Local lung responses following endobronchial elastase and lipopolysaccharide instillation in sheep

Chronic lipopolysaccharide (LPS) exposure may contribute to the pathogenesis of a number of lung diseases including COPD and emphysema. We sought to develop a large- animal model of emphysema using repeated LPS administration into sheep lung segments. An experimental protocol was designed to facilitate comparisons with elastase-treated and control segments within the same lung of individual sheep. Histopathologic evaluation of segments treated with LPS demonstrated low-grade inflammation characterized by an increase in the number of intra-alveolar macrophages and lymphocytes. Treated segments demonstrated a significant reduction in airspace surface area (ASA), an increase in percent disrupted alveolar attachments and the distance between normal alveolar attachments, and a reduction in the number of normal alveolar attachments surrounding nonrespiratory bronchioles. Coefficient of variation of individual ASA measurements in elastase-treated segments was indicative of a heterogeneous parenchymal response, in contrast to that associated with chronic LPS treatment. Our results demonstrate that chronic LPS treatment of individual lung segments in sheep induces microscopic emphysema qualitatively and quantitatively consistent with both accepted pathologic definitions of this condition and with that produced by airway instillation of elastolytic enzymes. Development of this phenotype is associated with evidence of downregulated activation of transforming growth factor beta

Venatorbacter cucullus gen. nov sp. nov a novel bacterial predator

A novel Gram-stain negative, aerobic, halotolerant, motile, rod-shaped, predatory bacterium ASxL5T, was isolated from a bovine slurry tank in Nottinghamshire, UK using Campylobacter hyointestinalis as prey. Other Campylobacter species and members of the Enterobacteriaceae were subsequently found to serve as prey. Weak axenic growth on Brain Heart Infusion agar was achieved upon subculture without host cells. The optimal growth conditions were 37°C, at pH 7. Transmission electron microscopy revealed some highly unusual morphological characteristics related to prey availability. Phylogenetic analyses using 16S rRNA gene sequences showed that the isolate was related to members of the Oceanospirillaceae family but could not be classified clearly as a member of any known genus. Whole genome sequencing of ASxL5T confirmed the relationship to members the Oceanospirillaceae. Database searches revealed that several ASxL5T share 16S rRNA gene sequences with several uncultured bacteria from marine, and terrestrial surface and subsurface water. We propose that strain ASxL5T represents a novel species in a new genus. We propose the name Venatorbacter cucullus gen. nov., sp. nov. with ASxL5T as the type strain

“Does isometric exercise improve leg stiffness and hop pain in subjects with Achilles tendinopathy? A feasibility study"

Background In Achilles tendinopathy (AT) the ability to store and recycle elastic energy during ground contact phase is often altered. A measure of this function is represented by leg stiffness (LS). Immediate responses in LS following therapeutic intervention have not been examined. Objective The aim of this paper was to examine the feasibility of the protocol in participants with AT. Design Single cohort feasibility study. Participants Adults with persistent AT pain, symptoms on palpation and less than 80 points on the Visa-A questionnaire. Intervention heavy isometric exercise sequence in plantarflexion Outcome Measures Feasibility was assessed by evaluating: the willingness of participants to enroll into the study, the number of eligible participants, the recruitment rate, adherence to the intervention, the drop-out rate, the tolerability of the protocol. LS, reactive strength index, pain and rate of perceived effort were secondary outcomes. Results 22 AT were eligible for data collection and 19 entered the statistical analysis. The intervention was well tolerated, no withdrawals. Pain scores were low during both the intervention and the assessment. Immediate improvements in LS and pain were recorded. Conclusions The isometric exercise protocol was feasible. Future research should investigate its effectiveness

Management strategies to minimize the dredging impacts of coastal development on fish and fisheries

Accelerating coastal development and shipping activities dictate that dredging operations will intensify, increasing potential impacts to fishes. Coastal fishes have high economic, ecological, and conservation significance and there is a need for evidencebased, quantitative guidelines on how to mitigate the impacts of dredging activities. We assess the potential risk from dredging to coastal fish and fisheries on a global scale.We then develop quantitative guidelines for two management strategies: threshold reference values and seasonal restrictions. Globally, threatened species and nearshore fisheries occur within close proximity to ports. We find that maintaining suspended sediment concentrations below 44 mg/L (15–121 bootstrapped CI) and for less than 24 hours would protect 95% of fishes from dredging-induced mortality. Implementation of seasonal restrictions during peak periods of reproduction and recruitment could further protect species from dredging impacts. This study details the first evidence-based defensible approach to minimize impacts to coastal fishes from dredging activities

Structured Observations Reveal Slow HIV-1 CTL Escape

The existence of viral variants that escape from the selection pressures imposed by cytotox- ic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Thera- py at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL es- cape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN- γ ELISpot and lon- gitudinal HIV-1 gag , pol , and nef sequence data were used to study the timing and preva- lence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero re- spectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two year

Quantitative and textural analysis of magnetization transfer and diffusion images in the early detection of brain metastases

Purpose: The sensitivity of the magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) for early detection of brain metastases was investigated in mice and humans. Methods: Mice underwent MRI twice weekly for up to 31 days following intra-cardiac injection of the brain-homing breast cancer cell line MDA-MB231-BR. Patients with small cell lung cancer underwent quarterly MRI for a year. MTR and ADC were measured in regions of metastasis and matched contralateral tissue at the final time-point and in registered regions at earlier time-points. Texture analysis and linear discriminant analysis were performed to detect metastasis-containing slices. Results: Compared with contralateral tissue, mouse metastases had significantly lower MTR and higher ADC at the final time-point. Some lesions were visible at earlier time-points on the MTR and ADC maps: 24% of these were not visible on corresponding T2-weighted images. Texture analysis using the MTR maps showed 100% specificity and 98% sensitivity for metastasis at the final time-point, with 77% sensitivity 2-4 days earlier and 46% 5-8 days earlier. Only 2/16 patients developed metastases, and their penultimate scans were normal. Conclusion: Some brain metastases may be detected earlier on MTR than conventional T2; however, the small gain is unlikely to justify ‘predictive’ MRI.The authors gratefully acknowledge the Cambridge Institute Biological Resources Unit for expert animal care and technical assistance, the Histopathology Core Facility, Drs Joe Frank and Diane Palmieri for providing the cell line, the advice of Dr. Dan Tozer, and the support of Cancer Research UK [grant number C14303/A17197], the Brian Cross Memorial Trust, the Addenbrooke’s Charitable Trust, the University of Cambridge, Hutchison Whampoa Ltd, the Cambridge Experimental Cancer Medicine Centre, and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/mrm.2625

Synthesis, characterisation and photochemistry of PtIV pyridyl azido acetato complexes

PtII azido complexes [Pt(bpy)(N3)2] (1), [Pt(phen)(N3)2] (2) and trans-[Pt(N3)2(py)2] (3) incorporating the bidentate diimine ligands 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen) or the monodentate pyridine (py) respectively, have been synthesised from their chlorido precursors and characterised by X-ray crystallography; complex 3 shows significant deviation from square-planar geometry (N3–Pt–N3 angle 146.7°) as a result of steric congestion at the Pt centre. The novel PtIV complexes trans, cis-[Pt(bpy)(OAc)2(N3)2] (4), trans, cis-[Pt(phen)(OAc)2(N3)2] (5), trans, trans, trans-[Pt(OAc)2(N3)2(py)2] (6), were obtained from 1–3via oxidation with H2O2 in acetic acid followed by reaction of the intermediate with acetic anhydride. Complexes 4–6 exhibit interesting structural and photochemical properties that were studied by X-ray, NMR and UV-vis spectroscopy and TD-DFT (time-dependent density functional theory). These PtIV complexes exhibit greater absorption at longer wavelengths (ε = 9756 M−1 cm−1 at 315 nm for 4; ε = 796 M−1 cm−1 at 352 nm for 5; ε = 16900 M−1 cm−1 at 307 nm for 6, in aqueous solution) than previously reported PtIV azide complexes, due to the presence of aromatic amines, and 4–6 undergo photoactivation with both UVA (365 nm) and visible green light (514 nm). The UV-vis spectra of complexes 4–6 were calculated using TD-DFT; the nature of the transitions contributing to the UV-vis bands provide insight into the mechanism of production of the observed photoproducts. The UV-vis spectra of 1–3 were also simulated by computational methods and comparison between PtII and PtIV electronic and structural properties allowed further elucidation of the photochemistry of 4–6

Quantitative and textural analysis of magnetization transfer and diffusion images in the early detection of brain metastases.

PURPOSE: The sensitivity of the magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) for early detection of brain metastases was investigated in mice and humans. METHODS: Mice underwent MRI twice weekly for up to 31 d following intracardiac injection of the brain-homing breast cancer cell line MDA-MB231-BR. Patients with small cell lung cancer underwent quarterly MRI for 1 year. MTR and ADC were measured in regions of metastasis and matched contralateral tissue at the final time point and in registered regions at earlier time points. Texture analysis and linear discriminant analysis were performed to detect metastasis-containing slices. RESULTS: Compared with contralateral tissue, mouse metastases had significantly lower MTR and higher ADC at the final time point. Some lesions were visible at earlier time points on the MTR and ADC maps: 24% of these were not visible on corresponding T2 -weighted images. Texture analysis using the MTR maps showed 100% specificity and 98% sensitivity for metastasis at the final time point, with 77% sensitivity 2-4 d earlier and 46% 5-8 d earlier. Only 2 of 16 patients developed metastases, and their penultimate scans were normal. CONCLUSIONS: Some brain metastases may be detected earlier on MTR than conventional T2 ; however, the small gain is unlikely to justify "predictive" MRI. Magn Reson Med 77:1987-1995, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.The authors gratefully acknowledge the Cambridge Institute Biological Resources Unit for expert animal care and technical assistance, the Histopathology Core Facility, Drs Joe Frank and Diane Palmieri for providing the cell line, the advice of Dr. Dan Tozer, and the support of Cancer Research UK [grant number C14303/A17197], the Brian Cross Memorial Trust, the Addenbrooke’s Charitable Trust, the University of Cambridge, Hutchison Whampoa Ltd, the Cambridge Experimental Cancer Medicine Centre, and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/mrm.2625

Perceived difficulty and appropriateness of decision making by General Practitioners: a systematic review of scenario studies

Background: Health-care quality in primary care depends largely on the appropriateness of General Practitioners’ (GPs; Primary Care or Family Physicians) decisions, which may be influenced by how difficult they perceive decisions to be. Patient scenarios (clinical or case vignettes) are widely used to investigate GPs’ decision making. This review aimed to identify the extent to which perceived decision difficulty, decision appropriateness, and their relationship have been assessed in scenario studies of GPs’ decision making; identify possible determinants of difficulty and appropriateness; and investigate the relationship between difficulty and appropriateness. Methods: MEDLINE, EMBASE, PsycINFO, the Cochrane Library and Web of Science were searched for scenario studies of GPs’ decision making. One author completed article screening. Ten percent of titles and abstracts were checked by an independent volunteer, resulting in 91% agreement. Data on decision difficulty and appropriateness were extracted by one author and descriptively synthesised. Chi-squared tests were used to explore associations between decision appropriateness, decision type and decision appropriateness assessment method. Results: Of 152 included studies, 66 assessed decision appropriateness and five assessed perceived difficulty. While no studies assessed the relationship between perceived difficulty and appropriateness, one study objectively varied the difficulty of the scenarios and assessed the relationship between a measure of objective difficulty and appropriateness. Across 38 studies where calculations were possible, 62% of the decisions were appropriate as defined by the appropriateness standard used. Chi-squared tests identified statistically significant associations between decision appropriateness, decision type and decision appropriateness assessment method. Findings suggested a negative relationship between decision difficulty and appropriateness, while interventions may have the potential to reduce perceived difficulty. Conclusions: Scenario-based research into GPs’ decisions rarely considers the relationship between perceived decision difficulty and decision appropriateness. The links between these decisional components require further investigation