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Background and aims: Anxiety and depression are prevalent in patients with inflammatory bowel diseases (IBD), especially during IBD flares. IBD therapies can profoundly affect the mood of patients with IBD. We aimed to determine the long-term impact of anti-tumor necrosis factor (anti-TNF) and immunomodulators (IM) on anxiety and depressive symptoms in IBD patients. Methods: We compared three treatment groups with IM only (group A), anti-TNF ± IM (group B) and no such therapy (group C). Patients completed the hospital anxiety and depression scale (HADS) at 1 year, 3 years, and 5 years after start of treatment. Results: In total, 581 patients with IBD (42.9% Crohn’s disease, 57.1% ulcerative colitis/IBD unclassified) participated in this study. Effects of treatment were analyzed in a mixed effects model, with and without correction for confounders. Compared with group C, group B showed a significant treatment-related improvement in both anxiety and depressive symptoms within the first 2.5 years and also thereafter. Group A showed a significant long-term improvement of anxiety and both short-term and long-term improvement in depressive symptoms. The significance of these results was maintained after correction for confounders, including corticosteroid treatment. Additionally, both groups A and B showed a significant decrease in disease activity in the first 2.5 years after start of treatment and also thereafter. Anti-TNF and IM treatment were associated with a similarly significant decrease in anxiety and depressive symptoms over an observation period of up to 5 years. Conclusion: Besides a clear benefit for disease activity, anti-TNF and IM apparently improve the mood of patients with IBD.

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P, Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Extraintestinal manifestations (EIM) have become an important source of morbidity and disability as well as an identified risk factor for an unfavorably course of disease in inflammatory bowel diseases (IBD). Therefore, efforts have been put into a more global and interdisciplinary management of IBD patients in collaboration with rheumatologists, dermatologists, and ophthalmologists. A real therapeutic success has also been obtained with a more “systemic” IBD treatment associated with the development of monoclonal antibodies against TNF alpha and biological agents derived from the treatment of rheumatological disease (also called biological Disease-Modifying Antirheumatic Drugs). The prevalence of these EIM remains too low to undergo randomized controlled trials with this specific focus and therefore the evidence relies on case series and experts’ opinions, which lowers the level of evidence. After a careful review of the most recent literature, this paper aims to update the reader on the latest therapeutic management of IBD patients with EIM.

Background: Loss of response is frequently encountered in patients with inflammatory bowel disease (IBD) treated with antitumor necrosis factor (TNF) agents. Therapeutic drug monitoring (TDM) and antidrug antibody measurement are increasingly used in this setting. Methods: To establish a consensus on the use of TDM in the context of loss of response to anti-TNFs, we performed a vote using a Delphi-style process followed by an expert panel discussion among 8 IBD specialists practicing in Switzerland, Europe. Statements were rated on an even Likert-scale ranging from 1 (strong disagreement) to 4 (strong agreement), based on expert opinion and the available literature. Results: The experts agreed on the following statements: (i) loss of response is associated with inadequate drug levels in both Crohn’s disease and ulcerative colitis; (ii) best timepoint for measuring drug levels is prior to the next application (= trough levels) with different thresholds for anti-TNF agents (infliximab 5 μg/mL, adalimumab 8 μg/mL, certolizumab pegol 10 μg/mL); (iii) antidrug antibodies are predictive for loss of response; and (iv) antidrug-antibody titers and drug trough levels are key determinants in the treatment algorithm. Data about non-anti-TNF biologics were considered too limited to propose recommendations. Conclusion: A Delphi-style consensus among 8 IBD experts shows that TDM and measurement of antidrug-antibody titers are useful in the context of loss of response to anti-TNF. Optimal cutoff levels depend on the type of anti-TNF. These values are critical in the decision making process. More studies are needed to address the value of such measurements for non-anti-TNF biologics.

The published data about the efficacy of the intercellular adhesion molecule-1 (ICAM-1) antisense oligonucleotide termed alicaforsen in inflammatory bowel disease (IBD) is rather inconsistent. This case series analyzes its efficacy in chronic refractory pouchitis, after proctocolectomy.We performed a retrospective analysis on all patients who had received at least one dose of alicaforsen for IBD at three referral centers in Switzerland. We assessed the drug's efficacy in patients treated for chronic refractory pouchitis, by comparing the clinical and/or endoscopic disease activity at baseline with a 2-3-month follow-up visit.We identified 22 patients who had received at least one dose. Among them, 13 patients were being treated for chronic refractory pouchitis. These patients had a median age of 38.0 years (95% CI 21.0-69.0) and five were female (38.5%). The median time since pouch surgery was 102.5 months (95% CI 16.0-288.0), with a median pouchitis duration of 16.0 months (95% CI 4.0-216.0). At 2-3 months after therapy, clinical and endoscopic disease activity was significantly reduced (stool frequency 9.0 versus 6.0, the Pouchitis Disease Activity Index (PDAI) clinical subscore was 4.0 versus 1.0, and the endoscopic disease activity was 4.0 versus 2.0). Clinical improvement was achieved in 11 out of 13 pouchitis patients (84.6%); however, a relapse was observed in nine of these patients (81.8%). The median time from clinical improvement to relapse was 16 weeks (95% CI 9.0-23.0).Alicaforsen seemed to be efficacious in inducing clinical and/or endoscopic improvement in chronic refractory pouchitis and may be a promising treatment alternative in those patients; however, given the high proportion of relapse, one 6-week course of alicaforsen may not be sufficient.

Background & Aims Inflammatory bowel disease (IBD) scoring systems combine patient-reported data with physicians’ observations to determine patient outcomes, but these systems are believed to have limitations. We used real-world data from a large IBD cohort in Switzerland to compare results between patients and healthcare professionals from scoring systems for Crohn’s disease (CD) and ulcerative colitis (UC). Methods We collected data from the Swiss IBD cohort, beginning in 2006, using 2453 reports for 1385 patients (52% female, 58% with CD). During office visits, physicians asked patients about signs and symptoms and recorded their answers (health care professional-reported outcomes). On a later date, patients received a questionnaire at home (independently of the medical visit), complete it, and sent it back to the data center. Patients also completed the short form 36 and IBD quality of life (QoL) questionnaires. We calculated Cohen’s kappa (κ) statistics to assess the level of agreement in scores between patients and health care professionals (Δt between reports collected less than 2 months apart). We used Spearman correlation coefficients (ρ) to compare general well-being (GWB) and QoL scores determined by patients vs health care professionals. Our primary aim was to investigate the overall and individual level of agreement on signs and symptoms reported by health care professionals vs patients. Results The best level of agreement (although moderate) was observed for number of stools last week in patients with CD (κ = 0.47), and nocturnal diarrhea in patients with UC (κ = 0.52). Agreement was low on level of abdominal pain (κ = 0.31 for patients with CD and κ = 0.37 for patients with UC) and GWB (κ = 0.23 for patients with CD and κ = 0.26 for patients with UC). Patients reported less severe abdominal pain and worse GWB (CD) or better GWB (UC) than that determined by health care professionals. Patient self-rated GWB correlated with IBD quality of life (ρ = 0.68 for patients with CD and ρ = 0.70 for patients with UC) and SF-36 physical scores (ρ = 0.55 for patients with CD and ρ = 0.60 for patients with UC); there was no correlation between health care professional-rated GWB and QoL. Conclusions In a comparison of patient vs health care provider-reported outcomes in a Swiss IBD cohort, we found that health care professionals seem to misinterpret patients’ complaints. Patients self-rated GWB correlated with QoL scores, indicating that reporting GWB in a single question is possible and relevant, but can vary based on how the data are collected.

Background: Data on the efficacy of intercellular adhesion molecule-1 antisense oligonucleotide alicaforsen in ulcerative colitis (UC) is inconsistent. Methods: All patients, who had received at least one dose of alicaforsen, were analyzed retrospectively. Alicaforsen’s efficacy was assessed in patients treated for left-sided UC and proctitis by comparing clinical and (if applicable) endoscopic disease activity before/after treatment. Results: Twelve patients were treated for left-sided UC or proctitis. Eleven patients received a 6-week course of a once-daily 240 mg alicaforsen enema formulation. In 1 patient, treatment was discontinued, because it was found to be inefficient. Disease activity measured by the partial Mayo score and 6-point symptom score was significantly reduced after treatment (6.0 vs. 2.4, p = 0.011 and 3.7 vs. 1.4, p = 0.008). Faecal calprotectin showed a trend towards reduction (484.4 vs. 179.5 μg/g, p = 0.063). Clinical improvement was achieved in 10 patients (83.3%). In 7 patients, a relapse occurred (70%). Median duration of clinical improvement was 18.0 weeks (range 1–112). Three patients showed an ongoing improvement of >9 months. No adverse events were reported. Conclusions: A 6-week course of alicaforsen seemed to be safe and efficacious in inducing clinical improvement in patients with left-sided UC and proctitis. Prolonged clinical improvement was observed in many but not all patients.

Background: The knowledge about risk factors for the onset of uveitis manifestations in patients with inflammatory bowel disease (IBD) is still limited. Here, we aimed to provide an overview of the clinical factors associated with the onset of uveitis in the Swiss IBD Cohort Study (SIBDCS). Methods: We included epidemiological and clinical data from 1840 patients with Crohn’s disease (CD) and 1426 patients with ulcerative colitis (UC) followed up in the SIBDCS between 2006 and 2018. Associations between disease characteristics and uveitis were assessed in univariate and multivariate analyses. Results: Overall, we identified 285 patients with uveitis. Uveitis was more frequent in patients with CD (11.1%; 205 of 1635) than UC (5.6%; 80 of 1346; odds ratio 2.11, p Conclusions: Our data demonstrate that uveitis in IBD occurs more often in CD as well as in women and is associated with a more severe disease course. This might guide physicians’ awareness in at-risk patients to the presence of uveitis extraintestinal manifestations and help to improve patient care.

Background Safety and economic issues have increasingly raised concerns about the long term use of immunomodulators or biologics as maintenance therapies for Crohn's disease (CD). Despite emerging evidence suggesting that stopping therapy might be an option for low risk patients, criteria identifying target groups for this strategy are missing, and there is a lack of recommendations regarding this question. Methods Multidisciplinary European expert panel (EPACT-II Update) rated the appropriateness of stopping therapy in CD patients in remission. We used the RAND/UCLA Appropriateness Method, and included the following variables: presence of clinical and/or endoscopic remission, CRP level, fecal calprotectin level, prior surgery for CD, and duration of remission (1, 2 or 4 years). Results Before considering withdrawing therapy, the prerequisites of a C-reactive protein (CRP) and fecal calprotectin measurement were rated as “appropriate” by the panellists, whereas a radiological evaluation was considered as being of “uncertain” appropriateness. Ileo-colonoscopy was considered appropriate 1 year after surgery or after 4 years in the absence of prior surgery. Stopping azathioprine, 6-mercaptopurine or methotrexate mono-therapy was judged appropriate after 4 years of clinical remission. Withdrawing anti-TNF mono-therapy was judged appropriate after 2 years in case of clinical and endoscopic remission, and after 4 years of clinical remission. In case of combined therapy, anti-TNF withdrawal, while continuing the immunomodulator, was considered appropriate after two years of clinical remission. Conclusion A multidisciplinary European expert panel proposed for the first time treatment stopping rules for patients in clinical and/or endoscopic remission, with normal CRP and fecal calprotectin levels.

Background & Aims We examined the relationship between symptoms of depression and anxiety and clinical recurrence of inflammatory bowel disease (IBD) in a large patient cohort. We considered the progression of depression and anxiety over time. Methods We collected clinical and treatment data on 2007 adult participants of the Swiss IBD study (56% with Crohn's disease [CD], 48% male) performed in Switzerland from 2006 through 2015. Depression and anxiety symptoms were quantified by using the Hospital Anxiety and Depression Scale. The relationship between depression and anxiety scores and clinical recurrence was analyzed by using survival-time techniques. Results We found a significant association between symptoms of depression and clinical recurrence over time (for all patients with IBD, P = .000001; for subjects with CD, P = .0007; for subjects with ulcerative colitis, P = .005). There was also a significant relationship between symptoms of anxiety and clinical recurrence over time in all subjects with IBD ( P = .0014) and in subjects with CD ( P = .031) but not ulcerative colitis ( P = .066). Conclusions In an analysis of a large cohort of subjects with IBD, we found a significant association between symptoms of depression or anxiety and clinical recurrence. Patients with IBD should therefore be screened for clinically relevant levels of depression and anxiety and referred to psychologists or psychiatrists for further evaluation and treatment.

Background & Aims: Hepatic fibrosis may occur in patients with intestinal failure requiring total parenteral nutrition, leading to liver dysfunction necessitating combined intestinal and liver transplantation. The decision to perform combined transplantation as opposed to an isolated intestinal transplant is based on the presence of hyperbilirubinemia, portal hypertension, and advanced hepatic fibrosis. Methods: We identified 4 patients who underwent isolated intestinal transplantation having significant liver fibrosis. A novel image analysis technique was applied to serial liver biopsies to more precisely quantitate posttransplantation fibrosis regression separately within both portal and centrilobular areas. Results: All patients were found to have significant portal and centrilobular fibrosis regression, which occurred more rapidly in the former. Two patients had improvement in fibrosis despite infections and continuation of total parenteral nutrition, suggesting that hepatic fibrosis associated with intestinal failure may in part be related to adequate anatomic and functional bowel length. Conclusions: Significant hepatic fibrosis and liver dysfunction may regress after intestinal transplantation and fibrosis regresses more rapidly in portal areas. This suggests that some patients with intestinal failure and associated liver disease may safely undergo isolated intestinal transplant without the need for concurrent liver transplantation and its attendant higher morbidity and mortality.

Diagnosis of intestinal transplant rejection depends on clinical assessment, endoscopy and most importantly, histology of intestinal biopsies. Plasma citrulline levels (P-Cit) reflect functional enterocyte mass in nontransplant patients and have been evaluated in two small series after transplant. This study was designed to determine the sensitivity and specificity of P-Cit as diagnostic tool for allograft injury, especially to distinguish between viral enteritis and rejection. We prospectively collected 403 P-Cit samples within 24 h of intestinal biopsy in 49 patients. P-Cit levels were correlated with the mucosal damage and histopathological diagnoses. P-Cit levels in bowels with significant mucosal damage (i.e. moderate or severe rejection, viral enteritis, PTLD, ischemia reperfusion injury, allergic enteritis) were significantly lower than in intestines with no or mild injury (i.e. indeterminate or mild rejection, nonspecific enteritis): 22.9 +/- 15.4 versus 38 +/- 23.2 nmol/mL (p < 0.0001). Sensitivity and specificity of the test were 80% and 58.1% for rejection, and 56.5% and 66% for viral enteritis, thereby unable to distinguish between both entities. In conclusion, P-Cit reflects the extent of mucosal injury regardless of the etiology, but does not seem to be a predictive marker for rejection or viral enteritis, as its values may decline only when diffuse mucosal damage has occurred.

We have previously shown that the local-membrane bound 4-1BB ligand and IL-12 gene transfer induced a significant antitumor response in a mouse colon carcinoma model. However, a high viral dose was required in order to achieve the best efficacy. In this study, we hypothesize that the systemic administration of soluble Ig-4-1BB ligand can give rise to better T-cell immune activation than local gene delivery. With potential clinical applications in mind, we further compare whether the natural 4-1BB ligand fused to mouse IgG2a (Ig-4-1BBL) would be as effective as the agonistic anti-4-1BB antibody. The dimeric form of Ig-4-1BBL was purified from HeLa cells transduced with a recombinant adenovirus (ADV/Ig-4-1BBL) expressing Ig-4-1BBL. Functional activity was confirmed by the ligand's ability to bind to activated splenic T cells or bone marrow (BM)-derived dendritic cells (DCs) that express 4-1BB receptor. The soluble Ig-4-1BBL efficiently costimulated CD3-activated T-cell proliferation in vitro. More importantly, it induced tumor-specific CTLs as effectively as the agonistic anti-4-1BB antibody. When combined with IL-12 gene transfer, systemic administration of the Ig-4-1BBL proved to be more potent than local gene delivery. In addition, the Ig-4-1BBL is as potent as the agonistic anti-4-1BB antibody for the treatment of hepatic MCA26 colon carcinoma, resulting in 50% complete tumor regression and long-term survival. In long-term surviving mice, both treatment modalities induced persistent tumor-specific CTL activity. In summary, these results suggest that the systemic delivery of Ig-4-1BBL can generate a better antitumor response than local gene delivery. Ig-4-1BBL had equivalent biological functions when compared to the agonistic anti-4-1BB antibody. Thus, soluble 4-1BBL dimmer can be developed as a promising agent for cancer therapy in humans.

Background— The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury. Methods and Results— Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury ( P P P P Conclusions— VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.

Background and Aims: The structured IBD Ahead ‘Optimised Monitoring' programme was designed to obtain the opinion, insight and advice of gastroenterologists on optimising the monitoring of Crohn's disease activity in four settings: (1) assessment at diagnosis, (2) monitoring in symptomatic patients, (3) monitoring in asymptomatic patients, and (4) the postoperative follow-up. For each of these settings, four monitoring methods were discussed: (a) symptom assessment, (b) endoscopy, (c) laboratory markers, and (d) imaging. Based on literature search and expert opinion compiled during an international consensus meeting, recommendations were given to answer the question ‘which diagnostic method, when, and how often'. The International IBD Ahead Expert Panel advised to tailor this guidance to the healthcare system and the special prerequisites of each country. The IBD Ahead Swiss National Steering Committee proposes best-practice recommendations adapted for Switzerland. Methods: The IBD Ahead Steering Committee identified key questions and provided the Swiss Expert Panel with a structured literature research. The expert panel agreed on a set of statements. During an international expert meeting the consolidated outcome of the national meetings was merged into final statements agreed by the participating International and National Steering Committee members - the IBD Ahead ‘Optimized Monitoring' Consensus. Results: A systematic assessment of symptoms, endoscopy findings, and laboratory markers with special emphasis on faecal calprotectin is deemed necessary even in symptom-free patients. The choice of recommended imaging methods is adapted to the specific situation in Switzerland and highlights the importance of ultrasonography and magnetic resonance imaging besides endoscopy. Conclusion: The recommendations stress the importance of monitoring disease activity on a regular basis and by objective parameters, such as faecal calprotectin and endoscopy with detailed documentation of findings. Physicians should not rely on symptoms only and adapt the monitoring schedule and choice of options to individual situations.

Hepatitis C virus (HCV) infection is associated with development of hepatocellular carcinoma (HCC). The aim of this study was to examine clinical characteristics and outcome of patients with HCV with or without HCC undergoing liver transplant.We reviewed the charts of all 55 patients transplanted between November 1990 and December 1996 for HCV cirrhosis with HCC and compared them with a control group of HCV patients without HCC. Patients with a history of alcohol abuse or HBsAg positivity were excluded. There were 37 men and 18 women, with a mean age of 57.6 yr (range, 19-70 yr) in the HCC group.There was no significant difference between the HCC and nonHCC groups regarding Child's class or United Network for Organ Sharing (UNOS) status at the time of transplant. Twenty-six (45%) patients were diagnosed or suspected of having HCC before transplant. Twenty-five patients (45.5%) had a single focus of HCC. Fourteen percent (seven of 50) of the patients with HCC had been treated with interferon, whereas 12% (six of 52) of patients in the nonHCC group had received interferon. Duration of interferon therapy ranged from 1 to 9 months. All interferon treatment occurred within 5 yr of transplant. A history of intravenous drug use or transfusion was identified in 37 (67%) of HCC patients. Thirty-two patients (58%) without HCC had a parenteral exposure. There was no significant difference in patient or graft survival rates between the patients with and without HCC.Approximately one-half of HCC was not detected before liver transplant. There was no significant difference in the mode of transmission, clinical status at the time of transplant, or outcome between the HCV patients with and without HCC.

Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1α) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF). Oxidized low-density lipoprotein (oxLDL) is generated in lipid-rich plaque by oxidative stress. It triggers an inflammatory response and was traditionally thought to inhibit endothelial cells. New data, however, suggest that oxLDL can activate HIF-1α in monocytes in a hypoxia-independent fashion. We hypothesized that HIF-1α activation in monocyte-macrophages could transmit proangiogenic effects of oxLDL linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. First, we examined the effect of oxLDL on HIF-1α and VEGF expression in monocyte-macrophages and on their proangiogenic effect on endothelial cells in vitro in a monocyte-macrophage/endothelial co-culture model. OxLDL strongly induced HIF-1α and VEGF in monocyte-macrophages and significantly increased tube formation in co-cultured endothelial cells. HIF-1α inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1α inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1α and VEGF expression. The administration of low-lipid diet significantly reduced the expression of both HIF-1α and VEGF, resulting in decreased plaque neovascularization. Our data point to oxLDL as a proangiogenic agent linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. This effect is dependent on macrophages and, at least in part, on the induction of the HIF-1α pathway.

Background: Uremic small-artery disease with medial calcification and intimal hyperplasia can lead to life-threatening skin necrosis or acral gangrene. It is a distinct complication of chronic renal failure that must be differentiated from soft-tissue calcification. An increased calcium-phosphate product and secondary hyperparathyroidism are the main underlying conditions. The benefit of parathyroidectomy is controversial. Objective: This article is based on a literature search to determine prognostic factors and, in particular, the benefit of parathyroidectomy. Methods: The literature on uremic small-artery disease (so-called calciphylaxis) was reveiwed (full data set: 104 cases, including five of our own). The therapeutic benefit of parathyroidectomy and the relation between prognostic predictors (localization, dialysis, and renal transplant) and outcome were analyzed. The relation between diabetes and acral gangrene was also examined. Further epidemiologic data on the reviewed group of patients were established. Results: Thirty-eight of 58 patients who underwent parathyroidectomy survived compared with 13 of 37 patients who did not undergo parathyroidectomy ( p = 0.007, n = 95). Forty of 53 patients with distal localization of necrosis survived compared with 11 of 42 patients with proximal pattern ( p n = 95). Dialysis and kidney transplantation followed by immunosuppression showed no relation to disease outcome. No association was found between diabetes and acral gangrene ( p = 0.50). Conclusion: Uremic small-artery disease is a distinct complication of chronic renal failure. Its recognition and early diagnosis should allow more effective treatment. In our retrospective study parathyroidectomy was significantly related to survival. Only a randomized, controlled, prospective trial (parathyroidectomy vs conservative treatment of secondary hyperparathyroidism) can establish the value of parathyroidectomy in uremic small-artery disease.

Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients.Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines.Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey-Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26.In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

Switzerland was the first country to approve certolizumab pegol (Cimzia, CZP) for the treatment of patients with moderate to severe Crohn's disease (CD) in September 2007. This phase IV study aimed to evaluate the efficacy and safety of CZP in a Swiss multicenter cohort of practice-based patients.Baseline and Week 6 evaluation questionnaires were sent to all Swiss gastroenterologists in hospitals and private practices. Disease activity was assessed with the Harvey-Bradshaw Index (HBI) and adverse events were evaluated according to WHO guidelines.Fifty patients (31 women, 19 men) were included; 56% had complicated disease (stricture or fistula) and 52% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 78% to infliximab, and 50% to adalimumab. A significant decrease in HBI was observed at Week 6 (versus Week 0) following induction therapy with CZP 400 mg subcutaneously at Weeks 0, 2, and 4 (12.6 +/- 4.7 Week 0 versus 6.2 +/- 4.4 Week 6, P0.001). Response and remission rates at Week 6 were 54% and 40%, respectively. We identified 8/11 CD patients undergoing a 50% fistula response (P = 0.021). The frequency of adverse drug reactions attributed to CZP was 6%. CZP was continued in 80% of patients beyond Week 6.In a population of CD patients with complicated disease behavior, CZP induced a response and remission in 54% and 40% of patients, respectively. This series provides the first evidence of the effectiveness of CZP in perianal fistulizing CD.

Introduction. Abdominal wall closure management has become an important challenge during recipient candidate selection, at the time of donor to recipient matching and during the planning of the surgical procedure for intestinal or multiorgan transplantation. Different strategies have been proposed to overcome the lack of abdominal domain: to reduce the graft size or to increase the abdominal domain. Based on the recent concept of using an acellular dermis matrix (Alloderm) and the availability of abdominal wall tissues from the same organ donor, we conceived the idea of using the fascia of the rectus muscle (FoRM) as a nonvascularized tissue allograft. Materials and Methods. This is a retrospective report of a series of 16 recipients of FoRM as part of a liver, intestinal, or multiorgan transplant procedure performed between October 2004 and May 2008 at three different transplant centers. Results. Of the 16 recipients of FoRM, all but one case was performed during their transplantation (four multivisceral, two modified multivisceral, three isolated intestine, and two livers). Five patients underwent a retransplant surgery (two livers, two multivisceral, and one isolated intestine). Abdominal wall infection was present in 7 of 16 cases. Nine patients are still alive. No deaths were related to wound infection. Long-term survival showed complete wound healing and only one ventral hernia. Discussion. The use of a nonvascularized FoRM is a novel and simple surgical option to resolve complex abdominal wall defects in liver/intestinal/multivisceral transplant recipients when it can be covered with the recipient skin.

Presence of preformed lymphocytotoxic antibodies may represent a barrier to isolated intestinal transplantation (IITx). We developed an intravenous immunoglobulins (IVIg) based desensitization protocol for candidates with high panel-reactive antibodies (PRA). Six patients with a mean PRA of 72+/-22% were included in a four-level (L) protocol with escalating doses of IVIg (L1, L2), addition of mycophenolate mofetil (MMF) or plasmapheresis (L3); and anti-CD20 (Rituximab) (L4). Four of six candidates improved their PRAs (from a mean of 66.2% to 25.5%; P=0.01) and were successfully transplanted. At a mean follow-up of 8 months, number and severity of rejection episodes of protocol patients did not differ from patients with low PRA transplanted during the same period. These data support the use of IVIg to desensitize patients waiting for IITx. It increases the applicability of IITx, and reduces the waiting time and mortality on the waiting list with outcomes comparable to nonsensitized recipients.

Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/35 may be useful in anticancer strategies targeting tumor endothelial cells.

The purpose of this letter is to elucidate on the pathophysiology of a disease that is often considered to be idiopathic. Chronic intestinal pseudo-obstruction (CIPO) is a clinical syndrome characterised by ineffective intestinal propulsion in the absence of organic intestinal obstruction. It is a common cause of intestinal failure requiring total parenteral nutrition (TPN). It can be either a primary/idiopathic (neurogenic or myogenic) disorder or secondary to another recognised underlying disease. Most cases of childhood CIPO are congenital enteral neuromuscular diseases; however, neuropathy due to Hirschprung’s disease, Chagas disease, infections, and toxins occur in later childhood. In adults, most cases of CIPO are secondary to progressive systemic sclerosis, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome.1,2 We report a case of an adult onset of CIPO secondary to an autoimmune process affecting exclusively …

Background— Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF. However, there is only limited knowledge of cell type, plaque component, and conditions associated with TF expression and apoptosis. We examined the hypothesis that macrophages exposed to conditions of lipid-rich plaque undergo apoptosis and express TF. Methods and Results— In human carotid (n=15) and coronary (n=6) atherosclerotic plaques, TF and caspase-3 mRNA and protein expression (evaluated by in situ hybridization and immunohistochemistry) were increased significantly in lipid-rich compared with fibrous plaque components ( P P P P Conclusions— The expression of TF as the primary cell-associated activator of the coagulation pathway proves to be closely related to macrophages undergoing apoptosis in conditions of lipid-rich plaque, pointing to a key role of lipid content and inflammatory cell viability in determining plaque thrombogenicity.

Background/Aims Liver regeneration is dependent upon coordinated proliferation of hepatocytes and endothelial cells. Vascular endothelial growth factor (VEGF) promotes angiogenesis. Hepatic steatosis delays regeneration and increases liver resection morbidity. We hypothesized that VEGF overexpression stimulates hepatic regeneration. Methods Recombinant adenovirus expressing human VEGF165 or adenovirus control-vector (Lac Z) were administered before 2/3 hepatectomy in lean and ob/ob mice. Galactose elimination capacity, a quantitative liver function test, was repeatedly measured before and after hepatectomy. Expression of VEGF receptors (flt1, flk1), endoglin and hypoxia inducible factor-1α (HIF-1α) was assessed by quantitative RT-PCR and for endoglin also by immunohistochemistry. Results After 2/3 hepatectomy, VEGF gene transfer increased galactose elimination capacity in lean and ob/ob mice. HIF-1α, endoglin and VEGF receptor mRNA increased during regeneration in lean but not in obese mice. Staining of endothelial cells by endoglin immunohistochemistry returned to baseline reactivity in lean mice by day 6 and remained decreased in ob/ob mice. VEGF treatment decreased HIF-1α and increased flk1 response in lean mice. Conclusions Hepatic resection elicits an angiogenic response in the remnant liver, which is impaired in case of steatosis. Adenovirus-mediated transfer of VEGF hastens functional hepatic recovery in lean, and more importantly also, in obese mice after partial hepatectomy.

Conditionally replicative adenovirus (CRAD) is an attractive anticancer agent as it can selectively replicate in tumor cells. Expression of telomerase reverse transcriptase (TERT) is a unique tumor cell characteristic, being absent in normal postmitotic cells. Thus, we constructed a TERT promoter regulated CRAD for tumor-specific oncolysis by replacing the endogenous adenovirus E1A promoter with that of human TERT (Adv-TERTp-E1A). We showed that its replication was severely attenuated in TERT-negative cells, but that it replicated almost as efficiently as wild-type adenovirus in TERT-positive cells. Accordingly, Adv-TERTp-E1A conferred cytopathicity to TERT-positive, but not TERT-negative, cells. In vivo replication of Adv-TERTp-E1A after local administration into a xenograft model of human hepatocellular carcinoma in nude mice was demonstrated by an increase in adenovirus titers in tumor extracts by several orders of magnitude between 6 h and 3 days postvector injection. Furthermore, significant inhibition of tumor growth with substantial necrotic tumor areas staining positively for adenovirus was observed with Adv-TERTp-E1A, but not with a control replication-deficient adenovirus. There was also the absence of hepatotoxicity in tumor-bearing animals after intratumoral delivery of the CRAD. The results indicate that the TERT promoter-driven CRAD is capable of tumor-selective replication and oncolysis in vitro and in vivo, and can be utilized as an adjuvant treatment agent for cancer.

Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. We constructed a recombinant adenovirus that expresses endostatin, which resulted in a significant delay of tumor progression of JC breast and Lewis lung carcinoma, and more importantly, in complete prevention of lung metastases formation in Lewis lung carcinoma. The inability to control pre-established tumors may be due to insufficient circulating endostatin levels or to inadequate local endostatin concentrations, both of which have been shown to be important for the anti-tumor effect of endostatin. Thus, we constructed a recombinant adenovirus expressing a murine Ig-endostatin fusion protein resulting in significantly higher circulating endostatin levels with improved anti-tumor activity. Furthermore, a tumor-targeted version of endostatin was made using homing peptides to activated endothelial cells (RGD, NGR) to increase directly endostatin concentrations in the tumor. Finally, conditionally replicating adenovirus (CRAD) targeted to the activated endothelium was very efficacious in selectively destroying 3-D capillary networks. In conclusion the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy in cancer. Changes in vector design resulting in higher transgene expression levels, tumor-targeted delivery of endostatin, or endothelial selective replication of adenovirus may prove to be an effective anti-cancer therapy.

Conditionally replicating adenoviruses (CRADs) are a novel strategy in cancer treatment and clinical trials using CRADs targeted to tumor cells have been reported recently. We hypothesized that it would be possible to construct CRADs targeted to dividing endothelial cells, which are present in the tumor endothelium. We utilized the regulatory elements of Flk-1 and endoglin genes, which have been shown to be highly overexpressed in angiogenic endothelial cells, to construct two CRADs: Ad.Flk-1, which has adenoviral E1A gene under the control of the Flk-1 enhancer/promoter, and Ad.Flk-Endo, which harbors the same Flk-1 enhancer/promoter as Ad.Flk-1, plus it has the adenoviral E1B gene under control of the endoglin promoter. Viral titer measurements by plaque assay showed that in human umbilical vein endothelial cells (HUVECs), both CRADs replicated at levels comparable to that of wild-type adenovirus. In Flk-1 and endoglin negative Hep3B and A549 cells, however, the replication of Ad.Flk-1 and Ad.Flk-Endo was reduced by 30-fold and 600-fold, respectively. Cytotoxicity assays demonstrated that both CRADs killed HUVECs as effectively as wild-type adenovirus and their cytotoxicity in Hep3B and A549 cells was comparable to nonreplicating control adenovirus. Furthermore, there was a striking inhibition (83-91%) of capillary network formation in an in vitro angiogenesis assay when HUVECs were infected with Ad.Flk-1 or Ad.Flk-Endo as compared with the nonreplicating control virus. These results demonstrate that CRADs can be transcriptionally targeted to dividing endothelial cells with high specificity, and that the combined use of Flk-1 and endoglin regulatory elements has a synergistic effect on targeting specificity. This principle may be incorporated into novel therapeutic agents to develop anti-angiogenic treatment for cancer.

Background: The success of immunomodulatory cancer therapy is frequently hampered by the transient nature of the antitumor immune response. We have shown previously in a mouse model that interleukin 12 (IL-12) generates a strong natural killer (NK) cell-mediated antitumor response and reduces liver metastases induced by a colon carcinoma cell line. However, only a small percentage of the treated animals developed the cytotoxic T-lymphocytic response required for a long-term systemic antitumor immunity. 4-1BB is a co-stimulatory molecule expressed on the surface of activated T cells. Interaction of 4-1BB with its natural ligand (4-1BBL) has been shown to amplify T-cell (especially CD8+)-mediated immunity. In this study, we investigated the effects of adenovirus-mediated gene therapy delivering both IL-12 and 4-1BBL genes on mice with hepatic metastases induced by colon cancer cells. Methods: Syngeneic BALB/c mice received intrahepatic injection of poorly immunogenic MCA26 colon cancer cells. Various combinations of replication-defective adenoviruses expressing IL-12 and 4-1BBL genes were injected into the established liver tumors. Changes in tumor size and animal survival were then monitored. All statistical tests were two-sided. Results: The long-term survival rate of mice treated with the combination of IL-12 and 4-1BBL was significantly improved over that of animals in the control group (P = .0001). In vivo depletion of NK cells or CD8+ T cells completely abolished the long-term survival advantage of the IL-12 plus 4-1BBL-treated animals (P

Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro , as determined in endothelial cell proliferation assays, and in vivo , by suppression of angiogenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605–1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma ( P < 0.001 and P < 0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma ( P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy as a component in cancer therapy.

Pimozide is a diphenylpiperidine neuroleptic with well characterized cardiovascular side effects including QT prolongation. So far, life-threatening cardiac arrhythmias, in particular torsades de pointes, have not been described in patients treated with pimozide. The authors describe a patient in whom torsades de pointes developed after the ingestion of 800 mg pimozide as a suicide attempt. After intravenous treatment with lidocaine and magnesium, the patient recovered completely and the QT interval had normalized 5 days after the intoxication. Potential mechanisms leading to torsades de pointes in patients treated with pimozide are discussed.

hepatc, cyte-denved cells. We also examined the effect of bile acid on LST-2 gene transcription. Methods: 1) Expression of [be LST-2 gene was analyzed by northern blot analysis 2) The promoter actb~ty of the 5'-upstream region of LST-2 gene was analyzed by' luciferase reporter gene assays. 3) The specihc pmtein-DNA complex was determined by electoruphoresis mobility-shih assays (EMSA). 4) The effects of bile acids on the LS%2 promoter activity were analyzed by lnciferase assays and EMSA Results: Norther blot analysis showed that LST-2 was expressed in the hepatocyte-derived cell lines, Hep3B and HT-17. Deletion analysis showed that the 5'-tlanking region from -180 to -20 bp is responsible top LST-2 trans~npticmal actwity There were several putative transcriptional factor recognition sites for STAT, HNFIa, FXR, and two binding sites tbr HNF3b in this region. By site-directed mutation analysis, It was revealed that all of the consensus binding sites for FXR, HNFla, HNF3b play important roles m the transcriptional activity of the LST-2 gene. By EMSA using specilic oligonucleotides and mmlear extract of Hep3B, we observed specific pmteinDNA complex of HNF1, FXR, and HNF3b. Moreover, we observed the super-shift bands using specific antibodies against HNF1, FXR and HNF3h Next, we carried out the luciterase assays in the presence of bile acids. The /uciterase activity was increased to 2.0 [bids when CDCA or DCA was added, g~scussion: These results indicate that the transcriptional regulation of IST-2 is controlled by FXR, HNF1, and HNF3b. HNF1 and HNF3b might depend on the tissue-specific expression and FXR might play a role in transcriptional activation by CDC)~ and DCA Interestingly, the transcription of LST-2 gene is regulated by the substrate which itself is taken in.

non-l, 26% in naive patients and 0% in previously treated patients. In 2 patients HCV RNA negative at 12 months, treatment was continued. The following dose adjustments were required: 6/22 (27%) decrease in peg interferon (neutropenia n=2, clinical depression n=4), lo/22 (45%) decrease in ribavirin therapy due to anemia. Therapy was discontinued in 14/22 (63%) patients: 8/22 (36%) due to lack of response and 6/22 (27%) related to drug intolerance (i.e. rejection n=3, acute pancreatitis n=l, depression n=l, death n=l). Conclusion: Sustained virologic response using pegylated interferon a2b and ribavirin combination was observed in 20% of LT patients with HCV infection. The high rate of drug intolerance and lower response rates observed as compared to those in the immunocompetent population were limiting factors in the transplant setting.

We describe a 32-year-old man with no history of pulmonary disease who presented with extensive cavernous destruction of the right upper lobe as an incidental finding on a chest x-ray film. All major criteria of allergic bronchopulmonary aspergillosis (ABPA) were present. Histologic examination of the resected lobe showed the typical features of ABPA. The differential diagnosis of multiple cavitating lesions should include ABPA.

Fragt man, ob und in welcher Weise dissonanztheoretische Aussagen sich als Entscheidungs- bzw. Gestaltungshilfe bei absatzpolitischen Masnahmen der Anbieter verwenden lassen, so ist zunachst zu klaren, obhinsichtlichder eigenen Unternehmung und ihrer LeistungendieSchaffung von Dissonanzen, das Vermeiden von Dissonanzen (bzw. der Abbau evtl. bestehender Dissonanzen) oder evtl. eine kombinierte Strategie alsabsatzpolitischeTeilzieleanzustreben sind.

Wie bereits implizit zum Ausdruck kam, lassen sich Probleme und Problematik der Theorie der kognitiven Dissonanz einteilen in solche im Bereich der Dissonanzentstehung und jene im Bereich der Dissonanzreduktion. Nach diesen beiden Hauptteilen der Theorie sind auch die folgenden Ausfuhrungen gegliedert.

Die Theorie der kognitiven Dissonanz hat mit vielen sozialwissenschaftlichen Theorien gemeinsam, das sie sich in das Innere der “lack box” Mensch hineinbegibt und deshalb mit einer Reihe hypothetischer Konstrukte arbeiten mus (11). Dies zeigt sich bereits darin, das Festinger ins Zentrum seines Ansatzes die Analyse des kognitiven Systems (12) des Individuums stellt. Er geht dabei von “Kognitionen” als elementaren Einheiten des kognitiven Systems aus darunter versteht er Bewustseinsinhalte wie FaktenwissenAnsichten, Meinungen, Uberzeugungen, Erfahrungen usw. des Individuums uber sich selbst und seine Umwelt: “These elements refer to what has been called cognition, that is, the things a person knows about himself, about his behavior, and about his surroundings” (13). Die Struktur des kognitiven Systems ist nach Festinger durch die Eigenart der einzelnen kognitiven Elemente (oder auch Elementgruppen als Subsysteme) und durch ihr Verhaltnis zueinander gekennzeichnet. Hieraus ergibt sich zunachst die Unterscheidung zwischen Kognitionen, die fureinander irrelevant sind: und Kognitionen, die fureinander relevant sind.

Bei der bisherigen Betrachtung wurden die Anwendungsmoglichkeiten dissonanztheoretischer Erkenntnisse auf den Bereich unternehmerischer Marketing-Entscheidungen untersucht. Dadurch wird implizit bis zu einem gewissen Grade auch dem Konsumenteninteresse Rechnung getragen, aber eben nur bis zu einem gewissen Grade. Es hiese, einem empirisch nicht haltbaren Harmoniekonzept zum Opfer fallen, wollte man ubersehen, das die Realisierung unternehmerischer Zielsysteme dem Konsumenten-Interessenurteilweise entgegenkommt, u. U. ihm sogar entgegengesetzt sein kann (63). Dies ist der Ansatzpunkt, von dem aus auch die Betriebswirtschaftslehre nach der eigenstandigen Interessenlage des Konsumenten zu fragen hat und ggf. Mittel und Wege zur besseren Erfullung von Konsumenten- bzw. Haushaltsinteressen aufzeigen soll (64).