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A simplified method for determining plasma glycerol is described. This assay utilizes the fluorometric measurement of the reduced adenine dinucleotide, NADH2 which is formed when glycerol is oxidized by glycerol dehydrogenase. Only three pipettings are necessary for each reaction tube, and a large number of samples can be included in each assay.

Objective: Distal radius fracture (DRF) in postmenopausal women is often the first clinical sign of osteoporosis (OP). Despite the availability of effective treatments, only a minority of patients who sustain a fragility fracture are tested for OP. The purpose of this study was to examine whether a simple intervention by the hospital staff increases rates of OP workup. Materials and Methods: We conducted a prospective randomized clinical trial. Ninety nine patients after DRF were randomized to two groups. Both groups were contacted after their fracture and were asked to answer a questionnaire and were informed about the possible relationship between DRF and OP. In the intervention group, patients were sent an explanatory pamphlet and a letter to their primary care physician. An additional survey was conducted to establish whether the intervention improved the number of patients who undergo OP workup. Results: The intervention increased the proportion of patients who turned to their primary care physician from 22.9% to 68.6%, and increased the proportion of patients undergoing OP workup from 14.3% to 40% (p

Physico-chemical characteristics of groundwater are often impacted by agricultural practices such as land use, fertilizer types, and groundwater pumping. This study aimed to identify contaminant sources and redox processes controlling the hydrogeochemistry of groundwater in riparian zones influenced by intensive agricultural activities, focusing on sulfur species. Groundwater samples were collected bimonthly from March 2014 to March 2015 from groundwater wells in two zones in South Korea with different agricultural systems. The water isotopic compositions of the groundwater indicated that all groundwater originated from the same meteoric water. Groundwater samples affected by periodic groundwater pumping exhibited wide variations in Mn 2+ (47.8 ± 18.2 μM) and Fe 2+ (123 ± 61.0 μM) and elevated SO 4 2- , while NO 3 - was below the detection limit. Groundwater chemistry was affected by fertilizer and manure, and denitrification. The oxidation of reduced sulfur compounds by oxygen and nitrate did not fully account for the elevated SO 4 2- concentrations and isotopic composition of sulfate (δ 34 S and δ 18 O) in the investigated aquifers. Therefore, we postulate that water level change due to periodic groundwater pumping and recharge enabled oxidants (MnO 2 and Fe 3+ ) to also contribute to oxidation of reduced sulfur. Additionally, fertilizers with distinct δ 34 S values and bacterial sulfate reduction (BSR) affected groundwater chemistry and its sulfur species, including δ 34 S SO4 and δ 18 O SO4 . Removal of sulfate from the aquifer during pumping limited BSR. Consequently, the agricultural practices may further increase sulfate concentrations in the groundwater. This environmental impact should be thoroughly managed because high sulfate concentrations in drinking water cause ingestion problems in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sulphate (SO 4 ), predominantly derived from sulphur (S)-bearing glacial sediments distributed widely across the Canadian Interior Plains, contributes to high groundwater salinity and can be detrimental to riparian and dry-land ecosystems, agricultural production, and water use. While previous researchers investigated SO 4 distribution and dynamics in shallow groundwater at local scales (<1500 km 2 ), we examine SO 4 occurrence in groundwater at larger scales, and to depths of ∼150 m, considering variations in geology, glacial history, climate, and geochemical and hydrogeological settings in the Canadian province of Alberta. Sulphate concentrations in groundwater vary considerably, with 15 % of 139,130 samples above the 500 mg/L Canadian drinking water aesthetic objective. Analysis of [Formula: see text] and [Formula: see text] from 179 wells throughout Alberta shows SO 4 is dominantly derived from oxidation of S-bearing material. At this large scale, marine shale bedrock subcrops, glacial ice flow directions, and climate control SO 4 distribution. Groundwater contains less SO 4 (<200 mg/L) in western Alberta compared to the east due to a lack of S-bearing bedrock, higher groundwater recharge rates, thinner glacial sediments, and increased groundwater circulation. Focusing on a region in south-central Alberta (Red Deer area), hydrogeological characteristics relating to SO 4 formation, recharge, permeability, hydraulic gradient, and travel time are included in a principal component analysis to identify six groundwater groups at varying stages of evolution and SO 4 concentrations depending on their hydrogeological setting. Low SO 4 concentrations are associated with areas of high recharge, where SO 4 has been leached from the sediments, or with more evolved bedrock groundwater where SO 4 has been reduced or was recharged in pre-glacial times. High SO 4 concentrations are found in areas of lower recharge and permeability, where flushing occurs more slowly. Combining the Red Deer area and province-wide analyses, we identify seven regions across Alberta with characteristic distribution and controls on SO 4 occurrence in shallow groundwater., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pauline Humez, Sheldon Thistle, Bernhard Mayer reports financial support was provided by Alberta Innovates. Pauline Humez, Sheldon Thistle, Bernhard Mayer reports financial support was provided by Alberta Energy Regulator. Pauline Humez, Sheldon Thistle, Bernhard Mayer reports financial support was provided by Alberta Environment and Protected Areas. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

The increase in extreme heavy rain due to climate change is a critical factor in the fate of urban and agricultural pollutants in aquatic system. Nutrients, including NO 3 - and PO 4 3- , are transported with surface and seepage waters into rivers, lakes and aquifers and can eventually lead to algal blooms. δ 15 N-NO 3 - B combined with hydrogeochemical and microbial data for groundwater and surface water samples were interpreted to evaluate the fate of nutrients in a riverside area around weirs in Daegu, South Korea. Most of the ions showed similar concentrations in the groundwater samples before and after heavy rain while concentrations of major ions in surface water samples were diluted after heavy rain. However, Si, PO 18 O-NO 3 B, δ - , and δ 11 B combined with hydrogeochemical and microbial data for groundwater and surface water samples were interpreted to evaluate the fate of nutrients in a riverside area around weirs in Daegu, South Korea. Most of the ions showed similar concentrations in the groundwater samples before and after heavy rain while concentrations of major ions in surface water samples were diluted after heavy rain. However, Si, PO 4 3- , Zn, Ce, La, Pb, Cu and a number of waterborne pathogens increased in surface water after heavy rain. The interpretation of δ 11 B, δ 15 N-NO 3 - , and δ 18 O-NO 3 - values using a Bayesian mixing model revealed that sewage and synthetic fertilizers were the main sources of contaminants in the groundwater and surface water samples. δ 18 O and SiO 2 interpreted using the Bayesian mixing model indicated that the groundwater component in the surface water increased from 4.4 % to 17.9 % during the wet season. This is consistent with numerical simulation results indicating that the direct surface runoff and the groundwater baseflow contributions to the river system had also increased 6.4 times during the wet season. The increase in proteobacteria and decrease of actinobacteria in the surface water samples after heavy rain were also consistent with an increase of surface runoff and an increased groundwater component in the surface water. This study suggests that source apportionment based on chemical and multi-isotope data combined with numerical modeling approaches can be useful for identifying main hydrological and geochemical processes in riverside areas around weirs and can inform suggestions of effective methods for water quality management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

'Fugitive' or 'stray' gas migration from deeper formations due to well bore integrity failure has prompted concern regarding environmental impacts. Unintended methane (CH 4 ) migration can increase greenhouse gas emissions and affect groundwater quality in the critical zone. Although the CH 4 transport in shallow aquifers has been investigated at experimental injection sites, no intensive groundwater studies have been published around an oil and gas well that has been leaking for a significant period of time. In this field study, groundwater samples were collected from sixteen groundwater monitoring wells (1.25 m below ground surface) installed around a suspended oil and gas well with decadal scale gas migration (estimated ~0.2 m 3 /day). Stray CH 4 distribution and preferential pathways in the shallow groundwater zone were evaluated though high-resolution profiling of equivalent concentrations of hydrocarbon gases (C1-C6; >85 % CH 4 at the study site) and bulk formation electrical conductivity to 6.0 m below ground surface. The highest dissolved CH 4 concentration (0.074 mmol/L or 1.18 mg/L) in groundwater (1.25 m bgs) was observed immediately downgradient (1.25 m) of the oil and gas well head. Similarly, high-resolution profiling data also revealed the occurrence of relatively high CH 4 concentrations in shallow groundwater along the groundwater flow direction and below fine-grained layers up to 10 m distance from the well head. Microbial DNA analysis from groundwater showed significant community shifts, with the highest relative abundance and diversity of methanotrophs observed in the vicinity of the oil and gas well. This study supports findings from experimental injection and laboratory studies, which also found that significant CH 4 transport i) dominantly occurs in the groundwater flow direction, and ii) laterally as free phase below fine-grained layers. The occurrence of CH 4 concentrations below saturation after more than two decades of gas migration suggests limited impacts have occurred in the shallow subsurface investigated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Plastic waste has become the most significant component of marine debris, while research on traces of marine plastic waste related to the condition of Indonesian waters is still limited. Therefore, this study examines the movement patterns of plastic marine debris in Indonesian waters. Simulations were carried out for one year (2013) using the HAMburg Shelf Ocean Model (hydrodynamic model) and Lagrange trajectory. The approach treated the simulated particles as conservative particles floating at sea. Even though the percentage is small (±16 %), Indonesia contributes to transboundary marine debris in the Pacific Ocean, Indian Ocean, and the South China Sea due to the influence of the south equatorial currents moving from north and south of Indonesia. Most of the plastic marine debris remains in Indonesian waters (±80-84 %) and moves back and forth due to the influence of the monsoon currents. Therefore, the Java Sea becomes a crossing point and accumulates plastic marine debris., Competing Interests: Declaration of competing interest Engki A Kisnarti reports financial support was provided by Ministry of Education, Culture, Research and Technology-Republic of Indonesia., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: A brachial plexus lesion is a devastating injury often affecting young, male adults after traffic accidents. Therefore, surgical restoration of elbow flexion is critical for establishing antigravity movement of the upper extremity. We analyzed different methods for musculocutaneous reconstruction regarding outcome., Methods: We conducted a retrospective analysis of 146 brachial plexus surgeries with musculocutaneous reconstruction performed at our department from 2013 to 2017. Demographic data, surgical method, donor and graft nerve characteristics, body mass index (BMI) as well as functional outcome of biceps muscle based on medical research council (MRC) strength grades before and after surgery were analyzed. Multivariate analysis was performed using SPSS., Results: Oberlin reconstruction was the procedure performed most often (34.2%, n = 50). Nerve transfer and autologous repair showed no significant differences regarding outcome (p = 0.599, OR 0.644 CI95% 0.126-3.307). In case of nerve transfers, we found no significant difference whether reconstruction was performed with or without a nerve graft (e.g. sural nerve) (p = 0.277, OR 0.619 CI95% 0.261-1.469). Multivariate analysis identifies patient age as a strong predictor for outcome, univariate analysis indicates that nerve graft length > 15 cm and BMI of > 25 could lead to inferior outcome. When patients with early recovery (n = 19) are included into final evaluation after 24 months, the general success rate of reconstructions is 62,7% (52/83)., Conclusion: Reconstruction of musculocutaneous nerve after brachial plexus injury results in a high rate of clinical improvement. Nerve transfer and autologous reconstruction both show similar results. Young age was confirmed as an independent predictor for better clinical outcome. Prospective multicenter studies are needed to further clarify., (Copyright © 2023. Published by Elsevier B.V.)

The excessive input of nutrients into groundwater can accelerate eutrophication in associated surface water systems. This study combined hydrogeochemistry, multi isotope tracers, and microbiological data to estimate nutrient sources and the effects of groundwater-surface water interactions on the spatiotemporal variation of nutrients in groundwater connected to a large weir-regulated river in South Korea. δ 11 B and δ 15 N-NO 3 - values, in combination with a Bayesian mixing model, revealed that manure and sewage contributed 40 % and 25 % respectively to groundwater nitrate, and 42 % and 27 % to nitrate in surface water during the wet season. In the dry season, the source apportionment was similar for groundwater while the sewage contribution increased to 52 % of nitrate in river water. River water displayed a high correlation between NO 3 - concentration and cyanobacteria (Microcystis and Prochlorococcus) in the wet season. The mixing model using multiple isotopes indicated that manure-derived nutrients delivered with increased contributions of groundwater to the river during the wet season governed the occurrence of cyanobacterial blooms in the river. We postulate that the integrated approach using multi-isotopic and microbiological data is highly effective for evaluating nutrient sources and for delineating hydrological interactions between groundwater and surface water, as well as for investigating surface water quality including eutrophication in riverine and other surface water systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H 2 S) emerged as an essential signaling molecule exerting beneficial effects in various cardiovascular, neurodegenerative, or musculoskeletal diseases with an inflammatory component, such as osteoarthritis. These protective effects were initially attributed to protein S-sulfhydration, a posttranslational modification of reactive cysteine residues. However, recent studies suggest that polysulfides and not H 2 S are responsible for S-sulfhydration. To distinguish between H 2 S and polysulfide-mediated effects in this study, we used the slow-releasing H 2 S and persulfide donor P*, which can be decomposed into polysulfides. The effects of P* on IL-1β-induced inducible nitric oxide synthase (iNOS), a pro-inflammatory mediator in osteoarthritis, were determined by nitrite measurement, qPCR, and Western blotting in the murine chondrocyte-like cell line ATDC5. Decomposed P* significantly reduced IL-1β-induced iNOS signaling via polysulfides, independently of H 2 S. In line with this, the fast-releasing H 2 S donor NaHS was ineffective. In RAW 264.7 macrophages, similar results were obtained. P*-derived polysulfides further diminished IL-1β-induced CCAAT/enhancer-binding protein (C/EBP) β and δ expression in ATDC5 cells, which might play a critical role in P*-mediated iNOS decline. In conclusion, our data support the view that polysulfides are essential signaling molecules as well as potential mediators of H 2 S signaling. Moreover, we propose that C/EBPβ/δ might be a novel target involved in H 2 S and polysulfide-mediated anti-inflammatory signaling., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Congenital and infantile hydrocephalus are assumed to be major contributors to pediatric morbidity, mortality and functional disability in low-income countries. Despite this, epidemiologic data and the overview of neurodevelopmental outcomes in these regions is very limited. We aimed to pilot the use of a wide range of more locally suitable tools to assess neurodevelopment to understand whether they were feasible for use and could provide estimates of developmental delay and poor functioning in a population of children with hydrocephalus in Malawi., Methods: We conducted a prospective observational cohort study, at the tertiary neurosurgery clinic in Blantyre, Malawi in 2018, recruiting consecutive children with congenital and infantile hydrocephalus who were previously treated with ventriculoperitoneal shunts and endoscopic third ventriculostomy (ETV) in the neurosurgery unit of the hospital. We assessed demographic details, and gained information on children's functioning using the Liverpool Outcome Score (LOS), and the Eating and Drinking Ability Classification System as well as full anthropometric assessment and child development with the Malawi Developmental Assessment Tool (MDAT)., Results: All tools were feasible for use, easy to train on, could be used for assessing children with hydrocephalus and were suitable to adapt for our environment. We evaluated 41 children, aged 2-60 months with a mean age of 22.6 months (interquartile range [IQR] = 8.3 months -36.5 months). Functional assessment using the Liverpool Outcome Score showed the majority of children 92.7% (CI 80.1-98.5, n = 38) had severe sequelae from the hydrocephalus and were dependent on their parents or caregivers. Only 27 children (65.9%, CI 49.4, 80.0) had full or expected control of their bowel and bladder and 6 children (14.6%, CI 5.6, 29.2), had a recent history of seizures. About two thirds (63.4% CI 45.0-77.9, n = 26/41) of children were able to eat and to drink safely and efficiently. Over two thirds of the children (70.7%, CI 56.8, 84.6, n = 29) were stunted and almost half of the cohort underweight (43.9%,(CI 28.5, 60.3, n = 18). Almost half 48.8% (CI 32.9, 64.9, n = 20/41) had developmental delay on MDAT with 41.5% (CI 26.4, 56.6, n = 17/41) graded as severely delayed (-<2sd on developmental age z score). We found significant associations between dependence identified by the LOS and developmental delay according to the MDAT (p = 0.014, Pearson's chi-squared test)., Conclusion: This pilot study demonstrates that the assessment tools we used identified a high proportion of children with hydrocephalus as having functional difficulties, stunted growth and developmental delay, in Malawi. Use of these tools can now be scaled up and will be helpful to support research in understanding what factors contribute to poor functioning, growth and development in these cohorts and help us to investigate what strategies may prevent and support children with hydrocephalus in African settings., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Background: Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps., Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797., Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment., Interpretation: Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population., Funding: GlaxoSmithKline., Competing Interests: Declaration of interests JKH has received consultancy fees from Sanofi Genzyme, Regeneron, Genentech, AstraZeneca, GlaxoSmithKline, and Gossamer Bio. CB has participated in advisory boards and received speaker fees from Sanofi, Novartis, AstraZeneca, GlaxoSmithKline, ALK-Abelló, and Meda Pharmaceuticals. WF has received clinical trial funding from Sanofi, Mylan, ALK-Abelló, Allergy Therapeutics, Novartis, and Chordate; and personal fees from Sanofi. MD has received clinical trial funding from AstraZeneca, GlaxoSmithKline, Probionase Therapies, and Sanofi; is an advisory board member for Regeneron Pharmaceuticals and Sanofi; and has equity in Probionase Therapies. MW has received advisory board fees or speaker fees from ALK-Abelló, Allergopharma, AstraZeneca, Bencard Allergie, Genzyme, HAL Allergie, InfectoPharm, LETIPharma, Meda Pharmaceuticals, Novartis, Sanofi, Stallergenes Greer, and Teva. SEL has participated in advisory boards and received clinical trial funding from Sanofi Genzyme, Regeneron, Genentech, AstraZeneca, and GlaxoSmithKline. SGS, NM, BM, SWY, ARS, and RC are employees of GlaxoSmithKline and own company stocks and shares. CH has received advisory board fees from Sanofi, AstraZeneca, Olympus, and Smith and Nephew., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Behavioral and psychological symptoms of dementia (BPSD) place a heavy burden on patients as well as caregivers. Recently, pain was identified as an important determinant of BPSD. However, it is not yet known what influence sex has on BPSD and pain. Thus, the present study aimed to identify possible associations between BPSD, pain, and sex., Design: A retrospective evaluation of cross-sectional data derived from the Services and Health for Elderly in Long-Term Care (SHELTER) Study database, a cross-national European study on nursing home residents., Setting and Participants: The study involved 4156 residents who were assessed using the interRAI instrument for Long-Term Care Facilities. Included in the analysis were only patients with cognitive impairment (n = 2822) (67.9%) of which 712 (25.2%) were male and 2110 (74.8%) were female., Methods: Differences in prevalence were tested using the χ 2 test while bivariate logistic regression models were used to evaluate factors associated with sex., Results: Men showed behavioral symptoms such as wandering, verbal and physical abuse as well as sexual uninhibited behavior significantly more often than women. Regarding psychiatric symptoms, only depression was significantly more frequent in women. Surprisingly, in the presence of pain these differences in BPSD incidence between men and women were no longer detectable. Logistic regression analysis showed that in women with dementia/communication problems, the presence of pain could be indicated by resistance to care, sleeping disorders, and possibly by the presence of delusions and anxiety whereas in men it was related to abnormal thought processes, and in both sexes to depression CONCLUSIONS AND IMPLICATIONS: From a clinical point of view, resistance to care and sleeping disorders in women and abnormal thought processes in men as well as depression in both sexes should be seen as indicators of possible underlying pain in noncommunicative people. Thus, knowledge of sex-specific BPSD presentations can improve pain management in this particularly patient group., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Metabolic dysfunctions after pancreatoduodenectomy (PD) need to be considered when pancreatic head resection is likely to lead to long-term survival., Methods: Medline, Embase and Cochrane Library were searched for studies reporting measured data of metabolic function after PD and duodenum-sparing total pancreatic head resection (DPPHR). Data from 23 cohort studies comprising 1019 patients were eligible; 594 and 910 patients were involved in systematic review and meta-analysis, respectively., Results: The cumulative incidence of postoperative new onset of diabetes mellitus (pNODM) after PD for benign tumors was 46 of 321 patients (14%) measured after follow-up of in mean 36 months postoperatively. New onset of postoperative exocrine insufficiency (PEI) was exhibited by 91 of 209 patients (44%) after PD for benign tumors measured in mean 23 months postoperatively. The meta-analysis indicated pNODM after PD for benign tumor in 32 of 208 patients (15%) and in 10 of 178 patients (6%) after DPPHR (p = 0.007; OR 3.01; (95%CI:1.39-6.49)). PEI was exhibited by 80 of 178 patients (45%) after PD and by 6 of 88 patients (7%) after DPPHR (p < 0.001). GI hormones measured in 194 patients revealed postoperatively a significant impairment of integrated responses of gastrin, motilin, insulin, secretin, PP and GIP (p < 0.050-0.001) after PD. Fasting and stimulated levels of GLP-1 and glucagon levels displayed a significant increase (p < 0.020/p < 0.030). Following DPPHR, responses of gastrin, motilin, secretin and CCK displayed no change compared to preoperative levels., Conclusions: After PD, duodenectomy, rather than pancreatic head resection is the main cause for long-term persisting, postoperative new onset of DM and PEI., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Rapid population growth and land-use intensification over the last century have resulted in a substantial increase in nutrient loads degrading marine and freshwater ecosystems worldwide. In mixed-use watersheds, elevated nitrogen loads from wastewater treatment plant (WWTP) effluent or agricultural runoff often drive the eutrophication of waterways. Accordingly, the objective of this research was to identify sources of riverine nitrate (NO 3 ), a deleterious dissolved species of nitrogen, with a combined isotopic tracing technique in the Bow River and the Oldman River in Alberta, Canada. Riverine NO 3 and boron (B) concentrations, mean daily flux and δ 15 N NO3 , δ 18 O NO3, and δ 11 B values were determined at 17 mainstem sites during high and low discharge periods in 2014 and 2015. The data for mainstem sites were then compared to results for effluent from seven WWTPs, eight synthetic fertilizers, cow manure, and three predominantly agricultural tributary sites to estimate point and non-point NO 3 sources. The NO 3 flux, δ 15 N NO3 and δ 18 O NO3 values indicated the city of Calgary's Bonnybrook WWTP effluent accounts for the majority of the NO 3 flux in the Bow River downstream of Calgary. δ 15 N NO3 and δ 11 B values in the Bow River highlighted an increase in agricultural NO 3 loading downstream of irrigation return-flows. A three-fold decrease in the NO 3 :B flux ratio indicated NO 3 -removal processes are active in the lower reaches of the Bow River. For the Oldman River, δ 11 B values revealed elevated nutrient loading from the Lethbridge WWTP effluent (10% of downstream B flux). Furthermore, the agricultural tributaries contributed 25% of the local B flux to the Oldman River. Overall, δ 11 B was proven to be an effective co-tracer for discriminating between urban and agricultural sources of NO 3 in these large mixed-use watersheds. This combined isotope tracing approach has significant potential to identify point and non-point NO 3 sources driving eutrophication around the world., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oil and gas development can result in natural gas migration into shallow groundwater. Methane (CH 4 ), the primary component of natural gas, can subsequently react with solutes and minerals in the aquifer to create byproducts that affect groundwater chemistry. Hydro-biogeochemical processes induced by fugitive gas from leaky oil and gas wells are currently not well understood. We monitored the hydro-biogeochemical responses of a controlled natural gas release into a well-studied Pleistocene beach sand aquifer (Canadian Forces Base Borden, Ontario, Canada). Groundwater samples were collected before, during, and up to 700 days after gas injection and analyzed for pH, major and minor ions, alkalinity, dissolved gases, stable carbon isotope ratios of CO 2 and CH 4 , and microbial community composition. Gas injection resulted in a dispersed plume of free and dissolved phase natural gas, affecting groundwater chemistry in two distinct temporal phases. Initially (i.e. during and immediately after gas injection), pH declined and major ions and trace elements fluctuated; at times increasing above baseline concentrations. Changes in the short-term were due to invasion of deep groundwater with elevated total dissolved solids entrained with the upward migration of free phase gas and, reactions that were instigated through the introduction of constituents other than CH 4 present in the injected gas (e.g. CO 2 ). At later times, more pronounced aerobic and anaerobic CH 4 oxidation led to subtle increases in major ions (e.g. Ca 2+ , H 4 SiO 4 ) and trace elements (e.g. As, Cr). Microbial community profiling indicated a persistent perturbation to community composition with a conspicuous ingrowth of taxa implicated in aerobic CH 4 oxidation as well anaerobic S, N and Fe species metabolism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Although multistage hydraulic fracturing is routinely performed for the extraction of hydrocarbon resources from low permeability reservoirs, the downhole geochemical processes linked to the interaction of fracturing fluids with formation brine and reservoir mineralogy remain poorly understood. We present a geochemical dataset of flowback and produced water samples from a hydraulically fractured reservoir in the Montney Formation, Canada, analyzed for major and trace elements and stable isotopes. The dataset consists in 25 samples of flowback and produced waters from a single well, as well as produced water samples from 16 other different producing wells collected in the same field. Additionally, persulfate breaker samples as well as anhydrite and pyrite from cores were also analyzed. The objectives of this study were to understand the geochemical interactions between formation and fracturing fluids and their consequences in the context of tight gas exploitation. The analysis of this dataset allowed for a comprehensive understanding of the coupled downhole geochemical processes, linked in particular to the action of the oxidative breaker. Flowback fluid chemistries were determined to be the result of mixing of formation brine with the hydraulic fracturing fluids as well as coupled geochemical reactions with the reservoir rock such as dissolution of anhydrite and dolomite; pyrite and organic matter oxidation; and calcite, barite, celestite, iron oxides and possibly calcium sulfate scaling. In particular, excess sulfate in the collected samples was found to be mainly derived from anhydrite dissolution, and not from persulfate breaker or pyrite oxidation. The release of heavy metals from the oxidation activity of the breaker was detectable but concentrations of heavy metals in produced fluids remained below the World Health Organization guidelines for drinking water and are therefore of no concern. This is due in part to the co-precipitation of heavy metals with iron oxides and possibly sulfate minerals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Due to increasing concerns over the potential impact of shale gas and coalbed methane (CBM) development on groundwater resources, it has become necessary to develop reliable tools to detect any potential pollution associated with hydrocarbon exploitation from unconventional reservoirs. One of the key concepts for such monitoring approaches is the establishment of a geochemical baseline of the considered groundwater systems. However, the detection of methane is not enough to assess potential impact from CBM and shale gas exploitation since methane in low concentrations has been found to be naturally ubiquitous in many groundwater systems. The objective of this study was to determine the methane sources, the extent of potential methane oxidation, and gas-water-rock-interactions in shallow aquifers by integrating chemical and isotopic monitoring data of dissolved gases and aqueous species into a geochemical PHREEQC model. Using data from a regional groundwater observation network in Alberta (Canada), the model was designed to describe the evolution of the concentrations of methane, sulfate and dissolved inorganic carbon (DIC) as well as their isotopic compositions (δ 34 S SO4 , δ 13 C CH4 and δ 13 C DIC ) in groundwater subjected to different scenarios of migration, oxidation and in situ generation of methane. Model results show that methane migration and subsequent methane oxidation in anaerobic environments can strongly affect its concentration and isotopic fingerprint and potentially compromise the accurate identification of the methane source. For example elevated δ 13 C CH4 values can be the result of oxidation of microbial methane and may be misinterpreted as methane of thermogenic origin. Hence, quantification of the extent of methane oxidation is essential for determining the origin of methane in groundwater. The application of this model to aquifers in Alberta shows that some cases of elevated δ 13 C CH4 values were due to methane oxidation resulting in pseudo-thermogenic isotopic fingerprints of methane. The model indicated no contamination of shallow aquifers by deep thermogenic methane from conventional and unconventional hydrocarbon reservoirs under baseline conditions. The developed geochemical and multi-isotopic model describing the sources and fate of methane in groundwater is a promising tool for groundwater assessment purposes in areas with shale gas and coalbed methane development., (Copyright © 2019. Published by Elsevier B.V.)

Water quality impacts to the Laurentian Great Lakes create bi-national issues that have been subject of investigation since the 1970s. However, distinguishing upgradient sources of nutrients, metals and legacy contaminants in rivers remains a challenge, as they are derived from multiple sources and flows typically vary throughout the region. These complications are especially pertinent in the Lake Huron to Lake Erie corridor and Detroit River. The Detroit River supplies 90% of the water to the western basin of Lake Erie (5300 m 3 /s) and is subject to a variety of co-occurring potential sources (e.g., agriculture, urbanization, and upgradient water bodies) of water quality indicators that limit source disaggregation. To find the source signal in the noise we used an integrative interpretation of dissolved chemical and isotopic parameters with sediment chemical, isotopic, and contaminant indicators. The approach combines archival data to distinguish point and non-point sources, and upgradient water bodies as sources of nutrients, metals and contaminants to the Detroit River and ultimately the western basin of Lake Erie. Persistent organic pollutants and metals cluster together as an urban group. Regional dissolved orthro-phosphate (PO 4 ) in the water column also groups with urban point sources rather than agricultural sources. Urbanization as the primary source of PO 4 in the Detroit River highlights the need for continued research on urban impacts and assessments of broader best management practices protecting Lake Erie., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nitric oxide synthase (NOS) catalyzes the transformation of l-arginine, molecular oxygen (O 2 ), and NADPH-derived electrons to nitric oxide (NO) and l-citrulline. Under some conditions, however, NOS catalyzes the reduction of O 2 to superoxide (O 2 - ) instead, a phenomenon that is generally referred to as uncoupling. In principle, both the heme in the oxygenase domain and the flavins in the reductase domain could catalyze O 2 - formation. In the former case the oxyferrous (Fe(II)O 2 ) complex that is formed as an intermediate during catalysis would dissociate to heme and O 2 - ; in the latter case the reduced flavins would reduce O 2 to O 2 - . The NOS cofactor tetrahydrobiopterin (BH4) is indispensable for coupled catalysis. In the case of uncoupling at the heme this is explained by the essential role of BH4 as an electron donor to the oxyferrous complex; in the case of uncoupling at the flavins it is assumed that the absence of BH4 results in NOS monomerization, with the monomers incapable to sustain NO synthesis but still able to support uncoupled catalysis. In spite of little supporting evidence, uncoupling at the reductase after NOS monomerization appears to be the predominant hypothesis at present. To set the record straight we extended prior studies by determining under which conditions uncoupling of the neuronal and endothelial isoforms (nNOS and eNOS) occurred and if a correlation exists between uncoupling and the monomer/dimer equilibrium. We determined the rates of coupled/uncoupled catalysis by measuring NADPH oxidation spectrophotometrically at 340 nm and citrulline synthesis as the formation of [ 3 H]-citrulline from [ 3 H]-Arg. The monomer/dimer equilibrium was determined by FPLC and, for comparison, by low-temperature polyacrylamide gel electrophoresis. Uncoupling occurred in the absence of Arg and/or BH4, but not in the absence of Ca 2+ or calmodulin (CaM). Since omission of Ca 2+ /CaM will completely block heme reduction while still allowing substantial FMN reduction, this argues against uncoupling by the reductase domain. In the presence of heme-directed NOS inhibitors uncoupling occurred to the extent that these compound allowed heme reduction, again arguing in favor of uncoupling at the heme. The monomer/dimer equilibrium showed no correlation with uncoupling. We conclude that uncoupling by BH4 deficiency takes place exclusively at the heme, with virtually no contribution from the flavins and no role for NOS monomerization., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Eutrophication of freshwater ecosystems and harmful algal blooms (HABs) are an ongoing concern affecting water quality in the Great Lakes watershed of North America. Despite binational management efforts, Lake Erie has been at the center of dissolved reactive phosphate driven eutrophication research due to its repeated cycles of algae blooms. We investigated the Detroit River, the largest source of water entering Lake Erie, with the objectives to (1) characterize Detroit River phosphate levels within water and sediment, and (2) use multiple chemical and isotopic tracers to identify nutrient sources in the Detroit River. Riverine water and sediment samples were collected at 23 locations across 8 transects of the Detroit River. The bulk δ 15 N values from sediments were enriched compared the δ 15 N values of nitrate from water samples, consistent with biogeochemical cycling in the sediment. Principle component analysis of multiple chemical tracers from water samples found spatial variation consistent with multiple sources including synthetic and manure-derived fertilizers and wastewater effluent. The concentrations of phosphate dissolved in water were within regulatory guidelines; however, sediments had elevated concentrations of both water- and acid-extractable phosphate. Sediment-sequestered legacy phosphorus historically deposited in the Detroit River may be transported into Lake Erie and, if mobilized into the water column, be an unrecognized internal-load that contributes to algal bloom events. Globally, freshwater ecosystems are impacted by numerous non-point source phosphorus inputs contributing to eutrophication and the use of multiple tracer approaches will increase our ability to effectively manage aquatic ecosystems., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background Aims: Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to suppress T-cell proliferation and used to alleviate the symptoms of graft-versus-host disease (GVHD). MSCs are a mixed cell population and at this time there are no tools to isolate the cells responsible for the T-cell suppression. We wanted to find a way to enhance the immune-modulatory actions of MSCs and tried varying the temperature at which they were cultured., Methods: We cultured human MSCs derived from healthy volunteers at different temperatures and tested their ability to switch macrophage character from pro-inflammatory to anti-inflammatory (M1 type to M2 type). Using an enzyme-linked immunosorbent assay (ELISA), we showed that when MSCs are cultured at higher temperatures their ability to induce co-cultured macrophages to produce more interleukin-10, (IL-10) (an anti-inflammatory cytokine) and less tumor necrosis factor alpha, (TNFα) (a pro-inflammatory cytokine) is increased. We performed Western blots and immunocytochemistry to screen for changes that might underlie this effect., Results: We found that in hyperthermia the heat shock protein, HSF1, translocated into the nucleus of MSCs. It appears to induce the COX2/PGE2 (Cyclooxygenase2/Prostaglandin E2) pathway described earlier as a major mechanism of MSC-directed immune-suppression., Conclusion: Hyperthermia increases the efficacy of MSC-driven immune-suppression. We propose that changing the time of MSC administration to patients to mid-to-late afternoon when the body temperature is naturally highest might be beneficial. Warming the patient could also be considered., (Copyright © 2018. Published by Elsevier Inc.)

Hyporheic zones are considered hot spots for numerically vast and phylogenetically diverse microbial communities. However, biogeochemical effects of hyporheic zones have rarely been investigated in detail because of the difficulty in accurately measuring denitrification in these zones. To date, little is known about the hydroecology of hyporheic zones. The effect of changes in hydraulic conditions on the community variations of indigenous microorganisms and water quality was examined based on the depth of the hyporheic zone. In particular, we report on the use of the pyrosequencing technique to elucidate denitrifying bacteria (DNB) community profiles combined with the stable isotope composition of nitrate and hydrological patterns in the hyporheic zones to reveal whether denitrification occurs. δ 15 N-NO 3 and δ 18 O-NO 3 values of nitrate were analyzed to evaluate the transformation processes of nitrate in upwelling and downwelling areas and mixed zones. The isotope values indicated different origins of water in upwelling and downwelling zones and that denitrification occurred predominantly in the upwelling areas. Analyses of microbial communities in the hyporheic zone showed that the new genera, species, and isotope data were associated with the hydrological uniqueness of the hyporheic zones. The 16S rRNA sequences were determined and phylogenetic analysis revealed that the DNB communities distributed and gathered the genus Comamonas denitrificans within the mixing patterns of the hyporheic zones and that the relative scarcity of these microbes in these zones was caused by the lack of appropriate substrates. The delineation of the surface water-groundwater mixing zone was quantitatively determined by systematically combining the hydrological and heat transfer analyses and by comparing denitrifying bacteria communities and N isotope data. This study showed that pyrosequencing and isotopic approaches are useful for evaluating the transformation processes of nitrate at the upwelling and downwelling points of a hyporheic zone., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Fugitive gas comprised primarily of methane (CH 4 ) with traces of ethane and propane (collectively termed C 1-3 ) may negatively impact shallow groundwater when unintentionally released from oil and natural gas wells. Currently, knowledge of fugitive gas migration, subsurface source identification and oxidation potential in groundwater is limited. To advance understanding, a controlled release experiment was performed at the Borden Research Aquifer, Canada, whereby 51m 3 of natural gas was injected into an unconfined sand aquifer over 72days with dissolved gases monitored over 323days. During active gas injection, a dispersed plume of dissolved C 1-3 evolved in a depth discrete and spatially complex manner. Evolution of the dissolved gas plume was driven by free-phase gas migration controlled by small-scale sediment layering and anisotropy. Upon cessation of gas injection, C 1-3 concentrations increased to the greatest levels observed, particularly at 2 and 6m depths, reaching up to 31.5, 1.5 and 0.1mg/L respectively before stabilizing and persisting. At no time did groundwater become fully saturated with natural gas at the scale of sampling undertaken. Throughout the experiment the isotopic composition of injected methane (δ 13 C of -42.2‰) and the wetness parameter (i.e. the ratio of C 1 to C 2+ ) constituted excellent tracers for the presence of fugitive gas at concentrations >2mg/L. At discrete times C 1-3 concentrations varied by up to 4 orders of magnitude over 8m of aquifer thickness (e.g. from <0.01 to 30mg/L for CH 4 ), while some groundwater samples lacked evidence of fugitive gas, despite being within 10m of the injection zone. Meanwhile, carbon isotope ratios of dissolved CH 4 showed no evidence of oxidation. Our results show that while impacts to aquifers from a fugitive gas event are readily detectable at discrete depths, they are spatially and temporally variable and dissolved methane has propensity to persist., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate changes in HbA1c, blood pressure, and LDLc levels in participants from practices where certified diabetes educators (CDEs) implemented standardized protocols to intensify treatment compared with those receiving usual care., Research Design and Methods: This clustered, randomized, clinical trial was implemented in community-based primary care practices. Fifteen primary care practices and 240 patients with type 2 diabetes were randomized to the intervention (n=175) or usual care (n=65). Participants had uncontrolled HbA1c, blood pressure, or LDLc. The one-year intervention included CDEs implementing pre-approved protocols to intensify treatment. Diabetes self-management education was also provided in both study groups., Results: The population was 50.8% male with a mean age of 61years. The HbA1c in the intervention group decreased from 8.8% to 7.8%, (p=0.001) while the HbA1c in the usual care group increased slightly from 8.2% to 8.3%. There was also a significant difference in HbA1c between the two groups (p=0.004). There was not a significant difference between groups for systolic blood pressure (SBP) or LDLc at the end of the intervention. Those in the intervention group were more likely to have glucose-lowering medications intensified and were more likely to have their HbA1c (35% vs 15%), SBP (80% vs 77%) and HbA1c, SBP, and LDLc at goal (11% vs 1.5%) compared with the usual care group. There was no significant difference in intensification of blood pressure or cholesterol medication., Conclusions: Findings suggest that CDEs following standardized protocols in primary care is feasible and can effectively intensify treatment and improve glycemic control., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease accompanied by both systemic and central nervous system-specific inflammation as well as deregulated energy metabolism. These potential pathogenetic factors have recently been found to mutually interact with the gut microbiota, raising the hypothesis of a link between microbiome alterations and ALS pathogenesis. The aim of our study was to assess whether ALS is associated with an altered composition of the fecal microbiota. We compared the fecal microbiota of 25 ALS patients with 32 age- and gender-matched healthy persons using 16S rRNA gene sequencing analysis. Confounding factors and secondary disease effects on the microbiome were minimized by selection of patients without dysphagia, gastrostomy, noninvasive ventilation, or reduced body mass index. Comparing the 2 carefully matched groups, the diversity and the abundance of the bacterial taxa on the different taxonomic levels as well as PICRUSt-predicted metagenomes were almost indistinguishable. Significant differences between ALS patients and healthy controls were only observed with regard to the overall number of microbial species (operational taxonomic units) and in the abundance of uncultured Ruminococcaceae. Conclusively, ALS patients do not exhibit a substantial alteration of the gut microbiota composition., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The members of the nitric oxide synthase (NOS) family, eNOS, nNOS and iNOS, are well-characterized enzymes. However, due to the lack of suitable direct NO sensors, little is known about the kinetic properties of cellular NO generation by the different nitric oxide synthase isoenzymes. Very recently, we developed a novel class of fluorescent protein-based NO-probes, the geNOps, which allow real-time measurement of cellular NO generation and fluctuation. By applying these genetic NO biosensors to nNOS-, eNOS- and iNOS-expressing HEK293 cells we were able to characterize the respective NO dynamics in single cells that exhibited identical Ca 2+ signaling as comparable activator of nNOS and eNOS. Our data demonstrate that upon Ca 2+ mobilization nNOS-derived NO signals occur instantly and strictly follow the Ca 2+ elevation while NO release by eNOS occurs gradually and sustained. To detect high NO levels in cells expressing iNOS, a new ratiometric probe based on two fluorescent proteins was developed. This novel geNOp variant allows the measurement of the high NO levels in cells expressing iNOS. Moreover, we used this probe to study the L-arginine-dependency of NO generation by iNOS on the level of single cells. Our experiments highlight that the geNOps technology is suitable to detect obvious differences in the kinetics, amplitude and substrate-dependence of cellular NO signals-derived from all three nitric oxide synthase isoforms., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The MENSA trial assessed the efficacy and safety of mepolizumab in patients with severe eosinophilic asthma. This report describes the efficacy and safety of mepolizumab in Japanese patients from MENSA., Methods: A post hoc analysis of the Japanese subgroup from the randomized, double-blind, placebo-controlled, double-dummy, Phase III MENSA trial (NCT01691521). Patients ≥12 years with severe eosinophilic asthma received mepolizumab 75 mg intravenously (IV), 100 mg subcutaneously (SC), or placebo, every 4 weeks for 32 weeks. The primary endpoint was the annualized rate of exacerbations. Secondary and other endpoints included annualized rate of exacerbations requiring emergency department (ED) visit/hospitalization, morning peak expiratory flow (PEF), St George's Respiratory Questionnaire (SGRQ) score and eosinophil counts. Adverse events (AEs) were monitored., Results: In the Japanese subgroup (N = 50), the rate of clinically significant exacerbations was reduced by 90% (rate ratio [RR]: 0.10; 95% confidence interval [CI]: 0.02-0.57; P = 0.010) with mepolizumab IV and 62% (RR: 0.38; 95% CI: 0.12-1.18; P = 0.094) with mepolizumab SC, versus placebo. No exacerbations requiring ED visit/hospitalization were reported with mepolizumab IV; exacerbations were reduced by 73% (RR: 0.27; 95% CI: 0.06-1.29; P = 0.102) with mepolizumab SC versus placebo. Compared with placebo, mepolizumab IV and SC numerically increased morning PEF from baseline by 40 L/min and 13 L/min, improved quality of life by greater than the minimal clinically important difference (SGRQ: 9.5 [P = 0.083] and 7.9 [P = 0.171] points) and reduced eosinophil counts. AE incidence was similar between treatments. Results were broadly consistent with the overall population., Conclusions: Mepolizumab was efficacious and well tolerated in Japanese patients with severe eosinophilic asthma, producing similar responses to the overall MENSA population., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

The tobacco-related plant Nicotiana benthamiana is gaining interest as a versatile host for the production of monoclonal antibodies and other protein therapeutics. However, the susceptibility of plant-derived recombinant proteins to endogenous proteolytic enzymes limits their use as biopharmaceuticals. We have now identified two previously uncharacterized N. benthamiana proteases with high antibody-degrading activity, the papain-like cysteine proteinases NbCysP6 and NbCysP7. Both enzymes are capable of hydrolysing a wide range of synthetic substrates, although only NbCysP6 tolerates basic amino acids in its specificity-determining S2 subsite. The overlapping substrate specificities of NbCysP6 and NbCysP7 are also documented by the closely related properties of their other subsites as deduced from the action of the enzymes on proteome-derived peptide libraries. Notable differences were observed to the substrate preferences of N. benthamiana cathepsin B, another antibody-degrading papain-like cysteine proteinase. The complementary activities of NbCysP6, NbCysP7 and N. benthamiana cathepsin B indicate synergistic roles of these proteases in the turnover of recombinant and endogenous proteins in planta, thus representing a paradigm for the shaping of plant proteomes by the combined action of papain-like cysteine proteinases., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Recently, high prevalence of cryofibrinogenaemia has been observed in plasma of untreated dermatitis herpetiformis (DH) patients, and the pathological IgA and TG3 deposits in the papillary dermis were found to co-localize with fibrin and fibrinogen., Objective: To study the fibrinolytic potential in plasma of untreated, dapsone and or/gluten-free diet treated DH patients as well as the in vitro effect of dapsone on the fibrinolytic profile., Method: Plasma samples of 23 DH patients, 19 healthy subjects and 5 pemphigus vulgaris patients were investigated by a turbidimetric-clot lysis assay. Out of them 5 DH plasma samples representing different fibrinolytic parameters, and 3 healthy controls were selected for parallel fibrin clot preparation. The clot fibrin structure was examined by scanning electron microscopy (SEM), and the diameters of 900 fibrin fibres were determined in each clot., Results: A significantly prolonged clot lysis time was detected in untreated DH patients. The turbidity values of DH plasma clots indicated an altered fibrin structure that was also confirmed by SEM: significantly thicker fibrin fibers were observed in untreated, TG3 antibody positive DH patients compared to healthy controls, whereas the fiber diameters of dapsone-treated patients were similar or thinner than the control values. In line with the structural changes of fibrin, the fibrinolytic profile of 5 DH patients under dapsone treatment approached the control values., Conclusion: This study revealed that the fibrinolytic potential was impaired in the plasma of untreated DH patients, whereas dapsone corrected the fibrinolytic defect. These data suggest a pathogenic role for plasma-derived factors in the development of skin symptoms and add a new aspect to the long-known beneficial, symptomatic effect of dapsone in active DH., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds., Methods: We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab (, Dream: 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis., Findings: Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced., Interpretation: Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab., Funding: GlaxoSmithKline., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Scavenging of nitric oxide (NO) often interferes with studies on NO signaling in cell-free preparations. We observed that formation of cGMP by NO-stimulated purified soluble guanylate cyclase (sGC) was virtually abolished in the presence of cytosolic preparations of porcine coronary arteries, with the scavenging activity localized in the tunica media (smooth muscle layer). Electrochemical measurement of NO release from a donor compound and light absorbance spectroscopy showed that cytosolic preparations contained a reduced heme protein that scavenged NO. This protein, which reacted with anti-human hemoglobin antibodies, was efficiently removed from the preparations by haptoglobin affinity chromatography. The cleared cytosols showed only minor scavenging of NO according to electrochemical measurements and did not decrease cGMP formation by NO-stimulated sGC. In contrast, the column flow-through caused a nearly 2-fold increase of maximal sGC activity (from 33.1 ± 1.6 to 54.9 ± 2.2 μmol × min(-1) × mg(-1)). The proteins retained on the affinity column were identified as hemoglobin α and β subunits. The results indicate that hemoglobin, presumably derived from vasa vasorum erythrocytes, is present and scavenges NO in preparations of porcine coronary artery smooth muscle. Selective removal of hemoglobin-mediated scavenging unmasked stimulation of maximal NO-stimulated sGC activity by a soluble factor expressed in vascular tissue., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

To assess potential future impacts on shallow aquifers by leakage of natural gas from unconventional energy resource development it is essential to establish a reliable baseline. Occurrence of methane in shallow groundwater in Alberta between 2006 and 2014 was assessed and was ubiquitous in 186 sampled monitoring wells. Free and dissolved gas sampling and measurement approaches yielded comparable results with low methane concentrations in shallow groundwater, but in 28 samples from 21 wells methane exceeded 10mg/L in dissolved gas and 300,000 ppmv in free gas. Methane concentrations in free and dissolved gas samples were found to increase with well depth and were especially elevated in groundwater obtained from aquifers containing coal seams and shale units. Carbon isotope ratios of methane averaged -69.7 ± 11.1‰ (n=63) in free gas and -65.6 ± 8.9‰ (n=26) in dissolved gas. δ(13)C values were not found to vary with well depth or lithology indicating that methane in Alberta groundwater was derived from a similar source. The low δ(13)C values in concert with average δ(2)HCH4 values of -289 ± 44‰ (n=45) suggest that most methane was of biogenic origin predominantly generated via CO2 reduction. This interpretation is confirmed by dryness parameters typically >500 due to only small amounts of ethane and a lack of propane in most samples. Comparison with mud gas profile carbon isotope data revealed that methane in the investigated shallow groundwater in Alberta is isotopically similar to hydrocarbon gases found in 100-250 meter depths in the WCSB and is currently not sourced from thermogenic hydrocarbon occurrences in deeper portions of the basin. The chemical and isotopic data for methane gas samples obtained from Alberta groundwater provide an excellent baseline against which potential future impact of deeper stray gases on shallow aquifers can be assessed., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Dry-processing environments are particularly challenging to clean and sanitize because introduced water can favor growth and establishment of pathogenic microorganisms such as Salmonella. Our objective was to determine the efficacy of an isopropyl alcohol quaternary ammonium (IPAQuat) formula for eliminating potential Salmonella contamination on food contact surfaces. Clean stainless steel coupons and conveyor belt materials used in dry-processing environments were spot inoculated in the center of coupons (5 by 5 cm) with a six-serotype composite of Salmonella (approximately 10 log CFU/ml), subjected to IPAQuat sanitizer treatments with exposure times of 30 s, 1 min, or 5 min, and then swabbed for enumeration of posttreatment survivors. A subset of inoculated surfaces was soiled with a breadcrumb-flour blend and allowed to sit on the laboratory bench for a minimum of 16 h before sanitation. Pretreatment Salmonella populations (inoculated controls, 0 s treatment) were approximately 7.0 log CFU/25 cm(2), and posttreatment survivors were 1.31, 0.72, and < 0.7 (detection limit) log CFU/25 cm(2) after sanitizer exposure for 30 s, 1 min, or 5 min, respectively, for both clean (no added soil) and soiled surfaces. Treatment with the IPAQuat formula using 30-s sanitizer exposures resulted in 5.68-log reductions, whereas >6.0-log reductions were observed for sanitizer exposures of 1 and 5 min. Because water is not introduced into the processing environment with this approach, the IPAQuat formula could have sanitation applications in dry-processing environments to eliminate potential contamination from Salmonella on food contact surfaces.

Introduction: Fetal unilateral ureteral obstruction (UUO) triggers complex pathophysiology involving not only the affected organ but also the contralateral kidney, which undergoes evident compensatory changes., Objective: We hypothesized that it would be possible to characterize a transcriptomic fingerprint and selected molecular mechanisms for compensatory growth of contralateral kidneys in UUO, specifically focusing on mediators, carriers, membrane transport, and organ crosstalk in an ovine fetal UUO model., Study Design: A fetal ovine model of complete UUO was created on the 60th day of gestation. For transcriptomics profiling, total RNA was extracted from vital renal biopsies of contralateral (non-obstructed) kidneys harvested on the 80th day of gestation, and kidneys of untreated fetuses served as controls. Statistical analysis provided the set of differentially regulated genes further forwarded to bioinformatics analysis for identification of eventual compensatory molecular mechanisms. Histological analysis was performed with hematoxylin and eosin and periodic acid-Schiff stains., Results: Contralateral kidneys showed compensatory hypertrophic renal growth, represented on the molecular side by 324 protein coding genes differentially regulated compared with the control kidney samples. Bioinformatics analysis identified an interactome (Figure) consisting of 102 genes with 108 interactions mainly involving transporters (protein transport and protein localization as well as in protein degradation), signaling molecules, DNA/nucleotide/RNA processing, and components of catabolism and cell cycle regulation. Within the interactome, nine receptors were identified as differentially regulated on the contralateral kidney, involving potential renoprotective ligands of the prostaglandin and the bradykinin receptor, arginine vasopressin receptor 1B, and integrin beta 4. Interestingly, a broad range of molecules found differentially expressed, has been previously described in stress response, renoprotection and repair (e.g., MAPK3, MCP1, DICER1, and others)., Discussion: The compensatory renal growth interactome provides a network of transcripts significantly altered in the contralateral kidney, potentially allowing novel insights into mechanisms, interactions, and signaling pathways associated with compensatory growth, and renal protection and repair. Interestingly, the finding of an embedded gene signature reflecting signaling and communication suggests a key role of these processes in CRG either by crosstalk, soluble substances, carriers, or membrane signaling., Conclusions: Using a transcriptomics approach, it was possible to identify a gene expression fingerprint of contralateral renal growth in a fetal UUO model. Further studies are warranted to validate those processes and to allow incorporation of this knowledge in new fetal diagnostic or even therapeutic strategies., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

An integrated study based on hydrogeochemical, microbiological and dual isotopic approaches for nitrate and sulfate was conducted to elucidate sources and biogeochemical reactions governing groundwater contaminants in different seasons and under different land use in a basin of Korea. The land use in the study area is comprised of forests (58.0%), vegetable fields (27.6%), rice paddy fields (11.4%) and others (3.0%). The concentrations of NO3-N and SO4(2-) in groundwater in vegetable fields were highest with 4.2-15.2 mg L(-1) and 1.6-19.7 mg L(-1) respectively, whereas under paddy fields NO3-N concentrations ranged from 0 to 10.7 mg L(-1) and sulfate concentrations were ~15 mg L(-1). Groundwater with high NO3-N concentrations of >10mgL(-1) had δ(15)N-NO3(-) values ranging from 5.2 to 5.9‰ and δ(18)O values of nitrate between 2.7 and 4.6‰ suggesting that the nitrate was mineralized from soil organic matter that was amended by fertilizer additions. Elevated concentrations of SO4(2-) with δ(34)S-SO4(2-) values between 1 and 6‰ in aquifers in vegetable fields indicated that a mixture of sulfate from atmospheric deposition, mineralization of soil organic matter and from synthetic fertilizers is the source of groundwater sulfate. Elevated δ(18)O-NO3(-) and δ(18)O-SO4(2-) values in samples collected from the paddy fields indicated that denitrification and bacterial sulfate reduction are actively occurring removing sulfate and nitrate from the groundwater. This was supported by high occurrences of denitrifying and sulfate reducing bacteria in groundwater of the paddy fields as evidenced by 16S rRNA pyrosequencing analysis. This study shows that dual isotope techniques combined with microbial data can be a powerful tool for identification of sources and microbial processes affecting NO3(-) and SO4(2-) in groundwater in areas with intensive agricultural land use., (Copyright © 2015 Elsevier B.V. All rights reserved.)

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and specific mircoRNA "fingerprints" are thought to contribute to and/or reflect certain disease conditions. Recently, we identified surprisingly homogeneous signatures of circulating miRNAs in the serum of familial amyotrophic lateral sclerosis (ALS) patients, which were already present in presymptomatic carriers of ALS gene mutations. Here, we characterize circulating miRNAs in the serum of sporadic ALS patients. We show that, in contrast to familial ALS, miRNA signatures of sporadic ALS are highly heterogeneous suggesting a number of different etiologies. Nevertheless, 2 miRNAs, miR-1234-3p and miR-1825, could be identified to be consistently downregulated in sporadic ALS. Bioinformatic analysis revealed miRNA fingerprints resembling those of familial ALS patients and mutation carriers in 61% of sporadic ALS patients, while the remaining subgroup had clearly different miRNA signatures. These data support a higher than expected contribution of genetic factors also to sporadic ALS. Moreover, our results indicate a more heterogeneous molecular etiology of sporadic ALS compared with (mono)genic cases, which should be considered for the development of disease modifying treatments., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Even though modern surgical techniques are dominating reconstructive facial procedures, the capability to use facial epitheses for reconstruction is still an important skill for the maxillofacial surgeon. We present an international multicenter analysis to clarify which techniques are used to fixate facial prostheses. We contacted all maxillofacial departments in Germany, Austria, Switzerland and Norway which were registered with the German society for oral and maxillofacial surgery (DGMKG). These centers were asked via electronical mail to provide information on the type of epithesis fixation systems currently in use. The return rate from 58 departments was 43.1% (n = 25). Overall, implant fixation was the preferred fixation system (92%). Plates were the second most common fixation technique (32%). No centers reported the standard use of non-invasive fixation techniques for permanent epithesis fixation. The main retention systems in use were magnets (24/25), other retention systems are used much less often. The current preferred fixation technique for facial epitheses consists of implant-based, magnet-fixated epitheses. For nasal prostheses, a plate-based, magnet-fixated system is often used., (Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease free survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms (n = 267) was 62.8% compared to 83.4% in patients without other tumors (n = 569) (P < .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths (n = 66 of n = 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted., (Copyright © 2014. Published by Elsevier Inc.)