticipate metabolic needs across the 24-h light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse displays severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor corepressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver.

Simultaneous determination of citalopram, fluoxetine, paroxetine and their metabolites in plasma and whole blood by high-performance liquid chromatography with ultraviolet and fluorescence detection.

A method for the simultaneous determination of the three selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, paroxetine and their metabolites in whole blood and plasma was developed. Sample clean-up and separation were achieved using a solid-phase extraction method with C8 non-endcapped columns followed by reversed-phase high-performance liquid chromatography with fluorescence and ultraviolet detection. The robustness of the solid-phase extraction method was tested for citalopram, fluoxetine, paroxetine, Cl-citalopram and the internal standard, protriptyline, using a fractional factorial design with nine factors at two levels. The fractional factorial design showed two significant effects for paroxetine in whole blood. The robustness testing for citalopram, fluoxetine, Cl-citalopram and the internal standard revealed no significant main effects in whole blood and plasma. The optimization and the robustness of the high-performance liquid chromatographic separation were investigated with regard to pH and relative amount of acetonitrile in the mobile phase by a central composite design circumscribed. No alteration in the elution order and no significant change in resolution for a deviation of +/-1% acetonitrile and +/-0.3 pH units from the specified conditions were observed. The method was validated for the concentration range 0.050-5.0 micromol/l with fluorescence detection and 0.12-5.0 micromol/l with ultraviolet detection. The limits of quantitation were 0.025 micromol/l for citalopram and paroxetine, 0.050 micromol/l for desmethyl citalopram, di-desmethyl citalopram and citalopram-N-oxide, 0.12 micromol/l for the paroxetine metabolites by fluorescence detection, and 0.10 micromol/l for fluoxetine and norfluoxetine by ultraviolet detection. Relative standard deviations for the within-day and between-day precision were in the ranges 1.4-10.6% and 3.1-20.3%, respectively. Recoveries were in the 63-114% range for citalopram, fluoxetine and paroxetine, and in the 38-95% range for the metabolites. The method has been used for the analysis of whole blood and plasma samples from SSRI-exposed patients and forensic cases.

An animal model of postmortem amitriptyline redistribution.

An experimental rat model was developed to study postmortem changes of drug concentration after an acute overdose. Overnight fasted rats were fed 75 mg of amitriptyline (AMI). Two h after dosing, the rats were anaesthetized and blood samples were drawn from the femoral vein (peripheral blood--PB) and the heart (HB). The rats were sacrificed by CO2 and left at room temperature for either 0.1, 0.5, 1, 2, 5, 10, 24, 48, or 96 hours, when samples of heart blood, blood from the inferior vena cava (PB) and tissue samples from different liver lobes, heart, lungs, kidney, thigh muscle, and brain were taken. Samples were analyzed by high performance liquid chromatography. The AMI concentration in HB increased fairly rapidly within the first 2 h postmortem and from then the average ratio was 6.4 +/- 0.8 (mean +/- sem) (n = 31). In PB, the post/antemortem AMI concentration ratio followed an approximately exponential rise; at 2 h postmortem the ratio was 1.6 +/- 0.3 (n = 5), and at 96 h 55.1 +/- 23.8 (n = 4). For the main metabolite nortriptyline (NOR), the concentration changes followed the same pattern, but to a lesser extent. Among the tissues, the liver lobes had high, but variable drug concentrations; lobes lying closest to the stomach had the highest drug concentrations. The drug concentration in the lungs declined significantly. This animal model demonstrates postmortem drug concentration changes similar to those described in humans. Probable mechanisms include drug diffusion from the stomach and GI tract to the surrounding tissues and blood; and postmortem drug release from the lungs and possibly other drug-rich tissues into the blood.

Diffusion as a mechanism of postmortem drug redistribution: an experimental study in rats.

In some cases of drug overdose there is a reservoir of unabsorbed drug in the stomach and gut. Furthermore, agonal aspiration might establish a second reservoir in the lungs. Two experimental rat models were used to study if diffusion from these reservoirs could contribute to the phenomenon of postmortem drug redistribution. Overnight fasted rats were sacrificed by CO2 and 75 mg of amitriptyline (AMI) was administered by a gastric tube. In the first series (n = 19), the tubes were removed after AMI administration. In the second series (n = 17), the trachea was ligated and cut prior to drug administration to prevent airways contamination. The rats were left at room temperature on their back for a period of 5, 10, 24, 48, 96 up to 192 h and samples of heart blood, blood from the inferior vena cava, tissue samples from heart, lungs, different liver lobes, kidney and psoas muscle were taken. In both series of rats we observed that as early as 5 h postmortem increasing concentrations of amitriptyline were found in the liver lobes lying closest to the stomach. In rats where the trachea was not ligated, drug contamination of the lungs also resulted in an increase in drug concentration within 5 h in heart blood and heart muscle. In rats where the trachea had been ligated, amitriptyline was found in the lungs after 96 h postmortem. The main metabolite nortriptyline was also detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Interference with analysis of amphetamine in blood by N-ethylbenzenamine from rubber septums.

When blood stored in glass vials sealed with natural rubber septums was screened for amphetamine, a contaminant was seen. The contamination originated from the rubber septums and was identified by GC/MS as N-ethylbenzenamine. Like amphetamine, N-ethylbenzenamine was extracted from strongly alkaline solutions. N-Ethylbenzenamine and amphetamine chromatographed with the same retention time on a packed Apiezon/KOH column and on nonpolar capillary columns. Separation was achieved on a medium polar capillary column. Trifluoroacetyl derivatives of amphetamine and N-ethylbenzenamine had the same retention time on a packed SP-2250 column, but separated on nonpolar capillary columns. The amounts of N-ethylbenzenamine found were high enough to give rise to significant false positive results if N-ethylbenzenamine was erroneously read as amphetamine. N-Ethylbenzenamine is believed to be formed by thermal decomposition of the vulcanizing agent zinc ethylphenyldithiocarbamate used in rubber production.

A three-year prospective study of rearrests for driving under influence of alcohol or drugs.

Fifty drunken drivers and 50 drivers with high blood drug concentrations arrested during the first four months of 1983 were selected for a study of rearrests for driving under influence of alcohol or drugs. Of the drugged drivers selected, 32 had been driving with high blood concentrations of diazepam (greater than 1.0 microM). 50% of these drivers were rearrested during the subsequent three years. The rearrest rate was low (6%) among those who had been driving with high blood concentrations of amphetamine (greater than 2.0 microM) or THC (greater than 0.010 microM). Among the drunken drivers arrested (BAC greater than 0.05%), the rearrest rate was 20%. The drivers were mostly rearrested for driving under the influence of alcohol.

A retrospective study of drugged driving in Norway.

The National Institute of Forensic Toxicology, Oslo, receives blood and urine samples from all Norwegian drivers apprehended on suspicion of driving under the influence of alcohol or drugs. In 1983 we received samples from 1446 drug-suspected drivers, out of which 445 underwent toxicological analysis. The drugs found most frequently were tetrahydrocannabinol (THC) (n = 199), diazepam (n = 166) and amphetamine (n = 102). A cautious interpretation of the data indicate that about 200 of the 445 subjects selected for toxicological analysis drove under severe influence of drugs. Because of the high percentage of submitted cases not analysed for drugs, this figure represents a minimum estimate. Compared with the results from 1978, we found a several-fold increase in detections of THC and amphetamine in 1983. The number of diazepam detections did not increase in a similar way, but we estimated that the diazepam detections would have increased 3-fold if we had analysed as frequent for this drug in 1983 as in 1978.

Determination of succinyldicholine in different tissue samples from guinea pigs after injection of a single intravenous dose.

The distribution and postmortem stability of succinyldicholine in different tissues and urine from guinea-pigs has been studied. Succinyldicholine was extracted from tissue homogenates and urine samples from animals sacrificed by intravenous injections of succinyldicholine hydrochloride (40 mg/kg). The bis-quaternary ammonium compound was demethylated and the tertiary amine was analysed by gas chromatography/mass spectrometry. The concentrations found in muscle, kidney and urine were often low; in muscle below 5 pmol/g, in kidney from 5 to 1500 pmol/g and in urine from 5 to 650 pmol/ml. The eye proved to be the best tissue sample, with a rather high and constant concentration (280 +/- 36 pmol/g) of succinyldicholine. The postmortem stability was studied by storing the bodies at 4 degrees C. After 6 days storage the drug concentrations in the eyes started to decline. Four weeks after death it was not possible to detect any succinyldicholine in this tissue.

Cannabinoids in blood and urine after passive inhalation of Cannabis smoke.

To test the possibility that cannabinoids are detectable following passive inhalation of Cannabis smoke the following study was performed. Five healthy volunteers who had previously never used Cannabis, passively inhaled Cannabis smoke for 30 min. Cannabis smoke was provided by other subjects smoking either marijuana or hashish cigarettes in a small closed car, containing approximately 1650 L of air. delta 9-Tetrahydrocannabinol (THC) could be detected in the blood of all passive smokers immediately after exposure in concentrations ranging from 1.3 to 6.3 ng/mL. At the same time total blood cannabinoid levels (assayed by radioimmunoassay [RIA] ) were higher than 13 ng/mL in four of the volunteers. Both THC and cannabinoid blood concentrations fell close to the cutoff limits of the respective assays during the following 2 h. Passive inhalation also resulted in the detection of cannabinoids in the urine by RIA and enzyme multiple immunoassay technique (EMIT) assays (above 13 and 20 ng/mL, respectively). It is concluded that the demonstration of cannabinoids in blood or urine is no unequivocal proof of active Cannabis smoking.

Cis(Z)-clopenthixol and clopenthixol in the treatment of acute psychoses and exacerbations of chronic psychoses. A double-blind clinical investigation.

The clinical effect of cis(Z)-clopenthixol has been compared with that of clopenthixol, which is a mixture of the pharmacologically active cis(Z)-isomer and the inactive trans(E)-isomer. In the 4-week double-blind trial were included 20 patients with acute psychoses and exacerbations of chronic psychoses, mainly schizophrenics. Ratings evaluating severity of illness, therapeutic effect, possible interference of side effects with the patient's functioning were done at weeks 0, 2, and 4, at which occasions also the BPRS was filled in. All patients improved, most of them so much that their final BPRS-score was less than half their initial score. In conclusion, the antipsychotic effect of cis(Z)-clopenthixol was found equal to that of clopenthixol whereas the cis(Z)-isomer on a mg/mg basis was twice as active as clopenthixol. Side effects were few, similar, and equally frequent in the two groups, extrapyramidal side effects and drowsiness being the most common.

Quantitative high-performance liquid chromatography of diazepam and N-desmethyldiazepam in blood.

High-performance liquid chromatography on porous silica has been employed to determine diazepam and N-desmethyldiazepam in human blood. For forensic purposes, 1.0 ml of blood is sufficient for a quantitative determination of the benzodiazepines in concentrations above 100 ng/ml. In cases where lower levels, 25-100 ng/ml, are of interest, 2.0 ml of blood together with a somewhat more elaborate extraction procedure are necessary.