The reliability of the All-Up concept Special technical report no. 13

Implementation approaches for conducting Saturn V launch vehicle program without dummy stage

Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations.

Animal studies have shown that dioxins influence plasma thyroid hormone concentrations. To investigate the effect of chlorinated dioxins and furans on thyroid hormone concentrations in humans, we studied 38 healthy breast-fed infants. The study population was divided into two groups according to the dioxin concentrations in milk fat of their mothers. Blood samples were taken at birth and at the ages of 1 and 11 weeks. At birth a tendency to higher total thyroxine (tT4) concentrations was found in the high exposure group. At the ages of 1 and 11 weeks the increase of mean tT4 concentrations and tT4/thyroxine-binding globulin ratios in the high exposure group reached significance as compared to the low exposure group. At birth and 1 week after birth, mean thyrotropin (TSH) concentrations were similar in both groups, but at the age of 11 weeks the mean TSH concentrations were significantly higher in the high exposure group. We postulate that the observed plasma tT4 elevation in infants exposed to dioxins before and after birth is the result of an effect on the thyroid hormone regulatory system

Chiari’s Network as a Cause of Fetal and Neonatal Pathology

Chiari’s network is a remnant of the eustachian valve located in the right atrium. Incomplete involution of the fetal sinus venosus valves results in “redundant” Chiari’s network, which may compromise cardiovascular function. This report describes a case with the novel finding of prenatal compromise due to redundant Chiari’s network and an uncommon case with significant postnatal symptoms. In both cases, the symptoms (fetal hydrops and postnatal cyanosis) resolved spontaneously. The variety of cardiovascular pathologies described in the literature is believed to be associated with persistence of a Chiari network. Knowledge about this not always harmless structure is important for perinatologists, pediatricians, and pediatric cardiologists alike. The clinical importance of this rare pathology is that prenatal counseling may anticipate a generally positive outcome and that surgical intervention generally should be avoided

Appraisals and coping mediate the relationship between resilience and distress among significant others of persons with spinal cord injury or acquired brain injury: A cross-sectional study

Background: Many significant others of persons with serious conditions like spinal cord injury (SCI) and acquired brain injury (ABI) report high levels of psychological distress. In line with the stress-coping model, the aim of the present study was to investigate the relationship between personal resource resilience and psychological distress, and whether appraisals of threat and loss, and passive coping mediate this relationship. Methods: Significant others (n = 228) of persons with SCI or ABI completed questionnaires shortly after admission to first inpatient rehabilitation after onset of the condition. The questionnaire included measures to assess psychological distress (Hospital Anxiety and Depression Scale), resilience (Connor-Davidson Resilience Scale-10), appraisals (Appraisals of Life Events scale, threat and loss) and passive coping (Utrecht Coping List). The PROCESS tool was used to test the presence of mediation. Confounding and differences between SCI and ABI were investigated. Results: High levels of psychological distress among significant others were found (34-41%). Fifty-five percent of the variance in psychological distress was explained by the relationship between resilience and psychological distress. This relationship was mediated by appraisals of threat and loss, and passive coping. The relationship between resilience and psychological distress was similar in the SCI and ABI groups. Conclusions: The results of our study indicate that appraisals of threat and loss and passive coping are mediating factors in the relationship between resilience and psychological distress. It seems useful to investigate if interventions focussing on psychological factors like resilience, appraisal and coping are effective to prevent or reduce psychological distress among significant others of persons with SCI or ABI

Knockdown of Amyloid Precursor Protein in Zebrafish Causes Defects in Motor Axon Outgrowth

Amyloid precursor protein (APP) plays a pivotal role in Alzheimer’s disease (AD) pathogenesis, but its normal physiological functions are less clear. Combined deletion of the APP and APP-like protein 2 (APLP2) genes in mice results in post-natal lethality, suggesting that APP performs an essential, if redundant, function during embryogenesis. We previously showed that injection of antisense morpholino to reduce APP levels in zebrafish embryos caused convergent-extension defects. Here we report that a reduction in APP levels causes defective axonal outgrowth of facial branchiomotor and spinal motor neurons, which involves disorganized axonal cytoskeletal elements. The defective outgrowth is caused in a cell-autonomous manner and both extracellular and intracellular domains of human APP are required to rescue the defective phenotype. Interestingly, wild-type human APP rescues the defective phenotype but APPswe mutation, which causes familial AD, does not. Our results show that the zebrafish model provides a powerful system to delineate APP functions in vivo and to study the biological effects of APP mutations

Efficacy and safety of the endothelin-1 receptor antagonist macitentan in epicardial and microvascular vasospasm: a proof-of-concept study

BACKGROUND: Treatment of patients diagnosed with angina due to epicardial or microvascular coronary artery spasm (CAS) is challenging because patients often remain symptomatic despite conventional pharmacological therapy. In this prospective, randomized, double-blind, placebo-controlled, sequential cross-over proof-of-concept study, we compared the efficacy and safety of macitentan, a potent inhibitor of the endothelin-1 receptor, to placebo in symptomatic patients with CAS despite background pharmacological treatment. METHODS: Patients with CAS diagnosed by invasive spasm provocation testing with >3 anginal attacks per week despite pharmacological treatment were considered for participation. Participants received either 10 mg of macitentan or placebo daily for 28 days as add-on treatment. After a wash-out period patients were crossed over to the alternate treatment arm. The primary endpoint was the difference in anginal burden calculated as [1] the duration (in minutes) * severity (on a Visual Analogue Scale (VAS) pain scale 1-10); and [2] the frequency of angina attacks * severity during medication use compared to the run-in phase. RESULTS: 28 patients of whom 22 females (79%) and a mean age of 55.3 ± 7.6 completed the entire study protocol (epicardial CAS n = 19 (68), microvascular CAS n = 9 (32)). Change in both indices of anginal burden were not different during treatment with add-on macitentan as compared to add-on placebo (duration*severity: -9 [-134 78] vs -45 [-353 11], p = 0.136 and frequency*severity: -1.7 [-5.8 1.2] vs -1.8 [-6.2 0.3], p = 0.767). The occurrence and nature of self-reported adverse events were closely similar between the treatment phase with macitentan and placebo. CONCLUSION: In patients with angina due to epicardial or microvascular CAS despite background pharmacological treatment, 28 days of add-on treatment with the ET-1 receptor antagonist, macitentan 10 mg daily, did not reduce anginal burden compared to add-on treatment with placebo.Trial Registrationhttps://trialsearch.who.int/, Identifier: EUCTR2018-002623-42-NL. Registration date: 20 February 2019

Congenital hypothyroidism

Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism