Showing papers by "Montreal Children's Hospital published in 2013"

A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy

Abstract: Systemic corticosteroids play an integral role in the management of many inflammatory and immunologic conditions, but these agents are also associated with serious risks. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing’s syndrome, psychiatric disturbances and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods. This comprehensive article reviews these adverse events and provides practical recommendations for their prevention and management based on both current literature and the clinical experience of the authors.

Glucocorticoids for acute viral bronchiolitis in infants and young children.

Abstract: Background Previous systematic reviews have not shown clear benefit of glucocorticoids for acute viral bronchiolitis, but their use remains considerable. Recent large trials add substantially to current evidence and suggest novel glucocorticoid-including treatment approaches. Objectives To review the efficacy and safety of systemic and inhaled glucocorticoids in children with acute viral bronchiolitis. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 12), MEDLINE (1950 to January week 2, 2013), EMBASE (1980 to January 2013), LILACS (1982 to January 2013), Scopus® (1823 to January 2013) and IRAN MedEx (1998 to November 2009). Selection criteria Randomised controlled trials (RCTs) comparing short-term systemic or inhaled glucocorticoids versus placebo or another intervention in children under 24 months with acute bronchiolitis (first episode with wheezing). Our primary outcomes were: admissions by days 1 and 7 for outpatient studies; and length of stay (LOS) for inpatient studies. Secondary outcomes included clinical severity parameters, healthcare use, pulmonary function, symptoms, quality of life and harms. Data collection and analysis Two authors independently extracted data on study and participant characteristics, interventions and outcomes. We assessed risk of bias and graded strength of evidence. We meta-analysed inpatient and outpatient results separately using random-effects models. We pre-specified subgroup analyses, including the combined use of bronchodilators used in a protocol. Main results We included 17 trials (2596 participants); three had low overall risk of bias. Baseline severity, glucocorticoid schemes, comparators and outcomes were heterogeneous. Glucocorticoids did not significantly reduce outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% confidence interval (CI) 0.78 to 1.08 and 0.86; 95% CI 0.7 to 1.06, respectively). There was no benefit in LOS for inpatients (mean difference -0.18 days; 95% CI -0.39 to 0.04). Unadjusted results from a large factorial low risk of bias RCT found combined high-dose systemic dexamethasone and inhaled epinephrine reduced admissions by day 7 (baseline risk of admission 26%; RR 0.65; 95% CI 0.44 to 0.95; number needed to treat 11; 95% CI 7 to 76), with no differences in short-term adverse effects. No other comparisons showed relevant differences in primary outcomes. Authors' conclusions Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalisation. Combined dexamethasone and epinephrine may reduce outpatient admissions, but results are exploratory and safety data limited. Future research should further assess the efficacy, harms and applicability of combined therapy.

Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

Abstract: Summary Background Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes ( TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 , and ADAR ). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r =−0·604; serum, r =−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union's Seventh Framework Programme; European Research Council.

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis

Abstract: Summary Background Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p Interpretation Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

Abstract: Background Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments. Methods We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis. Results Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients. Conclusions We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.

Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures

Abstract: The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3–5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.

Biallelic DICER1 mutations occur in Wilms tumours

Abstract: DICER1 is an endoribonuclease central to the generation of microRNAs (miRNAs) and short interfering RNAs (siRNAs). Germline mutations in DICER1 have been associated with a pleiotropic tumour predisposition syndrome and Wilms tumour (WT) is a rare manifestation of this syndrome. Three WTs, each in a child with a deleterious germline DICER1 mutation, were screened for somatic DICER1 mutations and were found to bear specific mutations in either the RNase IIIa ( n= 1) or the RNase IIIb domain ( n= 2). In the two latter cases, we demonstrate that the germline and somatic DICER1 mutations were in trans, suggesting that the two-hit hypothesis of tumour formation applies for these examples of WT. Among 191 apparently sporadic WTs, we identified five different missense or deletion somatic DICER1 mutations (2.6%) in four individual WTs; one tumour had two very likely deleterious somatic mutations in trans in the RNase IIIb domain (c.5438A>G and c.5452G>A). In vitro studies of two somatic single-base substitutions (c.5429A>G and c.5438A>G) demonstrated exon 25 skipping from the transcript, a phenomenon not previously reported in DICER1. Further we show that DICER1 transcripts lacking exon 25 can be translated in vitro. This study has demonstrated that a subset of WTs exhibits two ‘hits’ in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumours. Copyright  2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Recurrent PDGFRB Mutation Causes Familial Infantile Myofibromatosis

Abstract: Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.

Peroxisome Biogenesis Disorders: Biological, Clinical and Pathophysiological Perspectives.

Abstract: The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.

Developmental course of attention deficit hyperactivity disorder and its predictors.

Abstract: Objective To outline the key features of the developmental progression of ADHD and to consider the most prominent influences on its developmental course and outcomes. Methods This is a selective review focusing primarily on prospective follow-up studies. Relevant publications were selected by searching the MEDLINE and PubMed databases using keywords: ADHD, development, preschool, adolescent, adult, follow up, outcome, long-term, predictors, and treatment. Reference lists of the resulting articles were then reviewed for additional publications. Results Presentation of ADHD and associated impairments evolve across development, as do outcome predictors. In early development, in addition to genetics, some forms of prenatal adversity increase the risk for ADHD. In preschool years, symptom severity, cognitive function, and family factors become significant predictors of school age outcomes. These continue to predict long-term outcomes in school aged children, and comorbidity emerges as another significant long-term outcome predictor at this stage. Conclusions Presentation of ADHD and risk factors for later adversity evolve across development, which calls for developmentally-informed clinical practices.

Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS

Abstract: Background 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000–4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype. Methods We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals. Results and conclusions In four unrelated patients, we identified three novel mutations in SNAP29 , the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

Anastomotic stricture after esophageal atresia repair: a critical review of recent literature.

Abstract: Anastomotic strictures (ASs) complicate the postoperative course of roughly one-third of all patients with esophageal atresia with or without tracheoesophageal fistula. Its development is multifactorial, but is due in part to tension on the anastomosis, gastroesophageal reflux disease, and the presence of a leak in the early postoperative period. Efforts at reducing the rate of AS have been largely unsuccessful, although meticulous technique and aggressive acid suppression remain the cornerstones of perioperative care. Once an AS has been confirmed, the first-line treatment remains a course of esophageal dilatation. Adjuncts to dilatation are frequently required, including steroid injection or the topical application of mitomycin C. Currently, there is insufficient evidence to promote one at the expense of the other. Esophageal stenting has recently been added to the algorithm of treatment, although additional literature is required to confirm its safety and efficacy. Finally, stricture resection followed by primary esophageal anastomosis or, rarely, esophageal replacement with an interposition graft remain options for AS refractory to all other forms of treatment.

In Vitro and In Vivo Studies of IgG-derived Treg Epitopes (Tregitopes): A Promising New Tool for Tolerance Induction and Treatment of Autoimmunity

Abstract: Tregitopes are regulatory T cell epitopes derived from immunoglobulin G (IgG) that stimulate CD25+ FoxP3+ T cells to expand. In conjunction with these Tregs, Tregitopes can prevent, treat, and even cure autoimmune disease in mouse models, suppress allo-specific responses in murine transplant models, inhibit CD8+ T cell responses to recombinant adeno-associated virus (AAV) gene transfer vectors, and induce adaptive Tregs in DO11.10 mice. In this review of recent Tregitope studies, we summarize their effects in vitro and describe recent comparisons between intravenous IgG (IVIG) and Tregitopes in standard in vivo immune tolerance models. Further investigations of the mechanism of action of Tregitopes in the preclinical models described here will lead to clinical trials where Tregitopes may have the potential to alter the treatment of autoimmune disease, transplantation, and allergy, and to improve the efficiency of gene and protein replacement therapies.

Long-term functional benefits of selective dorsal rhizotomy for spastic cerebral palsy

Abstract: Object Large-scale natural history studies of gross motor development have shown that children with spastic cerebral palsy (CP) plateau during childhood and actually decline through adolescence Selective dorsal rhizotomy (SDR) is a well-recognized treatment for spastic CP, but little is known about long-term outcomes of this treatment The purpose of this study was to assess the durability of functional outcomes in a large number of patients through adolescence and into early adulthood using standardized assessment tools Methods The authors analyzed long-term follow-up data in children who had been evaluated by a multidisciplinary team preoperatively and at 1, 5, 10, and 15 years after SDR These evaluations included quantitative, standardized assessments of lower-limb tone (Ashworth Scale), Gross Motor Function Measure (GMFM), and performance of activities of daily living (ADLs) by the Pediatric Evaluation of Disability Inventory in children who had been stratified by motor severity using the Gross Mot

ARHGDIA: a novel gene implicated in nephrotic syndrome

Abstract: Background Congenital nephrotic syndrome arises from a defect in the glomerular filtration barrier that permits the unrestricted passage of protein across the barrier, resulting in proteinuria, hypoalbuminaemia, and severe oedema. While most cases are due to mutations in one of five genes, in up to 15% of cases, a genetic cause is not identified. We investigated two sisters with a presumed recessive form of congenital nephrotic syndrome. Methods and results Whole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that ARHGDIA that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor α (RhoGDIα, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies. The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)). Rho-GTPases are critical regulators of the actin cytoskeleton and when bound to RhoGDIα, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDIα was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDIα was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function. Conclusions Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome.

Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism

Abstract: Background Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies. Methods The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients. Results Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A : six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B , of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B : four missenses, two splice sites, and one intronic mutation. Conclusions To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.

Moderately high intake of folic acid has a negative impact on mouse embryonic development

Abstract: BACKGROUND The incidence of neural tube defects has diminished considerably since the implementation of food fortification with folic acid (FA) However, the impact of excess FA intake, particularly during pregnancy, requires investigation In a recent study, we reported that a diet supplemented with 20-fold higher FA than the recommended intake for rodents had adverse effects on embryonic mouse development at embryonic days (E)105 and 145 In this report, we examined developmental outcomes in E145 embryos after administering a diet supplemented with 10-fold higher FA than recommended to pregnant mice with and without a mild deficiency of methylenetetrahydrofolate reductase (MTHFR) METHODS Pregnant mice with or without a deficiency in MTHFR were fed a control diet (recommended FA intake of 2 mg/kg diet for rodents) or an FA-supplemented diet (FASD; 10-fold higher than the recommended intake [20 mg/kg diet]) At E145, mice were examined for embryonic loss and growth retardation, and hearts were assessed for defects and for ventricular wall thickness RESULTS Maternal FA supplementation was associated with embryonic loss, embryonic delays, a higher incidence of ventricular septal defects, and thinner left and right ventricular walls, compared to mothers fed control diet CONCLUSIONS Our work suggests that even moderately high levels of FA supplementation may adversely affect fetal mouse development Additional studies are warranted to evaluate the impact of high folate intake in pregnant women Birth Defects Research (Part A), 2013 © 2012 Wiley Periodicals, Inc

Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis

Abstract: Background Positive expiratory pressure (PEP) is the most commonly used method of airway clearance (AC) in Canada for patients with cystic fibrosis (CF) whereas, in some countries, high frequency chest wall oscillation (HFCWO) is the preferred form of AC. There have been no long-term studies comparing the efficacy of HFCWO and PEP in the CF population. Objectives To determine the long-term efficacy of HFCWO compared with PEP mask therapy in the treatment of CF as measured by the number of pulmonary exacerbations (PEs). Methods A randomised controlled study was performed in 12 CF centres in Canada. After a 2-month washout period, subjects were randomised to perform either HFCWO or PEP mask therapy for 1 year. Results 107 subjects were enrolled in the study; 51 were randomised to PEP and 56 to HFCWO. There were 19 dropouts within the study period, of which 16 occurred prior to or at the time of randomisation. There were significant differences between the groups in the mean number of PEs (1.14 for PEP vs 2.0 for HFCWO) and time to first PE (220 days for PEP vs 115 days for HFCWO, p=0.02). There was no significant difference in lung function, health-related quality of life scores or patient satisfaction scores between the two groups. PEP mask therapy required a shorter treatment time. Conclusions The results of this study favour PEP and do not support the use of HFCWO as the primary form of AC in patients with CF. Clinical Trial Registration number NCT00817180.

Current use of intralesional cidofovir for recurrent respiratory papillomatosis.

Abstract: Objectives/Hypothesis: The authors sought to define the indications, administration, and adverse events associated with intralesional cidofovir use for recurrent respiratory papillomatosis (RRP). Study Design: Cross-sectional study. Methods: A 21-question online survey was distributed to 115 selected adult and pediatric laryngeal surgeons internationally. Results were used to draft statements of best practice, which were approved by the full membership of the RRP Task Force. Results: Eighty-two surgeons, who altogether presently manage 3,043 patients with RRP, responded to the survey. Seventy-four surgeons previously used cidofovir, reporting 1,248 patients in the last decade (estimated 801 adults and 447 children). Single indications for adjuvant cidofovir included six or more surgeries per year, increasing frequency of surgery, and extralaryngeal spread (in children). Most adult surgeons use 20 to 40 mg in <4 mL; pediatric surgeons use <20 mg in <2 mL. Scheduled administration following an initiation trial of five injections is common; cidofovir is discontinued following a complete response. Most surgeons biopsy routinely, use special informed consent, and are willing to participate in multi-institutional clinical trials on cidofovir uses, efficacy, and safety. Conclusions: Eighteen statements were approved by the RRP Task Force after discussion of the survey results. Intralesional cidofovir may be initiated if surgical debulking is required every 2 to 3 months. The concept of an adjuvant regimen with regular biopsy is favored. Administration should remain below established safe limits of dosing (3 mg/kg) and volume. Informed consent, including discussion of off-label use and acute kidney injury in children, is important. A special consent form sample is included. There remains a need for high-quality data. Laryngoscope, 2013

Systemic inflammation perturbs developmental retinal angiogenesis and neuroretinal function.

Abstract: PURPOSE. Perinatal inflammatory stress in preterm babies is associated with increased rates of severe retinopathy of prematurity (ROP) and adverse neurological dysfunction. In this study, we set out to determine the consequences of severe systemic inflammatory stress on developmental retinal vascularization and evaluate the subsequent outcome on retinal function in later life. METHODS. Systemic inflammatory stress was induced in C57BL/6J mouse pups by an intraperitoneal injection of lipopolysaccharide (LPS; 1 mg/kg) at postnatal day 4. In response to LPS, retinal inflammation was confirmed by quantitative RT-PCR analysis of diverse inflammatory markers. A detailed and systematic analysis of retinal microglial infiltration, retinal vascular morphology, density, and growth rate was performed at key time points throughout retinal vascularization. Retinal function in adult life was assessed by using electroretinography at 6 weeks postinjection. RESULTS. As early as 48 hours after intraperitoneal administration of LPS, a significant increase in retinal vascular density was noted throughout the retina. A pronounced increase in the number of activated microglial cell was observed in the retinal ganglion cell layer and in the outer plexiform layer just prior to their vascularization; direct physical contact between activated microglia and sprouting vessels suggested that microglia partake in promoting the aberrant retinal vascularization. With maturity, animals subjected to perinatal inflammatory stress displayed depleted retinal vascular beds and had significantly decreased retinal function as determined by electroretinography. CONCLUSIONS. Our data reveal that early severe postnatal inflammatory stress leads to abnormal retinal vascular development and increased vessel anastomosis and, ultimately, permanently compromises retinal function. The aberrant and initially exaggerated retinal vascularization observed is associated with microglial activation, providing a cellular mechanism by which perinatal sepsis predisposes to ROP.

Characterization of esophageal motility following esophageal atresia repair using high-resolution esophageal manometry.

Abstract: Background: Esophageal dysmotility, a considerable issue following esophageal atresia (EA) repair, has been reported but has not been precisely described and characterized Using high-resolution esophageal manometry (HREM), we characterized the esophageal motility patterns in children with repaired EA and compared these patterns of dysmotility with symptomatology Methods: HREM was performed as an outpatient procedure in patients with repaired EA The tracings were analyzed using the software provided by the company and were then reviewed visually Charts were reviewed for medical/surgical histories and symptoms were assessed by a standardized questionnaire Results: Forty patients (25 boys, 15 girls) with a median age of 8 years (11 months–18 years) underwent an HREM Thirty-five patients had type C EA and 5 had type A EA Only 7 patients were asymptomatic at the time of the examination HREM results were abnormal in all of the patients Three different esophageal motility patterns were derived from HREM tracing analysis: aperistalsis (15 patients, 38%), pressurization (6 patients, 15%), and distal contractions (19 patients, 47%) Distal contractions pattern was found exclusively in type C EA Dysphagia was encountered in the 3 groups Gastroesophageal reflux disease-related symptoms predominated in the aperistalsis group Conclusions: HREM improves our understanding and allows precise characterization of esophageal dysmotility in patients who have undergone EA repair

Influence of ethnicity on childhood-onset systemic lupus erythematosus: results from a multiethnic multicenter Canadian cohort.

Abstract: Objective To determine the influence of ethnicity and sociodemographic factors on disease characteristics of the Canadian pediatric lupus population. Methods Childhood-onset systemic lupus erythematosus (SLE) patients at 4 pediatric centers in Halifax, Montreal, Toronto, and Vancouver were consecutively recruited. Sociodemographics and disease data were collected. Patients were categorized by their primary self-selected ethnicity, and exploratory cluster analyses were examined for disease expression by ethnicity. Results We enrolled 213 childhood-onset SLE patients, and ethnicity data were available for 206 patients: white (31%), Asian (30%), South Asian (15%), black (10%), Latino/Hispanic (4%), Aboriginal (4%), and Arab/Middle Eastern (3%). The frequency of clinical classification criteria (malar rash, arthritis, serositis, and renal disease) and autoantibodies significantly differed among ethnicities. Medications were prescribed equally across ethnicities: 76% were taking prednisone, 86% antimalarials, and 56% required additional immunosuppressants. Cluster analysis partitioned into 3 main groups: mild (n = 50), moderate (n = 82), and severe (n = 68) disease clusters. Only 20% of white patients were in the severe cluster compared to 51% of Asian and 41% of black patients (P = 0.03). However, disease activity indices and damage scores were similar across ethnicities. Conclusion Canadian childhood-onset SLE patients reflect our multiethnic population, with differences in disease manifestations, autoantibody profiles, and severity of disease expression by ethnicity.