International union of basic and clinical pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel.

The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.

Changes in Aortic Pulse Wave Velocity in Hypertension Post-Menopausal Women: Comparison Between Calcium Channel Blocker (CCB) Vs Angiotensin Receptor Blocker (ARB) Regimen

Objective: To compare effects of a non-renin-angiotensin system (RAS) blocker, using a CCB, or a RAS blocker, using an ARB regimen on the arterial stiffness reduction in postmenopausal hypertensive women. Methods: In this prospective study, a total of 125 hypertensive women (age: 61.4_6 yrs; 98% Caucasian; BW: 71.9_14 kg; BMI: 27.3_5 kg/m2; SBP/ DBP: 158_11/92_9 mmHg) were randomized between ARB (valsartan 320mg_HCTZ) and CCB (amlodipine 10mg _ HCTZ). The primary outcome was carotid-femoral pulse wave velocity (PWV) changes after 38 weeks of treatment. Results: There were no significant differences in baseline demographic data between the two groups. Both treatments effectively lowered BP at the end of the study with similar (p>0.05) reductions in the valsartan (_22.9/_10.9 mmHg) and amlodipine based (_25.2/_11.7 mmHg) treatment groups. Despite a lower (p<0.05 for DBP) central SBP/DBP in the CCB group (_19.2/_10.3 mmHg) compared to the valsartan group (_15.7/_7.6 mmHg) at week 38, a similar reduction in carotid-femoral PWV (_1.7 vs _1.9 m/sec; p>0.05) was observed between both groups. The numerically larger BP reduction observed in the CCB group was associated with a much higher incidence of peripheral edema (77% vs 14%) than the valsartan group. Conclusion: In summary, BP lowering in postmenopausal women led to a reduction in arterial stiffness assessed by PWV measurement. Both regimens reduced PWV at 38 weeks of treatment to a similar degree, despite differences in BP lowering suggesting that the effect of RAS blockade to influence PWV may partly be independent of BP.

Estimation du degré de couverture d'un registre pour les cancers notifiés au décès [Evaluation of the comprehensiveness of a cancer register from death certificates].

The comparison of cancer prevalence with cancer mortality can lead under some hypotheses to an estimate of registration rate. A method is proposed, where the cases with cancer as a cause of death are divided into 3 categories: (1) cases already known by the registry (2) unknown cases having occured before the registry creation date (3) unknown cases occuring during the registry operates. The estimate is then the number of cases in the first category divided by the total of those in categories 1 and 3 (these only are to be registered). An application is performed on the data of the Canton de Vaud. Survival rates of the Norvegian Cancer Registry are used for computing the number of unknown cases to be included in second and third category, respectively. The discussion focusses on the possible determinants of the obtained comprehensiveness rates for various cancer sites.

The estimation of PMP and PMF on alpine basins in Switzerland

This paper presents a very fine grid hydrological model based on the spatiotemporal repartition of precipitation and on the topography. The goal is to estimate the flood on a catchment area, using a Probable Maximum Precipitation (PMP) leading to a Probable Maximum Flood (PMF). The spatiotemporal distribution of the precipitation was realized using six clouds modeled by the advection-diffusion equation. The equation shows the movement of the clouds over the terrain and also gives the evolution of the rain intensity in time. This hydrological modeling is followed by a hydraulic modeling of the surface and subterranean flows, done considering the factors that contribute to the hydrological cycle, such as the infiltration, the exfiltration and the snowmelt. This model was applied to several Swiss basins using measured rain, with results showing a good correlation between the simulated and observed flows. This good correlation proves that the model is valid and gives us the confidence that the results can be extrapolated to phenomena of extreme rainfall of PMP type. In this article we present some results obtained using a PMP rainfall and the developed model.

Limitations and information needs for engineered nanomaterial-specific exposure estimation and scenarios: recommendations for improved reporting practices

The aim of this paper is to describe the process and challenges in building exposure scenarios for engineered nanomaterials (ENM), using an exposure scenario format similar to that used for the European Chemicals regulation (REACH). Over 60 exposure scenarios were developed based on information from publicly available sources (literature, books, and reports), publicly available exposure estimation models, occupational sampling campaign data from partnering institutions, and industrial partners regarding their own facilities. The primary focus was on carbon-based nanomaterials, nano-silver (nano-Ag) and nano-titanium dioxide (nano-TiO2), and included occupational and consumer uses of these materials with consideration of the associated environmental release. The process of building exposure scenarios illustrated the availability and limitations of existing information and exposure assessment tools for characterizing exposure to ENM, particularly as it relates to risk assessment. This article describes the gaps in the information reviewed, recommends future areas of ENM exposure research, and proposes types of information that should, at a minimum, be included when reporting the results of such research, so that the information is useful in a wider context.

Estimation of a maximum Lu diffusion rate in a natural eclogite garnet

Lutetium zoning in garnet within eclogites from the Zermatt-Saas Fee zone, Western Alps, reveal sharp, exponentially decreasing central peaks. They can be used to constrain maximum Lu volume diffusion in garnets. A prograde garnet growth temperature interval of 450-600 A degrees C has been estimated based on pseudosection calculations and garnet-clinopyroxene thermometry. The maximum pre-exponential diffusion coefficient which fits the measured central peak is in the order of D-0= 5.7*10(-6) m(2)/s, taking an estimated activation energy of 270 kJ/mol based on diffusion experiments for other rare earth elements in garnet. This corresponds to a maximum diffusion rate of D (600 A degrees C) = 4.0*10(-22) m(2)/s. The diffusion estimate of Lu can be used to estimate the minimum closure temperature, T-c, for Sm-Nd and Lu-Hf age data that have been obtained in eclogites of the Western Alps, postulating, based on a literature review, that D (Hf) < D (Nd) < D (Sm) a parts per thousand currency sign D (Lu). T-c calculations, using the Dodson equation, yielded minimum closure temperatures of about 630 A degrees C, assuming a rapid initial exhumation rate of 50A degrees/m.y., and an average crystal size of garnets (r = 1 mm). This suggests that Sm/Nd and Lu/Hf isochron age differences in eclogites from the Western Alps, where peak temperatures did rarely exceed 600 A degrees C must be interpreted in terms of prograde metamorphism.

Muscle moment-arms: a key element in muscle-force estimation.

A clear and rigorous definition of muscle moment-arms in the context of musculoskeletal systems modelling is presented, using classical mechanics and screw theory. The definition provides an alternative to the tendon excursion method, which can lead to incorrect moment-arms if used inappropriately due to its dependency on the choice of joint coordinates. The definition of moment-arms, and the presented construction method, apply to musculoskeletal models in which the bones are modelled as rigid bodies, the joints are modelled as ideal mechanical joints and the muscles are modelled as massless, frictionless cables wrapping over the bony protrusions, approximated using geometric surfaces. In this context, the definition is independent of any coordinate choice. It is then used to solve a muscle-force estimation problem for a simple 2D conceptual model and compared with an incorrect application of the tendon excursion method. The relative errors between the two solutions vary between 0% and 100%.

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State.

BACKGROUND:: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS:: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS:: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS:: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Predictive analysis and mapping of indoor radon concentrations in a complex environment using kernel estimation: an application to Switzerland.

PURPOSE: The aim of this study was to develop models based on kernel regression and probability estimation in order to predict and map IRC in Switzerland by taking into account all of the following: architectural factors, spatial relationships between the measurements, as well as geological information. METHODS: We looked at about 240,000 IRC measurements carried out in about 150,000 houses. As predictor variables we included: building type, foundation type, year of construction, detector type, geographical coordinates, altitude, temperature and lithology into the kernel estimation models. We developed predictive maps as well as a map of the local probability to exceed 300 Bq/m(3). Additionally, we developed a map of a confidence index in order to estimate the reliability of the probability map. RESULTS: Our models were able to explain 28% of the variations of IRC data. All variables added information to the model. The model estimation revealed a bandwidth for each variable, making it possible to characterize the influence of each variable on the IRC estimation. Furthermore, we assessed the mapping characteristics of kernel estimation overall as well as by municipality. Overall, our model reproduces spatial IRC patterns which were already obtained earlier. On the municipal level, we could show that our model accounts well for IRC trends within municipal boundaries. Finally, we found that different building characteristics result in different IRC maps. Maps corresponding to detached houses with concrete foundations indicate systematically smaller IRC than maps corresponding to farms with earth foundation. CONCLUSIONS: IRC mapping based on kernel estimation is a powerful tool to predict and analyze IRC on a large-scale as well as on a local level. This approach enables to develop tailor-made maps for different architectural elements and measurement conditions and to account at the same time for geological information and spatial relations between IRC measurements.

Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.

Active deformation fields: dense deformation field estimation for atlas-based segmentation using the active contour framework.

This paper presents a new and original variational framework for atlas-based segmentation. The proposed framework integrates both the active contour framework, and the dense deformation fields of optical flow framework. This framework is quite general and encompasses many of the state-of-the-art atlas-based segmentation methods. It also allows to perform the registration of atlas and target images based on only selected structures of interest. The versatility and potentiality of the proposed framework are demonstrated by presenting three diverse applications: In the first application, we show how the proposed framework can be used to simulate the growth of inconsistent structures like a tumor in an atlas. In the second application, we estimate the position of nonvisible brain structures based on the surrounding structures and validate the results by comparing with other methods. In the final application, we present the segmentation of lymph nodes in the Head and Neck CT images, and demonstrate how multiple registration forces can be used in this framework in an hierarchical manner.

Protease modulation of the activity of the epithelial sodium channel expressed in Xenopus oocytes.

We have investigated the effect of extracellular proteases on the amiloride-sensitive Na+ current (INa) in Xenopus oocytes expressing the three subunits alpha, beta, and gamma of the rat or Xenopus epithelial Na+ channel (ENaC). Low concentrations of trypsin (2 microg/ml) induced a large increase of INa within a few minutes, an effect that was fully prevented by soybean trypsin inhibitor, but not by amiloride. A similar effect was observed with chymotrypsin, but not with kallikrein. The trypsin-induced increase of INa was observed with Xenopus and rat ENaC, and was very large (approximately 20-fold) with the channel obtained by coexpression of the alpha subunit of Xenopus ENaC with the beta and gamma subunits of rat ENaC. The effect of trypsin was selective for ENaC, as shown by the absence of effect on the current due to expression of the K+ channel ROMK2. The effect of trypsin was not prevented by intracellular injection of EGTA nor by pretreatment with GTP-gammaS, suggesting that this effect was not mediated by G proteins. Measurement of the channel protein expression at the oocyte surface by antibody binding to a FLAG epitope showed that the effect of trypsin was not accompanied by an increase in the channel protein density, indicating that proteolysis modified the activity of the channel present at the oocyte surface rather than the cell surface expression. At the single channel level, in the cell-attached mode, more active channels were observed in the patch when trypsin was present in the pipette, while no change in channel activity could be detected when trypsin was added to the bath solution around the patch pipette. We conclude that extracellular proteases are able to increase the open probability of the epithelial sodium channel by an effect that does not occur through activation of a G protein-coupled receptor, but rather through proteolysis of a protein that is either a constitutive part of the channel itself or closely associated with it.

Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the alpha subunit of the epithelial sodium channel.

OBJECTIVE: Pseudohypoaldosteronism type I (PHA1) is a rare inborn disease causing severe salt loss. Mutations in the three coding genes of the epithelial sodium channel (ENaC) are responsible for the systemic autosomal recessive form. So far, no phenotype has been reported in heterozygous carriers. PATIENTS: A consanguineous family from Somalia giving birth to a neonate suffering from PHA1 was studied including clinical and hormonal characteristics of the family, mutational analysis of the SCNN1A, SCNN1B, SCNN1G and CFTR genes and in vitro analysis of the functional consequences of a mutant ENaC channel. RESULTS: CFTR mutations have been excluded. SCNN1A gene analysis revealed a novel homozygous c.1684T > C mutation resulting in a S562P substitution in the alphaENaC protein of the patient. Functional analysis showed a significantly reduced S562P channel function compared to ENaC wild type. Protein synthesis and channel subunit assembly were not altered by the S562P mutation. Co-expression of mutant and wild-type channels revealed a dominant negative effect. In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes. CONCLUSION: Hence, the novel mutation S562P is causing systemic PHA1 in the homozygous state. A thorough clinical investigation of the heterozygote SCNN1A mutation carriers revealed increased sweat sodium and chloride levels consistent with a dominant effect of the mutant S562P allele. Whether this subclinical phenotype is of any consequence for the otherwise asymptomatic heterozygous carriers has to be elucidated.