Where should the safe limits of alcohol consumption stand in light of liver enzyme abnormalities in alcohol consumers?

Abstract Objectives: To estimate the prevalence and risk factors for abnormal liver enzymes in a large age- and gender stratified population-based sample of apparently healthy individuals with or without alcohol consumption and other health-related risk factors (adiposity, physical inactivity, smoking). Methods: Data on alcohol use, smoking, diet and physical activity were recorded using structured questionnaires from 13,976 subjects (6513 men, 7463 women, aged 25±74 years) in the national FINRISK studies. Alcohol data was used to categorize the participants into abstainers, light drinkers, moderate drinkers and heavy drinkers. Serum gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) activities were measured using standard kinetic methods. Results: Male light drinkers, moderate drinkers and heavy drinkers showed significantly higher relative risks of abnormal GGT than abstainers: 1.37 (95% confidence interval 1.11 to 1.71, p < 0.01), 2.72 (2.08 to 3.56, p < 0.0005), and 6.10 (4.55 to 7.17, p < 0.0005), respectively. Corresponding values for women were 1.22 (0.99 to 1.51, p = 0.065), 1.90 (1.44 to 2.51, p < 0.0005), and 5.91 (3.80 to 9.17, p < 0.0005). Estimated threshold doses for a significant GGT elevation was 14 standard weekly alcohol doses for men and 7 for women. Excess body weight and age over 40 years modulated the thresholds towards smaller quantities of alcohol. The risk of abnormal GGT was also significantly influenced by physical inactivity and smoking. The relative risks of abnormal ALT activities were increased in male heavy drinkers, especially in those presenting with adiposity and sedentary lifestyle. Conclusions: Alcohol use markedly increases the risk for abnormal liver enzyme activities in those presenting with age over 40 years, obesity, smoking or sedentary lifestyle. The data should be considered in public health recommendations and in the definitions of safe limits of alcohol use

Acute changes in inflammatory biomarker levels in recreational runners participating in a marathon or half-marathon

Abstract Background: Strenuous physical activity activates the participant’s immune responses; however, few studies exist, observing exercise-induced simultaneous changes in mediators of inflammation. Methods: We examined individual responses in soluble urokinase-type plasminogen activator receptor (suPAR), a marker of immune activation, soluble endocytic receptor for haptoglobin-hemoglobin complexes (CD163), a marker of monocyte-macrophage activation, C-reactive protein (CRP), and pro- and anti-inflammatory cytokines from blood samples drawn at baseline, at 3- and 48-h post-races from recreational runners who successfully completed the marathon (199 ± 8 min, n = 4) or half-marathon (132 ± 4 min, n = 4) run. For comparisons, biomarkers reflecting muscle, heart, kidney, and liver functions were measured. Results: Significant 3-h post-race increases occurred in levels of suPAR (p < 0.01), CD163 (p < 0.05), white blood cells (p < 0.001), pro-inflammatory cytokines, interleukin-6 (IL-6) (p < 0.001), IL-8 (p < 0.05), and anti-inflammatory cytokine IL-10 (p < 0.05), whereas tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) remained relatively stable. Full-marathon running lead to more pronounced increases in suPAR, CD163, IL-8, and IL-10 than half-marathon running. In addition, 3-h post-race increases of all these parameters correlated significantly with changes in serum TNF-α and cortisol. The 48-h levels of serum suPAR and both pro- and anti-inflammatory cytokines had decreased to baseline levels, whereas CRP, a marker of acute phase response, increased in those with the most prominent IL-6 and IL-10 elevations in their preceding samples. The highest suPAR, CRP, IL-6, TNF-α, IL-10, and cortisol levels were noted in the individual with the most severe post-race fatigue. Conclusions: Prolonged running increases mediators of inflammation in an exercise-dose-dependent manner which should be considered in the assessment of health status of physically active individuals after recent acute bouts of strenuous exercise

Impacts of unfavourable lifestyle factors on biomarkers of liver function, inflammation and lipid status

Abstract Background: Adopting a healthy lifestyle is associated with prolonged life expectancy. The main modifiable lifestyle-related risk factors are hazardous alcohol drinking, smoking, excess body weight and lack of physical activity. Our aim was to estimate the impact of unfavourable lifestyle factors on abnormalities in laboratory tests reflecting liver status, inflammation and lipid metabolism in a population-based cross-sectional study. Methods: The study included 22,273 participants (10,561 men, 11,712 women) aged 25–74 years from the National FINRISK Study. Data on alcohol use, smoking, body weight, and physical activity were recorded from structured interviews. The risk scores for the various life style factors were established on a 0–8 scale and used to stratify the population in classes to allow estimates of their joint effects. Serum liver enzymes (GGT, ALT), C-reactive protein (CRP) and lipid profiles were measured using standard laboratory techniques. Results: Consistent dose-response relationships were observed between the number of unfavourable risk factors and serum levels of GGT, ALT, CRP, cholesterol, HDL, LDL and triglycerides (p < 0.0005 for linear trend in all comparisons). When compared with those with zero risk factors, the multivariable-adjusted odds ratios (ORs) for abnormalities in all biomarkers were significantly higher in those with a sum of risk score two or more. The most striking increases in ORs in the group with the highest numbers of risk factors were observed among men in serum GGT: 26.6 (12.4–57.0), ALT: 40.3 (5.3–307.8), CRP: 16.2 (7.8–33.7) and serum triglycerides: 14.4 (8.6–24.0). Conclusions: The data support the view that the presence of unfavourable life style risk factors is associated with distinct abnormalities in laboratory tests for liver function, inflammation and lipid status. Such biomarkers may prove to be of value in the assessment of interventions aimed at reducing unfavourable risk factors and in helping individuals in long-term maintenance of lifestyle modifications

Combined effects of lifestyle risk factors on fatty liver index

Abstract Background: Factors of lifestyle may have a major impact on liver-related morbidity and mortality. We examined independent and joint effects of lifestyle risk factors on fatty liver index (FLI), a biomarker of hepatic steatosis, in a population-based cross-sectional national health survey. Methods: The study included 12,368 participants (5784 men, 6584 women) aged 25–74 years. Quantitative estimates of alcohol use, smoking, adiposity and physical activity were used to establish a total score of risk factors, with higher scores indicating an unhealthier lifestyle. FLI was calculated based on an algorithm including body mass index, waist circumference, serum gamma-glutamyltransferase and triglycerides. Results: The occurrence of FLI ≥ 60% indicating fatty liver increased from 2.4% in men with zero risk factors to 81.9% in those with a total risk score of 7–8 (p <  0.0005 for linear trend) and in women from 0 to 73.5% (p <  0.0005). The most striking individual impacts on the likelihood for FLI above 60% were observed for physical inactivity (p <  0.0005 for both genders) and alcohol consumption (p <  0.0005 for men). Interestingly, coffee consumption was also found to increase with increasing risk factor scores (p <  0.0005 for linear trend in both genders). Conclusions: The data indicates that unfavorable combinations of lifestyle risk factors lead to a high likelihood of hepatic steatosis. Use of FLI as a diagnostic tool may benefit the assessment of interventions aimed at maintaining a healthy lifestyle and prevention of liver-related morbidity

Contribution of parental health to the subsequent social assistance entry of the family with children:a nationwide register-linked birth cohort study in Finland

Abstract Aim: Our aim in this paper was to estimate the contribution of different parental specialised health care diagnoses to the subsequent risk of entry into the social assistance system for families with children in the period 1998–2013. Methods: We used longitudinal population-level register data consisting of all children born in 1997 in Finland and their registered parents (54 960 one and two-parent families with 801 336 observations in the period 1998–2013). Diagnoses assigned in public specialised healthcare and social assistance records were derived from nationwide administrative registers. Measures of parental socioeconomic status and previous diagnoses and the birth weight of the child were adjusted for in regression models which estimated the association between parental diagnoses and entry into the social assistance system in the following year. Results: Families with a parent somatic diagnosis had a risk ratio of 1.4 for social assistance entry in the subsequent year of the diagnosis though substantial variation by diagnosis category was detected. Parent psychiatric diagnoses were linked to a higher, 3.01-fold risk of social assistance entry. Covariate adjustment reduced these risk ratios to 1.2 and 2.1, respectively. Some 2.9% of all social assistance entries may be attributed to parental psychiatric diagnoses while somatic health records account for another 7.2%, making their total contribution over 1/10th of all cases. Conclusions: Parental specialised healthcare records were associated with a higher risk of social assistance need. Thus more interventions to support financial management are required for parents with psychiatric diagnoses

Data from: Metabolic rate associates with, but does not generate covariation between, behaviours in western stutter-trilling crickets, Gryllus integer

The causes and consequences of among-individual variation and covariation in behaviours are of substantial interest to behavioural ecology, but the proximate mechanisms underpinning this (co)variation are still unclear. Previous research suggests metabolic rate as a potential proximate mechanism to explain behavioural covariation. We measured the resting metabolic rate (RMR), boldness and exploration in western stutter-trilling crickets, Gryllus integer, selected differentially for short and fast development over two generations. After applying mixed-effects models to reveal the sign of the covariation, we applied structural equation models to an individual-level covariance matrix to examine whether the RMR generates covariation between the measured behaviours. All traits showed among-individual variation and covariation: RMR and boldness were positively correlated, RMR and exploration were negatively correlated, and boldness and exploration were negatively correlated. However, the RMR was not a causal factor generating covariation between boldness and exploration. Instead, the covariation between all three traits was explained by another, unmeasured mechanism. The selection lines differed from each other in all measured traits and significantly affected the covariance matrix structure between the traits, suggesting that there is a genetic component in the trait integration. Our results emphasize that interpretations made solely from the correlation matrix might be misleading

Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells

Abstract Calcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.1 mg/kg given to one sheep) and intra-articular dose (0.054 mg/kg, 0.216 mg/kg and 0.560 mg/kg given to three sheep). The terminal half-life of calcipotriol was approximately 1 h after an IV dose. After intra-articular dosing, the systemic absorption was between 1 and 13% during the observed 24 h. Hypercalcemia or other clinical adverse effects did not occur in any animal during the study, and no macroscopic or microscopic alterations were seen in the synovium of the calcipotriol-injected knees compared to the vehicle knees. The in vitro metabolism of calcipotriol was analyzed with LC–MS from human synovial and mesenchymal stromal cell cultures. Both cell types were able to metabolize calcipotriol with MC1080 and MC1046 as the main metabolites. CYP24A1 transcripts were strongly induced by a 48-hour calcipotriol exposure in mesenchymal stromal cells, but not consistently in synovial stromal cells, as determined by RT-qPCR. Calcipotriol proved to be safe after a single intra-articular dose with applied concentrations, and it is metabolized by the cells of the joint. Slow dissolution of calcipotriol crystals in the joint can extend the pharmaceutical impact on the synovium, cartilage and subcortical bone

Genetic Risk Score for Intracranial Aneurysms : Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10-3per year [95% CI, -6.49×10-3to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.Peer reviewe