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Purpose To measure the rate of recall of study participation and study attrition in survivors of acute respiratory distress syndrome(ARDS). Materials/Methods In this ancillary study of the Re-evaluation of Systemic Early neuromuscular blockade(ROSE) trial, we measured the rate of study participation recall 3 months following discharge and subsequent study attrition at 6 months. We compared patient and hospital characteristics, and long-term outcomes by recall. As surrogate decision-makers provided initial consent, we measured the rate of patient reconsent and its association with study recall. Results Of 487 patients evaluated, recall status was determined in 386(82.7%). Among these, 287(74.4%) patients recalled participation in the ROSE trial, while 99(25.6%) did not. There was no significant difference in 6-month attrition among patients who recalled study participation (9.1%) and those who did not (12.1%) (p = 0.38). Patient characteristics were similar between groups, except SOFA scores, ventilator-free days, and length of stay. 330(68%) were reconsented. Compared to those not reconsented, significantly more patients who were reconsented recalled study participation(78% vs. 66%;p = 0.01). Conclusions One in 4 ARDS survivors do not recall their participation in a clinical trial during hospitalization 3 months following hospital discharge, which did not influence 6-month attrition. However, more patients recall study participation if reconsent is obtained.

OBJECTIVES Families identify overall health as a key outcome after pediatric critical illness. We conducted a planned secondary analysis of a scoping review to determine the methods, populations, and instruments used to evaluate overall health outcomes for both children and their families after critical illness. DESIGN Planned Secondary Analysis of a Scoping Review. SETTING We searched PubMed, EMBASE, PsycINFO, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Controlled Trials Registry databases from 1970 to 2017 to identify studies which measured postdischarge overall health of children who survived critical illness and their families. SUBJECTS Articles reporting overall health outcomes after pediatric critical illness. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Among the 407 articles which measured outcomes following pediatric critical illness, 161 (40%) measured overall health. The overall health domain was most commonly measured in traumatic brain injury (44%) and the general PICU populations (16%). In total, there were 39 unique measures used to evaluate overall health. Across all subjects, seven measures accounted for 89% of instruments, with the Glasgow Outcome Scale (47%) and the Pediatric Overall Performance Category (17%) being most commonly used. Excluding studies targeting survivors of traumatic brain injury, Pediatric Overall Performance Category, Glasgow Outcome Scale, and the General Health Questionnaire were the most commonly used instruments. Patients were followed for a median 10.5 months (interquartile range, 4.5-21 mo). CONCLUSIONS Overall health was commonly assessed post-PICU discharge, especially in the traumatic brain injury population, using a heterogenous array of measures. Evaluation and consensus are imperative to identify the most appropriate method to measure overall health with the goal of improving care efficacy and facilitating recovery across populations of critically ill children.

Objectives To determine clinician accuracy in the identification and prediction of multiple organ dysfunction syndrome. Design Prospective cohort study. Setting University of Michigan's C.S. Mott Children's Hospital PICU. Patients Patients admitted to the PICU with an anticipated PICU length of stay greater than 48 hours. Interventions None. Measurements and main results For each patient, the clinical team (attending, fellow, resident/nurse practitioner) was surveyed regarding existing and anticipated organ dysfunction. The primary outcomes were clinicians' accuracy at identifying multiple organ dysfunction syndrome and predicting new or progressive multiple organ dysfunction syndrome, compared to the objective assessment of multiple organ dysfunction syndrome using Proulx criteria. We also measured sensitivity, specificity, negative and positive predictive values, and negative and positive likelihood ratios of clinician assessments. We tested for differences in accuracy by clinician type using chi-square tests. Clinicians rated their confidence in prediction on a 5-point Likert scale. There were 476 eligible PICU admissions, for whom 1,218 surveys were completed. Multiple organ dysfunction syndrome was present in 89 patients (18.7%) at enrollment, and new or progressive multiple organ dysfunction syndrome occurred in 39 (8.2%). Clinicians correctly identified multiple organ dysfunction syndrome with 79.9% accuracy and predicted additional organ dysfunction with 82.6% accuracy. However, the positive and negative likelihood ratios for new or progressive multiple organ dysfunction syndrome prediction were 3.0 and 0.7, respectively, indicating a weak relationship between the clinician prediction and development of new or progressive multiple organ dysfunction syndrome. The positive predictive value of new or progressive multiple organ dysfunction syndrome prediction was just 22.1%. We found no differences in accuracy by clinician type for either identification of multiple organ dysfunction syndrome (80.2% vs 78.2% vs 81.0%; p = 0.57) or prediction of new or progressive multiple organ dysfunction syndrome (84.8% vs 82.8% vs 80.3%; p = 0.26) for attendings, fellows, and residents/nurse practitioners, respectively. There was a weak correlation between the confidence and accuracy of prediction (pairwise correlation coefficient, 0.26; p Conclusions PICU clinicians correctly identified multiple organ dysfunction syndrome and predicted new or progressive multiple organ dysfunction syndrome with 80% accuracy. However, only 8% of patients developed new or progressive multiple organ dysfunction syndrome, so accuracy was largely due to true negative predictions. The positive predictive value for new or progressive multiple organ dysfunction syndrome prediction was just 22%. Accuracy did not differ by clinician type, but was correlated with self-rated confidence and was higher for negative predictions.

Background Fluid overload and acute kidney injury are common and associated with poor outcomes among critically ill children. The prodrome of renal angina stratifies patients by risk for severe acute kidney injury, but the predictive discrimination for fluid overload is unknown. Methods Post-hoc analysis of patients admitted to a tertiary care pediatric intensive care unit (PICU). The primary outcome was the performance of renal angina fulfillment on day of ICU admission to predict fluid overload ≥15% on Day 3. Results 77/139 children (55%) fulfilled renal angina (RA+). After adjusting for covariates, RA+ was associated with increased odds of fluid overload on Day 3 (adjusted odds ratio (aOR) 5.1, 95% CI 1.23–21.2, p = 0.025, versus RA-). RA- resulted in a 90% negative predictive value for fluid overload on Day 3. Median fluid overload was significantly higher in RA+ patients with severe acute kidney injury compared to RA+ patients without severe acute kidney injury (% fluid overload on Day 3: 8.8% vs. 0.73%, p = 0.002). Conclusion Among critically ill children, fulfillment of renal angina was associated with increased odds of fluid overload versus the absence of renal angina and a higher fluid overload among patients who developed acute kidney injury. Renal angina directed risk classification may identify patients at highest risk for fluid accumulation. Expanded study in larger populations is warranted.

OBJECTIVE Cancer and its treatment are known to be important risk factors for sepsis, contributing to an estimated 12% of U.S. sepsis admissions in the 1990s. However, cancer treatment has evolved markedly over the past 2 decades. We sought to examine how cancer-related sepsis differs from non-cancer-related sepsis. DESIGN Observational cohort. SETTING National Readmissions Database (2013-2014), containing all-payer claims for 49% of U.S. POPULATION PATIENTS A total of 1,104,363 sepsis hospitalizations. INTERVENTIONS We identified sepsis hospitalizations in the U.S. National Readmissions Database using explicit codes for severe sepsis, septic shock, or Dombrovskiy criteria (concomitant codes for infection and organ dysfunction). We classified hospitalizations as cancer-related versus non-cancer-related sepsis based on the presence of secondary diagnosis codes for malignancy. We compared characteristics (site of infection and organ dysfunction) and outcomes (in-hospital mortality and 30-d readmissions) of cancer-related versus non-cancer-related sepsis hospitalizations. We also completed subgroup analyses by age, cancer types, and specific cancer diagnoses. MEASUREMENTS AND MAIN RESULTS There were 27,481,517 hospitalizations in National Readmissions Database 2013-2014, of which 1,104,363 (4.0%) were for sepsis and 4,150,998 (15.1%) were cancer related. In-hospital mortality in cancer-related sepsis was 27.9% versus 19.5% in non-cancer-related sepsis. The median count of organ dysfunctions was indistinguishable, but the rate of specific organ dysfunctions differed by small amounts (e.g., hematologic dysfunction 20.1% in cancer-related sepsis vs 16.6% in non-cancer-related sepsis; p < 0.001). Cancer-related sepsis was associated with an adjusted absolute increase in in-hospital mortality ranging from 2.2% to 15.2% compared with non-cancer-related sepsis. The mortality difference was greatest in younger adults and waned with age. Patients (23.2%) discharged from cancer-related sepsis were rehospitalized within 30 days, compared with 20.1% in non-cancer-related sepsis (p < 0.001). CONCLUSIONS In this cohort of over 1 million U.S. sepsis hospitalizations, more than one in five were cancer related. The difference in mortality varies substantially across age spectrum and is greatest in younger adults. Readmissions were more common after cancer-related sepsis.

Objectives To critically review, analyze, and synthesize the literature on parent medical traumatic stress from a child's critical illness requiring PICU admission and its association with outcomes of parent mental and physical health, and family functioning. Data sources Systematic literature search of Pubmed, Embase, CINAHL, and PsychInfo. Study selection Two reviewers identified peer-reviewed published articles with the following criteria: 1) published between January 1, 1980, and August 1, 2018; 2) published in English; 3) study population of parents of children with a PICU admission; and 4) quantitative studies examining factors associated with outcomes of parent mental health, parent physical health, or family functioning. Data extraction Literature search yielded 2,476 articles, of which 23 studies met inclusion criteria. Study data extracted included study characteristics, descriptive statistics of parent outcomes after critical illness, and variables associated with parent and family outcomes. Data synthesis Studies examined numerous variables associated with parent and family outcomes and used multiple survey measures. These variables were categorized according to their phase in the Integrative Trajectory Model of Pediatric Medical Traumatic Stress, which included peri-trauma, acute medical care, and ongoing care or discharge from care. The majority of objective elements of a child's illness, such as severity of illness and length of hospitalization, did not have a clear relationship with parent and family outcomes. However, familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge were often associated with parent and family outcomes. Conclusions This systematic literature review suggests that parent and family outcomes after pediatric critical illness are impacted by familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge. Developing parent interventions focused on modifying the parent's subjective experience in the PICU could be an effective approach to improve parent outcomes.

OBJECTIVE: Severe sepsis is a significant cause of healthcare use and morbidity among pediatric patients, but little is known about readmission diagnoses. We sought to determine the most common readmission diagnoses after pediatric severe sepsis, the extent to which post-sepsis readmissions may be potentially preventable, and whether patterns of readmission diagnoses differ compared to readmissions after other common acute medical hospitalizations. DESIGN: Observational Cohort Study SETTING: National Readmission Database (2013-2014), including all-payer hospitalizations from 22 states. PATIENTS: 4528 pediatric severe hospitalizations, matched by age, gender, comorbidities, and length of stay to 4528 pediatric hospitalizations for other common acute medical conditions. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: We compared rates of 30-day all-cause, diagnosis-specific, and potentially preventable hospital readmissions using McNemar’s chi-square tests for paired data. Among 5841 eligible pediatric severe sepsis hospitalizations with live discharge, 4528 (77.5%) were matched 1:1 to 4528 pediatric hospitalizations for other acute medical conditions. Of 4528 matched sepsis hospitalizations, 851 (18.8% (95% CI 16.0, 18.2)) were re-hospitalized within 30 days, compared to 775 (17.1% (95% CI 17.1, 20.0)) of matched hospitalizations for other causes (p=0.02). The most common readmission diagnoses were chemotherapy, device complication, and sepsis, all of which were several-fold higher after sepsis versus after matched non-sepsis hospitalization. Only 11.5% of readmissions were for ambulatory care sensitive conditions compared to 23% of rehospitalizations after common acute medical conditions. CONCLUSION: More than 1 in 6 children surviving severe sepsis were re-hospitalized within 30 days, most commonly for maintenance chemotherapy, medical device complications, or recurrent sepsis. Only a small proportion of readmissions were for ambulatory care sensitive conditions.

OBJECTIVE: To evaluate the physical and psychosocial domains of health-related quality of life (HRQL) among children during the first year following community-acquired septic shock, and explore factors associated with poor physical and psychosocial HRQL outcomes. DESIGN: Secondary analysis of the Life after Pediatric Sepsis Evaluation (LAPSE). SETTING: Twelve academic PICUs in the United States. PATIENTS: Children ≥1 month and

This cohort study examined the number and type of outpatient health visits before and after hospitalization for pediatric severe sepsis.

BACKGROUND: The consensus definition of acute kidney injury (AKI) has evolved since developing the original multiple organ dysfunction syndrome (MODS) definitions. Whether or not risk for adverse short- and long-term outcomes can be identified using the refined AKI criteria in the setting of MODS has not been studied. We hypothesize that incorporation of kidney disease: improving global outcome (KDIGO) AKI criteria into existing MODS definitions will have a higher association with major adverse kidney events at 30 days (MAKE30) and will increase the number of patients with MODS. METHODS: Post-hoc analysis of 410 children admitted to a tertiary care pediatric intensive care unit (PICU). MODS was defined using two existing criteria (Goldstein and Proulx) during the first 7 days following ICU admission and then modified by replacement of the kidney injury criteria using the KDIGO AKI definitions (G’ and P’). RESULTS: MAKE30 occurred in 65 of 410 (16%) children. After substituting KDIGO kidney injury criteria, identification of MAKE30 increased from 46 children (71%) to 53 (82%) and 29 children (45%) to 43 (66%) for the Goldstein and Proulx criteria, respectively. Additionally, identification of MODS increased from 194 (47%) by Goldstein to 224 (55%) by G’ and 95 children (23%) by Proulx to 132 (32%) by P’. CONCLUSION: Substituting KDIGO AKI criteria into existing MODS criteria increases the sensitivity for major adverse kidney events as well as the identification of MODS, improving the detection of children at risk for long-term adverse renal outcomes.

OBJECTIVES Severe sepsis is a significant cause of healthcare utilization and morbidity among pediatric patients. However, little is known about how commonly survivors acquire new medical devices during pediatric severe sepsis hospitalization. We sought to determine the rate of new device acquisition (specifically, tracheostomy placement, gastrostomy tube placement, vascular access devices, ostomy procedures, and amputation) among children surviving hospitalizations with severe sepsis. For contextualization, we compare this to rates of new device acquisition among three comparison cohorts: 1) survivors of all-cause pediatric hospitalizations; 2) matched survivors of nonsepsis infection hospitalizations; and 3) matched survivors of all-cause nonsepsis hospitalization with similar organ dysfunction. DESIGN Observational cohort study. SETTING Nationwide Readmission Database (2016), including all-payer hospitalizations from 27 states. PATIENTS Eighteen-thousand two-hundred ten pediatric severe sepsis hospitalizations; 532,738 all-cause pediatric hospitalizations; 16,173 age- and sex-matched nonsepsis infection hospitalizations; 15,025 organ dysfunction matched all-cause nonsepsis hospitalizations; and all with live discharge. MEASUREMENTS AND MAIN RESULTS Among 18,210 pediatric severe sepsis hospitalizations, 1,024 (5.6%) underwent device placement. Specifically, 3.5% had new gastrostomy, 3.1% new tracheostomy, 0.6% new vascular access devices, 0.4% new ostomy procedures, and 0.1% amputations. One-hundred forty hospitalizations (0.8%) included two or more new devices. After applying the Nationwide Readmissions Database sampling weights, there were 55,624 pediatric severe sepsis hospitalizations and 1,585,194 all-cause nonsepsis hospitalizations with live discharge in 2016. Compared to all-cause pediatric hospitalizations, severe sepsis hospitalizations were eight-fold more likely to involve new device acquisition (6.4% vs 0.8%; p < 0.001). New device acquisition was also higher in severe sepsis hospitalizations compared with matched nonsepsis infection hospitalizations (5.1% vs 1.2%; p < 0.01) and matched all-cause hospitalizations with similar organ dysfunction (4.7% vs 2.8%; p < 0.001). CONCLUSIONS In this nationwide, all-payer cohort of U.S. pediatric severe sepsis hospitalizations, one in 20 children surviving severe sepsis experienced new device acquisition. The procedure rate was nearly eight-fold higher than all-cause, nonsepsis pediatric hospitalizations, and four-fold higher than matched nonsepsis infection hospitalizations.

Objectives To determine the assessment and inter-rater reliability of echocardiographic evaluations of pulmonary vascular disease (PVD) in preterm infants at risk for bronchopulmonary dysplasia. Study design We prospectively studied echocardiograms from preterm infants (birthweights 500-1250 g) at 7 days of age and 36 weeks postmenstrual age (PMA). Echocardiograms were assessed by both a cardiologist on clinical service and a single research cardiologist. Interpretations were reviewed for inclusion of determinants of PVD and assessed for inter-rater reliability using the Prevalence Adjusted Bias Adjusted Kappa Score (PABAK). Results One hundred eighty and 188 matching research and clinical echocardiogram reports were available for the 7-day and 36-week PMA studies. At least one of the specific qualitative measures of PVD was missing from 54% of the clinical reports. PVD was diagnosed at 7 days in 31% and 20% of research and clinical interpretations, respectively (PABAK score of 0.54). At 36 weeks, PH was diagnosed in 15.6% and 17.8% of research and clinical interpretations, respectively (PABAK score of 0.80). Conclusions Although all qualitative variables of PVD are not consistently provided in echocardiogram reports, the inter-rater reliability of cardiologists evaluating measures of PVD revealed strong agreement, especially at 36 weeks PMA. We speculate that establishment of a protocol for echocardiographic evaluation may improve the identification of PVD in preterm infants.

Pediatric acute respiratory distress syndrome (PARDS) is a heterogenous process resulting in a severe acute lung injury. A single indicator does not exist for PARDS diagnosis. Rather, current diagnosis requires a combination of clinical and physiologic variables. Similarly, there is little ability to predict the path of disease, identify those at high risk of poor outcomes or target therapies specific to the underlying pathophysiology. Biomarkers, a measured indicator of a pathologic state or response to intervention, have been studied in PARDS due to their potential in diagnosis, prognostication and measurement of therapeutic response. Additionally, PARDS biomarkers show great promise in furthering our understanding of specific subgroups or endotypes in this highly variable disease, and thereby predict which patients may benefit and which may be harmed by PARDS specific therapies. In this chapter, we review the what, when, why and how of biomarkers in PARDS and discuss future directions in this quickly changing landscape.

This study examines the increasing costs of pediatric hospitalizations for cases of severe sepsis using the 2016 Nationwide Readmissions Database.

Studies have reported an increased risk for suicide in adults with schizophrenia, but limited data on younger populations are available.We hypothesize that first-episode psychosis is associated with an increased risk of suicidal behavior in adolescents.A retrospective study was conducted with patients (n=102) diagnosed with psychosis not otherwised specified (NOS), schizophreniform disorder, schizoaffective disorder or schizophrenia within six months prior to admission. A control group consisting of ninety-eight patients with other (nonpsychosis) psychiatric diagnoses admitted to the same unit was matched by age, gender and ethnicity. All patients and controls were administered the Brief Psychiatric Rating Scale-Children version to assess severity of psychiatric symptoms and suicidality, and medical records were used to assess suicidal behavior and possible risk factors.When compared to controls, patients with psychosis had over twice as many suicide attempts overall (p0.01). The 32% incidence of suicide attempts reported in this cohort is nearly double what is reported in adults with psychosis. Depressive symptoms were significantly correlated with increased suicide attempts (p0.05).There was no significant difference between the number of pediatric psychosis inpatients versus nonpsychotic psychiatric inpatients who attempted suicide. There was, however, a significant difference between the total number of attempts between groups, illustrating that children and adolescents with psychosis are more likely than nonpsychotic psychiatric inpatients to have repeat, or multiple, suicide attempts. Longer duration of untreated psychosis, ADHD and depressive symptoms were found to be the strongest risk factors for patients with psychosis.

Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium–pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1β levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1β is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.

Clostridial light chain (LC) inhibits synaptic transmission by digesting a vesicle-docking protein, syna- ptobrevin, without killing neurons. We here report the fea- sibility of creating a rat hemiparkinsonism model through LC gene expression in the substantia nigra (SN), inhibiting nigrostriatal transmission. 40 adult Sprague Dawley rats were divided into four groups for SN injections of PBS, 6- hydroxydopamine (6-OHDA), or adenoviral vectors for the expression of LC (AdLC), or GFP (AdGFP). Amphetamine and apomorphine induced rotations were assessed before and after SN injection, revealing significant rotational alterations at 8 or 10 days after injection in both AdLC and 6-OHDA but not PBS and AdGFP groups. Induced rotation recovered by one month in AdLC rats but persisted in 6- OHDA rats. Histological analysis of the SN revealed LC and GFP expression with corresponding synaptobrevin depletion in the LC, but not the GFP groups. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) immu- nohistochemistry (IHC) showed markedly decreased stain- ing in ipsilateral SN and striatum in 6-OHDA but not AdLC or AdGFP rats. Similarly, compared with contralateral, ipsilateral striatal dopamine level only decreased in 6- OHDA but not AdLC, AdGFP, or PBS treated rats. Thus, LC expression induces nigral synaptobrevin depletion with resulting inhibition of nigrostriatal synaptic transmission. Unlike 6-OHDA, LC expression inhibits synaptic activity without killing neurons. This approach, therefore, repre- sents a potentially reversible means of nigrostriatal pathway inhibition as a model for Parkinson's disease. Such a model might facilitate transient and controlled nigral inhibition for studying striatal recovery, dopaminergic re-innervation, and normalization of striatal receptors following the recovery of nigrostriatal transmission.

The present study examines gene delivery to cultured motor neurons (MNs) with the Rabies G protein (RabG)-pseudotyped lentiviral equine infectious anemia virus (RabG.EIAV) vector. RabG.EIAV-mediated β-galactosidase (RabG.EIAV-LacZ) gene expression in cultured MNs plateaus 120 h after infection. The rate and percent of gene expression observed are titer-dependent (P

Epilepsy imposes a significant clinical, epidemiologic and economic burden on societies throughout the world. Despite the development of more than ten new antiepileptic drugs over the past 15 years, approximately a third of patients with epilepsy remain resistant to pharmacotherapy. Individuals who fail to respond, or respond only partially, continue to have incapacitating seizures. Managing patients with medically refractory epilepsy is challenging and requires a structured multidisciplinary approach in specialized clinics. If the problems related to drug resistance could be resolved, even in part, by improving the pharmacokinetic profile of existing drugs, the economic savings would be remarkable and the time required to design drugs that achieve seizure control would be shorter than the discovery of new targets and molecules was required. A promising approach is the use of corticosteroids that may have a dual beneficial effect. Resective brain surgery remains the ultimate and highly successful approach to multiple drug resistance in epileptic patients.

The blood–brain barrier (BBB) protects the brain from harmful substances present in the blood stream, while supplying the brain with the nutrients required for proper functioning. The BBB strictly regulates the penetration of drugs into the brain. Failure of such barrier is often associated with CNS pathologies, including epilepsy. Due to the presence of such complex, yet delicate mechanisms of protection, pharmacological targeting of CNS pathologies is challenging. Introduction of pharmaceutical agents for such ends requires new approaches to drug delivery to outwit vascular barriers. Even though numerous antiepileptic drugs (AEDs) are now available, there have been no major improvements in the reduction of the total number of drug-resistant patients. This lack of progress underscores the nonspecificity of the refractory process itself, suggesting that rather general mechanisms may affect the efficacy of all available AEDs.

The development of the mammalian brain is both a highly organized and chaotic process that is nothing short of a miracle. The complexity with which the human brain develops from but a mere plate of ectodermal cells is still not fully understood. Numerous disorders have their etiology seeded in abnormal development during the prenatal and perinatal stages of central nervous system (CNS) development. Various signaling molecules and the precisely orchestrated expression and silencing of neural-specific genes may be disrupted in the CNS development of patients suffering from developmental disorders. In this chapter we present an overview of the normal neural mechanisms of mammalian brain development and how errors in this process contribute to developmental disorders. Developmental disorders are defined as those disorders of the CNS that impair normal functioning and development in early childhood. Developmental pathologies encompass various learning disabilities, dyslexias, dyspraxias, metabolic disorders, and anatomical abnormalities, including those that may result from teratogen exposure. Developmental disorders may affect one specific area of development, or may involve numerous areas as in the case of pervasive developmental disorders. More global developmental disorders result from inherent metabolic abnormalities and more recently described immune mediated mechanisms.

OBJECTIVE: Apoptosis has been shown to play an important role in motor neuron (MN) degeneration in both neurodegenerative disease and peripheral neuropathy. Bcl-xL, an antiapoptotic protein, is down-regulated in these etiologies [corrected] The carboxyl-terminal domain of the tetanus toxin heavy chain (Hc) has high affinity for axon terminal binding and uptake into motor and dorsal root ganglion (DRG) neurons. We report the development of a fusion protein between Hc and Bcl-xL to enhance uptake of Bcl-xL by MNs as a strategy for inhibiting peripheral neuronal apoptosis. METHODS: The genes for Hc, Bcl-xL, and green fluorescent protein were cloned into an Escherichia coli expression system in 2 different arrangements. Fusion proteins were purified through chromatography. Cultured E15 rat spinal cord MNs and DRG cells were used to demonstrate neuron-specific uptake and retrograde transport of the fusion proteins mediated by Hc. Finally, glutamate-induced apoptosis was used as an in vitro model to measure the antiapoptotic effects of the fusion proteins. RESULTS: Bcl-xL fusion proteins were found to bind specifically and undergo uptake into cultured rat spinal MNs. The fusion proteins were also taken up by DRG axonal terminals and transported back to the cell bodies in Campenot compartmentalized chambers (Tyler Research Corp., Edmonton, Canada). Finally, fusion protein application improved cell survival and decreased apoptosis in glutamate-mediated excitotoxicity of the SH-SY5Y neuronal cells. CONCLUSION: Hc can be applied as a universal carrier for therapeutic cargo delivery specifically to MNs or DRGs. The fusion proteins between Bcl-xL and Hc constructed in this study might bear applications to the treatment of MN disease, neuropathy, or nerve injury through nerve or intramuscular injection.

Background Amyotrophic lateral sclerosis (ALS) is a devastating disease that is characterized by the progressive loss of motor neurons. Patients with ALS usually die from respiratory failure due to respiratory muscle paralysis. Consequently, therapies aimed at preserving segmental function of the respiratory motor neurons could extend life for these patients. Insulin-like growth factor-I (IGF-I) is known to be a potent survival factor for motor neurons. In this study we induced high levels of IGF-I expression in the cervical spinal cord of hSOD1 G93A rats with intraspinal cord (ISC) injections of an adeno-associated virus serotype 2 vector (CERE-130). This approach reduced the extent of motor neuron loss in the treated segments of the spinal cord. However, a corresponding preservation of motor function was observed in male, but not female, hSOD1 G93A rats. We conclude that ISC injection of CERE-130 has the potential to protect motor neurons and preserve neuromuscular function in ALS.

Human and animal studies have suggested an underlying inflammatory mechanism for a variety of neuropsychiatric disorders, including schizophrenia. To date, most available reports focused on adult patients.We wished to test the hypothesis that the first psychotic episode in youth is associated with inflammation.We studied patients admitted to a pediatric inpatient psychiatric unit. Patients (n=80) had new-onset psychosis diagnosed using DSM-IV TR criteria for Psychosis NOS, Schizophreniform Disorder or Schizoaffective Disorder. Patients were matched for age, race and gender with inpatient controls without psychosis within the same unit (n=66). We also compared these values to normal pediatric hematologic values. To study the role of inflammation in youth with psychosis, we collected serum samples of 28 children presenting with first-episode psychosis and compared their serum cytokine and S100B levels to eight healthy controls.In this study, we measured serum markers of systemic inflammation.Leukocyte counts revealed a statistically significant increase in absolute monocytes compared to patients without psychosis (0.61 ± 0.282 k/ml vs. 0.496 ± 0.14 k/ml; p0.01) and lymphocytes (2.51 ± 0.84 k/ml vs. 2.24 ± 0.72 k/ml; p0.05) in patients with psychosis. All other hematologic values were similar between the groups. In addition, psychosis was characterized by increased serum levels of S100B, a peripheral marker of blood-brain barrier (BBB) damage. Several inflammatory mediators (e.g., TNF-α, IL-1β, IL-6, IL-5, IL-10, and IFN-γ) were elevated in children with psychosis.These results strongly support a link between systemic inflammation, blood-brain barrier disruption and first-episode psychosis in pediatric patients.