Bacterial bioassay for rapid and accurate analysis of arsenic in highly variable groundwater samples.

In this study, we report the first ever large-scale environmental validation of a microbial reporter-based test to measure arsenic concentrations in natural water resources. A bioluminescence-producing arsenic-inducible bacterium based on Escherichia coli was used as the reporter organism. Specific protocols were developed with the goal to avoid the negative influence of iron in groundwater on arsenic availability to the bioreporter cells. A total of 194 groundwater samples were collected in the Red River and Mekong River Delta regions of Vietnam and were analyzed both by atomic absorption spectroscopy (AAS) and by the arsenic bioreporter protocol. The bacterial cells performed well at and above arsenic concentrations in groundwater of 7 microg/L, with an almost linearly proportional increase of the bioluminescence signal between 10 and 100 microg As/L (r2 = 0.997). Comparisons between AAS and arsenic bioreporter determinations gave an overall average of 8.0% false negative and 2.4% false positive identifications for the bioreporter prediction at the WHO recommended acceptable arsenic concentration of 10 microg/L, which is far betterthan the performance of chemical field test kits. Because of the ease of the measurement protocol and the low application cost, the microbiological arsenic test has a great potential in large screening campaigns in Asia and in other areas suffering from arsenic pollution in groundwater resources.

Portal vein embolization: what do we know?

Portal vein embolization (PVE) has been developed to increase the size of the future remnant liver (FRL) left in place after major hepatectomy, thus reducing the risk of postoperative liver insufficiency. PVE consist in embolizing preoperatively portal branches of the segments that will be resected. Indication is based on preoperative measurements of the FRL by computed tomography and its ratio with either the theoretical liver volume or by direct measurement of the functional liver volume. After PVE, the volume and function of the FRL increases in 3 to 6 weeks, permitting extensive resections in patients otherwise contraindicated for liver resection. The PVE technique is variable from one center to another; however n-butyl-cyano-acrylate provides an interesting compromise between hypertrophy rate and procedure risk.

Advanced age increases the failure rate of non-operative management of blunt splenic injuries

Introduction: Non-operative management (NOM) of blunt splenic injuries in hemodynamically stable patients is nowadays considered the standard treatment. Material and Methods: The aim was to clarify the criteria used for primary operative management (OM) and planned NOM. Furthermore, the study aimed to identify risk factors for failure of NOM. All adult patients with blunt splenic injuries treated from 2000-2008 were reviewed and a logistic regression analysis employed. Results: There were 206 patients (146 men, 70.9%). Mean age was 38.2 ± 19.1 years. The mean Injury Severity Score (ISS) was 30.9 ± 11.6. The American Association for the Surgery of Trauma (AAST) classification of the splenic injury was: grade I, n = 43 (20.9%); grade II, n = 52 (25.2%); grade III, n = 60 (29.1%), grade IV, n = 42 (20.4%) and grade V, n = 9 (4.4%). 47 patients (22.8%) required immediate surgery (OM). More than 5 units of red cell transfusions (odds ratio [OR] 13.72, P < 0.001), a Glasgow Coma Scale < 11 (OR 9.88, P = 0.009) and age ? 55 years (OR 3.29, P = 0.038) were associated with primary OM. 159 patients (77.2%) qualified for a non-surgical approach (NOM), which was successful in 89.9% (143/159). The overall splenic salvage rate amounted to 69.4% (143/206). Multiple logistic regression analysis found age ? 40 years to be the only factor significantly and independently related to the failure of NOM (OR 13.58, P = 0.001). Conclusion: Advanced age is associated with an increased failure rate of NOM in patients with blunt splenic injuries.

Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension.

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis.

The efficacy of pharmacotherapy for decreasing the expansion rate of abdominal aortic aneurysms: a systematic review and meta-analysis.

BACKGROUND: Pharmacotherapy may represent a potential means to limit the expansion rate of abdominal aortic aneurysms (AAAs). Studies evaluating the efficacy of different pharmacological agents to slow down human AAA-expansion rates have been performed, but they have never been systematically reviewed or summarized. METHODS AND FINDINGS: Two independent reviewers identified studies and selected randomized trials and prospective cohort studies comparing the growth rate of AAA in patients with pharmacotherapy vs. no pharmacotherapy. We extracted information on study interventions, baseline characteristics, methodological quality, and AAA growth rate differences (in mm/year). Fourteen prospective studies met eligibility criteria. Five cohort studies raised the possibility of benefit of beta-blockers [pooled growth rate difference: -0.62 mm/year, (95%CI, -1.00 to -0.24)], but this was not confirmed in three beta-blocker RCTs [pooled RCT growth rate difference: -0.05 mm/year (-0.16 to 0.05)]. Statins have been evaluated in two cohort studies that yield a pooled growth rate difference of -2.97 (-5.83 to -0.11). Doxycycline and roxithromycin have been evaluated in two RCTs that suggest possible benefit [pooled RCT growth rate difference: -1.32 mm/year (-2.89 to 0.25)]. Studies assessing NSAIDs, diuretics, calcium channel blockers and ACE inhibitors, meanwhile, did not find statistically significant differences. CONCLUSIONS: Beta-blockers do not appear to significantly reduce the growth rate of AAAs. Statins and other anti-inflammatory agents appear to hold promise for decreasing the expansion rate of AAA, but need further evaluation before definitive recommendations can be made.

The Foundational Significance of Leggett's Non-local Hidden-Variable Theories

Laudisa (Found. Phys. 38:1110-1132, 2008) claims that experimental research on the class of non-local hidden-variable theories introduced by Leggett is misguided, because these theories are irrelevant for the foundations of quantum mechanics. I show that Laudisa's arguments fail to establish the pessimistic conclusion he draws from them. In particular, it is not the case that Leggett-inspired research is based on a mistaken understanding of Bell's theorem, nor that previous no-hidden-variable theorems already exclude Leggett's models. Finally, I argue that the framework of Bohmian mechanics brings out the importance of Leggett tests, rather than proving their irrelevance, as Laudisa supposes.

Glutamine synthesis rate in the hyperammonaemic rat brain using simultaneous localized in vivo H-1 and N-15 MRS

Objectives: Glutamine synthetase is a critical step in the glutamate-glutamine cycle, the major mechanism of glutamate neurotransmission and is implicated in the mechanism of ammonia toxicity. 15N MRS is an alternative approach to 13C MRS in studying glutamate- glutamine metabolism. 15N MRS studies allow to measure an apparent glutamine synthesis rate (Vsyn) which reflects a combination of the glutamate- glutamine cycle activity (Vnt) and net glutamine accumulation. The net glutamine synthesis (Vsyn-Vnt) can be directly measured from 1H NMR. Therefore, the aim of this study was to perform in vivo localized 1H MRS interleaved with 15N MRS to directly measure the net glutamine synthesis rate and the apparent glutamine synthesis rate under 15N labeled ammonia infusion in the rat brain, respectively. Methods: 1H and 15N MRS data were acquired interleaved on a 9.4T system (Varian/Magnex Scientific) using 5 rats. 15NH4Cl solution was infused continuously into the femoral vein for up to 10 h (4.5 mmol/h/kg).1 The plasma ammonia concentration was increased to 0.95±0.08 mmol/L (Analox GM7 analyzer). 1H spectra were acquired and quantified as described previously.2 15N unlocalized and localized spectra were acquired using the sequence;3 and quantified using AMARES and an external reference method.4 The metabolic model used to analyze the total Gln and 5-15N labeled Gln time courses is shown on Figure 1A. Results: Glutamine concentration increased from 2.5±0.3 to 15±3.3 mmol/kg whereas the total glutamate concentrations remained unchanged (Figure 1B). The linear fit of the time-evolution of the total Gln from the 1H spectra gave the net synthesis flux (Vsyn-Vnt), which was 0.021± 0.006 mmol/min per g (Figure 1D). The 5-15N Gln peak (_271 ppm) was visible in the first and all subsequent scans, whereas the 2-15N Gln/Glu peak (_342 ppm) appeared after B1.5 h (Figure 1C). From the in vivo 5-15N Gln time course, Vsyn = 0.29±0.1 mmol/min per g and a plasma NH3 fractional enrichment of 71%±6% were calculated. Vnt was 0.26±0.1 mmol/min/g, obtained assuming a negligible Gln efflux.5 Vsyn and Vnt were within the range of 13C NMR measurements.6 Conclusion: The combination of 1H and 15N NMR allowed for the first time a direct and localized measurement of Vnt and apparent glutamine synthesis rate. Vnt is approximately one order of magnitude faster than the net glutamine accumulation.

Impact of preoperative embolization of the left gastric artery on the rate of anastomotic leakage after esophageal resection

Objective: Impaired blood flow of the gastric tube represents a major cause of anastomotic leakage after esophageal resection. In order to improve local vascularisation, preoperative embolization (PE) of the left gastric artery has recently been proposed. The aimof this study was to assess our initial experience of this novel approach with a particular focus on anastomotic leakage.Methods: A consecutive series of 102 patients (81 male, 21 female, median age 64 years) underwent resection (82 Ivor-Lewis procedures, 9 transhiatal resections, 11 triple incisions) for esophageal malignancies at our institution from 2000 to 2009. Since 2004, PE was used selectively in 19 patients 21 days prior to elective esophagectomy. Selection criteria were normal gastric vascular anatomy, no pre-existing vascular disease, i.e. atheromatosis of the celiac trunk or superior mesenteric artery, and resectability of the tumor. PE was performed under local anesthesia on a dedicated system in a standard fashion. Following percutaneous transfemoral visceral angiography to identify gastric vascular anatomy, embolization was performed either with 5-F or with coaxial 3-F catheters and fibered metal coils. We analyzed retrospectively patient's data, operative data, and outcome from a prospective database.Results: The overall anastomotic leakage rate was 18・6% (19/102 patients); cervical anastomosis had a leak rate of 25% compared to intrathoracic anastomosis leak rate of 18・2%. While 17 of 83 patients without PE developed anastomotic leakage (20・5%), there were only 2 of 19 patients after PE revealing an anastomotic leakage (10・5%). Otherwise, patients with PE had no more other complications. There was only one PE-related complication (i.e. partial splenic necrosis).Mean hospital stay was 25 days versus 27 days for patients with PE and without PE, respectively. The mortality rate was 7・8% (8/102 patients), whereby four deaths were related to anastomotic leakage (1 and 3 patients with PE and without PE, respectively).Conclusion: PE is an interesting novel approach to improve gastric blood flow in order to minimize anastomotic leakage. Its application is safe and technically easy. Our preliminary experience revealed a decrease of the anastomotic leakage rate of almost 50%.

Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.

Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or incomplete puberty and characterised biochemically by low levels of sex steroids, with low or inappropriately normal gonadotropin hormones. IHH is frequently accompanied by non-reproductive abnormalities, most commonly anosmia, which is present in 50-60% of cases and defines Kallmann syndrome. The understanding of IHH has undergone rapid evolution, both in respect of genetics and breadth of phenotype. Once considered in monogenic Mendelian terms, it is now more coherently understood as a complex genetic condition. Oligogenic and complex genetic-environmental interactions have now been identified, with physiological and environmental factors interacting in genetically susceptible individuals to alter the clinical course and phenotype. These potentially link IHH to ancient evolutionary pressures on the ancestral human genome.

Impact of chlorhexidine-impregnated sponges on catheter-related infections rate

INTRODUCTION. Multimodal strategy targeted at prevention of catheter-related infection combine education to general measures of hygiene with specific guidelines for catheter insertion and dressing (1). OBJECTIVES. In this context, we tested the introduction of chlorhexidine(CHX)-impregnated sponges (2). METHODS. In our 32-beds mixed ICU, prospective surveillance of primary bacteremia and of microbiologically documented catheter-related bloodstream infections (CRBSI) is performed according to standardized definitions. New guidelines for central venous catheter (CVC) dressing combined a CHX-impregnated sponge (BioPatch_) with a transparent occlusive dressing (Tegaderm _) and planning for refection every 7 days. To contain costs, Biopatch_ was used only for internal jugular and femoral sites. Other elements of the prevention were not modified (overall compliance to hand hygiene 65-68%; non coated catheters except for burned patients [173 out of 9,542 patients];maximal sterile barriers for insertion; alcoholic solution ofCHXfor skin disinfection). RESULTS. Median monthly CVC-days increased from 710, to 749, 855 and 965 in 2006, 2007, 2008 and 2009, respectively (p\0.01). Following introduction of the new guidelines (4Q2007), the average monthly rate of infections decreased from 3.7 (95% CI: 2.6-4.8) episodes/1000 CVC-days over the 24 preceding months to 2.2 (95% CI: 1.5-2.8) over the 24 following months (p = 0.031). Dressings needed to be changed every 3-4 days. The decrease of catheter-related infections we observed in all consecutive admitted patients is comparable to that recently showed in a placeborandomized trial2. Further generalization to all CVC and arterial catheters access may be justified. CONCLUSIONS. Our data strongly suggest that combined with occlusive dressings, CHXimpregnated sponges for dressing of all CVC catheters inserted in internal jugular and/or femoral sites, significantly reduces the rate of primary bacteremia and CRBSI. REFERENCES. (1) Eggimann P, Harbarth S, Constantin MN, Touveneau S, Chevrolet JC, Pittet D. Impact of a prevention strategy targeted at vascular-access care on incidence of infections acquired in intensive care. Lancet 2000; 355:1864-1868. (2) Timsit JF, Schwebel C, Bouadma L, Geffroy A, Garrouste-Org, Pease S et al. Chlorhexidine- impregnated sponges and less frequent dressing changes for prevention of catheter-related infections in critically ill adults: a randomized controlled trial. JAMA 2009; 301(12):1231-1241.

Inhibition of Na(+)-K(+)-ATPase by digoxin and its relation with energy expenditure and nutrient oxidation rate.

This study investigates the effects of digoxin, an inhibitor of the Na+ pump (Na(+)-K(+)-ATPase), on resting metabolic rate (RMR), respiratory quotient (RQ), and nutrient oxidation rate. Twelve healthy male subjects followed a double-blind protocol design and received either 1 mg/day digoxin or a placebo 2 days before indirect calorimetry measurements. Digoxin induced a 0.22 +/- 0.07 kJ/min or 3.8 +/- 1.5% (mean +/- SE, P = 0.01) decrease in RMR and a 0.40 +/- 0.13 kJ/min (P = 0.01) decrease in fat oxidation rate, whereas carbohydrate and protein oxidation rates did not change significantly. A dose-response relationship between serum digoxin and RQ was observed. These results suggest that digoxin reduces not only RMR but also fat oxidation rate by mechanisms that remain to be elucidated. Because a linkage and an association between genes coding the Na(+)-K(+)-ATPase and the RQ have been previously observed, the present demonstration of an effect of Na(+)-K(+)-ATPase inhibition on fat oxidation rate strengthens the concept that the activity of this enzyme may play a role in body weight regulation.

Insight in protein S deficiency from mouse models

Protein S (ProS) is an important negative regulator of blood coagulation. Its physiological importance is evident in purpura fulminans and other life-threatening thrombotic disorders typical of ProS deficient patients. Our previous characterization of ProS deficiency in mouse models has shown similarities with the human phenotypes: heterozygous ProS-deficient mice (Pros+/-) had increased thrombotic risk whereas homozygous deficiency in ProS (Pros-/-) was incompatible with life (Blood 2009; 114:2307-2314). In tissues, ProS exerts cellular functions by binding to and activating tyrosine kinase receptors of the Tyro3 family (TAM) on the cell surface.To extend the analysis of coagulation defects beyond the Pros-/- phenotype and add new insights into the sites of synthesis ProS and its action, we generated mice with inactivated ProS in hepatocytes (Proslox/loxAlbCre+) as well as in endothelial and hematopoietic cells (Proslox/loxTie2Cre+). Both models resulted in significant reduction of circulating ProS levels and in a remarkable increased thrombotic risk in vivo. In a model of tissue factor (TF)-induced venous thromboembolism (VTE), only 17% of Proslox/loxAlbCre+ mice (n=12) and only 13% of Proslox/loxTie2Cre+ mice (n=14) survived, compared with 86% of Proslox/lox mice (n=14; P<0.001).To mimic a severe acquired ProS deficiency, ProS gene was inactivated at the adult stage using the polyI:C-inducible Mx1-Cre system (Proslox/loxMx1Cre+). Ten days after polyI:C treatment, Proslox/loxMx1Cre+ mice developed disseminated intravascular coagulation with extensive lung and liver thrombosis.It is worth noting that no skin lesions compatible with purpura fulminans were observed in any of the above-described models of partial ProS deficiency. In order to shed light on the pathogenesis of purpura fulminans, we exposed the different ProS-deficient mice to warfarin (0.2 mg/day). We observed that Pros+/-, Proslox/loxAlbCre+ and Proslox/loxTie2Cre+ mice developed retiform purpura (characterized by erythematous and necrotic lesions of the genital region and extremities) and died after 3 to 5 days after the first warfarin administration.In human, ProS is also synthesized by megakaryocytes and hence stored at high concentrations in circulating platelets (pProS). The role of pProS has been investigated by generating megakaryocyte ProS-deficient model using the PF4 promoter as Cre driver (Proslox/loxPf4Cre+). In the TF-induced VTE model, Proslox/loxPf4Cre+ (n=15) mice showed a significant increased risk of thrombosis compared to Proslox/lox controls (n=14; survival rate 47% and 86%, respectively; P<0.05). Furthermore, preliminary results suggest survival to be associated with higher circulating ProS levels. In order to evaluate the potential role of pProS in thrombus formation, we investigated the thrombotic response to intravenous injection of collagen-epinephrine in vivo and platelet function in vitro. Both in vivo and in vitro experiments showed similar results between Proslox/loxPf4Cre+ and Proslox/lox, indicating that platelet reactivity was not influenced by the absence of pProS. These data suggest that pProS is delivered at the site of thrombosis to inhibit thrombin generation.We further investigated the ability of ProS to function as a ligand of TAM receptors, by using homozygous and heterozygous deficient mice for both the TAM ligands ProS and Gas6. Gas6-/-Pros-/- mice died in utero and showed comparable dramatic bleeding and thrombotic phenotype as described for Pros-/- embryos.In conclusion, like complete ProS deficiency, double deficiency in ProS and Gas6 was lethal, whereas partial ProS deficiency was not. Mice partially deficient in ProS displayed a prothrombotic phenotype, including those with only deficiency in pProS. Purpura fulminans did not occur spontaneously in mice with partial Pros deficiency but developed upon warfarin administration.Thus, the use of different mice models of ProS deficiency can be instrumental in the study of its highly variable thrombotic phenotype and in the investigation of additional roles of ProS in inflammation and autoimmunity through TAM signaling.

Dose-dependent effect of atrial natriuretic peptide on blood pressure, heart rate, and skin blood flow of normal volunteers.

Synthetic atrial natriuretic peptide, containing 26 amino acids in the rat sequence, L-364, 343 (Ileu-ANP), was infused intravenously at increasing rates (1-40 micrograms/min) into four normal volunteers. Mean intraarterial blood pressure decreased and heart rate increased in cumulative-dose-dependent fashion. Skin blood flow as measured with a laser Doppler device rose already with a cumulative dose of 55 micrograms Ileu-ANP and further rises were directly related to dose. The only side effects observed were those accompanying symptomatic hypotension at higher doses. These findings provide strong evidence that Ileu-ANP acts as a vasodilator in normal volunteers.

Estimating biophysical variable dependences with kernels

This paper introduces a nonlinear measure of dependence between random variables in the context of remote sensing data analysis. The Hilbert-Schmidt Independence Criterion (HSIC) is a kernel method for evaluating statistical dependence. HSIC is based on computing the Hilbert-Schmidt norm of the cross-covariance operator of mapped samples in the corresponding Hilbert spaces. The HSIC empirical estimator is very easy to compute and has good theoretical and practical properties. We exploit the capabilities of HSIC to explain nonlinear dependences in two remote sensing problems: temperature estimation and chlorophyll concentration prediction from spectra. Results show that, when the relationship between random variables is nonlinear or when few data are available, the HSIC criterion outperforms other standard methods, such as the linear correlation or mutual information.

High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.

OBJECTIVE: Examination of the rate of grade III or grade IV radiation dermatitis during treatment of head and neck cancer (HNC) with radiotherapy (RT) and concurrent cetuximab in EORTC centres. MATERIALS AND METHOD: A questionnaire was sent to all members of the EORTC Radiation Oncology Group and Head and Neck Group (111 institutions) to evaluate the widespread use of cetuximab and radiotherapy in HNC and to estimate the frequency of grades III and IV skin reactions in the radiation portals associated with this protocol. Co-morbidities, RT schedules and co-medications were also recorded. RESULTS: We received responses from 28 institutions in 11 countries. A total of 125 HNC patients from 15 institutions were treated with cetuximab and concurrent RT. Information about the skin reactions was available from 71 patients. Of these 36 had no grade III/IV adverse effects in the RT field, 15 had a grade III and 20 had grade IV radiation dermatitis. No detectable relation of grades III and IV radiation dermatitis with co-morbidities such as liver insufficiency or renal dysfunction was found. CONCLUSION: According to the results of the questionnaire, grade III/IV radiation dermatitis is observed in 49% of HNC patients treated with cetuximab and concurrent RT. A systematic clinical monitoring of cutaneous side effects during RT plus cetuximab is advised to ensure the safety of this protocol.