Structural modification of the antidepressant mianserin suggests that its anti-inflammatory activity may be independent of 5-Hydroxytryptamine receptors

Antidepressants are increasingly recognized to have anti-inflammatory properties in addition to their ability to treat major depressive disorders. To explore if engagement of 5-hydroxytryptamine (5-HT) receptors was required for the anti-inflammatory effect of the tetracyclic antidepressant mianserin, a series of structural derivatives were generated with the aim of reducing 5-HT receptor binding. Primary human peripheral blood mononuclear cells were used to screen for anti-inflammatory activity. The lead compound demonstrated a significant loss in 5-HT receptor binding, as assessed by non-selective 5-HT binding of radiolabelled serotonin in rat cerebral cortex. However, it retained the ability to inhibit endosomal toll-like receptor 8 signaling in primary human macrophages and spontaneous cytokine production from human rheumatoid synovial tissue equivalent to that previously observed for mianserin. These data demonstrate that the anti-inflammatory mechanism of mianserin may be independent of 5-HT receptor activity. This research offers new insights into the mechanism and structural requirements for the anti-inflammatory action of mianserin

Understanding the lives of separating and separated families in the UK: what evidence do we need?

This study was designed to address three broad questions: What are the evidence – and data – needs around family separation in the UK? How far are these needs met by administrative, survey and other research data that currently exist or are in the process of being developed? What additional data are required, and how would these best be collected

Synergistic drug combinations from electronic health records and gene expression.

ObjectiveUsing electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.MethodWe applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.ResultsFrom EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.ConclusionsThis is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing

Undescended testis: 513 patients’ characteristics, age at orchidopexy and patterns of referral

10.1136/archdischild-2013-305225Archives of Disease in Childhood995401-40

Different domains of dengue research in Malaysia: A systematic review and meta-analysis of questionnaire-based studies

This review provided a systematic overview of the questionnaire-related dengue studies conducted in Malaysia and evaluated their reliability and validity used in the questionnaires. An extensive literature search was conducted using various electronic databases, including PubMed, EMBASE, Medline, and ScienceDirect. Systematic reviews and meta-analysis (PRISMA) were selected as the preferred item reporting method. Out of 88 identified dengue-related, 57 published from 2000 to April 2020 met the inclusion criteria and were included. Based on the meta-analysis, a poor mean score was obtained for knowledge (49%), attitude (44%), and preventive practice (55%). The study showed that the level of knowledge on cardinal signs and modes of transmission for dengue virus were highest among health care workers, followed by students (international and local) and lastly community residents. In treatment-seeking behaviours, only half of the respondents (50.8%) would send their child to the nearest health clinics or hospitals when a child became restless or lethargic. The acceptance rate for dengue vaccine, bacteria (Wolbachia), as a vector for dengue control and self-test diagnostic kit for dengue showed considerably high (88.4%, 70%, and 44.8%, respectively). Health belief model (HBM) constructs, such as perceived barriers, perceived severity, perceived susceptibility, self-efficacy, and perceived benefit influence prevention practices. Lastly, only 23 articles (40.3%) had piloted or pretested the questionnaire before surveying, in which three reported Cronbach’s alpha coefficient (0.70–0.90). A need for active participation of communities and healthcare personnel, promotion of awareness, and safe complementary medicines, as well as assessment of psychometric properties of questionnaire use in dengue surveys in Malaysia, in order for assessing dengue reliably and valid

G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in ∼1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA. © 2007 Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56014/1/21343_ftp.pd

Birth outcomes in Colorado's undocumented immigrant population

BACKGROUND: The birth outcomes of undocumented women have not been systematically studied on a large scale. The growing number of undocumented women giving birth in the United States has important implications for clinical care and public health policy. The objective of this study was to describe birth outcomes of undocumented immigrants in Colorado. METHODS: Retrospective descriptive study of singleton births to 5961 undocumented women using birth certificate data for 1998–1999. RESULTS: Undocumented mothers were younger, less educated, and more likely to be single. They had higher rates of anemia, were less likely to gain enough weight, and less likely to receive early prenatal care. They were much less likely to use alcohol or tobacco. Undocumented women had a lower rate of low birth weight (5.3% v 6.5%, P < .001) or preterm infants (12.9% v 14.5%; p = .001). Undocumented women experienced higher rates of labor complications including excessive bleeding (2.3% v 0.8%, p < .001) and fetal distress (8.7% v 3.6%, p < .001). CONCLUSION: Undocumented women have lower rates of preterm delivery and low birth weight infants, but higher rates of pregnancy related risk factors. Higher prevalence of some risk factors which are amenable to medical intervention reveals the need for improved prenatal care in this group

Adverse pregnancy and neonatal outcomes associated with Neisseria gonorrhoeae, Mycoplasma genitalium, M. hominis, Ureaplasma urealyticum and U. parvum: a systematic review and meta-analysis protocol.

INTRODUCTION Several bacterial sexually transmitted and genital mycoplasma infections during pregnancy have been associated with poor pregnancy and perinatal outcomes. Comprehensive and systematic information about associations between sexually transmitted infections (STI) and genital infections in pregnancy and adverse perinatal outcomes is needed to improve understanding about the evidence for causal associations between these infections and adverse pregnancy and neonatal outcomes. Our primary objective is to systematically review the literature about associations between: (1) in pregnancy and preterm birth; (2) in pregnancy and preterm birth; (3) and/or in pregnancy and preterm birth. METHODS AND ANALYSIS We will undertake a systematic search of Medline, Excerpta Medica database and the Cochrane Library and Cumulative Index to Nursing and Allied Health Literature. Following an initial screening of titles by one reviewer, abstracts will be independently assessed by two reviewers before screening of full-text articles. To exclude a manuscript, both reviewers need to agree on the decision. Any discrepancies will be resolved by discussion, or the adjudication of a third reviewer. Studies will be included if they report testing for one or more of during pregnancy and report pregnancy and/or birth outcomes. In this review, the primary outcome is preterm birth. Secondary outcomes are premature rupture of membranes, low birth weight, spontaneous abortion, stillbirth, neonatal mortality and ophthalmia neonatorum. We will use standard definitions, or definitions reported by study authors. We will examine associations between exposure and outcome in forest plots, using the I statistic to examine between study heterogeneity. Where appropriate, we will use meta-analysis to combine results of individual studies. ETHICS AND DISSEMINATION This systematic review of published literature does not require ethical committee approval. Results of this review will be published in a peer reviewed, open access journal. PROSPERO REGISTRATION NUMBER CRD42016050962

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX