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Background Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. Objective Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. Methods From 19 children (median age 4.9 years [range 9 months–15.3 years], median weight 18 kg [range 7.8–70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients’ clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. Results A two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. Conclusions The pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic–pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma. Electronic supplementary material The online version of this article (10.1007/s40262-019-00811-y) contains supplementary material, which is available to authorized users.

Most pediatric asthma guidelines offer evidence-based or best practice approaches to the management of asthma exacerbations but struggle with evidence-based approaches for severe acute asthma (SAA). We aimed to investigate current practices in children with SAA admitted to European pediatric intensive care units (PICUs), in particular, adjunct therapies, use of an asthma severity score, and availability of a SAA guideline. We designed a cross-sectional electronic survey across European PICUs. Thirty-seven PICUs from 11 European countries responded. In 8 PICUs (22%), a guideline for SAA management was unavailable. Inhaled beta-agonists and anticholinergics, combined with systemic steroids and IV MgSO4 was central in SAA treatment. Seven PICUs (30%) used a loading dose of a short-acting beta-agonist. Eighteen PICUs (49%) used an asthma severity score, with 8 different scores applied. Seventeen PICUs (46%) observed an increasing trend in SAA admissions.Conclusion: Variations in the treatment of children with SAA mainly existed in the use of adjunct therapies and asthma severity scores. Importantly, in 22% of the PICUs, a SAA guideline was unavailable. Standardizing SAA guidelines across PICUs in Europe may improve quality of care. However, the limited number of PICUs represented and the data compilation method are constraining our findings.What is Known:• Recent reports demonstrate increasing numbers of children with SAA requiring PICU admission in several countries across the world.• Most pediatric guidelines offer evidence-based approaches to the management of asthma exacerbations, but struggle with evidence-based approaches for SAA beyond these initial steps.What is New:• A large arsenal of adjunct therapies and 8 different asthma scores were used.• In a large number of PICUs, a written guideline for SAA management is lacking.

Background The COVID-19 pandemic has boosted the use of forced expiratory volume in 1 second (FEV1) telemonitoring in pediatric asthma, but a consensus on its most efficient and effective implementation is still lacking. To find answers, it is important to study how such an intervention is perceived, experienced, and used by both patients and health care professionals (HCPs). Objective The aim of this study was to provide perspectives on how FEV1 home monitoring should be used in pediatric asthma. Methods This is a qualitative, multicenter, prospective, observational study which included patients with asthma aged 6-16 and HCPs. Primary outcomes were results of 2 surveys that were sent to all participants at study start and after 3-4 months. Secondary outcomes consisted of FEV1 device usage during 4 months after receiving the FEV1 device. Results A total of 39 participants (26 patients and 13 HCPs) were included in this study. Survey response rates were 97% (38/39) at the start and 87% (34/39) at the end of the study. Both patients and HCPs were receptive toward online FEV1 home monitoring and found it contributive to asthma control, self-management, and disease perception. The main concerns were about reliability of the FEV1 device and validity of home-performed lung function maneuvers. FEV1 devices were used with a median frequency of 7.5 (IQR 3.3-25.5) during the 4-month study period. Conclusions Patients and HCPs are receptive toward online FEV1 home monitoring. Frequency of measurements varied largely among individuals, yet perceived benefits remained similar. This emphasizes that online FEV1 home monitoring strategies should be used as a means to reach individual goals, rather than being a goal on their own.

Objectives: During the last decade we observed a threefold increase in children with severe acute asthma (SAA) admitted to a Dutch pediatric intensive care unit (PICU). Previously, we found no differences in proportion of steroid-naive children, previous PICU admissions, sensibilisation, and viral infections in children admitted to the PICU versus general ward. We aimed to identify risk factors which characterize the clinical course in SAA children admitted to the PICU. Methods: a prospective study in children with SAA (2–18 years) admitted to all Dutch PICUs between 2016 – 2018. We compared (1) children with (non)-invasive mechanical ventilation (IMV), IV salbutamol dosage >1 mcg/kg/min, or resuscitation with (2) children with an IV salbutamol dosage ≤1 mcg/kg/min. Results: We included 110 children. In group 1 (72/110) the median IV salbutamol dosage was 3.5 mcg/kg/min (IQR 2.0-6.0), 13 children (18%) needed IMV and 2 (3%) died. Group 1 had a longer PICU length of stay (66 vs 34 hours, p Conclusions: Since the main risk factor for SAA severity was previous PICU admission, follow-up by a specialist after PICU admission is warranted. Children with an IV salbutamol dosage ≤1 mcg/kg/min had a significant lower severity of illness. Our national SAA guideline implies immediate referral to a PICU, regardless of IV salbutamol dosage. This may need to be reconsidered in the light of our findings.

Severe acute asthma (SAA) can lead to respiratory failure and can be fatal. For rational use of intravenous (IV) bronchodilators, evidence regarding the pharmacokinetics and pharmacodynamics is lacking in children. The use of a loading dose IV salbutamol is not mentioned in any international guideline, and its use varies greatly between PICUs worldwide. We describe a 17-year-old Caucasian female with SAA resulting in an out-of-hospital cardiac arrest. After basic life support and return of spontaneous circulation, the ambulance administered oxygen, inhaled salbutamol, IV magnesium sulphate, and systemic corticosteroids. Despite of this, she was still in severe respiratory distress. Therefore, a loading dose of IV salbutamol was administered, after which an immediate improvement was observed. Having a loading dose of IV salbutamol available for emergency medical services use for SAA in children with life-threatening SAA in the out-of-hospital setting is important to consider. Further study on the dose and the effect of a loading dose IV salbutamol in children with SAA is necessary.

Background: Despite their potential benefits, many electronic health (eHealth) innovations evaluated in major studies fail to integrate into organizational routines, and the implementation of these innovations remains problematic. Objective: The purpose of this study was to describe health care professionals’ self-identified perceived barriers and facilitators for the implementation of a Web-based portal to monitor asthmatic children as a substitution for routine outpatient care. Also, we assessed patients’ (or their parents) satisfaction with this eHealth innovation. Methods: Between April and November 2015, we recruited 76 health care professionals (from 14 hospitals). During a period of 6 months, participants received 3 questionnaires to identify factors that facilitated or impeded the use of this eHealth innovation. Questionnaires for patients (or parents) were completed after the 6-month virtual asthma clinic (VAC) implementation period. Results: Major perceived barriers included concerns about the lack of structural financial reimbursement for Web-based monitoring, lack of integration of this eHealth innovation with electronic medical records, the burden of Web-based portal use on clinician workload, and altered patient-professional relationship (due to fewer face-to-face contacts). Major perceived facilitators included enthusiastic and active initiators, a positive attitude of professionals toward eHealth, the possibility to tailor care to individual patients (“personalized eHealth”), easily deliverable care according to current guidelines using the VAC, and long-term profit and efficiency. Conclusions: The implementation of Web-based disease monitoring and management in children is complex and dynamic and is influenced by multiple factors at the levels of the innovation itself, individual professionals, patients, social context, organizational context, and economic and political context. Understanding and defining the barriers and facilitators that influence the context is crucial for the successful implementation and sustainability of eHealth innovations.

Contains fulltext : 177833.pdf (Publisher’s version ) (Closed access) eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6-16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42-2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09-2.25; p=0.03). No differences were found for other outcome measures.Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth.

Bronchiolitis is a common disorder in young children that often results in hospitalisation. Except for a possible effect of nebulised hypertonic saline (sodium chloride), no evidence-based therapy is available. This study investigated the efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis.In this multicentre, double-blind, randomised, controlled trial, children hospitalised with acute viral bronchiolitis were randomised to receive either nebulised 3%, 6% hypertonic saline or 0.9% normal saline during their entire hospital stay. Salbutamol was added to counteract possible bronchial constriction. The primary endpoint was the length of hospital stay. Secondary outcomes were need for supplemental oxygen and tube feeding.From the 292 children included in the study (median age 3.4 months), 247 completed the study. The median length of hospital stay did not differ between the groups: 69 h (interquartile range 57), 70 h (IQR 69) and 53 h (IQR 52), for 3% (n=84) and 6% (n=83) hypertonic saline and 0.9% (n=80) normal saline, respectively, (p=0.29). The need for supplemental oxygen or tube feeding did not differ significantly. Adverse effects were similar in the three groups.Nebulisation with hypertonic saline (3% or 6% sodium chloride) although safe, did not reduce the length of stay in hospital, duration of supplemental oxygen or tube feeding in children hospitalised with moderate-to-severe viral bronchiolitis.

Introduction Although several eHealth interventions have been shown to be effective, little is known about the actual use of these interventions among patients in real life. Aim of the study The aim were to describe and analyse website-use among children with asthma receiving online care through the virtual asthma clinic (VAC) and to develop recommendations for further use of the VAC in paediatric asthma care. Methods Observational study conducted alongside a randomized controlled trial on the efficacy of the VAC. Website log-data of the participants were analysed in retrospect: activity (page views of information pages and treatment plan), communication with the medical team (frequency and content of messages) and login (frequency and duration) were compared between different age groups (6-11 years and 12-16 years). Results 105 children (mean age 11.2 years (± SD 2.9 years; 61% male) were included. Younger participants or parents accessed the (general) information pages significantly more often than teenagers (median page views 10 versus 4, P =.003). The median number of messages was also significantly higher (median 4 versus 2, P =.04) in the younger group. No significant difference in login frequency was found between the two age groups, but the login-frequency decreased significantly within both groups during the 16-month study period. Conclusions The VAC was used significantly different by teenagers and younger children and/or their parents regarding the need of information and communication with the medical team. Younger children used the information and communication modules more often in comparison to teenagers. These differences should be taken into account while designing an eHealth intervention for children.

Kinderen met moeilijk behandelbaar astma (MBA) zijn een heterogene groep voor wie met behulp van gestructureerde diagnostiek een individueel behandelplan opgesteld moet worden. In de literatuur worden diverse protocollen voor de diagnostiek en behandeling van MBA bij kinderen en volwassenen beschreven. Deze stellen alle een gestructureerde aanpak voor met als doel kwaliteitsverbetering in diagnostiek en behandeling van MBA. Recent is er een protocol uitgebracht door de Sectie Kinderlongziekten van de Nederlandse Vereniging voor Kindergeneeskunde voor de Nederlandse praktijk. Dit protocol is gebaseerd op de wetenschappelijke kennis van dit moment. In dit protocol wordt een systematische benadering van het kind met MBA voorgesteld. Het protocol bestaat uit twee fasen. In de eerste fase worden andere diagnosen dan astma aangetoond dan wel uitgesloten, wordt beoordeeld of de therapie adequaat is, de symptoomperceptie beoordeeld, worden factoren die het astma verergeren geidentificeerd inclusief de comorbiditeit en wordt gepoogd het astma weer behandelbaar te maken. Nadat is vastgesteld dat het gaat om astma, waarbij alle astma verergerende factoren, inclusief de psychologische, bij het kind en zijn/haar omgeving zijn onderzocht en behandeld, blijft er een kleine groep kinderen met therapieresistent astma’ over. De tweede fase van het protocol, diagnostiek en behandeling van ‘therapieresistent astma’ volgt elders in dit tijdschrift. Op basis van de registratie van kinderen met MBA via het Nederlands Signaleringscentrum Kindergeneeskunde (www.pedianet.nl/nsck) wordt geevalueerd of dit protocol aanpassing behoeft.

Na opsporing en zo mogelijk eliminatie van comorbiditeiten of andere factoren die astma kunnen verergeren in fase 1 van het protocol ‘moeilijk behandelbaar astma’, blijft een kleine groep kinderen met therapieresistent astma over. Een geprotocolleerde en gecentraliseerde aanpak is van belang, waarbij in fase 2 de diagnostiek en behandeling gericht zijn op specifieke karakteristieken van de individuele patient. Het therapieresistente astma wordt nader gefenotypeerd op basis van symptomen, longfunctie, reactie op steroiden en type inflammatie. Na twee weken systemische steroiden wordt een bronchoscopie verricht, met lavageen afname van bronchusmucosabiopten. Bij therapieresistent astma hebben hoge doses inhalatiesteroiden soms een toenemend effect, en kunnen een reductie in de prednisonbehoefte geven. Het bewijs voor effectiviteit van de verschillende alternatieven voor systemische steroidtherapie is beperkt, en er is weinig ervaring mee. Omalizumab, intraveneuze immunoglobulinen of methotrexaat komen het meest in aanmerking. Etanercept en macroliden zijn interessant om verder te bestuderen.

Hoesten is een veelvoorkomend symptoom op de kinderleeftijd. Voor de dagelijkse praktijk is het belangrijk om een onderscheid te maken in niet-specifieke hoest (een droge hoest zonder andere symptomen en zonder afwijkingen bij aanvullend onderzoek) en specifieke hoest (met een duidelijke oorzaak). Bij niet-specifieke hoest kan het beleid vaak expectatief zijn, bij specifieke hoest is behandeling doorgaans aangewezen.We stellen een systematische evaluatie voor bij de diagnostiek en behandeling om belangrijke diagnosen niet te missen.

Summary background Defective male sex differentiation in patients with hypoplasia of Leydig cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH. patients and methods Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1–10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron–exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45–59 healthy persons using denaturation high-performance liquid chromatography. results Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1·7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27-bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified. conclusions Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed.

Online asthma management in children can (partly) substitute routine outpatient visits and is cost-effective http://ow.ly/oabk30f7Sre

Purpose: Hypospadias is a congenital anomaly occurring in 1250 to 1830 live male births, of which 20% involve a severe type. The recurrence risk in families is high. In the majority of cases the underlying etiology remains unknown, which hampers further management based on the specific requirements associated with a specific etiology.Materials and Methods: In a single center study 63 unselected cases of severe hypospadias were studied for all presently known causes of hypospadias using clinical as well as molecular biological techniques. Also, 16 families with hypospadias were analyzed for possible androgen receptor gene mutations.Results: In 31% of cases of severe hypospadias the underlying etiology was identified. Of these 31% of cases 17% were due to complex genetic syndromes, 9.5% were due to chromosomal anomalies, and 1 involved the vanishing testes syndrome, the androgen insensitivity syndrome and 5α-reductase type 2 deficiency, respectively. Based on hormone stimulation tests Leydig cell hypoplasia...

In the androgen receptor of a patient with androgen insensitivity, the alanine residue at position 564 in the first zinc cluster of the DNA-binding domain was substituted by aspartic acid. In other members of the steroid receptor family, either valine or alanine is present at the corresponding position, suggesting the importance of a neutral amino acid residue at this site. The mutant receptor was transcriptionally inactive, which corresponded to the absence of specific DNA binding in gel retardation assays, and its inactivity in a promoter interference assay. Two other receptor mutants with a mutation at this same position were created to study the role of position 564 in the human androgen receptor on DNA binding in more detail. Introduction of asparagine at position 564 resulted in transcription activation of a mouse mammary tumor virus promoter, although at a lower level compared with the wild-type receptor. Transcription activation of an (ARE)2-TATA promoter was low, and binding to different hormone response elements could not be visualized. The receptor with a leucine residue at position 564 was as active as the wild-type receptor on a mouse mammary tumor virus promoter and an (ARE)2-TATA promoter, but interacted differentially with several hormone response elements in a gel retardation assay. The results of the transcription activation and DNA binding studies could partially be predicted from three-dimensional modeling data. The phenotype of the patient was explained by the negative charge, introduced at position 564.

Summary In the coding part and the intron-exon boundaries of the androgen-receptor gene of a patient with partial androgen insensitivity, no mutation was found. The androgen receptor of this patient displayed normal ligand-binding parameters and migrated as a 110–112-kD doublet on SDS-PAGE in the absence of hormone. However, after culturing of the patient's genital skin fibroblasts in the presence of hormone, the slower-migrating 114-kD protein, which reflects hormone-dependent phosphorylation, was hardly detectable. Furthermore, receptor protein was undetectable in the nuclear fraction of the fibroblasts, after treatment with hormone, which is indicative of defective DNA binding. By sequencing part of intron 2, a T→A mutation was found 11 bp upstream of exon 3. In our screening of 102 chromosomes from unrelated individuals, this base-pair substitution was not found, indicating that it was not a polymorphism. mRNA analysis revealed that splicing involved a cryptic splice site, located 71/70 bp upstream of exon 3, resulting in generation of mRNA with an insert of 69 nucleotides. In addition, a small amount of a transcript with a deleted exon 3 and a very low level of wild-type transcript were detected. Translation of the extended transcript resulted in an androgen-receptor protein with 23 amino acid residues inserted between the two zinc clusters, displaying defective DNA binding and defective transcription activation.

Mutations in the androgen receptor gene in 46,XY individuals can be associated with the androgen insensitivity syndrome, of which the phenotype can vary from a female phenotype to an undervirilized or infertile male phenotype. We have studied the androgen receptor gene of androgen insensitivity patients to get information about amino acid residues or regions involved in DNA binding and transcription activation. Genomic DNA was analysed by PCR-SSCP under two different conditions. Three new mutations were found in exon 1 of three patients with a female phenotype. A cytosine insertion at codon 42 resulted in a frameshift and consequently in the introduction of a premature stop at codon 171. Deletion of an adenine at codon 263 gave rise to a premature stop at codon 292. In both these cases, receptor protein was not detectable and hormone binding was not measurable. In a third patient, a guanine-to-adenine transition at codon 493 converted a tryptophan codon into a stop codon. Genital skin fibroblasts from this patient were not available. In exon 2 of the androgen receptor gene of a patient with receptor-positive androgen insensitivity, a cytosine-to-adenine transition, converting alanine 564 into an aspartic acid residue, resulted in defective DNA binding and transactivation. In three other receptor-positive androgen insensitivity patients no mutations were found with PCR-SSCP.

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. The complete form of androgen insensitivity syndrome is characterized by 46,XY karyotype, external female phenotype, intra-abdominal testes, absence of uterus and ovaries, blindly ending vagina, and gynecomastia. There is also a group of disorders of androgen action that result from partial impairment of androgen receptor function. Clinical indications can be abnormal sexual development of individuals with a predominant male phenotype with severe hypospadias and micropenis or of individuals with a predominantly female phenotype with cliteromegaly, ambiguous genitalia, and gynecomastia. Complete or gross deletions of the androgen receptor gene have not been frequently found in persons with the complete androgen insensitivity syndrome, whereas point mutations at several different sites in exons 2–8 encoding the DNA- and androgen-binding domain have been reported in both partial and complete forms of androgen insensitivity, with a relatively high number of mutations in two clusters in exons 5 and 7. The number of mutations in exon 1 is extremely low, and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain. The X-linked condition of spinal and bulbar muscle atrophy (Kennedy's disease) is characterized by a progressive motor neuron degeneration associated with signs of androgen insensitivity and infertility. The molecular cause of spinal and bulbar muscle atrophy is an expanded length (>40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2–8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4–8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.

Contains fulltext : 109416.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Severe acute asthma in children is associated with substantial morbidity and may require pediatric ICU (PICU) admission. The aim of the study was to determine risk factors for PICU admission. METHODS: The study used a retrospective multicenter case-control design. The cases included children admitted to the PICU because of severe acute asthma and a history of out-patient treatment by pediatricians or pediatric pulmonologists. Controls were children with asthma without a PICU admission for severe acute asthma. The children were matched for sex, age, hospital, and time elapsed since the diagnosis of asthma. Fourteen possible risk factors were analyzed. RESULTS: Sixty-six cases were matched to 164 controls. In univariate analysis, all but one of the analyzed variables were significantly associated with PICU-hospitalization. After multivariate conditional logistic regression analysis, 4 risk factors remained significant. These included active or passive smoking, allergies, earlier hospitalization for asthma, and non-sanitized home. CONCLUSIONS: Physicians and parents should be aware of these risk factors, and efforts should be made to counteract them. 01 september 2012

Summary ‘Paediatric asthma: everything that seemed to be certain no longer is', holds the promise of leaving you with more questions than answers at the end of this review of paediatric asthma 2008–2009. This has often been true for asthma research, in particular over the past few years. Research with direct consequences for a clinician managing children with wheezing or asthma is discussed such as limitations in the characterisation of asthma phenotypes and the influence of early viral infections on asthma and the development of atopic sensitisation. It appears that wheezing in preschool children with specific viral pathogens confers differential rates of asthma risk. Viruses and day-care shift respiratory morbidity to an early age when it is more troublesome than at a later age but are not protective for sensitisation or asthma. What needs to be further explored is the relationship between viruses and recurrent wheeze or asthma in studies with stringently defined phenotypes including personal atopic status, timing of infection, and severity of infection. A modification of preschool wheeze phenotypes or replacement by other phenotypes that have been defined with the application of different methods is needed. Oral corticosteroids should not be prescribed in preschool children with acute mild to moderate viral wheeze, unless a severe outcome is anticipated or if the child has a classic atopic phenotype. Despite initial high expectations, FeNO was proven not to be beneficial for routine monitoring of asthma treatment.

Item does not contain fulltext The microsomal enzyme cytochrome P450c17 is an important regulator of steroidogenesis. The enzyme has two functions: 17alpha-hydroxylase and 17,20-lyase activities. These functions determine the ability of adrenal glands and gonads to synthesize 17alpha-hydroxylated glucocorticoids (17alpha-hydroxylase activity) and/or sex steroids (17,20-lyase activity). Both enzyme functions depend on correct steroid binding, but it was recently shown that isolated lyase deficiency can also be caused by mutations located in the redox partner interaction domain. In this article we present the clinical history and molecular analysis of two patients with combined 17alpha-hydroxylase/17,20-lyase deficiency and four patients with isolated 17,20-lyase deficiency. In these six patients, four missense CYP17 mutations were identified. Two mutations were located in the steroid-binding domain (F114V and D116V), and the other two mutations were found in the redox partner interaction domain (R347C and R347H). We investigated the activity of these mutated proteins by transfection experiments in COS-1 cells using pregnenolone, progesterone, or their hydroxylated products as a substrate and measuring 17alpha-hydroxylase- and 17,20-lyase-dependent metabolites in the medium. The mutations in the steroid-binding domain (F114V and D116V) of P450c17 caused combined, complete (F114V), or partial (D116V) 17alpha-hydroxylase and 17,20-lyase deficiencies, whereas mutations in the redox partner interaction domain (R347C and R347H) displayed less severe 17alpha-hydroxylase deficiency, but complete 17,20-lyase deficiency. These findings are consistent with the clinical data and support the observation that the redox partner interaction domain is essential for normal 17,20-lyase function of P450c17.

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.