Blockade of chemokine-induced signalling inhibits CCR5-dependent HIV infection in vitro without blocking gp120/CCR5 interaction.

BACKGROUND: Cellular infection with human immunodeficiency virus (HIV) both in vitro and in vivo requires a member of the chemokine receptor family to act as a co-receptor for viral entry. However, it is presently unclear to what extent the interaction of HIV proteins with chemokine receptors generates intracellular signals that are important for productive infection. RESULTS: In this study we have used a recently described family of chemokine inhibitors, termed BSCIs, which specifically block chemokine-induced chemotaxis without affecting chemokine ligands binding to their receptors. The BSCI termed Peptide 3 strongly inhibited CCR5 mediated HIV infection of THP-1 cells (83 +/- 7% inhibition assayed by immunofluoresence staining), but had no effect on gp120 binding to CCR5. Peptide 3 did not affect CXCR4-dependent infection of Jurkat T cells. CONCLUSION: These observations suggest that, in some cases, intracellular signals generated by the chemokine coreceptor may be required for a productive HIV infection

Stromal Cell Identity Influences the In Vivo Functionality of Engineered Capillary Networks Formed by Co-delivery of Endothelial Cells and Stromal Cells

A major translational challenge in the fields of therapeutic angiogenesis and tissue engineering is the ability to form functional networks of blood vessels. Cell-based strategies to promote neovascularization have been widely explored, and have led to the consensus that co-delivery of endothelial cells (ECs) (or their progenitors) with some sort of a supporting stromal cell type is the most effective approach. However, the choice of stromal cells has varied widely across studies, and their impact on the functional qualities of the capillaries produced has not been examined. In this study, we injected human umbilical vein ECs alone or with normal human lung fibroblasts (NHLFs), human bone marrow-derived mesenchymal stem cells (BMSCs), or human adipose-derived stem cells (AdSCs) in a fibrin matrix into subcutaneous pockets in SCID mice. All conditions yielded new human-derived vessels that inosculated with mouse vasculature and perfused the implant, but there were significant functional differences in the capillary networks, depending heavily on the identity of the co-delivered stromal cells. EC-alone and EC-NHLF implants yielded immature capillary beds characterized by high levels of erythrocyte pooling in the surrounding matrix. EC-BMSC and EC-AdSC implants produced more mature capillaries characterized by less extravascular leakage and the expression of mature pericyte markers. Injection of a fluorescent tracer into the circulation also showed that EC-BMSC and EC-AdSC implants formed vasculature with more tightly regulated permeability. These results suggest that the identity of the stromal cells is key to controlling the functional properties of engineered capillary networks.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140223/1/ten.tea.2012.0281.pd

EviAtlas : a tool for visualising evidence synthesis databases

Abstract: Systematic mapping assesses the nature of an evidence base, answering how much evidence exists on a particular topic. Perhaps the most useful outputs of a systematic map are an interactive database of studies and their meta-data, along with visualisations of this database. Despite the rapid increase in systematic mapping as an evidence synthesis method, there is currently a lack of Open Source software for producing interactive visualisations of systematic map databases. In April 2018, as attendees at and coordinators of the first ever Evidence Synthesis Hackathon in Stockholm, we decided to address this issue by developing an R-based tool called EviAtlas, an Open Access (i.e. free to use) and Open Source (i.e. software code is freely accessible and reproducible) tool for producing interactive, attractive tables and figures that summarise the evidence base. Here, we present our tool which includes the ability to generate vital visualisations for systematic maps and reviews as follows: a complete data table; a spatially explicit geographical information system (Evidence Atlas); Heat Maps that cross-tabulate two or more variables and display the number of studies belonging to multiple categories; and standard descriptive plots showing the nature of the evidence base, for example the number of studies published per year or number of studies per country. We believe that EviAtlas will provide a stimulus for the development of other exciting tools to facilitate evidence synthesis

Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study

The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood–CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease

Effectively Measuring Exercise-Related Variations in T1ρ and T2 Relaxation Times of Healthy Articular Cartilage.

BACKGROUND: Determining the compositional response of articular cartilage to dynamic joint-loading using MRI may be a more sensitive assessment of cartilage status than conventional static imaging. However, distinguishing the effects of joint-loading vs. inherent measurement variability remains difficult, as the repeatability of these quantitative methods is often not assessed or reported. PURPOSE: To assess exercise-induced changes in femoral, tibial, and patellar articular cartilage composition and compare these against measurement repeatability. STUDY TYPE: Prospective observational study. POPULATION: Phantom and 19 healthy participants. FIELD STRENGTH/SEQUENCE: 3T; 3D fat-saturated spoiled gradient recalled-echo; T1ρ - and T2 -prepared pseudosteady-state 3D fast spin echo. ASSESSMENT: The intrasessional repeatability of T1ρ and T2 relaxation mapping, with and without knee repositioning between two successive measurements, was determined in 10 knees. T1ρ and T2 relaxation mapping of nine knees was performed before and at multiple timepoints after a 5-minute repeated, joint-loading stepping activity. 3D surface models were created from patellar, femoral, and tibial articular cartilage. STATISTICAL TESTS: Repeatability was assessed using root-mean-squared-CV (RMS-CV). Using Bland-Altman analysis, thresholds defined as the smallest detectable difference (SDD) were determined from the repeatability data with knee repositioning. RESULTS: Without knee repositioning, both surface-averaged T1ρ and T2 were very repeatable on all cartilage surfaces, with RMS-CV SDD) average exercise-induced in T1ρ and T2 of femoral (-8.0% and -5.3%), lateral tibial (-6.9% and -5.9%), medial tibial (+5.8% and +2.9%), and patellar (-7.9% and +2.8%) cartilage were observed. DATA CONCLUSION: Joint-loading with a stepping activity resulted in T1ρ and T2 changes above background measurement error. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1 J. MAGN. RESON. IMAGING 2020;52:1753-1764.GlaxoSmithKline National Institute of Health Research (NIHR) Cambridge Biomedical Research Centr

Bone marrow lesions and magnetic resonanceImaging–detected structural abnormalities in patients with midfoot pain and osteoarthritis: A cross-sectional study

To compare magnetic resonance imaging (MRI)–detected structural abnormalities in patients withsymptomatic midfoot osteoarthritis (OA), patients with persistent midfoot pain, and asymptomatic controls, and toexplore the association between MRI features, pain, and foot-related disability. One hundred seven adults consisting of 50 patients with symptomatic and radiographically confirmedmidfoot OA, 22 adults with persistent midfoot pain but absence of radiographic OA, and 35 asymptomatic adultsunderwent 3T MRI of the midfoot and clinical assessment. MRIs were read for the presence and severity of abnormal-ities (bone marrow lesions [BMLs], subchondral cysts, osteophytes, joint space narrowing [JSN], effusion-synovitis,tenosynovitis, and enthesopathy) using the Foot Osteoarthritis MRI Score. Pain and foot-related disability wereassessed with the Manchester Foot Pain and Disability Index. The severity sum score of BMLs in the midfoot was greater in patients with midfoot pain and no signs ofOA on radiography compared to controls (P= 0.007), with a pattern of involvement in the cuneiform–metatarsal jointssimilar to that in patients with midfoot OA. In univariable models, BMLs (ρ= 0.307), JSN (ρ= 0.423), and subchondralcysts (ρ= 0.302) were positively associated with pain (P< 0.01). In multivariable models, MRI abnormalities were notassociated with pain and disability when adjusted for covariates. In individuals with persistent midfoot pain but no signs of OA on radiography, MRIfindings suggestedan underrecognized prevalence of OA, particularly in the second and third cuneiform–metatarsal joints, where BMLpatterns were consistent with previously recognized sites of elevated mechanical loading. Joint abnormalities werenot strongly associated with pain or foot-related disability

cAMP Receptor Protein Controls Vibrio cholerae Gene Expression in Response to Host Colonization

The bacterium Vibrio cholerae is native to aquatic environments and can switch lifestyles to cause disease in humans. Lifestyle switching requires modulation of genetic systems for quorum sensing, intestinal colonization, and toxin production. Much of this regulation occurs at the level of gene expression and is controlled by transcription factors. In this work, we have mapped the binding of cAMP receptor protein (CRP) and RNA polymerase across the V. cholerae genome. We show that CRP is an integral component of the regulatory network that controls lifestyle switching. Focusing on a locus necessary for toxin transport, we demonstrate CRP-dependent regulation of gene expression in response to host colonization. Examination of further CRP-targeted genes reveals that this behavior is commonplace. Hence, CRP is a key regulator of many V. cholerae genes in response to lifestyle changes.Cholera is an infectious disease that is caused by the bacterium Vibrio cholerae. Best known for causing disease in humans, the bacterium is most commonly found in aquatic ecosystems. Hence, humans acquire cholera following ingestion of food or water contaminated with V. cholerae. Transition between an aquatic environment and a human host triggers a lifestyle switch that involves reprogramming of V. cholerae gene expression patterns. This process is controlled by a network of transcription factors. In this paper, we show that the cAMP receptor protein (CRP) is a key regulator of V. cholerae gene expression in response to lifestyle changes

MRI identifies plantar plate pathology in the forefoot of patients with rheumatoid arthritis

Previous cadaveric studies have suggested that forefoot deformities at the metatarsophalangeal (MTP) joints in patients with rheumatoid arthritis (RA) might result from the failure of the ligamentous system and displacement of the plantar plates. This study aimed to examine the relationship between plantar plate pathology and the rheumatoid arthritis magnetic resonance imaging score (RAMRIS) of the lesser (second to fifth) MTP joints in patients with RA using high-resolution 3 T magnetic resonance imaging (MRI). In 24 patients with RA, the forefoot was imaged using 3 T MRI. Proton density fat-suppressed, T2-weighted fat-suppressed and T1-weighted post gadolinium sequences were acquired through 96 lesser MTP joints. Images were scored for synovitis, bone marrow oedema and bone erosion using the RAMRIS system and the plantar plates were assessed for pathology. Seventeen females and 7 males with a mean age of 55.5 years (range 37–71) and disease duration of 10.6 years (range 0.6–36) took part in the study. Plantar plate pathology was most frequently demonstrated on MRI at the fifth MTP joint. An association was demonstrated between plantar plate pathology and RAMRIS-reported synovitis, bone marrow oedema and bone erosion at the fourth and fifth MTP joints. In patients with RA, 3 T MRI demonstrates that plantar plate pathology at the lesser MTP joints is associated with features of disease severity. Plantar plate pathology is more common at the fourth and fifth MTP joints in subjects with RA in contrast to the predilection for the second MTP reported previously in subjects without RA

Plantar plate pathology is associated with erosive disease in the painful forefoot of patients with rheumatoid arthritis

Background: Disease-related foot pathology is recognised to have a significant impact on mobility and functional capacity in the majority of patients with rheumatoid arthritis (RA). The forefoot is widely affected and the metatarsophalangeal (MTP) joints are the most common site of symptoms. The plantar plates are the fibrocartilaginous distal attachments of the plantar fascia inserting into the five proximal phalanges. Together with the transverse metatarsal ligament they prevent splaying of the forefoot and subluxation of the MTP joints. Damage to the plantar plates is a plausible mechanism therefore, through which the forefoot presentation, commonly described as ‘walking on pebbles’, may develop in patients with RA. The aims of this study were to investigate the relationship between plantar plate pathology and clinical, biomechanical and plain radiography findings in the painful forefoot of patients with RA. Secondly, to compare plantar plate pathology at the symptomatic lesser (2nd-5th) MTP joints in patients with RA, with a group of healthy age and gender matched control subjects without foot pain. Methods: In 41 patients with RA and ten control subjects the forefoot was imaged using 3T MRI. Intermediate weighted fat-suppressed sagittal and short axis sequences were acquired through the lesser MTP joints. Images were read prospectively by two radiologists and consensus reached. Plantar plate pathology in patients with RA was compared with control subjects. Multivariable multilevel modelling was used to assess the association between plantar plate pathology and the clinical, biomechanical and plain radiography findings. Results: There were significant differences between control subjects and patients with RA in the presence of plantar plate pathology at the lesser MTP joints. No substantive or statistically significant associations were found between plantar plate pathology and clinical and biomechanical findings. The presence of plantar plate pathology was independently associated with an increase in the odds of erosion (OR = 52.50 [8.38–326.97], p < 0.001). Conclusion: The distribution of plantar plate pathology at the lesser MTP joints in healthy control subjects differs to that seen in patients with RA who have the consequence of inflammatory disease in the forefoot. Longitudinal follow-up is required to determine the mechanism and presentation of plantar plate pathology in the painful forefoot of patients with RA

Aerosol indirect effects

Aerosol indirect effects continue to constitute one of the most important uncertainties for anthropogenic climate perturbations. Within the international AEROCOM initiative, the representation of aerosol-cloud-radiation interactions in ten different general circulation models (GCMs) is evaluated using three satellite datasets. The focus is on stratiform liquid water clouds since most GCMs do not include ice nucleation effects, and none of the model explicitly parameterises aerosol effects on convective clouds. We compute statistical relationships between aerosol optical depth (tau a) and various cloud and radiation quantities in a manner that is consistent between the models and the satellite data. cloud droplet number concentration (N d) compares relatively well to the satellite data at least over the ocean. The relationship between (tau a) and liquid water path is simulated much too strongly by the models. This suggests that the implementation of the second aerosol indirect effect mainly in terms of an autoconversion parameterisation has to be revisited in the GCMs. A positive relationship between total cloud fraction (fcld) and tau a as found in the satellite data is simulated by the majority of the models, albeit less strongly than that in the satellite data in most of them. In a discussion of the hypotheses proposed in the literature to explain the satellite-derived strong fcld–tau a relationship, our results indicate that none can be identified as a unique explanation. Relationships similar to the ones found in satellite data between tau a and cloud top temperature or outgoing long-wave radiation (OLR) are simulated by only a few GCMs. The GCMs that simulate a negative OLR - tau a relationship show a strong positive correlation between tau a and fcld. The short-wave total aerosol radiative forcing as simulated by the GCMs is strongly influenced by the simulated anthropogenic fraction of tau a, and parameterisation assumptions such as a lower bound on Nd. Nevertheless, the strengths of the statistical relationships are good predictors for the aerosol forcings in the models. An estimate of the total short-wave aerosol forcing inferred from the combination of these predictors for the modelled forcings with the satellite-derived statistical relationships yields a global annual mean value of −1.5±0.5Wm−2. In an alternative approach, the radiative flux perturbation due to anthropogenic aerosols can be broken down into a component over the cloud-free portion of the globe (approximately the aerosol direct effect) and a component over the cloudy portion of the globe (approximately the aerosol indirect effect). An estimate obtained by scaling these simulated clearand cloudy-sky forcings with estimates of anthropogenic tau a and satellite-retrieved Nd–tau a regression slopes, respectively, yields a global, annual-mean aerosol direct effect estimate of −0.4±0.2Wm−2 and a cloudy-sky (aerosol indirect effect) estimate of −0.7±0.5Wm−2, with a total estimate of −1.2±0.4Wm−2