Decorin expression is decreased in first trimester placental tissue from pregnancies with small for gestation age infants at birth

Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. FGR pregnancies are often associated with histological evidence of placental vascular thrombosis. The proteoglycans are important components and regulators of vascular homeostasis. Previous studies from our laboratory highlighted mRNA and protein expression differences in placental proteoglycan decorin (DCN), within a clinically well-characterised cohort of third-trimester idiopathic FGR compared with gestation-matched uncomplicated control pregnancies. We also showed that decorin contributes to abnormal angiogenesis and increased thrombin generation in vitro. These observations suggest that DCN gene expression may contribute to the etiology of FGR. Small for gestational age (SGA) is frequently used as a proxy for FGR and is defined as a birth weight below the 10th percentile of a birth weight curve. We therefore made use of a unique resource of first trimester tissues obtained via chorionic villus sampling during the first trimester to investigate the temporal relationship between altered DCN expression and any subsequent development of SGA. We hypothesized that placental DCN expression is decreased early in gestation in SGA pregnancies. Surplus chorionic villus specimens from 15 women subsequently diagnosed with FGR and 50 from women with uncomplicated pregnancies were collected. DCN mRNA and DCN protein were determined using real-time PCR and immunoblotting, respectively. Both DCN mRNA and protein were significantly decreased in placentae from first-trimester SGA-pregnancies compared with controls (p < 0.05). This is the first study to report a temporal relationship between altered placental DCN expression and subsequent development of SGA.     

The Absence of HIV Mutations in Cerebrospinal Fluid and in Peripheral Blood Mononuclear Cells During a Regimen Containing Trizivir Plus Tenofovir

Abstract

Methotrexate (MTX) is widely used in the treatment of hematological diseases. The typical side-effects of high-dose MTX chemotherapy on the CNS range from asymptomatic white matter changes to severe CNS demyelination. MTX neuro - toxicity has been described to be associated with homocysteine and folate levels as well as genetic variants affecting methionine metabolism. Here we describe a case of severe, acute MTX-induced encephalopathy in a patient who was found to be homozygous for the rare missense variant methionine synthase (MTR) c.2756A>G (D919G), which may have modified the effect of MTX on homocysteine metabolism. This finding encourages further studies to determine to what extent the individual conditions of folate and methionine metabolism influence the effects or side-effects of MTX treatment.     

The effect of induced joint restriction on plantar pressure during gait – a pilot study

BackgroundThe aim of this study was to analyse the effect of induced lower limb joint restriction on plantar pressures during gait. Focusing on restricting a single joint, without the effect of other co-morbidities, would provide better understanding as to the resultant plantar loadings during gait, which would be especially beneficial in patients requiring offloading procedures.Research QuestionDoes induced lower limb joint restriction affect plantar pressure distribution during gait?MethodsA prospective, quasi-experimental study was conducted, recruiting ten healthy, adult participants who were instructed to walk barefoot over a Tekscan HR Mat™. This procedure was repeated after separately inducing restriction of the hip, knee and ankle joints. Mean peak plantar pressure (MPP) and pressure-time integral (PTI) data were analysed to compare between unrestricted and restricted data.ResultsSignificant plantar pressure changes were observed in the heel and first metatarsal regions. Rearfoot PTIs were increased with restriction of the contralateral hip (left p <0.001) (right p =0.02) and knee joints (left p =0.01) (right p =0.04). Both MPPs (left p =0.01; right p =0.01) and PTIs (left p =0.004; right p =0.03) were increased in the first metatarsal when restricting the hip joint of the same limb. MPP was decreased in the left first metatarsal with induced knee (left p =0.01; right p =0.04) and ankle (left and right p <0.001) joint restriction. Finally, MPP was decreased in the right first metatarsal with knee (left and right p =0.01) and ankle (left p =0.04; right p =0.01) joint restriction.SignificanceLimited joint mobility may have a direct effect on plantar pressure, particularly with restriction in the hip and knee joints, hence careful attention should be given especially in patients with conditions involving plantar loadings. Results in this study also show that PTI changes during gait should be equally evaluated clinically along with peak plantar pressure analysis.     

Gene Therapy Strategies to Exploit TRIM Derived Restriction Factors against HIV-1

Restriction factors are a collection of antiviral proteins that form an important aspect of the innate immune system. Their constitutive expression allows immediate response to viral infection, ahead of other innate or adaptive immune responses. We review the molecular mechanism of restriction for four categories of restriction factors; TRIM5, tetherin, APOBEC3G and SAMHD1 and go on to consider how the TRIM5 and TRIMCyp proteins in particular, show promise for exploitation using gene therapy strategies. Such approaches could form an important alternative to current anti-HIV-1 drug regimens, especially if combined with strategies to eradicate HIV reservoirs. Autologous CD4⁺ T cells or their haematopoietic stem cell precursors engineered to express TRIMCyp restriction factors, and provided in a single therapeutic intervention could then be used to restore functional immunity with a pool of cells protected against HIV. We consider the challenges ahead and consider how early clinical phase testing may best be achieved.     

Enhanced thymocyte apoptosis induced by maternal undernutrition in late gestation results in declined mature T cells in rat fetal thymus

This study was designed to observe the effects of maternal food restriction (MFR) on the development of fetal thymus in different gestation periods. Timed pregnant rats were randomized into 3 groups: CN (free access to standard chow throughout gestation), MFR_0-21 (50% MFR throughout gestation), MFR_0-14 (50% MFR from gestational day (GD) 0 to GD14, early-mid gestation). Results showed that MFR during early-mid period had few impact on the fetal thymus and T cell subpopulations. However, MFR throughout gestation resulted in thymic atrophy, deceased frequency of both CD4⁺ and CD8⁺ single positive (SP) T cells and enhanced thymocyte apoptosis in fetus. Our results suggest the fetal thymus is more vulnerable to the adverse intrauterine environments in the late gestation period, and the decreased number of SP T cells could result from the enhanced thymocyte apoptosis.     

Remembrance

Susceptibility to rheumatoid arthritis is, in part, conferred by genetic factors. Previous studies have suggested that inheritance of a particular allele of a restriction fragment length polymorphism (RFLP) detected in the T cell receptor β (TCRβ) gene complex is associated with rheumatoid arthritis (RA). We have specifically tested this hypothesis in ethnically and geographically matched populations of RA patients and controls. We were unable to confirm previous observations of a TCRβ association with RA even after stratifying our study and control populations by HLA type.