Cytogenetic characterization of telomeres in the holocentric chromosomes of the lepidopteran Mamestra brassicae

Telomeres of the Mamestra brassica holocentric chromosomes were studied by Southern blotting, in-situ hybridization and Bal31 assay evidencing the presence of the telomeric (TTAGG)(n) repeat. Successively, molecular analysis of telomeres showed that TRAS1 transposable elements were present at the subtelomeric regions of autosomes but not in the NOR-bearing telomeres of the Z and W sex chromosomes. TRAS1 appeared to be transcriptionally active and non-methylated, as evaluated by RT-PCR and digestion with MspI and HpaII. Finally, dot-blotting experiments showed that the 2.8 +/- 0.5% of the M. brassicae genome consists of TRAS1

Age-related Reference Values for Serum Selenium Concentrations in Infants and Children.

Background: Children are at particular risk for selenium deficiency, which has potentially serious medical implications. Reliable age-specific reference values for serum selenium concentrations in children are sparse, but are essential for the identification of selenium deficiency and decisions regarding selenium supplementation.Methods: Using electrothermal atomic absorption spectrometry we analyzed serum selenium concentrations from 1010 apparently healthy children (age range, 1 day to IS years) and from 60 patients on a protein-restricted diet because of inborn errors of metabolism. Reference intervals were defined according to recommended guidelines.Results: Medians for serum selenium concentrations showed a statistically significant age dependency: a decrease from the age <1 month (0.64 mumol/L) to 4 months (0.44 mumol/L); an increase to 0.62 mumol/L in the 4-12 months age group; constant values in children between I and 5 years of age (0.90 mumol/L); and an additional slight increase to reach a plateau between 5 and IS years (0.99 mumol/L). Of 43 children older than 1 year and on a protein-restricted diet, 87% showed serum selenium concentrations below the 2.5 percentile.Conclusions: Because of nutritional changes, serum selenium concentrations are significantly higher in older children than in infants under 1 year of age. The application of age-adjusted reference values may provide more specific criteria for selenium supplementation. Long-term protein restriction in children is reflected by a failure to achieve higher serum selenium concentrations with increasing age

Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p.

Four ABC half transporters (ALDP, ALDRP, PMP70, and PMP69) have been identified in the mammalian peroxisomal membrane but no function has been unambiguously assigned to any of them. To date X-linked adrenoleukodystrophy (X-ALD) is the only human disease known to result from a defect of one of these ABC transporters, ALDP. Using the yeast two-hybrid system and in vitro GST pull-down assays, we identified the peroxin PEX19p as a novel interactor of ALDP, ALDRP, and PMP70. The cytosolic farnesylated protein PEX19p was previously shown to be involved in an early step of the peroxisomal biogenesis. The PEX19p interaction occurs in an internal N-terminal region of ALDP which we verified to be important for proper peroxisomal targeting of this protein. Farnesylated wild-type PEX19p and a farnesylation-deficient mutant PEX19p did not differ in their ability to bind to ALDP. Our data provide evidence that PEX19p is a cytosolic acceptor protein for the peroxisomal ABC transporters ALDP, PMP70, and ALDRP and might be involved in the intracellular sorting and trafficking of these proteins to the peroxisomal membrane

Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production.

Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1β (IL-1β) as an antiviral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adaptor CARD9. Transfection of dendritic cells with dsDNA or infection of dendritic cells with a DNA virus induced the formation of dsDNA-Rad50-CARD9 signaling complexes for activation of the transcription factor NF-κB and the generation of pro-IL-1β. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL-1β, and Card9(-/-) mice had impaired inflammatory responses after infection with a DNA virus in vivo. Our results define a cytosolic DNA-recognition pathway for inflammation and a physical and functional connection between a conserved DNA-damage sensor and the innate immune response to pathogens

Exome sequencing in children undiagnosed developmental delay and neurological illness.

Background: In developed countries, global developmental disorders are encountered in approximately 1% of all children. The causes are manifold, and no exogenous cause can be identified in about half of the affected children. The parallel investigation of the coding sequences of all genes of the affected individual (whole exome sequencing, WES) has developed into a successful diagnostic method for identifying the cause of the problem. It is not yet clear, however, when WES should best be used in routine clinical practice in order to exploit the potential of this method to the fullest.Methods: In an interdisciplinary study, we carried out standardized clinical phenotyping and a systematic genetic analysis (WES of the index patient and his or her parents, so-called trio WES) in 50 children with developmental disturbances of unclear etiology and with nonspecific neurological manifestations.Results: In 21 children (42% of the collective), we were able to identify the cause of the disorder by demonstrating a mutation in a gene known to be associated with disease. Three of these children subsequently underwent specific treatment. In 22 other children (44%), we detected possibly etiological changes in candidate genes not currently known to be associated with human disease.Conclusion: Our detection rate of at least 42% is high in comparison with the results obtained in other studies from Germany and other countries to date and implies that WES can be used to good effect as a differential diagnostic tool in pediatric neurology. WES should be carried out in both the index patient and his or her parents (trio-WES) and accompanied by close interdisciplinary collaboration of human geneticists and pediatricians, by comprehensive and targeted phenotyping (also after the diagnosis is established), and by the meticulous evaluation of all gene variants

Follow-up and outcome of PKU patients on sapropterin/BH4 : Preliminary results of a retrospective European Multicenter Study

Background: Sapropterin/BH4 is an approved drug for treatment of responsive PKU patients. The purpose of this study was to collect data on the use of Sapropterin/BH4 and its long-term effect on metabolic control and patient-related outcome in five European countries. Methods: A questionnaire was developed to assess quality of life (QOL), mood changes, adherence to diet, changes in blood Phe levels and Phe tolerance and patients' phenotype and genotype. Results: 129 patients from 11 European centers (42,5% MHP, 49,6 mild PKU, 7,9% classical PKU) were accessed (62 male, 67 female, age 2-46 years). No adverse events on Sapropterin/BH4 were reported. Average dose of Sapropterin/BH4 was 10,45 mg/kg/day; range 5,15. Improvement in QOL was reported qualitively in 52,3% (31,3% did not report); improvement in adherence to diet in 52,3% (in 17,2% question not applicable); improvement in mood was reported in 14,1% (in 41,4% question not applicable) of patients. Conclusion: Our data suggest a beneficial effect of sapropterin/BH4 in PKU patients who respond to oral administration of BH4 by lowering their blood Phe levels by > 30%; it increases daily tolerance for dietary Phe intake and improves dietary adherence and QOL. Conflict of Interest declared

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Key European guidelines for the diagnosis and management of patients with phenylketonuria

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 mumol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 mumol/L and 600 mumol/L, and lifelong treatment is recommended if the concentration is more than 600 mumol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 mumol/L need to be reduced. Treatment target concentrations are as follows: 120-360 mumol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 mumol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy