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Background: Patients with Crohn's disease (CD) frequently undergo abdominopelvic computed tomography (APCT) in the emergency department (ED). It's essential to diagnose clinically actionable findings (CAF) as they may need immediate intervention, frequently surgical. However, repeated APCT's includes increased ionizing radiation exposure. Guidance regarding APCT performance is mostly clinical and empiric., Aims: We used a machine learning (ML) approach for predicting CAF on APCT in the ED., Methods: We performed a retrospective cohort study of patients with CD who presented to the ED and underwent APCT. CAF were defined as bowel obstruction, perforation, intra-abdominal abscess or complicated fistula. ML was used to predict the probability of having CAF on APCT, using routine clinical variables., Results: Of 101 admissions included, 44 (43.5%) had CAF on APCT. ML successfully identified patients at low (NPV 91.6%, CI-95% 90.6-92.5) and high (PPV 92.8%, CI-95%, 92.3-93.2) risk for CAF (AUROC = 0.774), using beats-per-minute, mean arterial pressure, neutrophil-to-lymphocyte ratio and sex. This allowed the construction of a risk stratification scheme according to patients' probability for CAF on APCT., Conclusion: We present a novel artificial intelligence-based approach, utilizing readily available clinical variables to better select patients with CD in the ED for APCT. This might reduce the number of APCTs performed, avoiding related hazards while ensuring high-risk patients undergo APCT., (Copyright © 2021. Published by Elsevier Ltd.)

Background and Aims: Skin eruptions are prevalent among patients with inflammatory bowel diseases (IBD), often associated with therapies and frequently leading to dermatological consults and treatment interruptions. We aimed to assess the impact of joint shared decision-making in a multidisciplinary (MDT) IBD-DERMA clinic., Methods: This retrospective cohort study assessed a consecutive group of patients with IBD who were referred for consultation in an MDT clinic at a tertiary referral center in Israel., Results: Over 1 year, 118 patients were evaluated in the MDT-IBD-DERMA clinic: 68 (57.6%) males; age - 35.2 ± 13.5 years, disease duration - 7.1 (interquartile range: 3.7-13.9) years; Crohn's disease - 94/118 (79.6%). Skin eruption induced by an anti-tumor necrosis factor (TNF) were the most common diagnoses [46/118 (39%)], including psoriasiform dermatitis (PD) - 31/46 (67.4%) and inflammatory alopecia (IA) - 15/46 (32.6%). Of these, 18 patients (39.1%) continued the anti-TNF agent concomitantly with a topical or systemic anti-inflammatory agent to control the eruption. The remaining 28 patients (60.9%) discontinued the anti-TNF, of whom 16/28 (57.1%) switched to ustekinumab. These strategies effectively treated the majority [38/46 (82.6%)] of patients. Continuation of the anti-TNF was possible in a significantly higher proportion of patients with PD: 12/31 (38.7%) than only one in the IA group, p  = 0.035. There was a higher switch to ustekinumab among the IA 7/15 (46.6%) compared with the PD 7/31 (22.6%) group, P  = .09. Following IBD-DERMA advised intervention, IBD deteriorated in 9/4 6(19.5%) patients, 5/9 on ustekinumab (PD versus IA, P  = NS)., Conclusion: Shared decision-making in an integrated IBD-DERMA clinic allowed successful control of skin eruptions while preserving control of the underlying IBD in more than 80% of cases. Patients with IA profited from a switch to ustekinumab., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Henit Yanai: reports institutional research grants from Pfizer; consulting fees from Abbvie, Ferring, Janssen, Neopharm Ltd., Pfizer, Takeda; honoraria for lectures from Abbvie, Janssen, Pfizer, Takeda; participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, Neopharm Ltd., Pfizer, Takeda. Hadar Amir Barak: none. Jacob E Ollech: none. Irit Avni Biron: none. Idan Goren: reports institutional research grants from Pfizer. Yifat Snir: none. Hagar Banai Eran: none. Yelena Broitman: none. Maya Aharoni Golan: none. Elena Didkovsky: none. Iris Amitay-Laish: none. Ayelet Ollech: none. Emmilia Hodak: none relevant. Iris Dotan: research grants from Altman Research, Pfizer; Advisory board/consulting fees: Pfizer, Janssen, Abbvie, Takeda, Genentech/Roche, Arena, Neopharm, Gilead, Galapagos, Celltrion, Rafa Laboratories, Ferring, DSM, Cambridge Healthcare, Sublimity, Sangamo, Wild Biotech, Food industries organization, Integra Holdings, Celgene/BMS, Abbott, 89 Bio, Alimentiv; Speakers Bureau: Roche/Genentech, Falk Pharma, Abbvie, Janssen, Pfizer, Takeda Neopharm, Celltrion, Ferring, Nestle, Celgene/BMS. Lev Pavlovsky has served as an investigator for Abbvie, Coherus, Novartis Pharmaceuticals Corporation, Janssen Biotech, Eli Lilly, Bristol Myers Squibb and as an advisor, consultant, and/or invited lecturer for Abbvie, Janssen Biotech, Novartis Pharmaceuticals Corporation, Pfizer Inc., Dexcel Pharma, Eli Lilly, and Boehringer Ingelheim., (© The Author(s), 2021.)

Background and Aims: The aim of this study was to assess the efficacy and safety of a novel, hydrophilic, bioenhanced curcumin (BEC) as add-on therapy in inducing clinical and endoscopic remission in mild to moderately active ulcerative colitis (UC)., Design: Mild to moderately active UC patients (partial Mayo score 2 to 6 with endoscopic Mayo score >1) on standard dose of mesalamine were randomized to either 50 mg twice daily BEC or an identical placebo. Clinical response (≥2 reduction of partial Mayo score), clinical remission (partial Mayo score ≤1), and endoscopic remission (endoscopic Mayo score of ≤1) were evaluated at 6 weeks and 3 months. Responders were followed-up at 6 and 12 months for assessing maintenance of remission., Results: Sixty-nine patients were randomly assigned to BEC (n=34) and placebo (n=35). At 6 weeks, clinical and endoscopic remission occurred in 44.1% (15/34) and 35.3% (14/34) patients, respectively, compared with none in the placebo group (P<0.01). Clinical response was also significantly higher in the BEC group (18/34, 52.9%) compared with placebo (5/35, 14.3%) (P=0.001). The clinical remission, clinical response, and endoscopic remission rates at 3 months were 55.9% (19/34), 58.8% (20/34), 44% (16/34) and 5.7% (2/35), 28.6% (10/35), 5.7% (2/35) in BEC and placebo groups, respectively. At 6 and 12 months, 95% (18/19) and 84% (16/19) of the responders to BEC maintained clinical remission. None of the responders to placebo maintained clinical remission at 6 months. BEC appeared safe with no significant side effects., Conclusion: A low-dose BEC as add-on therapy was superior to placebo in inducing sustained clinical and endoscopic remission in patients with mild-to-moderately active UC on maximal dose of mesalamine (ClinicalTrials.gov: NCT02683733)., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: The early stages of Crohn's disease (CD) course are heterogeneous, and it is a challenge to predict the course of disease in patients with new diagnosis., Methods: We performed an observational longitudinal study of 156 adults (79 male; median age, 27.7 years; 57 treatment naïve) with newly diagnosed CD (within 6 months of enrollment), referred from medical centers and community clinics in Israel from 2013 through 2017. Study participants each received semi-annual scheduled evaluations. Indolent disease was defined as a disease course without need for strict interventions to control complicated course of CD (hospitalization or surgery, or decision to start steroid, immunomodulator, or biologic therapy). Cox regression and receiver operating characteristic analyses were used to identify factors associated with early indolent or complicated course of CD. We validated our findings in an independent cohort of patients with CD from a separate medical center in Israel in 2018., Results: Over a median follow-up period of 17.2 months (interquartile range, 8.8-23.8 months), 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. The median time to first intervention was 3.4 months (95% CI, 2.4-4.4). We developed a model based on clinical factors that identified 4 factors associated with complicated course in treatment-naïve patients: body mass index <25 kg/m 2 (hazard ratio [HR], 2.45; 95% CI, 1.07-5.43; P = .033), serum level of vitamin B12 <350 pg/mL (HR, 2.78; 95% CI, 1.21-6.41; P = .016), white blood cells ≥7 × 10 3 /μL (HR, 2.419; 95% CI, 1.026-5.703; P = .044), and serum level of ALT ≥25 IU/L (HR, 2.680; 95% CI, 1.186-6.058; P = .018). This model discriminated between patients with vs without a complicated course of disease with 90% and 89% accuracy at 6 and 12 months after diagnosis, respectively. A validation cohort demonstrated a discriminatory ability of 79% at 3 months after diagnosis, and a nomogram was constructed., Conclusions: In an observational longitudinal study of 156 patients with newly diagnosed CD, we found that one third have an early indolent course of disease. We identified factors that can be measured at diagnosis to identify patients at risk for an early complicated course-these might be used in patient management and selection of treatment., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim of the Study: To compare [¹¹C] choline PET/CT findings between patients with cirrhosis and normal liver controls., Methods: Included 11 patients with cirrhosis and 14 controls. All underwent a dynamic [11C] choline PET/CT. The maximal standard uptake values (SUVmax), the area under the curve (AUC) and kinetic parameters (K1 and K2), clinical and laboratory data, were compared between groups., Results: Patients mean age was 68.4 ± 10.7 and controls, 69.7 ± 7.3 years. Mean SUVmax was higher in patients than controls (right lobe, 10.06 ± 12 vs. 6.3 ± 1.6, P = 0.011; left lobe, 8.6 ± 11.6 vs. 5.4 ± 0.9, P = 0.024; spleen 17.99 ± 27.8 vs. 13.4 ± 2.6, P = 0.027; kidney, 35.9 ± 59.5 vs. 19.3 ± 4.8, P = 0.025) and also AUC values (right lobe, 13,538 ± 20,020 vs. 8427.3 ± 1557.9, P = 0.026; left lobe 12,304 ± 18,871 vs. 6878.9 ± 1294.3, P = 0.024; spleen, 12,875 ± 17,930 vs. 8263.9 ± 1279.2, P = 0.023; kidney, 24,623 ± 36,025 vs. 13,667 ± 3873.9, P = 0.032). No difference in kinetic parameters was found. No correlations between severity of clinical signs and imaging-derived parametric data were found among patients with cirrhosis., Conclusions: [11C] choline PET/CT may serve as a noninvasive biomarker for patients with cirrhosis., Competing Interests: Declaration of Competing Interest No potential conflicts of interest were disclosed., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [ C57BL/6-Tg(TNFa-eGFP) ] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Lenz, Eichler, Kruse, Strehl, Rodriguez-Rozada, Goren, Yogev, Frank, Waisman, Deller, Jung, Maggio and Vlachos.)

Background: Recent studies reported that Nudix Hydrolase 15(NUDT 15) gene variant (C415T) can better predict thiopurine induced leucopenia in Asian patients with inflammatory bowel disease (IBD) than thiopurine S-methyl transferase (TPMT)., Aim: To evaluate the role of the NUDT variant compared with TPMT in predicting azathioprine induced leucopenia in Indian IBD patients., Methods: Prospectively collected data of consecutive patients treated with azathioprine from a large IBD registry were analysed for side effects, discontinuation time, and initial and maximum dose tolerated. Genotyping of NUDT15 C415T (rs116855232; p.R139C) was carried out retrieving blood samples from bio-repository employing real time polymerase chain reaction with age and sex-matched healthy volunteers. The association of NUDT15 C415T with leucopenia (<3 × 10 9 /L) and neutropenia (<1.5 × 10 9 /L) was evaluated. TPMT genotyping was done in patients who developed leucopenia., Results: Among 1014 patients (mean age 35.84 ± 12.74 years; 61% males; 54% ulcerative colitis, 44% Crohn's disease and 2% IBD-unclassified), 79 were excluded due to inadequate blood samples. Of the remaining 935, 81 (9%) developed leucopenia and 70 (7.5%) developed neutropenia. The variant "T" allele [heterozygous (CT) and homozygous (TT) versus wild type (CC)] was associated with a 19-fold higher odds (OR19.35, 95% CI11.55-32.42; P < 0.0001) of leucopenia and 21-fold higher odds of neutropenia (OR21.41, 95% CI12.25-37.41). There was significant difference in median dose tolerated between CC, CT and TT (1.35, 1.38 and 0.92 mg/kg body weight, respectively) (P = 0.037) and median duration of therapy (18, 15 and 10 months for CC/CT/TT) (P = 0.003). NUDT15 genotype was an independent risk factor for leucopenia (hazard ratio (HR): CT 11.31, 95% CI6.85-18.03, P < 0.0001 and TT 31.283, 95% CI14.76-66.30 compared to CC) and neutropenia (HR: CT 13.04, 95% CI7.65-22.22, P < 0.0001 and TT 43.39, 95% CI20.21-92.68 compared to CC). The sensitivities for predicting leucopenia and neutropenia by number of mutant NUDT 15 alleles based on additive predictive model were 66.67% and 70% with a receptor operator characteristic curve area under curve value of 0.791 and 0.807, respectively. Among patients with leucopenia, only 6.2% were heterozygous and none were homozygous for TPMT variants., Conclusion: NUDT15 variant genotyping appears to be a better predictor for azathioprine-induced leucopenia in an Indian population than TPMT with high accuracy and can be useful in optimizing azathioprine dosage., (© 2020 John Wiley & Sons Ltd.)

Background: Patients with inflammatory bowel disease might be at increased risk of invasive bacterial infections., Objectives: The objective of this study was to identify the rate of bacteremia in hospitalised patients with inflammatory bowel disease and risk factors., Methods: An observational cohort of hospitalised patients with inflammatory bowel disease, aged 16-80 years, from 2008 to 2017 in a large tertiary hospital. Patients with Charlson comorbidity index of 2 or greater were excluded. Patients with one or more positive blood culture were reviewed. Logistic regression was used to evaluate risk factors for bacteremia., Results: Of 5522 admitted patients, only 1.3% had bacteremia (73/5522) (39, Crohn's disease; 25, ulcerative colitis; nine, unclassified inflammatory bowel disease). The most common pathogen was Escherichia coli (19/73 patients). The mortality rate at 30 days of patients with bacteremia was 13.7% (10/73). Longer hospitalisations (mean length of stay (21.6 ± 31.0 vs. 6.4 ± 16.0 days; P  < 0.0001) and older age (mean age 47.5 ± 18.0 vs. 40.2 ± 15.4 years, P  < 0.0001)) were associated with an increased risk of bacteremia. In multivariate analysis, treatment with either anti-tumour necrosis factor α, purine analogues, steroids or amino salicylates was not associated with an increased risk of bacteremia. Risk was greatest among patients aged 65 years or older (relative risk 2.84, 95% confidence interval 1.6-4.8; P  = 0.0001) relative to those under 65 years., Conclusion: Age over 65 years, but not inflammatory bowel disease-related medications, is associated with an increased risk of bacteremia in hospitalised patients with inflammatory bowel disease.

The gaseous mediators nitric oxide (NO), carbon monoxide (CO) and lately also hydrogen sulfide (H 2 S) have been described to contribute to the interplay of protein type- and lipid mediators in the regulation of wound healing. In particular, the recently reported role of H 2 S in skin repair remains largely unresolved. Therefore we assessed the expressional kinetics of potential H 2 S-producing enzymes during undisturbed skin repair: the cystathionine-γ-lyase (CSE), the cystathionine-β-synthase (CBS) and the 3-mercaptopyruvate sulfurtransferase (MPST). All three enzymes were not transcriptionally induced upon wounding and remained silent through the acute inflammatory and proliferative phase of skin repair. By contrast, CSE expression started to increase significantly at the later stages of healing, when cellular proliferation ceases within the granulation tissue and neoepidermis. The importance of H 2 S production in late healing phases was supported by a strong induction of otherwise not-induced CBS to complement the loss of CSE function in CSE-deficient mice. Immunohistochemistry revealed hair follicle keratinocytes and basal keratinocytes of the neo-epidermis covering the wound area as sources of CSE expression. Subsequent in vitro studies implicated a role of CSE-derived H 2 S for keratinocyte differentiation: the H 2 S-donor GYY4137 markedly increased the Ca 2+ -triggered expression of the early keratinocyte differentiation markers cytokeratin 10 (CK10) and involucrin (IVN) in cultured human keratinocytes. Here, GYY4137-derived H 2 S strongly enhanced CK10 expression by increasing the binding of RNA polymerase II to the CK10 promoter., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value., Design: We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts., Results: We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%., Conclusions: Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed., Competing Interests: Competing interests: YC declares Abbvie grant support, advisory and lecture fees, Janssen advisory and lecture fees, Takeda grant support and advisory and lecture fees, Pfizer advisory and lecture fees and Protalix Advisory fees. RG and ESt declares CytoReason equity and advisory fees. RG declares equity in CytoReason. SSO-O declares CytoReason equity and advisory fees and Takeda grant support., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Aims: There are conflicting data on the association between inflammatory bowel diseases [IBD] and autoimmunity disorders. The aim of this study was to explore this association including the effect of medications., Methods: We utilized health administrative data collected by three of the four health maintenance organizations [HMOs] in Israel, covering 52% of the country's population. We explored the prevalence of the following autoimmune disorders: insulin-dependent diabetes mellitus [IDDM], psoriasis, Sjögren syndrome, coeliac disease, systemic lupus erythematosus [SLE], primary sclerosis cholangitis [PSC] and autoimmune thyroiditis, among all IBD patients vs non-IBD controls. Case ascertainment was determined according to validated computerized algorithms., Results: In total, 12625 IBD patients were compared to 12625 controls. A total of 1395 [11.1%] IBD patients had at least one autoimmune disease compared with 740 [5.9%] of non-IBD controls (odds ratio [OR] = 1.99 [95% confidence interval 1.81-2.19]; p < 0.05); all autoimmune diseases, except for thyroiditis, were more prevalent among IBD patients. Adjusted for confounding variables, anti-tumour necrosis factor [anti-TNF] medications were associated with a higher prevalence of psoriasis (54 [5.7%] in IBD vs 177 [4.1%] in controls; OR = 1.50 [1.07-2.08]; p < 0.05) but lower prevalence of Sjögren (1 [0.1%] vs 39 [0.9%]; OR [95% CI] = 0.13 [0.02-0.94]; p < 0.05) and coeliac disease (11 [1.2%] vs 68 [1.6%]; OR [95% CI] = 0.51 [0.27-0.99]; p < 0.05). Thiopurines and 5-aminosalicylates were not associated with any autoimmune disorder., Conclusion: IBD is associated with all autoimmune diseases explored here except for thyroiditis. Anti-TNF users have a higher prevalence of psoriasis, and lower prevalence of Sjögren and coeliac disease., (Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Inflammatory bowel diseases (IBDs) are characterized by serologic responses to glycans. Patients with ulcerative colitis (UC) after proctocolectomy with ileo-anal anastomosis (pouch surgery) may develop inflammation (pouchitis) that resembles Crohn's disease (CD). We hypothesized that patients' serologic responses were affected by their consumption of dietary sugars. This study analyzed the correlations between antiglycan antibody expression and dietary sugar consumption in patients with UC pouch and the evolution in antibody levels over time., Methods: Patients were followed prospectively for 2 consecutive visits. The following antiglycan carbohydrate antibodies were detected by enzyme-linked immunosorbent assay: antichitobioside (ACCA), antilaminaribioside (ALCA), antimannobioside (AMCA), and anti-Saccharomyces cerevisiae (ASCA) antibodies. Patients completed a food frequency questionnaire. The fungal community in patients' fecal samples was analyzed by sequencing the internal transcribed spacer 2 (ITS2) region of nuclear ribosomal DNA., Results: We included 75 UC pouch patients aged 45.2 ± 14 years who underwent pouch surgery 9.8 ± 6.7 years previously. Of these patients, 34.7% (n = 26) showed seropositivity for antiglycan antibodies. Starch consumption was significantly higher in patients with positive serologic responses (P = 0.05). Higher starch consumption was associated with higher AMCA and ACCA titers, which increased by 4.08% (0.8%-7.4%; P = 0.014) and 4.8% (0.7%-9.1%; P = 0.007), respectively, for each 10-g increase of dietary starch. The per-patient change in the relative abundance of Candida albicans in fecal samples correlated positively with changes in starch consumption (Spearman's r = 0.72; P = 0.012)., Conclusions: Starch consumption correlated with positive antiglycan serology (ACCA and AMCA), suggesting that increased dietary starch intake may promote a specific immune response in patients with IBD., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We evaluated the impact of variations in ATG16L1 and NOD2 and genes on serologic responses in patients with inflammatory bowel disease (IBD)., Methods: We recruited 308 IBD patients: 130 with Crohn's disease (CD), 67 with ulcerative colitis (UC), 111 with UC and an ileal pouch (UC-pouch), and 74 healthy controls. NOD2 variants (1007fs, G908R, R702W) and the ATG16L1 A300T variant were analyzed. The antiglycan antibodies anti-Saccharomyces cerevisiae (ASCA), antilaminaribioside (ALCA), antichitobioside (ACCA), and antimannobioside carbohydrate (AMCA) were analyzed by enzyme-linked immunosorbent assay., Results: Antichitobioside was positive in 28% of patients with CD carrying the ATG16L1 A300T variant (either heterozygote or homozygote) compared with only 3% in those without the variant (P < 0.001). Anti-Saccharomyces cerevisiae was positive in 86% of patients with CD carrying the NOD2 1007fs variant compared with 36% in those without the variant (P < 0.001). UC-pouch patients with the NOD2 1007fs variant had elevated ASCA and ALCA levels compared with those without the variant (50% vs 7%, P = 0.004, and 50% vs 8%, P = 0.006, respectively). Importantly, ATG16L1 A300T and NOD2 variants were not associated with serologic responses in healthy controls and unoperated UC patients. Multivariate analysis demonstrated that these genetic variants are the main factors associated with specific antiglycan antibody levels in CD and pouch patients., Conclusions: Genetic variants may have disease-specific phenotypic (serotypic) effects. This implies that genetic risk factors may also be disease modifiers.

Introduction: Inflammatory bowel diseases (IBD) are becoming a significant cause for chronic long term complex morbidity, particularly among adolescents and young adults. IBD patients require multidisciplinary management and considerable health resources. Recent advances and developments in the diagnostics and therapeutic options require identification and tight monitoring of these patients at both hospital and community level for better management and care., Aims: To establish at Maccabi Healthcare Services (MHS) a dedicated registry for inflammatory bowel disease patients for long term monitoring in order to optimize care, better use of health resources and to promote high quality research., Methods: A national project, initiated and headed by a team from Shaare Zedek Medical Center aimed to resolve the complexity in identifying IBD patients at the community setting. The project included data from all Israeli HMOs and major hospitals, that was incorporated into various algorithms to determine prevalence and incidence and to distinguish between Crohn's disease and ulcerative colitis diagnoses. Eventually, an algorithm that includes the number of diagnoses, number of purchases and duration of IBD-related medications showed the best results for separating those that suffer from IBD and those that do not. This algorithm was further validated by chart review., Results: According to the established registry criteria there were 14488 IBD patients in MHS, 13000 active. Additionally we have established an ongoing platform for ongoing monitoring of clinical, therapeutic, laboratory and imaging information., Discussion: Establishing an IBD registry in MHS was enabled by a national project that combined deep professional knowledge of the disease by leading academic centers together with advanced informatics and community large data. We now move on to operate the registry in real life, together with live monitoring of various parameters in order to promote excellent care, communication with patients, management and control and to enable prospective high quality research.

The gaseous mediator nitric oxide (NO) is a central regulatory molecule during the inflammatory phase of cutaneous tissue repair. The inducible NO-synthase (iNOS) represents the main isoform of the three NO producing enzymes at the wound site. In particular, keratinocytes and macrophages are described as main sources of iNOS-derived NO in skin wounds. Here we provide experimental evidence that Ly-6B2 + leukocytes are an additional cellular source of iNOS-derived NO in wounds. As wound iNOS protein expression temporally coincides with both macrophage and neutrophil infiltration, we used immunohistochemistry (IHC) and fluorescence-activated cell sorting (FACS) to address iNOS expression in both macrophages and neutrophil subsets. IHC analyses excluded F4/80 + macrophages as iNOS producers, but indicated Ly-6G/C (Gr-1) + neutrophils to express iNOS in wound granulation tissue. A subsequent FACS-based analysis from cellular wound tissue preparations revealed an iNOS-expressing fraction of Ly-6B2-determined leukocytes that consisted of Ly-6G + and Ly-6G - cells, meaning that mainly mature neutrophils (Ly-6B2 + /Ly-6G + ) as well as inflammatory monocytes (Ly-6B2 + /Ly-6G - ) are dominant iNOS-expressing cell types in the developing granulation tissue of acute wounds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Accurate pulse oximetry reading at hospital admission is of utmost importance, mainly for patients presenting with hypoxemia. Nevertheless, there is no accepted or evidence-based protocol for such structured measuring., Objectives: To devise and assess a structured protocol intended to increase the accuracy of pulse oximetry measurement at hospital admission., Methods: The authors performed a prospective comparison of protocol-based pulse-oximetry measurement with non-protocol based readings in consecutive patients at hospital admission. They also calculated the relative percentage of improvement for each patient (before and after protocol implementation) as a fraction of the change in peripheral capillary oxygen saturation (SpO2) from 100%., Results: A total of 460 patients were recruited during a 6 month period. Implementation of a structured measurement protocol significantly changed saturation values. The SpO2 values of 24.7% of all study participants increased after protocol implementation (ranging from 1% to 21% increase in SpO2 values). Among hypoxemic patients (initial SpO2 < 90%), protocol implementation had a greater impact on final SpO2 measurements, increasing their median SpO2 readings by 4% (3-8% interquartile range; P < 0.05). Among this study population, 50% of the cohort improved by 17% of their overall potential and 25% improved by 50% of their overall improvement potential. As for patients presenting with hypoxemia, the median improvement was 31% of their overall SpO2 potential., Conclusions: Structured, protocol based pulse-oximetry may improve measurement accuracy and reliability. The authors suggest that implementation of such protocols may improve the management of hypoxemic patients.

Deficiency of cyclooxygenase-2 (COX-2) activity in the early postnatal period causes impairment of kidney development leading to kidney insufficiency. We hypothesize that impaired NaCl reabsorption during the first days of life is a substantial cause for nephrogenic defects observed in COX-2 -/- mice and that salt supplementation corrects these defects. Daily injections of NaCl (0.8 mg·g -1 ·day -1 ) for the first 10 days after birth ameliorated impaired kidney development in COX-2 -/- pups resulting in an increase in glomerular size and fewer immature superficial glomeruli. However, impaired renal subcortical growth was not corrected. Increasing renal tubular flow by volume load or injections of KCl did not relieve the renal histomorphological damage. Administration of torsemide and spironolactone also affected nephrogenesis resulting in diminished glomeruli and cortical thinning. Treatment of COX-2 -/- pups with NaCl/DOCA caused a stronger mitigation of glomerular size and induced a slight but significant growth of cortical tissue mass. After birth, renal mRNA expression of NHE3, NKCC2, ROMK, NCCT, ENaC, and Na + /K + -ATPase increased relative to postnatal day 2 in wild-type mice. However, in COX-2 -/- mice, a significantly lower expression was observed for NCCT, whereas NaCl/DOCA treatment significantly increased NHE3 and ROMK expression. Long-term effects of postnatal NaCl/DOCA injections indicate improved kidney function with normalization of pathologically enhanced creatinine and urea plasma levels; also, albumin excretion was observed. In summary, we present evidence that salt supplementation during the COX-2-dependent time frame of nephrogenesis partly reverses renal morphological defects in COX-2 -/- mice and improves kidney function., (Copyright © 2017 the American Physiological Society.)

Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2-dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2 -/- mice was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P3 to P8, the critical time frame of renal COX-2 expression, led to hypoplastic glomeruli, a thinned subcapsular cortex and maturational arrest of superficial glomeruli quite similar to that observed in COX-2 -/- mice. In contrast, AT2 receptor antagonist PD123319 was without any effect on renal development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2 -/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L162313 rescued impaired renal function by reducing serum urea and creatinine and mitigated pathologic albumin excretion. Moreover, glomerulosclerosis in the kidneys of COX-2 -/- mice was reduced. Thus, angiotensin II-AT1-receptor signaling is necessary for COX-2-dependent normal postnatal nephrogenesis and maturation., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Classical antiphospholipid antibodies (aPLa) are found in 6-25% of blood samples from stroke patients. The frequency of novel aPLa antibodies in blood samples of CVA patients is not known. Enzyme-linked immunosorbent assays (ELISA) were performed on blood samples from 209 CVA patients (170 samples were obtained during the acute phase and 39 samples were from patients with complete carotid stenosis) and compared to 54 healthy controls. Subjects were tested for the presence of the classical aPL antibodies anticardiolipin (aCL) and anti-beta2-glycoprotein (aβ2gI), in addition to antiphosphatidylethanolamine (aPE), anti-phosphatidylserine (aPS), and Annexin V. All antibodies were tested for both IgM and IgG subclasses. Numeric analysis of the antibody titer levels (μ/ml) revealed a significantly higher subclinical titer by two standard deviations of many aPL autoantibodies among CVA patients (Pv < 0.05). However, according to the kit manufacturer's cutoff value, no positive antibodies were found except a trend toward higher percentage of positive aPS IgG titer in the CVA group compared to controls (6.2 vs. %0; P = 0.077). According to the manufacturer's cutoff, significantly higher levels of positive antibodies were not found among stroke patients. However, the absolute ELISA values of stroke patients were significantly higher. These results suggest that lower cutoff values than those used for APS diagnosis should be used for risk stratification of CVA among healthy individuals.

Inhibition of cyclooxygenase (Cox) enzymatic activity by non-steroidal anti-inflammatory drugs (NSAIDs) provides the molecular basis of analgesia following wounding or surgery. This study investigated the role of Cox activity in the regulation of vascular endothelial growth factor (VEGF) expression in keratinocytes and the formation of new blood vessels in acute wounds in mice. To this end, human HaCaT keratinocytes were stimulated with epidermal growth factor (EGF). EGF increased Cox-1 mRNA in the presence of the constitutively expressed Cox-1 protein in keratinocytes. EGF coinduced Cox-2 and VEGF 165 mRNA and protein expression and an accumulation of prostaglandin E 2 (PGE 2 ) in cell culture supernatants. Inhibition of Cox isozyme activity by Cox-1 and -2 siRNA or ibuprofen reduced PGE 2 and VEGF 165 release from keratinocytes. In a mouse model of excisional wound healing, Cox-2 and VEGF 165 expression were colocalized in the granulation tissue of acute wounds. Oral treatment of mice with the Cox-1 and -2 inhibitor diclofenac was associated with reduced levels of VEGF 165 protein and an impaired blood vessel formation in acute wound tissue. In summary, our data suggest that a reduction of PGE 2 -triggered VEGF 165 protein expression in wound keratinocytes is likely to contribute to the observed impairment of wound neovascularisation upon Cox inhibition., (© 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Krüppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-γ and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-γ, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1β/TNF-α) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-γ, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-γ agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-γ activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-γ might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the effect of immunosuppressive anticancer therapy on titre levels of anti-hepatitis B surface antibodies (anti-HBs) in hepatitis B surface antigen (HBsAg) negative and anti-HBs positive patients with haematological malignancies or solid tumours., Methods: This retrospective study reviewed the medical records of patients with haematological malignancies or solid tumours. Pretreatment HBsAg negative and anti-HBs positive patients were included in the analysis. Anti-hepatitis B core antibody status was used to evaluate vaccinated patients and those with resolved HBV infections., Results: The medical records of 237 patients were reviewed retrospectively. The median anti-HBs titre decreased significantly after anticancer therapy compared with the pretreatment median anti-HBs titre in all patients (71 mIU/ml versus 57 mIU/ml). Anti-HBs titre decreased significantly in patients with haematological malignancies (70 mIU/m versus 37 mIU/ml) and in patients administered rituximab-based chemotherapy (67 mIU/ml versus 33 mIU/ml) following chemotherapy, whereas there was no significant change in patients with solid tumours. After chemotherapy, patients with low pretreatment anti-HBs titres (<100 mIU/ml) were more likely to become seronegative (<10 mIU/ml)., Conclusion: High levels of anti-HBs may have a protective effect against the reactivation of HBV especially in patients with haematological malignancies who received immunosuppressive anticancer therapy., (© The Author(s) 2016.)

After initial evaluation in the Emergency Department (ED), many patients complaining of abdominal pain are classified as suffering from nonsurgical abdominal pain (NSAP). Clinical characteristics and risk factors for worse prognosis were not published elsewhere.Characterizing the clinical profile of patients hospitalized due to NSAP and identifying predictor variables for worse clinical outcomes.We made a retrospective cohort analysis of patients hospitalized due to NSAP compared to matched control patients (for age, gender, and Charlson comorbidity index) hospitalized due to other, nonsurgical reasons in a ratio of 1 to 10. We further performed in-group analysis of patients admitted due to NSAP in order to appreciate variables (clinical and laboratory parameters) potentially associated with worse clinical outcomes.Overall 23,584 patients were included, of which 2144 were admitted due to NSAP and 21,440 were matched controls. Patients admitted due to NSAP had overall better clinical outcomes: they had lower rates of in-hospital and 30-days mortality (2.8% vs 5.5% and 7.9% vs 10.4% respectively, P < 0.001 for both comparisons). They also had a significantly shorter length of hospital stay (3.9 vs 6.2 days, P < 0.001). Rates of re-hospitalization within 30-days were not significantly different between study groups. Among patients hospitalized due to NSAP, we found that vomiting or hyponatremia at presentation or during hospital stay were associated with worse clinical outcomes.Compared to patients hospitalized due to other, nonsurgical reasons, the overall prognosis of patients admitted due to NSAP is favorable. The combination of NSAP with vomiting and hyponatremia is associated with worse clinical outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder involving thrombotic microangiopathy and is characterized by increased platelet aggregation throughout the body. Acquired TTP can be triggered by a variety of conditions including infections. We hereby describe a case report of an 81-year-old female presenting to the internal medicine department with TTP and active chronic gastritis, positive for Helicobacter pylori (H. pylori) on biopsy. The TTP was highly resistant to medical therapy; however the patient underwent complete resolution of her TTP following H. pylori eradication. We conclude that acquired TTP may be triggered by H. pylori infection and that treating the underlying infection may play a role in improving TTP's outcome in some patients, especially when disease is refractory to medical therapy.

Background: Family history is considered an essential, obligatory part of the primary physician's intake interview. Including coded FH in a unified medical file can save expensive genetic tests and detect the early onset of diseases in young people who are not recommended to be screened routinely. The objectives of this study are to explore the frequency and point in time of recording the coded family history (FH) as a first step to increasing awareness of the importance of such information., Methods: All ICD-9 coded diagnoses of familial histories of disease (ICD-9 coded V16.0 - V19.8), including diseases related to gender, age, and indications of chronic diseases, were collected from the electronic medical records of patients ages 18 and above in Israel's Maccabi Health Care system. The study was carried out in 2012 on the basis of coded data for 1.9 million Maccabi members, which were collected from 2004 through 2011., Results: Of the Maccabi members (the second biggest HMO in Israel covering 2 million people), only 10 % had FH coded documentation. FH was significantly more frequent for females than for males (13.5 % vise 10.1 %) and increased with age. About 10 % of the FH documentation occurred before any disease was diagnosed. The most frequent FH documentation was observed for cardiovascular disease, hypertension, and diabetes. In the case of cancer FH was more frequent in females, whereas in the case of males it was cardiovascular disease., Discussion: Family history is an easy tool and need to be coded and implimented in most visits in order to get the best information of the potential health and disease of the patients., Conclusions: FH frequency is very low and varies with gender and age. The literature suggests that implementing it routinely in primary care will improve health care. Further research is needed to identify the factors that impede primary care givers from complying with FH guidelines.

Background: The serologic status of patients with ulcerative colitis (UC) who develop postoperative pouchitis was compared with that of patients with Crohn's disease (CD) and unoperated patients with UC., Methods: Pouch patients were stratified into normal pouch, acute/recurrent acute pouchitis, and chronic pouchitis/Crohn's-like disease of the pouch groups. Antibodies against glycans associated with CD (anti-Saccharomyces cerevisiae, anti-laminaribioside, anti-chitobioside, and anti-mannobioside carbohydrate antibodies [ASCA, ALCA, ACCA, and AMCA, respectively]) were detected and correlated with type of inflammatory bowel disease and pouch behavior., Results: A total of 501 patients with inflammatory bowel diseases were recruited: 250 (50%) CD, 124 (24.7%) unoperated UC, and 127 (25.3%) UC-pouch. At least 1 positive antibody was detected in 77.6% CD, 52.0% UC-pouch and 33.1% unoperated UC (P < 0.0001 for all). ACCA and AMCA prevalence in CD, UC-pouch and unoperated patients with UC were 33.2%, 24.4%, and 16.9% (P = 0.003 for all) and 35.2%, 26.8%, and 7.3%, respectively (P < 0.0001 for all). ALCA and ASCA were more prevalent in patients with CD than unoperated UC and UC-pouch patients. A longer interval since pouch surgery was associated with inflammatory pouch behavior: 12.45, 11.39, and 8.5 years for acute/recurrent acute pouchitis, chronic pouchitis/Crohn's-like disease of the pouch, and normal pouch, respectively, P = 0.01 for all., Conclusions: The prevalence of the CD-associated anti-glycan antibodies ACCA and AMCA is significantly increased in UC-pouch patients, suggesting that pouch surgery may trigger differential immune responses to glycans. The finding that the serology of UC-pouch patients shares similarities with that of patients with CD supports the notion that those 2 inflammatory bowel diseases share a common pathogenic pathway.

Silicone implants have been in use since the mid-twentieth century, especially in the field of reconstructive breast surgery, and have long been considered as biologically inert and harmless. However, growing body of evidence from the past two decades links silicone with subsequent autoimmunity-related complications, collectively known as autoimmune/inflammatory syndrome induced by adjuvant--ASIA. Previous data suggest that while some patients tend to develop post-exposure autoimmune phenomena such as ASIA, other do not. However, thus far, no criteria for risk stratification were suggested. This current review summarizes the data linking silicone implants and autoimmunity, suggesting means of defining individuals who are at increased risk to develop silicone-induced ASIA, and therefore, a recommendation was made to avoid silicone implantation, e.g., individuals with previously diagnosed autoimmune disorders or with genetic preponderance for hyperactive immune system should not be considered as candidates for silicone implantation.

Myocardial injury and anemia are common among patients in internal medicine departments. Nevertheless, the level of anemia in which blood should be given to these patients is ill defined. We conducted a retrospective, cohort analysis. A total of 209 patients hospitalized to internal medicine, with myocardial injury (troponin I > 0.2 mcg/L, not diagnosed as ACS, acute coronary syndrome) and anemia (Hb < 10 g/dL, without overt bleeding) were included. The overall in-hospital mortality rate was 20.7%. A total of 37 patients (17.8%) had severe anemia (Hb < 8 g/dL). A total of 73 patients (34.9%) were transfused. Severe anemia was not associated with increased long-term mortality in the whole cohort while survival of patients with severe anemia that were not transfused was significantly reduced compared to transfused patients (44% vs 80%; P = 0.03). Mortality rates were similar for all patients with Hb ≥ 8 g/dL, regardless of transfusion (54% vs 49%; P = 0.60). Consistently, lack of blood transfusion in patients with severe anemia was independently associated with a 2.27 (1.08-4.81) greater adjusted risk of all-cause mortality (P-value for interaction = 0.04), whereas it did not significantly increase in patients with Hb ≥ 8 g/dL. Avoidance of blood transfusion is associated with unfavorable outcomes among patients with myocardial injury and severe anemia.

The determination of regenerative wound-healing macrophages as alternatively activated macrophages is currently questioned by the absence of IL-4 in wound tissue. Yet, murine wound tissue expressed high levels of Ym1 (chitinase 3-like 3), an established marker of the IL-4-induced alternatively activated macrophage phenotype. Ym1 was expressed in wound neutrophils but not in macrophages. Initially, Ym1-free wound-healing macrophages, invading from the wound margins, became gradually positive for the protein in the absence of IL-4 signaling and Stat6 activation, as they entered the neutrophil-populated wound regions. IL-4 failed to induce Ym1 protein in ex vivo-cultured wound tissue explants containing wound-healing macrophages. Recombinant Ym1 protein was selectively taken up by macrophages but not by keratinocytes and endothelial cells. Cultured macrophages lost the ability to take up the recombinant protein when four highly conserved residues and the 70-amino acid small α+β domain essential for Ym1 function were removed. The data suggest that the IL-4/Stat6-independent presence of Ym1 protein in wound-healing macrophages is of exogenous origin, with Ym1 taken up from wound neutrophils as the cellular source. The data suggest that in situ determination of wound-healing macrophages, often defined by Ym1, might not essentially describe an IL-4-dependent macrophage phenotype. Consequently, wound-healing macrophages should not be classified by the established categories of the well-accepted but simplified paradigm of M1/M2 macrophage activation., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Type-2 diabetes mellitus (T2D) represents an important metabolic disorder, firmly connected to obesity and low level of chronic inflammation caused by deregulation of fat metabolism. The convergence of chronic inflammatory signals and nutrient overloading at the endoplasmic reticulum (ER) leads to activation of ER-specific stress responses, the unfolded protein response (UPR). As obesity and T2D are often associated with impaired wound healing, we investigated the role of UPR in the pathologic of diabetic-impaired cutaneuos wound healing. We determined the expression patterns of the three UPR branches during normal and diabetes-impaired skin repair. In healthy and diabetic mice, injury led to a strong induction of BiP (BiP/Grp78), C/EBP homologous protein (CHOP) and splicing of X-box-binding protein (XBP)1. Diabetic-impaired wounds showed gross and sustained induction of UPR associated with increased expression of the pro-inflammatory chemokine macrophage inflammatory protein (MIP)2 as compared to normal healing wounds. In vitro, treatment of RAW264.7 macrophages with tunicamycin, and subsequently stimulation with lipopolysaccharide (LPS) and interferon (IFN)-γ enhances MIP2 mRNA und protein expression compared to proinflammatory stimulation alone. However, LPS/IFNγ induced vascular endothelial growth factor (VEGF) production was blunted by tunicamycin induced-ER stress. Hence, UPR is activated following skin injury, and functionally connected to the production of proinflammatory mediators. In addition, prolongation of UPR in diabetic non-healing wounds aggravates ER stress and weakens the angiogenic phenotype of wound macrophages., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background/aims: Our purpose in this study was to analyze telomere length and telomerase activity before and after eradication treatment in gastric mucosa in patients positive for H. pylori., Methodology: There were two groups: a control group (n=17) and a study group (n=21). For H. pylori eradication, the patients were administrated proton pump inhibitor (PPI) + clarithromycin + amoxicillin or PPI + metronidazole + tetracycline + bismuth for 14 days. Telomere length was analyzed with RT-PCR and telomerase activity with PCR-ELISA on biopsy specimens from the antrum. The result p<0.05 was considered significant., Results: Prior to eradication, there was no significant difference between telomere lengths of the patient and control groups (2481.2±1823 and 2958.9±1345.7 bp, p=0.11, respectively). The telomere length of the study group became longer after eradication (before 2481.2±1823bp, after 3766.3±1608.8bp, p=0.01). Telomerase activity was not detected in either the patient or the control group., Conclusions: An increase in telomere length was observed with H. pylori eradication. This finding may indicate the importance of H. pylori eradication to avoid the development of gastric cancer.

Acetaminophen (APAP, paracetamol)-induced hepatotoxicity, although treatable by timely application of N-acetylcysteine, can be fatal. Because it is among the common causes of acute liver failure in intensive care units and in light of its gradually increasing incidence, the need for novel therapeutic strategies aimed at severe intoxication is apparent. Recently, it has been shown that IL-22, a STAT3-activating cytokine, has the capability to mediate liver protection. Herein, the protective potential of IL-22 in murine APAP-induced hepatotoxicity was assessed. Intravenous administration of prophylactic IL-22 significantly reduced serum alanine aminotransferase levels and histopathologic damage in APAP-induced liver injury, a process that coincided with increased hepatocyte proliferation in vivo. Concomitant gene expression analysis revealed hepatic induction of genes prototypically up-regulated by the IL-22/STAT3 axis, among others suppressor of cytokine signaling-3, lipocalin-2, and α1-antichymotrypsin. Notably, in a translational setting of therapeutic treatment 2 hours after APAP, IL-22 supported protection in the context of suboptimal N-acetylcysteine dosing. IL-22 likewise connected to augmented hepatocyte proliferation in this experimental setting. As detected by analysis of inflammatory cytokine production, systemically applied IL-22 did not display acute immunomodulation/stimulation in otherwise untreated or endotoxemic mice. Those latter observations clearly confirm acute tolerability of systemically applied IL-22. Observations presented altogether suggest that therapeutic IL-22 administration is a conceivable tissue-protective regimen aimed at hard-to-treat patients with severe APAP-induced hepatotoxicity., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: While Israel is by far number one in the world of in-vitro fertilization (IVF) treatments per capita, detailed information about the outcome of these treatments is not available., Objectives: To describe IVF activity during the years 2007-2010 in Maccabi Healthcare Services, an independent health provider that reimburses IVF treatments., Methods: Data on IVF cycles and live births were collected from the Maccabi Healthcare Services infertility registry and analyzed by year and age at cycle start., Results: During the four years surveyed, the average patients' age rose from 35.12 to 36.19 years. The number of IVF treatments increased by 50%, while the "live birth" rate fell from 18.8% in 2007, to 14.8% in 2010. A drop in success rate was noted in patients >35 years of age, and more so in patients >40 years of age. Beyond 43 years of age, the success rate was in the low one digit range. The estimated cost of a single live birth in this age group is NIS 399,000., Summary: The clinical results are not encouraging relative to IVF outcomes in Europe and the U.S.A. SurprisingLy, and contrary to worldwide trends, the success rate in Israel decreased during the surveyed years. We speculate that the main reason is that many IVF treatments are conducted in patients that a priori have a very low chance of success. A nationwide prospective IVF registry should be implemented.

Background: Infectious diseases have been associated with increased risk of type 1 diabetes (T1D). The objective of this case-crossover was to quantify the role of infectious diseases as triggers for T1D, 1 and 2 yr preceding disease diagnosis., Methods: All children aged 2-18 yr diagnosed with T1D between 2004 and 2009 among a two million member Israeli healthcare organization were identified (n = 368). For each patient, visits to physicians with symptomatic infectious diseases during 1 and 2 yr before T1D diagnosis were collected and compared. A similar analysis was conducted in a population of non-diabetic members matched on exact date of birth, sex and socioeconomic status (n = 307)., Results: The rate of systemic viral infections was significantly higher in the year before T1D onset, as compared to the prior year [27 vs. 7%, respectively, odds ratio (OR) = 4.7, 95% confidence intervals (CI): 2.9-8.2]. This difference was most significant among patients diagnosed with T1D at the age of 2 to 6 (5 vs. 46%, respectively, OR = 27.0, 95% CI: 4.5-1105.4). Among non-T1D patients of the same age group, no difference was found in the proportion of patients with viral diseases 1 and 2 yr prior to T1D diagnosis (44 vs. 49%, respectively, OR = 0.8, 95% CI: 0.4-1.6). This unique association was limited only to viral diseases and to patients diagnosed with T1D at young age., Conclusions: Our results indicate that T1D occurring in toddlers is characterized with a relatively low incidence of viral disease 2 yr prior to diagnosis and a much higher incidence in the subsequent year., (© 2012 John Wiley & Sons A/S.)

Purpose: Maccabi Healthcare Services, a large health maintenance organization (HMO) operating in Israel, has recently constructed a computerized registry of patients with severe mental illnesses (SMI). In the present study, we aimed to use this registry to investigate the epidemiology of schizophrenia and bipolar affective disorder among adults, and to assess their comorbidity and mortality compared to the general population., Methods: In this historical cohort study, we investigated the age- and sex-specific prevalence and incidence rates of HMO members diagnosed with schizophrenia or bipolar affective disorder between 2003 and 2009. We compared their medical comorbidity and mortality to the general HMO population., Results: A total of 8,848 and 5,732 patients were diagnosed with bipolar (crude prevalence rate of 5 per 1,000) and schizophrenia (3 per 1,000), respectively. The annual incidence rates were 4.2 and 2.4 per 1,000 for schizophrenia and bipolar disorder, respectively. On average, schizophrenic men were diagnosed 4-5 years earlier than schizophrenic women. Compared to the general population, schizophrenia and bipolar disorder patients had a 12- and 9-year shorter life expectancy, respectively. They were also more likely to be diagnosed with diabetes mellitus (odds ratio of 1.9 and 1.6, respectively)., Conclusions: The current study demonstrates the potential use of automated medical databases to characterize the epidemiology of SMI in the community. The increased comorbidity and mortality among these patients has important implication for health authorities for prevention and delivery of health-care services.

Background: The present study describes a computerized registry of cardiovascular disease patients in a large health maintenance organization in Israel. The registry is aimed to be used by health professionals to identify cardiovascular disease patients and to follow the courses of their illnesses and risk factors., Methods: In 1998, the registry was initiated using advanced information technology that integrated personal computerized community and hospital records, data from laboratory tests, dispensed medications, physiological signals, radiological images, and reports from investigations and procedures., Results: Between 1998 and 2007, the number of patients with cardiovascular diseases that were identified by the registry has increased from 34,144 to 80,339. During this period, the age-adjusted prevalence rates have risen from 3.7% to 5.1% and from 1.9% to 2.6%, among men and women, respectively. The percentage of ischemic heart disease patients who reached target LDL was doubled, from 21% in 2000 to 50% in 2006. The average stay in hospital declined from 11.7 to 8.6 days. Primary myocardial infarction rates declined 33% and 54% in men aged 54-65 and women aged 65-74 years, respectively., Conclusions: The present study provides, for the first time in Israel, data on selected quality of care and clinical outcomes using a large, population-based registry of cardiovascular disease patients. It demonstrates a significant improvement in the adherence with LDL tests and achieving target LDL levels and a subsequent decline in incidence of myocardial infarction within ten years since its establishment., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). IL-22 has both immunoregulatory and tissue-protective properties. Functional IL-22 receptor expression is restricted to nonleukocytic cells, such as alveolar epithelial cells. When applied via inhalation, IL-22 reaches the pulmonary system directly and in high concentrations, and may protect alveolar epithelial cells against cellular stress and biotrauma associated with VILI. In A549 lung epithelial cells, IL-22 was able to induce rapid signal transducer and activator of transcription (STAT)-3 phosphorylation/activation, and hereon mediated stable suppressor of cytokine signaling (SOCS) 3 expression detectable even 24 hours after onset of stimulation. In a rat model of VILI, the prophylactic inhalation of IL-22 before induction of VILI (peak airway pressure = 45 cm H(2)O) protected the lung against pulmonary disintegration and edema. IL-22 reduced VILI-associated biotrauma (i.e., pulmonary concentrations of macrophage inflammatory protein-2, IL-6, and matrix metalloproteinase 9) and mediated pulmonary STAT3/SOCS3 activation. In addition, despite a short observation period of 4 hours, inhaled IL-22 resulted in an improved survival of the rats. These data support the hypothesis that IL-22, likely via activation of STAT3 and downstream genes (e.g., SOCS3), is able to protect against cell stretch and pulmonary baro-/biotrauma by enhancing epithelial cell resistibility.

The protective effect of a probiotic mixture of 13 different bacteria and α-tocopherol on 98% ethanol-induced gastric mucosal injury was evaluated. Levels of gastric mucosal pro- and anti-inflammatory cytokines, malondialdehyde, and secretory immunglobulin A were measured. Rats were allocated into four groups: control, ethanol, probiotic, and α-tocopherol. The control and ethanol groups received skim milk for 14 days. Probiotic and α-tocopherol groups were administered probiotic mixture suspended in skim milk and 100 mg/kg α-tocopherol, respectively, by daily gavage for 14 days. On Day 15, gastric lesions were induced by administration of ethanol 98% (1 mL) to all rats except those in the control group. Probiotic, but not α-tocopherol, seemed to inhibit ethanol-induced gastric mucosal tumor necrosis factor-α, interferon-γ, and interleukin-2 production (P > .05). Ethanol caused the elevation of mucosal interleukin-4 level (compared to the control, P < .05). Probiotic pretreatment significantly suppressed the ethanol-induced increase of gastric mucosal interleukin-4 levels. Pretreatment with either probiotic or α-tocopherol inhibited the ethanol-induced increase of mucosal malondialdehyde concentration (P < .01 and P < .05, respectively). Probiotic pretreatment enhanced the gastric mucosal secretory immunoglobulin A concentration (P < .001). In conclusion, probiotic mixture and α-tocopherol reduced ethanol-induced gastric mucosal lipid peroxidation, suggesting that they may be beneficial for gastric lesions induced by lower ethanol concentration.

If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection.

Recently, the suppressor of cytokine signaling (SOCS)-3 has been shown to be expressed in disturbed wound margin epithelia during diabetes-impaired wound healing in mice. To functionally connect a potential contribution of SOCS-3 expression to the control of wound keratinocyte behavior in skin repair, we created a transgenic mouse (tsgn-K5/SOCS3) overexpressing SOCS-3 in keratinocytes using the bovine keratin 5 promoter. Tsgn-K5/SOCS3 mice showed a constitutive expression of SOCS-3 in the basal layer of skin epidermis. Keratinocytes of tsgn-K5/SOCS3 mice showed full inhibition of signal transducer and activator of transcription (STAT)-3 phosphorylation. Tsgn-K5/SOCS3 keratinocytes also showed a strong inhibition of migratory and proliferative potential in vitro. In addition, tsgn-K5/SOCS3 keratinocytes co-expressed the differentiation marker loricrin in the basal layer of nonwounded skin in vivo. Upon wounding, wound tissues of tsgn-K5/SOCS3 mice showed an impairment of wound closure characterized by strongly atrophied wound margin epithelia. Atrophied epithelia of tsgn-K5/SOCS3 mice exhibited a marked reduction in proliferating cells and reduced total keratinocyte numbers. In summary, this study suggests that the presence of SOCS-3 in keratinocytes strongly disturbs epithelial repair of cutaneous wounds by interfering with keratinocyte proliferation and migration.

The suppressor of cytokine signaling (SOCS)-3 has been shown to impair proliferation and migration of keratinocytes. To assess the functional dependency among wound inflammation, SOCS-3 induction in keratinocytes, and the outcome of healing, we generated a transgenic mouse that specifically overexpresses SOCS-3 in keratinocytes. Acute wound healing in transgenic mice was severely impaired. Keratinocyte-specific overexpression of SOCS-3 led to atrophied wound-margin epithelia and augmented the inflammatory response of wound keratinocytes by an increase in chemokine (MIP-2) and inflammatory enzyme (COX-2 and iNOS) expression. In addition, wound tissue of transgenic mice showed a prolonged persistence of neutrophils and macrophages. Remarkably, impaired wounds showed elevated levels of transforming growth factor (TGF)-beta1, which appeared to interfere with healing, as its neutralization markedly improved wound closure in transgenic mice. Interestingly, administration of a TGF-beta-neutralizing antibody increased wound inflammation in nontransgenic mice but not in transgenic littermates. This study suggests that SOCS-3-driven disturbances in wound keratinocytes are sufficient to induce inflamed wound conditions that resemble characteristics of chronic wounds in mice.

In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.

Whether the wound macrophage is a key regulatory inflammatory cell type in skin repair has been a matter of debate. A transgenic mouse model mediating inducible macrophage depletion during skin repair has not been used to date to address this question. Here, we specifically rendered the monocyte/macrophage leukocyte lineage sensitive to diphtheria toxin by expressing the lysozyme M promoter-driven, Cre-mediated excision of a transcriptional STOP cassette from the simian DT receptor gene in mice (lysM-Cre/DTR). Application of diphtheria toxin to lysM-Cre/DTR mice led to a rapid reduction in both skin tissue and wound macrophage numbers at sites of injury. Macrophage-depleted mice revealed a severely impaired wound morphology and delayed healing. In the absence of macrophages, wounds were re-populated by large numbers of neutrophils. Accordingly, macrophage-reduced wound tissues exhibited the increased and prolonged persistence of macrophage inflammatory protein-2, macrophage chemoattractant protein-1, interleukin-1beta, and cyclooxygenase-2, paralleled by unaltered levels of bioactive transforming growth factor-beta1. Altered expression patterns of vascular endothelial growth factor on macrophage reduction were associated with a disturbed neo-vascularization at the wound site. Impaired wounds revealed a loss of myofibroblast differentiation and wound contraction. Our data in the use of lysM-Cre/DTR mice emphasize the pivotal function of wound macrophages in the integration of inflammation and cellular movements at the wound site to enable efficient skin repair.

Objective: We aimed to elucidate to date unknown molecular patterns of dynamic inflammatory tissue responses during uncomplicated healing of caudally pedicled skin flap transplants in mice., Summary Background Data: Distal skin flap ischemic necrosis is a well-known complication in surgery. To improve ischemic conditions in impaired skin flaps, recent work attempted to increase insufficient vascularity by application of angiogenic growth factors or pluripotent cells. Wound inflammation is in the center of tissue repair, but its temporal and spatial regulation remains nearly unstudied in conditions of transplanted skin flap tissue., Methods: RNase protection assay, quantitative real-time polymerase chain reaction, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and immunoblot techniques were used to determine expression and cellular localization of central inflammation-related chemokines, cytokines, enzymes and cell types upon skin flap transplantation., Results: We observed a marked keratinocyte-driven inflammation that moved from the caudal base to distal flap regions during healing. Keratinocytes of the skin flap epithelium expressed increasingly large amounts of chemokines (MIP-2, MCP-1) and cyclooxygenase (Cox)-2 particularly in distal portions of the transplant. The underlying wound bed did not appear to contribute essentially to the inflammatory response. Despite strong attracting chemokine signals, distal flap tissue was not infiltrated by excess numbers of neutrophils and macrophages. Moreover, infiltrating macrophages exhibited an anti-inflammatory phenotype characterized by the absence of NFkappaB activation and Cox-2 in the presence of a marked heme oxygenase (HO)-1 expression in surviving skin flap tissue., Conclusion: Survival of skin flap tissue might be determined by a cytoprotective type of wound macrophage in the presence of an intense epithelium-derived inflammation.

Here we investigated the potential role of protein kinase B (Akt) in normal or diabetes-impaired wound healing in mice. Interestingly, Akt1 was predominant in skin, wound tissue, and human keratinocytes cell line. Acute skin repair was characterized by an increase of Akt1 phosphorylation in wound margin keratinocytes. By contrast, phosphorylated Akt1 was nearly completely absent and paralleled by a poor phosphorylation of the eucaryotic initiation factor 4E-binding protein 1 (4E-BP1) and reduced levels of vascular endothelial growth factor (VEGF) protein in chronic wounds of diabetic ob/ob mice. Inhibition of the phosphatidyl-inositol-3 kinase/Akt pathway by wortmannin and specific abrogation of Akt1 protein using small-interfering RNA revealed a regulatory function of Akt1 in insulin-mediated VEGF biosynthesis in keratinocytes. Insulin-induced VEGF protein biosynthesis in keratinocytes was mediated by Akt1 from a constitutive VEGF-encoding mRNA pool at the posttranscriptional level through a downstream phosphorylation 4E-BP1. Moreover, transfection experiments introducing a constitutively active mutant of Akt1 into keratinocytes revealed the mammalian target of rapamycin kinase as a downstream mediator of Akt1-linked 4E-BP1 phosphorylation and translational control. Our data suggest that the endocrine hormone insulin contributes to VEGF release in skin wounds through an Akt1-mediated posttranscriptional mechanism in keratinocytes.

The peroxisome proliferator-activated receptors (PPARs) represent pharmacological target molecules to improve insulin resistance in type 2 diabetes mellitus. Here we assessed a functional connection between pharmacological activation of PPAR and vascular endothelial growth factor (VEGF) expression in keratinocytes and during diabetes-impaired acute skin repair in obese/obese (ob/ob) mice. PPARbeta/delta agonist 4-[3-[4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid (L165,041) and PPARgamma agonists ciglitazone and troglitazone, but not rosiglitazone, potently induced VEGF mRNA and protein expression from cultured keratinocytes. Inhibitor studies revealed a strong functional dependence of troglitazone- and L165,041-induced VEGF expression on p38 and p42/44 mitogen-activated protein kinase (MAPK) activation in keratinocytes. Rosiglitazone also induced activation of p38 MAPK but failed to mediate the activation of p42/44 MAPK in the cells. Functional ablation of PPARbeta/delta and PPARgamma from keratinocytes by small interfering RNA did not abrogate L165,041- and troglitazone-induced VEGF biosynthesis and suggested VEGF induction as a pleiotropic, PPAR-independent effect of both drugs in the cells. In accordance with the in vitro situation, we found activated p38 MAPK in wound keratinocytes from acute wounds of rosiglitazone- and troglitazone-treated diabetic obese/obese mice, whereas keratinocyte-specific VEGF protein signals were only prominent upon troglitazone treatment. In summary, our data from cell culture and wound healing experiments suggested p38 MAPK activation as a side effect of thiazolidinediones; however, only troglitazone, but not rosiglitazone, seemed to translate p38 MAPK activation into a PPARgamma-independent induction of VEGF from keratinocytes.

The chemokine CXCL16 plays an important role in the recruitment of leukocytes to sites of inflammation influencing the course of experimental glomerulonephritis. Here we show that human kidneys highly express CXCL16 in the distal tubule, connecting tubule and principal cells of the collecting duct with weak expression in the thick ascending limb of Henle. Beside the membrane localization, a soluble form of CXCL16 can be proteolytically released which acts as a chemotactic factor. In human renal tissue the expression pattern of the disintegrin-like metalloproteinase ADAM10 is similar to that of CXCL16, suggesting ADAM10 can potentially cleave CXCL16 in vivo. When we tested this in primary tubular cells we found that blockade of ADAM10 activity inhibited the IFN-gamma induced release of soluble CXCL16. Acute tubular damage in renal allografts was associated with elevated urinary CXCL16 and this correlated with focally increased apical CXCL16 expression in the distal tubules and collecting ducts. Renal allograft biopsies, with a histopathological diagnosis of acute interstitial rejection, showed increased basolateral ADAM10 expression together with high numbers of infiltrating T cells. Our results suggest that CXCL16 and ADAM10 are involved in the recruitment of T cells to the kidney and play an important role in inflammatory kidney diseases.