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The increase in atmospheric greenhouse gases over the last 200 years has caused an increase in ocean acidity levels. Documenting how the ocean has changed is critical for assessing how these changes could impact marine ecosystems and for the management of marine resources. We use present day ocean carbon observations from shelf and offshore waters around Australia, combined with neural network mapping of CO2, to estimate the current seasonal and regional distributions of carbonate chemistry (pH and aragonite saturation state). These predicted changes in carbonate chemistry are combined with atmospheric CO2 concentration changes since to reconstruct pH and aragonite saturation state changes over the last 140 years (1870-2013). The comparison with data collected at Integrated Marine Observing System National Reference Station sites located on the shelf around Australia shows both the mean state and seasonality for the present day is well represented by our reconstruction, with the exception of sites such as the Great Barrier Reef. Our reconstruction predicts that since 1870 an average decrease in aragonite saturation state of 0.48 and of 0.09 in pH has occurred in response to increasing oceanic uptake of atmospheric CO2. Our reconstruction shows that seasonality is the dominant mode of variability, with only small interannual variability present. Large seasonal variability in pH and aragonite saturation state occur in Southwestern Australia driven by ocean dynamics (mixing) and in the Tasman Sea by seasonal warming (in the case of aragonite saturation state). The seasonal and historical changes in aragonite saturation state and pH have different spatial patterns and suggest that the biological responses to ocean acidification are likely to be non-uniform depending on the relative sensitivity of organisms to shifts in pH and saturation state. This new historical reconstruction provides an important to link to biological observations to help elucidate the consequences of ocean acidification. [ABSTRACT FROM AUTHOR]

Ocean acidification is a predictable consequence of rising atmospheric carbon dioxide (CO2/, and is highly likely to impact the entire marine ecosystem - from plankton at the base of the food chain to fish at the top. Factors which are expected to be impacted include reproductive health, organism growth and species composition and distribution. Predicting when critical threshold values will be reached is crucial for projecting the future health of marine ecosystems and for marine resources planning and management. The impacts of ocean acidification will be first felt at the seasonal scale, however our understanding how seasonal variability will influence rates of future ocean acidification remains poorly constrained due to current model and data limitations. To address this issue, we first quantified the seasonal cycle of aragonite saturation state utilizing new data-based estimates of global ocean-surface dissolved inorganic carbon and alkalinity. This seasonality was then combined with earth system model projections under different emissions scenarios (representative concentration pathways; RCPs 2.6, 4.5 and 8.5) to provide new insights into future aragonite undersaturation onset. Under a high emissions scenario (RCP 8.5), our results suggest accounting for seasonality will bring forward the initial onset of month-long undersaturation by 17±10 years compared to annual-mean estimates, with differences extending up to 35±16 years in the North Pacific due to strong regional seasonality. This earlier onset will result in large-scale undersaturation once atmospheric CO2 reaches 496 ppm in the North Pacific and 511 ppm in the Southern Ocean, independent of emission scenario. This work suggests accounting for seasonality is critical to projecting the future impacts of ocean acidification on the marine environment. [ABSTRACT FROM AUTHOR]

Using measurements of the surface-ocean CO2 partial pressure (pCO2) and 14 different pCO2 mapping methods recently collated by the Surface Ocean pCO2 Mapping intercomparison (SOCOM) initiative, variations in regional and global sea-air CO2 fluxes have been investigated. Though the available mapping methods use widely different approaches, we find relatively consistent estimates of regional pCO2 seasonality, in line with previous estimates. In terms of interannual variability (IAV), all mapping methods estimate the largest variations to occur in the Eastern equatorial Pacific. Despite considerable spead in the detailed variations, mapping methods with closer match to the data also tend to be more consistent with each other. Encouragingly, this includes mapping methods belonging to complementary types -- taking variability either directly from the pCO2 data or indirectly from driver data via regression. From a weighted ensemble average, we find an IAV amplitude of the global sea-air CO2 flux of 0.31 PgC yr-1 (standard deviation over 1992-2009), which is larger than simulated by biogeochemical process models. On a decadal perspective, the global CO2 uptake is estimated to have gradually increased since about 2000, with little decadal change prior to 2000. The weighted mean total ocean CO2 sink estimated by the SOCOM ensemble is consistent within uncertainties with estimates from ocean-interior carbon data or atmospheric oxygen trends. [ABSTRACT FROM AUTHOR]

Ocean acidification is a predictable consequence of rising atmospheric carbon dioxide (CO2), and is highly likely to impact the entire marine ecosystem - from plankton at the base to fish at the top. Factors which are expected to be impacted include reproductive health, organism growth and species composition and distribution. Predicting when critical threshold values will be reached is crucial for projecting the future health of marine ecosystems and for marine resources planning and management. The impacts of ocean acidification will be first felt at the seasonal scale, however our understanding how seasonal variability will influence rates of future ocean acidification remains poorly constrained due to current model and data limitations. To address this issue, we first quantified the seasonal cycle of aragonite saturation state utilizing new data-based estimates of global ocean surface dissolved inorganic carbon and alkalinity. This seasonality was then combined with earth system model projections under different emissions scenarios (RCPs 2.6, 4.5 and 8.5) to provide new insights into future aragonite under-saturation onset. Under a high emissions scenario (RCP 8.5), our results suggest accounting for seasonality will bring forward the initial onset of month-long under-saturation by 17 years compared to annual-mean estimates, with differences extending up to 35 ± 17 years in the North Pacific due to strong regional seasonality. Our results also show large-scale under-saturation once atmospheric CO2 reaches 486 ppm in the North Pacific and 511 ppm in the Southern Ocean independent of emission scenario. Our results suggest that accounting for seasonality is critical to projecting the future impacts of ocean acidification on the marine environment. [ABSTRACT FROM AUTHOR]

The Atlantic Ocean is one of the most important sinks for atmospheric carbon dioxide (CO2), but this sink has been shown to vary substantially in time. Here we use surface ocean CO2 observations to estimate this sink and the temporal variability from 1998 through 2007 in the Atlantic Ocean. We benefit from (i) a continuous improvement of the observations, i.e. the Surface Ocean CO2 Atlas (SOCAT) v1.5 database and (ii) a newly developed technique to interpolate the observations in space and time. In particular, we use a two-step neural network approach to reconstruct basin-wide monthly maps of the sea surface partial pressure of CO2 (pCO2) at a resolution of 1x1 . From those, we compute the air-sea CO2 flux maps using a standard gas exchange parameterization and high-resolution wind speeds. The neural networks fit the observed pCO2 data with a root mean square error (RMSE) of about 10 µatm and with almost no bias. A check against independent time-series data and new data from SOCAT v2 reveals a larger RMSE of 22.8 µatm for the entire Atlantic Ocean, which decreases to 16.3 µatm for data south of 40° N. We estimate a decadal mean uptake flux of -0.45±0.15 PgC yr-1 for the Atlantic between 44°S and 79°N, representing the sum of a strong uptake north of 18° N (-0.39±0.10 PgC yr-1), outgassing in the tropics (18° S-18° N, 0.11±0.07 PgC yr-1), and uptake in the subtropical/temperate South Atlantic south of 18° S (-0.16±0.06 PgC yr-1), consistent with recent studies. The strongest seasonal variability of the CO2 flux occurs in the temperature-driven subtropical North Atlantic, with uptake in winter and outgassing in summer. The seasonal cycle is antiphased in the subpolar latitudes relative to the subtropics largely as a result of the biologically driven winter-to-summer drawdown of CO2. Over the 10 yr analysis period (1998 through 2007), sea surface pCO2 increased faster than that of the atmosphere in large areas poleward of 40° N, while in other regions of the North Atlantic the sea surface pCO2 increased at a slower rate, resulting in a barely changing Atlantic carbon sink north of the Equator (-0.01±0.02 PgC yr-1 decade ). Surface ocean pCO2 increased at a slower rate relative to atmospheric CO2 over most of the Atlantic south of the Equator, leading to a substantial trend toward a stronger CO2 sink for the entire South Atlantic (-0.14±0.02 PgC yr-1 decade ). In contrast to the 10 yr trends, the Atlantic Ocean carbon sink varies relatively little on inter-annual timescales (±0.04 PgC yr-1 ; 1σ). [ABSTRACT FROM AUTHOR]

The ocean's role in modulating the observed 1-7 PgCyr-1 inter-annual variability in atmospheric CO2 growth rate is an important, but poorly constrained process due to sparse spatio-temporal ocean carbon measurements. Here, we investigate and develop a non-linear empirical approach to predict inorganic CO2 concentrations (total carbon dioxide (CT) and total alkalinity (AT) in the global ocean mixed-layer from hydrographic properties (temperature, salinity, dissolved oxygen and nutrients). The benefit of this approach is that once the empirical relationship is established, it can be applied to hydrographic datasets that have better spatio-temporal coverage, and therefore provide an additional constraint to diagnose ocean carbon dynamics globally. Previous empirical approaches have employed multiple linear regressions (MLR), and relied on ad-hoc geographic and temporal partitioning of carbon data to constrain complex global carbon dynamics in the mixed-layer. Synthesising a new global CT/AT carbon bottle dataset consisting of ∼33 000 measurements in the open ocean mixed- layer, we develop a neural network based approach to better constrain the non-linear carbon system. The approach classifies features in the global biogeochemical dataset based on their similarity and homogeneity in a self-organizing map (SOM; Kohonen, 1988). After the initial SOM analysis, which includes geographic constraints, we apply a local linear optimizer to the neural network which considerably enhances the predictive skill of the new approach. We call this new approach SOMLO, or self-organizing multiple linear output. Using independent bottle carbon data, we compare a traditional MLR analysis to our SOMLO approach to capture the spatial CT and AT distributions. We find the SOMLO approach improves predictive skill globally by 19% for CT, with a global capacity to predict CT to within 10.9 µmol kg-1 (9.2 µmol kg-1 for AT). The non- linear SOMLO approach is particularly powerful in complex, but important regions like the Southern Ocean, North Atlantic and equatorial Pacific where residual standard errors were reduced between 25-40% over traditional linear methods. We further test the SOMLO technique using the Bermuda Atlantic time-series (BATS) and Hawaiian ocean time-series (HOT) datasets, where hydrographic data was capable of explaining 90% of the seasonal cycle and inter-annual variability at those multi-decadal time-series stations. [ABSTRACT FROM AUTHOR]

Currently, primary osteoporosis is the most frequent metabolic disease in women after menopause [1]. The resulting loss of bone mass is accompanied by an increased risk of skeletal fragility. One reason for the development of osteoporosis might be an impaired function of mature osteoblasts. To evaluate the involvement of specific growth factors in bone remodeling, cell cultures of osteoblastic cells derived from nonosteoporotic and osteoporotic postmenopausal women were established. The influences of TGF beta-1 and IGF-I on proliferation and mRNA expression of TGF beta-1 were investigated by [3H]-thymidine incorporation and competitive RT-PCR. We found IGF-I to have no significant effect on proliferation in cells of osteoporotic and nonosteoporotic patients. In contrast, differences were found in TGF beta-1 mRNA expression after application of IGF-I. Application of TGF beta-1 enhanced its own mRNA expression in both groups in a similar manner. Whereas the proliferation of cells of nonosteoporotic patients was inhibited by (10(-10) M) TGF beta-1, this treatment led to an increased proliferation of cells of osteoporotic patients. [ABSTRACT FROM AUTHOR]

Background: Persistent left superior vena cava (PLSVC) is a rare venous anomaly, affecting 0.3-0.5% of the general population. Cardiac resynchronization therapy (CRT) implantation in patients with PLSVC is challenging due to a complex anatomy. Moreover, data on CRT implantation in this patient population is scarce. Our aim was to report a series of patients with PLSVC and CRT implantation focusing on challenges and pitfalls., Methods: Electronic medical databases on patients with CRT implantation at the University Heart Centers in Zurich, Switzerland, and Lübeck, Germany, were screened for individuals with a PLSVC. Clinical and demographic characteristics as well as procedural data were reported in all patients., Results: This study presents six cases with a median age of 66 years. CRT implantation was successful in five patients, leading to a reduced QRS duration and improved left ventricular ejection fraction. Atrial fibrillation, ischemic cardiomyopathy, valvular heart disease, and dilated cardiomyopathy were observed in this group as underlying conditions. Specialized tools, such as active fixation left ventricular leads, were utilized. One patient experienced major complications., Conclusions: This case series shows that although challenging, conventional endovascular CRT implantation is feasible in PLSVC patients. Specialized tools for visualization and fixation may help. Our experiences highlight the importance of preprocedural evaluation of the anatomy and precise intervention planning., (© 2024. The Author(s).)

Introduction: Transvenous lead extractions are increasingly performed for malfunction or infection of cardiac implantable electronic devices, but they harvest a potential for complications and suboptimal success. Apart from multicenter registries and reports from highly experienced single centers, the outcome in individual newly developing high-volume centers starting a lead extraction program is less well established. We aimed to evaluate the clinical and radiological success and complication rate at our center, having started a lead extraction program less than a decade ago., Methods: We retrospectively analyzed patients who underwent transvenous lead extraction at the University Hospital Zurich from 2013 to 2021 regarding success as well as complications and compared our results to previously reported outcome rates., Results: A total of 346 patients underwent 350 transvenous lead extractions from January 2013 to December 2021. Combined radiological success was achieved in 97.7% and clinical success in 96.0% of interventions. Procedure-related major complications occurred in 13 patients (3.7%). Death within 30 days after transvenous lead extractions occurred in 13 patients (3.7%), with a procedure-related mortality of 1.4% (five patients)., Summary: Transvenous lead extractions in newly developing high-volume centers can be performed with high clinical and radiological success rates, but procedure-related major complications may affect a relevant number of patients. Compared to large single or multicenter registries of experienced centers, the success rate may be lower and the complication rate higher in centers newly starting with lead extraction, which may have important implications for patient selection, procedural planning, proctoring, and safety measures., Competing Interests: Daniel Hofer reports educational grants, consultant or speaker fees, and fellowship support from Abbott, Medtronic, Biotronik, Boston Scientific, Biosense Webster, Novartis, Bayer, Pfizer, and Spectranetics. Alexander Breitenstein has received consultant and/or speaker fees from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Pfizer, and Spectranetics/Philipps. Jan Steffel has received consultant and/or speaker fees from Abbott, Alexion, Astra-Zeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, Saja, Servier, andWebMD. He reports ownership of CorXL and Swiss EP. Steffel has received grant support through his former institution from Abbott, Bayer Healthcare, BiosenseWebster, Biotronik, Boston Scientific, Daiichi Sankyo, and Medtronic. Sasse reports educational grants from Biotronik.

Background: SARS-CoV-2 antigen tests reliably detect individuals with high viral loads and provide an efficient diagnostic tool to manage the current SARS-CoV-2 pandemic . However, mutations in SARS-CoV-2 variants of concerns that appeared after validation of most antigen tests might impact their diagnostic performance., Objectives: To assess the impact of the Omicron variant on the performance of the DiaSorin LIAISON SARS-CoV-2 antigen test, we evaluated its sensitivity and specificity on nasopharyngeal swabs (NPS) compared to rRT-PCR in the second and the Omicron pandemic wave in Switzerland., Study Design: A random selection of NPS from patients undergoing SARS-CoV-2 diagnostics by rRT-PCR were collected during the second and the Omicron pandemic wave and further analyzed by the LIAISON antigen test. Sensitivity and specificity compared to rRT-PCR were calculated., Results: Test performance did not change in the two investigated periods. The overall sensitivity of 75.8% in the second and 76.5% in the Omicron wave increased to 87.1% and 88.4%, excluding samples with rRT-PCR Ct-value >30. By lowering the cut-off from 200 TCID 50 /ml to 62 TCID 50 /ml to discriminate between negative and positive samples using a ROC-curve, the sensitivity resulted in 88.8% for the second and 93.3% for the Omicron pandemic wave. The specificity of the LIAISON antigen test was 100% in both collectives., Conclusion: Omicron variant does not seem to affect the performance of the LIAISON antigen test. The WHO recommended sensitivity of ≥80% for antigen testing was fulfilled during both pandemic periods in samples with Ct-value <30 or by optimizing the assay cut-off., Competing Interests: The authors have no conflict of interest to declare., (© 2022 The Authors. Published by Elsevier Ltd.)

Introduction: Fluoroscopy is traditionally used for catheter interventions in electrophysiology but carries a long-term health risk. Besides additional invasive procedures to achieve zero-fluoroscopy (ZF) interventions, electroanatomic mapping may be an alternative to fluoroscopy without the need of additional procedures. We aimed to investigate the feasibility, safety, and efficiency of a ZF approach using only electroanatomic mapping (ZF) compared to a conventional fluoroscopic (CF) approach for patients with right sided cardiac arrhythmias., Methods: We performed a single centre retrospective cohort study of consecutive patients undergoing catheter interventions for electrophysiologic procedures from January 2019 to December 2020. Patients with left-sided arrhythmias, focal cryoablation, implanted endocardial devices, or additional interventions requiring fluoroscopy were excluded., Results: 202 patients underwent a ZF and 126 patients underwent a CF approach for right-sided cardiac arrhythmias. Apart from atrial fibrillation (ZF 16% vs. CF 9%, p = 0.044), baseline demographics were similar in both groups. Acute success rate was 100% in the ZF group and 97.9% in the CF group. Mean procedure time was lower in the ZF group (70 ± 36 vs. 87 ± 44 min, p = 0.0001), while ablation time (356 ± 324 vs. 320 ± 294 s, p = 0.157) was similar. Total complication rate was low in general (1.0 % major, 2% minor complications) and without a difference between both groups., Conclusion: A ZF approach using only electroanatomic mapping without additional invasive procedures to diagnose and treat right-sided cardiac arrhythmias is feasible, efficient, and safe., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background & Aims: Plasma citrulline, a non-protein amino acid, is a biochemical marker of small intestine enterocyte mass in humans. Indeed, citrulline is highly correlated with residual bowel length in patients with short bowel syndrome. It is known to be synthesised in epithelial cells of the small intestine from other amino acids (precursors). Citrulline is then released into systemic circulation and interconverted into arginine in kidneys. If plasma citrulline concentration depends on abundance of intestinal amino acid transporters is not known. The aim of the present study was to explore whether plasma citrulline concentration correlates with the expression of intestinal amino acid transporters. Furthermore, we assessed if arginine in urine correlates with plasma citrulline., Methods: Duodenal samples, blood plasma and urine were collected from 43 subjects undergoing routine gastroduodenoscopy. mRNA expression of seven basolateral membrane amino acid transporters/transporter subunits were assessed by real-time PCR. Plasma and urine amino acid concentrations of citrulline, its precursors and other amino acids were analysed using High Performance Liquid Chromatography measurements. Amino acid transporter mRNA expression was correlated with blood plasma and urine levels of citrulline and its precursors using Spearman's rank correlation. Likewise, urine arginine was correlated with plasma citrulline., Results: Plasma citrulline correlated with the mRNA expression of basolateral amino acid transporter LAT4 (Spearman's r = 0.467, p = 0.028) in small intestine. None of the other basolateral membrane transporters/transporter subunits assessed correlated with plasma citrulline. Plasma citrulline correlated with urinary arginine, (Spearman's r = 0.419, p = 0.017), but not with urinary citrulline or other proteinogenic amino acids in the urine., Conclusions: In this study, we showed for the first time that small intestinal basolateral LAT4 expression correlates with plasma citrulline concentration. This finding indicates that LAT4 has an important function in mediating citrulline efflux from enterocytes. Furthermore, urine arginine correlated with plasma citrulline, indicating arginine in the urine as possible additional marker for small intestine enterocyte mass. Finally, basolateral LAT4 expression along the human small intestine was shown for the first time., Competing Interests: Conflict of interest None., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young children (aged one year or less) and can be treated by laparoscopic (LP) or open (OP) longitudinal myotomy of the pylorus. Since the first description in 1990, LP is being performed more often worldwide., Objectives: To compare the efficacy and safety of open versus laparoscopic pyloromyotomy for IHPS., Search Methods: We conducted a literature search on 04 February 2021 to identify all randomised controlled trials (RCTs), without any language restrictions. We searched the following electronic databases: MEDLINE (1990 to February 2021), Embase (1990 to February 2021), and the Cochrane Central Register of Controlled Trials (CENTRAL). We also searched the Internet using the Google Search engine (www.google.com) and Google Scholar (scholar.google.com) to identify grey literature not indexed in databases., Selection Criteria: We included RCTs and quasi-randomised trials comparing LP with OP for hypertrophic pyloric stenosis., Data Collection and Analysis: Two review authors independently screened references and extracted data from trial reports. Where outcomes or study details were not reported, we requested missing data from the corresponding authors of the primary RCTs. We used a random-effects model to calculate risk ratios (RRs) for binary outcomes, and mean differences (MDs) for continuous outcomes. Two review authors independently assessed risks of bias. We used GRADE to assess the certainty of the evidence for all outcomes., Main Results: The electronic database search resulted in a total of 434 records. After de-duplication, we screened 410 independent publications, and ultimately included seven RCTs (reported in 8 reports) in quantitative analysis. The seven included RCTs enrolled 720 participants (357 with open pyloromyotomy and 363 with laparoscopic pyloromyotomy). One study was a multi-country trial, three were carried out in the USA, and one study each was carried out in France, Japan, and Bangladesh. The evidence suggests that LP may result in a small increase in mucosal perforation compared with OP (RR 1.60, 95% CI 0.49 to 5.26; 7 studies, 720 participants; low-certainty evidence). LP may result in up to 5 extra instances of mucosal perforation per 1,000 participants; however, the confidence interval ranges from 4 fewer to 44 more per 1,000 participants. Four RCTs with 502 participants reported on incomplete pyloromyotomy. They indicate that LP may increase the risk of incomplete pyloromyotomy compared with OP, but the confidence interval crosses the line of no effect (RR 7.37, 95% CI 0.92 to 59.11; 4 studies, 502 participants; low-certainty evidence). In the LP groups, 6 cases of incomplete pyloromyotomy were reported in 247 participants while no cases of incomplete pyloromyotomy were reported in the OP groups (from 255 participants). All included studies (720 participants) reported on postoperative wound infections or abscess formations. The evidence is very uncertain about the effect of LP on postoperative wound infection or abscess formation compared with OP (RR 0.59, 95% CI 0.24 to 1.45; 7 studies, 720 participants; very low-certainty evidence). The evidence is also very uncertain about the effect of LP on postoperative incisional hernia compared with OP (RR 1.01, 95% CI 0.11 to 9.53; 4 studies, 382 participants; very low-certainty evidence). Length of hospital stay was assessed by five RCTs, including 562 participants. The evidence is very uncertain about the effect of LP compared to OP (mean difference -3.01 hours, 95% CI -8.39 to 2.37 hours; very low-certainty evidence). Time to full feeds was assessed by six studies, including 622 participants. The evidence is very uncertain about the effect of LP on time to full feeds compared with OP (mean difference -5.86 hours, 95% CI -15.95 to 4.24 hours; very low-certainty evidence). The evidence is also very uncertain about the effect of LP on operating time compared with OP (mean difference 0.53 minutes, 95% CI -3.53 to 4.59 minutes; 6 studies, 622 participants; very low-certainty evidence)., Authors' Conclusions: Laparoscopic pyloromyotomy may result in a small increase in mucosal perforation when compared with open pyloromyotomy for IHPS. There may be an increased risk of incomplete pyloromyotomy following LP compared with OP, but the effect estimate is imprecise and includes the possibility of no difference. We do not know about the effect of LP compared with OP on the need for re-operation, postoperative wound infections or abscess formation, postoperative haematoma or seroma formation, incisional hernia occurrence, length of postoperative stay, time to full feeds, or operating time because the certainty of the evidence was very low for these outcomes. We downgraded the certainty of the evidence for most outcomes due to limitations in the study design (most outcomes were susceptible to detection bias) and imprecision. There is limited evidence available comparing LP with OP for IHPS. The included studies did not provide sufficient information to determine the effect of training, experience, or surgeon preferences on the outcomes assessed., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: The objective of this review was to systematically evaluate the incidence of a metachronous contralateral inguinal hernia (MCIH) in children with unilateral inguinal hernia and therefore to propose or to reject routine contralateral groin exploration., Methods: Electronic searches restricted to prospective studies with a minimal follow-up of 1year included MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials., Results: Six studies involving 1669 children were included. Overall MCIH was 6% (95% CI from 4% to 8%). The odds for MCIH development were significantly larger in children with an initial left-sided hernia (OR 2.66 with 95% CI from 1.56 to 4.53) and in children with open contralateral processus vaginalis (CPV) (OR 4.17 with 95% CI from 1.25 to 13.9)., Conclusions: The overall incidence of MCIH following unilateral inguinal hernia repair in children is 6%. Initial left-sided hernia (8.5%) and open CPV (13.8%) are risk factors for MCIH development. Female gender (8.2%) and younger age (<1year) (6.9%) non-significantly increase the risk of MCIH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression.

Background: In every pneumonectomy due to a malignant or benign pulmonary disease the pulmonary artery must be centrally ligated and dissected. If a thoracotomy is undertaken the vessel is usually doubly ligated with a non-absorbable suture and then dissected. Alternatively a vessel stapler can be used. In a thorascopic procedure only the stapler can be used. In the search for a cheaper alternative we investigated whether a bipolar instrument as employed in thorascopy could be used and reused. The aim of this study was to investigate the static pressure performance of the closed vessel in an ex vivo non-perfused vessel model., Material and Methods: From freshly slaughtered pigs the heart-lung block was removed. The central pulmonary artery was exposed. For sealing the vessel we used the bipolar sealing system MARSEAL®, Brothers Martin company (Tuttlingen, Germany), consisting of an HF generator and a MARSEAL slim instrument. Two groups were formed: group A (n = 49) Stromart SealSafe®, step G5 (automatic performance regulation, duration of use depending on impedance) and group B (n = 58) bipolar Stromart "Macrocoag" (power: 120 W, constant duration of use: 15 s). At the end of the pulmonary artery a pressure probe was implanted to digitally measure the pressure at the vessel sealing suture. After sealing the end of the artery, the vessel was slowly filled via an external source in order to determine the burst pressure. The burst pressure was reached as soon as the vessel suture started to leak. The average values of the 2 groups were then compared (t test for independent variables, significance set at p < 0.05)., Results: All examined vessels (n = 107) had the same vessel diameter of 15 ± 3 mm. The average value of the burst pressure in group A was 139.3 ± 62.17 mmHg, that in group B 124.8 ± 38.46 mmHg. The ranges of burst pressures were in group A 51-297.0 mmHg und in group B 60.75-244.5 mmHg. There was no significant difference between group A and group B (p = 0.071)., Conclusions: Satisfactory burst pressures in the central pulmonary artery can also be achieved with the bipolar sealing instrument MARSEAL® and the impedance-controlled Stromart SealSafe®. However, because of the large scattering of the measured values, further studies are required., (Georg Thieme Verlag KG Stuttgart · New York.)

Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP(1)) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K(b) values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt(1/2)) compared to bosentan and ambrisentan (ROt(1/2):17 minutes versus 70 seconds and 40 seconds, respectively). Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP(1) assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulation time beyond ROt(1/2) rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive ERA with significantly slower receptor dissociation kinetics than the currently approved ERAs. Slow dissociation caused insurmountable antagonism in functional PASMC-based assays and this could contribute to an enhanced pharmacological activity of macitentan in ET-1-dependent pathologies.

The development of erythroid progenitor cells is triggered via the expression of the erythropoietin receptor (EPOR) and its activation by erythropoietin. The function of the resulting receptor complex depends critically on the presence of activated JAK2, and the complex contains a large number of signaling molecules recruited to eight phosphorylated tyrosine residues. Studies using mutant receptor forms have demonstrated that truncated receptors lacking all tyrosines are able to support red blood cell development with low efficiency, whereas add-back mutants containing either Tyr343 or Tyr479 reconstitute EPOR signaling and erythropoiesis in vivo. To study the contribution of tyrosines to receptor function, we analyzed the activation of essential signaling pathways and early gene induction promoted by different receptor structural variants using human epidermal growth factor receptor/murine EPOR hybrids. In our experiments, receptors lacking all tyrosine residues or the JAK2-binding site did not induce mitogenic and anti-apoptotic signaling, whereas add-back mutant receptors containing single tyrosine residues (Try343 and Tyr479) supported the activation of these functions efficiently. Profiling of early gene expression using cDNA array hybridization revealed that (i) the high redundancy in the activation of signaling pathways is continued at the level of transcription; (ii) the expression of many genes targeted by the wild-type receptor is not supported by add-back mutants; and (iii) a small set of genes are exclusively induced by add-back receptors. We report the identification of several early genes that have not been implicated in the EPOR-dependent response so far.

Purpose: Activation of intracellular signaling cascades has been implicated in the growth control of benign meningiomas, but their role for meningioma progression and outcome is unknown. Here we determined the expression and function of proteins involved in mitogen-activated protein kinase (MAPK) and phosphinositol-3 kinase (PI3K)/Akt signaling in benign, atypical, and malignant meningiomas and studied their association with clinicopathologic data including meningioma recurrence., Experimental Design: Expression of various MAPK and PI3K signaling proteins was determined in 70 primary meningiomas and, if present, in recurrent tumors by immunohistochemistry and Western blotting. The expression patterns in primary and recurrent tumors were related to clinical data. The effect of MAPK and PI3K pathway inhibition on cell proliferation and apoptosis was determined using a primary malignant meningioma cell culture., Results: Atypical and malignant meningiomas showed higher levels of phospho-Akt compared with benign tumors, and their proliferation could be inhibited by PI3K blocking using wortmannin. PI3K inhibition did not induce apoptosis in malignant meningioma cells. In contrast, expression of phospho-Raf and phospho-MAPK was decreased in aggressive meningiomas compared with benign tumors, but MAPK inhibition by PD98059 resulted in tumor cell apoptosis and decreased proliferation. Reduced MAPK activation was associated with meningioma recurrence, and PI3K activation was associated with poor preclinical condition and brain invasion of malignant meningiomas., Conclusions: Both MAPK and PI3K/Akt pathways are activated at different levels in benign and malignant meningiomas. Activation of PI3K/Akt signaling contributes to the aggressive behavior of malignant meningiomas, whereas MAPK activation is involved in both proliferation and apoptosis of malignant meningiomas.

Proteomic techniques provide new tools for the global analysis of protein profiles but also for the investigation of specific protein functions. The analysis of signaling cascades has traditionally been performed by the determination of enzymatic or transcription factor activities representing a certain pathway. Functional proteomics now allows more comprehensive approaches to study cellular responses induced during ligand/receptor interactions. In this study we evaluated proteomic strategies for the investigation of structure-function relationships in the erythropoietin receptor signalling complex. After expression of epidermal growth factor/erythropoietin receptor mutant molecules in an identical cellular background we characterized their potential to induce cellular activities. Using this system we focused our efforts on post-translational modifications of signalling proteins reflecting a substantial part of receptor-dependent signaling events. Although tyrosine phosphorylated proteins were enriched by immunoprecipitation the analysis using the classical approach combining two-dimensional gel electrophoresis and identification by matrix assisted laser desorption/ionization-time of flight-mass spectrometry revealed that low expressed signaling proteins cannot be detected by this technique. An alternative strategy using one-dimensional gel separation of phosphoproteins and liquid chromatography-tandem mass spectrometry, however, allowed us to identify multiple proteins involved in intracellular signalling representing already established pathways but also proteins which have not been linked to EPO-induced signaling so far. This approach offers the potential to extend functional proteomic studies to complex signaling processes.

The transcription factor nuclear factor kappa B (NF-kappaB) has been implicated in the regulation of genes mainly involved in inflammation and immune response. We analysed the role of NF-kappaB in signalling pathways induced by the hematopoietic growth factor erythropoietin (EPO). Our data, obtained by electrophoretic mobility shift assays (EMSA) and reporter gene assays, show that the intracellular domain of the EPO receptor (EPOR) transmits signals leading to the activation of NF-kappaB. Studies employing an inhibitor specific for the EPOR-associated tyrosine kinase JAK2 suggest that JAK2-dependent pathways are not involved. The induction of an NF-kappaB-triggered reporter gene construct was inhibited by cotransfection of dominant negative forms of the src kinase Lyn, but not by dominant negative JAK2. Using epidermal growth factor (EGF)/EPOR hybrids containing mutant forms of the EPOR intracellular domain, we were able to further define the critical structures for the induction of NF-kappaB. The data show that although the activity of JAK2 seems to be dispensable, its association to the receptor, as well as the phosphorylation of membrane proximal tyrosine residues, are essential. Furthermore, the functional analysis of different receptor forms revealed a correlation of the abilities to induce NF-kappaB activity and to generate antiapoptotic signals.

The transcription factor STAT5 is activated by multiple hematopoietic cytokine receptors and has been implicated in the induction of cellular processes such as differentiation, proliferation and antiapoptotic activities. Here, we report cloning of the cDNA and characterization of a mutant STAT5a protein that is expressed in interleukin-3 (IL-3)-independently growing FDCP-1 cells. Analysis of the cDNA revealed a deletion of both the transactivation and the SH2 domains. Stable expression of the protein in parental IL-3-dependent cells results in elevated DNA binding activity of wild type (WT)-STAT5 in the nucleus, enhanced growth rates and a reduced susceptibility to undergo apoptosis after withdrawal of IL-3. Although the protein is not present in DNA/protein complexes in the nucleus, we observed pronounced effects on IL-3-induced signal transduction. The results suggest competition of the mutant protein with cytosolic mechanisms regulating STAT5 activity. In conclusion, the data support the hypothesis of an involvement of STAT5 in mitogenic and antiapoptotic signaling.