Microalbuminuria and retinopathy in adolescents and young adults with type 1 and type 2 diabetes.

AIM: To estimate the occurrence of complications related to early-onset type 2 diabetes compared with type 1 diabetes. METHODS: All individuals registered in the Swedish Pediatric Quality Diabetes Register and the Swedish National Diabetes Register with type 2 diabetes diagnosis at 10 to 25?years of age between 1996 and 2014 (n = 1413) were included. As controls, individuals with type 1 diabetes were randomly selected from the same registers and were matched for age, sex, and year-of-onset (n = 3748). RESULTS: Of the adolescents with type 2 diabetes in the pediatric register, 7.7% had microalbuminuria and 24.6% had signs of retinopathy 5?years after diagnosis, whereas the adolescents with type 1 diabetes 3.8% had microalbuminuria and 19.2% had retinopathy. Among the young adults with type 2 diabetes from the adult diabetes register 10?years after diagnosis 15.2% had microalbuminuria and 39.7% retinopathy, whereas the young adults with type 1 diabetes 4.8% had microalbuminuria and 43.8% retinopathy. After adjustment for established risk factors measured over time in the whole combined cohort, individuals with type 2 diabetes had significantly higher risk of microalbuminuria with a hazard ratio (HR) of 3.32 (95% confidence interval, CI 2.86-3.85, P?< .001), and retinopathy with a HR of 1.17 (95% CI 1.06-1.30, P 0.04). CONCLUSIONS: The prevalence of complications and comorbidities was higher among those with type 2 diabetes compared with type 1 diabetes, although prevalent in both groups. Early monitoring and more active treatment of type 2 diabetes in young individuals is required

The HARMONIE–AROME Model Configuration in the ALADIN–HIRLAM NWP System

The aim of this article is to describe the reference configuration of the convection-permitting numerical weather prediction (NWP) model HARMONIE-AROME, which is used for operational short-range weather forecasts in Denmark, Estonia, Finland, Iceland, Ireland, Lithuania, the Netherlands, Norway, Spain, and Sweden. It is developed, maintained, and validated as part of the shared ALADIN–HIRLAM system by a collaboration of 26 countries in Europe and northern Africa on short-range mesoscale NWP. HARMONIE–AROME is based on the model AROME developed within the ALADIN consortium. Along with the joint modeling framework, AROME was implemented and utilized in both northern and southern European conditions by the above listed countries, and this activity has led to extensive updates to themodel’s physical parameterizations. In this paper the authors present the differences inmodel dynamics and physical parameterizations compared with AROME, as well as important configuration choices of the reference, such as lateral boundary conditions, model levels, horizontal resolution, model time step, as well as topography, physiography, and aerosol databases used. Separate documentation will be provided for the atmospheric and surface data-assimilation algorithms and observation types used, as well as a separate description of the ensemble prediction system based on HARMONIE–AROME, which is called HarmonEPS

A Genetic Basis of Susceptibility to Acute Pyelonephritis

For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring

Pathogen Specific, IRF3-Dependent Signaling and Innate Resistance to Human Kidney Infection

The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3−/− mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3−/− mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response