Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice

INTRODUCTION: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis. METHODS: Healthy C57Bl/6 mice (n = 66) or BALB/c mice (n = 66) were ventilated (tidal volume = 7.5 ml/kg or 15 ml/kg; positive end-expiratory pressure = 2 cmH2O; fraction of inspired oxygen = 0.5) for five hours. Normal saline or sodium bicarbonate were used to correct for hypovolaemia. Lung histopathology, lung wet-to-dry ratio, bronchoalveolar lavage fluid protein content, neutrophil influx and levels of proinflammatory cytokines and coagulation factors were measured. RESULTS: Animals remained haemodynamically stable throughout the whole experiment. Lung histopathological changes were minor, although significantly more histopathological changes were found after five hours of MV with a larger tidal volume. Lung histopathological changes were no different between the strains. In both strains and with both ventilator settings, MV caused higher wet-to-dry ratios, higher bronchoalveolar lavage fluid protein levels and more influx of neutrophils, and higher levels of proinflammatory cytokines and coagulation factors. Also, with MV higher systemic levels of cytokines were measured. All parameters were higher with larger tidal volumes. Correcting for metabolic acidosis did not alter endpoints. CONCLUSIONS: MV induces VILI, in the absence of a priming pulmonary insult and even with use of relevant (least injurious) ventilator settings. This model offers opportunities to study the pathophysiological mechanisms behind VILI and the contribution of MV to lung injury in the absence of pre-existing lung injury

Chemotherapy-induced nausea and vomiting in daily clinical practice: a community hospital-based study

Background Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of cancer chemotherapy. This study investigated: (1) the impact of CINV on patients' health-related quality of life (HRQL) in daily clinical practice; (2) the association between patient characteristics and type of antiemetics and CINV; and (3) the role of CINV in physicians' decisions to modify antiemetic treatment. Patients and methods This prospective, multicenter study was conducted in nine general hospitals in the Netherlands. During three consecutive chemotherapy cycles, patients used a diary to record episodes of nausea, vomiting and antiemetic use. For each cycle, these ratings were made 1 day prior to and 7 days after having received chemotherapy. The influence of CINV on patients' HRQL was evaluated with the Functional Living Index-Emesis (FLIE) questionnaire at day 6 of each treatment cycle. (Changes in) antiemetic use were recorded by the treating nurse. Patient inclusion took place between May 2005 and May 2007. Results Two hundred seventy-seven patients were enrolled in the study. Acute and delayed nausea during the first treatment cycle was reported by 39% and 68% of the patients, respectively. The comparable figures for acute and delayed vomiting were 12% and 23%. During the first and subsequent treatment cycle, approximately one-third of the patients indicated that CINV had a substantial impact on their daily lives. Female patients and younger patients reported significantly more CINV than male and older patients. At all treatment cycles, patients receiving treatment with moderately emetogenic chemotherapy, containing anthracycline, reported more acute nausea than patients receiving highly emetogenic chemotherapy. Acute vomiting was associated significantly with change in (i.e., additional) antiemetic treatment. Delayed CINV did not influence antiemetic treatment. Conclusion CINV continues to be a problem that adversely affects the daily lives of patients. CINV is worse in women and in younger patients. In daily clinical practice, acute CINV, but not delayed CINV, results in changes in antiemetic treatment. In view of the effects of not only acute, but also delayed CINV on daily life, more attention should be paid to adjustment of antiemetic treatment to cover CINV complaints, later during the chemotherapy cycle

Aerobic exercise training improves not only brachial artery flow-mediated vasodilatation but also carotid artery reactivity: A randomized controlled, cross-over trial in older men.

It is well-known that aerobic exercise training beneficially affects endothelial function as measured by brachial artery flow-mediated vasodilation (FMD). This trial with older sedentary overweight and obese men, therefore, examined the effects of aerobic training on other non-invasive markers of the vasculature, which have been studied in less detail. Seventeen men (67 ± 2 years, BMI: 30.3 ± 2.8 kg/m2 ) participated in this controlled cross-over study. Study participants followed in random order a fully supervised, progressive, aerobic exercise training (three 50-min sessions each week at 70% maximal power) and a no-exercise control period for 8 weeks, separated by a 12-week wash-out period. At the end of each period, endothelial function was assessed by the carotid artery reactivity (CAR) response to a cold pressor test and FMD, and local carotid and regional aortic stiffness by the carotid-to-femoral pulse wave velocity (PWVc-f ). The retinal microvasculature, the serum lipid profile, 24-h ambulatory blood pressure, and 96-h continuous glucose concentrations were also determined. Aerobic training increased CAR from 1.78% to 4.01% (Δ2.23 percentage point [pp]; 95% CI: 0.58, 3.89 pp; p = 0.012) and FMD from 3.88% to 6.87% (Δ2.99 pp; 95% CI: 0.58, 5.41 pp; p = 0.019). The stiffness index β0 increased by 1.1 (95% CI: 0.3, 1.9; p = 0.012), while PWVc-f did not change. Retinal arteriolar width increased by 4 μm (95% CI: 0, 7 μm; p = 0.041). Office blood pressure decreased, but ambulatory blood pressure, and serum lipid and continuous glucose concentrations did not change. Aerobic exercise training improved endothelial function and retinal arteriolar width in older sedentary overweight and obese men, which may reduce cardiovascular risk

InP-based membrane photodetectors for optical interconnects to Si

We present the design, fabrication and a characterization of an InP-based membrane photodetector on an SOI wafer containing a Si-wiring photonic circuit. Waveguide losses in the Si-wiring circuit are below 5 dB/cm. Measured detector responsivity is 0.45 A/W. The photonic device fabrication is compatible with wafer scale processing steps, guaranteeing compatibility towards future generation electronic IC processing

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Collaboration with general practitioners: preferences of medical specialists – a qualitative study

BACKGROUND: Collaboration between general practitioners (GPs) and specialists has been the focus of many collaborative care projects during the past decade. Unfortunately, quite a number of these projects failed. This raises the question of what motivates medical specialists to initiate and continue participating with GPs in new collaborative care models. The following question is addressed in this study: What motivates medical specialists to initiate and sustain new models for collaborating with GPs? METHODS: We conducted semi-structured interviews with eighteen medical specialists in the province of Groningen, in the North of The Netherlands. The sampling criteria were age, gender, type of hospital in which they were practicing, and specialty. The interviews were recorded, fully transcribed, and analysed by three researchers working independently. The resulting motivational factors were grouped into categories. RESULTS: 'Teaching GPs' and 'regulating patient flow' (referrals) appeared to dominate when the motivational factors were considered. In addition, specialists want to develop relationships with the GPs on a more personal level. Most specialists believe that there is not much they can learn from GPs. 'Lack of time', 'no financial compensation', and 'no support from colleagues' were considered to be the main concerns to establishing collaborative care practices. Additionally, projects were often experienced as too complex and time consuming whereas guidelines were experienced as too restrictive. CONCLUSION: Specialists are particularly interested in collaborating because the GP is the gatekeeper for access to secondary health care resources. Specialists feel that they are able to teach the GPs something, but they do not feel that they have anything to learn from the GPs. With respect to professional expertise, therefore, specialists do not consider GPs as equals. Once personal relationships with the GPs have been established, an informal network with incidental professional contact seems to be sufficient to satisfy the collaborative needs of the specialist. The concerns seem to outweigh any positive motivational forces to developing new models of collaborative practice

Cultural Property Protection in the Context of Military Operations: The Case of Uruk, Iraq

This paper deals with the use of military or militarized experts for cultural property protection (CPP) during times of conflict. CPP activities generally take place within a juridical framework that gives obligations for all parties involved, primarily the 1954 Hague Convention for the Protection of Cultural Property in the Event of Armed Conflict, and attention is paid to various implications and challenges that occur when implementing military CPP obligations within this framework. To illustrate matters, the paper details a specific case study from the author’s own field experience in the safeguarding of the archaeological site of Uruk in Iraq. Aspects, including economic, legal, financial, and educational implications, are presented and these are especially relevant since they apply (to an extent) to other situations, such as the recent cultural disasters in Egypt, Libya, and Syria. The Uruk case study is used to suggest a number of key elements that are vital for the implementation of an effective CPP strategy in the context of military operations. Overall, the importance of international cooperation, training, and education, along with the assistance of civil reach-back capabilities, is emphasized. The paper argues that an effective way to protect Cultural Property during armed conflicts is through military channels and with military logistics and tools. To fulfil CPP in agreement with International Humanitarian Law (IHL) joint preparations in peacetime are necessary. The handover of military initiated CPP projects to civil authorities has to take place as soon as the situation permits. The paper concludes with a set of recommendations

Impact of flavonoid-rich black tea and beetroot juice on postprandial peripheral vascular resistance and glucose homeostasis in obese, insulin-resistant men: a randomized controlled trial.

BACKGROUND: Insulin-stimulated muscle blood flow facilitates plasma glucose disposal after a meal, a mechanism that is impaired in obese, insulin-resistant volunteers. Nitrate- or flavonoid-rich products, through their proposed effects on nitric oxide, may improve postprandial blood flow and, subsequently, glucose disposal. To investigate whether a single dose of nitrate-rich beetroot juice or flavonoid-rich black tea lowers postprandial muscle vascular resistance in obese volunteers and alters postprandial glucose or insulin concentrations. METHOD: In a randomised, controlled, cross-over study, 16 obese, insulin-resistant males consumed 75 g glucose, which was combined with 100 ml black tea, beetroot juice or control (water). Peripheral vascular resistance (VR), calculated as mean arterial pressure divided by blood flow, was assessed in the arm and leg conduit arteries, resistance arteries and muscle microcirculation across 3 h (every 30-min) after the oral glucose load. RESULTS: During control, we found no postprandial response in VR in conduit, resistance and microvessels (all P > 0.05). Black tea decreased VR compared to control in conduit, resistance and microvessels (all P < 0.05). Beetroot juice decreased postprandial VR in resistance vessels, but not in conduit artery and microvessels. Although postprandial glucose response was similar after all interventions, postprandial insulin response was attenuated by ~29 % after tea (P < 0.0005), but not beetroot juice. CONCLUSIONS: A single dose of black tea decreased peripheral VR across upper and lower limbs after a glucose load which was accompanied by a lower insulin response. Future studies in insulin-resistant subjects are warranted to confirm the observed effects and to explore whether long-term regular tea consumption affects glucose homeostasis. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov on 30(th) November 2012 (NCT01746329)

Synphilin-1 Enhances α-Synuclein Aggregation in Yeast and Contributes to Cellular Stress and Cell Death in a Sir2-Dependent Manner

© 2010 Büttner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Parkinson’s disease is characterized by the presence of cytoplasmic inclusions, known as Lewy bodies, containing both aggregated α-synuclein and its interaction partner, synphilin-1. While synphilin-1 is known to accelerate inclusion formation by α-synuclein in mammalian cells, its effect on cytotoxicity remains elusive. Methodology/Principal Findings: We expressed wild-type synphilin-1 or its R621C mutant either alone or in combination with α-synuclein in the yeast Saccharomyces cerevisiae and monitored the intracellular localization and inclusion formation of the proteins as well as the repercussions on growth, oxidative stress and cell death. We found that wild-type and mutant synphilin-1 formed inclusions and accelerated inclusion formation by α-synuclein in yeast cells, the latter being correlated to enhanced phosphorylation of serine-129. Synphilin-1 inclusions co-localized with lipid droplets and endomembranes. Consistently, we found that wild-type and mutant synphilin-1 interacts with detergent-resistant membrane domains, known as lipid rafts. The expression of synphilin-1 did not incite a marked growth defect in exponential cultures, which is likely due to the formation of aggresomes and the retrograde transport of inclusions from the daughter cells back to the mother cells. However, when the cultures approached stationary phase and during subsequent ageing of the yeast cells, both wild-type and mutant synphilin-1 reduced survival and triggered apoptotic and necrotic cell death, albeit to a different extent. Most interestingly, synphilin-1 did not trigger cytotoxicity in ageing cells lacking the sirtuin Sir2. This indicates that the expression of synphilin-1 in wild-type cells causes the deregulation of Sir2-dependent processes, such as the maintenance of the autophagic flux in response to nutrient starvation. Conclusions/Significance: Our findings demonstrate that wild-type and mutant synphilin-1 are lipid raft interacting proteins that form inclusions and accelerate inclusion formation of α-synuclein when expressed in yeast. Synphilin-1 thereby induces cytotoxicity, an effect most pronounced for the wild-type protein and mediated via Sir2-dependent processes.This work was supported by grants from IWT-Vlaanderen (SBO NEURO-TARGET), the K.U.Leuven Research Fund (K.U.Leuven BOF-IOF) and K.U.Leuven R&D to JW, a Tournesol grant from Egide (Partenariat Hubert Curien) in France in collaboration with the Flemish Ministry of Education and the Fund of Scientific Research of Flanders (FWO) in Belgium to JW, MCG and LB, a shared PhD fellowship of the EU-Marie Curie PhD Graduate School NEURAD to JW, MCG and LB, grants of the Austrian Science Fund FWF (Austria) to FM and DR (S-9304-B05), to FM and SB (LIPOTOX), and to SB (T-414-B09; Hertha-Firnberg Fellowship) and an EMBO Installation Grant, a Marie Curie IRG, and a grant of the Fundação para a Ciência e Tecnologia (PTDC/SAU-NEU/105215/2008) to TFO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Citral Sensing by TRANSient Receptor Potential Channels in Dorsal Root Ganglion Neurons

Transient receptor potential (TRP) ion channels mediate key aspects of taste, smell, pain, temperature sensation, and pheromone detection. To deepen our understanding of TRP channel physiology, we require more diverse pharmacological tools. Citral, a bioactive component of lemongrass, is commonly used as a taste enhancer, as an odorant in perfumes, and as an insect repellent. Here we report that citral activates TRP channels found in sensory neurons (TRPV1 and TRPV3, TRPM8, and TRPA1), and produces long-lasting inhibition of TRPV1–3 and TRPM8, while transiently blocking TRPV4 and TRPA1. Sustained citral inhibition is independent of internal calcium concentration, but is state-dependent, developing only after TRP channel opening. Citral's actions as a partial agonist are not due to cysteine modification of the channels nor are they a consequence of citral's stereoisoforms. The isolated aldehyde and alcohol cis and trans enantiomers (neral, nerol, geranial, and geraniol) each reproduce citral's actions. In juvenile rat dorsal root ganglion neurons, prolonged citral inhibition of native TRPV1 channels enabled the separation of TRPV2 and TRPV3 currents. We find that TRPV2 and TRPV3 channels are present in a high proportion of these neurons (94% respond to 2-aminoethyldiphenyl borate), consistent with our immunolabeling experiments and previous in situ hybridization studies. The TRPV1 activation requires residues in transmembrane segments two through four of the voltage-sensor domain, a region previously implicated in capsaicin activation of TRPV1 and analogous menthol activation of TRPM8. Citral's broad spectrum and prolonged sensory inhibition may prove more useful than capsaicin for allodynia, itch, or other types of pain involving superficial sensory nerves and skin