Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study

Background We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat.Methods Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs.Results We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively.Conclusion These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.Subject terms: Cancer epidemiology, Colorectal cancer, Cancer prevention     

Prenatal Genetic Testing for Intersex Conditions in Canada

Intersex individuals face human rights violations, discrimination, and stigmatization worldwide. Diagnosis in infants is uncommon, with between 1 in 2000 and 1 in 4500 infants born with ambiguous external genitalia sufficient to warrant genetic and endocrine studies. However, estimates of the actual proportion of the population falling under the broader umbrella of intersex, including sexual variation at the chromosomal, gonadal, hormonal, or genital level, are as high as 1.7%. As the rise of non-invasive prenatal screening (NIPS) capable of identifying intersex conditions at the fetal stage has increased the potential for prenatal detection, there is an urgent need for attention to the potential ethical challenges that may arise from earlier and more frequent detection.There has been growing attention in recent years to the harms faced by intersex individuals at the hands of the medical community. In the prenatal context, genetic counseling is one avenue by which prospective parents might be helped to understand the full spectrum of intersexuality and form realistic expectations for their children. However, best practices and medical policies to prevent stigmatization and discrimination against intersex individuals remain underdeveloped. There is presently a lack of Canadian-specific guidance or explicit legal protections for intersex individuals to guide health care providers in their relationship with these patients and their families.In this commentary, we argue that this gap calls for increased training for health care providers that incorporates the voices and concerns of the intersex community.     

Anxiety increases the place conditioning induced by cocaine in rats

Some clinical studies have shown that anxiety disorders are often associated with drug dependence, although it remains unclear whether these disorders are primary or secondary to drug abuse. We have investigated whether anxiety may be a factor that predisposes to cocaine use. From an outbred Wistar strain, we have selected male rats regarded as anxious or non-anxious on the basis of their scores on two behavioural tests of unconditioned anxiety, the elevated plus-maze and the light/dark box test. They were also screened for their locomotor activity in an inescapable novel environment and for their preference for novelty presented in a free-choice. Rewarding effects of cocaine (2.5-20 mg/kg; i.p.) were then determined in the conditioned place preference paradigm (CPP). Anxious and non-anxious rats showed no difference in their responsiveness to inescapable novelty or their preference for novelty in a free-choice procedure. Only anxious rats developed a CPP induced by increasing doses of cocaine, the magnitude of CPP induced by the 10 mg/kg dose of cocaine being significantly higher than that observed in anxious rats conditioned with saline. These results suggest that anxiety affects the sensitivity to aversive/anxiogenic effects of cocaine. Thus, anxious rats which were highly responsive to positive effects of cocaine may be more prone to develop cocaine addiction than non-anxious rats.     

Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure

The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1 mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50 mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3 h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment.     

Selective Adhesion of Nanoparticles to Inflamed Tissue in Gastric Ulcers

Purpose  Gastrointestinal deposition of nanoparticles was examined after oral administration to mice suffering from an experimental gastric ulcer model. Local drug delivery could reduce side effects and would be a distinct improvement compared to existing therapeutic approaches, e.g. in the local therapy of Helicobacter pylori. Methods  A gastric ulcer was induced to Swiss mice by acetic acid injection. Fluorescent polystyrene particles with a nominal size of 50, 200, and 750 nm were administered orally for 3 or 5 days and particle adhesion in the gastrointestinal tract analyzed. Results  In the ulcerated regions, an enhanced particle adhesion was observed compared to healthy controls. A size dependency of the deposition was found which further increased with a prolonged treatment period. For 750 nm particles only fair adhesion was observed (control, 2.0 ± 1.4%; ulcer, 4.5 ± 0.7% of daily administered particle mass), while already 200 nm particles showed higher binding (control, 2.9 ± 1.3%; ulcer, 7.8 ± 1.2%). Highest relative adhesion was found for 50 nm particles (control, 2.8 ± 1.3%; ulcer, 10.0 ± 1.5%). The targeting index of gastric ulcer versus healthy control was nearly constant around 2 after 3 days treatment, but increased distinctly for smaller particles after 5 days. Conclusions  The use of sub-micron sized carriers holds promise for the targeted delivery of drugs to the ulcerated mucosal areas in the stomach. An erratum to this article can be found at