Relationship between combat-related traumatic injury and ultrashort term heart rate variability in a UK military cohort: findings from the ADVANCE study

Introduction Combat-related traumatic injury (CRTI) has been linked to an increased cardiovascular disease (CVD) risk. The long-term impact of CRTI on heart rate variability (HRV)—a robust CVD risk marker—has not been explored. This study investigated the relationship between CRTI, the mechanism of injury and injury severity on HRV. Methods This was an analysis of baseline data from the ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE) prospective cohort study. The sample consisted of UK servicemen with CRTI sustained during deployment (Afghanistan, 2003–2014) and an uninjured comparison group who were frequency matched to the injured group based on age, rank, deployment period and role in theatre. Root mean square of successive differences (RMSSD) was measured as a measure of ultrashort term HRV via <16 s continuous recording of the femoral arterial pulse waveform signal (Vicorder). Other measures included injury severity (New Injury Severity Scores (NISS)) and injury mechanism. Results Overall, 862 participants aged 33.9±5.4 years were included, of whom 428 (49.6%) were injured and 434 (50.3%) were uninjured. The mean time from injury/ deployment to assessment was 7.91±2.05 years. The median (IQR) NISS for those injured was 12 (6–27) with blast being the predominant injury mechanism (76.8%). The median (IQR) RMSSD was significantly lower in the injured versus the uninjured (39.47 ms (27.77–59.77) vs 46.22 ms (31.14–67.84), p<0.001). Using multiple linear regression (adjusting for age, rank, ethnicity and time from injury), geometric mean ratio (GMR) was reported. CRTI was associated with a 13% lower RMSSD versus the uninjured group (GMR 0.87, 95% CI 0.80–0.94, p<0.001). A higher injury severity (NISS ≥25) (GMR 0.78, 95% CI 0.69–0.89, p<0.001) and blast injury (GMR 0.86, 95% CI 0.79–0.93, p<0.001) were also independently associated with lower RMSSD. Conclusion These results suggest an inverse association between CRTI, higher severity and blast injury with HRV. Longitudinal studies and examination of potential mediating factors in this CRTI-HRV relationship are needed

Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine

Immobilization stress upregulates c-Fos expression in several CNS areas. Repeated stress or the use of drugs can modulate stress-induced c-Fos expression. Here, we investigated in 40 different areas of the rat brain the effects of dexamethasone (SDX, a synthetic glucocorticoid), diazepam (SBDZ, a benzodiazepine), and imipramine (IMI, an antidepressant) on the c-Fos expression induced by restraint stress. Wistar rats were divided into four groups and submitted to 20 days of daily injection of saline (three first groups) or imipramine, 15 mg/kg, i.p. On day 21, animals were submitted to injections of saline (somatosensory, SS), SDX (1 mg/kg, i.p.), SBDZ (5 mg/kg, i.p.), or IMI (15 mg/kg, i.p.) before being submitted to restraint. Immediately after stress, the animals were perfused and their brains processed with immunohistochemistry for c-Fos (Ab-5 Oncogene Science). Dexamethasone reduced stress- induced c-Fos expression in SS cortex, hippocampus, paraventricular nucleus of the hypothalamus (PVH), and locus coeruleus (LC), whereas diazepam reduced c-Fos staining in the SS cortex, hippocampus, bed nucleus of stria terminalis, septal area, and hypothalamus (preoptic area and supramammillary nucleus). Chronic administration of imipramine decreased staining in the hippocampus, PVH, and LC, while increasing it in the nucleus raphe pallidus. We conclude that dexamethasone, diazepam and imipramine differentially modulate stress-induced Fos expression. the present study provides an important comparative background that may help in the further understanding of the effects of these compounds and on the brain activation as well as on the behavioral, neuroendocrine, and autonomic responses to stress.UFRRJ, Dept Physiol Sci, BR-23890000 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilWeb of Scienc

Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC)

This study was performed to determine the activity of adding continuous infusion (CI) of 5-fluorouracil (5-FU) to gemcitabine (GEM) vs GEM alone in advanced pancreatic cancer (APC). In all, 94 chemo-naïve patients with APC were randomised to receive GEM alone (arm A: 1000 mg m−2 per week for 7 weeks followed by a 2 week rest period, then weekly for 3 consecutive weeks out of every 4 weeks) or in combination with CI 5-FU (arm B: CI 5-FU 200 mg m−2 day−1 for 6 weeks followed by a 2 week rest period, then for 3 weeks every 4 weeks). Overall response rate (RR) was the primary end point and criteria for decision were planned according to the Simon's optimal two-stage design. The overall RR was 8% (arm A) and 11% (arm B) (95% confidence interval: 0.5–16% and 2–22%), respectively, and stable disease was 29 and 28%. The median duration of RR was 34 weeks (range 25–101 weeks) for GEM and 26 weeks (range 16–46 weeks) for the combination. The median progression-free survival (PFS) was 14 weeks (range 2–65 weeks) and 18 weeks (range 4–51 weeks), respectively. The median overall survival (OS) was 31 weeks (range 1–101 weeks) and 30 weeks (1–101 weeks). Toxicity was mild in both arms. This study does not show promising activity in terms of RR, PFS and OS for the double combination arm in APC

Stress-induced decreases in local cerebral glucose utilization in specific regions of the mouse brain

BACKGROUND: Restraint stress in rodents has been reported to activate the hypothalamic-pituitary-adrenocortical (HPA) axis and to increase c-fos expression in regions that express components of the corticotropin-releasing factor (CRF) system. We have previously reported that acute central administration of CRF increased a measure of relative local cerebral glucose utilization (LCGU), a measure of neuronal activity in specific brain regions, and activated the HPA axis in mice. It was hypothesized that the involvement of the CRF system in the stress response would lead to similar changes in relative LCGU after restraint stress. In the present studies the effect of restraint stress on relative LCGU and on the HPA axis in C57BL/6N mice were examined. FINDINGS: Restraint stress activated the HPA axis in a restraint-duration dependent manner, but in contrast to the reported effects of CRF, significantly decreased relative LCGU in frontal cortical, thalamic, hippocampal and temporal dissected regions. These findings support evidence that stressors enforcing limited physical activity reduce relative LCGU, in contrast to high activity stressors such as swim stress. CONCLUSIONS: In conclusion, the present studies do not support the hypothesis that stress-induced changes in relative LCGU are largely mediated by the CRF system. Further studies will help to delineate the role of the CRF system in the early phases of the relative LCGU response to stress and investigate the role of other neurotransmitter systems in this response

EAACI position paper on occupational rhinitis

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item

Dysfunction of Nrf-2 in CF Epithelia Leads to Excess Intracellular H2O2 and Inflammatory Cytokine Production

Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1β mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by ≥2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by ∼70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses

A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer

Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC50s under the Cmax in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients

Aberrant DNA Methylation of Matrix Remodeling and Cell Adhesion Related Genes in Pterygium

10.1371/journal.pone.0014687PLoS ONE62