East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Treatment and non-treatment related ocular manifestations in patients with chronic hepatitis B or C.

BACKGROUND: Worldwide, 480-520 million people are chronically infected with hepatitis B or C virus. In addition to their effects in the liver, chronic hepatitis viral infections may have serious extra hepatic manifestations. These manifestations have been more widely studied in chronic HCV infection, where they are more frequently described, but they have been also reported chronic HBV infection. AIM: Among those, of great interest are the ocular manifestations caused by the HBV or HCV infection or induced by chronic hepatitis therapy. These we attempted to review. MATERIALS AND METHODS: A PubMed search was conducted using the terms hepatitis, ocular, eye. RESULTS: This article describes the ocular symptoms related to HBV and HCV hepatitis such as xerophthalmia, Mooren's ulcer and retinopathy as well as other rare manifestations caused by either the infection or the therapy. CONCLUSIONS: The ocular manifestations of HCV infections best supported by the literature include a dry eye syndrome similar to Sjögren's syndrome, and ischemic retinopathy caused by either HCV-induced vasculitis or treatment with interferon. There are no serious ocular manifestations of HBV infection other than dry eye syndrome. Special consideration should be held for possible connection between HBV vaccine and uveitis.

Suppressors of cytokine signaling as tumor repressors. Silencing of SOCS3 facilitates tumor formation and growth in lung and liver.

The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Eight SOCS (SOCS1-SOCS7 and CIS /cytokine-inducible SH2-domain) proteins with similar structures have been identified. Cytokines bind to specifi c sites on the extracellular domains of their cognitive receptor, causing receptor dimerization. This allows the recruitment of JAKs to the receptors, which then cross-phosphorylate each other before phosphorylating the receptor on key tyrosine residues. STAT molecules bind to these phosphorylated docking sites, are in turn phosphorylated, dimerized, and enter the nucleus where they initiate transcription. Some of the genes transcribed by these factors include the SOCS genes. The SOCS proteins then act to negatively regulate activated receptor complexes by inactivating JAKs or blocking recruitment sites for STATs and also may target signaling complexes for ubiquitination and degradation. Lung cancer and hepatocellular carcinoma (HCC) are associated with abnormalities of the JAK/STAT pathway. In conclusion, determining the importance of SOCS family in health and disease will no doubt aid to the development of novel therapeutic strategies in human carcinogenesis.

Case series of transpancreatic septotomy as precutting technique for difficult bile duct cannulation.

BACKGROUND AND STUDY AIMS: Transpancreatic septotomy can be used instead of other precut techniques to facilitate bile duct cannulation after multiple failed attempts. Within the framework of a prospective randomized study on pentoxifylline, precut cases were retrospectively analyzed. PATIENTS AND METHODS: Of 320 endoscopic retrograde cholangiopancreatographies (ERCPs) in 306 patients with various indications who had a naïve papilla, 34 cases of transpancreatic septotomy were identified and compared with 15 needle-knife sphincterotomies; six patients had received both techniques for bile duct access. Complications were defined according to consensus criteria. RESULTS: In the 55 patients in whom precutting techniques were employed, the use of both techniques alone or in combination resulted in a final common bile duct cannulation rate of 81.8%. Five patients developed complications (9.1%). Of the two cases of pancreatitis (3.6%), one was mild and one severe (combined group). Of the three cases with hemorrhage, one was mild (transpancreatic septotomy) and two severe (needle knife). In patients who underwent conventional pull-type sphincterotomy (n = 242), 6.2% developed complications (nine pancreatitis and six hemorrhage). CONCLUSION: In cases of difficult bile duct cannulation, transpancreatic septotomy seems to be a safe alternative to needle-knife precutting with reasonable success rates. It should be studied in prospective randomized trials.

Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.

OBJECTIVE: To determine dysplasia and cancer in the 1991-2004 European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. PATIENTS AND METHODS: A patient questionnaire and a physician per patient form were completed for each of the 1,141 inflammatory bowel disease patients (776 ulcerative colitis/365 Crohn's disease) from 9 centers (7 countries) derived from the EC-IBD cohort. Rates of detection of intestinal cancer and dysplasia as well as extra-intestinal neoplasms were computed. RESULTS: Patient follow-up time was 10.3 +/- 0.8 (range 9.4-11) years. The mean age of the whole group of IBD patients was 37.8 +/- 11.3 (range 16-76) years. Thirty-eight patients (3.3%; 26 with ulcerative colitis/12 with Crohn's disease, 21 males/17 females, aged 61.3 +/- 13.4, range 33-77 years), were diagnosed with 42 cancers. Cancers occurred 5.4 +/- 3.3 (range 0-11) years after inflammatory bowel disease diagnosis. Colorectal cancer was diagnosed in 8 (1 Crohn's disease and 7 ulcerative colitis patients--0.3 and 0.9% of the Crohn's disease and ulcerative colitis cohort, respectively) of 38 patients and 30 cancers were extra-intestinal. Four of 38 patients (10.5%) were diagnosed as having 2 cancers and they were younger compared to patients with one cancer (p = 0.0008). There was a trend for a higher prevalence of intestinal cancer in the northern centers (0.9%) compared to southern centers (0.3%, p = NS). Southern centers had more cases of extra-intestinal cancer compared to northern centers (2 vs. 3.8%, p = 0.08). Ten patients (0.9%; 8 with ulcerative colitis/2 with Crohn's disease, 8 males, aged 62.3 +/- 14.1 years) had colorectal dysplasia. CONCLUSIONS: In the first decade of the EC-IBD Study Group cohort follow-up study, the prevalence of cancer was as expected with most patients having a single neoplasm and an extra-intestinal neoplasm. In northern centers there was a trend for more intestinal cancers, while in southern centers there was a trend for more extra-intestinal cancers compared to northern centers.

Interferon-alpha therapy in HBeAg-negative chronic hepatitis B: a long-term prospective study from north-western Greece.

AIMS: To determine the long-term response to interferon-alpha therapy in patients with hepatitis B e antigen-negative chronic hepatitis B, and the factors independently associated with response and survival. METHODS: Sixty-three patients with documented hepatitis B e antigen-negative chronic hepatitis B treated with interferon-alpha for a year were followed-up for a period of 6 years. RESULTS: Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow-up, respectively, and histological improvement in 54.5% of sustained responders compared with non-responders (7.1%, P = 0.004, chi-squared test), at 6 months of follow-up. Multivariate analysis showed that patients with hepatitis B virus-DNA levels at 6 months of treatment <10,000 copies/mL had a low probability of relapse, compared with those with levels >10 000 copies/mL (P = 0.032). Age (>65 years) and hepatitis B virus-DNA level at 6 months of treatment (>10,000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti-HBs. CONCLUSION: Hepatitis B virus-DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon-alpha, and may serve as an indicator of disease progression in the future.

Quinolones for brucellosis: treating old diseases with new drugs.

Although quinolones are theoretically interesting candidates for the treatment of brucellosis, the existing data concerning their efficacy are limited and conflicting. A number of small clinical studies with combination regimens that include quinolones have shown adequacy, but not superiority, although cost-effectiveness, excluding certain disease complications, is an important issue. The emergence of quinolone resistance and its implications is another drawback. Experimental data have yielded contradictory results, although most studies do not indicate a bactericidal effect for quinolones. However, in-vitro studies contrast repeatedly with the clinical response, both in terms of clinical failure, despite in-vitro success, and vice versa.

Treatment Steps, Surgery, and Hospitalization Rates During the First Year of Follow-up in Patients with Inflammatory Bowel Diseases from the 2011 ECCO-Epicom Inception Cohort.

BACKGROUND AND AIMS: The ECCO-EpiCom study investigates the differences in the incidence and therapeutic management of inflammatory bowel diseases [IBD] between Eastern and Western Europe. The aim of this study was to analyse the differences in the disease phenotype, medical therapy, surgery, and hospitalization rates in the ECCO-EpiCom 2011 inception cohort during the first year after diagnosis. METHODS: Nine Western, five Eastern European centres and one Australian centre with 258 Crohn's disease [CD], 380 ulcerative colitis [UC] and 71 IBD unclassified [IBDU] patients [female/male: 326/383; mean age at diagnosis: 40.9 years, SD: 17.3 years] participated. Patients' data were registered and entered in the web-based ECCO-EpiCom database [www.epicom-ecco.eu]. RESULTS: In CD, 36 [19%] Western Europe/Australian and 6 [9%] Eastern European patients received biological therapy [p = 0.04], but the immunosuppressive [IS] use was equal and high in these regions [Eastern Europe vs Western Europe/Australia: 53% vs 45%; p = 0.27]. Surgery was performed in 17 [24%] CD patients in Eastern Europe and 13 [7%] in Western Europe/Australia [p < 0.001, pLogRank = 0.001]. Of CD patients from Eastern Europe, 24 [34%] were hospitalized, and 39 [21%] from Western Europe/Australia, [p = 0.02, pLogRank = 0.01]. In UC, exposure to biologicals and colectomy rates were low and hospitalization rates did not differ between these regions during the 1-year follow-up period [16% vs 16%; p = 0.93]. CONCLUSIONS: During the first year after diagnosis, surgery and hospitalization rates were significantly higher in CD patients in Eastern Europe compared with Western Europe/Australia, whereas significantly more CD patients were treated with biologicals in the Western Europe/Australian centres.

The immunohistochemical expression of metallothionein in inflammatory bowel disease. Correlation with HLA-DR antigen expression, lymphocyte subpopulations and proliferation-associated indices.

Metallothionein (MT) expression in intestinal resection specimens from 41 patients with ulcerative colitis (UC) and 10 patients with Crohn's disease (CD ) was immunohistochemically studied by the avidin-biotin (ABC) method. In addition, the possible relationship of its expression with HLA-DR antigen expression, lymphocyte subpopulations and proliferation-associated indices was studied in order to elucidate the role of this molecule in inflammatory bowel disease (IBD). The MT immunoreactivity was recorded by staining and intensity-distribution scores. MT staining varied in and was mainly localized in the cytoplasm, although a combined nuclear/cytoplasmic reactive pattern was also seen in epithelial cells. MT expression was decreased in UC, and CD compared with normal mucosa. No difference in MT expression between UC and CD was noted. In UC, a gradually decreased expression from remission, to resolving and to active phase was observed. An inverse correlation of MT expression with HLA-DR antigen expression was detected (p = 0.018) in the cases of UC. The data suggest that a low level of MT expression in inflammatory bowel disease and particularly in active phase of UC may indicate a decreased endogenous intestinal protection and it may be implicated in the pathogenesis of the disease.

Bcl-2 expression in colorectal tumours. Correlation with p53, mdm-2, Rb proteins and proliferation indices.

Immunostaining for bcl-2 protein was performed in 27 colorectal adenomas and 108 colorectal adenocarcinomas. The aim of the study was to determine bcl-2 expression in correlation with p53, mdm-2 and Rb expression, with proliferation indices (Ki-67-LI, PCNA-LI) as well as with conventional clinicopathological variables. A higher proportion of adenomas (30.8%) than carcinomas (16.7%) expressed bcl-2 and conversely, a lower proportion of adenomas (7.4%) than carcinomas expressed p53 (57.1%), the difference being statistically significant (p<0.0001). No correlation of bcl-2 expression with p53 expression (parallel or inverse) as well as with the other parameters studied was observed in any tumour. The bcl-2+/p53- subgroup of cancers showed a trend for correlation with negative lymph node status. Our data suggest, that bcl-2 expression may be involved in the early phase of colorectal carcinogenesis regardless of p53 status, while p53 function may be involved in a late stage of the adenoma-carcinoma sequence. P53 is apparently not involved in the regulation of apoptosis in the colorectal neoplasias or perhaps bcl-2 expression, as an early event in colorectal tumours, may occur before changes of p53 take place. Tumours with bcl-2+/p53- immunophenotype are frequently associated with negative lymph node status and seem to have a less aggressive behavior.

Pulmonary and gastrointestinal manifestations of Sjögren's syndrome.

The respiratory system is frequently involved in primary SS but this involvement is rarely clinically significant. Its manifestations are secondary to desiccation of the tracheobronchial tree and lymphocytic infiltration of the lung parenchyma. The desiccation of the tracheobronchial tree gives rise to the most important clinical manifestation, dry cough (xerotrachea), but is rarely a cause of infection and obstructive airways disease. The lymphocytic infiltration of the lung parenchyma starts as lymphocytic alveolitis in a very large number of SS patients but rarely evolves into frank lymphocytic interstitial pneumonitis and fibrosis. Even more rare is the evolution of pseudolymphoma into malignant lymphoma. Pleurisy with or without effusion is not a frequent manifestation of primary SS. It occurs often in secondary SS and is due to the underlying rheumatic disorder. In general, secondary SS rarely has significant pulmonary manifestations other than those of the disorder it accompanies. The manifestations from the gastrointestinal system in patients with SS include mucosal dryness, accelerated dental decay, and enlargement of the major salivary glands, as well as dysphagia, nausea, epigastric pain, and dyspepsia. The dysphagia is probably secondary to esophageal dysfunction, and the gastric symptoms might be attributable to chronic atrophic gastritis. Whether the small bowel is affected in SS patients is not clear. Pancreatic involvement usually is being expressed as subclinical acute or chronic pancreatitis. Finally, the liver could be involved in SS patients, and some studies indicate that the pathogenic process responsible for the hepatic damage and for the salivary gland destruction could be similar.

Prognostic evaluation of metallothionein expression in human colorectal neoplasms.

AIM: To investigate the role of metallothionein in colorectal tumours and the possible relation with other factors associated with tumour progression: expression of cathepsin D (CD), CD44, p53, Rb, bcl-2, c-erbB-2, epidermal growth factor receptor (EGFR), proliferation indices (Ki-67, proliferating cell nuclear antigen (PCNA)), and conventional clinicopathological variables. METHODS: The immunohistochemical expression of metallothionein was investigated in 23 cases of colorectal adenoma and 94 adenocarcinomas. Metallothionein expression was examined by the avidinbiotin peroxidase immunoperoxidase (ABC) using the monoclonal mouse antibody E9, on formalin fixed, paraffin embedded tissue. RESULTS: Positive metallothionein expression (> 5% of neoplastic cells) was observed in 30.4% of adenomas and 25.5% of adenocarcinomas, while 8.7% of adenomas and 14.9% carcinomas showed focal metallothionein positivity. In contrast, 60.9% of adenomas and 59.6% of carcinomas almost completely lacked metallothionein expression. In the series of adenocarcinomas, metallothionein expression was inversely correlated with CD44 in neoplastic cells (p = 0.01). There was no statistically significant difference of metallothionein expression, or the other variables examined, between adenocarcinomas and adenomas. CONCLUSIONS: Metallothionein expression does not seem to indicate aggressive biological behaviour in colorectal adenocarcinomas, in comparison with the other types of carcinoma. The inverse correlation with CD44 could suggest that the decreased metallothionein expression may contribute to the metastatic spread of the lymph node involvement in colorectal cancer. Metallothionein expression does not seem to represent an independent prognostic marker in colorectal cancer.

Reduced serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in adults with inflammatory bowel disease.

In the present study, the changes in circulating IGF-1 and its binding protein IGFBP-3 were determined in adult patients with active inflammatory bowel disease (IBD) in order to assess the effect of this inflammatory condition on the IGF system. IGF-1 and IGFBP-3, as well as interleukin-6 (IL-6) were measured in serum obtained from 22 consecutive newly diagnosed patients (mean age 41.3 years) with active IBD, including 10 patients with Crohn's disease (CD), and 12 with ulcerative colitis (UC). For comparison the same parameters were determined in 30 healthy volunteers matched for age, sex and Body Mass Index (BMI). Serum IGF-1 and IGFBP-3 levels were similar in the two subgroups of patients and the values from all patients were combined for comparison with those from the control group. The mean (+/- SD) serum IGF-1 concentration (178 +/- 91 ng/ml) in the patients with IBD was lower compared with that in the controls (227 +/- 79 ng/ml, P<0.035). Similarly, the mean IGFBP-3 concentration in the patients was lower than in the controls (1.6 +/- 0.6 ng/ml vs 3.2 +/- 0.7 ng/ml respectively, P<0.001), Serum IL-6 levels were higher in the patients compared with the controls (5.5 +/- 4.2 vs 0.65 +/- 0.11 pg/ml, P<0.0001). The reduced IGF-1 and IGFBP-3 levels in patients with active IBD suggest that this systemic inflammatory condition is associated with a degree of acquired GH resistance, possibly induced by inflammatory cytokines.

Idiopathic dilated cardiomyopathy: lack of association with hepatitis C virus infection.

OBJECTIVE: To determine whether there is an association between hepatitis C virus (HCV) infection and dilated cardiomyopathy in a well defined area of north western Greece; such an association has been reported elsewhere. DESIGN: Evaluation of consecutive patients with chronic HCV infection for the presence of clinical or subclinical manifestations of dilated cardiomyopathy by history, physical examination, and non-invasive laboratory procedures (ECG, chest x ray, and echocardiography) before the initiation of interferon alpha treatment; investigation for HCV infection markers in patients with dilated cardiomyopathy by enzyme and immunoblot assays (antibodies to HCV) and the reverse transcriptase polymerase chain reaction (HCV RNA). SETTING: A tertiary referral centre for patients with chronic hepatitis and dilated cardiomyopathy. PATIENTS: 102 patients with well defined chronic HCV infection and 55 patients with well established dilated cardiomyopathy were evaluated. MAIN OUTCOME MEASURES: The need for HCV testing in patients with dilated cardiomyopathy, or follow up for heart disease in patients with chronic HCV infection. RESULTS: None of the patients with chronic HCV infection had clinical or subclinical evidence of dilated cardiomyopathy from history and laboratory findings. None of the patients with dilated cardiomyopathy was positive for antibodies to HCV or viraemic on HCV RNA testing. CONCLUSIONS: The study neither confirms the findings of other investigators, nor indicates a pathogenic link between HCV and dilated cardiomyopathy. For this reason, at least in Greece, testing for HCV in patients with dilated cardiomyopathy or follow up for heart disease in HCV patients appears unnecessary. Genetic or other factors could be the reason for this discrepancy if previously reported associations between HCV and dilated cardiomyopathy or hypertrophic cardiomyopathy were not coincidental.

Seropositive rheumatoid arthritis associated with Crohn's disease.

In the present study we report a patient with long-standing seropositive rheumatoid arthritis, who developed Crohn's disease. We discuss the possible pathophysiologic mechanisms and their associations between these two entities.

Immunohistochemical evaluation of cathepsin D expression in colorectal tumours: a correlation with extracellular matrix components, p53, pRb, bcl-2, c-erbB-2, EGFR and proliferation indices.

The immunohistochemical Cathepsin D (CD) expression of tumour and stromal cells was investigated in a series of 93 human colorectal adenocarcinomas and 22 adenomas with the intention to evaluate its prognostic significance and its contribution in the metastatic potential of colorectal cancer. CD expression was correlated with the expression of extracellular matrix components (collagen type IV, laminin and fibronectin), p53 protein, pRb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) as well as with other conventional clinicopathological features. CD expression (> 10% of positive tumour cells) was observed in 60.2% of carcinomas and in 72.7% of adenomas. Stromal CD expression was detected in all cases. A statistically significant positive correlation between neoplastic cells CD and stromal cells CD (SCCD) was observed in both carcinomas and adenomas. Cancer cells CD (CCCD) was positively correlated with collagen type IV and pRb expression as well as with PCNA score. In carcinomas, SCCD expression was statistically correlated with p53 protein and pRb expression and a trend for correlation with PCNA score was found. These data suggest that Cathepsin D of cancer and stromal cells, especially in combination with other markers, may provide more information about the biological behaviour of colorectal cancer.

Prevalence of viral markers among refugees from southern Albania: increased incidence of infection with hepatitis A, B and D viruses.

BACKGROUND: Since 1991, thousands of refugees from southern Albania have entered north-western Greece, an area with low-to-moderate endemicity for infection with hepatitis viruses. We examined the prevalence of several markers of viral infection in this population in order to ascertain the likely impact of its presence on the epidemiology of hepatitis infections in north-western Greece. DESIGN: Consecutive unselected serum samples were obtained from refugees resident in three different reception camps. SETTING: A university hospital. STUDY POPULATION: One thousand and twenty-five refugees (662 males and 363 females, age range 0-81 years) and 1984 healthy controls (1293 males and 691 females, age range 0-80 years). INTERVENTIONS: None. RESULTS: We found a significantly greater prevalence of markers of infection with hepatitis A virus (prevalence of antibodies to hepatitis A virus 98.2%), hepatitis B virus (HBV; prevalence of HBV s antigen 22.2%, prevalence of HBV c antibody 70.6%, prevalence of HBV s antibody 40.5%, prevalence of HBV e antigen 21.1%, prevalence of HBV e antibody 46.2%), hepatitis C virus (prevalence of antibodies to hepatis C virus 1.75%) and hepatitis D virus (prevalence of antibodies to hepatis D virus 12.7%) among refugees from southern Albania than in healthy Greek controls. These markers were found with significantly greater frequency among younger refugees (< 30 years of age) than in older members of the same population. CONCLUSIONS: We conclude that refugees from southern Albania are a new immigrant population characterized by a high incidence of infection with hepatitis A, B and D viruses. This finding may reflect the low socioeconomic status of the immigrant population and the poor hygienic conditions experienced by its members. The high incidence of HBV and HDV infections in the population from Albania will probably increase the prevalence of infection with these viruses in Ioannina and subsequently in the whole of the Epirus region. We therefore believe that rigorous adherence to general precautions and the initiation of hepatitis B vaccination programmes will be necessary in future, both in our area and in Albania.

Zinc, copper and immunological markers in the circulation of well nourished patients with ulcerative colitis.

OBJECTIVE: Few studies have been carried out on the trace element status in patients with ulcerative colitis (UC). Many trace elements are critical for the normal development and function of the immune system. This study was conducted in order to assess the serum levels of zinc and copper and the possible interrelation(s) between them and various immunological markers in the circulation of well nourished patients with UC. DESIGN/METHODS: The serum levels of zinc, copper, soluble interleukin-2 receptors (sIL-2Rs), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), non-organ specific autoantibodies (RF, ANA, ANCA, anti-dsDNA and anticardiolipin), C3C and C4 components of the complement system and ceruloplasmin were determined in 75 well nourished patients with UC (32 patients with active and 43 with inactive disease). Thirty-three healthy individuals were also investigated. RESULTS: The mean concentrations (microg/dl) of zinc and copper were significantly higher (P < 0.0005 and P = 0.0001, respectively) either in active (202.3 +/- 115.2 and 141.7 +/- 31.4, respectively) or in inactive disease (204.5 +/- 170.3 and 137.4 +/- 24.5, respectively) compared with healthy controls (93.6 +/- 49.8 and 85 +/- 41.2, respectively). The levels of copper were positively correlated with the C3C (r = 0.41, P < 0.0005), C4 (r = 0.38, P < 0.001) and ceruloplasmin (r = 0.44, P < 0.0005), whereas zinc was correlated with C3C (r = 0.32, P = 0.0005) and ANA (P = 0.01). Autoantibodies of at least one specificity (AUBS) were found in 77.3% of the patients. The mean levels (U/ml) of sIL-2Rs were significantly higher (P = 0.0001) in active disease (604.3 +/- 213.0) than in inactive UC (411.5 +/- 165.1) and in patients with ANA (P < 0.05), ANCA (P = 0.01) or AUBS (P < 0.05). The sIL-2Rs were correlated with the C4 (r = 0.40, P < 0.005) and the ESR (r = 0.43, P = 0.0001). CONCLUSION: These findings indicate that even in well nourished patients with UC, high serum levels of copper and zinc are present. The latter alterations of zinc and copper are correlated with haematological parameters of relapse of the disease or with acute phase proteins suggesting a relationship with the inflammatory process of UC. Further studies on the colonic tissue will address the role of zinc and copper in the inflammatory and immune reactions observed in this disease process.

A prospective evaluation of dermatological side-effects during alpha-interferon therapy for chronic viral hepatitis.

OBJECTIVE: Alpha-interferon therapy may occasionally account for immune-mediated phenomena. This study was conducted in an attempt to investigate the incidence of the development of immune-mediated dermatological diseases during alpha-interferon therapy in patients with chronic viral hepatitis. The latter has not been evaluated prospectively, whereas most of the previous studies examined small numbers of interferon treated patients or consisted of case reports. DESIGN: A prospective case-control study. SETTING: A tertiary referral centre. PARTICIPANTS: One hundred and twenty consecutive patients with chronic viral hepatitis (67 with hepatitis B, 45 with hepatitis C, six with both hepatitis viruses, and two with delta hepatitis) were evaluated during a course of alpha-interferon therapy. In addition, 120 consecutive patients with chronic liver diseases (disease control group), who had never received alpha-interferon therapy, were evaluated during the period of the study (at least for 12 months). INTERVENTIONS: Recombinant alpha-interferon at a dose of 4.5 or 5 million units subcutaneously (s.c.) three times per week for 6 to 12 months was administered to patients with hepatitis B. The patients with chronic hepatitis C were treated with 3 million units s.c. three times per week for 12 to 18 months. The patients with chronic hepatitis B and C infections received 4.5 million units for 6 months, and then 3 million units for an additional 6 to 12 months. Finally, the patients with chronic delta hepatitis received 5 million units for 1 year or more. MAIN OUTCOME MEASURES: To assess prospectively the incidence of these dermatological disorders during alpha-interferon therapy and to estimate if there is any relationship between their development and the clinical, laboratory or other characteristics of the patients with chronic hepatitis. RESULTS: Three to 6 months after the initiation of alpha-interferon three patients with chronic viral hepatitis (two with hepatitis C and one with hepatitis B) developed lichen planus, whereas one patient with hepatitis C developed relapsing aphthous stomatitis. The development of these disorders was significantly associated only with the presence of antinuclear antibodies before the initiation of alpha-interferon (P=0.000000). None of the patients from the disease control group had such a manifestation during the follow-up. Lichen planus resolved after the end of therapy in all of them. In contrast, therapy was discontinued in the patient who developed aphthous stomatitis, owing to the painful lesions. CONCLUSIONS: This study demonstrated that alpha-interferon may rarely (3.3%) induce immune-mediated dermatological disorders, especially lichen planus. The development of these disorders may reflect a subclinical or covert autoimmune background of patients, as suggested by the presence, although in low titres, of antinuclear antibodies. However, when lichen planus developed, it was mild, did not require the discontinuation of therapy and resolved after alpha-interferon administration had ceased.

Increased incidence of anti-cardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to anti-phospholipid syndrome.

OBJECTIVE: Chronic infection with hepatitis C virus (HCV) has been found to be associated with various diseases known as extra-hepatic manifestations of HCV. Recently, HCV has been implicated as a cause of the antiphospholipid syndrome (APLS). We conducted a study in a well-characterized area for epidemiological and prospective studies in the north-western part of Greece in order to address whether an aetiopathogenesis exists between HCV and APLS. DESIGN: Seventy-five patients with chronic hepatitis C were investigated for the presence of anti-cardiolipin antibodies (anti-CL) and for a past medical history supportive to the diagnosis of APLS. In addition, 24 patients with well-defined APLS (primary or secondary) and 12 patients with systemic lupus erythematosus (SLE) were tested for the presence of markers of HCV infection (anti-HCV and HCV RNA). The SLE patients were anti-CL-positive but none of them had developed any of the known clinical features of APLS. In addition, 267 healthy subjects were investigated for the presence of anti-CL. METHODS: IgG and IgM anti-CL were determined by a quantitative isotype-specific solid phase enzyme-linked immunosorbent assay set up in our laboratory. Anti-HCV was determined using a third-generation enzyme immunoassay and a confirmatory third-generation recombinant immunoblot assay. Active virus replication was defined by the detection of HCV RNA using a combination assay based on a reverse transcriptase polymerase chain reaction and a DNA enzyme immunoassay. RESULTS: Of the HCV patients, 37.3% had IgG and/or IgM anti-CL (P<0.00005 compared to healthy controls (2.25%)). However, the mean titres of each specific isotype were significantly lower in HCV patients compared with those found in the APLS patients (P<0.05 for IgM and P<0.001 for IgG isotypes). The mean titres of IgG anti-CL were also significantly lower in HCV patients compared with those found in the SLE patients (P<0.01). All patients with APLS or SLE (n = 36) tested negative for HCV infection markers. In addition, neither thrombotic events nor thrombocytopenia were associated with a positive anti-CL test in HCV patients. CONCLUSIONS: A significant proportion of HCV patients (37.3%) had detectable anti-CL of low titre. However, this finding was not associated with the development of APLS. On the other hand, none of the APLS patients was positive for HCV. Taken together, our data rather failed to reveal an aetiopathogenetic link between HCV and APLS. For this reason, testing for HCV in patients with APLS or follow-up for the possibility of the development of APLS in HCV patients cannot be suggested, at least in Greek patients. More prospective studies of longer duration are required in order to address whether HCV is involved or not in the aetiopathogenesis of APLS.