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The targeting of natural tolerogenic liver sinusoidal endothelial cells (LSEC) by nanoparticles (NPs), decorated with a stabilin receptor ligand, is capable of generating regulatory T-cells (Tregs), which can suppress antigen-specific immune responses, including to ovalbumin (OVA), a possible food allergen. In this regard, we have previously demonstrated that OVA-encapsulating poly(lactic-co-glycolic acid) (PLGA) nanoparticles eliminate allergic airway inflammation in OVA-sensitized mice, prophylactically and therapeutically. A competing approach is a nanocarrier platform that incorporates pharmaceutical agents interfering in mTOR (rapamycin) or NF-κB (curcumin) pathways, with the ability to induce a tolerogenic state in nontargeted antigen-presenting cells system-wide. First, we compared OVA-encapsulating, LSEC-targeting tolerogenic nanoparticles (TNPs) with nontargeted NPs incorporating curcumin and rapamycin (Rapa) in a murine eosinophilic airway inflammation model, which is Treg-sensitive. This demonstrated roughly similar tolerogenic effects on allergic airway inflammation by stabilin-targeting NPOVA versus nontargeted NPs delivering OVA plus Rapa. Reduction in eosinophilic inflammation and TH2-mediated immune responses in the lung was accompanied by increased Foxp3+ Treg recruitment and TGF-β production in both platforms. As OVA incorporates IgE-binding as well as non-IgE-binding epitopes, the next experiment explored the possibility of obtaining immune tolerance by non-anaphylactic T-cell epitopes. This was accomplished by incorporating OVA323-339 and OVA257-264 epitopes in liver-targeting NPs to assess the prophylactic and therapeutic impact on allergic inflammation in transgenic OT-II mice. Importantly, we demonstrated that the major histocompatibility complex (MHC)-II binding (former) but not the MHC-I binding (latter) epitope interfered in allergic airway inflammation, improving TNPOVA efficacy. The epitope-specific effect was transduced by TGF-β-producing Tregs. In the final phase of experimentation, we used an OVA-induced anaphylaxis model to demonstrate that targeted delivery of OVA and its MHC-II epitope could significantly suppress the anaphylaxis symptom score, mast cell release, and the late-phase inflammatory response. In summary, these results demonstrate comparable efficacy of LSEC-targeting versus pharmaceutical PLGA nanoparticles, as well as the ability of T-cell epitopes to achieve response outcomes similar to those of the intact allergens.

For centuries, temperature measurement deficiencies attributable to biological barriers and low thermo-conductivity (k) have precluded accurate surface-based fever assessment. At this stage of the pandemic, infection detection in children (who due to immature immune system may not effectively respond to vaccines) is critical because children can be readily infected and also become a large mutation reservoir. We reveal hitherto-unrecognized worldwide body temperature measurements (T°), in children and adults, over tissue typified by low-k similar to wood that may reach 6.8°C in thermal variability, hampering thereby COVID-19 control. Brain-eyelid thermal tunnels’ (BTT) integration of low-k and high-k regions creating a thermal pathway for undisturbed heat transmission from hypothalamus to high-k skin eliminates current shortcomings and makes the brain indispensable for defeating COVID-19 given that brain thermoregulatory signals are not limited by mutations. Anatomo-histologic, emissive, physiologic, and thermometric bench-to-bedside studies characterized and overcome biophysical limitations of thermometry through high-k eyelid-enabled brain temperature measurements in children and adults. BTT eyelid features fat-free skin (~900 µm) and unique light emission through a blood/fat configuration in the underlying tunnel. Contrarily, forehead features variable and thick dermis (2000–2500 µm) and variable fat layers (1100–2800 µm) resulting in variable low-k as well as temperatures 1.97 °C lower than BTT temperature (BTT°). Highest emission present in only ~3.1% of forehead averaged 1.08±0.49 °C (mean±SD) less than BTT° (p=0.008). Environmental and biological impacts during fanning revealed thermal imaging limitations for COVID-19 screening. Comparison of paired measurements for 100 pediatric patients showed that in the children subgroup above 37°C, BTT° exceeded body core temperature (Core°) in 60/72 patients; the average difference in the 72 patients was 0.62±0.7°C (p

We aimed to assess the risk of preterm birth in those with real-time dynamic cervical shortening.A retrospective matched case-control study. The study group comprised all women with dynamic cervical shortening (≥4 mm) noted from 24 to 34 weeks of gestation during 2010-2017 at a university hospital. Two control groups of women were established by matching the minimal and maximal cervical length measured, as well as age, parity, gestational age, history of spontaneous preterm birth, symptoms of preterm labor, and delivery year.Data from 339 women were analyzed, 113 with dynamic cervical shortening comprised the study group, and two groups with 113 women each, matched for the minimal and maximal cervical lengths measured comprised the control groups. Rates of spontaneous preterm birth rate at37 weeks (32.7% vs. 15.9%; OR [95% CI]: 2.60 (1.36, 4.87),The minimal cervical length measured should be used to guide patient management when dynamic cervix is noted. In the setting of dynamic cervical change, the value of cervical length as a negative predictor of preterm birth is limited.

NMDA receptors (NMDAR) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission in the nervous system. A central feature of NMDAR physiology is the opening of the ion channel driven by presynaptically-released glutamate. Using glutamate applications to outside-out patches containing a single NMDAR in the continuous presence of the co-agonist glycine, we find that agonist-bound receptors transition to the open state via two conformations, an ‘unconstrained pre-active’ state that can rapidly transition to the open state and contributes to synaptic events, and a ‘constrained pre-active’ state that requires more energy and hence time to open and does not contribute to fast signaling. To define how agonist binding might drive these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for the GluN1 and GluN2A subunits. Displacements of the central pore-forming M3 segments define the energy of fast channel opening. However, to enter the unconstrained conformation and contribute to fast signaling, a peripheral helix, the GluN2 pre-M1, must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of another nearby peripheral element, the GluN1 and GluN2A S2-M4. We conclude that peripheral structural elements – pre-M1 and S2-M4 – work in concert to remove constraints and prime the channel for rapid opening, thus facilitating fast synaptic transmission.

Altered sleep neurophysiology has consistently been reported in adult patients with schizophrenia. Converging evidence suggests that childhood onset schizophrenia (COS), a rare but severe form of schizophrenia, is continuous with adult onset schizophrenia. The aim of the current study was to characterize sleep neurophysiology in COS. An overnight sleep electroencephalogram (EEG) was recorded in 17 children and adolescents with COS (16 years ± 6.6) and 17 age and gender-matched controls. Non-rapid eye movement (NREM) and rapid eye movement (REM) sleep EEG power and coherence for the frequency bands delta (1.6-4.8 Hz), theta (5-8.4 Hz), alpha (8.6-11 Hz), beta 1 (16.4-20.2 Hz) and beta 2 (20.4-24.2 Hz) were compared between COS patients and controls. COS patients exhibited significant and widespread deficits in beta power during NREM and REM sleep. With regard to coherence, we found increases in COS patients across brain regions, frequency bands and sleep states. This study demonstrates the utility of the sleep EEG for studying vulnerable populations and its potential to aid diagnosis.

Neuroimaging studies of childhood onset schizophrenia (COS), a rare yet severe form of schizophrenia with an onset before the age of 13 years, have shown continuity with adult onset schizophrenia. Previous research in adult patients has shown reduced sleep spindle activity, transient oscillations in the sleep electroencephalogram (EEG) generated through thalamocortical loops. The current study examines sleep spindle activity in patients with COS. Seventeen children and adolescents with COS (16 years ± 6.6) underwent overnight sleep EEG recordings. Sleep spindle activity was compared between patients with COS and age and gender matched controls and correlated with clinical symptom severity. We found pronounced deficits in sleep spindle amplitude, duration, density and frequency in patients with COS (effect size = 0.61 to 1.96; dependent on metric and EEG derivation). Non-rapid eye movement (NREM) sleep EEG power and coherence in the sigma band (11–16 Hz) corresponding to spindle activity were also markedly diminished in patients with COS as compared to controls. Furthermore, the degree of deficit in power and coherence of spindles was strongly associated with clinician rated hallucinations and positive symptoms over widespread cortical regions. Our finding of diminished spindle activity and its association with hallucinations likely reflect dysfunction of the thalamocortical circuits in children and adolescents with COS. Given the relative ease of sleep EEG recordings in vulnerable populations, this study highlights the potential of such recordings to characterize brain function in schizophrenia.

Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity.A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS.Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on default-mode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P0.05, corrected) for both patient groups.A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is state-related.

We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (α7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.

Objective This study investigated the relationship between regional cortical gray matter thinning and symptoms of schizophrenia spectrum personality disorders (PDs) in siblings of patients with childhood-onset schizophrenia (COS). Method A total of 66 siblings of patients with COS were assessed for symptoms of schizophrenia spectrum PDs (avoidant, paranoid, schizoid, schizotypal). Structural magnetic resonance images were obtained at approximately 2-year intervals from the siblings and from 62 healthy volunteers matched for age, sex, ethnicity, and handedness. Cortical thickness measures were extracted. Mixed effect regression models were used to test the relationship between symptoms and cortical gray matter thickness in siblings. Cortical thinning was also tested longitudinally in healthy volunteers and siblings. Results Cortical thinning was found to correlate with symptoms of schizotypal and, to a lesser extent, schizoid PDs. Thinning was most pronounced in the left temporal and parietal lobes and right frontal and parietal regions. Gray matter loss was found to be continuous with that measured in COS. Longitudinal thinning trajectories were found not to differ between siblings and healthy volunteers. Conclusion The present investigation of cortical thinning in siblings of patients with COS indicates that symptoms of schizophrenia spectrum PDs correlate with regional gray matter loss. This finding supports the idea of cortical thinning as a schizophrenia endophenotype.

Background: Immunotherapy has drastically changed the outlook for melanoma patients over the past decade. Specifically, the dual blockade of immune checkpoints using ipilimumab and nivolumab has shown unprecedented response rates and survival outcomes. This immense achievement, though, is at the cost of toxicity, with 60% of the patients experiencing high-grade adverse events (AEs). Our study aims to report the efficacy and toxicity outcomes of an out-of-trial, real-life population. Methods: Data on metastatic melanoma patients treated with ipilimumab and nivolumab were retrieved from our melanoma database&mdash, a single-center prospectively updated, medical-records based oncologic registry. Data included demographics, clinical and pathological information, as well as tumor responses and survival. Associations between patient or treatment characteristics and outcomes were also evaluated. Results: We identified 172 metastatic melanoma patients, of whom 64% were treatment-na&iuml, ve. The median follow-up was 12 months. The response rates for treatment-na&iuml, ve and previously-treated patients were 61% and 25%, respectively, median progression-free survival (PFS) were 12.2 and 2.6 months, and median overall survival (OS) were not-reached (NR) and 6.1 months, respectively. The estimated three-year OS for treatment-na&iuml, ve patients was 58% (95% CI 42&ndash, 65). At data cutoff, 22% were still on-treatment. Grade 3&ndash, 4 adverse events (AEs) were reported in 60% of the patients, almost all of whom were exposed to steroid treatments (59%), AEs were fatal in 4 patients, and led to permanent treatment discontinuation in 31%. Factors significantly associated with outcome were cutaneous histology, low lactate dehydrogenase (LDH), low number of metastatic sites, performance status, first line of treatment and number of combinations administered during the induction phase. Conclusions: Despite the profoundly different baseline patient characteristics, the combination of ipilimumab and nivolumab is as effective in the real-world population as it was in clinical trials, including long-term outcomes. In addition to confirming the significance of baseline prognostic factors, our study reveals that the number of combinations effectively administered may also be correlated with good outcome.

Whereas highly penetrant variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. In developing a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons, we identified and accounted for a variety of technical and biological sources of variation. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal in hiPSC-based models and increased the concordance with post mortem datasets. Because this concordance was strongest in hiPSC-neurons, it suggests that this cell type may better model genetic risk for SZ. We predict a growing convergence between hiPSC and post mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones.

Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS.Adult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report.Patients with COS who were included scored significantly lower than controls on all tasks (p .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected).Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype.Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Objective This study investigated symptom dimensions and subgroups in the National Institute of Mental Health (NIMH) childhood-onset schizophrenia (COS) cohort and their similarities to adult-onset schizophrenia (AOS) literature. Method Scores from the Scales for the Assessment of Positive and Negative Symptoms (SAPS & SANS) from 125 COS patients were assessed for fit with previously established symptom dimensions from AOS literature using confirmatory factor analysis (CFA). K-means cluster analysis of each individual's scores on the best fitting set of dimensions was used to form patient clusters, which were then compared using demographic and clinical data. Results CFA showed the SAPS & SANS data was well suited to a 2-dimension solution, including positive and negative dimensions, out of five well established models. Cluster analysis identified three patient groups characterized by different dimension scores: (1) low scores on both dimensions, (2) high negative, low positive scores, and (3) high scores on both dimensions. These groups had different Full scale IQ, Children's Global Assessment Scale (CGAS) scores, ages of onset, and prevalence of some co-morbid behavior disorders (all p Conclusion Our analysis found distinct symptom-based subgroups within the NIMH COS cohort using an established AOS symptom structure. These findings confirm the heterogeneity of COS and were generally consistent with AOS literature.

OBJECTIVES Emergency medical services (EMS) prenotifications are critical, although they oftentimes inaccurately convey the arriving patient's true acuity, resulting in inappropriate preparation in the emergency department. The objectives of this study were (1) to determine interrater reliability of acuity prediction based on prenotifications among physicians and (2) to compare predicted versus actual patient acuity based on prenotifications. METHODS A panel of physicians reviewed recordings of EMS prenotifications and then predicted the patient's acuity using the Emergency Severity Index (ESI). The scores were analyzed for interrater reliability using the weighted κ statistic. In the prospective phase of the study, physicians predicted an ESI before patient arrival based solely on the EMS prenotification and then calculated an actual ESI upon arrival. Descriptive statistics were calculated, and comparisons between the predicted and actual ESI were performed using Wilcoxon signed rank for matched pairs. RESULTS Panelists reviewed a total of 23 recordings, and the interrater reliability was 0.23 overall (SE, 0.026; P < 0.001), indicating only fair agreement. One hundred patients were enrolled in the prospective analysis. There was a statistically significant difference between the predicted and actual ESI made by physicians (P = 0.0001). For 46 patients, the predicted and actual scores matched, but 13 patients were "undertriaged," and 41 patients were "overtriaged" based on predicted acuity. CONCLUSIONS Interpretation of acuity using EMS prenotifications among physicians was only fairly reliable, and physicians had difficulty predicting actual acuity based on prenotifications. Improper preparation based on these prenotifications can potentially impact patient care and resource allocation.

Background Large-scale Genome Wide Association Studies (GWAS) revealed that Schizophrenia (SZ) risk reflects both rare and common variants. Whereas highly penetrant rare variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. Childhood-Onset-SZ (COS) patients have both a higher rate of rare SZ-associated Copy Number Variations (CNVs), and also stronger common SZ polygenic risk scores. Methods We developed a case/control hiPSC cohort (12 individuals with COS and 10 controls) with which to conduct a comprehensive evaluation of global gene expression in hiPSC-derived neural progenitor cells (NPCs) and neurons. Results Although we identified many sources of variation across our 94 RNAseq samples, this was partially addressed by establishing a rigorous series of bioinformatic practices to reduce and assess the variance inherent in this approach. We report that the donor-specific signal is enriched for post- mortem brain Expression Quantitative Trait Loci (eQTLs), but also that there is a significant correlation between the case/control differential expression observed in our hiPSC-derived COS neurons and the CommonMind Consortium post-mortem study. While the issue of small sample size is shared between post-mortem and hiPSC-based studies, and may be exacerbated in hiPSC-based experiments through the variability that arises as a result of the reprogramming and neural differentiation processes, we find that the common variation effects predicted in GWAS and detected in much larger post-mortem analyses are reflected in hiPSC-neurons. Discussion We predict a growing convergence of common variation findings between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes.

Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.

ObjectiveGender differences, including younger age of onset and greater premorbid deficits in men, have been reported in adult-onset schizophrenia. This study comprehensively evaluated gender differences in childhood-onset schizophrenia (COS), a rare variant of the disorder.MethodDemographic, premorbid, clinical, familial, and cognitive characteristics, presence of chromosomal abnormalities, and brain magnetic resonance imaging cortical volumes were evaluated in 133 patients with COS. Cortical analyses included age- and gender-matched healthy volunteers (n = 124).ResultsMales with COS (n = 72) had a slightly but significantly younger age of onset than females with COS (mean age 9.51 ± 2.28 versus 10.29 ± 1.63 years, t131 = 2.21, p = .03), higher verbal IQ scores (83.00 ± 15.97 versus 75.58 ± 15.10, t89 = 2.24, p = .03), and higher rates of comorbid pervasive developmental disorder (28.17% versus 6.90%, χ21 = 9.54, p < .01) and attention-deficit/hyperactivity disorder (43.86% versus 21.43%, χ21 = 5.40, p = .02). There were no significant gender differences across other demographic, IQ, or clinical measurements, frequency of chromosomal abnormalities, family clinical measurements, premorbid functioning, or in gender-by-disorder interactions for magnetic resonance imaging brain measurements.ConclusionThe present comprehensive examination found few remarkable gender differences in COS. Although less striking than that seen in adult-onset schizophrenia, males with COS had a younger age of onset. Attention-deficit/hyperactivity disorder and pervasive developmental disorder rates were high in COS overall, suggesting greater neurodevelopmental vulnerability in COS. However, the gender ratios of these comorbidities in COS mirror those of the general populations, indicating that these gender differences might be unrelated to COS.

Childhood-onset schizophrenia (COS) is a rare but severe form of the disorder, which is often treatment refractory. Short-term studies have indicated a greater differential efficacy, evident through effect sizes, favoring clozapine over other agents in alleviating negative symptoms in COS patients compared with adult-onset patients (AOS). There have been no data for COS patients on long-term compliance with clozapine treatment. Therefore, we wanted to know, over a span of up to 24 years, how many of our COS cohort had remained on clozapine for at least 2 years. We review short-term treatment data and present updated long-term data on compliance and functioning for our patients.We present the results for long-term medication maintenance over a 24 year observation period for our cohort of 131 patients. Of this cohort, 91.6% (120) were available for follow-up information from either in-person or telephone contact with the patient and/or family members. We defined clozapine compliance as ≥2 years receiving this medication and doing well.We were able to contact 120 of the 131 patients. In spite of the additional cost and inconvenience of regular blood monitoring, 87 patients (72.5%, 87/120) adhered to long-term clozapine maintenance therapy with dosages ranging from 50 to 900 mg, and a median dosage of 500 mg. This rate exceeds the long-term clozapine maintenance rates reported for AOS patients.Short-term data on differential efficacy and long-term maintenance data suggest a possibly greater efficacy of clozapine, relative to other antipsychotics, in COS than in AOS. Our overall findings indicate that very early-onset schizophrenic patients may be more responsive to clozapine. This extends other support for clozapine as an option in the treatment of early-onset schizophrenia.

Objective Few studies have examined prediction of schizophrenia outcome in relation to brain magnetic resonance imaging measures. In this study, remission status at the time of discharge was examined in relation to admission cortical thickness for childhood-onset schizophrenia probands. We hypothesized that total, frontal, temporal, and parietal gray matter thickness would be greater in patients who subsequently remit. Method The relation between admission cortical brain thickness on magnetic resonance imaging and remission status at the time of discharge an average of 3 months later was examined for 56 individuals (32 males) ages 6 to 19 diagnosed with childhood-onset schizophrenia. Cortical thickness was measured across the cerebral hemispheres at admission. Discharge remission criteria were adapted from the 2005 Remission in Schizophrenia Working Group criteria. Results Patients remitted at discharge ( n = 16 [29%]) had thicker regional cortex in left orbitofrontal, left superior, and middle temporal gyri and bilateral postcentral and angular gyri ( p ≤ .008). Conclusions Our results provide neuroanatomic correlates of clinical remission in schizophrenia and evidence that response to treatment may be mediated by these cortical brain regions. J. Am. Acad. Child Adolesc. Psychiatry , 2008;47(10):1133–1140.

BackgroundFixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients.MethodWe prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume).ResultsFewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043).ConclusionsThese results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies.

Physicians are educated with the classical teaching that symptomatic patients with Meckel’s diverticulum (MD) most often present with painless rectal bleeding. However, a review of the literature reveals that young patients with MD will most commonly present with signs of intestinal obstruction, an etiology not frequency considered in patients presenting to the emergency department with obstruction. We present two cases of intestinal obstruction diagnosed in our emergency department, with Meckel’s diverticulum being the etiology.

Long-term outcomes in children with atypical psychosis have been poorly studied. Four to 6 weeks of inpatient observation and up to 11 years (mean, 4.0 +/- 1.3 years) of follow- up have afforded us some experience with this probably heterogeneous group of transiently psychotic patients commonly mislabeled as schizophrenic. Despite severe preadmission morbidity, some patients have successfully remained neuroleptic-free since discharge. Predictors of good versus poor outcome were sought.Of roughly 150 patients admitted with the presumptive diagnosis of schizophrenia, 32 patients were discharged meeting criteria for psychosis not otherwise specified (NOS), otherwise labeled by the NIMH team as "multidimensionally impaired" (MDI). Admission and biannual follow-up data included a semistructured clinical interview with the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS), IQ testing, clinical rating scales (e.g., Clinical Global Impression Scale (CGI), Children's Global Assessment Scale (C-GAS), Brief Psychiatric Rating Scale (BPRS), Scales for the Assessment Negative and Positive Symptoms (SANS and SAPS), and Bunney-Hamburg (B-H)). At follow-up (as of February 2005) 38% of patients (12 of 32) met criteria for bipolar 1 disorder, 12% (4 of 23) for major depressive disorder (MDD), and 3% (1 of 32) for schizoaffective disorder. The remaining 47% of patients (15 of 32) were divided into two groups on the basis of whether they were in remission and neuroleptic-free ("good outcome," n = 5) or still severely impaired and/or psychotic regardless of pharmacotherapy ("poor outcome," n = 10) at follow-up.Good-outcome patients had a significantly higher baseline level of functioning (on admission and on medications). This was demonstrated by better scores on CGI (3.5 +/- 0.6 versus 4.8 +/- 0.8; p = 0.03) and C-GAS (66.3 +/- 6.3 versus 38.6 +/- 11.5; p = 0.01). Groups were otherwise comparable in demographic data (gender, race, socioeconomic status, age at onset), months of neuroleptic exposure, severity of psychotic symptoms, and level of premorbid functioning.C-GAS (which correctly classified 85.7% of good-outcome subjects) and CGI at baseline appear to predict outcome. On other variables, MDI subgroups were remarkably similar.

Background Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. Aims To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). Method Eye-tracking performance for 70 COS parents, 64 AOS parents and 20 COS siblings was compared to their respective age-matched control groups. Results COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. Conclusions Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. Declaration of interest The study was done at the National Institutes of Health.

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

The administration of psychostimulants to children with psychotic symptoms is controversial. This study reports the stimulant drug response of 5 children, aged 8-15 years, with childhood-onset schizophrenia (COS) and comorbid attention deficit hyperactivity disorder (ADHD). Four COS inpatients were given stimulants for comorbid ADHD after stabilization of psychosis on antipsychotic medication. A fifth COS inpatient received stimulants while still actively psychotic, despite concurrent neuroleptic treatment. Data from the 10-item Brief Conners Teachers Ratings Scale (BCTRS) were examined the week before, and the week after, stimulant addition. A paired t test, conducted using Conners Teachers data from these 4 subjects, indicated significant improvement in ADHD symptoms (p = 0.02). Data obtained from a retrospective chart review indicated no significant worsening of psychosis. The 2 subjects treated with mixed salts of dextroamphetamine sulfate and amphetamine sulfate remained on that medication at 6 months and at the 2-year follow-up. Our results suggest that ADHD comorbid with COS may be safely treated with a stimulant, once the psychosis is stabilized. A systematic investigation of this question may be warranted.

Background Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. Methods Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). Results Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Asperger's disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD ( n = 12) than for the non-PDD ( n = 27) subgroup (−19.5 ± 11.3 mL/year vs. −9.6 ± 15.3 mL/year; p = .05). None of eight candidate genes for autism were associated with COS or COS-PDD. Conclusions Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.

OBJECTIVE: Childhood onset of “adult” psychiatric disorders may be caused, in part, by more salient genetic risk. In this study, the rates of schizophrenia spectrum disorders among parents of patients with childhood-onset and adult-onset schizophrenia and parents of community comparison subjects were compared. METHOD: To assess the presence of axis I and axis II disorders associated with schizophrenia, parents of patients with childhood-onset schizophrenia (95 parents), patients with adult-onset schizophrenia (86 parents), and community comparison subjects (123 parents) were interviewed directly by using semistructured instruments. Information on 19 additional parents (parents of childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of community comparison subjects, N=6) was obtained by using a family history interview with the same instruments. Transcribed interviews were scored by a rater blind to group membership, and the morbid risks for schizophrenia spectrum disorders in the ...

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.

Objective: Among children 90%, overall accuracy>77%, and areas under the curve (AUCs)>86%. Conclusions: COS can be distinguished from alternate disorders with psychosis in children and adolescents; greater levels of positive and negative symptoms and lower levels of depression combine to make COS more likely. We include a worksheet so that clinicians in the community and academic centers can predict the probability that a young patient may be schizophrenic, using only two ratings.

Objective The authors systematically examined a sample of patients who were referred to an ongoing National Institute of Mental Health (NIMH) study of childhood-onset schizophrenia (COS), but who received diagnoses of mood disorders at the NIMH, to analyze the reliability of these research-setting diagnoses and to characterize the patients clinically. Pilot data regarding the clinical course of these patients over a 2- to 7-year follow-up period were also obtained. Method Thirty-three cases were selected from the 215 pediatric patients who had been screened in person from 1991 to 1999 for admission to the COS study. These 33 patients had been excluded from the COS study on the basis of a day-long evaluation, including a structured diagnostic interview, which yielded a diagnosis of a mood disorder rather than schizophrenia. This subgroup, together with six COS subjects (for a total N = 39), were included in a diagnostic reliability study in which they were reevaluated by three psychiatrists who were blind to the initial research diagnosis. In addition, pilot follow-up data regarding current function and treatment status were obtained for 25 of the 33 patients with mood disorders. Results Overall, the interrater reliability of the three raters was excellent (κ = 0.90). Global reliability between these raters and the NIMH research diagnoses was good (average κ across diagnoses=0.61), and agreement for those patients who had mood disorders was good (86% agreement; κ = 0.60). Pilot follow-up data indicate that none of the subjects with a diagnosed mood disorder developed a clinical course resembling schizophrenia. Conclusions Many of the patients referred to the NIMH COS study with clinical diagnoses of schizophrenia had psychotic mood disorders diagnosed on the basis of a comprehensive research evaluation including structured diagnostic interviews, and these research diagnoses were reliable. The diagnosis of COS is difficult and requires a time-consuming evaluation process.

The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block receptors in Aplysia californica, and the effect on reflexes and escape behavior was examined. Four groups of 20 young adults were each injected with SCH-23390, raclopride, SCH-23390+raclopride, or seawater. The drug (0.0125 mg/g of body weight) was injected 2 mm anterior to the parapodia. After the injection of either SCH-23390 or SCH-23390+raclopride, there was a significant increase in parapodia opening (P

Although psychotic phenomena in children with disruptive behavior disorders are more common than expected, their prognostic significance is unknown. To examine the outcome of pediatric patients with atypical psychoses, a group of 26 patients with transient psychotic symptoms were evaluated with clinical and structured interviews at the time of initial contact (mean age, 11.6 +/- 2.7 years) and at follow-up 2 to 8 years later. Measures of functioning and psychopathology were also completed at their initial assessment. Risk factors associated with adult psychotic disorders (familial psychopathology, eyetracking dysfunction in patients and their relatives, obstetrical complications, and premorbid developmental course in the proband) had been obtained at study entry. On follow-up examination (mean age, 15.7 +/- 3.4 years), 13 patients (50%) met diagnostic criteria for a major axis I disorder: three for schizoaffective disorder, four for bipolar disorder, and six for major depressive disorder. The remaining 13 patients again received a diagnosis of psychotic disorder not otherwise specified (NOS), with most being in remission from their psychotic symptoms. Among this group who had not developed a mood or psychotic disorder, disruptive behavior disorders were exceedingly common at follow-up and were the focus of their treatment. Higher initial levels of psychopathology, lower cognitive abilities, and more developmental motor abnormalities were found in patients with a poor outcome. Obstetrical, educational, and family histories did not differ significantly between the groups. Through systematic diagnostic evaluation, children and adolescents with atypical psychotic disorders can be distinguished from those with schizophrenia, a difference with important treatment and prognostic implications. Further research is needed to delineate the course and outcome of childhood-onset atypical psychoses, but preliminary data indicate improvement in psychotic symptoms in the majority of patients and the development of chronic mood disorders in a substantial subgroup.

Purpose: Disturbances of the ocular tear film layer and dry eye symptoms are common complications following retinal surgery and ocular tumour therapy. Examined were the histopathological changes of the conjunctiva following posterior segment surgery and plaque radiotherapy. Methods: Biopsy specimens of the superior bulbar conjunctiva were obtained during cataract surgery between 2 weeks and 7 years following vitrectomy (n=92) or plaque radiotherapy for uveal melanoma (n=20) and from control subjects without previous ocular surgery (n=29). These were examined using conventional histology (HE, PAS, Van Gieson) and immunochemistry [APAAP, using antibodies directed against MUC1, MUC5AC, syndecan-1 and tenascin-C (TN-C)]. The histopathological changes were graded and statistical analysis was performed using Wilcoxon and Kruskal-Wallis rank sum tests. Results: Conjunctival specimens of patients following vitrectomy or plaque radiotherapy for uveal melanoma demonstrated increased epithelial stratification, a significant decrease in the number of PAS- and MUC5AC-positive goblet cells, and distributional changes in expression of MUC1, syndecan-1 and TN-C within conjunctival epithelium or stroma. These alterations – in particular the goblet cell reduction and stromal fibrosis – were most prominent in those patients who had undergone radiotherapy. Conclusions: Posterior segment surgery can lead to morphological alterations of the conjunctiva and distributional changes in ocular mucins, which may cause dry eye symptoms.

As both premorbid neurodevelopmental impairments and familial risk factors for schizophrenia are prominent in childhood-onset cases (with onset of psychosis by age 12), their relationship was examined.Premorbid language, motor, and social impairments were assessed in a cohort of 49 patients with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications were assessed without knowledge of premorbid abnormalities and were compared in the patients with and without developmental impairments.Over one-half of the patients in this group had developmental dysfunction in each domain assessed. The patients with premorbid speech and language impairments had higher familial loading scores for schizophrenia spectrum disorders and more obstetrical complications, and their relatives had worse smooth-pursuit eye movements. The boys had more premorbid motor abnormalities, but early language and social impairments did not differ significantly between genders. There were no other significant relationships between premorbid social or motor abnormalities and the risk factors assessed here.Premorbid developmental impairments are common in childhood-onset schizophrenia. The rates of three risk factors for schizophrenia (familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications) were increased for the probands with premorbid speech and language impairments, suggesting that the pathophysiology of schizophrenia involves the abnormal development of language-related brain regions.

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:749-753, 2000. Published 2000 Wiley-Liss, Inc.

As part of systematic treatment trials of haloperidol, clozapine, and olanzapine with a total of 35 children and adolescents with early onset psychosis, prolactin was measured at baseline and week 6 of treatment. The National Institute of Mental Health patients--13 females, 22 males (mean age, 14.1+/-2.3 years; range, 9.1-19 years) with childhood onset schizophrenia (n = 32), or Psychotic Disorder not otherwise specified (NOS) (n = 3) with onset of psychosis before age 13--were recruited for open or double-blind trials of haloperidol, clozapine, or olanzapine. Baseline serum prolactin was measured after a 3-week washout period and after 6 weeks of treatment. Mean prolactin concentration after 6 weeks of treatment was significantly elevated on all three drugs; however, on clozapine, mean prolactin remained within the normal range. Prolactin was increased above the upper limit of normal for 100% of 10 patients on haloperidol, 70% of 10 patients on olanzapine, and 0% of 15 patients on clozapine (chi2 analyses: H > C, p = 0.004; O > C, p = 0.001). Given the potential endocrine and possible cardiac correlates of hyperprolactinemia, these more robust prolactin elevations in pediatric patients after short-term exposure to olanzapine than those reported for adults justify longer observation intervals with bigger samples to establish treatment safety of atypical antipsychotics in adolescents.

Occult bacteremia affects approximately 5% of febrile children ages 2 to 36 months. Many physicians empirically treat children who have a temperature higher than 39 degrees C, a white blood cell (WBC) count of more than 15.0 x 10(9)/L, and no focus of infection with antibiotics. We undertook this investigation to better define predictive indicators for bacteremia. Specifically we were concerned with determining whether the absolute neutrophil count (ANC) is a better diagnostic indicator than the total WBC count and whether the manual differential (which includes a band cell count) is necessary or helpful. Three separate groups of patients aged 2 to 36 months were assessed retrospectively. Group A consisted of febrile children (temperature, > 39 degrees C) who had positive blood cultures (50 patients). Group B included febrile children (temperature, > 39 degrees C) who had negative blood cultures (59 patients). Group C, nonfebrile children admitted to the hospital was the control group (61 patients). The ANC and the total WBC count were significantly higher in group A than in group B. Although they were equally sensitive, the ANC was more specific than the total WBC count. Band cell counts of greater than 10% and the percentage of total neutrophils also were greater in group A than in group B. The values for group C were not significantly different from those for group B. Although a total WBC count of 15.0 x 10(9)/L is currently used to identify children at risk for occult bacteremia, the ANC seems to be as sensitive an indicator and may be more specific. Our study demonstrated that (1) the WBC count is a good indicator of occult bacteremia, (2) the ANC is as sensitive as the WBC count and may be more specific, (3) automated ANCs are comparable to manual ANCs, and (4) the band cell count is insensitive as an indicator and does not add any predictive value.

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P

The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine.A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35±2.46 years at hospitalization and a mean length of stay of 117±43 days.Mild neutropenia only (lowest ANC2000/mm3 but1500/mm3) was observed in 27 (31%) patients and moderate neutropenia (any ANC1500/mm3) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p=0.012) and younger age (p0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p=0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p=0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC2000/mm3.Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.

The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-onset schizophrenia (COS), that includes the onset of psychosis before age 13, is a severe and continuous form of the illness which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age. Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients, their nonpsychotic full siblings and healthy volunteers, we measured insular volume using the FreeSurfer automated software. COS patients (n=98; 234 scans) had significantly lower right (p=0.003), left (p

Chronic inflammation increases the risk of development of several types of malignancies including colon cancer. It also represents a paradigm for the connection between inflammation and cancer in terms of epidemiology and mechanistic studies in preclinical models. A key component of inflammation promoting cancer is the transcription factor NF-κB, which is known to play a critical role in the regulation of the inducible nitric oxide synthase (iNOS) gene. iNOS is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation and tumorigenesis, the role of iNOS activity in these diseases is still not well understood. Analysis of human biopsies of colitis and colon cancer using immunohistochemistry revealed elevated iNOS protein expression levels, which were strongly paralleled by increased expression of nitrotyrosine suggesting that iNOS has been highly activated in these tissues. These results were corroborated in an in vitro study showing the presence of high iNOS levels in a colon cancer cell line (HT-29) following inflammatory stimuli (TNF-α, peroxynitrite). In addition, the involvement of metastatic processes in the colon biopsies was assessed by means of in situ zymography of MMP activation. MMP 2 (gelatinase A) activation was higher in histopathological sections of colitis and cancer compared to controls. Overall, these data strengthen the findings that in inflammation and colon cancer in humans, iNOS expression and tyrosine nitration may be an indicator of cancer development and progression.

Objective. To assess the prevalence of laboratory abnormalities (complete blood cell count, electrolytes, blood urea nitrogen, creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, amylase, lipase, urinalysis [U/A]) and the sensitivity and specificity of the physical examination (PE) and screening laboratory tests for identifying intra-abdominal injury (IAI) in moderately injured pediatric patients. Design, participants, and setting. Phase I: Retrospective review of 285 consecutive level II (moderately injured) trauma patients seen at a children's hospital emergency department/pediatric trauma center. All patients were received directly from the scene and had the following data recorded: mechanism of injury, Glasgow coma score, trauma score, pediatric trauma score, systematically recorded PE findings, laboratory results, and injuries detected during hospitalization. Phase II: To confirm the sensitivity of the PE and U/A found in phase I, the model was applied to 91 additional trauma patients identified by International Classification of Diseases, 9th revision (ICD-9) codes as having IAI. Intervention. None. Results. Phase I: A total of 3939 tests were ordered for the 285 patients entered in phase I. Aspartate aminotransferase and alanine aminotransferase values were obtained in 59% of patients; glucose level was obtained in 78% of patients; complete blood cell count, U/A, and levels of electrolytes, blood urea nitrogen, creatinine, amylase, and lipase were obtained in more than 85% of patients. The overall prevalence of laboratory abnormalities was 5.7%. Fourteen patients (4.8%) were identified who had a total of 23 significant IAIs (9 pancreatic, 6 splenic, 5 renal, 3 hepatic). The PE combined with U/A showing more than five red blood cells per high-power field had a sensitivity of 100%, specificity of 64%, positive predictive value of 13%, and negative predictive value of 100% for the detection of IAI. The presence of laboratory abnormalities suggesting injury did not increase the sensitivity of the model and significantly decreased both specificity and positive predictive value. Phase II: The PE combined with U/A identified an abnormality in 89 (97.8%) of 91 cases (95% confidence interval = 94.8% to 100%). Conclusions. In the moderately injured pediatric trauma patient, (1) there is a low prevalence of laboratory abnormalities; (2) the PE combined with U/A is a highly sensitive screen for IAI; and (3) in patients with a normal PE of the abdomen and a normal U/A, laboratory testing seldom identifies unsuspected IAI.