Decreased levels of homoarginine and asymmetric dimethylarginine in children with type 1 diabetes: associations with cardiovascular risk factors but no effect by atorvastin

Objectives: To investigate homoarginine and asymmetric dimethylarginine (ADMA) in controls compared to children with type 1 diabetes (T1D) and if homoarginine and ADMA are affected by atorvastatin. Methods: Homoarginine and ADMA levels of 28 T1D patients were compared to levels of 41 controls. In T1D patients, homoarginine and ADMA were determined at baseline, 1 year, and 2 years at daily 10 mg atorvastatin or placebo within a double-blind study. Results: At baseline, both homoarginine and ADMA were lower (p<0.001) in T1D patients compared to controls. In T1D patients, homoarginine and ADMA were not influenced by atorvastatin. Inverse correlations between homoarginine and HbA1c (p<0.001) and between ADMA and systolic blood pressure (p=0.005) and pulse pressure (p=0.003) were shown. Conclusions: Homoarginine and ADMA levels are decreased and associated with cardiovascular risk factors in children with T1D without being affected by atorvastatin

Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency. Little is known about the management and long-term glycaemic control of CHI patients with diabetes after pancreatic surgery. We searched the German/Austrian DPV database and compared the course of 42 CHI patients with diabetes to that of patients with type 1 diabetes mellitus (T1DM). Study groups were compared at diabetes onset and after a follow-up period of 6.1 [3.3–9.7] (median [interquartile range]) years. Results: The majority of CHI patients with diabetes were treated with insulin (85.2% [70.9–99.5] at diabetes onset, and 90.5% [81.2–99.7] at follow-up). However, compared to patients with T1DM, significantly more patients in the CHI group with diabetes were treated with conventional insulin therapy (47.8% vs. 24.4%, p = 0.03 at diabetes onset, and 21.1% vs. 6.4% at follow-up, p = 0.003), and only a small number of CHI patients were treated with insulin pumps. Daily insulin dose was significantly lower in CHI patients with diabetes than in patients with T1DM, both at diabetes onset (0.3 [0.2–0.5] vs. 0.6 IE/kg/d [0.4–0.8], p = 0.003) and follow-up (0.8 [0.4–1.0] vs. 0.9 [0.7–1.0] IE/kg/d, p = 0.02), while daily carbohydrate intake was comparable in both groups. Within the first treatment year, HbA1c levels were significantly lower in CHI patients with diabetes (6.2% [5.5–7.9] vs. 7.2% [6.5–8.2], p = 0.003), but increased to a level comparable to that of T1DM patients at follow-up. Interestingly, in CHI patients, the risk of severe hypoglycaemia tends to be higher only at diabetes onset (14.8% vs. 5.8%, p = 0.1). Conclusions: In surgically treated CHI patients insulin treatment needs to be intensified in order to achieve good glycaemic control. Our data furthermore emphasize the need for improved medical treatment options for patients with diazoxide- and/or octreotide-unresponsive CHI

Heterozygous Nonsense Mutation in Exon 3 of the Growth Hormone Receptor (GHR) in Severe GH Insensitivity (Laron Syndrome) and the Issue of the Origin and Function of the GHRd3 Isoform

International audienceMutations in the GH receptor gene (GHR) cause congenital GH insensitivity, a genetic disorder characterized by severe growth retardation associated with high serum concentration of GH and low serum levels of IGF-I. Molecular defects have been identified in all GHR-coding exons, except exon 3, a sequence that encodes part of the extracellular domain of the receptor. In humans, GHR transcripts exist in two isoforms differing by the retention (GHRfl) or exclusion (GHRd3) of this particular exon. As shown recently, such a dimorphic expression pattern, of unknown significance, could result from a retrovirus-mediated deletion event involving exon 3. This model for the generation of those two isoforms, however, leaves open the possibility that GHRd3 transcripts also arise from GHRfl alleles through alternative splicing. Here we report the identification of the first mutation in exon 3 of the GHR (W16X) in a patient with GH insensitivity and who also carries another nonsense mutation in exon 4. Intrafamilial correlation analyses of genotypes (presence of normal or mutant GHRfl and/or GHRd3 alleles), GHR expression patterns, and phenotypes provided direct evidence against an alternative splicing of exon 3. In particular, this exon was retained into transcripts originating from the GHRfl-W16X allele in both the patient and his mother. These observations, given the normal phenotype of the heterozygous parents, revealed also that a single copy of either GHRfl or GHRd3 is sufficient for normal growth

Phylogenetic tree of RSV A/RSV B strains and reference sequences of identified genotypes.

<p>Phylogenetic trees for RSV A (A) and RSV B (B) strains were constructed with maximum-likelihood method with 1,000 bootstrap replicates using MEGA 6 software. RSV strains from Heidelberg/Germany are indicated by “•HD” followed by their strain identification number. Number of identical strains is indicated in brackets after the strain identifier. Reference strains representing known genotypes were retrieved from GenBank and included in the tree (labels include accession number). The genotype assignment is shown on the right by brackets. Prototype strains (M11486 for subgroup A and M17213 for subgroup B) were used as an outgroup. Bootstrap values greater than 70% are indicated at the branch nodes. The scale bar represents the number of nucleotide substitutions per site. cl.  =  cluster.</p

Basic and clinical characteristics of RSV positive children by genotype.

<p>*RSV A genotype GA5 was not included in this table as this genotype was only present in one patient. In total, 112 of 134 RSV positive patients could be sequenced and a genotype could be determined.</p>#<p>Hospital stay was only calculated for patients who stayed at least 24 hours in hospital.</p><p>SD =  standard deviation; RTI = respiratory tract infection, RSV =  Respiratory Syncytial Virus.</p><p>Basic and clinical characteristics of RSV positive children by genotype.</p

Alignment of deduced amino acid sequences of the second variable region of the G protein of RSV-B strains isolated in Heidelberg/Germany during 2012–2013 winter season.

<p>Alignments are shown relative to the sequence of a prototype BA strain (GenBank accession number AY333364). Alignment of sequences was performed using the Clustal W 1.6 method via MEGA 6 software. The amino acid positions correspond to positions 210 to 315 of the G protein of the BA strain. Identical residues are indicated by dots, asterisks indicate the position of stop codons. Number of identical strains is indicated in brackets after the strain identifier in the left column. Boxes frame the 20 amino acid duplication. Gray shading highlights predicted N-glycosylation sites. Open circles indicate predicted O-glycosylation sites of the prototype BA strain; potential O-glycosylation sites of Heidelberg strains are indicated by black dots. Genotypes are shown on the right by brackets.</p

Alignment of deduced amino acid sequences of RSV-A strains.

<p>A) Alignment of RSV-A genotype NA1 and GA5 are shown relative to the sequence of prototype strain A2 (GenBank accession number M11486). Alignment of sequences was performed using the Clustal W 1.6 method via MEGA 6 software. The amino acid positions correspond to positions 210 to 298 of the G protein of strain A2. Identical residues are indicated by dots, asterisks indicate the position of stop codons. Number of identical strains is indicated in brackets after the strain identifier in the left column. Gray shading highlights predicted N-glycosylation sites. Unfilled circles indicate predicted O-glycosylation sites of the prototype strain A2; potential O-glycosylation sites of Heidelberg strains are indicated by black dots. The genotype assignment is shown on the right by brackets. B) Alignments are shown relative to the sequence of ON1 strain first described in Canada (GenBank accession number JN257693). Alignment of sequences was performed using the Clustal W 1.6 method via MEGA 6 software. The amino acid positions correspond to positions 210 to 298 of the G protein of the prototype strain A2. Identical residues are indicated by dots, asterisks indicate the position of stop codons. Boxes frame the 23 amino acid duplicated region of the 24 amino acid insertion. Gray shading highlights predicted N-glycosylation sites. Unfilled circles indicate predicted O-glycosylation sites of the Canadian reference ON1 strain; potential O-glycosylation sites of Heidelberg strains are indicated by black dots. On the right hand site, GenBank and Heidelberg strains are labeled with the country and time of occurrence (month/year). ¹ Sequences were published in GenBank only. HD =  Heidelberg; WUE =  Wuerzburg, cl. =  cluster.</p

Weekly/monthly distribution of subgroup RSV A/RSV B in children ≤2 years with acute RTI in Heidelberg/Germany, winter season 2012/13.

<p>Weekly/monthly distribution of subgroup RSV A/RSV B in children ≤2 years with acute RTI in Heidelberg/Germany, winter season 2012/13.</p

Comparing clinical characteristics of pediatric patients with pancreatic diabetes to patients with type 1 diabetes: A matched case-control study

Background: Only few studies have been conducted on pancreatic diabetes and data from large epidemiological studies are missing. Our main objective was to study the most important differences and similarities between pediatric individuals with pancreatic diabetes and type 1 diabetes (T1D). Methods: Patients <20 years of age were identified from the diabetes patient followup registry (DPV). Data of the most recent treatment year between January 2000 and March 2018 were aggregated. Propensity score was used to match individuals with pancreatic diabetes to individuals with T1D. Matching was conducted one-toone by sex, age, diabetes duration, body mass index SD score (BMI-SDS), and migration background. Results: We studied 731 individuals with pancreatic diabetes and 74 460 with T1D. In the matched cohort of 631 pairs, HbA1c was significantly lower in pancreatic diabetes (7.4% [95% confidence interval: 7.2; 7.5%]) compared to T1D patients (8.7% [8.5; 8.8%]). Daily insulin dose (0.80 IU/kg [0.77; 0.84] vs 0.86 IU/kg [0.82; 0.90]) and insulin pump use (13.3% [10.7; 16.4] vs 22.1% [19.0; 25.6%]) were lower in patients with pancreatic diabetes. However, event rates of severe hypoglycemia were similar between pancreatic and T1D patients (8.8 [5.4; 14.2] vs 9.6 [5.9; 15.6] events per 100 patient years). Conclusions: With the use of robust epidemiological data, our study improves the knowledge on clinical characteristics in pediatric individuals with pancreatic diabetes. Moreover, our results serve as a basis to reconsider treatment options and for discussing clinical practice guidelines for patients with this rare medical condition