The influence of glucose-lowering therapies on cancer risk in type 2 diabetes

AIMS/HYPOTHESIS: The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. METHODS: This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. RESULTS: Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. CONCLUSIONS/INTERPRETATION: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin

Asymmetric growth-limiting development of the female conceptus

IntroductionSex differences in prenatal growth may contribute to sex-dependent programming effects on postnatal phenotype. MethodsWe integrated for the first time phenotypic, histomorphological, clinico-chemical, endocrine and gene expression analyses in a single species, the bovine conceptus at mid-gestation. ResultsWe demonstrate that by mid-gestation, before the onset of accelerated growth, the female conceptus displays asymmetric lower growth compared to males. Female fetuses were smaller with lower ponderal index and organ weights than males. However, their brain:body weight, brain:liver weight and heart:body weight ratios were higher than in males, indicating brain and heart ‘sparing’. The female placenta weighed less and had lower volumes of trophoblast and fetal connective tissue than the male placenta. Female umbilical cord vessel diameters were smaller, and female-specific relationships of body weight and brain:liver weight ratios with cord vessel diameters indicated that the umbilico-placental vascular system creates a growth-limiting environment where blood flow is redistributed to protect brain and heart growth. Clinico-chemical indicators of liver perfusion support this female-specific growth-limiting phenotype, while lower insulin-like growth factor 2 (IGF2) gene expression in brain and heart, and lower circulating IGF2, implicate female-specific modulation of key endocrine mediators by nutrient supply. ConclusionThis mode of female development may increase resilience to environmental perturbations in utero and contribute to sex-bias in programming outcomes including susceptibility to non-communicable diseases

Maternal and paternal genomes differentially affect myofibre characteristics and muscle weights of bovine fetuses at midgestation

Postnatal myofibre characteristics and muscle mass are largely determined during fetal development and may be significantly affected by epigenetic parent-of-origin effects. However, data on such effects in prenatal muscle development that could help understand unexplained variation in postnatal muscle traits are lacking. In a bovine model we studied effects of distinct maternal and paternal genomes, fetal sex, and non-genetic maternal effects on fetal myofibre characteristics and muscle mass. Data from 73 fetuses (Day153, 54% term) of four genetic groups with purebred and reciprocal cross Angus and Brahman genetics were analyzed using general linear models. Parental genomes explained the greatest proportion of variation in myofibre size of Musculus semitendinosus (80–96%) and in absolute and relative weights of M. supraspinatus, M. longissimus dorsi, M. quadriceps femoris and M. semimembranosus (82–89% and 56–93%, respectively). Paternal genome in interaction with maternal genome (P<0.05) explained most genetic variation in cross sectional area (CSA) of fast myotubes (68%), while maternal genome alone explained most genetic variation in CSA of fast myofibres (93%, P<0.01). Furthermore, maternal genome independently (M. semimembranosus, 88%, P<0.0001) or in combination (M. supraspinatus, 82%; M. longissimus dorsi, 93%; M. quadriceps femoris, 86%) with nested maternal weight effect (5–6%, P<0.05), was the predominant source of variation for absolute muscle weights. Effects of paternal genome on muscle mass decreased from thoracic to pelvic limb and accounted for all (M. supraspinatus, 97%, P<0.0001) or most (M. longissimus dorsi, 69%, P<0.0001; M. quadriceps femoris, 54%, P<0.001) genetic variation in relative weights. An interaction between maternal and paternal genomes (P<0.01) and effects of maternal weight (P<0.05) on expression of H19, a master regulator of an imprinted gene network, and negative correlations between H19 expression and fetal muscle mass (P<0.001), suggested imprinted genes and miRNA interference as mechanisms for differential effects of maternal and paternal genomes on fetal muscle.Ruidong Xiang, Mani Ghanipoor-Samami, William H. Johns, Tanja Eindorf, David L. Rutley, Zbigniew A. Kruk, Carolyn J. Fitzsimmons, Dana A. Thomsen, Claire T. Roberts, Brian M. Burns, Gail I. Anderson, Paul L. Greenwood, Stefan Hiendlede

Modelling and Simulation of a Transformer With Inter-turn Fault Including Saturation Effect and Variable Fault Parameters

This investigation deals with a mathematical model for a distribution transformer including saturation effect. To this end, the equations related to a three phase transformer are specified and the effect of an inter-turn fault is included. Naturally by applying an inter-turn fault the inductance and resistance matrix will change. Thus, unknown quantities of inductances and resistances for completing the matrix are calculated and the inputs, outputs and state variables are specified. All the equations will be rewritten in terms of state variables, subsequently saturation effect is added to the model. Finally the block diagram of the specified model based on the obtained equations are designed and the ultimate model is simulated. The saturation effect, added to the mathematical model and also the variable fault parameters are known as two significant contributions which distinguish this study from other investigations. Various results obtained from the simulation of the final model confirm the changes in the behavior of faulty transformer such as: a large circulating current flowing in the shorted turns, lower impact on terminal voltages and currents, a sudden increase in current flowing in the primary winding, asymmetrical flux distribution and inverse proportion of the fault severity and the limiting resistor

Association between aggressive behaviors, life satisfaction, self-rated health and counseling with family members among children and adolescents: The CASPIAN- IV study

Background: Aggressive behaviors are common in the pediatric age and counseling with parents should be one of the main preventive and therapeutic starategies. This study aimed to assess the relationship between the frequency of aggressive behaviors, life satisfaction (LS) and self- rated health (SRH) and counseling with family members and friends in a representative sample of Iranian children and adolescents. Materials and Methods: In this nationwide study, 14,880 school students, aged 6-18 years, were selected by cluster and stratified multi-stage sampling method from 30 provinces in Iran. The World Health Organization Global School-based Health Survey questionnaire(WHO-GSHS) was used. Mental disorders were assessed through the WHO-GSHS questionnaire that consisted of worthless, angriness, anxiety, insomnia, confusion, depression, and worried. Results: Overall, 13,486 students (49.2 girls) with mean (standard deviationSD) age of 12.47(3.36) years participated the study. The prevalence of physical fight, victim, and bully was lower in children and adolescents who consulted with their father compared those who did not consult (P < 0.05). Physical fight and bully were less prevalent in children and adolescents who consulted with their mother and friends compared those who did not consult (P < 0.001). Also, the prevalence of LS and SRH "good" was also lower in children and adolescents who share their problem with their father or mother compared with those who did not consult (P < 0.001). Conclusion: Counseling with family members was associated with low physical fight, low bully, good sexual and reproductive health (SRH) and LS. So, children and adolescents should be encouraged to consult with their parents about their problems

Association between aggressive behaviors, life satisfaction, self-rated health and counseling with family members among children and adolescents: The CASPIAN- IV study

Background: Aggressive behaviors are common in the pediatric age and counseling with parents should be one of the main preventive and therapeutic starategies. This study aimed to assess the relationship between the frequency of aggressive behaviors, life satisfaction (LS) and self- rated health (SRH) and counseling with family members and friends in a representative sample of Iranian children and adolescents. Materials and Methods: In this nationwide study, 14,880 school students, aged 6-18 years, were selected by cluster and stratified multi-stage sampling method from 30 provinces in Iran. The World Health Organization Global School-based Health Survey questionnaire(WHO-GSHS) was used. Mental disorders were assessed through the WHO-GSHS questionnaire that consisted of worthless, angriness, anxiety, insomnia, confusion, depression, and worried. Results: Overall, 13,486 students (49.2 girls) with mean (standard deviationSD) age of 12.47(3.36) years participated the study. The prevalence of physical fight, victim, and bully was lower in children and adolescents who consulted with their father compared those who did not consult (P < 0.05). Physical fight and bully were less prevalent in children and adolescents who consulted with their mother and friends compared those who did not consult (P < 0.001). Also, the prevalence of LS and SRH "good" was also lower in children and adolescents who share their problem with their father or mother compared with those who did not consult (P < 0.001). Conclusion: Counseling with family members was associated with low physical fight, low bully, good sexual and reproductive health (SRH) and LS. So, children and adolescents should be encouraged to consult with their parents about their problems