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Vibrios, a group of bacteria that are among the most abundant in marine environments, include several species such as Vibrio cholerae and Vibrio parahaemolyticus, which can be pathogenic to humans. Some species of Vibrio contain prophages within their genomes. These prophages can carry genes that code for toxins, such as the zonula occludens toxin (Zot), which contribute to bacterial virulence. Understanding the association between different Vibrio species, prophages and Zot genes can provide insights into their ecological interactions. In this study, we evaluated 4619 Vibrio genomes from 127 species to detect the presence of prophages carrying the Zot toxin. We found 2030 potential prophages with zot‐like genes in 43 Vibrio species, showing a non‐random association within a primarily modular interaction network. Some prophages, such as CTX or Vf33, were associated with specific species. In contrast, prophages phiVCY and VfO3K6 were found in 28 and 20 Vibrio species, respectively. We also identified six clusters of Zot‐like sequences in prophages, with the ZOT2 cluster being the most frequent, present in 34 Vibrio species. This analysis helps to understand the distribution patterns of zot‐containing prophages across Vibrio genomes and the potential routes of Zot‐like toxin dissemination. [ABSTRACT FROM AUTHOR]

Background: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic, transfusion of coronavirus disease 2019 (COVID‐19) convalescent plasma (CCP) emerged as a potential therapeutic strategy to help patients severely afflicted by COVID‐19. The efficacy of CCP has been controversial as it depends on many variables pertaining to the plasma donor and the patient with COVID‐19, for example, time of convalescence or symptoms onset. This feasibility and descriptive study aimed to assess the safety of multiple doses of CCP in mechanically ventilated, intubated patients with respiratory failure due to COVID‐19. Methods: A cohort of 30 patients all experiencing severe respiratory failure and undergoing invasive mechanical ventilation in an intensive care unit, received up to five doses of 300–600 mL of CCP on alternate days (0, 2, 4, 6, and 8) until extubation, futility, or death. Results: Nineteen patients received five doses, seven received four, and four received two or three doses. At 28‐day follow‐up mark, 57% of patients recovered and were sent home, and the long‐term mortality rate was 27%. Ten severe adverse events reported in the study were unrelated to CCP transfusion. Independent of the number of transfused doses, most patients had detectable levels of total and neutralizing antibodies in plasma. Conclusion: This study suggests that transfusion of multiple doses of CCP is safe. This strategy may represent a viable option for future studies, given the potential benefit of CCP transfusions during the early stages of infection in unvaccinated populations and in settings where monoclonal antibodies or antivirals are contraindicated or unavailable. Highlights: Transfusion of multiple doses (up to 5) of 300–600 mL of convalescent plasma from COVID‐19‐recovered patients is deemed safe, as it does not induce more severe effects than a single dose.Regardless of the number of transfused doses and the titer of neutralizing antibodies, most transfused patients had detectable levels of total and neutralizing antibodies in their plasma.Future studies are needed to determine if multiple transfusion doses are more efficient in preventing disease severity than a single dose. [ABSTRACT FROM AUTHOR]

Background & Aims: Disorders of gut‐brain interaction (DGBI) are complex conditions that result in decreased quality of life and a significant cost burden. Linaclotide, a guanylin cyclase C (GCC) receptor agonist, is approved as a DGBI treatment. However, its efficacy has been limited and variable across DGBI patients. Microbiota and metabolomic alterations are noted in DGBI patients, provoking the hypothesis that the microbiota may impact the GCC response to current therapeutics. Methods: Human‐derived intestinal organoids were grown from pediatric DGBI, non‐IBD colon biopsies (colonoids). Colonoids were treated with 250 nM linaclotide and assayed for cGMP to develop a model of GCC activity. Butyrate was administered to human colonoids overnight at a concentration of 1 mM. Colonoid lysates were analyzed for cGMP levels by ELISA. For the swelling assay, colonoids were photographed pre‐ and post‐treatment and volume was measured using ImageJ. Principal coordinate analyses (PCoA) were performed on the Bray–Curtis dissimilarity and Jaccard distance to assess differences in the community composition of short‐chain fatty acid (SCFA) producing microbial species in the intestinal microbiota from pediatric patients with IBS and healthy control samples. Key Results: Linaclotide treatment induced a significant increase in [cGMP] and swelling of patient‐derived colonoids, demonstrating a human in vitro model of linaclotide‐induced GCC activation. Shotgun sequencing analysis of pediatric IBS patients and healthy controls showed differences in the composition of commensal SCFA‐producing bacteria. Butyrate exposure significantly dampened linaclotide‐induced cGMP levels and swelling in patient‐derived colonoids. Conclusions & Inferences: Patient‐derived colonoids demonstrate that microbiota‐derived butyrate can dampen human colonic responses to linaclotide. This study supports incorporation of microbiota and metabolomic assessment to improve precision medicine for DGBI patients. [ABSTRACT FROM AUTHOR]

Background: Irritable bowel syndrome (IBS), a disorder of the gut–brain axis, is affected by the microbiome. Microbial studies in pediatric IBS, especially for centrally mediated treatments, are lacking. We compared the microbiome between pediatric IBS patients and healthy controls (HC), in relation to symptom severity, and with percutaneous electrical nerve field stimulation (PENFS), a non‐invasive treatment targeting central pain pathways. Methods: We collected a stool sample, questionnaires and a 1–2 week stool and pain diary from 11 to 18 years patients with IBS. A patient subset completed 4 weeks of PENFS and repeated data collection immediately after and/or 3 months after treatment. Stool samples were collected from HC. Samples underwent metagenomic sequencing to evaluate diversity, composition, and abundance of species and MetaCyc pathways. Key Results: We included 27 cases (15.4 ± 2.5 year) and 34 HC (14.2 ± 2.9 year). Twelve species including Firmicutes spp., and carbohydrate degradation/long‐chain fatty acid (LCFA) synthesis pathways, were increased in IBS but not statistically significantly associated with symptom severity. Seventeen participants (female) who completed PENFS showed improvements in pain (p = 0.012), disability (p = 0.007), and catastrophizing (p = 0.003). Carbohydrate degradation and LCFA synthesis pathways decreased post‐treatment and at follow‐up (FDR p‐value <0.1). Conclusions and Inferences: Firmicutes, including Clostridiaceae spp., and LCFA synthesis pathways were increased in IBS patients suggesting pain‐potentiating effects. PENFS led to marked improvements in abdominal pain, functioning, and catastrophizing, while Clostridial species and LCFA microbial pathways decreased with treatment, suggesting these as potential targets for IBS centrally mediated treatments. [ABSTRACT FROM AUTHOR]

We examined the effects of different small-sided games (SSG) configurations on heart rate (HR), rating of perceived exertion (RPE), and running demands in soccer players. Twelve male soccer players (U18) participated in this randomized cross-over study. Players performed three SSG in different "fixed" and "dynamic" pitch sizes (3v3 in large (SSGL) and small (SSGS) fixed area; or 3v3 in dynamic dimensions [SSGD]), with 4x4 minutes interspersed by 2 minutes of rest. HR measures (maximum [HRmax], average [HRavg], and percentage of maximum [%HRmax]), RPE, and running demands were collected across the SGG sessions. The following running activities were recorded: total distance covered (TD), distance covered (DC) at 6–12 km·h−1, ≥ 12–18 km·h−1, and >18 km·h−1, peak running speed, acceleration (ACC) and deceleration (DEC) at 1–2 m·s−2 and 2–3 m·s−2, player load, and high metabolic load distance (HMLD). SSGL displayed higher HRavg, %HRmax, and RPE values than SSGS (p < 0.05). SSGL resulted in higher TD, DC at 6–12 km·h−1, ≥ 12–18 km·h−1, > 18 km·h−1, and higher peak speed than SSGS and SSGD (p < 0.05). Moreover, SSGD presented higher TD and DC at 6–12 km·h−1 and ≥ 12–18 km·h−1 than SSGS (p < 0.05). In contrast, SSGD and SSGS showed higher number of ACC and DEC at 1–2 m·s−2 than SSGL (p < 0.05). In conclusion, the pitch size and playing area of the SSG can be manipulated to promote desired physiological and physical demands in young soccer players. Highlights We examined how fixed (small and large) or variable (dynamic) pitch sizes affected the psychophysiological and running demands of young soccer players during small-sided games. Small-sided games with larger pitch sizes and areas per player elicited greater psychophysiological and running demands than small areas. The pitch size designed in the current study does not appear to affect the number of acceleration and deceleration (> 2 m·s−2). Varying the pitch size during the small-sided games (i.e. dynamic condition) could be an interesting constraint to be considered by soccer coaches in order to enhance task variability. [ABSTRACT FROM AUTHOR]

An 11 year old female‐neutered Labrador presented for facial swelling. Clinicopathological abnormalities included hyperglobulinemia, azotemia, hypercalcemia, nonregenerative anemia, thrombocytopenia, and spurious hypoglycemia. Normoglycemia was subsequently confirmed using a cage‐side analyzer (AlphaTRAK, Zoetis, UK). Serum and urine protein electrophoresis documented monoclonal (immunoglobulin M) gammopathy with Bence‐Jones proteinuria. Computed tomography imaging revealed a monostotic osteolytic bone‐lesion, and bone marrow cytology and histopathology documented plasmacytosis with multiple myeloma oncogene 1 / interferon regulatory factor 4 positivity, consistent with multiple myeloma. Infectious disease testing initially indicated seropositivity for Leishmania, Borrelia, and Anaplasma spp.; however, Leishmania PCR (splenic and bone marrow aspirates), and paired serological titers for Borrelia and Anaplasma were negative. Consequently, initial serological results were considered to be false positive because of paraproteinemia‐associated assay interference. Chemotherapy (prednisolone and melphalan combination therapy) was initiated, but the dog was euthanased 30 days later because of the development of pericardial effusion. This is a report of spurious serological (and other laboratory) results occurring secondary to monoclonal gammopathy in a dog. [ABSTRACT FROM AUTHOR]

This study presents a novel methodology to generate computational replicates of nanostructures of multiphase materials, such as asphalt binders, by integrating image analysis techniques with stochastic random field (RF) modeling. Image analysis techniques are used to identify and segment nanostructure images obtained by atomic force microscopy, while RF is used to model the spatial distribution of their material properties. The results of this process are images showing probable arrangements of nanostructures with stochastic material properties that replicate the experimentally obtained images. The computationally generated nanostructures are then used as inputs in a finite element model to evaluate the effect of heterogeneity on their mechanical response. The efficacy of the developed approach is demonstrated through simulations of asphalt binders' nanostructures, which reveal novel insights regarding their nanoscale mechanical behavior and response. The FE simulations provided the link between the distribution of nanoscale properties of asphalt binders and variations in their mechanical response. The application of this methodology expands the body of knowledge beyond the deterministic analysis of asphalt binders toward probabilistic analysis and uncertainty quantification that considers their heterogeneous, multiphase structures. Consequently, the methodology can be used to design multiphase materials, such as asphaltic blends, with tailored properties and enhanced performance. [ABSTRACT FROM AUTHOR]

Flavobacteria are among the most important pathogens in freshwater salmonid aquaculture worldwide. Due to concerns regarding development of antibiotic resistance, phage therapy has been proposed as a solution to decrease pathogen load. However, application of phages is challenged by the development of phage resistance, and knowledge of the mechanisms and implications of phage resistance is therefore required. To study this, 27 phage‐resistant isolates of F. psychrophilum were genome sequenced and characterized to identify genetic modifications and evaluate changes in phenotypic traits, including virulence against rainbow trout. Phage‐resistant isolates showed reduction or loss of gliding motility, proteolytic activity, and adhesion to surfaces, and most isolates were completely non‐virulent against rainbow trout fry. Genomic analysis revealed that most phage‐resistant isolates had mutations in genes associated with gliding motility and virulence. Reversal of these mutations in a sub‐set of isolates led to regained motility, proteolytic activity, virulence and phage susceptibility. Although costly, the fast generation of phage resistance driven by single, reversible mutations likely represents a flexible and efficient phage defence mechanism in F. psychrophilum. The results further suggest that phage administration in aquaculture systems to prevent F. psychrophilum outbreaks selects for non‐virulent phage‐resistant phenotypes. [ABSTRACT FROM AUTHOR]

Background: The cytologic diagnosis of inflammation on canine hepatic aspirates can be confounded by neutrophilic infiltrates in the liver of dogs with nodular regeneration, by extramedullary hematopoiesis, and by marked blood contamination. Objectives: We aimed to assess the association between neutrophil counts on hepatic cytology and the histopathologic diagnosis in dogs with hepatitis and non‐inflammatory hepatopathy. We also sought to determine a cut‐off value for the cytologic diagnosis of hepatitis. Methods: In a retrospective blinded pilot study, three observers independently reviewed hepatic aspirates that had corresponding histopathologic examinations performed within 2 days. The number of neutrophils per 200 hepatocytes was determined and averaged among observers. Only neutrophils within or directly in contact with a cluster of ≥5 hepatocytes were counted, and only intact hepatocytes within an approximate monolayer were included. Data are presented as the median (range), and the Mann‐Whitney U test is used to make comparisons between groups. Results: Eighteen cases were included (13 hepatitis and five vacuolar hepatopathy). Aspirates with a histopathologic diagnosis of hepatitis had increased numbers of neutrophils compared with those of vacuolar hepatopathy (7.7 [0.3‐18.3] vs 3.0 [1.0‐5.3]; P =.038). Receiver operating characteristic curve analysis indicated that ≥6 neutrophils were 61.5% (CI 31.6%‐86.1%) sensitive and 100% (CI 47.8%‐100%) specific for identifying hepatitis. Conclusions: Liver aspirates from hepatitis cases have a higher number of neutrophils on cytology compared with those from vacuolar hepatopathy; however, larger studies, including those with dogs with other liver pathologies, are required. Identification of six or more neutrophils per 200 hepatocytes is highly suggestive of hepatitis. [ABSTRACT FROM AUTHOR]

Background: Canine stomatocytosis is a well‐recognized rare erythrocyte disorder characterized by nonsyndromic forms with selective erythroid involvement, syndromic forms with extra‐hematologic disease, and acquired forms. Objectives: We describe serial clinicopathologic changes in two dogs with stomatocytosis of breeds that are different from those previously reported. Methods: Blood samples were obtained from a 12‐year‐old female neutered Australian Cattle Dog and a 12‐year‐old male neutered Beagle for hematologic and biochemical analyses, including a morphologic examination of peripheral blood films. Serial clinicopathologic data were reviewed, including CBCs performed by the referring veterinary surgeons. Results: Serial CBC data in both cases reported a variable decrease in RBC numbers commonly associated with a normal hematocrit, macrocytosis, hypochromasia, changes in red cell distribution width parameters including marked histogram abnormalities in volume distribution of the RBC population, and mildly increased or normal reticulocyte counts. Morphologic examination of peripheral blood films identified variable numbers of stomatocytes, knizocytes (Case 1, Day 1, Day 4), mild anisocytosis, mild macrocytosis, and mild polychromasia. Conclusions: In both cases, the changes exhibited in the erythrogram raise suspicion for an RBC membrane disorder with cell volume dysregulation and stomatocytosis, although they did not appear to cause clinically relevant hemolysis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Glucagon‐like peptide‐2 (GLP‐2) is a gastrointestinal hormone released in response to nutritional intake that exerts a wide range of effects by activating GLP‐2 receptors. In addition to its intestinotrophic effects, GLP‐2 also positively influences glucose metabolism under conditions of obesity, but the mechanisms behind this remain unclear. Here, we have investigated the molecular role of the GLP‐2/GLP‐2 receptor axis in energetic metabolism, focusing on its potential modulatory effects on adipose tissue. Experimental Approach Physiological measurements (body weight, food intake, locomotor activity, and energy expenditure) and metabolic studies (glucose and insulin tolerance tests) were performed on lean and obese mice treated with the protease‐resistant GLP‐2 analogue teduglutide. Key Results: Acute but not chronic centrally administered teduglutide decreased food intake and weight‐gain. By contrast, chronic activation of peripheral GLP‐2 receptors increased body weight‐independent glucose tolerance and had anti‐inflammatory effects on visceral adipose tissue. Using a gene silencing approach, we found that adipose tissue is necessary for these beneficial effects of teduglutide. Finally, teduglutide regulates the inflammatory state and acts as an anabolic signal in human adipocytes. Conclusion and Implications: Overall, our data identify adipose tissue as a new, clinically relevant, site of action for GLP‐2 activity in obesity. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc [ABSTRACT FROM AUTHOR]

Successful management of Cesarean Delivery complicated by emergent CPB and AVR requires meticulous multidisciplinary planning. This case also represents the volatility that can arise from severe aortic regurgitation during pregnancy. [ABSTRACT FROM AUTHOR]

Summary: Obesity and metabolic syndrome are among the most prevalent health problems in developed countries. The impairment of adipose tissue (AT) function is partially responsible for the aetiology of these conditions. Epigenetics refers to several processes that add modifications to either the DNA or chromatin architectural proteins (histones). These processes can regulate gene expression, chromatin compaction and DNA repair. Epigenetics includes mechanisms by which the cell can adapt the cellular response to the environmental conditions. Here, we review the role of epigenetics in the onset of obesity and related metabolic disorders, with special focus on AT. We highlight the importance of nutrients and lifestyle in the regulation of the epigenetic mechanisms and how they can impact on AT plasticity and function in obesity and metabolic diseases. Thus, the epigenetic landscape emerges as a fine‐tune regulator of the cellular responses according to the energetic, metabolic and physiological conditions of the cell. Alterations in metabolic pathways deregulated during obesity and metabolic syndrome could in part explain the disturbances in the epigenetic marks of the AT in these disorders. The understanding of how this epigenetic deregulation may affect AT biology and function could lead to new therapeutic approaches based on epigenetic strategies. [ABSTRACT FROM AUTHOR]

Objective: This cohort study aimed to explore the relationship between the Notch signaling pathway and the degree of nonalcoholic fatty liver disease (NAFLD). Moreover, this study intended to investigate whether this pathway is related to hepatic lipid metabolism and Toll-like receptors (TLRs).Methods: This study used real-time polymerase chain reaction analysis to evaluate the hepatic expression level of all genes studied (Notch receptors NOTCH1, NOTCH2, NOTCH3, and NOTCH4, transcription factors HES1 and HES5, and Hes-related repressor proteins HEY1 and HEY2) in hepatic tissue from two cohorts: women with severe obesity (n = 57) and normal liver structure (n = 20) or NAFLD (n = 37).Results: In women with severe obesity and NAFLD, this study found downregulation of hepatic HES5 expression. This expression correlated positively with the hepatic expression of HES1, HEY1, and NOTCH3. This study also found a positive correlation between HES5 expression and sterol regulatory element-binding protein 1c (SREBP1c) and between NOTCH3 and several genes related to hepatic lipid metabolism (encoding liver X nuclear receptor α variant 1, farnesoid X nuclear receptor, SREBP1c, acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1, carnitine O-octanoyltransferase, ATP-binding cassette subfamily A member 1, and ATP-binding cassette subfamily G member 1). Finally, this study found a positive correlation between NOTCH2 and TLR2, TLR4, and TLR9 and a positive relationship between NOTCH1 and TLR9.Conclusions: Taken together, these findings suggest that hepatic expression of Notch proteins and ligands in relation to lipid metabolism pathways in the liver could have a role in NAFLD pathogenesis. [ABSTRACT FROM AUTHOR]

Classification is a hot topic in Paralympic sport, making the development of evidence‐based and sport‐specific classification systems mandatory. However, the development of measurements for exploring the relationships between the athletes' impairment and their activity limitation is a considerable scientific challenge in team Paralympic sport such as 7‐side football (ie, CP Football). The aims of this study were 1) to describe the activity limitation and external match load (ML) differences among impairment profiles (FT) in international level footballers with cerebral palsy (CPFP) and 2) to analyze the relationship among the activity limitation and external ML variables. Forty‐eight international male CPFP (23 ± 7 y; 174.7 ± 7.2 cm; 69.4 ± 9.2 kg; 22.7 ± 2.6 kg·m−2) participated in this study and were divided according to their impairment profile (FT5/6, FT7, and FT8). Significant differences (P <.05) have been observed among FT profiles in the activity limitation tests (ie, static balance, coordination, vertical jump, horizontal jump, acceleration capacity, and change of direction ability). Additionally, significant differences have been observed among FT profiles in certain ML values (ie, Velmax, High Acc and in Mod and High Dec), where generally, FT8 players reported the best performance values. On the other hand, especially in the FT5/6 and in the FT8 profiles, a large‐to‐very large significant relationship was observed between the CPFP activity limitation and the ML values. In general, the results of the present study show that players with a lower impairment have less activity limitation and better ML. This study concludes that the potential relationships between the impairments of hypertonia, ataxia, or athetosis and performance in this para‐sport might be impairment‐specific. [ABSTRACT FROM AUTHOR]

Summary: Background: Obesity can influence hepatic mitochondrial function, and cause non‐alcoholic steatohepatitis (NASH). Diagnosis and follow‐up rely on invasive liver biopsy so blood‐based markers are urgently required. Aim: To investigate whether values of circulating metabolites from energy and one‐carbon (1‐C) metabolism may: (a) reflect hepatic mitochondrial flexibility failure and (b) act as NASH biomarkers. Methods: Patients with severe obesity undergoing bariatric surgery (n = 270) were investigated using quantitative targeted plasma metabolomics. Comparisons were with non‐obese controls without liver disease (n = 50). Obese patients with NASH (n = 53) and without NASH (n = 130) representing extreme groups of liver disease were assessed to test the diagnostic ability of the measured circulating metabolites. Paired liver biopsy and plasma samples from NASH patients were available 1 year post‐surgery and were evaluated to monitor metabolomic changes with liver damage resolution. Results: We identified correlations between human liver metabolism and obesity. High‐plasma α‐ketoglutarate (α‐KG) and lactate concentrations in NASH patients indicating citric acid cycle replenishment via glutaminolysis might also be a crucial point in NASH onset. Plasma measurements of α‐KG, β‐hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH [area under receiver operating characteristic curve (AUC) of 0.826] and predicted NASH resolution without ambiguity (AUC of 0.999). Conclusion: Changes in plasma mitochondrial metabolites appear to be associated with NASH. These metabolic responses may be dynamically remodelled following resolution of liver damage through massive weight loss. [ABSTRACT FROM AUTHOR]

Objective: Obesity-associated hypoandrogenemia is increasing in parallel to the obesity epidemic. The prevalence of hypoandrogenemia in nondiabetic young men with obesity is not known. This study aimed to evaluate the prevalence of hypoandrogenemia and associated risk factors in this population.Methods: This cross-sectional study included 266 nondiabetic men < 50 years of age with obesity who were referred from primary care. Total testosterone (high-performance liquid chromatography mass spectrometry), sex hormone-binding globulin, free testosterone (FT), luteinizing hormone (LH), high-sensitivity C-reactive protein, and homeostatic model assessment of insulin resistance were determined. Body composition and erectile function were also assessed. Hypoandrogenemia was defined as FT level < 70 pg/mL.Results: Subnormal FT concentrations were found in 25.6% of participants. Hypoandrogenemia prevalence was different along the BMI continuum, being > 75% in individuals with BMI ≥ 50 kg/m2 . A multivariate regression analysis indicated that increasing BMI (P < 0.001), age (P = 0.049), and reduced LH levels (P = 0.003) were independent risk factors for hypoandrogenemia.Conclusions: In a primary care-based cohort of nondiabetic young men with obesity, hypoandrogenemia was a very prevalent finding and was directly associated with adiposity. Obesity, age, and reduced LH levels were independent risk factors associated with hypoandrogenemia. Further prospective studies are needed to evaluate the long-term consequences of hypoandrogenemia in this population. [ABSTRACT FROM AUTHOR]

In many European countries, greater importance is accorded to labour market policies in which employers are involved in activating unemployed people. Such employer‐oriented policies target employers' demand for labour and attempt to influence their willingness to hire, train or guide (often disadvantaged) unemployed groups. Using data from a qualitative interview study of an employer‐oriented programme in a medium‐size city in Sweden, the present article aims to develop knowledge about how these policies are used to influence employers to hire unemployed workers and how jobs created in this context differ from regular jobs. The article argues that creating jobs through new arrangements for the division of labour, with the promise of relieving regular staff of unskilled tasks, may influence employers' willingness to hire the unemployed when used alongside other kinds of policy instruments. However, the article also shows that this new division of labour, with programme participants performing mainly unskilled tasks, has been difficult to realize, as new staff gradually come to perform an increasing number of regular working tasks. [ABSTRACT FROM AUTHOR]

Objective: This study was performed to investigate neurotensin plasma levels in patients with nonalcoholic fatty liver disease (NAFLD) associated with severe obesity.Methods: The plasma levels of neurotensin in 20 women with normal weight and 51 women with morbid obesity (MO) were measured, and women were subclassified according to their hepatic histology as having MO without NAFLD (n = 18) or MO with NAFLD (n = 33). The NAFLD group included 15 women with simple steatosis (SS) and 18 women with nonalcoholic steatohepatitis (NASH). To quantify neurotensin in plasma, a multiplex sandwich immunoassay with a Luminex magnetic bead-based platform was used.Results: Neurotensin levels were significantly decreased (P = 0.001) in women with MO and NAFLD (3.62 ± 0.85 ng/mL), compared with women with MO and normal liver function (11.65 ± 1.95 ng/mL; P = 0.001) and women with normal weight (13.68 ± 2.58 ng/mL; P = 0.001). There was no difference in levels between women with SS and women with NASH (P = 0.415).Conclusions: Circulating levels of neurotensin were decreased in women with NAFLD associated with MO. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to analyse the expression of crucial genes in fatty acid metabolism in visceral (VAT) and subcutaneous (SAT) adipose tissue samples from morbidly obese women. Methods The VAT and SAT expression of key genes in 145 morbidly obese women (MO, BMI > 40 Kg/m2) and 18 normal weight control women by RT-PCR and Western Blot was analyzed. Results In SAT, the expression levels of the genes related to lipogenesis and fatty acid oxidation were significantly lower in MO than in controls. In VAT, most of the lipogenic genes studied had similar expression levels in MO and control cohort. Regarding inflammation, IL6 was significantly higher in MO in both tissues whereas TNFα mRNA expression was significantly higher only in VAT. Conclusions Our results indicate that in morbidly obese patients, lipogenesis and fatty acid oxidation are downregulated in SAT, whereas in VAT these pathways are almost unchanged. By contrast, inflammation is induced in both adipose tissues. It is hypothesized that, in this type of extreme obesity, SAT works to limit any further development of fat mass, decreasing the expression of lipogenic and FA oxidative genes whereas VAT depot might have lost this capability. [ABSTRACT FROM AUTHOR]

Objective Recent studies report the effect of bariatric surgery on glycaemia control and prevention of type-2-diabetes in obese patients. This study is about the pathophysiological mechanisms associated to these changes. Design and Methods Circulating levels of receptors of tumor necrosis factor (TNF-RI, TNF-RII), visfatin, high molecular weight (HMW) adiponectin, and C reactive protein (CRP) in 30 morbidly obese women (body mass index, BMI>40 kg/m2) and 60 normal-weight controls (BMI>25 kg/m2) were analyzed. Morbidly obese were studied at three time-points: before surgery (baseline), and 6 and 12 months after. Results After surgery, the levels of TNF-RI, TNF-RII, visfatin, and CRP were significantly lower than its baseline levels, whereas HMW adiponectin was higher. Fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA2-IR) levels were markedly lower postoperatively. High density lipoproteins (HDL) moderately increased, and triglyceride levels had sharply decreased. The study of the predictive value of variables indicated that preoperative levels of TNF-RI and visfatin correlated positively with levels of glucose, insulin, glycosylated hemoglobin A1c, and HOMA2-IR postoperatively, whereas adiponectin levels correlated negatively. Baseline CRP levels negatively linked to HDL and TNF-RII positively to triglyceride. Conclusions The preoperative profile with high levels of proinflammatory adipocytokines is linked to smaller improvements in glucose homeostasis and lipid factors. The use of a range of biomarkers may predict the level of metabolic changes following bariatric surgery. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis The antitussive properties of ( ±) baclofen on laryngeal muscle activities have not been determined. The hypothesis of this study was that administration of ( ±) baclofen would suppress upper airway muscle motor activity in a dose-dependent manner during cough. Study Design This is a prospective, preclinical, hypothesis-driven, paired design. Methods Electromyograms of the parasternal, rectus abdominis, thyroarytenoid, posterior cricoarytenoid, and thyrohyoid were measured, along with esophageal pressure. Cough was elicited by mechanical stimulation of the lumen of the intrathoracic trachea in spontaneously breathing cats. Results Baclofen ( ±) (3-10 μg kg−1 i.a.) induced decreases in the electromyogram amplitude of the rectus abdominis motor drive during coughing, the inspiratory and active expiratory (E1) phases of cough, and cough number per epoch. There was no effect of ( ±) baclofen on the EMG amplitudes of any of the laryngeal muscles, the parasternal, or the duration of the passive expiratory (E2) phase. Conclusions Results from the present study indicate differential control mechanisms for laryngeal and inspiratory motor drive during cough, providing evidence of a control system regulating laryngeal activity and inspiratory spinal drive that is divergent from the control of expiratory spinal motoneurons. Level of Evidence N/A. Laryngoscope, 123:3088-3092, 2013 [ABSTRACT FROM AUTHOR]

RATIONALE Polyethylene glycols (PEGs) are soluble molecules utilized in a wide range of applications. Mass spectrometry and fragmentation patterns of positively charged PEG oligomers are well-known, but decomposition mechanisms of the deprotonated ions have not been studied. METHODS Deprotonated PEGs were generated by electrospray ionization of PEG in water/acetonitrile. Collision-induced dissociation (CID) experiments were carried out in a tandem mass spectrometer. The anions were studied using a tandem mass spectrometer to carry out CID experiments. A series of small PEG oligomers, with 1 to 8 monomer units, were studied in order to monitor size-dependent effects on fragmentation reactions. RESULTS Because deprotonated PEG ions have a unique charge site, their dissociation pathways can easily be monitored. The ions fragment by loss of C2H4O monomer units, with an alternating intensity pattern that suggests the loss of an even number of monomer units is favored. Smaller oligomers and oligomer fragments also yielded fragments corresponding to H2 elimination and H2O loss. H2 elimination occurs by the generation of a hydride ion which deprotonates an alcohol upon leaving, while dehydration appears to be a charge-remote process. CONCLUSIONS The fragmentation of deprotonated PEG is dominated by intramolecular SN2 reactions involving the terminal oxide anion. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

RATIONALE Polyethylene glycols (PEGs) are soluble molecules utilized in a wide range of applications. Mass spectrometry and fragmentation patterns of positively charged PEG oligomers are well-known, but decomposition mechanisms of the deprotonated ions have not been studied. METHODS Deprotonated PEGs were generated by electrospray ionization of PEG in water/acetonitrile. Collision-induced dissociation (CID) experiments were carried out in a tandem mass spectrometer. The anions were studied using a tandem mass spectrometer to carry out CID experiments. A series of small PEG oligomers, with 1 to 8 monomer units, were studied in order to monitor size-dependent effects on fragmentation reactions. RESULTS Because deprotonated PEG ions have a unique charge site, their dissociation pathways can easily be monitored. The ions fragment by loss of C2H4O monomer units, with an alternating intensity pattern that suggests the loss of an even number of monomer units is favored. Smaller oligomers and oligomer fragments also yielded fragments corresponding to H2 elimination and H2O loss. H2 elimination occurs by the generation of a hydride ion which deprotonates an alcohol upon leaving, while dehydration appears to be a charge-remote process. CONCLUSIONS The fragmentation of deprotonated PEG is dominated by intramolecular SN2 reactions involving the terminal oxide anion. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Early investigations of protonated polyethylene glycol fragmentation suggested the dissociation mechanism includes both direct and sequential processes. Experiments designed to study the proposed mechanisms of sequential dissociation are absent from the literature. In order to obtain additional experimental details about the fragmentation reactions, the dissociation of protonated polyethylene glycol was studied by energy-dependent collision-induced dissociation (CID). Key fragment ions were separated by mass differences corresponding to the loss of single monomer units. Several fragment ions were also generated by in-source fragmentation and studied by CID. These experiments indicate the primary ions undergo sequential dissociation by the loss of either one or two monomer units. The results suggest that at least two different mechanisms must be considered to explain the sequential dissociation of protonated polyethylene glycols. The reaction involving the elimination of two subunits suggests the loss of a six-membered 1,4-dioxane product, while the elimination of a single subunit involves the loss of acetaldehyde by a 1,2-hydride shift rearrangement. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: We aimed to analyze the retinol binding protein-4 (RBP4) messenger RNA (mRNA) expression profiles in adipose tissues and liver of morbidly obese (MO) women with or without nonalcoholic fatty liver disease (NAFLD), and to study the relationships with other pro- and anti-inflammatory adipokines in vivo and in vitro. Design and Methods: We performed a cross-sectional analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver samples from four lean and 45 MO women with or without NAFLD by enzyme-linked immunosorbent assay and real-time reverse transcription-PCR. We also studied RBP4 expression in HepG2 hepatocytes under various inflammatory stimuli. Results: Circulating RBP4 levels were higher in MO women, and specifically, in MO subjects with NAFLD compared with normal liver controls (lean and MO). RBP4 liver expression was higher in nonalcoholic steatohepatitis (NASH)-moderate/severe than in NASHmild. Overall RBP4 gene expression was higher in liver than in adipose tissues. Among them, the higher expression corresponded to SAT. VAT expression was lower in the MO cohort. In HepG2, RBP4 mRNA expression was reduced by tumor necrosis factor (TNF)-α and increased by adiponectin treatment. Conclusions: The results obtained in MO women with NAFLD, brings up the use of RBP4 and other adipokines as a panel of noninvasive molecular biomarkers when NAFLD is suspected. Further studies are needed with other obesity groups. [ABSTRACT FROM AUTHOR]

Objective The controversial results on the physiopathological role of visfatin led us to examine both circulating visfatin levels and gene expression in visceral (VAT) and subcutaneous fat (SAT) in a homogeneous group of morbidly obese women. Design, patients and measurements We analysed circulating levels of several adipo/cytokines in 133 Spanish women: 40 lean (C) [body mass index (BMI) < 25 kg/m2] and 93 morbidly obese (MO) (BMI > 40 kg/m2). In the MO group, we found 31 diabetic and 62 nondiabetic subjects. We obtained follow-up blood samples at 6 and 12 months after bariatric surgery from 30 MO patients. We determined the circulating levels of visfatin, adiponectin, interleukin-6 (IL6), C-reactive protein (CRP), resistin and tumour necrosis factor-α (TNFα) by ELISA, and visfatin, adiponectin, IL6, resistin and TNFα gene expression in SAT and VAT by real-time RT-PCR. Results Circulating visfatin levels were higher in MO women compared with lean controls (C = 1·43 ± 0·14 μg/l, MO = 3·60 ± 0·29 μg/l, P < 0·001). After bariatric surgery-induced weight loss, visfatin levels were reduced significantly over 12 months. Visfatin expression in SAT and VAT was similar, but significantly higher in MO compared to C and independent of the presence of diabetes mellitus. Circulating visfatin levels were positively related to IL6 and CRP levels. Visfatin gene expression in VAT and SAT was strongly related to IL6 and TNFα expression. Conclusion In a homogeneous cohort of morbidly obese women, our findings show that visfatin has a strong relationship with pro-inflammatory factors in severe obesity. [ABSTRACT FROM AUTHOR]

Because the role of lipocalin 2 (LCN2) in morbid obesity is still not well defined, the aim of this study was to evaluate the circulating levels and the expression of LCN2 in visceral (VAT) and subcutaneous adipose tissue (SAT) in severely obese (SO) women. We also analyzed its relationship with inflammatory cytokines in the same subjects. The study comprised 90 white women, 39 of whom were lean controls (BMI ≤25 kg/m2) and 51 SO (BMI ≥40 kg/m2). Both circulating and adipose tissue levels of LCN2 were quantified by enzyme-linked immunosorbent assays. LCN2 mRNA levels from VAT and SAT were assessed by real-time reverse transcriptase-PCR (n = 60). LCN2 serum levels were significantly higher in the SO women than in the lean controls (P = 0.042), and were found to be strongly correlated with tumor necrosis factor receptor I (TNFR1) circulating levels. In the SO cohort, LCN2 serum levels were also associated with higher BMI values, but not with the homeostasis model assessments of insulin resistance (HOMA2-IR). LCN2 mRNA expression was markedly higher in SO women than in lean women in both VAT (P = 0.043) and SAT (P = 0.031). In SAT, LCN2 was negatively correlated with adiponectin and adiponectin receptor-2 expression, and positively with interleukin-6 (IL-6) expression. A strong positive correlation was also found between LCN2 expression and the mean diameter of adipocytes in VAT. Our results revealed that the circulating level of LCN2 is associated with obesity and BMI. LCN2 mRNA is over-expressed in adipose tissue from SO subjects. Finally, the expression of LCN2 is strongly related to an expression profile of proinflammatory cytokines but not to insulin resistance in nondiabetic SO women. [ABSTRACT FROM AUTHOR]

Background The paraoxonase (PON) enzyme family comprising PON1, PON2 and PON3 are antioxidant enzymes that degrade bioactive oxidised lipids and are thus antiatherogenic. Materials and methods We investigated the localisation of the PON proteins during the development of atherosclerosis by immunohistochemical analysis. Results In normal aortas, PON1 and PON3 were localised to smooth muscle cells (SMC) and endothelial cells. PON3 staining was stronger than that of PON1. During atherosclerosis development, SMC staining for PON1 and PON3 was greatly reduced, while macrophage staining for both proteins increased with PON1 predominating. Macrophage staining for PON1 and PON3 was significantly and positively related to the amount of aortic inflammation (both P < 0·001). Conclusions Our data add support to the growing body of evidence for a cellular protective effect of PON1 and PON3 against the proinflammatory / proatherosclerotic effects of lipid peroxidation. [ABSTRACT FROM AUTHOR]

The efficacy of deferoxamine, deferiprone, and a combination of these chelating agents in the mobilization and promotion of aluminium (Al) excretion was compared in two age groups of uraemic rats which had previously received Al nitrate nonahydrate intraperitoneally in a daily dose of 45 mg/kg for 5 weeks. At the end of the period of Al exposure, Al-loaded rats of each age (young and adult) group were given one of the following treatments for 5 days: 0.90 mmol/kg/day of deferoxamine (subcutaneously), 0.90 mmol/kg/day of deferiprone (orally), and 0.45 mmol/kg/day of deferoxamine (subcutaneously) plus 0.45 mmol/kg/day of deferiprone (orally). Control rats were given 0.9% saline (subcutaneously) and deionized water (orally). Total urines were collected 24 hr after each chelator administration. Although young rats treated with deferoxamine, deferiprone, or deferoxamine plus deferiprone showed significant increases in the total amount of Al excreted into urine during 5 consecutive days, the effect of combined administration of deferoxamine and deferiprone was lower than that caused by deferoxamine or deferiprone only. On the other hand, after administration of deferoxamine and deferiprone, a significant reduction of Al was noted only in the liver of young rats, while no significant effects of the chelators were seen in any of the examined tissues of adult animals. The results of the current study show that a combined therapy with deferoxamine and deferiprone (at half-doses of each drug) can also be effective in mobilizing Al from the body of Al-loaded uraemic rats. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Limitations Conclusion Consensus is lacking on adequate deep histological margins in cutaneous squamous cell carcinoma (cSCC). Deep clearance for tumours located on the scalp is limited by anatomic constraints.To determine whether clear but close deep histological margins (<1 mm) confer a higher risk of recurrence in cSCCs of the scalp treated by wide local excision, compared to deep histological margins ≥1 mm.Multicentre retrospective observational cohort study and multivariate competing risk analysis to evaluate risk factors for recurrence.In total, 295 patients with 338 cSCCs were included. Close deep histological margins were not associated with an increased cumulative incidence of recurrence (subhazard ratio [SHR] 1.96 [95% CI 0.87–4.41]). However, an increased risk of recurrence was observed for those tumours that presented concurrent invasion of the galea aponeurotica and close deep margins, as opposed to patients without these factors (SHR 3.52 [1.24–10.01]). Tumours with clear but close peripheral margins (<1 mm) also had higher risk of recurrence (SHR 5.01 [1.68–14.97]).Retrospective observational study based on pathology reports.Deep histological margins <1 mm do not confer a greater risk of recurrence as long as the tumour is completely excised and the galea aponeurotica is not involved. Surgical excision of cSCC on the scalp should include the galea to ensure proper assessment of deep margins. [ABSTRACT FROM AUTHOR]

Background: Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, this role is considered relegated to side‐effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO‐inhibitory treatments in patients with psychiatric disease. Methods: In the present work we have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m2 and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml. Results: MAOB rs3027452‐A allele carriers were significantly over‐represented among hypertensive (HT) patients (25.49%) in comparison to either the non‐HT patients (10%, OR = 3.079 CI95 [1.364–6.952], p =.005, Chi‐square test) and the control population series of nonobese nor hypogonadic males (also 10%, p =.003 Chi‐square test). Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics (Beta = 3.653, p =.005). When quantitative analysis was performed, hypertensive patients harboring rs3027452‐A allele showed higher systolic blood pressure values (p =.038, Mann–Whitney U‐test) as well as an increased Systolic‐Diastolic range despite following HT treatment (∆mmHg 54 vs. 48 for rs3027452‐A and rs3027452‐G respectively, p‐value.019, Mann–Whitney U‐test). Previous studies on MAOB revealed that rs3027452‐A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation. Conclusion: If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension. [ABSTRACT FROM AUTHOR]