A new mutation in the promoter region of the PAX8 gene causes true congenital hypothyroidism with thyroid hypoplasia in a girl with Down's syndrome

<b>Background:</b> Thyroid dysfunction is common in newborn infants with Down's syndrome (DS), but defects causing classic thyroid dysgenesis (TD) with permanent congenital hypothyroidism (CH) have not been described.<p></p> <b>Objective:</b> We studied a girl with DS and CH who had a mutation in the promoter sequence of the PAX8 gene.<p></p> <b>Results:</b> A female infant was found to have trisomy 21 and CH, with a venous thyrotropin (TSH) of >150 mU/L and a free thyroxine (fT4) of 15.1 pmol/L (day 12). Thyroid peroxidase antibodies and thyroglobulin antibodies were elevated. Scintigraphy showed normal uptake, but ultrasound identified a small gland with heterogenous echotexture and cystic changes. Sequence analysis of the PAX8 gene revealed a new heterozygous maternally inherited mutation (−3C>T) close to the transcription initiation site. Electromobility shift assay studies of the wild type and the mutant PAX8 sequence incubated with nuclear extracts from PCCL3 cells exhibited that the sequence at position −3 is not involved in specific protein binding. However, the mutant PAX8 promoter showed a significantly reduced transcriptional activation of a luciferase reporter gene in vitro tested in HEK, PCCL3, as well as in HeLa cells, indicating that this mutation is very likely to lead to reduced PAX8 expression.<p></p> <b>Conclusions:</b> The persistent CH in this patient with DS is likely to be attributable to the diminished PAX8 expression due to a new heterozygous mutation in the PAX8 promoter sequence. Our case shows that true CH may occur in DS, as in the general population. Furthermore, it is possible that the trisomy 21 itself may have resulted in a more severe phenotypic expression of the PAX8 mutation in the child than the mother

Cross-sectional study: prevalence of oedema disease Escherichia coli (EDEC) in weaned piglets in Germany at pen and farm levels

Background Escherichia coli bacteria capable of producing the toxin Stx2e and possessing F18-fimbriae (edema disease E. coli, EDEC) are considered causative agents of porcine oedema disease. This disease, which usually occurs in piglets shortly after weaning, has a high lethality in affected animals and can lead to high economic losses in piglet rearing. The aim of this cross-sectional field study was to determine the prevalence of EDEC in weaned piglets in Germany at pen and farm levels. Results Ninety-nine farms with unknown history of infections with shigatoxin-producing E. coli (STEC) and oedema disease were sampled. On each farm, up to five pens were selected for sampling (n = 481). The piglets in these pens were at an age 1–3 weeks after weaning. Single faecal samples (n = 2405) and boot swabs (n = 479) were collected from the floor. On 50 farms, cotton ropes were additionally used to collect oral fluid samples (n = 185) and rope wash out samples (n = 231) from the selected pens. All samples were analyzed by bacterial culture combined with a duplex PCR for the presence of the corresponding genes stx2e and fedA (major subunit protein of F18 fimbriae). In addition, whole DNA specimens extracted from boot swabs, oral fluid samples, and rope wash out samples were directly examined by duplex PCR for DNA of stx2e and fedA. A pen was classified as positive if at least one of the samples, regardless of the technique, yielded a positive result in the PCR, and farms were considered positive if at least one pen was classified as positive. Overall, genes stx2e and fedA were found simultaneously in 24.9% (95% CI 22.1–29.1%) of sampled pens and in 37.4% (95% CI 27.9–47.7%) of sampled farms. Regardless of the presence of F18-fimbriae, Escherichia coli encoding for Stx2e (STEC-2e) were found in 35.1% (95% CI 31.0–39.1%) of the pens and 53.5% (95% CI 44.4–63.6%) of the farms sampled. Conclusions Escherichia coli strains considered capable to cause oedema disease in swine (EDEC) are highly prevalent in the surveyed pig producing farms in Germany. Due to intermittent shedding of EDEC and a potentially low within-farm prevalence, we recommend a combination of different sampling techniques for EDEC monitoring at pen and farm levels. Further studies are needed to understand which STEC-2e strains really pose the risk of causing severe porcine disease

Assessing attitudes towards insulin pump therapy in adults with type 1 diabetes: Italian validation of the Insulin Pump Attitudes Questionnaire (IT-IPA questionnaire)

Aims: The aim of the study was to adapt the German version of the insulin pump therapy (IPA) questionnaire to Italian (IT-IPA) and to evaluate its psychometric properties in adults with type 1 diabetes. Methods: We conducted a cross-sectional study, data were collected through an online survey. In addition to IT-IPA, questionnaires evaluating depression, anxiety, diabetes distress, self-efficacy, and treatment satisfaction were administered. The six factors identified in the IPA German version were assessed using confirmatory factor analysis; psychometric testing included construct validity and internal consistency. Results: The online survey was compiled by 182 individuals with type 1 diabetes: 45.6% continuous subcutaneous insulin infusion (CSII) users and 54.4% multiple daily insulin injection users. The six-factor model had a very good fit in our sample. The internal consistency was acceptable (Cronbach's α = 0.75; 95% IC [0.65-0.81]). Diabetes treatment satisfaction was positively correlated with a positive attitude towards CSII therapy (Spearman's rho = 0.31; p < 0.01), less Technology Dependency, higher Ease of Use, and less Impaired Body Image. Furthermore, less Technology Dependency was associated with lower diabetes distress and depressive symptoms. Conclusions: The IT-IPA is a valid and reliable questionnaire evaluating attitudes towards insulin pump therapy. The questionnaire can be used for clinical practice during consultations for shared decision-making to CSII therapy

Klinischer Verlauf von Patienten mit einer diabetischen Neuroosteoarthropathie in Bezug auf Komplikationen und Mortalität

Fragestellung: Die diabetische Neuro-Osteoarthropathie (DNOAP) stellt eine Sonderform des diabetischen Fußsyndroms dar, die mit einer erhöhten Mortalität sowie schwerwiegenden Fußdeformitäten einhergeht. Verlauf und Outcome solcher Patienten im Bezug auf Ulcera, Amputationen und andere Komplikationen sind bisher nur unzureichend untersucht. Methodik: Der Verlauf von Patienten mit einer DNOAP im Hinblick auf Amputationen, Ulcera, Folgeerkrankungen und Mortalität wurde retrospektiv untersucht. Die Daten dazu wurden an einem großen deutschen Fachkrankenhaus für Patienten mit Diabetes gewonnen. Hierbei wurden insgesamt 111 Patienten über einen Zeitraum von 10 Jahren beobachtet. Ergebnisse: Es handelte sich meist um übergewichtige Patienten mittleren Alters mit einer langjährigen Diabetesdauer. Es konnte nachgewiesen werden, dass Patienten mit einer DNOAP überzufällig häufig auch eine diabetische Retinopathie aufweisen (p = 0,047). Die DNOAP war signifikant mit plantaren Ulcera (p < 0,001), Ulcera im Bereich von Mittelfuß (p = 0,010) und Fußwurzel (p = 0,032) sowie Amputationen (p = 0,022) assoziiert. Das Risiko für weitere Amputationen war durch die DNOAP alleine nicht erhöht, wohl aber durch Begleiterkrankungen wie die Retinopathie, eine arterielle Verschlusskrankheit und eine koronare Herzerkrankung (KHK). In einem logistischen Regressionsmodell konnte die KHK als unabhängiger Prädiktor der Mortalität in dem hier untersuchten Kollektiv identifiziert werden (Odds ratio 4,845, 95%-Konfidenzintervall 20,813 – 1,128, p = 0,034). Die Überlebensdauer der DNOAP mit einer KHK war signifikant kürzer als die Überlebensdauer der Patienten ohne KHK (p = 0,0045). Schlussfolgerungen: Daraus folgt, dass neben einer optimalen Behandlung der DNOAP, der Versorgung mit entsprechendem Schuhwerk und der Schulung der Patienten im Wesentlichen das Management der Folgeerkrankungen für das Überleben bedeutsam ist. Der KHK kommt in diesem Zusammenhang ein besonderer Stellenwert zu

Determination of thyroid volume in infants with suspected congenital hypothyroidism—the limitations of both subjective and objective evaluation

Objective: To compare two methods of assessing gland size on thyroid ultrasound in newborn infants with suspected congenital hypothyroidism (CH). Methods: Images from infants with eutopic glands referred between 2007 and 2013 were evaluated blind by two sets of observers. Subjective gland size was categorised as small, borderline-small, normal, borderline-large and large. Objective gland volume, calculated as the sum of each lobe using the prolate ellipsoid formula (length x width x depth x π/6), was put into corresponding categories: &lt;0.8, 0.81–1.0, 1.1– &lt;2.2, 2.2–2.4 and &gt;2.4 ml, derived from normative Scottish data. Results: Of 36 infants, permanent CH was present in 17, transient CH in 17, status uncertain in 2. Mean (SD) intraobserver error for thyroid volume measurement was 0.11 (0.23) ml [8.3%]. Subjective assessment by two observers was discordant in only four (10.8%) infants. However, subjective vs objective evaluation was discordant in 14 (39%). Eight (three permanent, five transient CH) had large glands subjectively but normal glands objectively; and six (four transient CH) had normal glands subjectively but small glands objectively. The former infants all showed a single flattened curve to the anterior thyroid margin, giving an impression of bulkiness. Gland shape was normal in the latter infants. Conclusion: Neither subjective nor objective evaluation predicts permanent vs transient CH. Altered gland shape may confound both methods, and undermine use of the conventional formula for measuring lobe volume. Advances in knowledge: Until more refined methods are available for assessing thyroid size, both subjective and objective evaluation are recommended in CH

Viperin mRNA is a novel target for the human RNase MRP/RNase P endoribonuclease

RNase MRP is a conserved endoribonuclease, in humans consisting of a 267-nucleotide RNA associated with 7–10 proteins. Mutations in its RNA component lead to several autosomal recessive skeletal dysplasias, including cartilage-hair hypoplasia (CHH). Because the known substrates of mammalian RNase MRP, pre-ribosomal RNA, and RNA involved in mitochondrial DNA replication are not likely involved in CHH, we analyzed the effects of RNase MRP (and the structurally related RNase P) depletion on mRNAs using DNA microarrays. We confirmed the upregulation of the interferon-inducible viperin mRNA by RNAi experiments and this appeared to be independent of the interferon response. We detected two cleavage sites for RNase MRP/RNase P in the coding sequence of viperin mRNA. This is the first study providing direct evidence for the cleavage of a mRNA by RNase MRP/RNase P in human cells. Implications for the involvement in the pathophysiology of CHH are discussed

Reception Test of Petals for the End Cap TEC+ of the CMS Silicon Strip Tracker

The silicon strip tracker of the CMS experiment has been completed and was inserted into the CMS detector in late 2007. The largest sub system of the tracker are its end caps, comprising two large end caps (TEC) each containing 3200 silicon strip modules. To ease construction, the end caps feature a modular design: groups of about 20 silicon modules are placed on sub-assemblies called petals and these self-contained elements are then mounted onto the TEC support structures. Each end cap consists of 144 such petals, which were built and fully qualified by several institutes across Europe. Fro

Integration of the End Cap TEC+ of the CMS Silicon Strip Tracker

The silicon strip tracker of the CMS experiment has been completed and inserted into the CMS detector in late 2007. The largest sub-system of the tracker is its end cap system, comprising two large end caps (TEC) each containing 3200 silicon strip modules. To ease construction, the end caps feature a modular design: groups of about 20 silicon modules are placed on sub-assemblies called petals and these self-contained elements are then mounted into the TEC support structures. Each end cap consists of 144 petals, and the insertion of these petals into the end cap structure is referred to as TEC integration. The two end caps were integrated independently in Aachen (TEC+) and at CERN (TEC--). This note deals with the integration of TEC+, describing procedures for end cap integration and for quality control during testing of integrated sections of the end cap and presenting results from the testing