A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents.

BACKGROUND Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. OBJECTIVE To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). METHODS All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. RESULTS Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. CONCLUSION Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.

Combined Ultrasmall Superparamagnetic Particles of Iron Oxide–Enhanced and Diffusion-weighted Magnetic Resonance Imaging Facilitates Detection of Metastases in Normal-sized Pelvic Lymph Nodes of Patients with Bladder and Prostate Cancer

Background Conventional cross-sectional imaging with computed tomography and magnetic resonance imaging (MRI) has limited accuracy for lymph node (LN) staging in bladder and prostate cancer patients. Objective To prospectively assess the diagnostic accuracy of combined ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and diffusion-weighted (DW) MRI in staging of normal-sized pelvic LNs in bladder and/or prostate cancer patients. Design, setting, and participants Examinations with 3-Tesla MRI 24–36 h after administration of USPIO using conventional MRI sequences combined with DW-MRI (USPIO-DW-MRI) were performed in 75 patients with clinically localised bladder and/or prostate cancer staged previously as N0 by conventional cross-sectional imaging. Combined USPIO-DW-MRI findings were analysed by three independent readers and correlated with histopathologic LN findings after extended pelvic LN dissection (PLND) and resection of primary tumours. Outcome measurements and statistical analysis Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus histopathologic findings were evaluated per patient (primary end point) and per pelvic side (secondary end point). Time required for combined USPIO-DW-MRI reading was assessed. Results and limitations At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17–68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged from 58% to 67% and 94% to 97%, respectively. Median reading time for the combined USPIO-DW-MRI images was 9 min (range: 3–26 min). A potential limitation is the absence of a node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis. Conclusions Combined USPIO-DW-MRI improves detection of metastases in normal-sized pelvic LNs of bladder and/or prostate cancer patients in a short reading time.

Combined effect of soil bund with biological soil and water conservation measures in the northwestern Ethiopian highlands

Excessive runoff and soil erosion in the upper Blue Nile Basin poses a threat that has attracted the attention of the Ethiopian government because of the serious on-site effects in addition to downstream effects, such as the siltation of water harvesting structures and reservoirs. The objective of the study was to evaluate and recommend effective biophysical soil and water conservation measure(s) in the Debre Mewi watershed, about 30 km south of the Lake Tana. Six conservation measures were evaluated for their effects on runoff, soil loss, and forage yield using runoff plots. There was a significant difference between treatments for both runoff and soil loss. The four-year average annual soil loss in the different plots ranged from 26 to 71 t ha−1, and total runoff ranged from 180 to 302 mm, while annual rainfall varied between 854 mm in 2008 and 1247 mm in 2011. Soil bund combined with elephant grass had the lowest runoff and soil loss as compared to the other treatments, whereas the untreated control plot had the highest for both parameters. As an additional benefit, 2.8 and 0.7 t ha−1 year−1 of dried forage was obtained from elephant and local grasses, respectively. Furthermore, it was found that soil bund combined with Tephrosia increased soil organic matter by 13% compared to the control plot. Soil bund efficiency was significantly enhanced by combining them with biological measures and improved farmers’ perception of soil and water conservation measures.

Specimen specific parameter identification of ovine lumbar intervertebral discs: On the influence of fibre-matrix and fibre-fibre shear interactions.

Numerical models of the intervertebral disc, which address mechanical questions commonly make use of the difference in water content between annulus and nucleus, and thus fluid and solid parts are separated. Despite this simplification, models remain complex due to the anisotropy and nonlinearity of the annulus and regional variations of the collagen fibre density. Additionally, it has been shown that cross-links make a large contribution to the stiffness of the annulus. Because of this complex composite structure, it is difficult to reproduce several sets of experimental data with one single set of material parameters. This study addresses the question to which extent the ultrastructure of the intervertebral disc should be modelled so that its moment-angle behaviour can be adequately described. Therefore, a hyperelastic constitutive law, based on continuum mechanical principles was derived, which does not only consider the anisotropy from the collagen fibres, but also interactions among the fibres and between the fibres and the ground substance. Eight ovine lumbar intervertebral discs were tested on a custom made spinal loading simulator in flexion/extension, lateral bending and axial rotation. Specimen-specific geometrical models were generated using CT images and T2 maps to distinguish between annulus fibrosus and nucleus pulposus. For the identification of the material parameters the annulus fibrosus was described with two scenarios: with and without fibre-matrix and fibre-fibre interactions. Both scenarios showed a similar behaviour on a load displacement level. Comparing model predictions to the experimental data, the mean RMS of all specimens and all load cases was 0.54±0.15° without the interaction and 0.54±0.19° when the fibre-matrix and fibre-fibre interactions were included. However, due to the increased stiffness when cross-links effects were included, this scenario showed more physiological stress-strain relations in uniaxial and biaxial stress states. Thus, the present study suggests that fibre-matrix and fibre-fibre interactions should be considered in the constitutive law when the model addresses questions concerning the stress field of the annulus fibrosus.

Combined effect of a fluoride-, stannous- and chitosan-containing toothpaste and stannous-containing rinse on the prevention of initial enamel erosion-abrasion.

OBJECTIVES The aim of this study was to assess the preventive effect of a fluoride-, stannous- and chitosan-containing (F/Sn/chitosan-) toothpaste (TP) on initial enamel erosion and abrasion. METHODS In total, 150 human premolar enamel specimens were ground, polished and divided into 5 toothpaste/rinse groups (n=30): (G1) placebo-TP/tap water, (G2) sodium fluoride (NaF-) TP/tap water, (G3) F/Sn/chitosan-TP/tap water, (G4) F/Sn/chitosan-TP/Sn-rinse, (G5) NaF-TP/NaF-rinse. The 8-day erosion-abrasion cyclic treatment (one cycle/day) consisted of incubating the samples in artificial saliva (30min), then submitting the samples to toothbrush abrasion (2min incubation in toothpaste slurry; brushing with 20 toothbrush strokes) and rinsing (2min; 10ml) with the respective solution: tap water (G1-G3), Sn-rinse (G4) or NaF-rinse (G5). Afterwards, the samples were submitted to erosion (2min; 30ml 1% citric acid, pH=3.6). Surface microhardness (SMH) was measured initially and after every abrasion and erosion treatment. Enamel substance loss was calculated after each abrasion. Non-parametric ANOVA followed by Wilcoxon rank tests were used for analysis. RESULTS G1 presented the greatest SMH decrease, while G4 presented the least SMH decrease (p<0.001). G3 had a similar SMH decrease to G2 and G5. Substance loss was significantly lower in G4 than all other groups (p<0.05), closely followed by G3. Both G2 and G5 showed similar calculated enamel substance loss to G1. CONCLUSION The treatment with F/Sn/chitosan-TP and tap water provided a similar SMH decrease to both NaF-TP groups, but significantly lower substance loss. F/Sn/Chitosan-TP and Sn-rinse showed a better preventive effect, which promoted less SMH decrease and reduced substance loss. CLINICAL SIGNIFICANCE The toothpaste containing fluoride, stannous and chitosan shows promising results in reducing substance loss from erosion and abrasion. The combination of this toothpaste with the stannous-containing rinse showed even better prevention against erosion-abrasion.

"Of course I will...": The combined effect of certainty and level of expectancies on persistence and performance

The importance of performance expectancies for the prediction of regulation of behavior and actual performance has long been established. Building on theories from the field of social cognition, we suggest that the level of performance expectancies, as well as the certainty of the expectancy, have a joint influence on an individual’s beliefs and behavior. In two studies (one cross sectional using a sample of secondary school students and one longitudinal using a sample of university students) we found that expectancies more strongly predicted persistence, and subsequent performance, the more certain the expectancy was. This pattern was found even if prior performance was controlled, as in Study 2. The data give an indication that it may be useful to include certainty as an additional variable in expectancy models.

Doppler Orbit Determination of Deep Space Probes by the Bernese GNSS Software: First Results of the Combined Orbit Determination from DSN and Inter-Satellite Ka-Band Data from the Grail Mission

Navigation of deep space probes is most commonly operated using the spacecraft Doppler tracking technique. Orbital parameters are determined from a series of repeated measurements of the frequency shift of a microwave carrier over a given integration time. Currently, both ESA and NASA operate antennas at several sites around the world to ensure the tracking of deep space probes. Just a small number of software packages are nowadays used to process Doppler observations. The Astronomical Institute of the University of Bern (AIUB) has recently started the development of Doppler data processing capabilities within the Bernese GNSS Software. This software has been extensively used for Precise Orbit Determination of Earth orbiting satellites using GPS data collected by on-board receivers and for subsequent determination of the Earth gravity field. In this paper, we present the currently achieved status of the Doppler data modeling and orbit determination capabilities in the Bernese GNSS Software using GRAIL data. In particular we will focus on the implemented orbit determination procedure used for the combined analysis of Doppler and intersatellite Ka-band data. We show that even at this earlier stage of the development we can achieve an accuracy of few mHz on two-way S-band Doppler observation and of 2 µm/s on KBRR data from the GRAIL primary mission phase.

A systematic review on the innervation of peri-implant tissues with special emphasis on the influence of implant placement and loading protocols

OBJECTIVES To systematically review the available literature on the influence of dental implant placement and loading protocols on peri-implant innervation. MATERIAL AND METHODS The database MEDLINE, Cochrane, EMBASE, Web of Science, LILACS, OpenGrey and hand searching were used to identify the studies published up to July 2013, with a populations, exposures and outcomes (PEO) search strategy using MeSH keywords, focusing on the question: Is there, and if so, what is the effect of time between tooth extraction and implant placement or implant loading on neural fibre content in the peri-implant hard and soft tissues? RESULTS Of 683 titles retrieved based on the standardized search strategy, only 10 articles fulfilled the inclusion criteria, five evaluating the innervation of peri-implant epithelium, five elucidating the sensory function in peri-implant bone. Three included studies were considered having a methodology of medium quality and the rest were at low quality. All those papers reported a sensory innervation around osseointegrated implants, either in the bone-implant interface or peri-implant epithelium, which expressed a particular innervation pattern. Compared to unloaded implants or extraction sites without implantation, a significant higher density of nerve fibres around loaded dental implants was confirmed. CONCLUSIONS To date, the published literature describes peri-implant innervation with a distinct pattern in hard and soft tissues. Implant loading seems to increase the density of nerve fibres in peri-implant tissues, with insufficient evidence to distinguish between the innervation patterns following immediate and delayed implant placement and loading protocols. Variability in study design and loading protocols across the literature and a high risk of bias in the studies included may contribute to this inconsistency, revealing the need for more uniformity in reporting, randomized controlled trials, longer observation periods and standardization of protocols.

Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14.

Sepsis is an infection-induced systemic inflammatory syndrome, potentially causing organ failure. We previously showed attenuating effects on inflammation, thrombogenicity and haemodynamics by inhibiting the Toll-like receptor co-factor CD14 and complement factor C5 in a porcine Escherichia coli-induced sepsis model. The present study explored the effect on organ inflammation in these pigs. Tissue samples were examined from the combined treatment group (n = 8), the positive (n = 8) and negative (n = 6) control groups after 4h of sepsis. Inflammatory biomarkers were measured using ELISA, multiplex and qPCR analysis. Combined inhibition of C5 and CD14 markedly attenuated IL-1β by 31-66% (P < 0.05) and IL-6 by 54-96% (P < 0.01) in liver, kidney, lung and spleen; IL-8 by 65-100% in kidney, lung, spleen, and heart (P < 0.05) and MCP-1 by 46-69% in liver, kidney, spleen and heart (P < 0.05). Combined inhibition significantly attenuated tissue factor mRNA upregulation in spleen (P < 0.05) and IP-10 mRNA upregulation in four out of five organs. Finally, C5aR mRNA downregulation was prevented in heart and kidney (P < 0.05). Combined inhibition of C5 and CD14 thus markedly attenuated inflammatory responses in all organs examined. The anti-inflammatory effects observed in lung and heart may explain the delayed haemodynamic disturbances observed in septic pigs receiving combined inhibition of C5 and CD14.

Ease of Application of Medical Compression-stocking Systems for the Treatment of Venous Ulcers

OBJECTIVE: To evaluate the ease of application of two-piece, graduated, compression systems for the treatment of venous ulcers. METHODS: Four kits used to provide limb compression in the management of venous ulcers were evaluated. These have been proven to be non-inferior to various types of bandages in clinical trials. The interface pressure exerted above the ankle by the under-stocking and the complete compression system and the force required to pull the over-stocking off were assessed in vitro. Ease of application of the four kits was evaluated in four sessions by five nurses who put stockings on their own legs in a blinded manner. They expressed their assessment of the stockings using a series of visual analogue scales (VASs). RESULTS: The Sigvaris Ulcer X((R)) kit provided a mean interface pressure of 46 mmHg and required a force in the range of 60-90 N to remove it. The Mediven((R)) ulcer kit exerted the same pressure but required force in the range of 150-190 N to remove it. Two kits (SurePress((R)) Comfort and VenoTrain((R)) Ulcertec) exerted a mean pressure of only 25 mmHg and needed a force in the range of 100-160 N to remove them. Nurses judged the Ulcer X and SurePress kits easiest to apply. Application of the VenoTrain kit was found slightly more difficult. The Mediven kit was judged to be difficult to use. CONCLUSIONS: Comparison of ease of application of compression-stocking kits in normal legs revealed marked differences between them. Only one system exerted a high pressure and was easy to apply. Direct comparison of these compression kits in leg-ulcer patients is required to assess whether our laboratory findings correlate with patient compliance and ulcer healing.

Stability of Contour Augmentation and Esthetic Outcomes of Implant Supported Single Crowns in the Esthetic Zone. 3-Year Results of a Prospective Study With Early Implant Placement Post Extraction

Early implant placement is one of the treatment options after tooth extraction. Implant surgery is performed after a healing period of 4 to 8 weeks and combined with a simultaneous contour augmentation using the guided bone regeneration technique to rebuild stable esthetic facial hard- and soft-tissue contours.

Expression, localization, and functional model of cholesterol transporters in lactating and nonlactating mammary tissues of murine, bovine, and human origin

Members of the ATP-binding cassette (ABC) transporters play a pivotal role in cellular lipid efflux. To identify candidate cholesterol transporters implicated in lipid homeostasis and mammary gland (MG) physiology, we compared expression and localization of ABCA1, ABCG1, and ABCA7 and their regulatory genes in mammary tissues of different species during the pregnancy-lactation cycle. Murine and bovine mammary glands (MGs) were investigated during different functional stages. The abundance of mRNAs was determined by quantitative RT-PCR. Furthermore, transporter proteins were localized in murine, bovine, and human MGs by immunohistochemistry. In the murine MG, ABCA1 mRNA abundance was elevated during nonlactating compared with lactating stages, whereas ABCA7 and ABCA1 mRNA profiles were not altered. In the bovine MG, ABCA1, ABCG1, and ABCA7 mRNAs abundances were increased during nonlactating stages compared with lactation. Furthermore, associations between mRNA levels of transporters and their regulatory genes LXRalpha, PPARgamma, and SREBPs were found. ABCA1, ABCG1, and ABCA7 proteins were localized in glandular MG epithelial cells (MEC) during lactation, whereas during nonlactating stages, depending on species, the proteins showed distinct localization patterns in MEC and adipocytes. Our results demonstrate that ABCA1, ABCG1, and ABCA7 are differentially expressed between lactation and nonlactating stages and in association with regulatory genes. Combined expression and localization data suggest that the selected cholesterol transporters are universal MG transporters involved in transport and storage of cholesterol and in lipid homeostasis of MEC. Because of the species-specific expression patterns of transporters in mammary tissue, mechanisms of cholesterol homeostasis seem to be differentially regulated between species.

Expression patterns of Bmi-1 and p16 significantly correlate with overall, disease-specific, and recurrence-free survival in oropharyngeal squamous cell carcinoma

BACKGROUND: The objective of this study was to link expression patterns of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC). METHODS: Expression levels of Bmi-1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease-specific, and recurrence-free survival. RESULTS: The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi-1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi-1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167-2.838); this correlation was also observed for atypical cytoplasmic Bmi-1 expression (P = .001; HR, 2.164; 95% CI, 1.389-3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178-0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237-16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146-2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869-13.635) were correlated with overall survival, disease-specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477-5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850-15.679), and the combined markers also were correlated with recurrence-free survival (P = .001; HR, 8.943; 95% CI, 2.562-31.220). CONCLUSIONS: Cytoplasmic Bmi-1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease-specific and recurrence-free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow-up. Cancer 2011;. © 2011 American Cancer Society.

Domains of physical activity and all-cause mortality: systematic review and dose-response meta-analysis of cohort studies

Background The dose–response relation between physical activity and all-cause mortality is not well defined at present. We conducted a systematic review and meta-analysis to determine the association with all-cause mortality of different domains of physical activity and of defined increases in physical activity and energy expenditure. Methods MEDLINE, Embase and the Cochrane Library were searched up to September 2010 for cohort studies examining all-cause mortality across different domains and levels of physical activity in adult general populations. We estimated combined risk ratios (RRs) associated with defined increments and recommended levels, using random-effects meta-analysis and dose–response meta-regression models. Results Data from 80 studies with 1 338 143 participants (118 121 deaths) were included. Combined RRs comparing highest with lowest activity levels were 0.65 [95% confidence interval (95% CI) 0.60–0.71] for total activity, 0.74 (95% CI 0.70–0.77) for leisure activity, 0.64 (95% CI 0.55–0.75) for activities of daily living and 0.83 (95% CI 0.71–0.97) for occupational activity. RRs per 1-h increment per week were 0.91 (95% CI 0.87–0.94) for vigorous exercise and 0.96 (95% CI 0.93–0.98) for moderate-intensity activities of daily living. RRs corresponding to 150 and 300 min/week of moderate to vigorous activity were 0.86 (95% CI 0.80–0.92) and 0.74 (95% CI 0.65–0.85), respectively. Mortality reductions were more pronounced in women. Conclusion Higher levels of total and domain-specific physical activity were associated with reduced all-cause mortality. Risk reduction per unit of time increase was largest for vigorous exercise. Moderate-intensity activities of daily living were to a lesser extent beneficial in reducing mortality.