Hypomorphic mutations in genes associated with severe combined immunodeficiency (SCID) or Omenn syndrome can also cause milder immunodeficiencies. We report 10 new patients with such "atypical" SCID and summarize 63 patients from the literature. The patient groups with T(low)B(low) (n=28), T(low)B(+) (n=16) and ADA (n=29) SCID variants had similar infection profiles but differed in the frequency of immune dysregulation, which was observed predominantly in patients with recombinationdefects. Most immunological parameters were remarkably similar inthe three groups. Of note, 19/68 patients with "atypical" SCID had normal T cell counts, 48/68 had normal IgG and 23/46 had at least one normal specific antibody titer. Elevated IgE was a characteristic feature of ADA deficiency. This overview characterizes "atypical" SCID as a distinct disease with immune dysregulation in addition to infection susceptibility. Lymphopenia, reduced naive T cells and elevated IgE are suggestive, but not consistent features of the disease.
COBISS.SI-ID: 28966873
Purpose The objectives of this study were (1) to develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukaemia (ALL) and malignant lymphoma (ML) in order to investigate the influence of common polymorphisms in SLC19A1, MTHFR and ABCB1 on plasma levels of MTX and (2) to estimate MTX exposure in individual patients to study the association of genetic variability in the folate metabolic pathway with MTX toxicity. Methods The study population comprised 64 children with ALL/ML (age 1.6-16.8 years) who had received a total of 252 MTX courses (2-4 per patient). Common putative functional polymorphisms in the SLC19A1, MTHFR, MS, MTRR, TS and ABCB1 genes were analysed by PCR-based genotyping. Nonlinear mixed effects modelling was used for the pharmacokinetic analysis. Results The population typical value of clearance was 7.43 L/h (inter-individual variability 43.9%), central compartment volume was 16.7 L (46.6%), peripheral compartment volume was 2.6 L (63.3%) and distribution clearance was 0.0952 L/h (66.6%). MTX clearance decreased to 73.8% in patients with the MTHFR 677TT genotype. Patients homozygous for the variant MTHFR 1298A ) C [odds ratio (OR) 0.14, 95% confidence interval (CI) 0.037-0.54] and SLC19A1 80A ) G (OR 0.15, 95% CI 0.039-0.60) were at decreased risk for leucopenia. The TS 2R ) 3R polymorphism was associated with a lower incidence of thrombocytopenia (OR 0.15, 95% CI 0.039-0.61) and mucositis (OR 0.016, 95% CI 0.0012-0.20). In contrast, the MTHFR 677TT polymorphism was associated with an increased incidence of mucositis (OR 23, 95% CI 2.1-240). Conclusions A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.
COBISS.SI-ID: 3002737
OBJECTIVE: To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A(1c) (HbA(1c)) (7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearinga masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration (63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. RESULTS: The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean +/- SD 0.48 +/- 0.57 and 0.97 +/- 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26-0.76; P = 0.03). HbA(1c) at 26 weeks was lower in the continuous monitoring group than in the control group (difference -0.27%; 95% CI -0.47 to -0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemiawas significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009). CONCLUSIONS: Continuous glucose monitoring was associated with reducedtime spent in hypoglycemia and a concomitant decrease in HbA(1c) in children and adults with type 1 diabetes.
COBISS.SI-ID: 29623001