The effect of active toe movement (AToM) on calf pump function and deep vein thrombosis in patients with acute foot and ankle trauma treated with cast - a prospective randomized study

Background Patients with foot and ankle trauma treated with cast are advised to perform toe movements to prevent venous thromboembolism (VTE). Our aim was to determine the effect of active toe movement on asymptomatic deep vein thrombosis (DVT) and venous calf pump function. Methods Patients aged 18–60 years with acute foot and ankle trauma requiring below knee non weight bearing cast were randomized to intervention (regular active toe movement) or control groups (n = 100). Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. Patients requiring chemical thromboprophylaxis were excluded. Results 78 completed the study. 27% sustained asymptomatic DVT, with no statistically significant difference in calf pump function or DVT incidence between groups. All DVT's occurred in the injured lower limb. Conclusion Active toe movement is not a viable strategy for thromboprophylaxis in patients with acute foot and ankle trauma treated with cast

Post-exercise hot or cold water immersion does not alter perception of effort or neuroendocrine responses during subsequent moderate-intensity exercise

Post-exercise hot (HWI) and cold (CWI) water immersion are popular strategies used by athletes in a range of sporting contexts, such as enhancing recovery or adaptation. However, prolonged heating bouts increase neuroendocrine responses that are associated with perceptions of fatigue. Fourteen endurance-trained runners performed three trials consisting of two 45-min runs at 95% lactate threshold on a treadmill separated by 6 h of recovery. Following the first run, participants completed one of HWI (30 min, 40°C), CWI (15 min, 14°C) or control (CON, 30 min rest in ambient conditions) in a randomised order. Perceived effort and recovery were measured using ratings of perceived exertion (RPE) and the Acute Recovery and Stress Scale (ARSS), whilst physiological responses including venous concentrations of a range of neuroendocrine markers, superficial femoral blood flow, heart rate and rectal temperature were measured. Exercise increased neuroendocrine responses of interleukin-6, adrenaline and noradrenaline (all P &lt; 0.001). Additionally, perceptions of overall recovery (P &lt; 0.001), mental performance capacity (P = 0.02), physical performance capability (P = 0.01) and emotional balance (P = 0.03) were reduced prior to the second run. However, there was no effect of condition on these variables (P &gt; 0.05), nor RPE (P = 0.68), despite differences in rectal temperature, superficial femoral blood flow following the first run, and participants’ expected recovery prior to the intervention (all P &lt; 0.001). Therefore, athletes may engage in post-exercise hot or cold-water immersion without negatively impacting moderate-intensity training sessions performed later the same day.</p

The health benefits of passive heating and aerobic exercise: to what extent do the mechanisms overlap?

Exercise can induce numerous health benefits that can reduce the risk of chronic diseases and all-cause mortality, yet a significant percentage of the population do not meet minimal physical activity guidelines. Several recent studies have shown that passive heating can induce numerous health benefits, many of which are comparable to exercise, such as improvements to cardiorespiratory fitness, vascular health, glycaemic control and chronic low-grade inflammation. As such, passive heating is emerging as a promising therapy for populations who cannot perform sustained exercise or display poor exercise adherence. There appears to be some overlap between the cellular signalling responses that are regulated by temperature and the mechanisms that underpin beneficial adaptations to exercise, but detailed comparisons have not yet been made. Therefore, the purpose of this mini review is to assess the similarities and distinctions between adaptations to passive heating and exercise. Understanding the potential shared mechanisms of action between passive heating and exercise may help to direct future studies to implement passive heating more effectively and identify differences between passive heating and exercise induced adaptations

Lubrication regime of the contact between fat and bone in bovine tissue

Fat pads are masses of encapsulated adipose tissue located throughout the human body. Whilst a number of studies describe these soft tissues anatomically little is known about their biomechanics, and surgeons may excise them arthroscopically if they hinder visual inspection of the joint or bursa. By measuring the coefficient of friction between, and performing Sommerfeld analysis of, the surfaces approximating the in vivo conjuncture, this contact has been shown to have a coefficient of friction of the order of 0.01. The system appears to be lubricated hydrodynamically, thus possibly promoting low levels of wear. It is suggested that one of the functions of fat pads associated with subtendinous bursae and synovial joints is to generate a hydrodynamic lubricating layer between the opposing surfaces

Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism

BACKGROUND Inflammation impairs cognitive performance and is implicated in the progression of neurodegenerative disorders. Rodent studies demonstrated key roles for inflammatory mediators in many processes critical to memory, including long-term potentiation, synaptic plasticity, and neurogenesis. They also demonstrated functional impairment of medial temporal lobe (MTL) structures by systemic inflammation. However, human data to support this position are limited. METHODS Sequential fluorodeoxyglucose positron emission tomography together with experimentally induced inflammation was used to investigate effects of a systemic inflammatory challenge on human MTL function. Fluorodeoxyglucose positron emission tomography scanning was performed in 20 healthy participants before and after typhoid vaccination and saline control injection. After each scanning session, participants performed a virtual reality spatial memory task analogous to the Morris water maze and a mirror-tracing procedural memory control task. RESULTS Fluorodeoxyglucose positron emission tomography data demonstrated an acute reduction in human MTL glucose metabolism after inflammation. The inflammatory challenge also selectively compromised human spatial, but not procedural, memory; this effect that was independent of actions on motivation or psychomotor response. Effects of inflammation on parahippocampal and rhinal glucose metabolism directly mediated actions of inflammation on spatial memory. CONCLUSIONS These data demonstrate acute sensitivity of human MTL to mild peripheral inflammation, giving rise to associated functional impairment in the form of reduced spatial memory performance. Our findings suggest a mechanism for the observed epidemiologic link between inflammation and risk of age-related cognitive decline and progression of neurodegenerative disorders including Alzheimer's disease

Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SqCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SqCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, which are each observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. Additionally, we report a patient with an FGFR2-mutated oral squamous cell carcinoma who responded to the multi-targeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SqCC

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476)

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10−9) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group

Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition

Detectable Clonal Mosaicism from Birth to Old Age and its Relationship to Cancer

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18)