Urinary Glycosaminoglycans are Selectively Included into Calcium Oxalate Crystals Precipitated from Whole Human Urine

Urinary glycosaminoglycans are selectively included into calcium oxalate (CaOx) crystals precipitated from whole human urine: The presence of glycosaminoglycans (GAGs) in the organic matrix of urinary stones, and their known effects on CaOx crystallization have prompted speculation regarding their role in CaOx urolithiasis. The aim of this study was to examine the involvement of GAGs in the early stages of CaOx crystallization in human urine. Urine samples were collected from healthy men and CaOx crystallization was induced by the addition of a sodium oxalate load. The crystals were harvested and demineralized, and the GAG content of the resulting extract analysed by cellulose acetate electrophoresis. Only one GAG, heparan sulphate (HS) was detected in the organic matrix of the crystals; chondroitin sulphate (ChS), the most abundant urinary GAG, was conspicuously absent. Further experiments, in which varying amounts of HS and ChS were added to ultrafiltered (10,000 Da) urine prior to induction of calcium oxalate crystallization, showed that ChS was included into the crystals only when HS was absent from the urine. It was concluded that the selective inclusion of GAGs into crystals and stones is a function related more to relative binding affinity than to ambient GAG concentration and that HS and ChS compete for specific binding sites on the crystal surface

Legitimacy in conflict: concepts, practices, challenges

The study of legitimacy in situations of conflict and peacebuilding has increased in recent years. However, current work on the topic adopts many assumptions, definitions, and understandings from classical legitimacy theory, which centers on the relationship between the nation-state and its citizens. In this introduction, we provide a detailed critical overview of current theories of legitimacy and legitimation and demonstrate why they have only limited applicability in conflict and post-conflict contexts, focusing on the three main areas that the articles included in this special issue examine: audiences for legitimacy, sources of legitimacy, and legitimation. In particular, we show how conflict and post-conflict contexts are marked by the fragmentation and personalization of power; the proliferation and fragmentation of legitimacy audiences; and ambiguity surrounding legitimation strategies

Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while <scp>CNS</scp> entry is required for locomotor and taste avoidance effects

ObjectivesOxytocin (OT) has a well‐established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT‐R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT‐R activation is sufficient to alter energy intake and expenditure.Methods and ResultsWe first show that systemic OT potently reduced food intake and food‐motivated behaviour for a high‐fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood‐brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled‐OT (fAF546‐OT, Roxy), for the presence of IP‐injected Roxy in CNS tissue relevant to feeding control and compared such with BBB‐impermeable fluorescent OT‐B$_{12}$ (fCy5‐OT‐B$_{12;}$ BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT‐R, we generated a novel BBB‐impermeable OT (OT‐B$_{12}$), with equipotent binding at OT‐R in vitro. In vivo, IP‐injected OT and OT‐B$_{12}$ were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT‐R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT‐B$_{12}$ did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose‐dependent reduction of emesis in male shrews. While both OT and OT‐B$_{12}$ proved to have similar effects on body temperature, only OT resulted in home‐cage locomotor depression.ConclusionsTogether our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT‐R may be a viable strategy to achieve appetite suppression with better patient outcomes

The impact of preexisting and post-transplant diabetes mellitus on outcomes following liver transplantation

Background: Diabetes mellitus (DM) is said to adversely affect transplant outcomes. The aim of this study was to investigate the impact of pre-existing and post-transplant DM on liver transplant (LT) recipients.Method: A single centre retrospective analysis of prospectively collected data of LT recipients (1990–2015) was undertaken.Results: Of the 2,209 patients, 13% (n=298) had Pre-DM, 16% (n=362) developed PTDM, 5% (n=118) developed transient hyperglycemia (t-HG) post-LT, and 65% (n=1,431) never developed DM (no DM). Baseline clinical characteristics of patients with PTDM was similar to that of patients with pre-DM. Incidence of PTDM peaked during first-year (87%) and plateaued thereafter. On multivariate analysis (Bonferroni-corrected), non-alcoholic fatty liver disease and the use of Tacrolimus and Sirolimus use were independently associated with PTDM development. Both Pre-DM and PTDM patients had satisfactory and comparable glycaemic control throughout the follow-up period. Those who developed t-HG seems to have a unique characteristic compared to others. Overall, 9%, 5%, and 8% developed end-stage renal disease (ESRD), major cardiovascular event (mCVE), and de novo cancer, respectively. Both Pre-DM and PTDM did not adversely affect patient survival, re-LT, or de novo cancer. The risks of ESRD and mCVE were significantly higher in patients with Pre-DM followed by PTDM and no DM.Conclusions: In this largest non-registry study, patients with pre-DM and PTDM share similar baseline clinical characteristics. Pre-DM increases the risk of ESRD and mCVE; however, patient survival was comparable to those with PTDM and without diabetes. Understanding the impact of PTDM would need prolonged follow-up

Increased Oxidative Burden Associated with Traffic Component of Ambient Particulate Matter at Roadside and Urban Background Schools Sites in London

As the incidence of respiratory and allergic symptoms has been reported to be increased in children attending schools in close proximity to busy roads, it was hypothesised that PM from roadside schools would display enhanced oxidative potential (OP). Two consecutive one-week air quality monitoring campaigns were conducted at seven school sampling sites, reflecting roadside and urban background in London. Chemical characteristics of size fractionated particulate matter (PM) samples were related to the capacity to drive biological oxidation reactions in a synthetic respiratory tract lining fluid. Contrary to hypothesised contrasts in particulate OP between school site types, no robust size-fractionated differences in OP were identified due high temporal variability in concentrations of PM components over the one-week sampling campaigns. For OP assessed both by ascorbate (OPAA m−3) and glutathione (OPGSH m−3) depletion, the highest OP per cubic metre of air was in the largest size fraction, PM1.9–10.2. However, when expressed per unit mass of particles OPAA µg−1 showed no significant dependence upon particle size, while OPGSH µg−1 had a tendency to increase with increasing particle size, paralleling increased concentrations of Fe, Ba and Cu. The two OP metrics were not significantly correlated with one another, suggesting that the glutathione and ascorbate depletion assays respond to different components of the particles. Ascorbate depletion per unit mass did not show the same dependence as for GSH and it is possible that other trace metals (Zn, Ni, V) or organic components which are enriched in the finer particle fractions, or the greater surface area of smaller particles, counter-balance the redox activity of Fe, Ba and Cu in the coarse particles. Further work with longer-term sampling and a larger suite of analytes is advised in order to better elucidate the determinants of oxidative potential, and to fuller explore the contrasts between site types.\ud \u

Predicting inpatient violence using an extended version of the Brøset-Violence-Checklist: instrument development and clinical application

BACKGROUND: Patient aggression is a common problem in acute psychiatric wards and calls for preventive measures. The timely use of preventive measures presupposes a preceded risk assessment. The Norwegian Brøset-Violence-Checklist (BVC) is one of the few instruments suited for short-time prediction of violence of psychiatric inpatients in routine care. Aims of our study were to improve the accuracy of the short-term prediction of violence in acute inpatient settings by combining the Brøset-Violence-Checklist (BVC) with an overall subjective clinical risk-assessment and to test the application of the combined measure in daily practice. METHOD: We conducted a prospective cohort study with two samples of newly admitted psychiatric patients for instrument development (219 patients) and clinical application (300 patients). Risk of physical attacks was assessed by combining the 6-item BVC and a 6-point score derived from a Visual Analog Scale. Incidents were registered with the Staff Observation of Aggression Scale-Revised SOAS-R. Test accuracy was described as the area under the receiver operating characteristic curve (AUC(ROC)). RESULTS: The AUC(ROC )of the new VAS-complemented BVC-version (BVC-VAS) was 0.95 in and 0.89 in the derivation and validation study respectively. CONCLUSION: The BVC-VAS is an easy to use and accurate instrument for systematic short-term prediction of violent attacks in acute psychiatric wards. The inclusion of the VAS-derived data did not change the accuracy of the original BVC

CONTRA: copy number analysis for targeted resequencing

Motivation: In light of the increasing adoption of targeted resequencing (TR) as a cost-effective strategy to identify disease-causing variants, a robust method for copy number variation (CNV) analysis is needed to maximize the value of this promising technology

Outcomes of Radiofrequency Ablation as First-Line Therapy for Hepatocellular Carcinoma less than 3 cm in Potentially Transplantable Patients

© 2019 European Association for the Study of the Liver Background & Aims: Radiofrequency ablation (RFA) is an effective treatment for single hepatocellular carcinoma (HCC) ≤3 cm. Disease recurrence is common, and in some patients will occur outside transplant criteria. We aimed to assess the incidence and risk factors for recurrence beyond Milan criteria in potentially transplantable patients treated with RFA as first-line therapy. Methods: We performed a retrospective cohort study of potentially transplantable patients with new diagnoses of unifocal HCC ≤3 cm that underwent RFA as first-line therapy between 2000-2015. We defined potentially transplantable patients as those aged 2 cm). Competing risks Cox regression was used to identify predictors of recurrence beyond Milan criteria. Results: We included 301 patients (167 HCC ≤2 cm and 134 HCC >2 cm). Recurrence beyond Milan criteria occurred in 36 (21.6%) and 47 (35.1%) patients in the HCC ≤2 cm and the HCC >2 cm groups, respectively (p = 0.01). The 1-, 3- and 5-year actuarial survival rates after RFA were 98.2%, 86.2% and 79.0% in the HCC ≤2 cm group vs. 93.3%, 77.6% and 70.9% in the HCC >2 cm group (p = 0.01). Tumor size >2 cm (hazard ratio 1.94; 95% CI 1.25–3.02) and alpha-fetoprotein levels at the time of ablation (100–1,000 ng/ml: hazard ratio 2.05; 95% CI 1.10–3.83) were found to be predictors of post-RFA recurrence outside Milan criteria. Conclusion: RFA for single HCC ≤3 cm provides excellent short- to medium-term survival. However, we identified patients at higher risk of recurrence beyond Milan criteria. For these patients, liver transplantation should be considered immediately after the first HCC recurrence following RFA. Lay summary: Radiofrequency ablation and liver transplantation are treatment options for early stages of hepatocellular carcinoma (HCC). After ablation some patients will experience recurrence or metastatic spread of the initial tumor or may develop new tumors within the liver. Despite close follow-up, these recurrences can progress rapidly and exceed transplant criteria, preventing the patient from receiving a transplant. We identified that patients with HCC >2 cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond the transplant criteria. These data suggest that liver transplantation should be considered immediately after the first HCC recurrence for these patients

Evaluation of genetic isolation within an island flora reveals unusually widespread local adaptation and supports sympatric speciation

It is now recognized that speciation can proceed even when divergent natural selection is opposed by gene flow. Understanding the extent to which environmental gradients and geographical distance can limit gene flow within species can shed light on the relative roles of selection and dispersal limitation during the early stages of population divergence and speciation. On the remote Lord Howe Island (Australia), ecological speciation with gene flow is thought to have taken place in several plant genera. The aim of this study was to establish the contributions of isolation by environment (IBE) and isolation by community (IBC) to the genetic structure of 19 plant species, from a number of distantly related families, which have been subjected to similar environmental pressures over comparable time scales. We applied an individual-based, multivariate, model averaging approach to quantify IBE and IBC, while controlling for isolation by distance (IBD). Our analyses demonstrated that all species experienced some degree of ecologically driven isolation, whereas only 12 of 19 species were subjected to IBD. The prevalence of IBE within these plant species indicates that divergent selection in plants frequently produces local adaptation and supports hypotheses that ecological divergence can drive speciation in sympatry