The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.      

Breast cancer among Danish women occupationally exposed to diesel exhaust and polycyclic aromatic hydrocarbons, 1964–2016

Objective:The aim of this study was to explore the association between occupational exposure to diesel exhaust and polycyclic aromatic hydrocarbons (PAH), respectively, and breast cancer subtypes.Methods:The study included 38 375 women <70 years with incident breast cancer, identified in the Danish Cancer Registry, and 5 breast cancer-free controls per case who were randomly selected from the Danish Civil Registration System and matched on year of birth. Full employment history was obtained for all study subjects from a nationwide pension fund, and exposure to diesel exhaust and PAH was assessed using a job exposure matrix. Conditional logistic regression was used for estimation of odds ratios (OR) with adjustment for reproductive factors and socioeconomic status.Results:No noteworthy associations were observed for overall breast cancer in women exposed to diesel exhaust. However, diesel exhaust modestly elevated the risk of estrogen receptor negative breast tumors before age 50 [OR 1.26, 95% confidence interval (CI) 1.09–1.46]. Duration– and dose–response relationships were further observed for this subtype in this age group. No notable risk patterns were generally observed for PAH exposure.Conclusion:Occupational exposure to diesel exhaust may increase the risk of early-onset estrogen receptor negative breast tumors in women. Future studies exploring this association are warranted.     

Nasal histamine challenge in nonallergic and allergic subjects evaluated by acoustic rhinometry

Nasal patency shows spontaneous variations but is influenced by a number of factors like exercise and allergic conditions. Nasal histamine challenge has been used to define nasal hypersensitivity. We have applied acoustic rhinometry as a new objective method to study the spontaneous variations of the nasal mucosa and its response to histamine challenge in 12 nonallergic subjects and 12 subjects with nasal allergy to pollen, but out of the pollen season. Measurements of the minimum cross-sectional area and the volume of the nasal cavities were done every 15 min for 6 h. More pronounced spontaneous variations, defined by the coefficient of variation of the measurements, were encountered in the allergic than in the nonallergic subjects, especially with regard to the minimum cross-sectional areas in the nasal cavities (P < 0.02). Allergic subjects showed increased sensitivity to histamine, as compared with nonallergic subjects, during low-concentration (0.1%) challenge (P < 0.05) and a prolonged effect of histamine challenge (P = 0.01). Antihistamine (cetirizine) had a significant effect on the histamine-induced symptoms and decrease of nasal dimensions during histamine challenge, but no significant effect on pollen-induced changes. In the allergic group, the decrease in minimum area during allergen provocation correlated with the level of specific IgE (r = 0.81; P = 0.0015).     

Zur Kenntnis der Symptomatologie der parieto-occipitalen übergangsregion

Ohne Zusammenfassung     

The genetics of congenital aniridia—a guide for the ophthalmologist

Congenital aniridia is a rare panocular disease caused by fundamental disturbances in the development of the eye, characterized primarily by hypoplasia of the iris and macula. Severe secondary complications such as keratopathy, cataract, and glaucoma are common and often lead to considerable visual impairment or blindness. Many complications in aniridia patients are difficult to treat and present a challenge for the ophthalmologist. Increasingly, associated nonocular features of the disease are also being recognized. Over the past decades, major steps have been made in the understanding of the genetic basis of aniridia. Moreover, recent studies have prepared the ground for future treatment options based on specific mutations. Therefore, specific knowledge about genetics in aniridia has become more important than ever. We provide an overview of the field of aniridia genetics and its clinical implications.     

Acoustic rhinometry in persons recruited from the general population and diagnosed with chronic rhinosinusitis according to EPOS

Chronic rhinosinusitis (CRS) is a disease related to the nose and the paranasal sinus as defined by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) criteria. The criteria include subjective symptoms, such as nasal obstruction, and objective findings by endoscopy. Acoustic rhinometry (AR) is an objective method to determine nasal cavity geometry. The technique is based on a sound pulse reflection analysis in the nasal cavity and determines cross-sectional areas as a function of distance as well as volume. AR measurements in persons recruited from the general population, with and without CRS based on the clinical EPOS criteria, were investigated. As part of a trans-European study, 362 persons, comprising 91 persons with CRS and 271 persons without CRS, were examined by an otolaryngologist including rhinoscopy. Minimum cross-sectional area, distance to minimum cross-sectional area, and volume in the nasal cavity were measured by acoustic rhinometry and all participants underwent Peak Nasal Inspiratory Flow (PNIF) and allergy test. A difference in AR was found before and after decongestion, but no difference was seen between CRS patients and controls. Positive correlation between AR and PNIF was found and AR was capable of identifying mucosal oedema and septum deviation visualised by rhinoscopy. In conclusion, AR, as a single instrument, was not capable of discriminating persons with CRS from persons without CRS in the general population. However, AR correlates well with PNIF and was capable of identifying septum deviation and mucosal oedema.     

Anthropometry in 5- to 9-Year-Old Greenlandic and Ukrainian Children in Relation to Prenatal Exposure to Perfluorinated Alkyl Substances

Background

In some animal studies, perfluorinated alkyl substances are suggested to induce weight gain. Human epidemiological studies investigating these associations are sparse.

Objective

We examined pregnancy serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and the prevalence of offspring overweight (> 1 SD) and waist-to-height ratio (WHtR) > 0.5 at 5–9 years of age.

Methods

Sera from 1,022 pregnant women enrolled in the INUENDO cohort (2002–2004) from Greenland and Kharkiv (Ukraine) were analyzed for PFOA and PFOS using liquid chromatography–tandem mass spectrometry. Relative risks (RR) of being overweight and having WHtR > 0.5 in relation to continuous and categorized (tertiles) PFOA and PFOS were calculated at follow-up (2010–2012) using generalized linear models.

Results

Pooled PFOA median (range) was 1.3 (0.2–5.1) and PFOS median (range) was 10.8 (0.8–73.0) ng/mL. For each natural logarithm-unit (ln-unit) increase of pregnancy PFOA, the adjusted RR of offspring overweight was 1.11 [95% confidence interval (CI): 0.82, 1.53] in Greenlandic children. In Ukrainian children, the adjusted RR of offspring overweight was 1.02 (95% CI: 0.72, 1.44) for each ln-unit increase of pregnancy PFOA. Prenatal exposure to PFOS was not associated with overweight in country-specific or pooled analysis. The adjusted RR of having WHtR > 0.5 for each ln-unit increase of prenatal exposure to PFOA was 1.30 (95% CI: 0.97, 1.74) in the pooled analysis. For 1–ln-unit increase of prenatal exposure to PFOS, the adjusted RR of having a WHtR > 0.5 was 1.38 (95% CI: 1.05, 1.82) in the pooled analysis.

Conclusions

The results indicate that prenatal PFOA and PFOS exposures may be associated with child waist-to-height ratio > 0.5. Prenatal PFOA and PFOS exposures were not associated with overweight.

Citation

Høyer BB, Ramlau-Hansen CH, Vrijheid M, Valvi D, Pedersen HS, Zviezdai V, Jönsson BA, Lindh CH, Bonde JP, Toft G. 2015. Anthropometry in 5- to 9-year-old Greenlandic and Ukrainian children in relation to prenatal exposure to perfluorinated alkyl substances. Environ Health Perspect 123:841–846; http://dx.doi.org/10.1289/ehp.1408881     

Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer's disease

We previously reported aberrant stress responses and impaired glucose tolerance in transgenic Tg2576 mice, a model of Alzheimer's disease (AD). Here we report that by 8 months of age, Tg2576 mice had lower basal serum insulin concentrations and exhibited a delayed insulin-induced reduction in blood glucose levels relative to wild-type mice. However, the basal levels of blood glucose and percent glycosylated hemoglobin (%HbA1c) were similar between the two groups of mice. While the basal levels of serum corticosterone were similar between Tg2576 and wild-type mice, an overnight fasting caused a greater rise in serum corticosterone levels and an excessive reduction in serum insulin concentrations in the transgenics. At 9 months of age, we began administering Tg2576 mice rosiglitazone, an agonist of peroxisome proliferator-activated receptor-gamma that increases peripheral insulin sensitivity, and after 6 weeks of administration the Tg2576 mice had the same response to insulin and increase in serum corticosterone levels after an overnight fast as did wild-type mice. By 13 months of age, untreated Tg2576 mice had become hyperinsulinemic, in contrast to Tg2576 mice administered rosiglitazone for 4 months where the serum insulin concentrations were maintained at levels observed in wild-type mice. These results provide evidence for a relationship between insulin resistance, impaired regulation of insulin and glucose levels, and aberrant stress responses in Tg2576 mice.