Frequent delay of coeliac disease diagnosis in symptomatic patients with type 1 diabetes mellitus: Clinical and genetic characteristics

BackgroundPatients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM.MethodsWe studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type.ResultsThirty-three percent of T1DM + CD patients reported CD related complaints for at least 5 years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45 years of age. Women were diagnosed with CD at a younger age than men (median 25 years (IQR 9–38) versus 39 (12–55) years, respectively, P < 0.05).ConclusionA delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5 years interval.     

Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis

Osteoarthritis [MIM 165720] is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. Additional replication was tested in 1582 population-based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (log of odds = 3.03, P = 1.9 x 10(-4)). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413]) which significantly explained the linkage signal (P = 0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37-2.34 with P = 2.02 x 10(-5) in female cases with advanced/symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3',5,5'-tetraiodothyronine (T4) into the active thyroid hormone 3,3',5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.     

Acute rejection of vascular heart allografts by perforin-deficient mice

To study the role of perforin in cell-mediated graft rejection, vascularized hearts were grafted to perforin-deficient C57BL/6 and control C57BL/6 recipient mice. Fully allogeneic heart grafts (BALB/c) were acutely rejected by both recipients within 6 days. Peritoneal exudate lymphocytes from control mice but not from perforin-deficient mice exhibit a strong alloreactive cytotoxic activity in vitro. Histological analysis of the rejected tissues demonstrated extensive mononuclear cell infiltrates in both recipients. Flow cytometry analysis and immunohistology of graft-infiltrating cells showed similar proportions of lymphocyte subsets (CD8 ≧ CD4). Collectively, these data indicate that perforin is not essential in the cell-mediated acute rejection of a fully mismatched heart allograft. However, perforin-dependent effector mechanisms appeared to be limiting in the T cellmediated rejection of heart allografts differing only at a single major histocompatibility complex class I antigen (bm1), because these grafts survived longer (mean 87.8 days) in perforin-deficient than in control mice (mean 31.5 days).     

Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer

BackgroundNext to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients.MethodsGermline DNA was isolated from 246 KRAS wild-type mCRC patients who were treated in the phase III CAIRO2 study with chemotherapy and bevacizumab alone or with the addition of cetuximab. Associations of epidermal growth factor (EGF) 61A > G, EGF receptor (EGFR) CA_14–22, cyclin D1 (CCND1) 932G > A, fragment-C gamma receptor (FCGR) 2A 535A > G and FCGR3A 818A > C polymorphisms with progression-free survival (PFS) and cetuximab-related skin toxicity were studied.ResultsIn cetuximab-treated patients, the FCGR3A 818C-allele was associated with decreased PFS compared with the FCGR3A 818AA genotype (median PFS, 8.2 [95%CI, 6.7–10.3] versus 12.8 [95%CI, 10.3–14.7] months, respectively; HR, 1.57 [95%CI, 1.06–2.34]; P = .025). The EGFR ? 20 genotype was associated with decreased PFS compared with the EGFR < 20 genotype (median PFS, 7.6 [95%CI, 6.7–10.0] versus 12.4 [95%CI, 10.3–13.4] months, respectively; HR, 1.58 [95%CI, 1.06–2.35]; P = .024). The FCGR3A and EGFR polymorphisms were not associated with PFS in patients treated without cetuximab. None of the polymorphisms were associated with the incidence of grades 2–3 skin toxicity.ConclusionEGFR and FCGR3A germline polymorphisms are associated with PFS in KRAS wild-type mCRC patients treated with cetuximab, bevacizumab and chemotherapy.     

Quality of the parent-child interaction in young children with type 1 diabetes mellitus: study protocol

Background  

In young children with type 1 diabetes mellitus (T1DM) parents have full responsibility for the diabetes-management of their child (e.g. blood glucose monitoring, and administering insulin). Behavioral tasks in childhood, such as developing autonomy, and oppositional behavior (e.g. refusing food) may interfere with the diabetes-management to achieve an optimal blood glucose control. Furthermore, higher blood glucose levels are related to more behavioral problems. So parents might need to negotiate with their child on the diabetes-management to avoid this direct negative effect. This interference, the negotiations, and the parent's responsibility for diabetes may negatively affect the quality of parent-child interaction. Nevertheless, there is little knowledge about the quality of interaction between parents and young children with T1DM, and the possible impact this may have on glycemic control and psychosocial functioning of the child. While widely used global parent-child interaction observational methods are available, there is a need for an observational tool specifically tailored to the interaction patterns of parents and children with T1DM. The main aim of this study is to construct a disease-specific observational method to assess diabetes-specific parent-child interaction. Additional aim is to explore whether the quality of parent-child interactions is associated with the glycemic control, and psychosocial functioning (resilience, behavioral problems, and quality of life).