Colin D. Gause

Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: A pregnant dam mouse model.

A pregnant mouse model was used to compare the effect of IgG, administered E13-E18, from mothers of children with autistic disorder (MCAD), to controls (simple- and IgG-) on behavioral testing in offspring. Mice, exposed in-utero to MCAD-IgG, as adolescents, were more active during the first ten minutes of central field novelty testing and, as adults, displayed anxiety-like behavior on a component of the elevated plus maze and had a greater magnitude of startle following acoustic stimulation. On a social interaction paradigm, adult mice had alterations of sociability. Pilot studies of immune markers in MCAD IgG-exposed embryonic brains suggest evidence of cytokine and glial activation. These studies demonstrate that the transplacental passage of IgG from MCAD is capable of inducing long-term behavioral consequences.

Frontal dopaminergic abnormality in Tourette syndrome: A postmortem analysis

Frontal-subcortical abnormalities have been implicated in the pathophysiology of Tourette syndrome (TS). The goal of this study was to more extensively evaluate a possible underlying neurochemical abnormality in frontal cortex. Postmortem brain tissue from frontal and occipital regions (Brodmanns areas 4, 6, 9, 10, 11, 12, and 17) from three TS patients and three age-and sex-matched controls were analyzed by semiquantitative immunoblotting. Relative densities were measured for a variety of neurochemical markers including dopamine (D1, D2), serotonin (5HT-1A), and alpha-adrenergic (alpha-2A) receptors, the dopamine transporter (DAT), a monoamine terminal marker (vesicular monoamine transporter type 2, VMAT-2), and vesicular docking and release proteins (VAMP-2, synaptotagmin, SNAP-25, syntaxin, synaptophysin). Data from each TS sample, corrected for actin content, was expressed as a percentage value of its control. Results identified consistent increases of DAT and D2 receptor density in five of six frontal regions in all three TS subjects. D1 and alpha-2A receptor density were increased in a few frontal regions. These results support the hypothesis of a dopaminergic dysfunction in the frontal lobe and a likely role in the pathophysiology of TS.

Serial Immune Markers Do Not Correlate With Clinical Exacerbations in Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

OBJECTIVE. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is hypothesized to be a poststreptococcal autoimmune disorder. If clinical exacerbations are triggered by a streptococcal infection that activates cross-reacting antibodies against neuronal tissue or alters the production of cytokines, then a longitudinal analysis would be expected to identify a correlation between clinical symptoms and a change in autoimmune markers. PATIENTS AND METHODS. Serial serum samples were available on 12 children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections participating in a prospective blinded study: 2 samples before an exacerbation point, 1 during the clinical exacerbation, and 2 after the exacerbation. Six subjects had a well-defined clinical exacerbation in association with a documented streptococcal infection, and 6 had a clinical exacerbation without an associated streptococcal infection. All of the serum samples were assayed for antibodies against human postmortem caudate, putamen, and prefrontal cortex; commercially prepared antigens; and complex sugars. Cytokines were measured by 2 different methodologies. RESULTS. No correlation was identified between clinical exacerbations and autoimmune markers, including: enzyme-linked immunosorbent assay measures of antineuronal antibodies; Western immunoblotting with emphasis on brain region proteins located at 40, 45, and 60 kDa or their corresponding identified antigens; competitive inhibition enzyme-linked immunosorbent assay to evaluate lysoganglioside GM1 antibodies; and measures of inflammatory cytokines. No differences were identified between individuals with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections with or without exacerbations triggered by streptococcal infections. CONCLUSIONS. The failure of immune markers to correlate with clinical exacerbations in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections raises serious concerns about the viability of autoimmunity as a pathophysiological mechanism in this disorder.

Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls

PANDAS and some cases of Tourette syndrome (TS) have been proposed to be post-streptococcal movement disorders in which antibodies produced against group A beta-hemolytic streptococcus cross react against brain epitopes. Attempts to identify disease specific anti-striatal antibodies in the serum of affected patients have focused on the use of Western immunoblotting and ELISA methodologies. In this study, immunohistochemical techniques were used to identify serum anti-striatal antibody reactivity. In positive samples, double staining with anti-GFAP (glial) and anti-MAP2 (neuronal) was used to establish localization of the immunofluorescence. No significant differences in immunofluorescence or localization were identified in patients with PANDAS (n=30) and TS (n=30) as compared to controls (n=30). IF reactivity did not correlate with tic severity or elevated titers of antistreptococcal antibodies. Further comparisons showed no correlation between autoreactivity determined by immunofluorescence and the presence of previously measured immunoblot reactivity against human caudate or putative antigens (pyruvate kinase M1 and aldolase C). These results confirm an inability to distinguish patient populations by antibody measurements and raise further concerns about the presence of an autoimmune mechanism in PANDAS and TS.

Antineuronal antibodies in OCD: comparisons in children with OCD-only, OCD+chronic tics and OCD+PANDAS.

Autoimmunity associated with a streptococcal infection has been proposed as a pathogenic mechanism for obsessive-compulsive disorder (OCD) in children. Antibrain antibody profiles were compared in children with OCD-only (n = 13; 14.1 +/- 3.1 years), OCD+PANDAS (n = 20; 11.3 +/- 1.5 years), OCD+Chronic Tic Disorder (n = 23; 13.4 +/- 3.5 years), and controls (n = 29; 12.4 +/- 2.4 years) using ELISA (orbitofrontal (OFC) and dorsolateral prefrontal cortex (DLPFC), caudate (CD), cingulate gyrus (CG)), immunoblotting (four regions plus putative antigens), and immunohistochemistry. ELISA and immunohistochemistry showed no differences among groups. Immunoblot showed that a greater percentage of individuals in the OCD+PANDAS cohort had reactive bands at 27 kDa (CD, CG, DLPFC), 36 kDa (CD), and 100 kDa (CD, OFC) and increased peak height at 67 kDa (all regions). Immunoblotting studies using the putative antigens (pyruvate kinase M1, aldolase C, alpha- and gamma-enolase) did not differ among groups. ASO titers were similar in all groups and did not correlate with immunoassays. It remains controversial whether childhood OCD is associated with autoimmune mechanisms.

Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome

Objective Abnormalities in neurotransmission within the cortico-striatal-thalamo-cortical circuitry are implicated in the pathogenesis of Tourette syndrome. Glutamate is a major excitatory neurotransmitter and an important member in the cortico-striatal-thalamo-cortical circuitry. To explore the role of glutamatergic neurotransmission in genetic susceptibility of Tourette syndrome, we carried out the genetic and functional characterization of sequence variants in SLC1A3 gene, which encodes the main glutamate transporter in astrocytes in individuals with well-characterized Tourette syndrome (n=256) and normal controls (n=224). Methods Exon-containing regions of SLC1A3 gene were screened using capillary electrophoresis-single strand conformation polymorphism followed by direct sequencing. Sequence variants were genotyped by restriction enzyme digestion and studied using glutamate uptake assay and membrane protein pull-down for transporter function. Results A missense variant involving a highly conserved residue, E219D, was identified in 11 heterozygous individuals with Tourette syndrome and four in the controls. The allele frequency for E219D was 2.4 folds higher in the Tourette syndrome (0.022) compared with the control cohort (0.009) although the difference did not reach statistical significance in the current cohorts (P=0.09). A 3H-glutamate-uptake assay showed that E219D conveys a significant increase (1.66 fold) in the SLC1A3-mediated glutamate uptake in HEK293 cells. A biotin-mediated membrane pull-down analysis showed a similar increase (1.5 fold) of mutant SLC1A3 protein in the membrane fraction of transfected HEK293 cells compared with that in the wild type controls. Conclusion These results indicate that E219D is a functional SLC1A3 variant that is presented in a small number of individuals with Tourette syndrome. Further studies on possible changes in glutamate transport in the pathogenesis of Tourette syndrome are warranted.

Regionalization of Pediatric Surgery: Trends Already Underway

Introduction:This study aims to characterize the delivery of pediatric surgical care based on hospital volume stratified by disease severity, geography, and specialty. Longitudinal regionalization over the 10-year study period is noted and further explored. Methods:The Kids’ Inpatient Database (KID) was queried from 2000 to 2009 for patients <18 years undergoing noncardiac surgery. Hospitals nationwide were grouped into commutable regions and identified as high-volume centers (HVCs) if they had more than 1000 weighted procedures per year. Regions that had at least one HVC and one or more additional lower volume center were included for analysis. Low-risk, high-risk neonatal, and surgical subspecialties were analyzed separately. Results:A total of 385,242 weighted pediatric surgical admissions in 33 geographical regions and 224 hospitals were analyzed. Overall, HVCs comprised 33 (14.7%) hospitals, medium-volume center (MVC) 33 (14.7%), and low-volume center (LVC) 158 (70.5%). The four low-risk procedures analyzed were increasingly regionalized: appendectomy (52% in HVCs in 2000 to 60% in 2009, P < 0.001), fracture reduction (63% to 68%, P < 0.001), cholecystectomy (54% to 63%, P < 0.001), and pyloromyotomy (65% to 85%, P < 0.001). Neonatal surgery showed significant regionalization trends for tracheoesophageal fistula (66% to 87%, P < 0.001) and gastroschisis (76% to 89%, P < 0.001). Conclusions:This is the first large-scale, multi-region analysis to demonstrate that pediatric surgical care has transitioned to HVCs over a recent decade, particularly for low-risk patients. It is important for practitioners and policymakers alike to understand such volume trends in order to ensure hospital capacity while maintaining an optimal quality of care.

The impact of obesity on laparoscopic appendectomy: Results from the ACS National Surgical Quality Improvement Program pediatric database

BACKGROUND Childhood obesity is a worsening epidemic. Little is known about the impact of elevated BMI on perioperative and postoperative complications in children who undergo laparoscopic surgery. The purpose of this study was to examine the effects of obesity on surgical outcomes in children using laparoscopic appendectomy as a model for the broader field of laparoscopic surgery. STUDY DESIGN Using the Pediatric National Surgical Quality Improvement Program (NSQIP) data from 2012, patients aged 2-18years old with acute uncomplicated and complicated appendicitis who underwent laparoscopic appendectomy were identified. Children with a body mass index (BMI)≥95th percentile for their age and gender were considered obese. Primary outcomes, including overall morbidity and wound complications, were compared between nonobese and obese children. Multivariate regression analysis was conducted to identify the impact of obesity on outcome. RESULTS A total of 2812 children with acute appendicitis who underwent appendectomy were included in the analysis; 22% were obese. Obese children had longer operative times but did not suffer increased postoperative complications when controlling for confounders (OR 1.3, 95% CI: 0.83-0.072 for overall complications, OR 1.3, 95% CI: 0.84-1.95 for wound complications). CONCLUSIONS Obesity is not an independent risk factor for postoperative complications following laparoscopic appendectomy. Although operative times are increased in obese children, obesity does not increase the likelihood of 30-day postoperative complications.

Patient Satisfaction After Minimally Invasive Repair of Pectus Excavatum in Adults: Long-Term Results of Nuss Procedure in Adults

BACKGROUND Extensive literature has proved that the Nuss procedure leads to permanent remodeling of the chest wall in pediatric patients with pectus excavatum (PE). However, limited long-term follow-up data are available for adults. Herein, we report a single-institution experience in the management of adult PE with the Nuss procedure, evaluating long-term outcomes and overall patient satisfaction after bar removal. METHODS Adult patients who underwent PE repair with a modified Nuss procedure between January 1998 and June 2011 were retrospectively identified. Outcomes of interest were postoperative pain, recurrence, and patient satisfaction. A modified single-step Nuss questionnaire was administered to evaluate patient satisfaction and quality-of-life improvement after PE repair. RESULTS Ninety-eight patients with a median age of 30.9 years (range, 21.8 to 55.1 years) at the time of repair were identified. One bar was placed in most patients (89.7%). Four patients (4.1%) required reoperation for bar displacement. Results after bar removal were overall satisfactory in 94.4% of patients; 2 patients required reoperation for recurrence. Thirty-nine patients participated in the survey. Satisfaction with chest appearance was reported by 89.7% of responders. Seven patients reported dissatisfaction with the overall results; the most common complaints were severe postoperative chest pain and dissatisfaction with surgical scars. CONCLUSIONS Favorable long-term results can be achieved with the Nuss procedure in adults. However, postoperative pain may require a more aggressive analgesic regimen, and it may be the overriding factor in the patients perception of the quality of the postoperative course.

Advances in Pediatric Surgical Education: A Critical Appraisal of Two Consecutive Minimally Invasive Pediatric Surgery Training Courses

BACKGROUND Mandates for improved patient safety and increasing work hour restrictions have resulted in changes in surgical education. Educational courses increasingly must meet those needs. We sought to determine the experience, skill level, and the impact of simulation-based education (SBE) on two cohorts of pediatric surgery trainees. MATERIALS AND METHODS After Institutional Review Board (IRB) exempt determination, a retrospective review was performed of evaluations for an annual advanced minimally invasive surgery (MIS) course over 2 consecutive years. The courses included didactic content and hands-on skills training. Simulation included neonatal/infant models for rigid bronchoscopy-airway foreign body retrieval, laparoscopic common bile duct exploration, and real tissue diaphragmatic hernia (DH), duodenal atresia (DA), pulmonary lobectomy, and tracheoesophageal fistula models. Categorical data were analyzed with chi-squared analyses with t-tests for continuous data. RESULTS Participants had limited prior advanced neonatal MIS experience, with 1.95 ± 2.84 and 1.16 ± 1.54 prior cases in the 2014 and 2015 cohorts, respectively. The 2015 cohort had significantly less previous experience in lobectomy (P = .04) and overall advanced MIS (P = .007). Before both courses, a significant percentage of participants were not comfortable with DH repair (39%-42%), DA repair (50%-74%), lobectomy (34%-43%), and tracheoesophageal fistula repair (54%-81%). After course completion, > 60% of participants reported improvement in comfort with procedures and over 90% reported that the course significantly improved their perceived ability to perform each operation safely. CONCLUSION Pediatric surgery trainees continue to have limited exposure to advanced MIS during clinical training. SBE results in significant improvement in both cognitive knowledge and trainee comfort with safe operative techniques for advanced MIS.