Accumulation of lipid in muscular arteries of short-term diabetic rats

Summary Lipid accumulation in muscular (pulmonary, coronary and tibial) arteries and elastic (aorta and pulmonary) arteries of streptozotocin diabetic (65 mg/kg) rats was studied with an electron microscope. Arterial tissue specimens taken 4 days after the induction of diabetes showed lipid deposits in smooth muscle cells in the muscular arteries of 9 out of 24 diabetic rats, but in none of the 17 control rats. Histochemically the lipid was identified as triacylglycerol. Lipid accumulation was not seen in the elastic arteries of either diabetic or control rats. The diabetic animals with lipid deposits had slightly but significantly higher plasma glucose concentrations (p<0.02), higher non-esterified fatty acids levels (p<0.01), and lower concentrations of plasma insulin (p<0.02) than those without arterial deposits. The amount of lipid deposited in the arteries was closely related to the plasma non-esterified fatty acid level, which was in the ranges 0.8–1.1 mmol/l in diabetic rats without deposits, and 1.1–2.4 mmol/l in those with deposits. The findings suggest that lipid accumulation in smooth muscle cells of muscular arteries during acute diabetes could result from the high plasma non-esterified fatty acid concentrations.     

Exercise-induced proteinuria in children and adolescents with Type 1 (insulin dependent) diabetes

Summary The urinary excretion of albumin and -₂microglubulin was measured by radioimmunoassay in 64 children and adolescents with Type 1 (insulin dependent) diabetes and in 68 non-diabetic subjects aged from 9 to 19 years. At rest the albumin excretion of the diabetic subjects did not differ from that of the non-diabetic children and adolescents but during exercise the albumin excretion was significantly higher in children and adolescents with Type 1 diabetes (p<0.02). The excretion rate of ₂-microglobulin in diabetic subjects did not differ from that of the healthy subjects. Both at rest and during exercise the albumin excretion rate was highest in those diabetics with poorest metabolic control of their disease.     

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study

BRCA1 and BRCA2 screening in women at high‐risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population‐based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA‐binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. © 2010 Wiley‐Liss, Inc.     

Diet,cow's milk protein antibodies and the risk of IDDM in Finnish children

Summary Associations of infant feeding patterns and milk consumption with cow's milk protein antibody titres were studied in 697 newly-diagnosed diabetic children, 415 sibling-control children and 86 birth-date-and sex-matched population-based control children in the nationwide Childhood Diabetes in Finland study. IgA and IgG antibody titres to the proteins of cow's milk formula, BLG and BSA, and IgM antibody titres to cow's milk formula proteins were measured by ELISA. Several inverse correlations were observed between the duration of breast-feeding or age at introduction of dairy products and antibody titres, and positive correlations were observed between milk consumption and antibody titres in all three populations studied. Multivariate analyses which included the infant feeding variables, milk consumption and current age simultaneously showed that the earlier the introduction of dairy products and the greater the consumption of milk was, the higher several antibody titres were. High IgA antibody titres to cow's milk formula were associated with a greater risk of IDDM both among diabeticpopulation-control and diabetic-sibling-control pairs when adjusted for other cow's milk antibody titres, dietary variables and in diabetic-sibling-control pairs also for ICA. The results suggest that young age at introduction of dairy products and high milk consumption during childhood increase the levels of cow's milk antibodies and that high IgA antibodies to cow's milk formula are independently associated with increased risk of IDDM.Abbreviations IDDM Insulin-dependent diabetes mellitus - BLG betalactoglobulin - BSA bovine serum albumin - ICA islet cell antibodies - IAA insulin autoantibodies - OR odds ratio - CI confidence interval     

Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes

Glutamic acid decarboxylase (GAD)₆₅ formulated with aluminium hydroxide (GAD‐alum) was effective in preserving insulin secretion in a Phase II clinical trial in children and adolescents with recent‐onset type 1 diabetes. In addition, GAD‐alum treated patients increased CD4⁺CD25^hi forkhead box protein 3⁺ (FoxP3⁺) cell numbers in response to in‐vitro GAD₆₅ stimulation. We have carried out a 4‐year follow‐up study of 59 of the original 70 patients to investigate long‐term effects on the frequency and function of regulatory T cells after GAD‐alum treatment. Peripheral blood mononuclear cells were stimulated in vitro with GAD₆₅ for 7 days and expression of regulatory T cell markers was measured by flow cytometry. Regulatory T cells (CD4⁺CD25^hiCD127^lo) and effector T cells (CD4⁺CD25^–CD127⁺) were further sorted, expanded and used in suppression assays to assess regulatory T cell function after GAD‐alum treatment. GAD‐alum‐treated patients displayed higher frequencies of in‐vitro GAD₆₅‐induced CD4⁺CD25⁺CD127⁺ as well as CD4⁺CD25^hiCD127^lo and CD4⁺FoxP3⁺ cells compared to placebo. Moreover, GAD₆₅ stimulation induced a population of CD4^hi cells consisting mainly of CD25⁺CD127⁺, which was specific of GAD‐alum‐treated patients (16 of 25 versus one of 25 in placebo). Assessment of suppressive function in expanded regulatory T cells revealed no difference between GAD‐alum‐ and placebo‐treated individuals. Regulatory T cell frequency did not correlate with C‐peptide secretion throughout the study. In conclusion, GAD‐alum treatment induced both GAD₆₅‐reactive CD25⁺CD127⁺ and CD25^hiCD127^lo cells, but no difference in regulatory T cell function 4 years after GAD‐alum treatment.     

Quality of life and clinical features in Swedish children with psoriasis

Psoriasis is a common, chronic disease and in one-third of the patients it begins during the first 2 decades of life. The burdens of psoriasis are many, and some can be assessed with quality of life questionnaires. The aim was to investigate the impact of childhood psoriasis on quality of life in children and their parents and to correlate certain clinical findings with quality of life. Forty-five Swedish children (4-16 years, 28 girls) with psoriasis, and their parents, were investigated with the validated questionnaires Children's Dermatology Life Quality Index (5-16 years, n = 42), The Infant's Dermatitis Quality of Life Index (4 years, n = 3), and Dermatitis Family Impact (n = 45), the two latter with the word eczema replaced by psoriasis. Clinical examination was performed, and psoriasis severity was scored with Psoriasis Area and Severity Index. Chronic plaque psoriasis was the most common clinical type (87%). Four of the children had joint complaints. Ninety-three percent had pruritus the preceding 3 days. Ninety-three percent were receiving treatment. Median Psoriasis Area and Severity Index score was 3.3 (range 0.5-12.3). Median score for the Infant's Dermatitis Quality of Life Index was 4.0 (range 2-12), for Children's Dermatology Life Quality Index 4.0 (0-24), and for Dermatitis Family Impact questionnaire 4.0 (0-25). No significant gender difference existed. The Children's Dermatology Life Quality Index scores were higher for younger (5-8 yrs) than older (9-16 yrs) children and higher for those with joint complaints. The Dermatitis family impact scores correlated significantly with Children's Dermatology Life Quality Index and Psoriasis Area and Severity Index scores, but the Children's Dermatology Life Quality Index did not correlate with Psoriasis Area and Severity Index. The Visual Analog Scale and quality of life scores were significantly correlated. Psoriasis in children affects quality of life in the subjects and their parents. Joint complaints and pruritus significantly impair quality of life.