Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis on sexuality and inflammatory bowel disease. / Documento de posicionamiento. Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa sobre sexualidad y enfermedad inflamatoria intestinal.

It is widely acknowledged that inflammatory bowel disease (IBD) is associated with a high prevalence of sexual dysfunction (SD). However, there is a notable paucity of specific literature in this field. This lack of information impacts various aspects, including the understanding and comprehensive care of SD in the context of IBD. Furthermore, patients themselves express a lack of necessary attention in this area within the treatment of their disease, thus creating an unmet need in terms of their well-being. The aim of this position statement by the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) is to provide a review on the most relevant aspects and potential areas of improvement in the detection, assessment, and management of SD in patients with IBD and to integrate the approach to sexual health into our clinical practice. Recommendations are established based on available scientific evidence and expert opinion. The development of these recommendations by GETECCU has been carried out through a collaborative multidisciplinary approach involving gastroenterologists, gynecologists, urologists, surgeons, nurses, psychologists, sexologists, and, of course, patients with IBD.

Benefits of Paediatric to Adult Transition Programme in Inflammatory Bowel Disease: The BUTTERFLY Study of GETECCU and SEGHNP.

(1) Background: Transition is a planned movement of paediatric patients to adult healthcare systems, and its implementation is not yet established in all inflammatory bowel disease (IBD) units. The aim of the study was to evaluate the impact of transition on IBD outcomes. (2) Methods: Multicentre, retrospective and observational study of IBD paediatric patients transferred to an adult IBD unit between 2017-2020. Two groups were compared: transition (≥1 joint visit involving the gastroenterologist, the paediatrician, a programme coordinator, the parents and the patient) and no-transition. Outcomes within one year after transfer were analysed. The main variable was poor clinical outcome (IBD flare, hospitalisation, surgery or any change in the treatment because of a flare). Predictive factors of poor clinical outcome were identified with multivariable analysis. (3) Results: A total of 278 patients from 34 Spanish hospitals were included. One hundred eighty-five patients (67%) from twenty-two hospitals (65%) performed a structured transition. Eighty-nine patients had poor clinical outcome at one year after transfer: 27% in the transition and 43% in the no-transition group (p = 0.005). One year after transfer, no-transition patients were more likely to have a flare (36% vs. 22%; p = 0.018) and reported more hospitalisations (10% vs. 3%; p = 0.025). The lack of transition, as well as parameters at transfer, including IBD activity, body mass index < 18.5 and corticosteroid treatment, were associated with poor clinical outcome. One patient in the transition group (0.4%) was lost to follow-up. (4) Conclusion: Transition care programmes improve patients' outcomes after the transfer from paediatric to adult IBD units. Active IBD at transfer impairs outcomes.

Questionnaires for the subjective evaluation of patients with fibromyalgia: a systematic review.

INTRODUCTION: The objective of this study was to identify and review the subjective assessment tools validated in patients with fibromyalgia, identifying their most significant structural characteristics, as well as the psychometric characteristics analyzed in each of the identified instruments. EVIDENCE ACQUISITION: This systematic review was registered in PROSPERO with the following reference: CRD42022306878. It analyzed documents published until June 30, 2022, through the Medline, Pedro and Scopus, Dialnet, Cinahl and Latin Index databases. The keywords used were: 1) fibromyalgia; 2) assessment; 3) questionnaire; 4) reliability; 5) validity; 6) scale; and 7) validation study. Combined using the Boolean operators "AND" and "OR." The included articles were analyzed to extract: data on the structural characteristics of the questionnaires (including acronym, year of publication, number of items, sub-categories, time to complete the questionnaire, measurement range, cutoff score and cost) and psychometric characteristics of the selected questionnaires, including data on reliability (Cronbach's alpha and test-retest) and data on the validity of the questionnaires (content, construct and criterion validity). EVIDENCE SYNTHESIS: Twenty-two studies containing 16 questionnaires were analyzed. The quality and risk of bias assessment was performed following the COSMIN checklist. In general, the quality of the subjective assessment studies validated in the population with fibromyalgia was good, with the exception of 5 studies, which did not exceed 5 points out of 10. The first questionnaire analyzed was published in 1991, and the last in 2020; the number of items ranged from 3 to 60. The most measured subcategories are function, overall impact and symptoms; other studies also include sleep and cognition disturbances. Only 6 studies described the time to complete them. The most analyzed psychometric characteristics were reliability (analyzed by 13 questionnaires), validity (analyzed by 7) and error measures (provided by only 3 of them). CONCLUSIONS: There is a wide range of questionnaires specifically designed for patients with fibromyalgia that present good and/or excellent basic psychometric characteristics. The structural characteristics of the identified instruments were very heterogeneous, which makes it possible to select those that best adapt to the clinical/investigator scenario where the tool will be used.

Barriers and applied activity, quality of life and self-efficacy in prostate cancer survivors 1 year after completing radiotherapy.

PURPOSE: The aims of the study were to assess self-reported physical activity (PA) levels, barriers to PA, quality of life and self-efficacy to manage chronic disease of prostate cancer survivor 1 year after radiotherapy treatment. METHODS: A cross-sectional case-control study was performed. Prostate cancer survivor patients treated with radiotherapy were recruited from the Radiation Oncology Service of the "Complejo Hospitalario Universitario" (Granada) and compared with age-matched healthy men. Outcomes included were perception of benefits for physical activity and potential barriers (Exercise Benefits/Barriers Scale), physical activity levels assessed by the International Physical Activity Questionnaire (IPAQ), quality of life (EuroQol five-dimension three-levels) and self-efficacy (Self-Efficacy to Manage Chronic Disease). RESULTS: A total of 120 patients were included in our study. Significant differences were found between groups with worse results for the prostate cancer patient group in the variable perception of the benefit of physical activity, potential barriers, and physical activity. Regarding quality of life and self-efficacy, significant differences were also observed between groups with a greater score in the control group. CONCLUSION: In conclusion, the results of this study reveal that self-reported PA levels, as measured using the IPAQ, were low in prostate cancer survivors after treatment. Results also showed worse perception of benefits for PA and potential barriers by the cancer survivors. Similarly, the quality of life and self-efficacy to manage chronic disease of prostate cancer survivors was lower.

Oleoylethanolamide attenuates the stress-mediated potentiation of rewarding properties of cocaine associated with an increased TLR4 proinflammatory response.

The lipid-derived messenger oleoylethanolamide (OEA) has been involved in multiple physiological functions including metabolism and the immune response. More recently, OEA has been observed to affect reward-related behavior. Stress is a major risk factor for drug use and a predictor of drug relapse. In the laboratory, social stress has been largely studied using the social defeat (SD) model. Here, we explored the effects of different OEA administration schedules on the increased rewarding properties of cocaine induced by SD. In addition, we evaluated the anti-inflammatory action of OEA pretreatment in TLR4 expression caused by SD in the cerebellum, a novel brain structure that has been involved in the development of cocaine addiction. Adult OF1 mice were assigned to an experimental group according to the stress condition (exploration or SD) and treatment (OEA before SD, OEA before conditioning or subchronic OEA treatment). Mice were administered with OEA i.p (10 mg/kg) 10 min previously to the corresponding event. Three weeks after the last SD encounter, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg). As expected, socially defeated mice presented greater vulnerability to the cocaine reinforcing effects and expressed CPP. Conversely, this effect was not observed under a non-stressed condition. Most importantly, we observed that OEA pretreatment before SD or before conditioning prevented cocaine CPP in defeated mice. Biochemical analysis showed that OEA administration before SD decreased proinflammatory TLR4 upregulation in the cerebellum caused by social stress. In summary, our results suggest that OEA may have a protective effect on stress-induced increased cocaine sensitivity by exerting an anti-inflammatory action.

Treatment With Adalimumab 80 mg Every Other Week in Inflammatory Bowel Disease: Results of Treatment Intensification in Clinical Practice.

Background: Loss of response to anti-tumor necrosis factor drugs in patients with inflammatory bowel disease (IBD) is frequent and, in case of low drug levels, treatment intensification is recommended. In addition, in cases in which clinical response without attainment of remission (clinical, endoscopic, or radiological), intensification could be justified since higher drug levels are associated with better outcomes. For adalimumab (ADA), the standard intensification regimen is 40 mg every week (ew). Availability of ADA 80 mg prefilled pens has enabled every other week (eow) intensification. We assessed the clinical efficacy of intensification with ADA 80 mg eow. Methods: This retrospective study was conducted at a tertiary hospital in Spain. Patients with IBD receiving maintenance ADA 80 mg eow with clinical, biomarker, and drug-level assessments were included. Demographics and clinical, biological, and endoscopic evaluation of the disease before and after ADA intensification, and pharmacokinetic assessments, were collected. Results: Eighty-seven patients (72 Crohn's disease, 15 ulcerative colitis; average age 50 years) were included. Reasons for ADA intensification were: low ADA levels-<5 µg mL-1-(17%), low ADA levels-<5 µg mL-1-without clinical response (63%), clinical response without clinical remission (15%) and active disease on objective evaluation (including colonoscopy, magnetic resonance imaging, capsule endoscopy, and/or intestinal ultrasound; 5%). Following treatment intensification to ADA 80 mg eow, 75 patients (86%) were in clinical remission and 69 (79.3%) were in biologic remission (clinical remission and normalization of biomarkers). After a median follow-up of 19 months (interquartile range 13-25), 63 patients (72%) remained on treatment and in clinical remission. There were no serious infections, hospitalizations, or deaths. Drug costs did not increase with the 80 mg eow regimen versus a standard intensification regimen. Conclusions: ADA intensification to 80 mg eow was safe, effective, and did not increase drug costs versus standard intensification to 40 mg ew in our experience.

Effectiveness and Safety of Ustekinumab in Elderly Patients with Crohn's Disease: Real World Evidence From the ENEIDA Registry.

BACKGROUND AND AIMS: Clinical trials and real-life studies with ustekinumab in Crohn's disease [CD] have revealed a good efficacy and safety profile. However, these data are scarcely available in elderly patients. Therefore, we aim to assess the effectiveness and safety of ustekinumab in elderly patients with CD. METHODS: Elderly patients [>60 years old] from the prospectively maintained ENEIDA registry treated with ustekinumab due to CD were included. Every patient was matched with two controls under 60 years of age, according to anti-tumour necrosis factor use and smoking habit. Values for the Harvey-Bradshaw Index [HBI], endoscopic activity, C-reactive protein [CRP] and faecal calprotectin [FC] were recorded at baseline and at weeks 16, 32 and 54. RESULTS: In total, 648 patients were included, 212 of whom were elderly. Effectiveness was similar between young and elderly patients during the follow-up. Steroid-free remission was similar at week 16 [54.6 vs 51.4%, p = 0.20], 32 [53.0% vs 54.5%, p = 0.26] and 54 [57.8% vs 51.1%, p = 0.21]. Persistence of ustekinumab as maintenance therapy was similar in both age groups [log-rank test; p = 0.91]. There was no difference in the rate of adverse effects [14.2% vs 11.2%, p = 0.350], including severe infections [7.1% vs 7.3%, p = 1.00], except for the occurrence of de novo neoplasms, which was higher in older patients [0.7% vs 4.3%, p = 0.003]. CONCLUSIONS: Ustekinumab is as effective in elderly patients with CD as it is in non-elderly patients. The safety profile also seems to be similar except for a higher rate of de novo neoplasms, probably related to the age of the elderly patients.

Psychological distress prior to surgery is related to symptom burden and health status in lung cancer survivors.

PURPOSE: Patients with lung cancer experience a variety of distressing symptoms which could adversely affect quality of life. The aim of this study was to determine whether psychological distress prior to surgery is associated to health status and symptom burden in lung cancer survivors. METHODS: A longitudinal observational study with 1-year follow-up was carried out. Health status was measured by the WHO Disability Assessment Scale (WHO-DAS 2.0), the Euroqol-5 dimensions (EQ-5D) and the Pittsburgh Sleep Quality Index (PSQI). Symptoms severity included dyspnoea (Multidimensional Profile of Dyspnoea); pain (Brief Pain Inventory); fatigue (Fatigue Severity Scale); and cough (Leicester Cough Questionnaire). RESULTS: One hundred seventy-four lung cancer patients were included. Patients in the group with psychological distress presented a worse self-perceived health status, functionality and sleep quality. The group with psychological distress also presented higher dyspnoea, fatigue and pain. CONCLUSION: Patients with psychological distress prior surgery present with a greater symptom burden and a poorer self-perceived health status, lower functionality and sleep quality, than patients without distress 1 year after the lung resection.

Effects of Alcohol Binge Drinking and Oleoylethanolamide Pretreatment in the Gut Microbiota.

Introduction: Chronic alcohol consumption is known to cause gut dysbiosis (changes in microbiota composition and/or function, disruptive of the normal host-microbiota interactions). However, little is known about the changes that alcohol binge drinking induces in the gut microbiota. Here, we have tested the hypothesis that a protocol of alcohol binge drinking, known to induce neuroinflammation in previous studies, also promotes intestinal dysbiosis, and we explored how oleoylethanolamide (OEA, an acylethanolamide proven to counteract alcohol binge drinking-induced neuroinflammation) pretreatment modulates alcohol-induced dysbiosis. Methods: Alcohol binges were forced by gavage three times per day during 4 consecutive days; OEA pretreatment (intraperitoneal or intragastric) was administered before each alcohol gavage. Stool microbiota composition was assessed by next-generation 16S rRNA gene sequencing, prior and after the 4-day alcohol binge protocol. Results: Alcohol binge drinking reduced the richness of the gut microbiota and changed the microbial community, reducing Lactobacillus among other genera. Pretreatment with OEA in the alcohol-administered rats decreased the richness, evenness, and Shannon indices to a greater extent with respect to alcohol alone, also changing the community structure. Microbial interactions in the association network were further decreased following OEA administration in the alcohol group, with respect to the water administration. The synergistic interaction between alcohol binge and OEA was affected by the route of administration of OEA, since oral and i.p. administrations differently changed the community structure. Conclusion: Results suggest that alcohol binge drinking produces a clear dysbiosis in animals; we observed that the well-known protective actions of OEA in the context of alcohol abuse might not be related to OEA-induced changes in alcohol-induced dysbiosis. These are observational results, and thus, further research will be needed for a complete understanding of the biological significance of the observed changes.

Cerebellar and cortical TLR4 activation and behavioral impairments in Wernicke-Korsakoff Syndrome: Pharmacological effects of oleoylethanolamide.

Wernicke-Korsakoff Syndrome (WKS) is a neuropsychiatric disorder whose etiology is a thiamine deficiency (TD), with alcoholism being the main underlying cause. Previous evidence suggests the presence of initial neuroinflammation and oxidative/nitrosative stress in the physiopathology, although the specific molecular mechanisms underlying TD-induced brain damage and behavioral disabilities are unknown. We explored the specific role of the innate immune receptor TLR4 in three murine models of WKS, based on the combination of a thiamine-deficient diet and pyrithiamine injections (0.25 mg/kg, i.p.) over time. The Symptomatic Model (SM) allowed us to describe the complete neurological/neurobehavioral symptomatology over 16 days of TD. Animals showed an upregulation of the TLR4 signaling pathway both in the frontal cortex (FC) and cerebellum and clear motor impairments related with cerebellar dysfunction. However, in the Pre-Symptomatic Model (PSM), 12 days of TD induced the TLR4 pathway upregulation in the FC, which correlated with disinhibited-like behavior, but not in the cerebellum, and no motor impairments. In addition, we tested the effects of the biolipid oleoylethanolamide (OEA, 10 mg/kg, i.p., once daily, starting before any symptom of the pathology is manifested) through the Glucose-Precipitated Model (GPM), which was generated by glucose loading (5 g/kg, i.v., last day) in thiamine-deficient animals to accelerate damage. Pretreatment with OEA prevented the TLR4-induced signature in the FC, as well as an underlying incipient memory disability and disinhibited-like behavior. This study suggests a key role for TLR4 in TD-induced neuroinflammation in the FC and cerebellum, and it reveals different vulnerability of these brain regions in WKS over time. Pre-treatment with OEA counteracts TD-induced TLR4-associated neuroinflammation and may serve as co-adjuvant therapy to prevent WKS-induced neurobehavioral alterations.

Usefulness of Thiopurine Monotherapy for Crohn's Disease in the Era of Biologics: A Long-Term Single-Center Experience.

BACKGROUND: Thiopurines are classically used in Crohn's disease (CD). Treatment fails in a proportion of patients either due to adverse events (AE) or lack of efficacy. Increasing use of anti-TNFα biologic drugs may have had impact on thiopurines usage. AIM: To evaluate the evolving use of azathioprine (AZA) monotherapy in the era of biologics. METHODS: The study retrospectively analyzed clinical records of all CD patients who started treatment with AZA monotherapy at our center since 1990. Dates of starting AZA and treatment failure (TF) were collected. We defined AZA TF if it was withdrawn due to lack of efficacy or AE, or biologics were added. RESULTS: A total of 383 patients were included: 46.5% were males and mean age was 31 (range 17-84) years. Median follow-up was 43 (range 0.2-289) months. Overall, 147 patients (38%) experienced TF. Median cumulative survival time of AZA was 126 (95% CI 105-147) months. Proportion of patients with AZA TF increased along time: 7 patients in 1990-1995 (4.7% of all TF); 8 in 1996-2000 (5.4%); 22 in 2001-2005(15%); 41 in 2006-2010 (28%); 69 in 2011-2014 (47%) (p = 0.04). 7%, 21%, 4%, 45%, and 33.3% of patients moved to biologics in each period, respectively (χ2 = 13.07; p < 0.05). Seventy-four patients (18.4%) stopped AZA due to AE, and 73(19%) due to lack of efficacy. Regarding AZA indication, prevention of postoperative recurrence obtained better results than steroid dependency (p = 0.001); perianal fistulizing CD predicted poorer outcomes (p = 0.002). CONCLUSION: An important proportion of CD patients under AZA monotherapy experienced TF in our experience. Although AZA monotherapy remains useful for CD in the era of biologics, current clinical practice is shifting to anti-TNFα biologic drugs in an increasing proportion of patients.

Idiopathic portal hypertension regarding thiopurine treatment in patients with inflammatory bowel disease.

INTRODUCTION: The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown. MATERIAL AND METHODS: A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment. RESULTS: At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn's disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3). CONCLUSION: Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage.

A simple transcriptomic signature able to predict drug-induced hepatic steatosis.

It is estimated that only a few marketed drugs are able to directly induce liver steatosis. However, many other drugs may exacerbate or precipitate fatty liver in the presence of other risk factors or in patients prone to non-alcoholic fatty liver disease. On the other hand, current in vitro tests for drug-induced steatosis in preclinical research are scarce and not very sensitive or reproducible. In the present study, we have investigated the effect of well-characterized steatotic drugs on the expression profile of 47 transcription factors (TFs) in human hepatoma HepG2 cells and found that these drugs are able to up- and down-regulate a substantial number of these factors. Multivariate data analysis revealed a common TF signature for steatotic drugs, which consistently and significantly repressed FOXA1, HEX and SREBP1C in cultured cells. This signature was also observed in the livers of rats and in cultured human hepatocytes. Therefore, we selected these three TFs as predictive biomarkers for iatrogenic steatosis. With these biomarkers, a logistic regression analysis yielded a predictive model, which was able to correctly classify 92 % of drugs. The developed algorithm also predicted that ibuprofen, nifedipine and irinotecan are potential steatotic drugs, whereas troglitazone is not. In summary, this is a sensitive, specific and simple RT-PCR test that can be easily implemented in preclinical drug development to predict drug-induced steatosis. Our results also indicate that steatotic drugs affect expression of both common and specific subsets of TF and lipid metabolism genes, thus generating complex transcriptomic responses that cause or contribute to steatosis in hepatocytes.

The human liver fatty acid binding protein (FABP1) gene is activated by FOXA1 and PPARα; and repressed by C/EBPα: Implications in FABP1 down-regulation in nonalcoholic fatty liver disease.

Liver fatty acid binding protein (FABP1) prevents lipotoxicity of free fatty acids and regulates fatty acid trafficking and partition. Our objective is to investigate the transcription factors controlling the human FABP1 gene and their regulation in nonalcoholic fatty liver disease (NAFLD). Adenovirus-mediated expression of multiple transcription factors in HepG2 cells and cultured human hepatocytes demonstrated that FOXA1 and PPARα are among the most effective activators of human FABP1, whereas C/EBPα is a major dominant repressor. Moreover, FOXA1 and PPARα induced re-distribution of FABP1 protein and increased cytoplasmic expression. Reporter assays demonstrated that the major basal activity of the human FABP1 promoter locates between -96 and -229bp, where C/EBPα binds to a composite DR1-C/EBP element. Mutation of this element at -123bp diminished basal reporter activity, abolished repression by C/EBPα and reduced transactivation by HNF4α. Moreover, HNF4α gene silencing by shRNA in HepG2 cells caused a significant down-regulation of FABP1 mRNA expression. FOXA1 activated the FABP1 promoter through binding to a cluster of elements between -229 and -592bp, whereas PPARα operated through a conserved proximal element at -59bp. Finally, FABP1, FOXA1 and PPARα were concomitantly repressed in animal models of NAFLD and in human nonalcoholic fatty livers, whereas C/EBPα was induced or did not change. We conclude that human FABP1 has a complex mechanism of regulation where C/EBPα displaces HNF4α and hampers activation by FOXA1 and PPARα. Alteration of expression of these transcription factors in NAFLD leads to FABP1 gen repression and could exacerbate lipotoxicity and disease progression.

[Risk of thromboembolic phenomena in patients with inflammatory bowel disease]. / Riesgo de fenómenos tromboembólicos en pacientes con enfermedad inflamatoria intestinal.

INTRODUCTION: Inflammatory bowel disease (IBD) is an independent risk factor for thromboembolic phenomena (TEP). We evaluated the prevalence and the possible risk factors associated with developing TEP in patients with IBD in our center. MATERIAL AND METHODS: Data were retrospectively collected from January 1995 to December 2011 from 23 patients. A total of 61% were diagnosed with Crohn's disease (CD) and 39% with ulcerative colitis (UC) according to routine criteria. RESULTS: When the Montreal classification was used, 58% of the patients with CD had an inflammatory pattern (B1), 25% a stenosing pattern (B2) and 17% a fistulizing pattern (B3). Half the patients had ileocolic involvement (L3), one-third had colonic involvement (L2) and the remainder had ileal involvement (L1). Among patients with UC according to the Montreal classification, 78% had extensive colitis (E3), 11% had left colonic involvement (E2) and 11% had proctocolitis (E1). During the event, almost half the patients with UC had severe inflammatory activity (S3; 44%), 33% had mild-moderate activity (S1: 22%, S2: 11%) and only 22% were in remission (S0). Overall, at the time of the TEP, 48% of the patients had mild-moderate activity and 22% had severe activity. Likewise, 44% were hospitalized at the time of the event. In UC, an increase in the prevalence of TEP was found in admitted patients (66%). None of the patients had a family history of TEP, two patients (9%) had associated thrombophilia and 26% were active smokers. There were no TEP during pregnancy. Only one patient was taking contraceptive pills when the event occurred. The most frequent forms of TEP were deep vein thrombosis of the legs (55%) followed by pulmonary thromboembolism (25%). CONCLUSIONS: TEP are relatively frequent in patients with IBD, with a strong impact on morbidity and mortality. In our series, risk factors for these events were more extensive involvement (any of the groups) and severe inflammatory activity. No significant association between classical risk factors such as the use of contraceptives, pregnancy, coagulation disorders or smoking and the risk of TEP were found.

Vascular endothelial growth factor-mediated islet hypervascularization and inflammation contribute to progressive reduction of ß-cell mass.

Type 2 diabetes (T2D) results from insulin resistance and inadequate insulin secretion. Insulin resistance initially causes compensatory islet hyperplasia that progresses to islet disorganization and altered vascularization, inflammation, and, finally, decreased functional ß-cell mass and hyperglycemia. The precise mechanism(s) underlying ß-cell failure remain to be elucidated. In this study, we show that in insulin-resistant high-fat diet-fed mice, the enhanced islet vascularization and inflammation was parallel to an increased expression of vascular endothelial growth factor A (VEGF). To elucidate the role of VEGF in these processes, we have genetically engineered ß-cells to overexpress VEGF (in transgenic mice or after adeno-associated viral vector-mediated gene transfer). We found that sustained increases in ß-cell VEGF levels led to disorganized, hypervascularized, and fibrotic islets, progressive macrophage infiltration, and proinflammatory cytokine production, including tumor necrosis factor-α and interleukin-1ß. This resulted in impaired insulin secretion, decreased ß-cell mass, and hyperglycemia with age. These results indicate that sustained VEGF upregulation may participate in the initiation of a process leading to ß-cell failure and further suggest that compensatory islet hyperplasia and hypervascularization may contribute to progressive inflammation and ß-cell mass loss during T2D.

Foxa1 reduces lipid accumulation in human hepatocytes and is down-regulated in nonalcoholic fatty liver.

Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid ß-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance.

Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile.

Steatosis is the first step in the development of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms involved in its pathogenesis are not fully understood. Many nuclear receptors (NRs) involved in energy homeostasis and biotransformation constitute a network connecting fatty acids, cholesterol and xenobiotic metabolisms; therefore, multiple NRs and their ligands may play a prominent role in liver fat metabolism and accumulation. In this study we have attempted to gain insight into the relevance of the NR superfamily in NAFLD by investigating the steatogenic potential of 76 different NR ligands in fatty acid overloaded human hepatocytes and hepatoma cells. Moreover, we have determined the mRNA expression level of 24 NRs to correlate the steatogenic potential of the ligands with the expression of their associated NRs in the cultured cells. Our results demonstrate that 18% of the examined NR ligands enhanced lipid accumulation in human hepatocytes and/or hepatoma cells. Among them, ligands of PPARgamma (e.g., thiazolidinediones), LXR (paxilline and 24(S),25-epoxycholesterol), PXR (hyperforin), CAR (3alpha,5alpha-androstenol), ERalpha (tamoxifen), FXR (Z-guggulsterone), VDR (25-hydroxyvitamin D3) and particular retinoids and farnesoids showed a significant pro-steatotic effect. The mRNA level of most of the NRs examined was well preserved in human hepatocytes, but HepG2 showed a deranged profile, where many of the receptors had a marginal or negligible level of expression in comparison with the human liver. By comparing the steatogenic effect of NR ligands with the NR expression levels, we conclude that LXR, PXR, RAR and PPARgamma ligands likely induce fat accumulation by a NR-dependent mechanism. Indeed, over-expression of PXR in HepG2 cells enhanced the steatogenic effect of hyperforin and rifampicin. However, the accumulation of fat induced by other ligands did not correlate with the expression of their associated NR. Our results also suggest that human hepatocytes cultured with free fatty acids offer a highly valuable in vitro system to investigate the pathogenesis and therapeutics of the human fatty liver.

In vivo gene transfer to healthy and diabetic canine pancreas.

Gene therapy may provide new treatments for severe pancreatic disorders. However, gene transfer to the pancreas is difficult because of its anatomic location and structure, and pancreatitis is a serious concern. Like the human pancreas, the canine pancreas is compact, with similar vascularization and lobular structure. It is therefore a suitable model in which to assess gene transfer strategies. Here we examined the ability of adenoviral vectors to transfer genes into the pancreas of dogs in which pancreatic circulation had been clamped. Adenoviruses carrying the beta-galactosidase (beta-gal) gene were injected into the pancreatic-duodenal vein and the clamp was released 10 min later. These dogs showed beta-gal-positive cells throughout the pancreas, with no evidence of pancreatic damage. beta-Gal was expressed mainly in acinar cells, but also in ducts and islets. Moreover, transduction was prominent in connective tissue of the lobe septa. beta-Gal expression in the exocrine pancreas of a diabetic dog was also found to be similar to that observed in healthy dogs. Thus, efficient gene transfer to canine pancreas in vivo may be achieved by adenovirus injection after clamping pancreatic circulation. This technique may be used to assay new gene therapy approaches for diabetes mellitus and other pancreatic disorders.