Placental expression of matrix metalloproteinases MMP-2 and MMP-9 in pregnancy: the use of villous explants and high altitude pregnancy studies to explore the role of oxygen in the pathogenesis of pre-eclampsia

The first aim of this study was to investigate levels of MMP-2, MMP-9, TIMP-1, TIMP-2 and HIF-1? in placentae throughout pregnancy using various techniques. The study used immunohistochemistry to detect and quantify MMP-2 and MMP 9 expression in placentae from 7-19 and at 40 weeks of gestation. A reduction was found in extravillous trophoblast (EVT) expression of both MMPs as pregnancy progressed. In contrast endothelial expression of both MMPs increased. MMP-2 expression in villous CTB (vCTB) was highest in early pregnancy but decreased with gestation. MMP-9 expression in vCTB was very low throughout pregnancy. Zymography studies revealed a significant decrease in pro-MMP-2 but not pro-MMP-9 activity through gestation although the latter did decrease during the first trimester. The results of the study suggest a role for MMP-2 and MMP-9 not only in early placental development but also in vascular remodelling in the later stages of gestation. Moreover it also suggests that the role of MMP-2, often regarded as less important than MMP-9 in placental development, warrants further study. Immunohistochemical studies on the same placentae showed that TIMP-1 expression in muscle surrounding the villous endothelium and in the villous stroma increased with gestation while vCTB expression did not alter and EVT expression increased during the second trimester. TIMP-2 staining in vCTB decreased with gestation while staining on endothelium, muscle and stroma increased. EVT expression of TIMP-2 was negatively correlated with gestation. Thus TIMP-2 appeared to have a high degree of co-distribution with MMP-2 both spatially and temporally. HIF-1alpha staining on vCTB and EVT decreased with gestation while expression on the endothelium increased. These results suggest both paracrine and autocrine regulation of MMPs may occur early in pregnancy. Furthermore TIMPs and HIF-1alpha may have a role in regulating the processes in which MMPs are involved in later on in pregnancy. Pregnant women living at high altitude are exposed to chronic hypoxia throughout gestation. It has been reported that high altitude pregnancies show physiology intermediate between normal pregnancy and pre-eclampsia and thus may provide a useful in vivo model of the disease. This study compared MMP-9 and MMP-2 expression in placentae from high, moderate and low altitude. Endothelial expression of MMP-9 was lower at high altitude than low altitude while MMP-9 expression in the villous stroma was higher. This may implicate MMP-9 in adaptive responses to hypoxia and villous remodelling in high altitude placentae. There were no differences in MMP-2 expression between high and low altitude placentae supporting previous studies, which have reported that MMP-2 expression may not be subject to regulation by oxygen. Maternal serum markers of endothelial cell activation were measured throughout pregnancy at high and moderate altitude. It was hypothesised that since circulating VCAM-1 and E-Selectin are increased in pre-eclampsia, they might also be elevated in high altitude pregnancy. This hypothesis was not supported and another marker of endothelial activation, ICAM-1, was not found to be increased either. (Abstract shortened by ProQuest.)

Enhanced flood hydraulic modelling using topographic remote sensing.

Available from British Library Document Supply Centre-DSC:DXN044421 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

HIV-Associated Neurocognitive Disorder: Pathogenesis and Therapeutic Opportunities

Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach

Safety and Pharmacokinetics of a Four Monoclonal Antibody Combination Against Botulinum C and D Neurotoxins.

Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as Tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A-G), which differ between 35% to 68% in amino acid sequence, necessitates the development of serotype specific countermeasures. We present results of a Phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (mAbs), each binding to non-overlapping epitopes on BoNT serotypes C and D resulting in potent toxin neutralization in rodents. This first-in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults (NCT03046550). Three cohorts of eight healthy subjects received a single intravenous dose of NTM-1634 or placebo at 0.33 mg/kg, 0.66 mg/kg or 1 mg/kg. Follow-up examinations and pharmacokinetic evaluations were continued up to 121 days post-infusion. Subjects were monitored using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetic parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well-tolerated with the expected half-lives for human mAbs and with minimal anti-drug antibodies detected over the dose ranges and duration of the study

Protection conferred by typhoid fever against recurrent typhoid fever in urban Kolkata.

We evaluated the protection conferred by a first documented visit for clinical care of typhoid fever against recurrent typhoid fever prompting a visit. This study takes advantage of multi-year follow-up of a population with endemic typhoid participating in a cluster-randomized control trial of Vi capsular polysaccharide typhoid vaccine in Kolkata, India. A population of 70,566 individuals, of whom 37,673 were vaccinated with one dose of either Vi vaccine or a control (Hepatitis A) vaccine, were observed for four years. Surveillance detected 315 first typhoid visits, among whom 4 developed subsequent typhoid, 3 due to reinfection, defined using genomic criteria and corresponding to -124% (95% CI: -599, 28) protection by the initial illness. Point estimates of protection conferred by an initial illness were negative or negligible in both vaccinated and non-vaccinated subjects, though confidence intervals around the point estimates were wide. These data provide little support for a protective immunizing effect of clinically treated typhoid illness, though modest levels of protection cannot be excluded

Considering sex as a biological variable in preclinical research

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154390/1/fsb2fj201600781r.pd

A global resource for genomic predictions of antimicrobial resistance and surveillance of Salmonella Typhi at pathogenwatch.

As whole-genome sequencing capacity becomes increasingly decentralized, there is a growing opportunity for collaboration and the sharing of surveillance data within and between countries to inform typhoid control policies. This vision requires free, community-driven tools that facilitate access to genomic data for public health on a global scale. Here we present the Pathogenwatch scheme for Salmonella enterica serovar Typhi (S. Typhi), a web application enabling the rapid identification of genomic markers of antimicrobial resistance (AMR) and contextualization with public genomic data. We show that the clustering of S. Typhi genomes in Pathogenwatch is comparable to established bioinformatics methods, and that genomic predictions of AMR are highly concordant with phenotypic susceptibility data. We demonstrate the public health utility of Pathogenwatch with examples selected from >4,300 public genomes available in the application. Pathogenwatch provides an intuitive entry point to monitor of the emergence and spread of S. Typhi high risk clones

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease

Tracking the embryonic stem cell transition from ground state pluripotency

Mouse embryonic stem (ES) cells are locked into self-renewal by shielding from inductive cues. Release from this ground state in minimal conditions offers a system for delineating developmental progression from naive pluripotency. Here we examined the initial transition process. The ES cell population behaves asynchronously. We therefore exploited a short-half-life $\textit{Rex1::GFP}$ reporter to isolate cells either side of exit from naive status. Extinction of ES cell identity in single cells is acute. It occurs only after near-complete elimination of naïve pluripotency factors, but precedes appearance of lineage specification markers. Cells newly departed from the ES cell state display features of early post-implantation epiblast and are distinct from primed epiblast. They also exhibit a genome-wide increase in DNA methylation, intermediate between early and late epiblast. These findings are consistent with the proposition that naive cells transition to a distinct formative phase of pluripotency preparatory to lineage priming.This research was funded by the Wellcome Trust (091484/Z/10/Z and 095645/Z/11/Z), the Biotechnology and Biological Sciences Research Council (BB/M004023/1 and BB/K010867/1), a European Commission Framework 7 project EuroSyStem (HEALTH-F4-2007-200720 EUROSYSTEM), SysStemCell (ERC-2013-AdG 339431), the Medical Research Council (MRC) (G1100526/1) the Louis-Jeantet Foundation and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO-VIDI 864.12.007). The Cambridge Stem Cell Institute receives core funding from the Wellcome Trust and Medical Research Council (MRC). A.S. is an MRC Professor. Deposited in PMC for immediate release