Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample ( Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.     

Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice

Interferon‐induced transmembrane protein 3 (IFITM3) ?plays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long‐lasting neuronal impairments in mice following polyriboinosinic‐polyribocytidylic acid (polyI:C, a synthetic double‐stranded RNA)‐induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C‐treated astrocytes (polyI:C‐ACM), neurite development was impaired. These polyI:C‐ACM‐induced neurodevelopmental abnormalities were alleviated by ifitm3^?/? astrocyte‐conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C‐treated wild‐type mice, but such neuronal impairments were not observed in ifitm3^?/? mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non‐cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes. GLIA 2013     

The Pregnancy,Arsenic, and Immune Response (PAIR) Study in rural northern Bangladesh

Background

Arsenic exposure and micronutrient deficiencies may alter immune reactivity to influenza vaccination in pregnant women, transplacental transfer of maternal antibodies to the foetus, and maternal and infant acute morbidity.

Objectives

The Pregnancy, Arsenic, and Immune Response (PAIR) Study was designed to assess whether arsenic exposure and micronutrient deficiencies alter maternal and newborn immunity and acute morbidity following maternal seasonal influenza vaccination during pregnancy.

Population

The PAIR Study recruited pregnant women across a large rural study area in Gaibandha District, northern Bangladesh, 2018–2019.

Design

Prospective, longitudinal pregnancy and birth cohort.

Methods

We conducted home visits to enrol pregnant women in the late first or early second trimester (11–17 weeks of gestational age). Women received a quadrivalent seasonal inactivated influenza vaccine at enrolment. Follow-up included up to 13 visits between enrolment and 3 months postpartum. Arsenic was measured in drinking water and maternal urine. Micronutrient deficiencies were assessed using plasma biomarkers. Vaccine-specific antibody titres were measured in maternal and infant serum. Weekly telephone surveillance ascertained acute morbidity symptoms in women and infants.

Preliminary Results

We enrolled 784 pregnant women between October 2018 and March 2019. Of 784 women who enrolled, 736 (93.9%) delivered live births and 551 (70.3%) completed follow-up visits to 3 months postpartum. Arsenic was detected (≥0.02 μg/L) in 99.7% of water specimens collected from participants at enrolment. The medians (interquartile ranges) of water and urinary arsenic at enrolment were 5.1 (0.5, 25.1) μg/L and 33.1 (19.6, 56.5) μg/L, respectively. Water and urinary arsenic were strongly correlated (Spearman's ⍴ = 0.72) among women with water arsenic ≥ median but weakly correlated (⍴ = 0.17) among women with water arsenic < median.

Conclusions

The PAIR Study is well positioned to examine the effects of low-moderate arsenic exposure and micronutrient deficiencies on immune outcomes in women and infants. Registration : NCT03930017.     

Subthalamic deep brain stimulation affects heading perception in Parkinson’s disease

Journal of Neurology - Parkinson’s disease (PD) presents with visuospatial impairment and falls. It is critical to understand how subthalamic deep brain stimulation (STN DBS) modulates...     

Controlled Release in Transdermal Pressure Sensitive Adhesives using Organosilicate Nanocomposites

Polydimethyl siloxane (PDMS) based pressure sensitive adhesives (PSA) incorporating organo-clays at different loadings were fabricated via solution casting. Partially exfoliated nanocomposites were obtained for the hydroxyl terminated PDMS in ethyl acetate solvent as determined by X-ray diffraction and atomic force microscopy. Drug release studies showed that the initial burst release was substantially reduced and the drug release could be controlled by the addition of organo-clay. Shear strength and shear adhesion failure temperature (SAFT) measurements indicated substantial improvement in adhesive properties of the PSA nanocomposite adhesives. Shear strength showed more than 200% improvement at the lower clay loadings and the SAFT increased by about 21% due to the reinforcement provided by the nano-dispersed clay platelets. It was found that by optimizing the level of the organosilicate additive to the polymer matrix, superior control over drug release kinetics and simultaneous improvements in adhesive properties could be attained for a transdermal PSA formulation.     

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2

Prostanoids generated by COX-2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX-2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX-2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX-2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (DeltaU) or ExoU and ExoT (DeltaUT). COX-2(-/-) mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX-2 products such as prostaglandin E(2) on the function of phagocytic cells. Our studies indicate that prostaglandin E(2) may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E(2) suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor(-/-) mice compared to the wild-type controls. Thus it is possible that inhibition of COX-2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.     

Implications of Off‐Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach

Study Objective

Serotonergic adverse drug events (ADEs) are caused by enhanced intrasynaptic concentrations of 5‐hydroxytryptamine (5‐HT). No systematic process currently exists for evaluating cumulative 5‐HT and off‐target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5‐HT drugs in serotonin syndrome (SS) reports.

Data Sources

Publicly available databases including the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data.

Design

An in‐house bioinformatics TargetSearch program ( http://dxulab.org/software ) was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes and serotonin reuptake transporter protein (SERT). In addition, off‐target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define seven polypharmacological drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS by using the Sternbach and Hunter criteria.

Measurements and Main Results

A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple‐receptor interactions had a disproportionately higher number of SS cases using both the Hunter criteria (mean PRR 1.72, 95% CI 1.05–2.39) and Sternbach (mean PRR 1.54, 95% CI 1.29–1.79). 5‐Hydroxytryptamine agonists were associated with a significantly lower proportion of SS cases using the Hunter and Sternbach criteria, respectively (mean PRR 0.49, 95% CI 0.17–0.81 and mean PRR 0.49, 95% CI 0.15–0.83). Drugs with disproportionately higher participation in SS vary considerably between the two diagnostic criteria.

Conclusion

The SEBM model suggests a possible polypharmacological role in SS. Although further research is needed, off‐target receptor activity may help explain differences in severity of toxicity and clinical presentation.     

Nano in nano: Biosynthesized gold and iron nanoclusters cargo neoplastic exosomes for cancer status biomarking

Timely detection is crucial for successful treatment of cancer. The current study describes a new approach that involves utilization of the tumor cell environment for bioimaging with in-situ biosynthesized nanoscale gold and iron probes and subsequent dissemination of Au-Fe nanoclusters from cargo exosomes within the circulatory system. We have isolated the Au-Fe cargo exosomes from the blood of the treated murine models after in situ biosyntheses from their respective pre-ionic solutions (HAuCl₄, FeCl₂), whereas Na₂SeO₃ supplementation added into Au lethal effect. The microarray data of various differentially expressed genes revealed the up-regulated tumor ablation and metal binding genes in SGC-7901 cell lines after treatment with Au-Fe-Se triplet ionic solution. The isolation of Au-Fe nanoclusters cargo exosomes (nano in nano) after secretion from deeply seated tumors may help in early diagnosis and reveal the tumor ablation status during and after the relevant treatment like radio-chemo therapies et al.     

Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group

OBJECTIVE: To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within participating centers. METHODS: In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of > or =25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145-155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation. CONCLUSIONS: The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.