Mechanisms underlying gas exchange alterations in an experimental model of pulmonary embolism

The aim of the present study was to determine the ventilation/perfusion ratio that contributes to hypoxemia in pulmonary embolism by analyzing blood gases and volumetric capnography in a model of experimental acute pulmonary embolism. Pulmonary embolization with autologous blood clots was induced in seven pigs weighing 24.00 ± 0.6 kg, anesthetized and mechanically ventilated. Significant changes occurred from baseline to 20 min after embolization, such as reduction in oxygen partial pressures in arterial blood (from 87.71 ± 8.64 to 39.14 ± 6.77 mmHg) and alveolar air (from 92.97 ± 2.14 to 63.91 ± 8.27 mmHg). The effective alveolar ventilation exhibited a significant reduction (from 199.62 ± 42.01 to 84.34 ± 44.13) consistent with the fall in alveolar gas volume that effectively participated in gas exchange. The relation between the alveolar ventilation that effectively participated in gas exchange and cardiac output (V Aeff/Q ratio) also presented a significant reduction after embolization (from 0.96 ± 0.34 to 0.33 ± 0.17 fraction). The carbon dioxide partial pressure increased significantly in arterial blood (from 37.51 ± 1.71 to 60.76 ± 6.62 mmHg), but decreased significantly in exhaled air at the end of the respiratory cycle (from 35.57 ± 1.22 to 23.15 ± 8.24 mmHg). Exhaled air at the end of the respiratory cycle returned to baseline values 40 min after embolism. The arterial to alveolar carbon dioxide gradient increased significantly (from 1.94 ± 1.36 to 37.61 ± 12.79 mmHg), as also did the calculated alveolar (from 56.38 ± 22.47 to 178.09 ± 37.46 mL) and physiological (from 0.37 ± 0.05 to 0.75 ± 0.10 fraction) dead spaces. Based on our data, we conclude that the severe arterial hypoxemia observed in this experimental model may be attributed to the reduction of the V Aeff/Q ratio. We were also able to demonstrate that V Aeff/Q progressively improves after embolization, a fact attributed to the alveolar ventilation redistribution induced by hypocapnic bronchoconstriction.

Identification of the divergent calmodulin binding motif in yeast Ssb1/Hsp75 protein and in other HSP70 family members

Yeast soluble proteins were fractionated by calmodulin-agarose affinity chromatography and the Ca2+/calmodulin-binding proteins were analyzed by SDS-PAGE. One prominent protein of 66 kDa was excised from the gel, digested with trypsin and the masses of the resultant fragments were determined by MALDI/MS. Twenty-one of 38 monoisotopic peptide masses obtained after tryptic digestion were matched to the heat shock protein Ssb1/Hsp75, covering 37% of its sequence. Computational analysis of the primary structure of Ssb1/Hsp75 identified a unique potential amphipathic alpha-helix in its N-terminal ATPase domain with features of target regions for Ca2+/calmodulin binding. This region, which shares 89% similarity to the experimentally determined calmodulin-binding domain from mouse, Hsc70, is conserved in near half of the 113 members of the HSP70 family investigated, from yeast to plant and animals. Based on the sequence of this region, phylogenetic analysis grouped the HSP70s in three distinct branches. Two of them comprise the non-calmodulin binding Hsp70s BIP/GR78, a subfamily of eukaryotic HSP70 localized in the endoplasmic reticulum, and DnaK, a subfamily of prokaryotic HSP70. A third heterogeneous group is formed by eukaryotic cytosolic HSP70s containing the new calmodulin-binding motif and other cytosolic HSP70s whose sequences do not conform to those conserved motif, indicating that not all eukaryotic cytosolic Hsp70s are target for calmodulin regulation. Furthermore, the calmodulin-binding domain found in eukaryotic HSP70s is also the target for binding of Bag-1 - an enhancer of ADP/ATP exchange activity of Hsp70s. A model in which calmodulin displaces Bag-1 and modulates Ssb1/Hsp75 chaperone activity is discussed.

Effect of pentoxifylline on lung inflammation and gas exchange in a sepsis-induced acute lung injury model

Experimental models of sepsis-induced pulmonary alterations are important for the study of pathogenesis and for potential intervention therapies. The objective of the present study was to characterize lung dysfunction (low PaO2 and high PaCO2, and increased cellular infiltration, protein extravasation, and malondialdehyde (MDA) production assessed in bronchoalveolar lavage) in a sepsis model consisting of intraperitoneal (ip) injection of Escherichia coli and the protective effects of pentoxifylline (PTX). Male Wistar rats (weighing between 270 and 350 g) were injected ip with 10(7) or 10(9) CFU/100 g body weight or saline and samples were collected 2, 6, 12, and 24 h later (N = 5 each group). PaO2, PaCO2 and pH were measured in blood, and cellular influx, protein extravasation and MDA concentration were measured in bronchoalveolar lavage. In a second set of experiments either PTX or saline was administered 1 h prior to E. coli ip injection (N = 5 each group) and the animals were observed for 6 h. Injection of 10(7) or 10(9) CFU/100 g body weight of E. coli induced acidosis, hypoxemia, and hypercapnia. An increased (P < 0.05) cell influx was observed in bronchoalveolar lavage, with a predominance of neutrophils. Total protein and MDA concentrations were also higher (P < 0.05) in the septic groups compared to control. A higher tumor necrosis factor-alpha (P < 0.05) concentration was also found in these animals. Changes in all parameters were more pronounced with the higher bacterial inoculum. PTX administered prior to sepsis reduced (P < 0.05) most functional alterations. These data show that an E. coli ip inoculum is a good model for the induction of lung dysfunction in sepsis, and suitable for studies of therapeutic interventions.

Effect of age and gender on sweat lactate and ammonia concentrations during exercise in the heat

The dependence of sweat composition and acidity on sweating rate (SR) suggests that the lower SR in children compared to adults may be accompanied by a higher level of sweat lactate (Lac-) and ammonia (NH3) and a lower sweat pH. Four groups (15 girls, 18 boys, 8 women, 8 men) cycled in the heat (42ºC, 20% relative humidity) at 50% VO2max for two 20-min bouts with a 10-min rest before bout 1 and between bouts. Sweat was collected into plastic bags attached to the subject's lower back. During bout 1, sweat from girls and boys had higher Lac- concentrations (23.6 ± 1.2 and 21.2 ± 1.7 mM; P < 0.05) than sweat from women and men (18.2 ± 1.9 and 14.8 ± 1.6 mM, respectively), but Lac- was weakly associated with SR (P > 0.05; r = -0.27). Sweat Lac- concentration dropped during exercise bout 2, reaching similar levels among all groups (overall mean = 13.7 ± 0.4 mM). Children had a higher sweat NH3 than adults during bout 1 (girls = 4.2 ± 0.4, boys = 4.6 ± 0.6, women = 2.7 ± 0.2, and men = 3.0 ± 0.2 mM; P < 0.05). This difference persisted through bout 2 only in females. On average, children's sweat pH was lower than that of adults (mean ± SEM, girls = 5.4 ± 0.2, boys = 5.0 ± 0.1, women = 6.2 ± 0.5, and men = 6.2 ± 0.4 for bout 1, and girls = 5.4 ± 0.2, boys = 6.5 ± 0.5, women = 5.2 ± 0.2, and men = 6.9 ± 0.4 for bout 2). This may have favored NH3 transport from plasma to sweat as accounted for by a significant correlation between sweat NH3 and H+ (r = 0.56). Blood pH increased from rest (mean ± SEM; 7.3 ± 0.02) to the end of exercise (7.4 ± 0.01) without differences among groups. These results, however, are representative of sweat induced by moderate exercise in the absence of acidosis.

Effect of saline infusion for the maintenance of blood volume on pulmonary gas exchange during temporary abdominal aortic occlusion

We analyzed the effects of saline infusion for the maintenance of blood volume on pulmonary gas exchange in ischemia-reperfusion syndrome during temporary abdominal aortic occlusion in dogs. We studied 20 adult mongrel dogs weighing 12 to 23 kg divided into two groups: ischemia-reperfusion group (IRG, N = 10) and IRG submitted to saline infusion for the maintenance of mean pulmonary arterial wedge pressure between 10 and 20 mmHg (IRG-SS, N = 10). All animals were anesthetized and maintained on spontaneous ventilation. After obtaining baseline measurements, occlusion of the supraceliac aorta was performed by the inflation of a Fogarty catheter. After 60 min of ischemia, the balloon was deflated and the animals were observed for another 60 min of reperfusion. The measurements were made at 10 and 45 min of ischemia, and 5, 30, and 60 min of reperfusion. Pulmonary gas exchange was impaired in the IRG-SS group as demonstrated by the increase of the alveolar-arterial oxygen difference (21 ± 14 in IRG-SS vs 11 ± 8 in IRG after 60 min of reperfusion, P = 0.004 in IRG-SS in relation to baseline values) and the decrease of oxygen partial pressure in arterial blood (58 ± 15 in IRG-SS vs 76 ± 15 in IRG after 60 min of reperfusion, P = 0.001 in IRG-SS in relation to baseline values), which was correlated with the highest degree of pulmonary edema in morphometric analysis (0.16 ± 0.06 in IRG-SS vs 0.09 ± 0.04 in IRG, P = 0.03 between groups). There was also a smaller ventilatory compensation of metabolic acidosis after the reperfusion. We conclude that infusion of normal saline worsened the gas exchange induced by pulmonary reperfusion injury in this experimental model.

Gentamicin-induced preconditioning of proximal tubular LLC-PK1 cells stimulates nitric oxide production but not the synthesis of heat shock protein

Nephrotoxicity is the main side effect of antibiotics such as gentamicin. Preconditioning has been reported to protect against injuries as ischemia/reperfusion. The objective of the present study was to determine the effect of preconditioning with gentamicin on LLC-PK1 cells. Preconditioning was induced in LLC-PK1 cells by 24-h exposure to 2.0 mM gentamicin (G/IU). After 4 or 15 days of preconditioning, cells were again exposed to gentamicin (2.0 mM) and compared to untreated control or G/IU cells. Necrosis and apoptosis were assessed by acridine orange and HOESCHT 33346. Nitric oxide (NO) and endothelin-1 were assessed by the Griess method and available kit. Heat shock proteins were analyzed by Western blotting. After 15 days of preconditioning, LLC-PK1 cells exhibited a significant decrease in necrosis (23.5 ± 4.3 to 6.5 ± 0.3%) and apoptosis (23.5 ± 4.3 to 6.5 ± 2.1%) and an increase in cell proliferation compared to G/IU. NO (0.177 ± 0.05 to 0.368 ± 0.073 µg/mg protein) and endothelin-1 (1.88 ± 0.47 to 2.75 ± 0.53 pg/mL) production significantly increased after 15 days of preconditioning compared to G/IU. No difference in inducible HSP 70, constitutive HSC 70 or HSP 90 synthesis in tubular cells was observed after preconditioning with gentamicin. The present data suggest that preconditioning with gentamicin has protective effects on proximal tubular cells, that involved NO synthesis but not reduction of endothelin-1 or production of HSP 70, HSC 70, or HSP 90. We conclude that preconditioning could be a useful tool to prevent the nephrotoxicity induced by gentamicin.

Effect of heat and moisture exchangers on the prevention of ventilator-associated pneumonia in critically ill patients

Ventilator-associated pneumonia (VAP) remains one of the major causes of infection in the intensive care unit (ICU) and is associated with the length of hospital stay, duration of mechanical ventilation, and use of broad-spectrum antibiotics. We compared the frequency of VAP 10 months prior to (pre-intervention group) and 13 months after (post-intervention group) initiation of the use of a heat and moisture exchanger (HME) filter. This is a study with prospective before-and-after design performed in the ICU in a tertiary university hospital. Three hundred and fourteen patients were admitted to the ICU under mechanical ventilation, 168 of whom were included in group HH (heated humidifier) and 146 in group HME. The frequency of VAP per 1000 ventilator-days was similar for both the HH and HME groups (18.7 vs 17.4, respectively; P = 0.97). Duration of mechanical ventilation (11 vs 12 days, respectively; P = 0.48) and length of ICU stay (11 vs 12 days, respectively; P = 0.39) did not differ between the HH and HME groups. The chance of developing VAP was higher in patients with a longer ICU stay and longer duration of mechanical ventilation. This finding was similar when adjusted for the use of HME. The use of HME in intensive care did not reduce the incidence of VAP, the duration of mechanical ventilation, or the length of stay in the ICU in the study population.

Effects of propofol on damage of rat intestinal epithelial cells induced by heat stress and lipopolysaccharides

Gut-derived endotoxin and pathogenic bacteria have been proposed as important causative factors of morbidity and death during heat stroke. However, it is still unclear what kind of damage is induced by heat stress. In this study, the rat intestinal epithelial cell line (IEC-6) was treated with heat stress or a combination of heat stress and lipopolysaccharide (LPS). In addition, propofol, which plays an important role in anti-inflammation and organ protection, was applied to study its effects on cellular viability and apoptosis. Heat stress, LPS, or heat stress combined with LPS stimulation can all cause intestinal epithelial cell damage, including early apoptosis and subsequent necrosis. However, propofol can alleviate injuries caused by heat stress, LPS, or the combination of heat stress and LPS. Interestingly, propofol can only mitigate LPS-induced intestinal epithelial cell apoptosis, and has no protective role in heat-stress-induced apoptosis. This study developed a model that can mimic the intestinal heat stress environment. It demonstrates the effects on intestinal epithelial cell damage, and indicated that propofol could be used as a therapeutic drug for the treatment of heat-stress-induced intestinal injuries.

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

Influence of exercise modality on agreement between gas exchange and heart rate variability thresholds

The main purpose of this study was to investigate the level of agreement between the gas exchange threshold (GET) and heart rate variability threshold (HRVT) during maximal cardiopulmonary exercise testing (CPET) using three different exercise modalities. A further aim was to establish whether there was a 1:1 relationship between the percentage heart rate reserve (%HRR) and percentage oxygen uptake reserve (%V˙O2R) at intensities corresponding to GET and HRVT. Sixteen apparently healthy men 17 to 28 years of age performed three maximal CPETs (cycling, walking, and running). Mean heart rate and V˙O2 at GET and HRVT were 16 bpm (P<0.001) and 5.2 mL·kg-1·min-1 (P=0.001) higher in running than cycling, but no significant differences were observed between running and walking, or cycling and walking (P>0.05). There was a strong relationship between GET and HRVT, with R2 ranging from 0.69 to 0.90. A 1:1 relationship between %HRR and %V˙O2R was not observed at GET and HRVT. The %HRR was higher during cycling (GET mean difference=7%; HRVT mean difference=11%; both P<0.001), walking (GET mean difference=13%; HRVT mean difference=13%; both P<0.001), or running (GET mean difference=11%; HRVT mean difference=10%; both P<0.001). Therefore, using HRVT to prescribe aerobic exercise intensity appears to be valid. However, to assume a 1:1 relationship between %HRR and %V˙O2R at HRVT would probably result in overestimation of the energy expenditure during the bout of exercise.

Inflammatory cytokines and plasma redox status responses in hypertensive subjects after heat exposure

Hypertension is characterized by a pro-inflammatory status, including redox imbalance and increased levels of pro-inflammatory cytokines, which may be exacerbated after heat exposure. However, the effects of heat exposure, specifically in individuals with inflammatory chronic diseases such as hypertension, are complex and not well understood. This study compared the effects of heat exposure on plasma cytokine levels and redox status parameters in 8 hypertensive (H) and 8 normotensive (N) subjects (age: 46.5±1.3 and 45.6±1.4 years old, body mass index: 25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure: 98.0±2.8 and 86.0±2.3 mmHg, respectively). They remained at rest in a sitting position for 10 min in a thermoneutral environment (22°C) followed by 30 min in a heated environmental chamber (38°C and 60% relative humidity). Blood samples were collected before and after heat exposure. Plasma cytokine levels were measured using sandwich ELISA kits. Plasma redox status was determined by thiobarbituric acid reactive substances (TBARS) levels and ferric reducing ability of plasma (FRAP). Hypertensive subjects showed higher plasma levels of IL-10 at baseline (P<0.05), although levels of this cytokine were similar between groups after heat exposure. Moreover, after heat exposure, hypertensive individuals showed higher plasma levels of soluble TNF receptor (sTNFR1) and lower TBARS (P<0.01) and FRAP (P<0.05) levels. Controlled hypertensive subjects, who use angiotensin-converting-enzyme inhibitor (ACE inhibitors), present an anti-inflammatory status and balanced redox status. Nevertheless, exposure to a heat stress condition seems to cause an imbalance in the redox status and an unregulated inflammatory response.

Effect of heat input on the mechanical properties of welded joints in high strength steels

Experiments were carried out to determine the properties of the welded joints in 8mm thick high-strength steels produced by quenching and tempering and thermomechanical rolling with accelerated cooling (tensile strength 821–835 MPa). The dependence of the strength, elongation, hardness, impact energy and crack opening displacement on the heat input in the range 1.0–0.7 kJ mm21 was determined. The results show that the dependence of the strength of the welded joints decreases and that of the elongation increases. The heat input has only a slight effect on the impact energy and crack opening displacement in the heat-affected zone.

A Bayesian Approach for Forecasting Heat Load in a District Heating System

The growing population in cities increases the energy demand and affects the environment by increasing carbon emissions. Information and communications technology solutions which enable energy optimization are needed to address this growing energy demand in cities and to reduce carbon emissions. District heating systems optimize the energy production by reusing waste energy with combined heat and power plants. Forecasting the heat load demand in residential buildings assists in optimizing energy production and consumption in a district heating system. However, the presence of a large number of factors such as weather forecast, district heating operational parameters and user behavioural parameters, make heat load forecasting a challenging task. This thesis proposes a probabilistic machine learning model using a Naive Bayes classifier, to forecast the hourly heat load demand for three residential buildings in the city of Skellefteå, Sweden over a period of winter and spring seasons. The district heating data collected from the sensors equipped at the residential buildings in Skellefteå, is utilized to build the Bayesian network to forecast the heat load demand for horizons of 1, 2, 3, 6 and 24 hours. The proposed model is validated by using four cases to study the influence of various parameters on the heat load forecast by carrying out trace driven analysis in Weka and GeNIe. Results show that current heat load consumption and outdoor temperature forecast are the two parameters with most influence on the heat load forecast. The proposed model achieves average accuracies of 81.23 % and 76.74 % for a forecast horizon of 1 hour in the three buildings for winter and spring seasons respectively. The model also achieves an average accuracy of 77.97 % for three buildings across both seasons for the forecast horizon of 1 hour by utilizing only 10 % of the training data. The results indicate that even a simple model like Naive Bayes classifier can forecast the heat load demand by utilizing less training data.

Benefits of gas driven ground source heat pump systems

This thesis studies energy efficiencies and technical properties of gas driven ground source heat pumps and pump systems. The research focuses on two technologies: gas engine driven compressor heat pump and thermally driven gas absorption heat pump. System consist of a gas driven compressor or absorption ground source heat pump and a gas condensing boiler, which covers peak load. The reference system is a standard electrically powered compressor heat pump with electric heating elements for peak load. The systems are compared through primary energy ratios. Coefficient of performances of different heat pump technologies are also compared. At heat pump level, gas driven heat pumps are having lower coefficient of performances as compared with corresponding electric driven heat pump. However, gas heat pumps are competitive when primary energy ratios, where electricity production losses are counted in, are compared. Technically, gas heat pumps can potentially achieve a slightly higher temperatures with greater total energy efficiency as compared to the electric driven heat pump. The primary energy ratios of gas heat pump systems in relation to EHP-system improves when the share of peak load increases. Electric heat pump system's overall energy efficiency is heavily dependent on the electricity production efficiency. Economy as well as CO2-emissions were not examined in this thesis, which however, would be good topics for further study.