Benzolamide improves oxygenation and reduces acute mountain sickness during a high-altitude trek and has fewer side effects than acetazolamide at sea level.

Acetazolamide is the standard carbonic anhydrase (CA) inhibitor used for acute mountain sickness (AMS), however some of its undesirable effects are related to intracellular penetrance into many tissues, including across the blood-brain barrier. Benzolamide is a much more hydrophilic inhibitor, which nonetheless retains a strong renal action to engender a metabolic acidosis and ventilatory stimulus that improves oxygenation at high altitude and reduces AMS. We tested the effectiveness of benzolamide versus placebo in a first field study of the drug as prophylaxis for AMS during an ascent to the Everest Base Camp (5340 m). In two other studies performed at sea level to test side effect differences between acetazolamide and benzolamide, we assessed physiological actions and psychomotor side effects of two doses of acetazolamide (250 and 1000 mg) in one group of healthy subjects and in another group compared acetazolamide (500 mg), benzolamide (200 mg) and lorazepam (2 mg) as an active comparator for central nervous system (CNS) effects. At high altitude, benzolamide-treated subjects maintained better arterial oxygenation at all altitudes (3-6% higher at all altitudes above 4200 m) than placebo-treated subjects and reduced AMS severity by roughly 50%. We found benzolamide had fewer side effects, some of which are symptoms of AMS, than any of the acetazolamide doses in Studies 1 and 2, but equal physiological effects on renal function. The psychomotor side effects of acetazolamide were dose dependent. We conclude that benzolamide is very effective for AMS prophylaxis. With its lesser CNS effects, benzolamide may be superior to acetazolamide, in part, because some of the side effects of acetazolamide may contribute to and be mistaken for AMS

Comparative efficacy of ultrasound-guided and stimulating popliteal-sciatic perineural catheters for postoperative analgesia

Perineural catheter insertion using ultrasound guidance alone is a relatively new approach. Previous studies have shown that ultrasound-guided catheters take less time to place with high placement success rates, but the analgesic efficacy compared with the established stimulating catheter technique remains unknown. We tested the hypothesis that popliteal-sciatic perineural catheter insertion relying exclusively on ultrasound guidance results in superior postoperative analgesia compared with stimulating catheters. Preoperatively, subjects receiving a popliteal-sciatic perineural catheter for foot or ankle surgery were assigned randomly to either ultrasound guidance (bolus via needle with non-stimulating catheter insertion) or electrical stimulation (bolus via catheter). We used 1.5% mepivacaine 40 mL for the primary surgical nerve block and 0.2% ropivacaine (basal 8 mL·hr−1; bolus 4 mL; 30 min lockout) was infused postoperatively. The primary outcome was average surgical pain on postoperative day one. Forty of the 80 subjects enrolled were randomized to each treatment group. One of 40 subjects (2.5%) in the ultrasound group failed catheter placement per protocol vs nine of 40 (22.5%) in the stimulating catheter group (P = 0.014). The difference in procedural duration (mean [95% confidence interval (CI)]) was −6.48 (−9.90 - −3.05) min, with ultrasound requiring 7.0 (4.0-14.1) min vs stimulation requiring 11.0 (5.0-30.0) min (P < 0.001). The average pain scores of subjects who provided data on postoperative day one were somewhat higher for the 33 ultrasound subjects than for the 26 stimulation subjects (5.0 [1.0-7.8] vs 3.0 [0.0-6.5], respectively; P = 0.032), a difference (mean [95%CI]) of 1.37 (0.03-2.71). For popliteal-sciatic perineural catheters, ultrasound guidance takes less time and results in fewer placement failures compared with stimulating catheters. However, analgesia may be mildly improved with successfully placed stimulating catheters. Clinical trial registration number NCT00876681

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Human influenza A H5N1 in Indonesia: health care service-associated delays in treatment initiation.

BACKGROUND: Indonesia has had more recorded human cases of influenza A H5N1 than any other country, with one of the world's highest case fatality rates. Understanding barriers to treatment may help ensure life-saving influenza-specific treatment is provided early enough to meaningfully improve clinical outcomes. METHODS: Data for this observational study of humans infected with influenza A H5N1 were obtained primarily from Ministry of Health, Provincial and District Health Office clinical records. Data included time from symptom onset to presentation for medical care, source of medical care provided, influenza virology, time to initiation of influenza-specific treatment with antiviral drugs, and survival. RESULTS: Data on 124 human cases of virologically confirmed avian influenza were collected between September 2005 and December 2010, representing 73% of all reported Indonesia cases. The median time from health service presentation to antiviral drug initiation was 7.0 days. Time to viral testing was highly correlated with starting antiviral treatment (p < 0.0001). We found substantial variability in the time to viral testing (p = 0.04) by type of medical care provider. Antivirals were started promptly after diagnosis (median 0 days). CONCLUSIONS: Delays in the delivery of appropriate care to human cases of avian influenza H5N1 in Indonesia appear related to delays in diagnosis rather than presentation to health care settings. Either cases are not suspected of being H5N1 cases until nearly one week after presenting for medical care, or viral testing and/or antiviral treatment is not available where patients are presenting for care. Health system delays have increased since 2007

Very Low Tidal Volume Ventilation with Associated Hypercapnia - Effects on Lung Injury in a Model for Acute Respiratory Distress Syndrome

BACKGROUND: Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome. METHODOLOGY/PRINCIPAL FINDINGS: In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8-10 ml/kg/PaCO(2) = 40 mm Hg; Group 2: tidal volume = 4-5 ml/kg/PaCO(2) = 80 mm Hg; Group 3: tidal volume = 3-4 ml/kg/PaCO(2) = 120 mm Hg; Group 4: tidal volume = 2-3 ml/kg/PaCO(2) = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO(2) were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4-5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy. CONCLUSION: Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4-5 ml/kg/PaCO(2) 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained

Factors associated with antenatal care adequacy in rural and urban contexts-results from two health and demographic surveillance sites in Vietnam

<p>Abstract</p> <p>Background</p> <p>Antenatal Care (ANC) is universally considered important for women and children. This study aims to identify factors, demographic, social and economic, possibly associated with three ANC indicators: number of visits, timing of visits and content of services. The aim is also to compare the patterns of association of such factors between one rural and one urban context in northern Vietnam.</p> <p>Methods</p> <p>Totally 2,132 pregnant women were followed from identification of pregnancy until birth in two Health and Demographic Surveillance Sites (HDSS). Information was obtained through quarterly face to face interviews.</p> <p>Results</p> <p>Living in the rural area was significantly associated with lower adequate use of ANC compared to living in the urban area, both regarding quantity (number and timing of visits) and content. Low education, living in poor households and exclusively using private sector ANC in both sites and self employment, becoming pregnant before 25 years of age and living in poor communities in the rural area turned out to increase the risk for overall inadequate ANC. High risk pregnancy could not be demonstrated to be associated with ANC adequacy in either site. The medical content of services offered was often inadequate, in relation to the national recommendations, especially in the private sector.</p> <p>Conclusion</p> <p>Low education, low economic status, exclusive use of private ANC and living in rural areas were main factors associated with risk for overall inadequate ANC use as related to the national recommendations. Therefore, interventions focussing on poor and less educated women, especially in rural areas should be prioritized. They should focus the importance of early attendance of ANC and sufficient use of core services. Financial support for poor and near poor women should be considered. Providers of ANC should be educated and otherwise influenced to provide sufficient core services. Adherence to ANC content guidelines must be improved through enhanced supervision, particularly in the private sector.</p

Vicrostatin – An Anti-Invasive Multi-Integrin Targeting Chimeric Disintegrin with Tumor Anti-Angiogenic and Pro-Apoptotic Activities

Similar to other integrin-targeting strategies, disintegrins have previously shown good efficacy in animal cancer models with favorable pharmacological attributes and translational potential. Nonetheless, these polypeptides are notoriously difficult to produce recombinantly due to their particular structure requiring the correct pairing of multiple disulfide bonds for biological activity. Here, we show that a sequence-engineered disintegrin (called vicrostatin or VCN) can be reliably produced in large scale amounts directly in the oxidative cytoplasm of Origami B E. coli. Through multiple integrin ligation (i.e., αvβ3, αvβ5, and α5β1), VCN targets both endothelial and cancer cells significantly inhibiting their motility through a reconstituted basement membrane. Interestingly, in a manner distinct from other integrin ligands but reminiscent of some ECM-derived endogenous anti-angiogenic fragments previously described in the literature, VCN profoundly disrupts the actin cytoskeleton of endothelial cells (EC) inducing a rapid disassembly of stress fibers and actin reorganization, ultimately interfering with EC's ability to invade and form tubes (tubulogenesis). Moreover, here we show for the first time that the addition of a disintegrin to tubulogenic EC sandwiched in vitro between two Matrigel layers negatively impacts their survival despite the presence of abundant haptotactic cues. A liposomal formulation of VCN (LVCN) was further evaluated in vivo in two animal cancer models with different growth characteristics. Our data demonstrate that LVCN is well tolerated while exerting a significant delay in tumor growth and an increase in the survival of treated animals. These results can be partially explained by potent tumor anti-angiogenic and pro-apoptotic effects induced by LVCN

Testing the Water–Energy Theory on American Palms (Arecaceae) Using Geographically Weighted Regression

Water and energy have emerged as the best contemporary environmental correlates of broad-scale species richness patterns. A corollary hypothesis of water–energy dynamics theory is that the influence of water decreases and the influence of energy increases with absolute latitude. We report the first use of geographically weighted regression for testing this hypothesis on a continuous species richness gradient that is entirely located within the tropics and subtropics. The dataset was divided into northern and southern hemispheric portions to test whether predictor shifts are more pronounced in the less oceanic northern hemisphere. American palms (Arecaceae, n = 547 spp.), whose species richness and distributions are known to respond strongly to water and energy, were used as a model group. The ability of water and energy to explain palm species richness was quantified locally at different spatial scales and regressed on latitude. Clear latitudinal trends in agreement with water–energy dynamics theory were found, but the results did not differ qualitatively between hemispheres. Strong inherent spatial autocorrelation in local modeling results and collinearity of water and energy variables were identified as important methodological challenges. We overcame these problems by using simultaneous autoregressive models and variation partitioning. Our results show that the ability of water and energy to explain species richness changes not only across large climatic gradients spanning tropical to temperate or arctic zones but also within megathermal climates, at least for strictly tropical taxa such as palms. This finding suggests that the predictor shifts are related to gradual latitudinal changes in ambient energy (related to solar flux input) rather than to abrupt transitions at specific latitudes, such as the occurrence of frost

Historical Legacies in World Amphibian Diversity Revealed by the Turnover and Nestedness Components of Beta Diversity

Historic processes are expected to influence present diversity patterns in combination with contemporary environmental factors. We hypothesise that the joint use of beta diversity partitioning methods and a threshold-based approach may help reveal the effect of large-scale historic processes on present biodiversity. We partitioned intra-regional beta diversity into its turnover (differences in composition caused by species replacements) and nestedness-resultant (differences in species composition caused by species losses) components. We used piecewise regressions to show that, for amphibian beta diversity, two different world regions can be distinguished. Below parallel 37, beta diversity is dominated by turnover, while above parallel 37, beta diversity is dominated by nestedness. Notably, these regions are revealed when the piecewise regression method is applied to the relationship between latitude and the difference between the Last Glacial Maximum (LGM) and the present temperature but not when present energy-water factors are analysed. When this threshold effect of historic climatic change is partialled out, current energy-water variables become more relevant to the nestedness-resultant dissimilarity patterns, while mountainous areas are associated with higher spatial turnover. This result suggests that nested patterns are caused by species losses that are determined by physiological constraints, whereas turnover is associated with speciation and/or Pleistocene refugia. Thus, the new threshold-based view may help reveal the role of historic factors in shaping present amphibian beta diversity patterns