Showing papers by "Hospital for Sick Children published in 2010"

Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry

Abstract: Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease-associated NOD2 frameshift mutation, mutant Nod2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.

The distribution and function of phosphatidylserine in cellular membranes.

Abstract: Phosphatidylserine (PS) is the most abundant negatively charged phospholipid in eukaryotic membranes. PS directs the binding of proteins that bear C2 or gamma-carboxyglutamic domains and contributes to the electrostatic association of polycationic ligands with cellular membranes. Rather than being evenly distributed, PS is found preferentially in the inner leaflet of the plasma membrane and in endocytic membranes. The loss of PS asymmetry is an early indicator of apoptosis and serves as a signal to initiate blood clotting. This review discusses the determinants and functional implications of the subcellular distribution and membrane topology of PS.

Whole-Genome Profiling of Pediatric Diffuse Intrinsic Pontine Gliomas Highlights Platelet-Derived Growth Factor Receptor α and Poly (ADP-ribose) Polymerase As Potential Therapeutic Targets

Abstract: Purpose Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of pediatric malignancies and one for which no effective therapy exists. A major contributor to the failure of therapeutic trials is the assumption that biologic properties of brainstem tumors in children are identical to cerebral high-grade gliomas of adults. A better understanding of the biology of DIPG itself is needed in order to develop agents targeted more specifically to these children’s disease. Herein, we address this lack of knowledge by performing the first high-resolution single nucleotide polymorphism (SNP) – based DNA microarray analysis of a series of DIPGs.

Perception of risk regarding the use of medications and other exposures during pregnancy.

Abstract: Background Perception of risk may impact a woman’s decision to take a needed drug during pregnancy. There is a paucity of research on this topic in the literature. Objectives (1) To evaluate the perception of risk of 17 commonly used drugs and other substances by pregnant women. (2) To investigate which sources of information regarding exposures during pregnancy were most commonly used by women. Methods A questionnaire was developed through the University of Oslo’s website for Internet surveys and posted on four Web pages used by pregnant women and mothers, from mid-September 2008 through October 2008. The inclusion criteria included women who were (1) pregnant or 2) a mother of a child less than 5 years old. Results A total of 1,793 eligible women completed the questionnaire. Most women overestimated the teratogenic risk associated with all the drugs during pregnancy. Characteristics of the women that were associated with a high perception of risk were primiparity, higher age, higher education, and choosing not to use a drug during pregnancy. More than 80% of the women had used drugs during pregnancy, mostly paracetamol, penicillins and reflux medications. The physician, the product information leaflet and the pharmacist were the three most frequently used sources of information. Conclusion Women overestimate the risk of drug use and other exposures during pregnancy. Therefore, it is important for health care providers to use evidence-based information, to reduce unnecessary anxiety, and to ensure safe and appropriate treatment during pregnancy.

The many roles of NOX2 NADPH oxidase-derived ROS in immunity

Abstract: Reactive oxygen species (ROS) have long been studied in the context of their direct toxic effects on cells. As a result, ROS have conventionally been thought of as a necessary nuisance to aerobic living. However, in recent years, much work has been done to examine the contribution of ROS to the field of immunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases were identified as one of the key sources of ROS in immune cells. The NOX2 NADPH oxidase in particular has been assigned multiple roles, functioning as a source of antimicrobial ROS, an activator of many signaling pathways, a participant in chemotaxis, an immune modulator, and a critical player in the initiation of antigen cross-presentation. Furthermore, recent studies have revealed a novel role for the NOX2 NADPH oxidase in the activation of autophagy, a cellular degradative pathway. Here, we examine these functions of NOX2 NADPH oxidase in immunity.

Telesimulation: an effective method for teaching the fundamentals of laparoscopic surgery in resource-restricted countries

Abstract: Several challenges exist with laparoscopic skills training in resource-restricted countries, including long travel distances required by mentors for onsite teaching. Telesimulation (TS) is a novel concept that uses the internet to link simulators between an instructor and a trainee in different locations. The purpose of this study was to determine the effectiveness of telesimulation for teaching the Fundamentals of Laparoscopic Surgery (FLS) to surgeons in Botswana, Africa. A total of 16 surgeons from two centers in Botswana participated in this 8-week study. FLS TS was set up using two simulators, computers, webcams, and Skype™ software for eight surgeons in the TS group. A standard FLS simulator was available for the eight surgeons in the self-practice (SP) group. Participants in the TS group had one remote training session per week with an FLS proctor at the University of Toronto who provided feedback and demonstrated proper technique. Participants in the SP group had access to the FLS DVD and were instructed to train on FLS at least once per week. FLS post-test scores were obtained in Botswana by a trained FLS proctor at the conclusion of the study. Participants in the TS group had significantly higher post-test FLS scores than those in the SP group (440 ± 56 vs. 272 ± 95, p = 0.001). All trainees in the TS group achieved an FLS simulator certification passing score, whereas only 38% in the SP group did so (p = 0.03). Remote telesimulation is an effective method for teaching the Fundamentals of Laparoscopic Surgery in Africa, achieving a 100% FLS skills pass rate. This training platform provides a cost-effective method of teaching in resource-restricted countries and could be used to teach laparoscopic skills anywhere in the world with internet access.

Functions of Notch Signaling in the Immune System: Consensus and Controversies

Abstract: Mammalian genomes encode up to four Notch receptors (Notch1–4) and five Notch ligands of the DSL (Delta/Serrate/Lag-2) family, and Notch signaling controls a wide spectrum of developmental processes. Intrathymic Notch1 signaling is essential for several distinct aspects of early T cell development. Notch signaling has also been implicated as a key regulator of peripheral T cell activation and effector cell differentiation, but its functions in these processes remain poorly understood. Notch signaling is dispensable for B cell development in the bone marrow, but it is required to generate the innate-like marginal zone B cell subset in the spleen and may also regulate plasma cell functions. Modification of Notch receptors by fringe glycosyltransferases influences many Notch-dependent aspects of hematopoiesis by altering Notch responsiveness to Delta-like versus Jagged DSL ligands. Here we review recent advances in general aspects of Notch signaling, as well as studies probing Notch functions in these immuno...

TP53 Alterations Determine Clinical Subgroups and Survival of Patients With Choroid Plexus Tumors

Abstract: Purpose Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic predictors, most children are treated with aggressive chemoradiation protocols. Patients and Methods We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. Highresolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 ( 9%), respectively (P .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy.

Assessment and management of hypertension in children and adolescents

Abstract: The epidemic of overweight and obesity in youth is increasing the prevalence of prehypertension and hypertension among children and adolescents. The younger the child is at presentation and the more severe the blood pressure abnormality, the more likely a secondary cause of hypertension is to be present. Measurement of blood pressure in children requires adaptation to the age and size of the child. Interpretation must be related to normative values specific for age, sex, and height. Evaluation is primarily aimed at identifying secondary causes of hypertension, associated comorbidities, additional risk factors, and evidence of target-organ damage. Ambulatory blood pressure monitoring is emerging as a useful tool for evaluation of some patients, particularly for those with suspected 'white coat' hypertension. Management of prehypertension and hypertension is directed at the underlying cause, exacerbating factors, and the magnitude of the blood pressure abnormality. Healthy behavioral changes are a primary management tool for treating hypertension and, more particularly, prehypertension and for addressing other cardiovascular risk factors, such as obesity. Pharmacological management is reserved for patients with hypertension who do not respond to behavioral changes, have additional cardiovascular risk factors or diabetes, are symptomatic, or have developed target-organ damage.

Quantitative magnetization transfer and myelin water imaging of the evolution of acute multiple sclerosis lesions

Abstract: Quantitative magnetization transfer imaging provides in vivo estimates of liquid and semisolid constituents of tissue, while estimates of the liquid subpopulations, including myelin water, can be obtained from multicomponent T(2) analysis. Both methods have been suggested to provide improved myelin specificity compared to conventional MRI. The goal of this study was to investigate the sensitivity of each technique to the progression of acute, gadolinium-enhancing regions of multiple sclerosis. Magnetization transfer and T(2) relaxometry data were acquired longitudinally over the course of 1 year in five relapsing-remitting multiple sclerosis patients and in five healthy controls. Parametric maps were analyzed in enhancing lesions and normal-appearing white matter regions. Quantitative magnetization transfer parameters in lesions were most abnormal at the time of enhancement and followed a pattern of recovery over subsequent months. Lesion myelin water fraction was abnormal but did not show a significant trend over time. Quantitative magnetization transfer was able to track the degree and timing of the partial recovery in enhancing multiple sclerosis lesions in a small group of patients, while the recovery was not detected in myelin water estimates, possibly due to their large variability. Our data suggest the recovery is characterized by quick resolution of inflammation and a slower remyelination process.

Efficacy of sweet solutions for analgesia in infants between 1 and 12 months of age: a systematic review

Abstract: Objective To compare the efficacy of oral sweet solutions to water or no treatment in infants aged 1–12 months during immunisation. Methods Randomised controlled trials (RCTs) were retrieved through internet searches or manual searches of reference lists. Search terms included newborn, infant, pain, sucrose and alternative names for sweet solutions. Summary estimates with 95% CIs were calculated and included relative risk (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, and weighted mean differences (WMD) for continuous outcomes. Where pooling of results was not possible, a narrative summary of study results is presented. Results Of the 695 studies identified, 14 RCTs with 1674 injections met the inclusion criteria. Sucrose or glucose, compared to water or no treatment decreased crying during or following immunisation in 13 of the 14 studies. Infants receiving 30% glucose (three trials, 243 infants) had a decreased RR in crying incidence following immunisation (typical RR 0.80, 95% CI 0.69 to 0.93; RD −0.17, 95% CI −0.29 to −0.05; NNTB 6, 95% CI 3 to 20). With sucrose or glucose, there was a 10% WMD reduction in proportion of crying time (95% CI −18 to −2) and a 12 s reduction in crying duration (95% CI −23 to −0.7 s). An optimal dose of sucrose or glucose could not be ascertained due to the varied volumes and concentrations used. Conclusion Infants aged 1–12 months administered sucrose or glucose before immunisation had moderately reduced incidence and duration of crying. Healthcare professionals should consider using sucrose or glucose before and during immunisation.

Thyroid cancer in childhood: a retrospective review of childhood course.

Abstract: Background: Thyroid cancer (TC) is an uncommon childhood malignancy, but the incidence may be increasing. Recent American Thyroid Association guidelines focus primarily on adult data. Natural histo...

Muscle insulin resistance: assault by lipids, cytokines and local macrophages.

Abstract: Purpose of reviewThe present review outlines possible mechanisms by which high fatty acids, associated with high-fat diet and obesity, impose insulin resistance on glucose uptake into skeletal muscle.Recent findingsIt is well established that muscle insulin resistance arises in conditions of high-fa

[Crohn's disease].

Abstract: Introduction Conversation with Burrill B. Crohn, Leon Ginzburg, and Gordon Oppenheimer 63 Years after the Discovery of Crohn's Disease, Henry D. Janowitz Causes and Mechanisms, Jeffry A. Katz and Claudio Fiocchi Commentary, Derek Jewell Epidemiology of Crohn's Disease, Anders Ekbom Commentary, Robert S. Sandler Consideration of Smoking in Patients with Crohn's Disease, Bret A. Lashner Evaluation of the Patient Pathology and Pathophysiology of Symptoms, William J. Tremaine Commentary, Sidney F. Phillips Endoscopic Evaluation, Geert D'Haens and Paul Rutgeerts The Role of Contrast Barium X-Rays vs. Endoscopy, Burton I. Korelitz Commentary, Robert Modigliani Cross-Sectional Imaging in the Evaluation of Crohn's Disease, Richard M. Gore, Gary G. Ghahremani, and Frank H. Miller Commentary, Daniel Maklansky Proposed Measures of Disease Activity: How Useful Are They?, Cosimo Prantera and Anna Kohn Commentary, John W. Singleton Different Patterns of Crohn's Disease, Lloyd R. Sutherland Commentary, David B. Sachar General Therapeutic Approach Immunosuppressive Therapy of Crohn's Disease: A Historical Perspective, Burton I. Korelitz Treatment of Active Crohn's Disease with Salazopyrine and Derivatives of Aminosalicylic Acid (5-ASA), Cosimo Prantera, Maria Lia Scribano, and Eva Berto The Role of Steroids in the Management of Crohn's Disease, Burton I. Korelitz Clinical Picture of Crohn's Disease: Upper Gastrointestinal Tract, Adrian J. Greenstein and James Aisenberg Clinical Picture of Crohn's Disease: Lower Intestinal Tract, Norman Sohn Commentary, John Alexander-Williams Special Situations Prevention of Relapse and Recurrence, Cosimo Prantera and Arnaldo Andreoli, Commentary, David B. Sachar Nutrition and Special Diets, John E. Lennard-Jones Commentary, Arthur D. Heller Crohn's Disease in Childhood and Adolescence, Jay A. Barth and Richard J. Grand Commentary, Frederic Daum Crohn's Disease in the Elderly, Geetanjali A. Akerkar and Mark A. Peppercorn Commentary, Nadir Arber and Peter R. Holt Refractory Crohn's Disease, Stephen B. Hanauer Commentary, Theodore M. Bayless The Role of Antibiotics in Crohn's Disease, Peter S. Margolis and Walter R. Thayer, Jr. Commentary, Cosimo Prantera Pregnancy and Fertility in Crohn's Disease, Daniel H. Present Commentary, Robert Burakoff Psychosocial Issues in Crohn's Disease, Susan Levenstein Quality of Life Issues in Crohn's Disease, Douglas A. Drossman Commentary, Barbara S. Kirschner The Psychiatric Treatment of Patients with Crohn's Disease, Marvin Kaplan Commentary, Barbara S. Kirschner Extraintestinal Manifestations, Andrew S. Warner and Richard P. MacDermott Commentary The Systemic Nature of Inflammatory Bowel Disease, Lloyd Mayer Liver Complications, Harvey M. Lieberman Commentary, Nicholas F. LaRusso Malignancy in Crohn's Disease, Paul M. Choi Commentary, Burton I. Korelitz Ileal Pouch in Crohn's Disease, R. John Nicholls The Effects of Nonsteroidal Anti-Inflammatory Drugs on Crohn's Disease, Joseph B. Felder Commentary, Burton I. Korelitz Medical Therapy of Crohn's Disease: Obsolete or Unproven Approaches, Samuel Meyers The Experience of Crohn's Disease: Is the Bed Now a Table?, Howard M. Spiro The Future of Crohn's Disease: New Developments in Etiopathogenesis and Therapeutics, Maria T. Abreu and Stephan R. Targan

Human growth hormone and glutamine for patients with short bowel syndrome.

Abstract: Background There has been clinical enthusiasm for treating short bowel patients with human recombinant growth hormone and/or glutamine in hopes of reducing parenteral nutrition dependency. It has been more than a decade since Byrne and colleagues reported enhanced absorption of nutrients, improved weight gain, and reduction in parenteral nutrition requirements with the administration of a combination of human growth hormone (HGH) and glutamine in patients with short bowel syndrome. Other studies have reported inconsistent results. Objectives The purpose of this systematic review was to evaluate the efficacy of growth hormone with or without glutamine supplementation for adult patients with short bowel syndrome. Search methods Electronic searches were performed to identify all publications describing randomised controlled trials of the use of human growth hormone with or without glutamine for the treatment of patients with short bowel syndrome. Selection criteria Randomised controlled trials of human growth hormone with or without glutamine for patients with short bowel syndrome were considered for inclusion. Data collection and analysis Two authors independently extracted data from the published studies. The statistical analyses were performed using RevMan 5 software. Follmann's method was used for cross-over studies. Main results Five studies were included in the review. Human growth hormone with or without glutamine appears to provide benefit in terms of increased weight (MD 1.66 Kg; 95% CI 0.69 to 2.63;P = 0.0008), lean body mass (MD 1.93 Kg; 95% CI 0.97 to 2.90; P = 0.0001) energy absorption (MD 4.42 Kcal; 95% CI 0.26 to 8.58; P = 0.04) and nitrogen absorption (MD 44.85 g; 95%CI 0.20 to 9.49; P = 0.04) for patients with short bowel syndrome. The single RCT that focused on parenteral nutrition (PN) requirements demonstrated decreased PN volume and calories and number of infusions in patients who received HGH with or without glutamine supplementation. Only patients who received HGH with glutamine maintained statistically significant PN reductions at 3 month follow-up. Authors' conclusions The results suggest a positive effect of human growth hormone on weight gain and energy absorption. However, in the majority of trials, the effects are short-lived returning to baseline shortly after cessation of therapy. The temporary benefit calls into question the clinical utility of this treatment. To date, the evidence is inconclusive to recommend this therapy. Consideration should be made to studying patients during the active phase of intestinal adaptation rather than in the setting of chronic intestinal failure. The role of HGH in paediatric short bowel syndrome remains unknown.

Transition from pediatric to adult diabetes care: smooth or slippery?

Abstract: de Beaufort C, Jarosz-Chobot P, Frank M, Frank M, de Bart J, Deja G. Transition from pediatric to adult diabetes care: smooth or slippery? Objectives: The purpose of this study is to evaluate the practices of diabetes health care providers concerning the transition from pediatric to adult diabetes care. The information presented here may help increase awareness of the organization of transitional care for young people with diabetes and prevent the loss of follow-up during this vulnerable period in their lives. Methods: A questionnaire with an explanatory letter was sent to all members (n = 578) of the International Society for Pediatric and Adolescent Diabetes (ISPAD). A follow-up mailing was sent 4 months later. Results: In total, 92 questionnaires (16%) from members representing 36 countries were included in the analysis. In 76% of the centers, youth are seen until the age of 18 yr; 36% of the pediatric centers see adults > 25 yr; 30% report children under the age of 16 receive follow up from adult diabetologists or internists. About half of the programs already have a structured transition process usually targeting youth 16–25 yr of age. The majority of responders propose that preparation for transition starts at least 1 yr prior to leaving the pediatric center. Conclusion: Youth with type 1 diabetes often struggle to keep diabetes management a priority and find it challenging to maintain optimal metabolic control. When they graduate from pediatric care, some of these young people opt out of care altogether, only to resurface in the medical system when they develop complications which may have been prevented. Our survey of diabetes health care professionals in 36 countries worldwide shows that the actual transition practices in many places are far from optimal and require improvement. Transitional care should start early and strategies should promote uninterrupted, comprehensive, and accessible adult care.

Predicting factors for the follow-up outcome and management decisions in vein of Galen aneurysmal malformations

Abstract: Vein of Galen aneurysmal malformations (VGAMs) are choroidal arteriovenous malformations that develop during an early embryonic stage Although recent reports have shown improved outcome for these patients, the overall outcome still is poor In this study, we evaluated the clinical, imaging, and angiographic features that may predict the outcome in VGAM patients Twenty-five patients diagnosed with VGAM were reviewed for clinical symptoms, including neonatal scoring systems, imaging findings, angioarchitecture, treatment decision, initial treatment age, follow-up timing, and follow-up outcome Factors that were significantly associated with a poor outcome (p < 005) included neurological symptoms at presentation, a medium-to-low overall neonatal score (<12/21), a very poor score (<2/5) in one (or more) categories, focal parenchymal changes, calcifications, tonsillar herniation, arterial steal, or more than two groups of multiple arterial feeders The venous drainage pattern and treatment age were not significantly associated with the overall outcome The presence of multiple factors that are related with poor outcome may warrant withholding aggressive treatment, while a small subgroup of carefully selected patients without any of these factors who are clinically asymptomatic may have a good outcome even with conservative management and close follow-up For all other patients in which treatment is considered, the optimal treatment time is at 4–5 months of age; however, urgent treatment, regardless of age, should be indicated in those that do not have permanent brain damage on imaging with deteriorating congestive heart failure, evidence of arterial steal, or progressive occlusion of the venous outflow

The Genetics of Pediatric Brain Tumors

Abstract: Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors.

Long-term neurodevelopment of children exposed in utero to ciclosporin after maternal renal transplant.

Abstract: Background: Immunosuppressant therapy is essential in the prevention of organ transplant rejection.

Cross-cultural adaptation of the dysfunctional voiding score symptom (DVSS) questionnaire for Brazilian children

Abstract: Purpose: To translate and culturally adapt the Dysfunctional Voiding Symptom Score (DVSS), questionnaire into Brazilian Portuguese. Materials and Methods: The 10-item Dysfunctional Voiding Symptom Score (DVSS) was translated into Brazilian Portuguese according to a standard methodology: translation, synthesis, back-translation, Expert Committee, and pre-testing. After the translation process the final version was pre-tested and patient responses were analyzed to identify necessary modifications. Reliability was evaluated using the test-retest method, and internal consistency was assessed using Cronbach’s alpha. Results: The Cronbach’s alpha coefficient was calculated in the test and retest phases. Internal consistency was found to be satisfactory, as confirmed by a Cronbach’s alpha coefficient of 0.76 for the test and 0.77 for the retest. A high degree of stability was found in the test/retest, with an intraclass correlation coefficient (ICC) of 0.960 (p < 0.001; 95% CI: 0.9430.972). Conclusions: The cross-cultural adaptation process of the Dysfunctional Voiding Symptom Score questionnaire to be used on Brazilian children was successfully completed following internationally accepted methodologies.

A Chemical Corrector Modifies the Channel Function of F508del-CFTR

Abstract: The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27°C) temperature. Chemical “correctors” have been identified that are also effective in rescuing the biosynthetic defect in F508del-CFTR, thereby permitting its functional expression at the cell surface. The mechanism of action of chemical correctors remains unclear, but it has been suggested that certain correctors [including 4-cyclohexyloxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-325)] may act to promote trafficking by interacting directly with the mutant protein. To test this hypothesis, we assessed the effect of VRT-325 addition on the channel activity of F508del-CFTR after its surface expression had been “rescued” by low temperature. It is noteworthy that short-term pretreatment with VRT-325 [but not with an inactive analog, 4-hydroxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-186)], caused a modest but significant inhibition of cAMP-mediated halide flux. Furthermore, VRT-325 decreased the apparent ATP affinity of purified and reconstituted F508del-CFTR in our ATPase activity assay, an effect that may account for the decrease in channel activity by temperature-rescued F508del-CFTR. These findings suggest that biosynthetic rescue mediated by VRT-325 may be conferred (at least in part) by direct modification of the structure of the mutant protein, leading to a decrease in its ATP-dependent conformational dynamics. Therefore, the challenge for therapy discovery will be the design of small molecules that bind to promote biosynthetic maturation of the major mutant without compromising its activity in vivo.

Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I

Abstract: Scheie syndrome is the most attenuated and rarest form of mucopolysaccharidosis type I (MPS I), an inherited lysosomal storage disorder. Only small patient series have previously been reported. Using natural history data from the uniquely large population of 78 Scheie patients enrolled in the MPS I Registry, we characterized the onset and prevalence of clinical manifestations and explored reasons for delayed diagnosis of the disease. Median patient age was 17.5 years; 46% of the patients were male, and 88% were Caucasian. Of 25 MPS I-related clinical features, cardiac valve abnormalities, joint contractures, and corneal clouding were each reported by >80% and all three by 53% of patients. Carpal tunnel syndrome, hernia, coarse facial features, and hepatomegaly were each reported by >50% of patients. Age at onset of the clinical features varied widely between individuals, but the median age at onset was 3 years for hernia and between 5 and 12 years for most features, including coarse facial features, hepatomegaly, joint contractures, bone deformities, cardiac valve abnormalities, cognitive impairment, and corneal clouding. Carpal tunnel syndrome, cardiomyopathy, and myelopathy arose more commonly during adolescence or adulthood. Delays up to 47 years intervened between symptom onset and disease diagnosis, and the longest delays were associated with later age at symptom onset and symptom onset before 1980. In summary, Scheie syndrome usually emerges during childhood, and recognition of attenuated MPS I requires awareness of the multisystemic disease manifestations and their diverse presentation. Given the availability of etiologic treatment, prompt diagnosis is important.

Renin-angiotensin blockade is associated with increased mortality after vascular surgery

Abstract: The outcome of patients with preoperative renin-angiotensin system (RAS) blockade, achieved either by angiotensin converting enzyme inhibitors or angiotensin receptor blocking agents, was assessed using 30-day mortality as a primary end point An observational cohort study of 883 consecutive patients undergoing elective open abdominal aortic aneurysm repair (AAA) was undertaken and analyzed using a propensity score matched study The data collected included medical history, anesthetic techniques, and postoperative outcomes Logistic regression analysis identified predictors of RAS blockade: hypertension, stroke, congestive heart failure, diabetes, and heart disease A propensity score for RAS blockade was calculated for each subject using several factors: age, sex, serum creatinine, hypertension, heart disease, congestive heart failure, stroke, diabetes, and exposure to cardiovascular medications Subjects and controls were matched using the calculated propensity score The overall 30-day mortality rate was 35% (31/883 patients) The crude mortality rate in RAS blocked patients was 58% (21/359) vs 19% (10/524) in unexposed patients (odds ratio 32, with 95% confidence intervals [CI95] 15-67; P < 0001) Analysis of 261 propensity score matched pairs showed a 30-day mortality rate of 61% (16/261) in the RAS blocked group vs 15% (4/261) in unblocked patients (P = 0008) The estimated odds ratio for 30-day mortality associated with RAS blockade was 50 (CI95 14-27) Examination of 883 cases of AAA repair showed increased mortality associated with preoperative RAS blockade A better understanding of perioperative pharmacology and physiology of RAS blockade is needed as well as future studies to identify causality

Milrinone for persistent pulmonary hypertension of the newborn

Abstract: Background Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by suboptimal oxygenation as a result of sustained elevation in pulmonary vascular resistance after birth Currently, the therapeutic mainstay for PPHN is optimal lung inflation and selective vasodilatation with inhaled nitric oxide (iNO) However, iNO is not available in all countries and not all infants will respond to iNO Milrinone is a phosphodiesterase III inhibitor which induces pulmonary vasodilatation by its actions through a cyclic adenylate monophosphate mediated signaling pathway Objectives To assess efficacy and safety in infants with PPHN either treated with: milrinone compared with placebo or no treatment; milrinone compared with iNO; milrinone as an adjunct to iNO compared with iNO alone; milrinone compared with potential treatments for PPHN other than iNO Search methods We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE and EMBASE databases from their inception until January 2010 We searched the reference lists of potentially relevant studies without any language restriction Selection criteria Fully published randomized controlled trials (RCTs) and quasi-RCTs comparing milrinone with placebo, iNO or potential treatments other than iNO in neonates with PPHN were included if trials reported any clinical outcome Data collection and analysis We found no studies meeting the criteria for inclusion in this review Main results We found no studies meeting the criteria for inclusion in this review Authors' conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or, in well resourced countries, should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone

Magnetic resonance imaging of inflammatory and demyelinating white-matter diseases of childhood

Abstract: Magnetic resonance imaging (MRI) was performed on 36 children and two adults (with clinical presentation during childhood) with white-matter disease of the central nervous system. Abnormalities were readily demonstrated in patients with multiple sclerosis, acute disseminated encephalomyelitis, leucodystrophies and subacute sclerosing panencephalitis: MRI demonstrated the extent and distribution of abnormalities more clearly than computed tomography for all these disorders. The abnormalities tended to be asymmetrical and multifocal in multiple sclerosis and acute disseminated encephalomyelitis, and more confluent and symmetrical in the leucodystrophies. Children with clinically isolated optic neuritis had a significantly lower frequency of MRI brain-lesions than adults with the same disorder. MRI should be regarded as the radiological investigation of choice when white-matter disease is suspected in children.