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Objective: To construct and validate an assessment instrument to evaluate the feet of people with diabetes mellitus in Brazil., Methods: Methodological research developed in three stages: construction of the Assessment Instrument for the Feet of People with Diabetes Mellitus, validation of face and content validity, and field research with 131 participating patients. The Pearson (r) and Spearman correlation coefficients (ρ) were used for criterion validity. To test reliability, the internal consistency of the Cronbach α domains was evaluated and simple κ, weighted κ, and intraclass correlation coefficients for interobserver evaluation were determined., Results: The instrument demonstrated validity and reliability. The content validity index represented a high internal consistency (α > .70). The interclass correlation coefficient was high (>0.98). The Pearson (r) and Spearman (ρ) correlation tests confirmed a correlation between the two variables., Conclusions: The instrument was valid and reliable for assessing the feet of people with diabetes mellitus in Brazil. Future studies should identify the cut off point for the diagnosis of neuropathic and vascular impairment of the feet of diabetic persons through appropriate statistical methods.

One of the causes of foodborne diseases is contamination during food preparation; food handlers carrying pathogens might be involved in the origin of this condition. This problem is more serious in health care facilities, since consumers of contaminated food are already ill. Therefore, operational procedures should be formulated to prevent incidents. We performed a review of scientific studies, legislation and regulations on this subject. The results indicate that the main causes of food contamination involving food handlers to be considered in strategies to reduce, or even eliminate foodborne diseases include: flaws in hand hygiene, intestinal parasites, lack of knowledge of good manufacturing practices (GMP) and of the etiologic agents of foodborne diseases, and lack of GMP monitoring. We conclude that standardized operational procedures should be developed, including clear and objective flowcharts (suggested here) to be managed by the safety and occupational medicine staff, in addition to providing training to food handlers on GMP and correct use of personal protective equipment and work clothes.

In Europe at present, but also in 2040, 1 in 3 cancer-related deaths are expected to be caused by digestive cancers. Endoscopic technologies enable diagnosis, with relatively low invasiveness, of precancerous conditions and early cancers, thereby improving patient survival. Overall, endoscopy capacity must be adjusted to facilitate both effective screening programs and rigorous control of the quality assurance and surveillance systems required. 1 : For average-risk populations, ESGE recommends the implementation of organized population-based screening programs FOR COLORECTAL CANCER: , based on fecal immunochemical testing (FIT), targeting individuals, irrespective of gender, aged between 50 and 75 years. Depending on local factors, namely the adherence of the target population and availability of endoscopy services, primary screening by colonoscopy or sigmoidoscopy may also be recommendable. 2 : In high-risk populations, endoscopic screening FOR GASTRIC CANCER: should be considered for individuals aged more than 40 years. Its use in countries/regions with intermediate risk may be considered on the basis of local settings and availability of endoscopic resources. 3 : For esophageal and pancreatic cancer, endoscopic screening may be considered only in high-risk individuals:- FOR SQUAMOUS CELL CARCINOMA: , in those with a personal history of head/neck cancer, achalasia, or previous caustic injury; - FOR BARRETT'S ESOPHAGUS (BE)-ASSOCIATED ADENOCARCINOMA: , in those with long-standing gastroesophageal reflux disease symptoms (i. e., > 5 years) and multiple risk factors (age ≥ 50 years, white race, male sex, obesity, first-degree relative with BE or esophageal adenocarcinoma [EAC]). - FOR PANCREATIC CANCER SCREENING: , endoscopic ultrasound may be used in selected high-risk patients such as those with a strong family history and/or genetic susceptibility., Competing Interests: R. Bisschops has received research grants from Pentax, Fujifilm, Cook, and Medtronic; he has been/is on advisory boards for Pentax, Fujifilm, Cook, Boston Scientific, Medtronic, and CDX Diagnostic; he has been a speaker for Pentax, Fujifilm, Medtronic, and Medivators; he has received organizational support for educational events from Pentax, and organizational and financial support for educational events from Cook, Boston Scientific, Medtronic, Erbe, and Olympus. E. Dekker has received honoraria from Fujifilm, Olympus, Tillots, and GI Supply, and speaker’s fees from CPP-FAP and Olympus; she is a Co-Editor of Endoscopy journal. H. Messmann has received, in the past 3 years: grants from the Falk Foundation, Olympus, Roche, Bayer, MSD, Novartis, and Amgen; honoraria from the Falk Foundation, Olympus, and Covidien; consultation fees from Lumendi, Boston Scientific, Erbe, and Olympus; and research support from Olympus (ESD-Register). A. Saftoiu has received lecture fees from Pentax Medical Singapore (2016–2019); his department at Ponderas Academic Hospital received 3000 FIT tests (pilot colorectal cancer screening) from Johnson and Johnson (2019–2020). P.D. Siersema is receiving research support from Pentax (2018–2021) and Yakult (2017–2020); his department is receiving research support from The eNose Company (2019–2021); he is Editor-in-Chief of Endoscopy journal. T. Ponchon is providing consultancy to Olympus, Norgine, Ipsen, and Alfa Sigma (from 1 January 2019 to present); his department is receiving research funding from Boston Scientific. J.E. van Hooft has received lecture fees from Medtronics (2014–2015, 2018) and Cook Medical (2019), and consultancy fees from Boston Scientific (2014–2017); her department has received research grants from Cook Medical (2014–2018) and Abbott (2014–2017). G. Antonelli, M. Areia, M.S. Bhutani, E. Bories, R. Capocaccia, I.M. Cazacu, P.H. Deprez, M. Dinis-Ribeiro, C. Hassan, S.P. Pereira, and C. Senore declare no competing interests., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The use of ultrasound for localized fat treatment on possible psychological influences is little explored to date. Therefore, it is relevant to elaborate studies that include a placebo group in order to measure the real effects of the exclusive application of ultrasound., Objectives: To verify the influence of ultrasound application for localized fat treatment on clinical, functional, and psychological outcomes., Methods: Thirty female participants who were candidates for localized abdominal fat treatment were included and randomly divided into three groups: control (CG, n = 10), experimental (EG, n = 10), and placebo (PG, n = 10). The CG did not receive any intervention. The EG received 10 ultrasound sessions for 20 minutes. For the PG, ultrasound was also applied for 20 minutes, but with zero intensities. Anthropometric assessment, cardiovascular parameters, circumference measurements, photography, endurance test, and subjective questionnaires were performed before and after the treatment protocols., Results: The EG photographs show an improvement of 60% in the visual appearance. Regarding the other analyzed outcomes, no statistically significant differences were found between moments and groups ( P > 0.05)., Conclusions: Pretreatment and posttreatment photographs analysis demonstrate visual improvement in the appearance of abdominal localized fat in the EG. However, ultrasound application, when compared with CG and PG, is not a superior method for improving clinical, functional, and psychological parameters., (© 2020 The Aesthetic Society.)

Parkinson's Disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra. The exact mechanism by which dopaminergic neurodegeneration occurs is still unknown; however, mitochondrial dysfunction has long been implicated in PD pathogenesis. To investigate the sub-cellular events that lead to disease progression and to develop personalized interventions, non-neuronal cells which are collected in a minimally invasive manner can be key to test interventions aimed at improving mitochondrial function. We used human skin fibroblasts from sporadic PD (sPD) patients as a cell proxy to detect metabolic and mitochondrial alterations which would also exist in a non-neuronal cell type. In this model, we used a glucose-free/galactose- glutamine- and pyruvate-containing cell culture medium, which forces cells to be more dependent on oxidative phosphorylation (OXPHOS) for energy production, in order to reveal hidden metabolic and mitochondrial alterations present in fibroblasts from sPD patients. We demonstrated that fibroblasts from sPD patients show hyperpolarized and elongated mitochondrial networks and higher mitochondrial ROS concentration, as well as decreased ATP levels and glycolysis-related ECAR. Our results also showed that abnormalities of fibroblasts from sPD patients became more evident when stimulating OXPHOS. Under these culture conditions, fibroblasts from sPD cells presented decreased basal respiration, ATP-linked OCR and maximal respiration, and increased mitochondria-targeting phosphorylation of DRP1 when compared to control cells. Our work validates the relevance of using fibroblasts from sPD patients to study cellular and molecular changes that are characteristic of dopaminergic neurodegeneration of PD, and shows that forcing mitochondrial OXPHOS uncovers metabolic defects that were otherwise hidden., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests None

To increase the efficiency of enzyme cocktails in deconstructing cellulose and hemicelluloses present in the plant cell wall, a combination of enzymes with complementary activities is required. Xylan is the main hemicellulose component of energy crops and for its complete hydrolysis a system consisting of several enzymes acting cooperatively, including endoxylanases (XYN), β-xylosidases (XYL) and α-l-arabinofuranosidases (ABF) is necessary. The current work aimed at evaluating the effect of recombinant hemicellulolytic enzymes on the enzymatic hydrolysis of steam-exploded sugarcane bagasse (SEB). One recombinant endoxylanase (HXYN2) and one recombinant β-xylosidase (HXYLA) from Humicola grisea var thermoidea, together with an α-l-arabinofuranosidase (AFB3) from Penicillium pupurogenum, all produced in Pichia pastoris, were used to formulate an efficient enzyme mixture for SEB hydrolysis using a 2 3 Central Composite Rotatable Design (CCRD). The most potent enzyme for SEB hydrolysis was ABF3. Subsequently, the optimal enzyme mixture was used in combination with commercial cellulases (Accellerase 1500), either simultaneously or in sequential experiments. The supplementation of Accellerase 1500 with hemicellulases enhanced the glucose yield from SEB hydrolysis by 14.6%, but this effect could be raised to 50% when hemicellulases were added prior to hydrolysis with commercial cellulases. These results were supported by scanning electron microscopy, which revealed the effect of enzymatic hydrolysis on SEB fibers. Our results show the potential of complementary enzyme activities to improve enzymatic hydrolysis of SEB, thus improving the efficiency of the hydrolytic process., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Pancreatic cystic lesions (PCL) are being detected with increasing frequency. Current methods of stratifying risk of malignant transformation are imperfect. This study aimed to determine the frequency of pancreatic malignancy in patients with PCL and define clinical and radiological features that predict malignant transformation in patients managed by surgery and/or surveillance. Methods: A retrospective cohort of adults who were evaluated in a tertiary hepatopancreaticobiliary centre between January 2000 - December 2013 with a confirmed PCL and followed up for at least 5 years. All cystic lesions were discussed at a weekly multidisciplinary meeting. Results: Of the 1,090 patients diagnosed with a PCL, 768 patients were included in the study: 141 patients were referred for immediate pancreatic resection, 570 entered surveillance while 57 had a malignant PCL which was unresectable at diagnosis (n=47) or were unfit for surgery (n=10). In those who were resected following presentation, malignancy was present in 38%. During follow-up 2% of those entering a surveillance programme underwent malignant transformation. Clinical and radiological features associated with a high-risk PCL included older age, symptoms, associated solid component or dilated main pancreatic duct. In intraductal papillary mucinous neoplasms, larger size was not a feature of malignant transformation (benign vs. malignant 30mm vs. 23mm; P= 0.012). Conclusion: The sensitivity of standard diagnostic tests leading to immediate surgery for high-risk PCL (malignant or mucinous) was 92% but with a specificity of just 5%. Surveillance of PCL without high-risk features within a multidisciplinary meeting was associated with a low incidence of cancer development, supporting the use of worrisome clinical and radiological features in the initial stratification of PCL., Competing Interests: No competing interests were disclosed.

Effect of sonication on the quality parameters of juçara, banana and strawberry smoothie was evaluated using a rotational central composite design with power (73.5-250.0 W) and time (7-36 min) as independent variables. The sonicated smoothie was evaluated regarding anthocyanins, instrumental color and rheological and physicochemical parameters. Within the evaluated processing conditions, 86% of anthocyanins were retained. The pH and acidity of the smoothie wasn't affected by the independent variables. Regarding instrumental color parameters, only luminosity was affected by the operational conditions. The cavitation phenomenon decreased the apparent viscosity of the smoothie. The sonicated smoothie presented non-Newtonian behavior, with characteristics of a pseudoplastic fluid (n < 1) in all treatments and control. Taking into account that the highest anthocyanin retention was observed at 147 W for 2 min, this condition was the most recommended for the processing of the product., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Association of Food Scientists & Technologists (India) 2019.)

During antiretroviral therapy (ART), human immunodeficiency virus type 1 (HIV-1) persists as a latent reservoir in CD4 + T cell subsets in central memory (T CM ), transitional memory (T TM ), and effector memory (T EM ) CD4 + T cells. We have identified differences in mechanisms underlying latency and responses to latency-reversing agents (LRAs) in ex vivo CD4 + memory T cells from virally suppressed HIV-infected individuals and in an in vitro primary cell model of HIV-1 latency. Our ex vivo and in vitro results demonstrate the association of transcriptional pathways of T cell differentiation, acquisition of effector function, and cell cycle entry in response to LRAs. Analyses of memory cell subsets showed that effector memory pathways and cell surface markers of activation and proliferation in the T EM subset are predictive of higher frequencies of cells carrying an inducible reservoir. Transcriptional profiling also demonstrated that the epigenetic machinery (known to control latency and reactivation) in the T EM subset is associated with frequencies of cells with HIV-integrated DNA and inducible HIV multispliced RNA. T CM cells were triggered to differentiate into T EM cells when they were exposed to LRAs, and this increase of T EM subset frequencies upon LRA stimulation was positively associated with higher numbers of p24 + cells. Together, these data highlight differences in underlying biological latency control in different memory CD4 + T cell subsets which harbor latent HIV in vivo and support a role for differentiation into a T EM phenotype in facilitating latency reversal. IMPORTANCE By performing phenotypic analysis of latency reversal in CD4 + T cells from virally suppressed individuals, we identify the T EM subset as the largest contributor to the inducible HIV reservoir. Differential responses of memory CD4 + T cell subsets to latency-reversing agents (LRAs) demonstrate that HIV gene expression is associated with heightened expression of transcriptional pathways associated with differentiation, acquisition of effector function, and cell cycle entry. In vitro modeling of the latent HIV reservoir in memory CD4 + T cell subsets identify LRAs that reverse latency with ranges of efficiency and specificity. We found that therapeutic induction of latency reversal is associated with upregulation of identical sets of T EM -associated genes and cell surface markers shown to be associated with latency reversal in our ex vivo and in vitro models. Together, these data support the idea that the effector memory phenotype supports HIV latency reversal in CD4 + T cells., (Copyright © 2019 Kulpa et al.)

The synthesis of support materials with suitable coordination sites and confined structures for the controlled growth of ultrasmall metal nanoparticles is of great importance in heterogeneous catalysis. Here, by rational design of a cross-linked β-cyclodextrin polymer network (CPN), various metal nanoparticles (palladium, silver, platinum, gold, and rhodium) of subnanometer size (<1 nm) and narrow size distribution are formed via a mild and facile procedure. The presence of the metal coordination sites and the network structure are key to the successful synthesis and stabilization of the ultrasmall metal nanoparticles. The as-prepared CPN, loaded with palladium nanoparticles, is used as a heterogeneous catalyst and shows outstanding catalytic performance in the hydrogenation of nitro compounds and Suzuki-Miyaura coupling reaction under mild conditions. The CPN support works synergistically with the metal nanoparticles, achieving high catalytic activity and selectivity. In addition, the catalytic activity of the formed catalyst is controllable., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

In the present work, the bioaccessibility of the main phenolic compounds of a juçara, banana and strawberry homogenized smoothie (control), subjected to pasteurization and sonication, was evaluated. The smoothie was also evaluated in terms of its main chemical and physical characteristics. Pasteurized smoothie showed higher apparent viscosity, as well as higher initial shear stress when compared to the control and sonicated samples. The increase in the apparent viscosity of the pasteurized smoothie was associated with the smaller particle size of this sample (68 μm). These characteristics conferred to the pasteurized smoothie higher physical stability than the control and sonicated smoothies. Phenolic compounds bioaccessibility was higher in the pasteurized and sonicated smoothies than in the control sample, which confirmed the positive effect of the treatments for the preservation of these compounds after gastrointestinal digestion. Compared to the sonication process, the pasteurization provided higher total phenolic compounds bioaccessibility (47%), as well as of ferulic (16%) and ellagic (80%) acids. Antioxidant capacity was higher in gastric digest for all the samples evaluated by ABTS assay. These results confirm the importance of processing on the physical stability and phenolic compounds bioaccessibility of the juçara-based smoothie, standing out the thermally treated product., (© Association of Food Scientists & Technologists (India) 2019.)

Background and study aims  Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) as a method of obtaining preoperative diagnosis of pancreatic neuroendocrine tumors (PanNETs) has been reported in several series. Fine-needle biopsies (FNB) are increasingly employed to obtain core specimens during EUS. However, the differences in efficacy between these sampling methods in the diagnosis of PanNETs still needs to be defined. Patients and methods  Over a 13-year period, all patients who underwent EUS-guided tissue sampling of suspicious pancreatic lesions with clinical, endoscopic and pathologic details were entered into an electronic database. Lesions underwent EUS-FNA or FNB sampling, or a combination of the two. The accuracy and safety of different EUS-guided sampling methods for confirmed PanNETs were investigated. Results  A total of 91 patients (M/F: 42/49, median age: 57 years), who underwent 102 EUS procedures had a final diagnosis of PanNET. Both EUS-guided sampling modalities were used in 28 procedures, EUS-FNA alone was used in 61 cases, while EUS-FNB alone in 13 cases. Diagnostic yield of EUS-FNA and EUS-FNB alone, including the inadequate specimens, was 77.5 % (95 %CI: 68.9 - 86.2 %) and 85.4 % (95 %CI: 74.6 - 96.2 %), respectively. The combination of both sampling modalities established the diagnosis in 96.4 % of cases (27/28) (95 %CI: 89.6 - 100 %), significantly superior to EUS-FNA alone ( P  = 0.023). Diagnostic sensitivity among the adequate samples for EUS-FNA, EUS-FNB and for the combination of the two methods was 88.4 % (95 %CI: 80.9 - 96.0 %), 94.3 % (95 %CI: 86.6 - 100 %) and 100 % (95 %CI: 100 - 100 %). There was one reported complication, a post-FNA bleeding, treated conservatively. Conclusions  EUS-FNB improves diagnostic sensitivity and confers additional information to cytological assessment of PanNETs.

Purpose: To analyze how students with Language Disorders receive remedial teaching in inclusive settings in Portugal., Methods: We developed a questionnaire based on the literature review, and applied it to 123 elementary teachers in Portugal. We performed a descriptive and inferential statistical analysis of the dependent variables using parametric tests., Results: Descriptive analysis revealed that most teachers know the concept of language disorders and consider it important to the development of language when supporting students with this problem. However, over half of the respondents answered that they have no training and enough information about the acquisition and development of language, and don´t consider having sufficient knowledge to contribute to the identification of students with language disorders. Results for inferential statistics showed statistically significant differences regarding gender; length of service and district, as well as a good internal consistency in relation to the questionnaire., Conclusion: Results highlight the need for training and information about acquisition and development of language, and more specifically in relation to language disorders. It also showed that elementary teachers may find difficulties in intervention with students with language disorders, and particularly, to adequate strategies to their needs, particularly when developing Individualized Educational Programs for their students in a team.

Background: Zika virus infections and suspected microcephaly cases have been reported in Angola since late 2016, but no data are available about the origins, epidemiology, and diversity of the virus. We aimed to investigate the emergence and circulation of Zika virus in Angola., Methods: Diagnostic samples collected by the Angolan Ministry of Health as part of routine arboviral surveillance were tested by real-time reverse transcription PCR by the Instituto Nacional de Investigação em Saúde (Ministry of Health, Luanda, Angola). To identify further samples positive for Zika virus and appropriate for genomic sequencing, we also tested samples from a 2017 study of people with HIV in Luanda. Portable sequencing was used to generate Angolan Zika virus genome sequences from three people positive for Zika virus infection by real-time reverse transcription PCR, including one neonate with microcephaly. Genetic and mobility data were analysed to investigate the date of introduction and geographical origin of Zika virus in Angola. Brain CT and MRI, and serological assays were done on a child with microcephaly to confirm microcephaly and assess previous Zika virus infection., Findings: Serum samples from 54 people with suspected acute Zika virus infection, 76 infants with suspected microcephaly, 24 mothers of infants with suspected microcephaly, 336 patients with suspected dengue virus or chikungunya virus infection, and 349 samples from the HIV study were tested by real-time reverse transcription PCR. Four cases identified between December, 2016, and June, 2017, tested positive for Zika virus. Analyses of viral genomic and human mobility data suggest that Zika virus was probably introduced to Angola from Brazil between July, 2015, and June, 2016. This introduction probably initiated local circulation of Zika virus in Angola that continued until at least June, 2017. The infant with microcephaly in whom CT and MRI were done had brain abnormalities consistent with congenital Zika syndrome and serological evidence for Zika virus infection., Interpretation: Our analyses show that autochthonous transmission of the Asian lineage of Zika virus has taken place in Africa. Zika virus surveillance and surveillance of associated cases of microcephaly throughout the continent is crucial., Funding: Royal Society, Wellcome Trust, Global Challenges Research Fund (UK Research and Innovation), Africa Oxford, John Fell Fund, Oxford Martin School, European Research Council, Departamento de Ciência e Tecnologia/Ministério da Saúde/National Council for Scientific and Technological Development, and Ministério da Educação/Coordenação de Aperfeicoamento de Pessoal de Nível Superior., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Indigofera suffruticosa Mill (Fabaceae) is abundant in northeastern Brazil and popularly used in the treatment of infectious and inflammatory processes. Several biological properties, such as anti-inflammatory, anticancer, antitumor, hepatoprotective and low toxicity, are reported for this plant., Objective: This study investigated hepatoprotective activity and the antioxidant effect of methanolic extract of I. suffruticosa leaves (MEIS) on Swiss albino mice submitted to experimental models of acetaminophen-induced liver injury., Methods: MEIS (50 mg/kg; p.o.) was standardized according to the LD50 and its hepatoprotective property on Swiss albino mice evaluated during a 7-day period. On the eighth day, the acetaminophen-induced hepatic injury was performed. Histomorphometric analysis of liver tissue, antioxidant activity and serum levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT) and bilirubin were measured., Results: MEIS (50 mg/kg; p.o.) restored serum enzyme levels and results were close to those of positive control (silymarin) when compared to the negative control. Histopathological and histomorphometric analyzes confirmed MEIS hepatoprotective activity, showing reorganization of structural units of cells, nuclei and sinusoidal capillaries of hepatocytes, reducing the damage on liver tissue and increasing organ regeneration rate. MEIS showed high antioxidant potential at concentrations of 1000 and 500 µg/mL., Conclusion: This study suggests that MEIS has hepatoprotective activity and high antioxidant potential.

Objective: Current surveillance strategies for duodenal adenomatosis in familial adenomatous polyposis (FAP) miss malignancies and underestimate cancer risk in ampullary disease. This study aimed to evaluate the utility of endoscopic ultrasound (EUS) in the assessment of FAP patients with duodenal and/or ampullary polyposis referred for surgical intervention., Design: A retrospective analysis of FAP patients undergoing index EUS between December 2006 and May 2015 was performed. Follow-up was completed in January 2018, including review of all EUS procedures and surgical interventions (median follow-up 6 years)., Results: Fifty-five patients underwent 188 EUS procedures. Six patients (11%) developed malignancy (three duodenal, three ampullary). Ampullary cancer risk was underestimated by Spigelman stage and overestimated by Kashiwagi classification. Ultrasound findings were poor predictors of malignancy, with common bile duct dilatation being the only finding present in one EUS prior to a diagnosis of ampullary cancer. The best predictors of ampullary malignancy were an ampullary polyp size >3 cm and an increase >1 cm in ampullary polyp size. Ampullary polyp size >3 cm provided the best predictive value, correctly identifying two of the three cases of ampullary cancer and both patients with high-grade dysplasia. EUS biopsy failed to detect malignancy later confirmed by surgical histology in two patients., Conclusion: EUS surveillance confers little additional benefit to standard endoscopic surveillance in FAP patients. The best predictor of ampullary malignancy is an ampullary polyp >3 cm; this could be regarded as a relative indication for surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.

Background and study aims  Pancreatic cystic lesions (PCL) are common. While some harbor malignant potential, accurate preoperative diagnosis remains challenging. Needle-based confocal laser endomicroscopy (nCLE) via a 19G FNA needle enables real-time imaging of the cyst wall. This study evaluated the safety and utility of nCLE in patients with an indeterminate PCL undergoing EUS-FNA. Patients and methods  The CONCYST study prospectively recruited patients with indeterminate PCL attending three hepatopancreaticobiliary (HPB) referral centers in the UK, with indeterminate PCL, who required EUS-FNA between July 2014 and October 2016. Following the procedure, all patients were followed up in telephone clinic for at least 12 months. Ethical approval for the study was granted by the National Research Ethics Service (14/LO/0040). Results  Sixty-seven patient were recruited, 11 excluded and 56 included in the final analysis: 35 male, 21 female; median age 68 (range 28 - 80). Recognizable confocal images were obtained in 48 of 56 cases. Median nCLE scanning time was 5 minutes and did not exceed 10 minutes in any case. EUS-nCLE findings correlated with final diagnosis (based on imaging, cytology and multidisciplinary team review) in 43/56 (77 %) of cases, compared with 37/56 (66 %) for cytology alone ( P  = 0.12). One patient experienced mild pruritus following the procedure and another developed an infected pseudocyst, which resolved with antibiotics. Conclusions  EUS-nCLE under conscious sedation in the day case setting is safe and provides additional information to standard EUS-FNA for diagnosing indeterminate PCL.

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations., Competing Interests: Competing interests: DT – involvement in clinical trials in PSC (NGM, Takeda, Shire), funding from British Liver Trust, PSC Partners, PSC Support, EASL, SMR – Involvement in clinical trials in PSC and sits on the advisory board for FALK and Intercept. GH - medical adviser for PSC Support, speaker fees and educational support from Falk Pharma., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study investigated how the quality of avocado oil is affected by the fruit ripening stage and peeling, and the drying process used. Expeller pressed avocado oils were obtained from unripe or ripe pitted avocados after drying peeled or unpeeled pulps by convection oven, microwave or freeze-drying. Oils from the unpeeled microwave dried pulp (from unripe or ripe avocados) showed the highest induction period (54.2-83.6 h) and antioxidant capacity (4.07-5.26 mmol TE/kg), and high amounts (mg/100 g) of α-tocopherol (11.6-21.0), β-carotene (0.49-0.65) and chlorophyll (44.3-54.0), and unsaponifiable matter (2.48-2.99 g/100 g). Pulp drying process and avocado (un)peeling were the major contributors to the induction period (R 2  = 0.61; p = 0.0139) and antioxidant capacity (R 2  = 0.62; p = 0.011), and the oils from microwave dried unpeeled pulp were those that presented the best performance. The phenolic composition of these oils improved with ripening and keeping the peel during the pressing process., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cyanobacteria are known to produce a wide variety of bioactive, toxic secondary metabolites generally described as hepatotoxins, neurotoxins, cytotoxins, or dermatoxins. In Brazil, the regular monitoring of cyanobacterial toxins has intensified after the death of 65 patients in a hemodialysis clinic in Caruaru in the state of Pernambuco due to microcystin exposure. The primary objective of this study was to use multivariate statistics that incorporated environmental parameters (both biotic and abiotic) to forecast blooms of cyanobacteria and their toxic secondary metabolites in 20 drinking water reservoirs managed by the Water Treatment Company of Ceará (CAGECE) in the semi-arid region of Ceará, Brazil. Across four years (January 2013 to January 2017), 114 different phytoplankton taxa were identified, including 24 cyanobacterial taxa. In general, Ceará reservoirs were dominated by cyanobacteria due to eutrophication but also because of the dry and warm climate found throughout the region. Interestingly, specific cyanobacterial taxa were influenced by different biotic and abiotic factors. For example, nitrogen-to-phosphorus (N:P) and evaporation were positively related to saxitoxin-producing taxa, especially Raphidiopsis raciborskii, while temperature, electrical conductivity, total phosphorus, and transparency (measured as Secchi depth) were positively associated with microcystin-producing taxa, such as Microcystis aeruginosa. Climate forecasts predict higher evaporation and temperatures in the semi-arid Ceará region, which will likely magnify droughts and water scarcity as well as promote toxic cyanobacterial blooms in reservoirs in the future. Therefore, understanding the factors associated with algal blooms dominated by specific taxa is paramount for water resource management., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To carry out a systematic review to identify the prevalence of overweight and obesity in the adult indigenous population in Brazil. The databases used were PubMed, Scopus, Virtual Health Library (VHL), and Science Direct, with the following search strategy: "overweight" OR "obesity" AND "indigenous" OR "tribe" AND "Brazil". For the meta-analysis, RStudio ® software was used. Were 22 articles included. The combined effect of the meta-analysis studies showed a global prevalence of overweight and obesity of 45%. Approximately half (45%) of indigenous Brazilian adults have excess weight. These findings highlight the need to implement public policies for the prevention and treatment of these morbidities., (Copyright © 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background: Cholangiocarcinoma (CCA) complicates primary sclerosing cholangitis (PSC) in 10%-20% of cases, but current tools for prediction of a CCA diagnosis are inadequate. Recently, we demonstrated the utility of the enhanced liver fibrosis (ELF) test to stratify prognosis in PSC. We observed that patients with PSC + CCA had significantly higher ELF score than those with PSC alone. In this study, we aimed to investigate further this association in a larger cohort of PSC patients with CCA compared with patients with PSC or CCA alone., Materials and Methods: Stored sera from patients with PSC (n = 119), CCA without known chronic liver disease (n = 36) and PSC + CCA (n = 32) were tested for ELF. ELF score, gender, age, age at disease diagnosis, inflammatory bowel disease, PSC duration and severity, and CCA features were compared amongst the three cohorts. Factors related to an elevated ELF score were investigated., Results: Enhanced liver fibrosis score was significantly higher in patients with CCA without underlying chronic liver disease and in patients with PSC + CCA compared to those with PSC alone (P < 0.001). In multivariate analysis, elevated ELF score was associated with the diagnosis of CCA independently of age and PSC status (P < 0.001)., Conclusions: Enhanced liver fibrosis score was elevated in patients with CCA irrespective of the presence of PSC, and independently of liver disease stage. Our results indicate that the association between high ELF score and CCA may be related to the tumour's desmoplastic nature, independent of background liver fibrosis, suggesting that ELF score could be used to risk stratify for CCA in PSC., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Doxorubicin (DOX) is an anticancer drug widely used to treat human and nonhuman tumors but the late and persistent cardio-toxicity reduces the therapeutic utility of the drug. The full mechanism(s) of DOX-induced acute, subchronic and delayed toxicity, which has a preponderant mitochondrial component, remains unclear; therefore, it is clinically relevant to identify early markers to identify patients who are predisposed to DOX-related cardiovascular toxicity. To address this, Wistar rats (16 weeks old) were treated with a single DOX dose (20 mg/kg, i.p.); then, mRNA, protein levels and functional analysis of mitochondrial endpoints were assessed 24 h later in the heart, liver, and kidney. Using an exploratory data analysis, we observed cardiac-specific alterations after DOX treatment for mitochondrial complexes III, IV, and preferentially for complex I. Conversely, the same analysis revealed complex II alterations are associated with DOX response in the liver and kidney. Interestingly, H2O2 production by the mitochondrial respiratory chain as well as loss of calcium-loading capacity, markers of subchronic toxicity, were not reliable indicators of acute DOX cardiotoxicity in this animal model. By using sequential principal component analysis and feature correlation analysis, we demonstrated for the first time alterations in sets of transcripts and proteins, but not functional measurements, that might serve as potential early acute markers of cardiac-specific mitochondrial toxicity, contributing to explain the trajectory of DOX cardiac toxicity and to develop novel interventions to minimize DOX cardiac liabilities., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The high mortality rate of cholangiocarcinoma (CCA) is due, in part, to the lack of non-invasive approaches able to accurately detect this silent tumour at early stages, when therapeutic options can be potentially curative or may at least increase the overall survival of patients. The fact that the majority of CCA tumours are not linked to any known aetiological factor highly compromises the monitoring of patients at risk for tumour development and also their early diagnosis. Combination of clinical/biochemical features, imaging techniques and analysis of non-specific tumour biomarkers in serum are commonly used to help in the diagnosis of CCA, but tumour biopsy is usually required to confirm the diagnosis. Moreover, no prognostic biomarkers are currently used in the clinical setting, deserving more innovative research, and international validation and consensus. Important efforts have been made in the last few years to identify accurate non-invasive biomarkers, by using innovative techniques and high-throughput omics technologies. This review summarizes and discusses the advances in the investigation of novel diagnostic and prognostic biomarkers in CCA and envisions the future directions in this field of research., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Life expectancy is increasing worldwide. Lung aging is a process marked by changes in multiple morphological, physiological and age-related biomarkers (e.g., sirtuins) and is influenced by external factors, such as air pollution. Hence, the elderly are considered more vulnerable to the air pollution hazards. We hypothesized that diesel exhaust (DE) exposure intensifies changes in lung inflammatory and structural parameters in aging subjects. Two- and fifteen-month-old mice were exposed to DE for 30 days. Lung function was measured using the forced oscillation method. The inflammatory profile was evaluated in the bronchoalveolar lavage fluid (BALF) and blood, and lung volumes were estimated by stereology. Antioxidant enzyme activity was evaluated by spectrophotometry, sirtuin 1 (SIRT1), sirtuin 2 (SIRT2) and sirtuin 6 (SIRT6) expression was assessed by reverse transcription polymerase chain reaction (RT-PCR), and levels of the sirtuin proteins were evaluated by immunohistochemical staining in lung tissues. Older mice presented decreased pulmonary resistance and elastance, increased macrophage infiltration and decreased tumor necrosis factor (TNF) and interleukin 10 (IL-10) levels in the BALF, reduced activities of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), and increased activity glutathione S-transferase (GST); increased lung volumes with decreased elastic fiber and increased airway collagen content. SIRT1 gene expression was decreased in older animals, but protein levels were increased. DE exposure increased macrophage infiltration and oxidative stress in the lungs of animals of both ages. SIRT6 gene expression was decreased by DE exposure, with increased protein levels. In older animals, DE affected lung structure and collagen content. Lung aging features, such as decreased antioxidant reserves, lower IL-10 expression, and decreased SIRT1 levels may predispose subjects to exacerbated responses after DE exposure. Our data support the hypothesis that strategies designed to reduce ambient air pollution are an important step towards healthy aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In recent years, endomicroscopy has become increasingly used for diagnostic purposes and interventional guidance. It can provide intraoperative aids for real-time tissue characterization and can help to perform visual investigations aimed for example to discover epithelial cancers. Due to physical constraints on the acquisition process, endomicroscopy images, still today have a low number of informative pixels which hampers their quality. Post-processing techniques, such as Super-Resolution (SR), are a potential solution to increase the quality of these images. SR techniques are often supervised, requiring aligned pairs of low-resolution (LR) and high-resolution (HR) images patches to train a model. However, in our domain, the lack of HR images hinders the collection of such pairs and makes supervised training unsuitable. For this reason, we propose an unsupervised SR framework based on an adversarial deep neural network with a physically-inspired cycle consistency, designed to impose some acquisition properties on the super-resolved images. Our framework can exploit HR images, regardless of the domain where they are coming from, to transfer the quality of the HR images to the initial LR images. This property can be particularly useful in all situations where pairs of LR/HR are not available during the training. Our quantitative analysis, validated using a database of 238 endomicroscopy video sequences from 143 patients, shows the ability of the pipeline to produce convincing super-resolved images. A Mean Opinion Score (MOS) study also confirms this quantitative image quality assessment., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Understanding of the significant genetic risk factors for Cholangiocarcinoma (CC) remains limited. Polymorphisms in the natural killer cell receptor G2D (NKG2D) gene have been shown to increase risk of CC transformation in patients with Primary Sclerosing Cholangitis (PSC). We present a validation study of NKG2D polymorphisms in CC patients without PSC., Methods: Seven common Single Nucleotide Polymorphisms (SNPs) of the NKG2D gene were genotyped in 164 non-PSC related CC subjects and 257 controls with HaploView. The two SNPs that were positively identified in the previous Scandinavian study, rs11053781 and rs2617167, were included., Results: The seven genotyped SNPs were not associated with risk of CC. Furthermore, haplotype analysis revealed that there was no evidence to suggest that any haplotype differs in frequency between cases and controls ( P  > 0.1)., Conclusion: The common genetic variation in NKG2D does not correlate significantly with sporadic CC risk. This is in contrast to the previous positive findings in the Scandinavian study with PSC-patients. The failure to reproduce the association may reflect an important difference between the pathogenesis of sporadic CC and that of PSC-related CC. Given that genetic susceptibility is likely to be multifaceted and complex, further validation studies that include both sporadic and PSC-related CC are required.

Background: Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development., Risk Factors for Cholangiocarcinogenesis: Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders., Molecular Pathogenesis of Cholangiocarcinoma: Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis., Conclusion: Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.

The RV144 vaccine trial showed reduced risk of HIV-1 acquisition by 31.2%, although mechanisms that led to protection remain poorly understood. Here we identify transcriptional correlates for reduced HIV-1 acquisition after vaccination. We assess the transcriptomic profile of blood collected from 223 participants and 40 placebo recipients. Pathway-level analysis of HIV-1 negative vaccinees reveals that type I interferons that activate the IRF7 antiviral program and type II interferon-stimulated genes implicated in antigen-presentation are both associated with a reduced risk of HIV-1 acquisition. In contrast, genes upstream and downstream of NF-κB, mTORC1 and host genes required for viral infection are associated with an increased risk of HIV-1 acquisition among vaccinees and placebo recipients, defining a vaccine independent association with HIV-1 acquisition. Our transcriptomic analysis of RV144 trial samples identifies IRF7 as a mediator of protection and the activation of mTORC1 as a correlate of the risk of HIV-1 acquisition.

Aging is associated with cognitive decline. Herein, we studied a large cohort of old age and young adult male rats and confirmed that, as a group, old  rats display poorer spatial learning and behavioral flexibility than younger adults. Surprisingly, when animals were clustered as good and bad performers, our data revealed that while in younger animals better cognitive performance was associated with longer dendritic trees and increased levels of synaptic markers in the hippocampus and prefrontal cortex, the opposite was found in the older group, in which better performance was associated with shorter dendrites and lower levels of synaptic markers. Additionally, in old, but not young individuals, worse performance correlated with increased levels of BDNF and the autophagy substrate p62, but decreased levels of the autophagy complex protein LC3. In summary, while for younger individuals "bigger is better", "smaller is better" is a more appropriate aphorism for older subjects.

Leishmaniasis is an infectious disease caused by a protozoan belonging to Leishmania genus. Different clinical outcomes can be observed depending on the parasite species and patient's health condition. The outcomes can range from single cutaneous lesions to lethal visceral form. The treatment of all forms of leishmaniasis is based on pentavalent antimonials, and, in some cases, the second-line drug, amphotericin B, is used. Beside the toxicity of both classes of drugs, in some areas of the world, parasites are resistant to antimonial. These detrimental features make fundamental the discovery and characterization of new drugs or plant extracts with leishmanicidal effects. Brazil is a well-known country for its biodiversity. Additionally, the common knowledge inherited for generations in small villages makes Brazil a source of new information and resources for the discovery and development of new drugs. Based on ethnopharmacology, elderlies were interviewed about plants they commonly used for skin diseases and infections. Five native plants from Atlantic forest were indicated; EtOH and n -hexane extracts were prepared with the vegetative organs of the plants and assayed against promastigote and amastigote forms of L. (L.) amazonensis . The major molecules of each extract were detected using qualitative nuclear magnetic resonance. Among all tested extracts, the n -hexane extract from the leave of Eugenia uniflora (Myrtaceae), enriched in myricitrin and quercitrin flavonoids, was the most effective against L. (L.) amazonensis amastigotes. This data supports the ethnopharmacology approach as a successful tool for the discovery of new drugs with leishmanicidal effects.

Integrin-mediated laminin adhesions mediate epithelial cell anchorage to basement membranes and are critical regulators of epithelial cell polarity. Integrins assemble large multiprotein complexes that link to the cytoskeleton and convey signals into the cells. Comprehensive proteomic analyses of actin network-linked focal adhesions (FA) have been performed, but the molecular composition of intermediate filament-linked hemidesmosomes (HD) remains incompletely characterized. Here we have used proximity-dependent biotin identification (BioID) technology to label and characterize the interactome of epithelia-specific β4-integrin that, as α6β4-heterodimer, forms the core of HDs. The analysis identified ∼150 proteins that were specifically labeled by BirA-tagged integrin-β4. In addition to known HDs proteins, the interactome revealed proteins that may indirectly link integrin-β4 to actin-connected protein complexes, such as FAs and dystrophin/dystroglycan complexes. The specificity of the screening approach was validated by confirming the HD localization of two candidate β4-interacting proteins, utrophin (UTRN) and ELKS/Rab6-interacting/CAST family member 1 (ERC1). Interestingly, although establishment of functional HDs depends on the formation of α6β4-heterodimers, the assembly of β4-interactome was not strictly dependent on α6-integrin expression. Our survey to the HD interactome sets a precedent for future studies and provides novel insight into the mechanisms of HD assembly and function of the β4-integrin., (© 2019 Myllymäki et al.)

Objectives: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC., Methods: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred., Results: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63)., Conclusions: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Central cholinergic activation stimulates water intake, but also NaCl intake when the inhibitory mechanisms are blocked with injections of moxonidine (α 2 adrenergic/imidazoline agonist) into the lateral parabrachial nucleus (LPBN). In the present study, we investigated the involvement of central M 1 and M 2 muscarinic receptors on NaCl intake induced by pilocarpine (non-selective muscarinic agonist) intraperitoneally combined with moxonidine into the LPBN or by muscimol (GABA A agonist) into the LPBN. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN and in the lateral ventricle were used. Pirenzepine (M 1 muscarinic antagonist, 1 nmol/1 μl) or methoctramine (M 2 muscarinic antagonist, 50 nmol/1 μL) injected intracerebroventricularly (i.c.v.) reduced 0.3 M NaCl and water intake in rats treated with pilocarpine (0.1 mg/100 g of body weight) injected intraperitoneally combined with moxonidine (0.5 nmol/0.2 μL) into the LPBN. In rats treated with muscimol (0.5 nmol/0.2 μL) into the LPBN, methoctramine i.c.v. also reduced 0.3 M NaCl and water intake, however, pirenzepine produced no effect. The results suggest that M 1 and M 2 muscarinic receptors activate central pathways involved in the control of water and sodium intake that are under the influence of the LPBN inhibitory mechanisms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tuberculosis patients taking second line drugs such as ethionamide (ETH) have often experienced previous treatment failure and usually have a complex history of disease and treatment that can span decades. Mutations in the ETH activating enzyme, EthA, confer resistance through undescribed mechanisms. To explore the impact of EthA mutations on ETH resistance, data from a total of 160 ETH R isolates was analysed. The most frequently mutated positions are within regions that display sequence conservation with the active site of OTEMO, another FAD-containing NADH-binding Baeyer-Villiger monooxygenase (BVMO), or with the sugar binding site of galectin-4N. Additionally, to look at a possible role of EthR on ETH resistance we purified an EthR mutant identified in a clinical isolate, F110L, and found it to bind the ethA-ethR intergenic region with higher affinity than the wild type regulator in gel shift assays. The ability of cyclic di-GMP to enhance DNA binding is maintained in the EthR mutant. To our knowledge, this is the first ETH resistance study that combines sequence and resistance data of clinical isolates with functional and structural information., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The Conscripts Survey has been conducted periodically by the Brazilian Department of Sexually Transmitted Infections (STIs), AIDS, and Viral Hepatitis (DIAHV) in collaboration with the Brazilian Ministry of Defense for over 2 decades. It aims to assess the syphilis prevalence and obtain data on knowledge regarding STIs and their risk factors among conscripts enlisted for the Brazilian Army.This cross-sectional study was conducted among conscripts across Brazil aged 17 to 22 years from August to December 2016. It included a self-reported questionnaire and blood testing for syphilis, HIV, and hepatitis B and C.In total 38,247 conscripts were enrolled; after exclusion due to a lack of information, 37,282 (93.2%) conscripts were included. The estimated syphilis prevalence rates were: 1.63%, 1.09%, and 0.62% for screened, confirmed, and active syphilis, respectively. Among those with active syphilis, 81.1% reported not having syphilis infection in their lifetime. Higher confirmed syphilis prevalence rates were observed in the South region, followed by North and Southeast regions. Independent factors associated with confirmed syphilis infection were: self-reported STIs in one's lifetime (odds ratio [OR] = 7.24; P < .001), same-sex sexual relationships (OR = 3.43; P = .001), and having the 1st sexual intercourse encounter before 15 years of age (OR = 2.62; P = .04). The proportion of conscripts who reported having sex with other men (MSM) was 4.3%, and the estimated syphilis prevalence in this group was 5.23%, 4.61%, and 3.60% for screened, confirmed, and active syphilis, respectively. The sexual behaviors most frequently associated with confirmed syphilis were: sexual relationship with casual partners in the last year (P < .001), same-sex sexual relationships (P < .001), more than 10 partners (P = .006), and having sexual intercourse before 15 years of age (P = .003). Although not significant, only 25.4% of the conscripts who had a confirmed syphilis reported the use of condoms with steady partners, 32.4% with casual partner, and 24.3% with any partner.We found that syphilis is on the rise among the young Brazilian male population. The increase in its prevalence, particularly among MSM, highlights the need for urgent public health interventions, action plans, and implementation of risk reduction strategies aimed at this population.

Understanding the burden and pattern of mental disorders as well as mapping the existing resources for delivery of mental health services in India, has been a felt need over decades. Recognizing this necessity, the Ministry of Health and Family Welfare, Government of India, commissioned the National Mental Health Survey (NMHS) in the year 2014-15. The NMHS aimed to estimate the prevalence and burden of mental health disorders in India and identify current treatment gaps, existing patterns of health-care seeking, service utilization patterns, along with an understanding of the impact and disability due to these disorders. This paper describes the design, steps and the methodology adopted for phase 1 of the NMHS conducted in India. The NMHS phase 1 covered a representative population of 39,532 from 12 states across 6 regions of India, namely, the states of Punjab and Uttar Pradesh (North); Tamil Nadu and Kerala (South); Jharkhand and West Bengal (East); Rajasthan and Gujarat (West); Madhya Pradesh and Chhattisgarh (Central) and Assam and Manipur (North East). The NMHS of India (2015-16) is a unique representative survey which adopted a uniform and standardized methodology which sought to overcome limitations of previous surveys. It employed a multi-stage, stratified, random cluster sampling technique, with random selection of clusters based on Probability Proportionate to Size. It was expected that the findings from the NMHS 2015-16 would reveal the burden of mental disorders, the magnitude of the treatment gap, existing challenges and prevailing barriers in the mental-health delivery systems in the country at a single point in time. It is hoped that the results of NMHS will provide the evidence to strengthen and implement mental health policies and programs in the near future and provide the rationale to enhance investment in mental health care in India. It is also hoped that the NMHS will provide a framework for conducting similar population based surveys on mental health and other public health problems in low and middle-income countries., Competing Interests: The authors have declared that no competing interests exist.

Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus., Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used., Results: We replicated previously reported risk loci CLDN2-MORC4 , CTRC , PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956 . The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk., Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To assess the influence of pre-pregnancy body mass index (BMI), total gestational weight gain (TGWG), and pre-pregnancy surgical success on the nutritional status of vitamin D, calcium, and parathyroid hormone (PTH) in the trimesters of pregnancy of women who previously underwent Roux-en-Y gastric bypass (RYGB)., Methodology: This is an analytical, longitudinal, and retrospective study comprising 42 pregnant women who previously underwent RYGB. Concentrations of vitamin D 3 , calcium, and PTH were assessed in all trimesters. Anthropometric variables necessary for calculating TGWG, surgical success, and BMI were collected preoperatively and over the trimesters of pregnancy., Results: A total of 97.1% had vitamin D 3 inadequacy at some point in pregnancy. Pre-pregnancy BMI, even when classified as overweight, may have exacerbated the serum concentrations of this vitamin in the third trimester (p = 0.011), and it was significantly lower in women with normal weight and/or obesity (p = 0.039). It was evidenced that both pre-pregnancy BMI and TGWG above the recommended optimal weight can be associated with calcium homeostasis, especially early in pregnancy. It was also shown that surgical success in the pre-pregnancy period may have influenced the serum concentrations of vitamin D in the second trimester of pregnancy (p = 0.013)., Conclusion: This study draws attention to the importance of monitoring the nutritional status of vitamin D 3 and calcium in the prenatal period due to its relationship with pre-pregnancy BMI, TGWG, and surgical success.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition of which IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation. In this review, we provide an overview of IgG4-RD, with a focus on the biliary manifestations. In particular, we describe the important differential diagnoses of IgG4-SC, namely, primary sclerosing cholangitis and cholangiocarcinoma, outline diagnostic criteria for IgG4-SC, provide insight into possible pathophysiological mechanisms underlying the disease and discuss short and long-term management options of this recently described disease.

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms., Competing Interests: Competing interests: GMH: Advisory boards for Falk, GfK, GSK, Intercept, Novartis; consultancy for CymaBay; clinical trial investigator for Falk, FF Pharma, Gilead, GSK, Intercept, Novartis, NGM Bio, Shire. JKD: member of BSG and BASL. GJMA: department receives/received financial support for clinical trials from GSK, Intercept and Cymabay. IP: honorarium received for chairing sessions/lectures/meetings and sponsorship to attend Falk Symposium from Dr Falk Pharma. DT: department receives/received financial support for hosting and speaking at meetings from Dr Falk Pharma. MW: holds a voluntary position as the chair of Trustees for PSC Support. DEJJ: grant funding from Pfizer and Intercept; consultancy for Intercept, GSK and Novartis; speaker bureau for Dr Falk Pharma. Member of medical advisory board for PBC Foundation., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The aim of the present report was to detail the advantages of using 3-dimensional (3D) prototyping in the planning, modeling, and manufacturing of an immediate palatal obturator for a 62-year-old man who underwent a left total maxillectomy to remove a solid, multicystic ameloblastoma. The prosthesis provided favorable restoration of stomatognathic functions, including speech, swallowing, and mastication. The use of an immediate obturator prosthesis made with 3D technology is an important aid in the treatment of patients diagnosed with tumors in the head and neck region.

This study aimed to evaluate the effect of processing steps on bioactive compounds and physicochemical and rheological characteristics of a juçara, banana and strawberry smoothie. The product was obtained by mixing the pulps of these fruits in previously defined proportions. The mixture was standardized in a pilot disintegrator, homogenized at 60 MPa in continuous mode and pasteurized at 90 °C for 35 s. The homogenization step increased the concentration of cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside, major anthocyanins in the smoothie. However, these anthocyanins, as well as perlagonidin-3-O-glucoside, have been reduced (p<0.05) after the pasteurization step. The pasteurization also affected the instrumental color of the smoothie, expressed by Hue angle (p<0.05). Regarding to the rheological behavior, the smoothie, in all processing steps, presented a non-Newtonian fluid behavior with pseudoplastic characteristics (n<1). After homogenization, the smoothie became more fluid and homogeneous. Thus, despite the negative impact of pasteurization on the smoothie's color, the pasteurized product preserves the bioactive compounds such as flavonoids and phenolic acids that are of great importance to human health. Furthermore, the development of this product contributes to add value to the juçara agro-chain and Atlantic Forest preservation.

Background & Aims: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC., Methods: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures., Results: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001)., Conclusions: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Lipid metabolites play an important role in parasite differentiation and virulence. Studies have revealed that Leishmania sp. uses prostaglandins to evade innate barriers, thus enabling the parasites to survive inside immune cells. Despite the role of the enzyme Phospholipase A 2 (PLA 2 ) in prostaglandins production, few studies have investigated the role of parasite PLA 2 during the interaction between L. (L.) amazonensis and the host (in vitro and in vivo) immune cells., Methods: In the present work, the leishmanicidal effect of PLA 2 inhibitors, methyl arachidonyl fluorophosphonate (MAFP), bromoenol lactone (BEL) and aristolochic acid (AA) were investigated in vitro (promastigote and intracellular amastigote forms of L. (L.) amazonensis ) and during in vivo infection using BALB/c mice., Results: The aforementioned inhibitors were deleterious to promastigote and amastigote forms of the L. (L.) amazonensis and were non-toxic to peritoneal macrophages from BALB/c mice. L. (L.) amazonensis -infected BALB/c mice treated with the inhibitor BEL presented decreased lesion size and skin parasitism; however, BEL treatment induced hepatotoxicity in BALB/c mice., Conclusions: Results presented herein suggested that PLA 2 inhibitors altered L. (L.) amazonensis viability. In spite of liver toxicity, treatment with BEL was the most selective compound in vitro, as well in vivo, resulting in lower skin parasitism in the infected mice. These findings corroborate the role of PLA 2 in parasite virulence and maintenance in vertebrate hosts, and suggest that molecules structurally related to BEL should be considered when planning compounds against Leishmania sp., Competing Interests: Animal experiments were carried out using protocols approved by the Ethics Committee for Animal Experimentation of São Paulo University under the number CEP 067/1.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Automatic segmentation of abdominal anatomy on computed tomography (CT) images can support diagnosis, treatment planning, and treatment delivery workflows. Segmentation methods using statistical models and multi-atlas label fusion (MALF) require inter-subject image registrations, which are challenging for abdominal images, but alternative methods without registration have not yet achieved higher accuracy for most abdominal organs. We present a registration-free deep-learning-based segmentation algorithm for eight organs that are relevant for navigation in endoscopic pancreatic and biliary procedures, including the pancreas, the gastrointestinal tract (esophagus, stomach, and duodenum) and surrounding organs (liver, spleen, left kidney, and gallbladder). We directly compared the segmentation accuracy of the proposed method to the existing deep learning and MALF methods in a cross-validation on a multi-centre data set with 90 subjects. The proposed method yielded significantly higher Dice scores for all organs and lower mean absolute distances for most organs, including Dice scores of 0.78 versus 0.71, 0.74, and 0.74 for the pancreas, 0.90 versus 0.85, 0.87, and 0.83 for the stomach, and 0.76 versus 0.68, 0.69, and 0.66 for the esophagus. We conclude that the deep-learning-based segmentation represents a registration-free method for multi-organ abdominal CT segmentation whose accuracy can surpass current methods, potentially supporting image-guided navigation in gastrointestinal endoscopy procedures.