Occupational physical activity, all-cause, cardiovascular disease, and cancer mortality in 349,248 adults: Prospective and longitudinal analyses of the MJ Cohort

Background:Evidence on the health benefits of occupational physical activity(OPA)is inconclusive.We examined the associations of baseline OPA and OPA changes with all-cause,cardiovascular disease(CVD),and cancer mortality and survival times.Methods:This study included prospective and longitudinal data from the MJ Cohort,comprising adults over 18 years recruited in 1998-2016,349,248 adults(177,314 women)with baseline OPA,of whom 105,715(52,503 women)had 2 OPA measures at 6.3±4.2 years(mean±SD)apart.Exposures were baseline OPA,OPA changes,and baseline leisure-time physical activity.Results:Over a mean mortality follow-up of 16.2±5.5 years for men and 16.4±5.4 years for women,11,696 deaths(2033 of CVD and 4631 of cancer causes)in men and 8980 deaths(1475 of CVD and 3689 of cancer causes)in women occurred.Combined moderately heavy/heavy baseline OPA was beneficially associated with all-cause mortality in men(multivariable-adjusted hazard ratio(HR)=0.93,95%confidence interval(95%CI):0.89-0.98 compared to light OPA)and women(HR=0.86,95%CI:0.79-0.93).Over a mean mortality follow-up of 12.5±4.6 years for men and 12.6±4.6 years for women,OPA decreases in men were detrimentally associated(HR=1.16,95%CI:1.01-1.33)with all-cause mortality,while OPA increases in women were beneficially(HR=0.83,95%CI:0.70-0.97)associated with the same outcome.Baseline or changes in OPA showed no associations with CVD or cancer mortality.Conclusion:Higher baseline OPA was beneficially associated with all-cause mortality risk in both men and women.Our longitudinal OPA analyses partly confirmed the prospective findings,with some discordance between sex groups.

Plethysmograph training:A refinement for collection of respiration data in mice

Inhaled chemicals can harm the airways.Different effects can result in distinct changes in respiratory patterns;the type of change indicates where and how the respiratory system is affected.Furthermore,changes in respiratory patterns may be detected at much lower substance concentrations than those that cause more serious effects,such as histopathological changes.Changes in respiratory patterns can be studied experimentally by monitoring the breathing of mice placed in plethysmographs and exposing head-out to the test substance.The method is well established;however,it is not known if training mice in being restrained in the plethysmograph could increase the quality of data collection.Here we report the results of training mice to be restrained in plethysmographs for 5 consecutive days,with respect to body weight,respiratory parameters,and time spent in the plethysmograph,before they are removed because of unstable breathing patterns.The mice tolerated the procedure better(measured by time in the plethysmograph)on the second day of training than the first day.Training did not change the breathing parameters between days.Breathing parameters stabilized within 5 min after the mice were placed in the plethysmographs on all days.There was an average of 3%weight loss between the first and last days of the training,indicating that the training procedure placed some strain on the animals.Training reduces the number of mice attempting to escape from the plethysmograph.

Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells which were resistant to treatment with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak. CONCLUSION: ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies.

Polymorphisms in NF-κB,PXR,LXR,PPARγ and risk of inflammatory bowel disease

AIM:To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease(IBD) . METHODS:Genotypes of nuclear factor(NF) -κB(NFKB1) NFκB-94ins/del(rs28362491) ;peroxisome proliferatoractivated receptor(PPAR) -γ(PPARγ) PPARγPro12Ala(rs1801282) and C1431T(rs 3856806) ;pregnane X receptor(PXR) (NR1I2) PXR A-24381C(rs1523127) ,C8055T(2276707) ,and A7635G(rs 6785049) ;and liver X receptor(LXR) (NR1H2) LXR T-rs1405655-C and T-rs2695121-C were assessed in a Danish case-control study of 327 Crohn's disease patients,495 ulcerative colitis(UC) patients,and 779 healthy controls.Odds ratio(OR) and 95%CI were estimated by logistic regression models. RESULTS:The PXR A7635G variant,the PPARγPro12Ala and LXR T-rs2695121-C homozygous variant genotypes were associated with risk of UC(OR:1.31,95% CI:1.03-1.66,P=0.03,OR:2.30,95%CI:1.04-5.08,P=0.04,and OR:1.41,95%CI:1.00-1.98,P=0.05,respectively) compared to the corresponding homozygous wild-type genotypes.Among never smokers,PXR A7635G and the LXR T-rs1405655-C and T-rs2695121-C variant genotypes were associated with risk of IBD(OR:1.41,95%CI:1.05-1.91,P=0.02,OR:1.63,95%CI:1.21-2.20,P=0.001,and OR:2.02,95%CI:1.36-2.99,P=0.0005,respectively) compared to the respective homozygous variant genotypes.PXR A7635G(rs6785049) variant genotype was associated with a higher risk of UC diagnosis before the age of 40 years and with a higher risk of extensive disease(OR:1.34,95%CI:1.03-1.75 and OR:2.49,95%CI:1.24-5.03,respectively) . CONCLUSION:Common PXR and LXR polymorphisms may contribute to risk of IBD,especially among never smokers.

Colorectal cancer in patients with inflammatory bowel disease:Can we predict risk?

The inflammatory bowel diseases(IBD),Crohn's disease(CD) and ulcerative colitis(UC),may be complicated by colorectal cancer(CRC).In a recent populationbased cohort study of 47 347 Danish patients with IBD by Tine Jess and colleagues 268 patients with UC and 70 patients with CD developed CRC during 30 years of observation.The overall risk of CRC among patients with UC and CD was comparable with that of the general population.However,patients diagnosed with UC during childhood or as adolescents,patients with long duration of disease and those with concomitant primary sclerosing cholangitis were at increased risk.In this commentary,we discuss the mechanisms underlying carcinogenesis in IBD and current investigations of genetic susceptibility in IBD patients.Further advances will depend on the cooperative work by epidemiologist and molecular geneticists in order to identify genetic polymorphisms involved in IBD-associated CRC.The ultimate goal is to incorporate genotypes and clinical parameters into a predictive model that will refine the prediction of risk for CRC in colonic IBD.The challenge will be to translate these new findings into clinical practice and to determine appropriate preventive strategies in order to avoid CRC in IBD patients.The achieved knowledge may also be relevant for other inflammation-associated cancers.

GLTSCR1, ATM, PPPIR13L and CD3EAP Genetic Variants and Lung Cancer Risk in a Chinese Population

Genetic variants in glioma tumor suppressor candidate region gene 1 （GLTSCR1） and ATM serine/threonine kinase （ATM） have been associated with various cancer risks. Epidemiological studies also revealed the association of variants of GLTSCR1 and ATM genes with different brain tumors. However, little is known about the relationship between both gene polymorphisms and lung cancer risk. We conducted a Chinese hospital-based casecontrol study involving 384 lung cancer cases and 387 cancer-free controls. No significant differences in the single polymorphism （GLTSCR1 rs1035938 and ATM rs11212592） association were found in five genetic models （co-dominant, dominant, recessive, overdominant and log-additive models） （adjusted by smoking duration）. Join effect of three SNPs （PPPIR13L rs1970764, CD3EAP rs967591, GLTSCR1 rs1035938） on chromosome 19q 13.3 showed that the designated haplotype2 （rs 1970764 G-rs967591 A-rs 1035938 C） [OR （95% CI）=1.60 （1.11-2.32）, P=0.012] and haplotype8 （rs 1970764 G-rs967591 G-rs 1035938 T） [OR （95% CI）=2.45 （1.17-5.12）, P=0.018] were associated with increased risk of lung cancer （adjusted by smoking duration）. The analysis ofmultifactor dimensionality reduction revealed that two 3-way models were the best fit models in analyses of 2 loci （P〈0.001） or 4 loci （P=0.015-0.016）. The entropy-based analysis indicated the strongest synergistic effect between PPPIR13L rs1970764 and ATM rs11212592 in analysis of four genes. In conclusion, our study suggests that haplotypes consisting of PPPIR13L rs1970764- CD3EAP rs967591-GLTSCR1 rs1035938 on Chr19q13.3, interaction of smoking and GLTSCR1 rs1035938-ATM rs11212592, and synergistic action of PPPIR13L rs1970764 and ATM rs 11212592 may associate with lung cancer risk in the Chinese population.

Relationship between apoptotic markers in semen from fertile men and demographic, hormonal and seminal characteristics

Apoptosis in the testis has two putative roles during normal spermatogenesis; limitation of the germ cell population to numbers that can be supported by the Sertoli cells, and, possibly, selective depletion of meiotic and postmeiotic abnormal germ cells. We investigated the demographic and biological correlates of the pro-apoptotic marker Fas and the anti-apoptotic marker Bcl-xL in sperm cells of fertile men. Six hundred and four men from Greenland, Poland and Ukraine were consecutively enrolled during their pregnant wife＇s antenatal visits. Semen analysis was performed as recommended by the World Health Organization. Immunofluorescence coupled to flow cytometry was utilized for detection of apoptotic markers in the sperm cell. DNA damage was assessed by flow cytometry using both the sperm chromatin structure assay （SCSA） and the terminal deoxynucleotidyl transferase dUTP nick end labelling （TUNEL） assay. The percentage of Fas-positive sperm cells was higher in men with high total sperm count （P〈O.01）, more motile sperms （P=-O.04） and fewer sperm head defects （P=-O.05）. These associations were consistent within and across study regions. Furthermore, testosterone, follicle-stimulating hormone （FSH） and sexual hormone-binding globulin （SHBG） were significantly negatively correlated with Fas within and across regions as well. The data indicated no association between the anti-apoptotic Bcl-xL marker and semen or personal characteristics. The finding of Fas-positive sperm cells associated with better semen quality in a cohort of spouses of pregnant women seems different from previous data obtained in infertile men and warrants further investigation to clarify the biological significance of sperm apoptotic markers.

Association between Depression, Pressure Pain Sensitivity, Stress and Autonomous Nervous System Function in Stable Ischemic Heart Disease: Impact of Beta-Adrenergic Receptor Blockade

Background: Depression and ischemic heart disease (IHD) are associated with persistent stress and autonomic nervous system (ANS) dysfunction. The former can be measured by pressure pain sensitivity (PPS) of the sternum, and the latter by the PPS and systolic blood pressure (SBP) response to a tilt table test (TTT). Beta-blocker treatment reduces the efferent beta-adrenergic ANS function, and thus, the physiological stress response. Objective: To test the effect of beta-blockers on changes in depression score in patients with IHD, as well as the influence on persistent stress and ANS dysfunction. Methods: Three months of non-pharmacological intervention aiming at reducing PPS and depression score in patients with stable IHD. Beta-blocker users (N = 102) were compared with non-users (N = 75), with respect to signs of depression measured by the Major Depressive Inventory questionnaire (MDI), resting PPS, and PPS and SBP response to TTT. Results: MDI score decreased 30% in non-users (p = 0.005) compared to 4% (p > 0.1) among users (between-group p = 0.003;effect size = 0.4). Resting PPS decreased in both the groups. Among most vulnerable patients with MDI ≥ 15, reductions in MDI score and resting PPS score correlated in non-users, only (r = 0.69, p = 0.007). Reduction in resting PPS correlated with an increase in PPS and SBP response to TTT. Conclusions: Stress intervention in patients with IHD was anti-depressive in non-users, only. Similarly, the association between the reduction in depression, reduction in persistent stress, and restoration of ANS dysfunction was only seen in non-users, suggesting a central role of beta-adrenergic receptors in the association between these factors.

Occupational risk of exposure to methicillin-resistant Staphylococcus aureus(MRSA)and the quality of infection hygiene in nursing homes

Methicillin-resistant Staphylococcus aureus(MRSA)is an increasing health concern across the globe and is often prevalent at long-term care facilities,such as nursing homes.However,we know little of whether nursing home staff is exposed to MRSA via air and surfaces.We investigated whether staff members at nursing homes are colonised with and exposed to culturable MRSA,and assessed staff members'self-reported knowledge of MRSA and compliance with infection hygiene guidelines.Five nursing homes with MRSA positive residents were visited in Copenhagen,Denmark.Personal bioaerosol exposure samples and environmental samples from surfaces,sedimented dust and bioaerosols were examined for MRSA and methicillin-suscqjtible S.aureus(MSSA)to determine occupational exposure.Swabs were taken from staffs*nose,throat,and hands to determine whether they were colonised with MRSA.An online questionnaire about MRSA and infection control was distributed.No staff members were colonised with MRSA,but MRSA was detected in the rooms of the colonised residents in two out of the five nursing homes.MRSA was observed in air(n=4 out of 42,ranging from 2.9-1.9 CFU/m^(3)),sedimented dust(n=1 out of 58,1.1 ×10^(3) CFU/m^(2)/d),and on surfaces(n=9 out of 113,0.04-70.8 CFU/m^(2)).The questionnaire revealed that half of the staff members worry about spreading MRSA to others.Identified aspects for improvement were improved availability and use of protective equipment,not transferring cleaning supplies(e.g.,vacuum cleaners)between residents'rooms and to reduce worry of MRSA,e.g.,through education.