Effects of overinflation on procollagen type III expression in experimental acute lung injury

Abstract Introduction In acute lung injury (ALI), elevation of procollagen type III (PC III) occurs early and has an adverse impact on outcome. We examined whether different high-inflation strategies of mechanical ventilation (MV) in oleic acid (OA) ALI alter regional expression of PC III. Methods We designed an experimental, randomized, and controlled protocol in which rats were allocated to two control groups (no injury, recruited [alveolar recruitment maneuver after tracheotomy without MV; n = 4 rats] and control [n = 5 rats]) or four injured groups (one exposed to OA only [n = 10 rats] and three OA-injured and ventilated). The three OA-injured groups were ventilated for 1 hour according to the following strategies: LVHP-S (low volume-high positive end-expiratory pressure [PEEP], supine; n = 10 rats, tidal volume [VT] = 8 ml/kg, PEEP = 12 cm H2O), HVLP-S (high volume-low PEEP, supine; n = 10 rats, VT = 20 ml/kg, PEEP = 5 cm H2O), and HVLP-P (high volume-low PEEP, prone; n = 10 rats). Northern blot analysis for PC III and interleukin-1-beta (IL-1β) and polymorphonuclear infiltration index (PMI) counting were performed in nondependent and dependent regions. Regional differences between groups were assessed by two-way analysis of variance after logarithmic transformation and post hoc tests. Results A significant interaction for group and region effects was observed for PC III (p = 0.012) with higher expression in the nondependent region for HVLP-S and LVHP-S, intermediate for OA and HVLP-P, and lower for control (group effect, p < 0.00001, partial η2 = 0.767; region effect, p = 0.0007, partial η2 = 0.091). We found high expression of IL-1β (group effect, p < 0.00001, partial η2 = 0.944) in the OA, HVLP-S, and HVLP-P groups without regional differences (p = 0.16). PMI behaved similarly (group effect, p < 0.00001, partial η2 = 0.832). Conclusion PC III expression is higher in nondependent regions and in ventilatory strategies that caused overdistension. This response was partially attenuated by prone positioning.

Psychometric validation of the Portuguese version of the Neuropathic Pain Symptoms Inventory

Backgroud: It has been shown that different symptoms or symptom combinations of neuropathic pain (NeP) may correspond to different mechanistic backgrounds and respond differently to treatment. The Neuropathic Pain Symptom Inventory (NPSI) is able to detect distinct clusters of symptoms (i.e. dimensions) with a putative common mechanistic background. The present study described the psychometric validation of the Portuguese version (PV) of the NPSI. Methods: Patients were seen in two consecutive visits, three to four weeks apart. They were asked to: (i) rate their mean pain intensity in the last 24 hours on an 11-point (0-10) numerical scale; (ii) complete the PV-NPSI; (iii) provide the list of pain medications and doses currently in use. VAS and Global Impression of Change (GIC) were filled out in the second visit. Results: PV-NPSI underwent test-retest reliability, factor analysis, analysis of sensitivity to changes between both visits. The PV-NPSI was reliable in this setting, with a good intra-class correlation for all items. The factorial analysis showed that the PV-NPSI inventory assessed different components of neuropathic pain. Five different factors were found. The PV-NPSI was adequate to evaluate patients with neuropathic pain and to detect clusters of NeP symptoms. Conclusions: The psychometric properties of the PV-NPSI rendered it adequate to evaluate patients with both central and peripheral neuropathic pain syndromes and to detect clusters of NeP symptoms.

Role of an indole-thiazolidine molecule PPAR pan-agonist and COX inhibitor on inflammation and microcirculatory damage in acute gastric lesions

The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan) and cyclooxygenase (COX) inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl) gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o.) 1 hour before oral administration of Et/HCl (60%/0.03M). In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME) before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO), as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H(+) in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling neutrophil influx and microcirculatory blood flow mediated by NO

On the mechanisms that limit oxygen uptake during exercise in acute and chronic hypoxia: role of muscle mass

[EN] Peak aerobic power in humans (VO2,peak) is markedly affected by inspired O2 tension (FIO2). The question to be answered in this study is what factor plays a major role in the limitation of muscle peak VO2 in hypoxia: arterial O2 partial pressure (Pa,O2) or O2 content (Ca,O2)? Thus, cardiac output (dye dilution with Cardio-green), leg blood flow (thermodilution), intra-arterial blood pressure and femoral arterial-to-venous differences in blood gases were determined in nine lowlanders studied during incremental exercise using a large (two-legged cycle ergometer exercise: Bike) and a small (one-legged knee extension exercise: Knee)muscle mass in normoxia, acute hypoxia (AH) (FIO2 = 0.105) and after 9 weeks of residence at 5260 m (CH). Reducing the size of the active muscle mass blunted by 62% the effect of hypoxia on VO2,peak in AH and abolished completely the effect of hypoxia on VO2,peak after altitude acclimatization. Acclimatization improved Bike peak exercise Pa,O2 from 34 +/- 1 in AH to 45 +/- 1 mmHg in CH(P <0.05) and Knee Pa,O2 from 38 +/- 1 to 55 +/- 2 mmHg(P <0.05). Peak cardiac output and leg blood flow were reduced in hypoxia only during Bike. Acute hypoxia resulted in reduction of systemic O2 delivery (46 and 21%) and leg O2 delivery (47 and 26%) during Bike and Knee, respectively, almost matching the corresponding reduction in VO2,peak. Altitude acclimatization restored fully peak systemic and leg O(2) delivery in CH (2.69 +/- 0.27 and 1.28 +/- 0.11 l min(-1), respectively) to sea level values (2.65 +/- 0.15 and 1.16 +/- 0.11 l min(-1), respectively) during Knee, but not during Bike. During Knee in CH, leg oxygen delivery was similar to normoxia and, therefore, also VO2,peak in spite of a Pa,O2 of 55 mmHg. Reducing the size of the active mass improves pulmonary gas exchange during hypoxic exercise, attenuates the Bohr effect on oxygen uploading at the lungs and preserves sea level convective O2 transport to the active muscles. Thus, the altitude-acclimatized human has potentially a similar exercising capacity as at sea level when the exercise model allows for an adequate oxygen delivery (blood flow x Ca,O2), with only a minor role of Pa,O2 per se, when Pa,O2 is more than 55 mmHg.

Effects of ocean acidification on the brown alga "Padina pavonica": decalcification due to acute and chronic events

[EN] Since the industrial revolution, anthropogenic CO2 emissions have caused ocean acidification, which particularly affects calcified organisms. Given the fan-like calcified fronds of the brown alga Padina pavonica, we evaluated the acute (shortterm) effects of a sudden pH drop due to a submarine volcanic eruption (October 2011–early March 2012) affecting offshore waters around El Hierro Island (Canary Islands, Spain). We further studied the chronic (long-term) effects of the continuous decrease in pH in the last decades around the Canarian waters. In both the observational and retrospective studies (using herbarium collections of P. pavonica thalli from the overall Canarian Archipelago), the percent of surface calcium carbonate coverage of P. pavonica thalli were contrasted with oceanographic data collected either in situ (volcanic eruption event) or from the ESTOC marine observatory data series (herbarium study). Results showed that this calcified alga is sensitive to acute and chronic environmental pH changes. In both cases, pH changes predicted surface thallus calcification, including a progressive decalcification over the last three decades. This result concurs with previous studies where calcareous organisms decalcify under more acidic conditions. Hence, Padina pavonica can be implemented as a bio-indicator of ocean acidification (at short and long time scales) for monitoring purposes over wide geographic ranges, as this macroalga is affected and thrives (unlike strict calcifiers) under more acidic conditions

Effects of acute temperature increase on performance and survival of Caribbean echinoids

Climate change is occurring at a faster rate than in the past, with an expected increase of mean sea surface temperatures up to 4.8°C by the end of this century. The actual capabilities of marine invertebrates to adapt to these rapid changes has still to be understood. Adult echinoids play a crucial role in the tropical ecosystems where they live. Despite their role, few studies about the effect of temperature increase on their viability have been reported in literature. This thesis work reports a first systematic study on several Caribbean echinoids about their tolerance to temperature rise in the context of global warming. The research - carried out at the Bocas del Toro Station of the Smithsonian Tropical Research Institute, in Panama - focalized on the 6 sea urchins Lytechinus variegatus, L. williamsi, Echinometra lucunter, E. viridis, Tripneustes ventricosus and Eucidaris tribuloides, and the 2 sand dollars Clypeaster rosaceus and C. subdepressus. Mortality and neuromuscular well-being indicators - such as righting response, covering behaviour, adhesion to the substrate, spine and tube feet movements - have been analysed in the temperature range 28-38°C. The righting time RT (i.e., the time necessary for the animal to right itself completely after inversion) measured in the 6 sea urchin species, demonstrated a clearly dependence on the water temperature. The experiments allowed to determine the “thermal safety margin” (TSM) of each species. Echinometra lucunter and E. viridis resulted the most tolerant species to high temperatures with a TSM of 5.5°C, while T. ventricosus was the most vulnerable with a TSM of only 3°C. The study assessed that all the species already live at temperatures close to their upper thermal limit. Their TSMs are comparable to the predicted temperature increase by 2100. In absence of acclimatization to such temperature change, these species could experience severe die-offs, with important consequences for tropical marine ecosystems.

Predictors of early mortality after acute ischaemic stroke.

BACKGROUND The study set out to identify clinical, laboratory and radiological predictors of early mortality after an acute ischaemic stroke (AIS) and to analyse medical and neurological complications that caused death. METHODS A total of 479 consecutive patients (mean age 63+/-14 years) with AIS underwent stroke examination and treatment. Examination included clinical evaluation, laboratory tests, and brain CT and/or MRI. Follow-up data at 30 days were available for 467 patients (93%) who were included in the present analysis. RESULTS The median National Institute of Health Stroke Study (NIHSS) score on admission was 6. A total of 62 patients (13%) died within 30 days. The cause of death was the initial event in 43 (69%), pneumonia in 12 (19%), intracerebral haemorrhage in 9 (15%), recurrent stroke in 6 (10%), myocardial infarction in 2 (3%), and cancer in 1 (2%) of the patients. In univariate comparisons, advanced age (p<0.001), hypertension (p=0.013), coronary disease (p=0.001), NIHSS score (p<0.001), undetermined stroke etiology (p=0.031), relevant co-morbidities (p=0.008), hyperglycemia (p<0.001), atrial fibrillation (p<0.001), early CT signs of ischemia (p<0.001), dense artery sign (p<0.001), proximal vessel occlusion (p<0.001), and thrombolysis (p=0.008) were associated with early mortality. In multivariate analysis, advanced age (HR=1.12; 95% CI 1.05-1.19; p<0.001) and high NIHSS score on admission (HR=1.15, 95% CI 1.05-1.25; p=0.002) were independent predictors of early mortality. CONCLUSIONS We report 13% mortality at 30 days after AIS. More than two thirds of the deaths are related to the initial stroke. Advanced age and high NIHSS score are the only independent predictors of early mortality in this series.

Stroke, coronary and peripheral artery disease survey on antithrombotic treatment (START IT)

QUESTIONS UNDER STUDY: To determine the perception of primary care physicians regarding the risk of subsequent atherothrombotic events in patients with established cardiovascular (CV) disease, and to correlate this perception with documented antithrombotic therapy. METHODS: In a cross-sectional study of the general practice population in Switzerland, 381 primary care physicians screened 127 040 outpatients during 15 consecutive workdays in 2006. Perception of subsequent atherothrombotic events in patients with established CV disease was assessed using a tick box questionnaire allowing choices between low, moderate, high or very high risk. Logistic regression models were used to determine the relationship between risk perception and antithrombotic treatment. RESULTS: Overall, 13 057 patients (10.4%) were identified as having established CV disease and 48.8% of those were estimated to be at high to very high risk for subsequent atherothrombotic events. Estimated higher risk for subsequent atherothrombotic events was associated with a shift from aspirin monotherapy to clopidogrel, vitamin K antagonist or aspirin plus clopidogrel (p <0.001 for trend). Clopidogrel (12.7% vs 6.8%, p <0.001), vitamin K antagonist (24.5% vs 15.6%, p <0.001) or aspirin plus clopidogrel (10.2% vs 4.2%, p <0.001) were prescribed in patients estimated to be at high to very high risk more often than in those at low to moderate risk. CONCLUSIONS: Perception of primary care physicians regarding risk of subsequent atherothrombotic events varies in patients with CV disease, and as a result antithrombotic therapy is altered in patients with anticipated high to very high risk even though robust evidence and clear guidelines are lacking.

Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: the SWIss Venous ThromboEmbolism Registry (SWIVTER)

Venous thromboembolism (VTE) prophylaxis remains underutilized, particularly in cancer patients. We explored clinical predictors of prophylaxis in hospitalized cancer patients before the onset of acute VTE.

Progression of coronary artery disease during long-term follow-up of the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II)

Background: This study evaluates cardiovascular risk factors associated with progression of coronary artery disease (CAD) in patientswith silent ischemia followingmyocardial infarction. Hypothesis: Coronary artery disease only progresses slowly with comprehensive risk factor intervention. Methods: A total of 104 of 201 patients (51.7%) of the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II) with baseline and follow-up coronary angiography were included. All patients received comprehensive cardiovascular risk factor intervention according to study protocol. Logistic regression was used to evaluate associationsbetween baseline cardiovascular risk factors and CAD progression. Results: The mean duration of follow-upwas 10.3 ± 2.4 years. At baseline, 77.9% of patients were smokers, 45.2% had hypertension, 73.1% had dyslipidemia, 7.7% had diabetes, and 48.1% had a family history of CAD. At last follow-up, only 27 patients of the initial 81 smokers still smoked, only 2.1% of the patients had uncontrolled hypertension, 10.6%of the patientshad uncontrolled dyslipidemia, and 2.1%of the patientshad uncontrolled diabetes. Coronary artery disease progression was found in up to 81 (77.9%) patients. Baseline diabetes and younger age were associatedwith increased odds of CAD progression.The time intervalbetween baseline and follow-up angiography was also associatedwith CAD progression. Conclusion: Coronary artery disease progressionwas highly prevalent in these patients despite comprehensive risk factor intervention. Further research is needed to optimize treatment of known risk factors and to identify other unknown and potentiallymodifiable risk factors.

Inconsistencies in the planning of the duration of anticoagulation among outpatients with acute deep-vein thrombosis. Results from the OTIS-DVT Registry

Three-month anticoagulation is recommended to treat provoked or first distal deep-vein thrombosis (DVT), and indefinite-duration anticoagulation should be considered for patients with unprovoked proximal, unprovoked recurrent, or cancer-associated DVT. In the prospective Outpatient Treatment of Deep Vein Thrombosis in Switzerland (OTIS-DVT) Registry of 502 patients with acute objectively confirmed lower extremity DVT (59% provoked or first distal DVT; 41% unprovoked proximal, unprovoked recurrent, or cancer-associated DVT) from 53 private practices and 11 hospitals, we investigated the planned duration of anticoagulation at the time of treatment initiation. The decision to administer limited-duration anticoagulation therapy was made in 343 (68%) patients with a median duration of 107 (interquartile range 91-182) days for provoked or first distal DVT, and 182 (interquartile range 111-184) days for unprovoked proximal, unprovoked recurrent, or cancer-associated DVT. Among patients with provoked or first distal DVT, anticoagulation was recommended for < 3 months in 11%, 3 months in 63%, and for an indefinite period in 26%. Among patients with unprovoked proximal, unprovoked recurrent, or cancer-associated DVT, anticoagulation was recommended for < 6 months in 22%, 6-12 months in 38%, and for an indefinite period in 40%. Overall, there was more frequent planning of indefinite-duration therapy from hospital physicians as compared with private practice physicians (39% vs. 28%; p=0.019). Considerable inconsistency in planning the duration of anticoagulation therapy mandates an improvement in risk stratification of outpatients with acute DVT.

A comparison of acute and long-term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitro

The close resemblance of carbon nanotubes to asbestos fibers regarding their high aspect ratio, biopersistence and reactivity increases public concerns on the widespread use of these materials. The purpose of this study was not only to address the acute adverse effects of industrially produced multiwalled carbon nanotubes (MWCNTs) on human lung and immune cells in vitro but also to further understand if their accumulation and biopersistence leads to long-term consequences or induces adaptive changes in these cells. In contrast to asbestos fibers, pristine MWCNTs did not induce overt cell death in A549 lung epithelial cells and Jurkat T lymphocytes after acute exposure to high doses of this material (up to 30 g/ml). Nevertheless, very high levels of reactive oxygen species (ROS) and decreased metabolic activity were observed which might affect long-term viability of these cells. However, the continuous presence of low amounts of MWCNTs (0.5 g/ml) for 6 months did not have major adverse long-term effects although large amounts of nanotubes accumulated at least in A549 cells. Moreover, MWCNTs did not appear to induce adaptive mechanisms against particle stress in long-term treated A549 cells. Our study demonstrates that despite the high potential for ROS formation, pristine MWCNTs can accumulate and persist within cells without having major long-term consequences or inducing adaptive mechanisms.

The impact of body mass index on the one year outcomes of patients treated by percutaneous coronary intervention with Biolimus- and Sirolimus-eluting stents (from the LEADERS Trial)

The aim of this analysis was to assess the effect of body mass index (BMI) on 1-year outcomes in patients enrolled in a contemporary percutaneous coronary intervention trial comparing a sirolimus-eluting stent with a durable polymer to a biolimus-eluting stent with a biodegradable polymer. A total of 1,707 patients who underwent percutaneous coronary intervention were randomized to treatment with either biolimus-eluting stents (n = 857) or sirolimus-eluting stents (n = 850). Patients were assigned to 1 of 3 groups according to BMI: normal (<25 kg/m(2)), overweight (25 to 30 kg/m(2)), or obese (>30 kg/m(2)). At 1 year, the incidence of the composite of cardiac death, myocardial infarction, and clinically justified target vessel revascularization was assessed. In addition, rates of clinically justified target lesion revascularization and stent thrombosis were assessed. Cox proportional-hazards analysis, adjusted for clinical differences, was used to develop models for 1-year mortality. Forty-five percent of the patients (n = 770) were overweight, 26% (n = 434) were obese, and 29% (n = 497) had normal BMIs. At 1-year follow-up, the cumulative rate of cardiac death, myocardial infarction, and clinically justified target vessel revascularization was significantly higher in the obese group (8.7% in normal-weight, 11.3% in overweight, and 14.5% in obese patients, p = 0.01). BMI (hazard ratio 1.47, 95% confidence interval 1.02 to 2.14, p = 0.04) was an independent predictor of stent thrombosis. Stent type had no impact on the composite of cardiac death, myocardial infarction, and clinically justified target vessel revascularization at 1 year in the 3 BMI groups (hazard ratio 1.08, 95% confidence interval 0.63 to 1.83, p = 0.73). In conclusion, BMI was an independent predictor of major adverse cardiac events at 1-year clinical follow-up. The higher incidence of stent thrombosis in the obese group may suggest the need for a weight-adjusted dose of clopidogrel.