Showing papers by "Hospital for Sick Children published in 2008"

Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease

Abstract: Tissue organization in Drosophila is regulated by the core planar cell polarity (PCP) proteins Frizzled, Dishevelled, Prickle, Van Gogh and Flamingo. Core PCP proteins are conserved in mammals and function in mammalian tissue organization. Recent studies have identified another group of Drosophila PCP proteins, consisting of the protocadherins Fat and Dachsous (Ds) and the transmembrane protein Four-jointed (Fj). In Drosophila, Fat represses fj transcription, and Ds represses Fat activity in PCP. Here we show that Fat4 is an essential gene that has a key role in vertebrate PCP. Loss of Fat4 disrupts oriented cell divisions and tubule elongation during kidney development, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 and Fjx1 in cyst formation. In addition, Fat4 represses Fjx1 expression, indicating that Fat signaling is conserved. Together, these data suggest that Fat4 regulates vertebrate PCP and that loss of PCP signaling may underlie some cystic diseases in humans.

Patient characteristics affecting the prognosis of total hip and knee joint arthroplasty: a systematic review.

Abstract: Background: Total joint arthroplasty is a highly efficacious and cost-effective procedure for moderate to severe arthritis in the hip and knee. Although patient characteristics are considered to be important determinants of who receives total joint arthroplasty, no systematic review has addressed how they affect the outcomes of total joint arthroplasty. This study addresses how patient characteristics influence the outcomes of hip and knee arthroplasty in patients with osteoarthritis. Methods: We searched 4 bibliographic databases (MEDLINE 1980‐2001, CINAHL 1982‐2001, EMBASE 1980‐2001, HealthStar 1998‐1999) for studies involving more than 500 patients with osteoarthritis and 1 or more of the following outcomes after total joint arthroplasty: pain, physical function, postoperative complications (short- and long-term) and time to revision. Prognostic patient characteristics of interest included age, sex, race, body weight, socioeconomic status and work status. Results: Sixty-four of 14 276 studies were eligible for inclusion and had extractable data. Younger age (variably defined) and male sex increased the risk of revision 3-fold to 5-fold for hip and knee arthroplasty. The influence of weight on the risk of revision was contradictory. Mortality was greatest in the oldest age group and among men. Function for older patients was worse after hip arthroplasty (particularly in women). Function after knee arthroplasty was worse for obese patients. Conclusion: Although further research is required, our findings suggest that, after total joint arthroplasty, younger age and male sex are associated with increased risk of revision, older age and male sex are associated with increased risk of mortality, older age is related to worse function (particularly among women), and age and sex do not influence the outcome of pain. Despite these findings, all subgroups derived benefit from total joint arthroplasty, suggesting that surgeons should not restrict access to these procedures based on patient characteristics. In addition, future research needs to provide standardized measures of outcomes. Contexte : L’arthroplastie totale est une intervention tres efficace et rentable pour soulager l’arthrite moderee ou grave a la hanche ou au genou. Bien que les caracteristiques du patient soient considerees comme des facteurs importants pour choisir les recipiendaires d’une arthroplastie totale, aucune synthese systematique ne fait etat de leur incidence sur les resultats. La presente etude traite de l’incidence des caracteristiques des patients atteints d’arthrose sur les resultats d’une arthroplastie de la hanche ou du genou. Methodes : Nous avons consulte 4 bases de donnees bibliographiques (MEDLINE 1980‐2001, CINAHL 1982‐2001, EMBASE 1980‐2001 et HealthStar 1998‐1999) pour trouver des etudes sur plus de 500 patients atteints d’arthrose et ayant presente un ou plusieurs des resultats suivants apres une arthroplastie totale : douleur, fonction physique, complications postoperatoires (a court et a long terme) et attente d’une revision. Les caracteristiques pronostiques retenues comprenaient l’âge, le sexe, la race, le poids corporel, la situation socioeconomique et l’etat relatif a l’emploi. Resultats : Des 14 276 etudes, 64 pouvaient etre incluses et contenaient des donnees extractibles. On a constate un risque de revision de 3 a 5 fois plus eleve pour les arthroplasties de la hanche ou du genou realisees dans les groupes plus jeunes (definis de facon variable) et chez les hommes. L’influence du poids

Pain in Hospitalized Children: A Prospective Cross-Sectional Survey of Pain Prevalence, Intensity, Assessment and Management in a Canadian Pediatric Teaching Hospital

Abstract: BACKGROUND: Pain is under-recognised and undertreated. Although standards now exist for pain management, it is not known if this has improved care of hospitalized children.

Dietary fructose and the metabolic syndrome.

Abstract: Purpose of reviewFructose, a naturally found sugar in many fruits, is now commonly used as an industrial sweetener and is excessively consumed in Western diets. High fructose intake is increasingly recognized as causative in development of prediabetes and metabolic syndrome. The mechanisms underlyin

Clinical assessment of autism in high-risk 18-month-olds

Abstract: Earlier intervention improves outcomes for children with autism spectrum disorders (ASDs), but existing identification tools are at the limits of standardization with 18-month-olds. We assessed potential behavioural markers of ASD at 18 months in a high-risk cohort of infant siblings of children with ASD. Prospective data were collected using the Autism Diagnostic Observation Schedule (ADOS) and Autism Observation Scale for Infants (AOSI) on 155 infant siblings and 73 low-risk controls at 18 months. Infants were classified into three groups (ASD sibs, non-ASD sibs, controls) based on blind best-estimate diagnosis at age 3. Fisher's exact tests, followed by discriminant function analyses, revealed that the majority of informative ADOS items came from the social and behavioural domains, and AOSI items measuring behavioural reactivity and motor control contributed additional information. Findings highlight the importance of considering not only social-communication deficits, but also basic dimensions of temperament including state regulation and motor control when assessing toddlers with suspected ASD.

Age-specific effective doses for pediatric MSCT examinations at a large children’s hospital using DLP conversion coefficients: a simple estimation method

Abstract: There is a need for an easily accessible method for effective dose estimation in pediatric CT. To estimate effective doses for a variety of pediatric neurological and body CT examinations in five age groups using recently published age- and region-specific dose length product (DLP) to effective dose conversion coefficients. A retrospective review was performed of 1,431 consecutive CT scans over a 12-week period using age- and weight-adjusted CT protocols. Age- and region-specific DLP to effective dose conversion coefficients were applied to console-displayed DLP data. Effective dose estimates for single-phase head CT scans in neonatal, and 1-, 5-, 10- and 15-year-old age groups were 4.2, 3.6, 2.4, 2.0 and 1.4 mSv, respectively. For abdomen/pelvis CT scans the corresponding effective doses were 13.1, 11.1, 8.4, 8.9 and 5.9 mSv. The range of pediatric CT effective doses is wide, from ultralow dose protocols (<1 mSv) to extended-coverage body examinations (10–15 mSv). Age- and region-specific pediatric DLP to effective dose conversion coefficients provide an accessible and user-friendly method for estimating pediatric CT effective doses that is available to radiologists working without medical physics support.

Evaluation of selective dorsal rhizotomy for the reduction of spasticity in cerebral palsy: a randomized controlled trial

Abstract: Selective dorsal rhizotomy (SDR) is widely used to treat spasticity in children with diplegic cerebral palsy (CP) but has never been shown conclusively to improve functional outcome. The study was designed to measure changes in gross motor function in children 1 year following rhizotomy compared with a control group receiving equivalent physiotherapy (PT) and occupational therapy (OT) with the exception that the rhizotomy group initially underwent a 6-week postoperative in-patient therapy program. Twenty-four children (mean age 58 months) with mild to moderate CP with spastic diplegia were randomly assigned to a therapy-only control group (CG) (N=12) or rhizotomy and therapy group (RG) (N=12). The Gross Motor Function Measure (GMFM) was administered at the baseline, 6-, and 12-month assessments. Extremity tone, range of motion (ROM), biomechanics of the ankle-stretch reflex, isometric contraction, and temporal gait components were also evaluated. GMFM scores in the RG improved by 12.1 percentage points versus 4.4 percentage points in the CG (P<0.02). RG knee and ankle tone was significantly reduced (P<0.005), associated with increased passive ankle ROM (P<0.001), and decreased soleus EMG reflex activity on forced dorsiflexion (P<0.008). Foot-floor contact pattern improved in the RG compared with the CG (P<0.05). In conclusion, SDR combined with PT and OT leads to significantly greater functional motor improvement at 1 year following surgery compared with PT and OT alone. This was achieved in part through reduced knee and ankle tone, increased ankle dorsiflexion ROM, and more normal foot-floor contact during walking.

Traditional corticosteroids for induction of remission in Crohn's disease

Abstract: Background Historically, corticosteroids have been the most commonly used class of medication for induction of remission in Crohn's disease (CD). Corticosteroids down regulate production of inflammatory cytokines and interfere with NF-κB production, thereby blunting inflammatory response. Objectives The primary objective was to systematically review the efficacy and safety of traditional corticosteroids (given orally or intravenously) for induction of remission in CD. Search methods The following electronic databases were searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders (IBD/FBD) Group Specialized Trial Register, and ClinicalTrials.gov. No language restrictions were applied. Reference lists of trials and review articles, as well as recent proceedings from major gastroenterology meetings were manually searched. Selection criteria Randomized, controlled clinical trials of traditional, systemic corticosteroids for the induction of remission of active CD were included in this review. Control groups included patients receiving either placebo or 5-aminosalicylates (5-ASA). The study population included patients of any age with active CD (as defined by the study authors or validated clinical activity indices), receiving any formulation of systemically available corticosteroid by any oral or parenteral methods of delivery. The primary outcome was induction of remission of CD. Secondary outcomes included clinical response, change in mean CDAI, adverse events and the proportion of patients withdrawing due to adverse events. Data collection and analysis Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using Jadad's criteria. A random or fixed effects model was chosen based on an assessment of heterogeneity, and studies were weighted using the DerSimonian & Laird or the Mantel-Haenszel method accordingly. Meta-analysis was performed using RevMan 4.2.10 software. Main results Two studies compared corticosteroids to placebo and six studies compared corticosteroids to 5-ASA. Corticosteroids were found to be significantly more effective than placebo at inducing remission in CD (RR 1.99; 95% CI 1.51 to 2.64; P 15 weeks; RR 1.65; 95% CI 1.33 to 2.03; P < 0.00001). Corticosteroids induced adverse events in a higher proportion of patients than placebo (RR 4.89; 95% CI 1.98 to 12.07; P = 0.0006), or low-dose 5-ASA (RR 2.38; 95% CI 1.34 to 4.25; P = 0.003). No difference existed in the proportion of patients experiencing adverse events when steroids were compared to high-dose 5-ASA. Steroids did not induce more study withdrawals due to adverse events than either placebo or 5-ASA. Authors' conclusions Corticosteroids are effective for induction of remission in patients with CD, particularly when used for more than 15 weeks. Although corticosteroids cause more adverse events than either placebo or low-dose 5-ASA, these adverse events did not lead to increased study withdrawal in the included studies. Further information is required to determine the optimal duration of treatment and tapering protocol to maximize the efficacy of treatment with corticosteroids. Additionally, further study is required to determine whether corticosteroids are more effective in patients with certain phenotypes or when administered intravenously.

JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer

Abstract: Expression of the JAG1 Notch ligand has previously been shown to correlate with poor overall survival in women with advanced breast cancer. We undertook to test whether expression of JAG1 is associated with reduced disease free survival (DFS) in 887 samples from a prospectively accrued LNN cohort with a median follow-up greater than 8 years. Moderate to high JAG1 mRNA expression was associated with reduced DFS in univariate analysis (hazard ratio of 1.58; 95% confidence interval, 1.03–2.40; P = 0.034) and correlated with large tumor size, ER and PgR negativity, high tumor grade, and p53 antibody reactivity. Although elevated risk of reduced DFS in patients with high JAG1 mRNA did not persist with adjustment for other prognostic factors, it did in combination with HER2. JAG1 mRNA was positively associated with expression of basal breast cancer markers, however, in contrast to the finding that basal gene expression is most strongly associated with reduced DFS in the first 36 months of follow-up, JAG1 mRNA expression was associated with reduced DFS through the full follow-up period. Also, tumors expressing high levels of both mRNA and protein showed reduced DFS as compared to all other groups in univariate analysis (hazard ratio of 1.73; 95% confidence interval, 1.09–2.74; P = 0.020). Thus, JAG1 expression is associated with poor DFS in LNN breast cancer. As JAG1 is a target of several oncogenic signaling pathways, and is a ligand for Notch, these data provide novel insights into signaling that may contribute to progression of early stage breast cancer.

Changes in the neural bases of emotion regulation associated with clinical improvement in children with behavior problems.

Abstract: Children's behavior problems may stem from ineffective cortical mechanisms for regulating negative emotions, and the success of interventions may depend on their impact on such mechanisms. We examined neurophysiological markers associated with emotion regulation in children comorbid for externalizing and internalizing problems before and after treatment. We hypothesized that treatment success would correspond with reduced ventral prefrontal activation, and increased dorsomedial prefrontal activation, at the time point of an event-related potential (ERP) associated with inhibitory control. Twenty-seven 8- to 12-year-old children (with usable data) were tested before and after a 14-week community-based treatment program and assessed as to improvement status. Fifteen 8- to 12-year-olds from the normal population (with usable data) were tested over the same interval. All children completed an emotion-induction go/no-go task while fitted with a 128-channel electrode net at each test session. ERP amplitudes, and estimates of cortical activation in prefrontal regions of interest, were measured at the peak of the "inhibitory" N2 and compared between improvers, nonimprovers, and nonclinical children. ERP amplitudes showed no group differences. However, improvers showed an overall reduction in ventral prefrontal activation from pretreatment to posttreatment, bringing them in line with nonclinical children, whereas ventral activation remained high for nonimprovers. Both improvers and nonimprovers showed high dorsal activation relative to nonclinical children. Supplementary analyses indicated that only ventral prefrontal regions, and only within the N2 time window, showed decreased activity from pre- to posttreatment, suggesting changes in regulatory processes rather than in overall emotional arousal. These cortically mediated changes may permit a reduction in the overengaged, rigid style of emotion regulation characteristic of children with behavior problems.

The old and the new: supratentorial MR findings in Chiari II malformation.

Abstract: The objective of this study was to use magnetic resonance imaging to develop an improved morphological understanding of the abnormalities of the forebrain in Chiari II malformation Seventy-four patients with Chiari II malformations investigated between 1999 and 2007 were enrolled Imaging was retrospectively reviewed by two pediatric neuroradiologists, with special attention given to diencephalon, midline commissures, hemispheric white matter, and cortex An abnormal gray matter structure that we called hypothalamic adhesion across the anterior-inferior portion of the third ventricle was noted in 486% The anterior commissure was in a low position in the lamina terminalis in 38% Gross abnormalities of the corpus callosum/hippocampal commissure were found in 57%; they were, however, different from the abnormalities seen in classical commissural agenesis An abnormal bundle of white matter forming a callosal ridge was noted on the dorsal callosal surface in 60%; it is believed to represent the aberrant cingular bundle recently identified using diffusion tensor imaging Hemispheric white matter could be considered as normal in 48%, deficient posteriorly in 55%, and globally in 10% Cortical posterior medial stenogyria was observed in 72% Gray matter heterotopias were found in 19% The posterior limbic cortex was thin and dysplastic in 46% Hippocampi were commonly abnormal (85%), with atypical sulcation of the adjacent temporo-mesial cortex (93%) Major structural abnormalities were common in Chiari II malformation and were probably not related to hydrocephalus Important anatomical structures involved in neurocognitive function should be considered as factors in the prognostic assessment of Chiari II patients

The rationale for the use of parenteral omega-3 lipids in children with short bowel syndrome and liver disease.

Abstract: Parenteral nutrition associated liver disease (PNALD) is the major source of morbidity and mortality in children with short bowel syndrome (SBS). There is emerging evidence that omega-6 fatty acids (ω6FA) within the parenteral solution play a major role in PNALD and their effects may be reversed or ameliorated by substitution with omega-3 fatty acids (ω3FA). This paper reviews the mechanisms whereby ω3FAs may influence PNALD by improving bile flow, inhibiting steatosis, and having immunomodulatory effects. The early clinical experience with ω3FAs in SBS and PNALD is briefly reviewed and the implications of such, and future directions are considered.

An exploratory study of parents' approaches to health promotion in families of adolescents with physical disabilities.

Abstract: Background The life expectancy of children with physical disabilities now extends into adulthood and has been accompanied by the transfer of rehabilitation services from institutions to the home. Thus, families must increasingly partner with health service providers to promote their child's health and prevent the development of secondary conditions that may contribute to heart disease, stroke, respiratory diseases, low endurance and emotional difficulties. Aim To investigate within a family context the health promotion efforts of parents on behalf of a child with a physical disability. Method The Long Interview Method was used to interview 15 families (11 two-parent and 4 single-parent) having a child 11–16 years of age with a physical disability including cerebral palsy (7), spina bifida (3), muscular dystrophy (3) and other conditions (2). Results Parents' health promotion efforts were characterized by three main themes. First, parents emphasized traditional lifestyle health behaviours including nutrition, physical activity, tobacco, alcohol and drug use, and personal hygiene. Second, parents tried to foster their adolescent's social life and friendships. They expressed particular concern about how, and if, their child would develop a sense of purpose and have a productive future. Third, parents invested a great deal of effort into observing daily routines, making arrangements for their child's social inclusion and supporting their child in a way that balanced independence with safety and energy conservation. Conclusions Parents recognize that their child with a physical disability faces greater obstacles, and work hard at health promotion. Healthcare workers need to work with parents to: (1) provide information about specific lifestyle health behaviours including nutrition, physical activity and sexuality; (2) advocate for resources to foster social inclusion; and (3) discuss family strategies that balance parental involvement with their child's need for independence and energy conservation for daily activities.

Closing the Gaps in Paediatric Reference Intervals: The CALIPER Initiative

Abstract: Screening, diagnosis and monitoring of paediatric diseases relies on the measurement of a spectrum of disease biomarkers in clinical laboratories to guide important clinical decisions. Physicians rely on the availability of suitable and reliable reference intervals to accurately interpret laboratory test results with data collected during medical history and physical examination. However, critical gaps currently exist in accurate and up-to-date reference intervals (normal values) for accurate interpretation of laboratory tests performed in children and adolescents. These gaps in the available paediatric laboratory reference intervals have the clear potential of contributing to erroneous diagnosis or misdiagnosis of many diseases of childhood and adolescence. Most of the available reference intervals for laboratory tests were determined over two decades ago on older instruments and technologies, and are no longer relevant considering the current testing technology used by clinical laboratories. It is thus critical and of utmost urgency that a more acceptable and comprehensive database be established. There are however many challenges when attempting to establish paediatric reference intervals. Paediatric specimen collection is a major concern for health care providers as it is frequently difficult to obtain sufficient volumes of blood or urine from paediatric patients. Common reference intervals have not been widely implemented due to lack of harmonisation of methods and differences in patient populations. Consequently, clinical laboratory accreditation organisations and licensing agencies require that each laboratory verify or establish reference intervals for each method. To provide such reference intervals requires selection criteria for suitable reference individuals, defined conditions for specimen collection and analysis, method selection to determine reference limits and validation of the reference interval. The current review will provide a brief introduction to the current approach to establishment of reference intervals, will highlight the current gaps in data available in paediatric populations, and review a recent Canadian initiative, CALIPER (Canadian Laboratory Initiative on Paediatric Reference Intervals), to establish a comprehensive database for both traditional and emerging biomarkers of paediatric disease.

Supratentorial primitive neuroectodermal tumors: a Canadian pediatric brain tumor consortium report.

Abstract: Introduction Supratentorial primitive neuroectodermal tumors (SPNET) are rare tumors accounting for only 2.5% of childhood brain tumors. The purpose of this study was to describe the range of treatment regimens used to treat pediatric SPNET in Canada and to identify prognostic factors for overall survival in this population. Methods This study was a retrospective clinical analysis of SPNET patients treated over the last 10 years in Canada. A questionnaire was developed and distributed to all institutions in Canada who treat pediatric patients. Data were collected for patients 2 years. Overall survival was not affected by metastatic disease at diagnosis, tumor site, or degree of initial resection. Conclusions Survival is poor in SPNET patients but highest in those who received chemotherapy and radiation therapy. Further studies are needed to improve the survival of these patients.

Does mechanical stimulation have any role in urinary bladder tissue engineering

Abstract: Tissue engineering of the urinary bladder currently relies on biocompatible scaffolds that deliver biological and physical functionality with negligible risks of immunogenic or tumorigenic potential. Recent research suggests that autologous cells that are propagated in culture and seeded on scaffolds prior to implantation improve clinical outcomes. For example, normal urinary bladder development in utero requires regular filling and emptying, and current research suggests that bladders constructed in vitro may also benefit from regular mechanical stimulation. Such stimulation appears to induce favorable cellular changes, proliferation, and production of structurally suitable extracellular matrix (ECM) components essential for the normal function of hollow dynamic organs. To mimic in vivo urinary bladder dynamics, tissue bioreactors that imitate the filling and emptying of a normal bladder have been devised. A “urinary bladder tissue bioreactor” that is able to recapitulate these dynamics while providing a cellular environment that facilitates cell–cell and cell–matrix interactions normally seen in-vivo may be necessary to successfully engineer bladder tissue. The validation of a urinary bladder tissue bioreactor that permits careful control of physiological conditions will generate a broad interest from researchers interested in urinary bladder physiology and tissue engineering.

Establishing Causality of CNS Depression in Breastfed Infants Following Maternal Codeine Use

Abstract: Background: We recently reported on a breastfed infant who succumbed to opioid toxicity following exposure to morphine, the active metabolite of codeine, which was prescribed to his mother who was a cytochrome P450 2D6 (CYP2D6) ultrarapid metabolizer. This report is believed to be the first case of neonatal fatality as a direct result of maternal drug excretion into breast milk and, therefore, it is critical to corroborate the causative relationship between maternal codeine use during breastfeeding and neonatal opioid toxicity with other existing evidence.

BMP receptor ALK3 controls collecting system development

Abstract: The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.

Simple preservation of a maxillary extraction socket using beta-tricalcium phosphate with type I collagen: preliminary clinical and histomorphometric observations.

Abstract: Alveolar atrophy following tooth extraction remains a challenge for future dental implant placement. Immediate implant placement and postextraction alveolar preservation are 2 methods that are used to prevent significant postextraction bone loss. In this article, we report the management of a maxillary tooth extraction socket using an alveolar pres- ervation technique involving placement of a cone of beta-tricalcium phosphate (s-TCP) combined with type I collagen without the use of barrier membranes or flap surgery. Clinical examination revealed solid new bone formation 9 months after the procedure. At the time of implant placement, histomorphometric analysis of the biopsied bone showed that it contained 62.6% mineralized bone, 21.1% bone marrow and 16.3% residual s-TCP graft. The healed bone was able to support subsequent dental implant placement and loading.

Tyrosine kinase expression in pediatric high grade astrocytoma.

Abstract: The over-expression of several receptor tyrosine kinases in adult high grade astrocytomas (HGA) led to trials of tyrosine kinase inhibitors in these patients. Similar molecular genetic analysis of pediatric HGA is only beginning to be published. Thus it is unclear to what degree these pathways are also involved in the pediatric age group and whether they may also serve as useful therapeutic targets for children with HGAs. Here we investigated the protein expression profile of a series of pediatric HGAs. Following institutional ethical approval, clinical information and tumor samples were obtained for 42 HGA patients. Mean age at presentation was 10.1 years (range 0.13–19.3 years). OS was 12% and PFS was 3.7%. Extent of resection was associated with improved PFS (P = 0.0015) with a trend towards improved OS (P = 0.08). There was no significant effect of age or adjuvant therapy use on PFS or OS. Immunopositivity for each of the markers was as follows: p53 35%; PDGFR-α 45%; PDGFR-β 31%; PTEN 67%; EGFR wild type 58%; EGFRvIII 2%. No significant effect on OS or PFS was found for any of the markers by log rank analysis. However, all long-term survivors expressed PTEN and were EGFRvIII negative. Further, there were distinct differences in protein expression between pediatric and adult HGAs suggesting that EGFR kinase inhibitors may not be beneficial for treatment of HGA in the pediatric age group and pointing to the need to study pediatric astrocytomas as distinct entities from adult astrocytomas.

Empyema associated with community-acquired pneumonia: A Pediatric Investigator's Collaborative Network on Infections in Canada (PICNIC) study

Abstract: Although the incidence of serious morbidity with childhood pneumonia has decreased over time, empyema as a complication of community-acquired pneumonia continues to be an important clinical problem. We reviewed the epidemiology and clinical management of empyema at 8 pediatric hospitals in a period before the widespread implementation of universal infant heptavalent pneumococcal vaccine programs in Canada. Health records for children < 18 years admitted from 1/1/00–31/12/03 were searched for ICD-9 code 510 or ICD-10 code J869 (Empyema). Empyema was defined as at least one of: thoracentesis with microbial growth from pleural fluid, or no pleural fluid growth but compatible chemistry or cell count, or radiologist diagnosis, or diagnosis at surgery. Patients with empyemas secondary to chest trauma, thoracic surgery or esophageal rupture were excluded. Data was retrieved using a standard form with a data dictionary. 251 children met inclusion criteria; 51.4% were male. Most children were previously healthy and those ≤ 5 years of age comprised 57% of the cases. The median length of hospitalization was 9 days. Admissions occurred in all months but peaked in winter. Oxygen supplementation was required in 77% of children, 75% had chest tube placement and 33% were admitted to an intensive care unit. While similarity in use of pain medication, antipyretics and antimicrobial use was observed, a wide variation in number of chest radiographs and invasive procedures (thoracentesis, placement of chest tubes) was observed between centers. The most common organism found in normally sterile samples (blood, pleural fluid, lung biopsy) was Streptococcus pneumoniae. Empyema occurs most commonly in children under five years and is associated with considerable morbidity. Variation in management by center was observed. Enhanced surveillance using molecular methods could improve diagnosis and public health planning, particularly with regard to the relationship between immunization programs and the epidemiology of empyema associated with community-acquired pneumonia in children.

SBDS-deficient cells undergo accelerated apoptosis through the Fas-pathway.

Abstract: Background Shwachman-Diamond syndrome is an inherited multisystem disorder characterized by bone marrow and pancreatic dysfunction as well as metaphyseal dysostosis. Ninety percent of the patients have mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS). The relationship between SBDS and cell survival is unknown. In this study we investigated whether deficiency of the SBDS protein can cause increased apoptosis and, if so, what pathways are involved in this process.Design and Methods To determine whether accelerated apoptosis of Shwachman-Diamond syndrome cells is caused by a deficiency in SBDS we generated two SBDS-knockdown cell clones. We then evaluated, Fas expression and levels of the intracellular proteins, BAX, BCL-2 and BCL-XL and determined the effects of apoptosis inhibitors. Using oligonucteotide-microarrays we also analyzed apoptosis-related gene expression in Shwachman-Diamond syndrome marrow cells.Results We found that knocking down SBDS by short interfering hairpin RNA in HeLa cells resulted in a prominent increase in cell death. The mechanism for the accelerated apoptosis was related to marked hypersensitivity to Fas stimulation, and increased Fas expression. In contrast, there was no increase in the expression ratio of the pro-apoptotic factor, BAX, to the pro-survival factors, BCL2 and BCL-XL in the SBDS-knockdown cells and in the patients’ marrow cells. Furthermore, inhibition of Fas and caspase 8, but not caspase 9, significantly improved the defective cell growth phenotype.Conclusions Our work provides new data about the pro-survival properties of SBDS, whose inhibition results in accelerated apoptosis through the Fas pathway.

Risk of hypospadias in offspring of women using loratadine during pregnancy: a systematic review and meta-analysis.

Abstract: Background: Loratadine, a second-generation antihistamine, is commonly used to treat seasonal allergies. Some studies have suggested that use of loratadine by pregnant women increases the risk of hypospadias in male offspring. Objective: This meta-analysis was designed to assess the strength of the association between loratadine and hypospadias. Methods: To locate pertinent articles published in any language from January 1989 until August 2007, we searched electronic databases (MEDLINE, OVID, EMBASE, SCOPUS, TOXLINE Special, ReproTox, TERIS, CINAHL and others), conference proceedings and bibliographies. Studies were eligible for this analysis if they were cohort, case-control or case series studies that reported the incidence of hypospadias in the offspring of women who were or were not exposed to loratadine during pregnancy. Two authors independently extracted information on study design, participant characteristics, measures of outcome, control for potential confounding factors and risk estimates using a standardized data collection form. The Newcastle-Ottawa Scale was then used to assess the quality of each study. We used a random-effects meta-analysis model to combine the risk data. Results: In 1402 potentially relevant titles, we found three case-control studies and seven cohort studies that reported the incidence of hypospadias or other congenital malformations in offspring of women who did or did not use loratadine during pregnancy. Together the studies in our meta-analysis provided information about 453 053 male births in Brazil, Canada, Denmark, Israel, Italy, Sweden, the UK and the US.

Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis

Abstract: Background Diamond-Blackfan anemia is a fatal congenital anemia characterized by a specific disruption in erythroid progenitor cell development. Approximately 25% of patients have mutations in the ribosomal protein RPS19 suggesting that Diamond-Blackfan anemia may be caused by a defect in ribosome biogenesis and translation. However, it is unclear how these defects specifically disrupt early erythropoiesis. Recent studies have shown that the retroviral receptor/heme exporter FLVCR1 is critical for early erythropoiesis. FLVCR1 null mice, despite dying in utero and having reduced myeloid and lymphoid cell growth, show a disruption in early erythropoiesis and have craniofacial and limb deformities similar to those found in some Diamond-Blackfan anemia patients.Design and Methods In this study, we recapitulated the Diamond-Blackfan anemia hematologic features of reduced erythropoiesis but normal myelopoiesis by disrupting FLVCR1 in human hematopoietic stem cells.Results We found that CD71high cells, which are enriched for immature erythroid cells, from Diamond-Blackfan anemia patients negative for RPS19 gene mutations express alternatively spliced isoforms of FLVCR1 transcript which encode proteins whose expression and function are disrupted. More importantly, our results suggest alternative splicing of FLVCR1 is significantly enhanced in Diamond-Blackfan anemia immature erythroid cells. Furthermore, we also observed enhanced FLVCR1 alternative splicing and a dramatic reduction of FLVCR1 protein expression in RPS19 down-regulated human K562 cells, which were used as a model to represent RPS19 gene mutated Diamond-Blackfan anemia.Conclusions Taken together, our results suggest enhanced alternative splicing of FLVCR1 transcripts and subsequent FLVCR1 insufficiency as an additional contributing factor to the erythropoietic defect observed in Diamond-Blackfan anemia.

Working out the kinks: testing the feasibility of an electronic pain diary for adolescents with arthritis

Abstract: BACKGROUND: Current approaches to evaluating pain in children with chronic arthritis suffer from methodological problems. A real-time data capture approach using electronic diaries has been proposed as a new standard for pain measurement. However, there is limited information available regarding the development and feasibility of this approach in children.

Quantification of redox conditions in the nucleus.

Abstract: Many nuclear proteins contain thiols, which undergo reversible oxida- tion and are critical for normal function. These proteins include enzymes, transport machinery, structural proteins, and transcription factors with conserved cysteine in zinc fingers and DNA-binding domains. Uncontrolled oxidation of these thiols causes dysfunction, and two major thiol-dependent antioxidant systems provided protection. The redox states of these systems, including the small redox active pro- tein thioredoxin-1 (Trx1) and the abundant, low molecular weight thiol antioxidant glutathione (GSH), in nuclei provide means to quantify nuclear redox conditions. Redox measurements are obtained under conditions with excess thiol-reactive rea- gents. Here we describe a suite of methods to measure nuclear redox state, which include a redox Western blot technique to quantify the redox state of Trx1, a bioti- nylated iodoacetamide (BIAM) method for thioredoxin reductase-1 (TrxR1), GSH redox measurement using total protein S-glutathionylation, and a redox isotope- coded affinity tag (ICAT) method for measuring oxidation of specific cysteines in high-abundance nuclear proteins.