Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer

BackgroundHyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk.ObjectiveTo determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality.Design, setting, and participantsWe prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986–2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr.Outcome measurements and statistical analysisTotal, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns—empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern—and prostate cancer risk estimated using Cox proportional hazard regression.Results and limitationsDuring 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01–1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00–1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06–1.35) for advanced, 1.22 (1.04–1.42) for fatal, and 1.20 (1.04–1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00–1.35).ConclusionsHyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease.Patient summaryAvoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.     

MICA is associated with type 1 diabetes in the Belgian population, independent of HLA-DQ

To ascertain association of MICA with type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients were analyzed for MICA transmembrane gene polymorphism in both an association study and a nuclear family study. The frequency of MICA5 was significantly increased in the T1D patient group (18%) compared with the control population (12%, OR=1.6, pc<10(-3)), whereas MICA9 was decreased (11% versus 16%, OR=0.7, pc<0.01). A p value<10(-3) for the association of MICA conditional on HLA class II and p=0.01 for the conditional extended transmission disequilibrium test were obtained, indicating that MICA is associated with type 1 diabetes, independent of HLA-DQ. Analysis of estimated extended HLA-DQ-MICA haplotypes revealed individual effects of MICA alleles. The most significant effect was seen for MICA5 on the HLA-DQA1*03-DQB1*0302-MICA haplotype (OR=2.5, p<10(-3)). A significant protective effect was seen for the combination of DQA1*01-DQB1*0602/3 and MICA5.1 (OR=0.3, p<10(-3)). However, patients stratified according to the presence or absence of the different MICA alleles did not differ in terms of age at onset, sex, or other diabetes-related clinical and epidemiological data. In conclusion, MICA is associated with type 1 diabetes in the Belgian population and the observed association does not result from the HLA-DQ associated risk.     

Regression with a right-censored predictor using inverse probability weighting methods

In a longitudinal study, measures of key variables might be incomplete or partially recorded due to drop-out, loss to follow-up, or early termination of the study occurring before the advent of the event of interest. In this paper, we focus primarily on the implementation of a regression model with a randomly censored predictor. We examine, particularly, the use of inverse probability weighting methods in a generalized linear model (GLM), when the predictor of interest is right-censored, to adjust for censoring. To improve the performance of the complete-case analysis and prevent selection bias, we consider three different weighting schemes: inverse censoring probability weights, Kaplan-Meier weights, and Cox proportional hazards weights. We use Monte Carlo simulation studies to evaluate and compare the empirical properties of different weighting estimation methods. Finally, we apply these methods to the Framingham Heart Study data as an illustrative example to estimate the relationship between age of onset of a clinically diagnosed cardiovascular event and low-density lipoprotein among cigarette smokers.     

An immunocytochemical study of the distribution of proline-4- hydroxylase in normal, osteoarthritic and rheumatoid arthritic synovium at both the light and electron microscopic level

The monoclonal antibody 5B5 reacts with the beta subunit of proline-4- hydroxylase, the enzyme which catalyses the formation of 4-hydroxyl proline in collagen and other proteins with collagen-like amino acid sequences. This study aims to assess the production and tissue distribution of this enzyme in normal and diseased synovia from patients with various joint diseases, on the basis that it is a putative marker of collagen-producing cells and, therefore, in this context, of fibroblasts. Sections from five normal, 10 osteoarthritic (OA) and 26 rheumatoid arthritic (RA) synovia were labelled with a mouse monoclonal antibody to proline-4-hydroxylase. The enzyme was found to be expressed by a proportion of synovial intimal cells and by fibroblasts in the underlying connective tissue in normal, OA and RA synovia. Labelling was more pronounced in OA and RA cases. The intimal cells labelling positively showed type B synoviocyte morphology, which was confirmed by subsequent double immunolabelling with 5B5 and antibody against type IV collagen using immunocytochemistry and immunoelectron microscopy.      

IFIH1 gene polymorphisms in type 1 diabetes: Genetic association analysis and genotype–phenotype correlation in the Belgian population

The evaluation of susceptibility loci in a registry-based setting could be an important addition to the current predictive and screening models in T1D. Therefore, the aim of this study was to evaluate the importance of one of these loci, IFIH1. T1D patients (n=1981), control subjects (n=2092) and 430 families were genotyped for HLA-DQ and IFIH1 nsSNP rs1990760 (Ala946Thr). In the association analysis, the allelic frequencies, A (62.4% vs. 61.3%) and G (37.6% vs. 38.7%) were similar in cases and controls (χ² = 0.98, p = 0.32), the genotypic frequencies reveals a weak association with T1D (χ² = 6.79, p = 0.03), no significant transmission distortions in families (%T; A = 51.4%, G = 48.0 %, χ² = 1.76, p = 0.19) and no interaction with HLA-DQ-linked risk. Furthermore, no genotype-phenotype correlation was observed. In conclusion, IFIH1 has no important role in T1D risk assessment in a registry-based Belgian population.     

A model system for the study of human retinal angiogenesis: activation of monocytes and endothelial cells and the association with the expression of the monocarboxylate transporter type 1 (MCT-1)

Aims/hypothesis. The growth of retinal vessels is associated with a number of disease conditions, including diabetic retinopathy and proliferative vitreo-retinopathy. In this study we describe a model of human retinal angiogenesis and show how this may be used to explain the mechanisms that are associated with the growth of new retinal vessels. Methods. A 4 mm diameter disc of retinal tissue was placed within a fibrin matrix and the appearance was monitored daily by light microscopy. Immunohistochemical techniques were used for the detection of, glial fibrillary acidic protein, CD68, the Ki-67 antigen, vascular endothelial growth factor, monocarboxylate transporter type 1 and von Willebrand's factor. Results. Vessels were evident extending from the periphery of the explant and the activation of endothelial cells was shown by immuno-peroxidase staining of paraffin embedded sections of the explants for the expression of the Ki-67 antigen, a marker of cell proliferation. The expression of glial fibrillary acidic protein and von Willebrand's factor increased with duration in culture and the presence of activated macrophages or microglia or both was shown by positive immunoreactivity for CD68 and Ki-67 and were identified by day 3. The presence of endogenous vascular endothelial growth factor and the activation of monocarboxylate transporter type 1 by vascular endothelial growth factor, showed the involvement of specific growth factors. Conclusion/interpretation. The explant model provides evidence for the involvement of macrophages and glial fibrillary acidic protein activation in human retinal angiogenesis and for the expression of monocarboxylate transporter type 1, which is likely to be important in the use of lactate in the hypoxic retina. [Diabetologia (1999) 42: 870–877] Received: 9 December 1998 and in final revised form: 26 January 1999     

TNFa microsatellite polymorphism modulates the risk of type 1 diabetes in the Belgian population, independent of HLA-DQ

To determine the contribution of the tumor necrosis factor alpha gene (TNFA) to the immunogenetic risk prediction of type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients with type 1 diabetes (T1D), nondiabetic control subjects, and nuclear families were analyzed for HLA-DQA1-DQB1, TNFA -308 G/A promoter single nucleotide polymorphism (SNP) and TNFa microsatellite markers in both case-control and transmission studies. A total of 1,029 patients (mean age at onset, 18 years; male/female ratio, 1.2), 575 control subjects and 179 nuclear families were analyzed for the -308 SNP and 1,082 patients (mean age at onset, 17 years; and male/female ratio, 1.3), 606 control subjects, and 261 nuclear families were analyzed for the TNFa microsatellite marker. All subjects were typed initially for HLA-DQ. No primary association was detected with the -308 G/A promoter SNP. In contrast, we found evidence of a contribution of TNFa1 allele to susceptibility for T1D independently of HLA-DQ. We observed that the conserved HLA-DQ-TNFa extended haplotype, HLA-DQA1 0501-DQB1 0201-TNFa1 is a diabetogenic haplotype in the Belgian population and is independent of age at onset and gender and confers an estimated relative risk of 4.55 and an absolute risk of 1.7%. In conclusion, our observations suggest that the-308 G/A promoter SNP is not a genetic marker for T1D, but that the TNFa microsatellite may have an added value to further refine the immunogenetic risk conferred by the HLA-DQ region in the Belgian population.