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Reducing the open probability of the ryanodine receptor (RyR) has been proposed to have beneficial effects in heart failure. We investigated whether conditional FKBP12.6 overexpression at the time of myocardial infarction (MI) could improve cardiac remodelling and cell Ca(2+) handling. Wild-type (WT) mice and mice overexpressing FKBP12.6 (Tg) were studied on average 7.5 ± 0.2 weeks after MI and compared with sham-operated mice for in vivo, myocyte function and remodelling. At baseline, unloaded cell shortening in Tg was not different from WT. The [Ca(2+)](i) transient amplitude was similar, but sarcoplasmic reticulum (SR) Ca(2+) content was larger in Tg, suggesting reduced fractional release. Spontaneous spark frequency was similar despite the increased SR Ca(2+) content, consistent with a reduced RyR channel open probability in Tg. After MI, left ventricular dilatation and myocyte hypertrophy were present in both groups, but more pronounced in Tg. Cell shortening amplitude was unchanged with MI in WT, but increased with MI in Tg. The amplitude of the [Ca(2+)](i) transient was not affected by MI in either genotype, but time to peak was increased; this was most pronounced in Tg. The SR Ca(2+) content and Na(+)- Ca(2+) exchanger function were not affected by MI. Spontaneous spark frequency was increased significantly after MI in Tg, and larger than in WT (at 4 Hz, 2.6 ± 0.4 sparks (100 μm)(-1) s(-1) in Tg MI versus 1.6 ± 0.2 sparks (100 μm)(-1) s(-1) in WT MI; P < 0.05). We conclude that FKPB12.6 overexpression can effectively reduce RyR open probability with maintained cardiomyocyte contraction. However, this approach appears insufficient to prevent and reduce post-MI remodelling, indicating that additional pathways may need to be targeted.

Uranium deposits form in a wide range of geological settings, including deep magmatic to surficial conditions, and range in age from Archaean to recent. These temporal and spatial variations have given rise to an extreme diversity of ore deposits. However, understanding their conditions of formation has remained challenging. This article reports rare earth element (REE) abundances, measured by microbeam methods in uranium oxides, for a series of worldwide uranium occurrences. The REE patterns are very specific to each deposit type and directly reflect the conditions of their genesis. We propose an evaluation of the first-order parameters controlling the REE behaviour in each mineralised system. This study demonstrates that the REE pattern is the most efficient tool for constraining the geological models of uranium deposits and for genetically discriminating new uranium discoveries. This approach may form the starting point for a new procedure in the fight against nuclear trafficking.

Objectives: The aim of this study was to compare efficacy and safety outcomes among patients receiving enoxaparin or unfractionated heparin (UFH) while undergoing percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Background: Primary PCI (pPCI) for ST elevation has traditionally been supported by UFH. The low molecular weight heparin enoxaparin may provide better outcomes when used for pPCI. Methods: Consecutive eligible patients (580) undergoing pPCI enrolled in the prospective electronic Pitie-Salpetriere registry of ischemic coronary syndromes (e-PARIS) registry were grouped according to whether they received UFH or enoxaparin as the sole anticoagulant. Logistic regression modeling, propensity-weighted adjustment, and sensitivity analyses were used to evaluate efficacy and safety endpoints for enoxaparin vs. UFH. Results: Enoxaparin was administered to 346 patients and UFH to 234 without ACT or anti-Xa guided dose adjustment. PCI was performed through the radial artery in 90%, with frequent (75%) use of GPIIb/IIIa antagonists. Patients receiving enoxaparin were more likely to be therapeutically anticoagulated during the procedure (68% vs. 50%, P < 0.0001) and were less likely to experience death or recurrent myocardial infarction (MI) in hospital (adjusted OR 0.28 95% CI (0.12–0.68) or by 30 days (adjusted OR 0.35 95% CI 0.16–0.81). All cause mortality was also reduced in hospital (adjusted OR 0.32, 95% CI (0.12–0.85) and to 30 days (adjusted OR 0.40 95% CI 0.17–0.99). Other ischemic endpoints were similarly reduced with enoxaparin. Thrombolysis in myocardial infarction (TIMI) major bleeding events were numerically fewer among patients receiving enoxaparin (1.2% vs. 2.6%, P = 0.2). Conclusions: In patients with STEMI presenting for PCI, enoxaparin was associated with a reduction in all ischemic complications, more frequent therapeutic anticoagulation, and no increase in major bleeding when compared against unfractionated heparin. © 2010 Wiley-Liss, Inc.

BACKGROUND: Weak D Types 1, 2, and 3 recipients cannot be immunized when exposed to D antigen. Molecular biology is very efficient to type weak D variants but rarely implemented in daily practice. The serologic typing practice of weak D in a Caucasian patient population was analyzed and a transfusion strategy is proposed. STUDY DESIGN AND METHODS: Samples typed either ddCcee or ddccEe in routine laboratories were tested with the indirect antiglobulin test (Du test). Du-positive samples were screened for weak D alleles Types 1, 2, and 3 and further tested with immunoglobulin M (IgM) anti-D reagents, used in a fully automated device. RESULTS: A total of 468 of 55,162 samples were found to be ddCcee or ddccEe. Ninety-three expressed weak D after the Du test leading to D+ assignment for transfusion. Seventy-three percent of Du-positive samples were weak D alleles Type 1, 2, or 3. Almost all weak D Types 1, 2, and 3 were positive with IgM reagents in gel matrix with an automated device. Other variants that could be potentially associated with anti-D alloimmunization, however, were also positive. CONCLUSION: Serology is very sensitive to detect weak D Types 1, 2, and 3, but there is no cutoff to distinguish variants of clinical significance. When molecular analysis is not available, it is proposed that a D+ status for blood recipients found to be weak D with a sensitive method be assigned, except for women of childbearing age or younger, because of the remaining possibility to be partial D or other rare weak D who can be immunized.

The best conditions for the production of 5-hydroxymethyl-2-furancarboxaldehyde (HMF) in an ion exchange resin-water-solvent triphasic system have been determined using static operating conditions.

The effects of the sugar and catalyst concentrations on the dehydration reaction of D-fructose to 5-hydroxymethyl-2-furancarboxaldehyde when a triphasic medium water-solvent-ion exchange resin is used, are described.

In this preliminary study, it was shown that strong acid ion exchange resins allowed the dehydration of D-fructose to 5-hydroxymethyl-2-furancarboxaldehyde at mild temperatures and pressures. Evidence was given that the use of a solvent (i.e. methyl isobutylketone) with high extracting power toward the obtained compound improved the yield of this reaction. In order to take into account the treatment of aqueous solutions of sugars as well as the peculiar use of ion exchange resins, particularly a good hydration mode, a water:solvent ratio of 1:9 was chosen. These conditions were shown to lead to satisfactory yields and conversion rates.

Summary Background Mortality related to complications of cirrhosis is increasing in patients with insulin-resistance factors. Hyperlipidaemic patients have multiple risk factors of insulin resistance. It is impossible to perform liver biopsy in such a large number of hyperlipidaemic patients to identify patients with advanced liver fibrosis or with steatohepatitis (non-alcoholic steatohepatitis, NASH). Aims To use the non-invasive biomarkers, FibroTest (FT), SteatoTest and NashTest, and to assess the prevalence of advanced liver disease in a large population of hyperlipidaemic patients. Methods A consecutive cohort of hyperlipidaemic patients was followed prospectively in a lipid centre and the sera were analysed retrospectively. Results A total of 2834 subjects were included: 1909 hyperlipidaemic patients and 925 blood donors (BD). Advanced fibrosis was identified by FT in 53/1909 (2.8%) hyperlipidaemic patients vs. 0/925 BD (0%) (P

Hydrothermal oxidation is an efficient and clean way for the treatment of wastewater containing organic matter. The purpose of this work is to develop a mathematical model of a reactor for hydrothermal oxidation. This reactor is horizontal and tubular and is designed with multi-injection points of oxidant. Its diameter is very small with regard to its length. The mathematical model is based on the plug flow assumption. The governing equations are: momentum, mass, species, and energy balances. Thanks to this model, the profiles of temperature, and concentration of chemical species are computed along the reactor. The numerical predictions of the model are compared to experimental profiles obtained in the case of supercritical oxidation of methanol. These comparisons show very good agreement. © 2005 American Institute of Chemical Engineers AIChE J, 2006

Background In most animal models of chronic hemodynamic overload of the left ventricle (LV) as well as in human end stage heart failure, the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) mRNA levels are decreased in parallel with increased atrial natriuretic peptide (ANP) mRNA levels. The situation in the remote myocardium following myocardial infarction (MI) is unclear. Aims (1) To examine SERCA2a mRNA levels in the non-infarcted LV myocardium of rats at the chronic stage of experimental MI and (2) To examine whether a negative linear correlation exists between SERCA2a and ANP mRNA levels in this model. Methods Anesthetized adult male Wistar rats underwent left coronary artery ligation or sham operation. Three months later, the rats were divided into three groups: sham-operated rats (sham, n=21), HF-free rats with MI (non-failing (NF)-MI, n=29) and rats with both MI and HF (congestive heart failure (CHF)-MI, n=14). LV remodelling and function were assessed by echocardiography and hemodynamic measurements. SERCA2a and ANP mRNA levels were determined by Northern and dot blot analysis with specific cDNA probes. Results LV SERCA2a mRNA levels varied markedly in sham-operated rats (0.9–1.8). Mean ANP mRNA level increased markedly and mean SERCA2a mRNA level decreased moderately in the remote myocardium. In some NF-MI rats, SERCA2a mRNA levels were higher than those in some sham controls. Whereas ANP mRNA levels correlated well with MI severity (r2=0.79, p

An isolate of Paecilomyces fumosoroseus was obtained from Coptotermes formosanus collected in Hong Kong, and a commercially available isolate of Metarhizium anisopliae, were both tested against C. formosanus shipped live from China. Survivorship of termites treated with a suspension of 5 x 10 5 M. anisopliae conidia/ml and kept alone declined more rapidly than for those treated at the same concentration of P. fumosoroseus conidia. At a 5 x 10 6 conidia/ml concentration, no significant differences in terms of termite survivorship were observed between the two fungal species. However, among termites kept in groups of 10 after treatment, those sprayed with P. fumosoroseus conidia at either 5 × 10 5 or 5 × 10 6 conidia/ml had significantly lower survivorship than those sprayed with M. anisopliae conidia. All the cadavers of termites treated with P. fumosoroseus and kept alone sporulated and among grouped termites 29% of the cadavers sporulated. By comparison, 53% of the cadavers of termites treated with M. anisopliae and kept alone sporulated, and only 4% of the cadavers of treated termites kept in groups sporulated.

Background: Pulmonary endothelium is an early upstream hemodynamic target of left ventricular dysfunction. Interleukin 6 (IL-6) is a pro-inflammatory cytokine reported to increase in congestive heart failure (CHF) patients. Aims: We sought to determine the origin of IL-6, IL-6 receptor (IL-6R) and gp130 in experimental CHF. Methods: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure. Lung and aorta samples were analysed by RT-PCR, ELISA and immunohistochemistry for IL-6 and its receptors. Results: IL-6 mRNA expression increased in the lung of rats with decompensated heart failure and was positively correlated with infarct severity whereas IL-6R mRNA decreased in the lung of myocardial infarction rats and gp130 mRNA remained unchanged. In contrast, there were no changes in IL-6 mRNA expression in the aorta and left ventricular myocardium. IL-6 peptide content as determined by ELISA and Western Blot in lung tissue was 2-fold higher in decompensated heart failure as compared to control rats. These data were confirmed by immunohistochemistry showing a preferential endothelial localization of IL-6 in the CHF lung. IL-6 peptide was also present in the pleural effusion of decompensated heart failure and was positively correlated with IL-6 mRNA expression in the lungs of decompensated HF rats. Pulmonary IL-6 overexpression was associated with nuclear translocation of NF-κB and cytosolic degradation of IκB. Conclusion: Dysfunctional pulmonary endothelium is a source of synthesis and storage of IL-6 in an experimental model of CHF.

In numerous studies of symptoms in patients with chronic hepatitis C there has been no systematic assessment of both fatigue and extrahepatic manifestations. Our objective was to assess the prevalence of fatigue in patients with hepatitis C virus (HCV) infection, and to identify associations between fatigue and clinical and biological hepatic and extrahepatic manifestations. We studied 1614 patients. Data were prospectively recorded during the first visit of patients infected with HCV and the prevalence of fatigue and its association with dermatological, rheumatological, neurological and nephrological manifestations; diabetes; arterial hypertension; auto-antibodies, and cryoglobulinaemia were assessed. Then, using multivariate analysis, we identified demographic, biochemical, immunological, virological, and histological factors associated with the presence of fatigue. Fatigue was present in 53% of patients (95% confidence interval 51-56). In 17% of patients (95% confidence interval 15-19) fatigue was severe, impairing activity. Five other extrahepatic manifestations had a prevalence above 10% including, in decreasing order: arthralgia, paresthesia, myalgia, pruritus, and sicca syndrome. In univariate and multivariate analyses, fatigue, in comparison with the absence of fatigue, was associated with female gender, age over 50 years, cirrhosis, depression and purpura. Independent of these associations, fatigue was associated with arthralgia, myalgia, paresthesia, sicca syndrome and pruritus. The prevalence of fibromyalgia (as defined by the association of fatigue with arthralgia or myalgia) was 19% (95% confidence interval 17-21). There was no significant association between fatigue and the following characteristics: viral load or genotype, alcohol consumption, abnormal thyroid function, and type and level of cryoglobulinaemia. Hence, fatigue is the most frequent extrahepatic manifestation in patients infected with HCV. Fatigue is independently associated with female gender, age over 50 years, cirrhosis, depression and purpura.

Besides the well-documented effect of the chemotherapeutic drug doxorubicin on free radical generation, the exact signaling mechanisms by which it causes cardiac damage remain largely unknown and are of fundamental importance in understanding anthracycline cardiotoxicity. In this study, we describe that a 1 h treatment of isolated adult rat cardiac myocytes with doxorubicin (0.5 microM) induced DNA fragmentation associated with the classical morphological features of apoptosis observed after 7 days of culture. The doxorubicin toxicity was preceded by an increase in intracellular ceramide levels with a concurrent decrease in sphingomyelin. Anthracycline-induced ceramide accumulation resulted from the activation of a sphingomyelinase assayed under acidic conditions, an effect related to an increase in V(max). Pretreatment of cardiac myocytes with L-carnitine (200 microgram/ml), a compound known for its protective effect on cardiac metabolic injuries, was found to dose-dependently inhibit the doxorubicin-induced sphingomyelin hydrolysis and ceramide generation as well as subsequent cell death. However, L-carnitine did not protect cardiac myocytes from apoptosis induced by exogenous cell-permeant ceramide. L-carnitine pretreatment did not affect the sphingomyelinase basal activity but abolished the doxorubicin-induced increase in V(max). Moreover, in vitro studies conducted on cell extracts or with purified acid sphingomyelinase demonstrated that L-carnitine exerted a dose-dependent, sphingomyelinase inhibitory effect (through V(max) reduction). Taken together, these findings show that by inhibiting a (perhaps novel) drug-activated acid sphingomyelinase and ceramide generation, L-carnitine can prevent doxorubicin-induced apoptosis of cardiac myocytes.

1 In whole-cell patch-clamped human atrial myocytes, the antiarrhythmic agent bertosamil (10 μM) inhibited the sustained component, Isus (38.6±3.1%), and enhanced the inactivating component, It (9.1±6.1%), of the outward K+ current elicited by 750 ms test pulses from −60 mV to +50 mV. Higher concentrations of bertosamil (>10 μM) inhibited both It and Isus. 2 Suppression of Isus and stimulation of It by 10 μM bertosamil was observed on renewed stimulation following a 2 min rest period during which the drug was applied and persisted after washout, indicating a rest-dependent effect of bertosamil on the outward K+ current. 3 Cell dialysis with an internal solution containing 10 μM bertosamil increased both It (78.0±14.7%) and Itotal (26.7±8.4%) and inhibited Isus (28.9±6.3%, n=6). In the presence of intracellular bertosamil, external application of the drug inhibited It and Isus in a concentration-dependent and use-dependent manner. 4 Following the suppression of Isus by 200 μM 4-aminopyridine (4-AP), bertosamil (10 μM) inhibited It. Washout of 4-AP was associated with a larger It amplitude than that observed in control conditions. In myocytes characterized by a prominent Isus and lack of It, bertosamil (10 μM) induced a rapid and partial inactivation of the current, together with inward rectification of the current measured at the end of the test pulse. 5 In the presence of bertosamil the activation/voltage relationships, steady-state inactivation and recovery from inactivation of It were markedly modified, pointing to changes in the conductance underlying It. 6 We conclude that bertosamil induces rapid inactivation of sustained outward current which leads to an apparent increase in It and decrease in Isus. This effect, which was distinct from the use-dependent inhibition of the outward K+ current, could represent a new antiarrhythmic mechanism. British Journal of Pharmacology (1997) 122, 291–301; doi:10.1038/sj.bjp.0701369

SPECIFIC AIMSCalcium is involved in various aspects of the physiology and growth of cardiac myocytes including apoptosis, an important factor underlying the progression of a number of cardiovascular diseases. The aim of this study was to determine how Ca2+ regulates cardiac myocyte apoptosis induced by ceramide.PRINCIPAL FINDINGS1. Ceramide-induced apoptosis of adult rat ventricular myocytes is sensitive to calciumAfter 6 h of ceramide (Cer) treatment, 38.5 ± 1.3% of myocytes exhibited an apoptotic phenotype. The permeant Ca2+ chelator BAPTA-AM (50 μM) reduced Cer-treated myocyte apoptosis whereas pretreatment with the Ca2+ ionophore ionomycin (1 μM) markedly increased it.2. Calcium homeostasis is altered in the late stages of Cer-induced myocyte apoptosisIn control conditions (control), few local Ca2+ events were observed and rarely propagated Ca2+ events. In contrast, after more than 3 h both local and propagated Ca2+ events were increased, indicating that altered Ca2+ homeostasis. Ni2+, which blocks L-...

Terra Nova, 22, 303–308, 2010 Abstract The nature of uranium source rocks, transport conditions and deposition processes are still highly controversial for world-class unconformity-related U deposits. This article presents the first detailed chemistry of brines associated with the giant McArthur River U deposit, Canada. LA-ICP-MS analysis of individual fluid inclusions suggests mixing between a Na–Ca–Mg–K–Sr–Ba brine and a Ca–Mg–Na–K–Sr–Ba brine. The brines share a common origin (evaporated seawater) and show evidence for contrasting interaction with basement rocks. The Na-rich brine lost Mg and K in alteration haloes around U ores, while the Ca-rich brine results from Na–Ca exchange and Sr–Ba gain. U concentrations (0.3–530 μg g−1) are anomalously high compared with usual basinal fluids, this indicating that U uptake occurred within basement rocks. The two brine end-members have mixed within the main U deposit area, which could be one of the major driving forces for U deposition.