Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants

BACKGROUND: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method: We used an established mouse model of maternal immune activation (MIA) by the viral mimic Polyl:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results: Polyl:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life. © 2009 Li et al.published_or_final_versio

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

PART I. ANALYTICAL APPLICATIONS OF MASS SPECTROMETRY/MASS SPECTROMETRY (MS/MS). PART II. INVESTIGATIONS OF ION-MOLECULE REACTIONS PRODUCTS BY MS/MS. PART III. THE QUESTION OF TAUTOMERISM OF ALKYLNITRILE AND ISONITRILE RADICAL CATIONS

Part I. We describe the design of a unique high resolution mass spectrometry/mass spectrometry (ms/ms) instrument having the configuration electrostatic analyzer, magnetic sector, and electrostatic analyzer (EBE). Suitable experiments are reported which evaluate the instrument in terms of the requirements for analytical ms/ms applications: high resolution mass selection, high dynamic range, and good transmission for collision-induced decomposition (CID) fragments. The unique capability of triple-sector instruments to monitor consecutive collision-induced reactions is applied to the analysis of mixtures of ions which are isobaric and isomeric, respectively. In addition, a method for the analysis of tetrachlorodibenzo-p-dioxin (TCDD) suitable for use with double or triple sector instruments is described in which the loss of COCl from the molecular ion is monitored. The precision, quality of calibration, and detection limit are evaluated directly, and the accuracy and specificity are tested by comparing the results of an analysis of soil samples with those obtained using GC/HRMS. Part II. We employ ms/ms techniques to study the ion-molecule reaction products created and collisionally-stabilized in a high-pressure ion source. By comparison of unimolecular and collision-induced dissociation spectra, it is demonstrated that the stabilized collision complex from the reaction of {o-quinodimethane}(\u27+) and styrene is shown to have the structure of 2-phenyltetralin, the anticipated product of a {4+2}-cycloaddition mechanism. The stabilized complex from the reaction of {styrene}(\u27+) and neutral styrene is shown not to have the structure of 1-phenyltetralin, and we offer evidence in favor of a formal {4+2}-cycloaddition mechanism. The stabilized complexes of {1,3-butadiene}(\u27+) and olefins are shown not to possess the structures expected for a {4+2}-cycloaddition mechanism. Part III. We use unimolecular and collision-induced dissociations to establish that the isomeric pairs {CH(,3)CN}(\u27+) and {CH(,2)CNH}(\u27+) and {CH(,3)NC}(\u27+) and {CH(,2)NCH}(\u27+) are stable, noninterconverting structures, even when activated to decompose. The same conclusion pertains to the ions {CH(,3)CH(,2)CN}(\u27+) and {CH(,3)CHCNH}(\u27+) and for {NCCH(,2)CH(,2)CN}(\u27+), {NCCH(,2)CHCNH}(\u27+), and {HNCCHCHCNH}(\u27+). The energy barrier of a {1,3}-hydrogen shift, a possible isomerization mechanism, is determined to be at least 76 kcal mol(\u27-1) for the {CH(,3)CN}(\u27+) and {CH(,2)CNH}(\u27+) pair

Complete Monosaccharide Analysis by High-Performance Anion-Exchange Chromatography with Pulsed Amperometric Detection

Monosaccharide analysis is a critical way to profile the composition of complex carbohydrates. Methods to analyze neutral and amino sugars have been established for a long time, but methods for acidic sugars are rare. The acidic sugars, including uronic acids and sialic acids, are also important components in some complex carbohydrates. In this report, a high-performance anion-exchange chromatography method with pulsed amperometric detection was initially developed to analyze acidic sugars including different uronic acids and sialic acids. Subsequently, a method to profile complete monosaccharides, including most neutral, amino, and acidic sugars, was developed. This method has a limit of quantitation of ∼12.5 × 10^–3 nmol for each sugar as well as good linearity over a wide range. This is a convenient procedure because it avoids additional derivatization of monosaccharides and has a broad application to a wide range of complex carbohydrates. The monosaccharide compositions of a variety of complex carbohydrates such as different glycosaminoglycans, alginate, fucoidan, and glycans were profiled by this comprehensive method. In addition, the hydrolysis patterns of these complex carbohydrates are discussed

Attack of the 50-foot social justice warrior: the discursive construction of SJW memes as the monstrous feminine

This essay considers the origin and meaning of “social justice warrior” (SJW) memes. Despite each term within the phrase suggesting potentially positive connotations, we argue that as deployed within “alt-right” communities, it implies a kind of monstrous feminine: a woman who is unwieldy and out of control. We catalogue and analyze this meme using a visual discourse analysis of texts gathered through Google Images and Reddit. Our findings suggest that the SJW meme is deployed to emphasize opponents as having non-normative, problematic bodies, different brains (ones ruled by emotion rather than logic), and monstrous characteristics. We argue that such discourse is potentially dangerous, but that feminists may have the tools to recreate the SJW as an image of power