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Behcet’s disease (131)) is widely known to be strongly associated with human leukocyte antigen (HLA) B51 in many different ethnic groups. Recently, HLA-B51 allele typing of Greek BD patients was performed to study the distribution of B*5101-B*5107 alleles in this Greek population, the B51 antigen strongly associated with BD was found to be predominantly encoded by allele B*5101.As it is now known that the B51 antigen can be encoded by 21 alleles, B*5101-B*5121, we performed HLA-B*51 allele genotyping among 58 Greek patients with BD. After serological HLA typing, typing of HLA-B*51 alleles was performed using the polymerasse chain reaction-sequencing-based typing (PCR-SBT) method. The frequency of the B51 antigen was found to be significantly higher in the patient group as compared with the control group (75.9% of patients vs 22.0% of controls. In the genotyping of B51 alleles, 34 out of 44 B51-positive patients possessed B*5101. 13 out of the 44 carried B*5108. In contrast, all of the 9 B51-positive normal controls carried B*5101. This study revealed a strong, association between Greeks with BD, both B*5101, B*5108, provided important insights into the molecular mechanism underlying the association between HLA status, Us disease.

During a 4-year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of hepatocellular carcinoma (HCC), as well as from 360 controls who were hospitalized for eye, ear, nose, throat or orthopedic conditions in Athens, Greece. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) by third-generation enzyme immunoassays, and information on smoking habits and beverage consumption was obtained. We found a significant dose-response, positive association between smoking and HCC risk [greater than or equal to 2 packs per day, odds ratio (OR) = 2.5]. This association was stronger in individuals without chronic infection with either HBV or HCV (greater than or equal to 2 packs per day, OR = 2.8). Consumption of alcoholic beverages above a threshold of 40 glasses per week increased the risk of HCC (OR = 1.9). We also found evidence of a strong, statistically significant and apparently super-multiplicative effect of heavy smoking and heavy drinking in the development of HCC (OR for both exposures = 9.6). This interaction was particularly evident: among individuals without either HBsAg or anti-HCV (OR for both exposures = 10.9). Coffee intake was not positively associated with HCC risk, but the reverse could not be excluded for the subgroup of chronically infected individuals. In conclusion, tobacco smoking and heavy alcohol consumption are associated with increased risk of HCC, especially when these 2 exposures occur together. Int. J. Cancer 85:498-502, 2000. (C) 2000 Wiley-Liss, Inc.

Understanding of the genetic basis of autoimmune diseases is currently incomplete. Cytokine gene polymorphisms warrant consideration as factors explaining variation in the human immune and inflammatory responses and as candidate susceptibility genes for related pathological states. Interleukin 12 (IL-12) is a key regulator of the polarisation of immune responses to T helper 1 or 2 categories and plays a role in autoimmune and infectious diseases. Using a bioinformatic strategy, we aligned cDNA and expressed sequence tag sequences to identify putative polymorphic regions of the IL-12 p40 gene. Position 1188 in the 3′ untranslated region (UTR) was polymorphic with the frequency of the common allele around 80% in healthy UK Caucasoids. PCR genotyping of multiple Caucasoid groups and an African group showed significant population variation. In a case-control design, the polymorphism was not associated with rheumatoid arthritis, Felty's syndrome or large granular lymphocyte syndrome with arthritis or multiple sclerosis. A nonsignificant increase in the B allele frequency was observed in the rare large granular lymphocyte syndrome without arthritis (odds ratio 2.02 95% Cl 0.95-4.3). This new genetic marker could be useful in anthropological studies and should be investigated in other autoimmune, allergic, inflammatory and infectious diseases.

The serum levels of several cytokines were determined in 94 patients with Adamantiades-Behcet’s disease (ABD), aged 36.1 +/- 11.0 years, during the active stage (n = 75) and the inactive stage (n = 19) of the disease, A group of 75 healthy individuals matched for age and sex served as controls. Cytokine levels were determined using commercially available ELISA kits. Of the 75 patients with active disease and 19 with inactive disease, 38 (51%) and 4 (21%), respectively, and 23 healthy controls (31%) were found to have detectable levels of interleukin 8 (IL-8) in their serum (P < 0.05). Also, increased IL-8 serum levels were found in patients with active disease (median 12 pg/ml, P = 0.010) compared to patients with inactive disease (less than or equal to 10 pg/ml) and to healthy controls (less than or equal to 10 pg/ml). In particular, patients with oral aphthous ulcers (n = 51, 34 pg/ml) and neurological features (n = 4, 71 pg/ml) exhibited increased IL-8 levels. In contrast, there was no correlation between disease activity and the serum levels of IL-1 alpha, IL-1 beta, tumor necrosis factor alpha (TNF-alpha), soluble intercellular adhesion molecule-1 or basic fibroblast growth factor (bFGF). In a second set of experiments, the involvement of dermal microvascular endothelial cells in IL-8 secretion was investigated. Immortalized human dermal microvascular endothelial cells (HMEC-1 cells) were maintained for 4 h in vitro with serum from 18 ABD patients or with IL-1 beta, a known stimulator of IL-8 synthesis, TNF-alpha or their combination at five- to tenfold higher concentrations than those found in the serum of ABD patients. Increased IL-8 secretion was found after incubation with ABD patients’ serum (median 20 pg/ml), but IL-1 beta, TNF-alpha and IL-1 beta + TNF-alpha failed to induce IL-8 secretion by HMEC-1 cells (less than or equal to 1-1.2 pg/ml) in biologically relevant concentrations. Our study showed increased IL-8 serum levels in ABD patients with active oral and neurological manifestations. Human microvascular endothelial cells may, at least partially, be responsible for the enhanced IL-8 secretion in the active stage of the disease.

Purpose: insulin-like growth factor (IGF-1) and its major binding protein (IGF-BP3) have recently been implicated in the pathogenesis of several malignancies. However, anthropometric and lifestyle predictors of these hormones have not been elucidated Here we report the results of a cross-sectional study. Subjects and Methods: This cross-sectional study examines the relationship of a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) with IGF-1 and IGF-BP3 in a sample of 130 healthy adults. Results: We observed that serum levels of IGF-1 are higher, whereas levels of IGF-BP3 are lower, in men than in women. In addition, serum levels of IGF-l are independently and negatively associated with age and positively associated with pack-year history of smoking. Finally serum levels of IGF-BP3 are independently and negatively associated with the number of cigarettes smoked per day or pack-year history of smoking. Conclusion: Age, sex, and smoking are independent predictors of IGF-1 and/or IGF-BP3. The influence of these epidemiologic variables on the pathogenesis of disease states associated with IGF-1 and IGF-BP3 warrants further exploration. (C) 1999 by American Society of Clinical Oncology.

Purpose: To evaluate and quantity the association between consumption of specific food groups/macronutrients and concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3), Subjects and Methods: Data from a comprehensive food-frequency questionnaire administered to 115 healthy subjects were used to study cross-sectionally the relationship between nutritional factors and circulating IGF-1 and IGFBP-3 concentrations. Adjustment for the effect of fetal energy intake and a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) was implemented through multivariate linear regression. Results: We observed that serum levels of IGF-1 are positively associated with consumption of red meats, fats, and oils. In addition, serum levels of IGF-1 are independently and positively associated with energy intake from lipids and negatively associated with energy intake from carbohydrates. finally serum levels of IGFBP-3 are independently and negatively associated with energy intake from saturated fat. Conclusion: Serum IGF-1 and/or IGFBP-3 concentrations are associated with red meat, carbohydrate intake, and fat intake and, thus, may mediate the effect of these dietary factors on the pathogenesis of several disease states. Additional studies are needed to further quantify these associations and elucidate the underlying mechanisms, (C) 1999 by American Society of Clinical Oncology.

Behcet’s disease (BD) is a recurrent systemic vasculitis of unknown etiology. Genetic factors and infectious agents seem to be related ro the etiology and pathogenesis of the disease. ED is strongly associated with HLA-B51 antigen in many ethnic groups. As there are differences in HLA profile in different ethnic groups, we designed this case-control study to examine the association of HLA-B51 alleles and ED as well as to investigate the influence of sex, age at development of the International Study Group (ISG) for Behcet’s Disease criteria and certain features of disease severity on the strength of this association. The study includes 62 Greek ED patients who fulfil the ISG criteria for Behcet’s disease and 87 controls. Serological HLA Class-I typing was performed by standard microlymphocytotoxicity technique. HLA-DNA typing for the B5 group was performed in all B51 subjects and controls by PCR-SSO. Allele B*5101 was found in 80% of ED patients and in 26% of controls (odds ratio (OR) 10.48, p < 10(-6)). Males who carry this allele have a higher risk than females for ED (OR 16.97 and 5.74 respectively). B*5101 predisposes to ED at a younger age in both sexes and to the development of erythema nodosum (OR = Il, P = 0.004). This was confirmed by multiple logistic regression analysis. A weak but not significant association was found between B*5101 and uveitis (OR = 2). No association was found between B*5101 and vasculitis or skin lesions in either sex. It was concluded that in the Greek population allele B*5101 is a predisposing marker for ED, as in most ethnic groups, and that this allele predisposes to the development of the disease at a younger age in both sexes and to the development of erythema nodosum. (C) American Society for Histocompatibility and Immunogenetics, 1998. Published by Elsevier Science Inc.

The association of certain HLA-DRB1 alleles in Greek rheumatoid arthritis (RA) patients with several features of the disease, the gender of the patient and the age at onset was investigated. This case control study includes 86 Greek RA patients and 130 healthy controls unrelated to the patients. HLA typing was performed by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide (SSO) probes. HLA-DR4 was significantly increased in RA patients. The alleles *0101, *0401, *0405 and *1001 were associated with a higher risk of RA. The *0408 allele was absent from our patients. Sixty-five per cent of RA patients carried the ‘shared epitope’ (SE) compared with 31.5% of controls. The risk for RA in individuals carrying a single allele positive for SE was 2.85 times higher, and for those carrying two alleles positive for SE 8.57 times higher, than in SE-negative individuals. The risk was higher in those carrying the *0401 allele, followed by *0405 and *0101, while the genotype *0401/*0404 was absent. Alleles positive for SE comprise a predisposing factor for RA at an early age, particularly in men, and are associated with positive rheumatoid factor, nodules and erosions.

In an ongoing case-control study in Athens on the etiology of hepatocellular carcinoma (HCC), an analysis was made in order to assess whether HCV genotype Ib is associated with hepatocellular carcinoma (HCC). The HCV genotype was determined in 17 HCC patients, 87 patients with chronic hepatitis C (CHC) without cirrhosis (NC-CHC) and 23 patients with CHC and cirrhosis (C-CHC). HCV genotype Ib was detected in 14/17, 16/23 and 23/87 of HCC, C-CHC and NC-CHC respectively. The age- and gender-adjusted odds ratios contrasting HCC with NC-CHC and C-CHC with NC-CHC were 8.3 and 3.8 respectively. These data strongly support the hypothesis that HCV 1b is a stronger liver carcinogen than other HCV genotypes, probably through increased HCV replication and enhanced liver cytopathicity. (C) 1996 Wiley-Liss, Inc.

During a 16-month period in 1991-1992, blood samples and questionnaire data were obtained from 65 incident cases of hepatocellular carcinoma (HCC) as well as from 2 control groups of hospitalized patients matched on gender and age, which included 65 metastatic liver cancer (MLC) patients and 65 patients hospitalized for eye, ear, nose or throat conditions. Coded sera were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen, antibody to HBsAg and antibody to hepatitis C virus (anti-HCV) by enzyme immunoassay. The odds ratios (with 95% confidence intervals) in logistic regression modeling comparing the HCC cases to the combined control series were 18.8 (8.2-3.2) for the presence of HBsAg and 7.7 (1.7-35.1) for anti-HCV. In the present hospital-based case-control study anti-HCV testing was conducted on recently collected sera, using a second-generation enzyme immunoassay with confirmation by immunoblot assay. Comparisons with previous work in a similar population demonstrated that, when second-generation anti-HCV assays are applied to sera stored for 7-15 years, confirmatory assays or a higher diagnostic cut-off point may be necessary to ensure that the testing is specific. (C) 1995 Wiley-Liss, Inc.

The aim of this study was to evaluate the prevalence of hepatitis C virus infection (HCV) in Greece, to estimate its frequency in chronic liver disease and to explore the role of HCV infection in the aetiology of hepatocellular carcinoma. A series of 1034 patients with chronic liver disease of various aetiologies and 299 patients with hepatocellular carcinoma allocated to two case-control studies was tested for anti-HCV. Twelve recent reports on HCV infection in Greece were reviewed and analyzed. The results of the present study indicate the existence of a large pool of HCV infection in Greece and an impressive spread of the virus in high-risk groups. Chronic HCV infection was found to account for 83.6% of patients with chronic non-A, non-B hepatitis parenterally transmitted, 56.5% of cases of sporadic community-acquired disease and for almost 1/4 of all patients with chronic liver disease. The relative risks for development of hepatocellular carcinoma of patients with chronic HCV infection was 6.3 in the first and 13.7 in the second case-control study, increasing to 20.0 and 18.7, respectively, when hepatitis B surface antigen (HBsAg) was positive. Serum HBV-DNA was positive and/or anti-HBc IgM levels were high in 12 of 15 (80%) patients with hepatocellular carcinoma positive only for HBsAg, and in 7 of 15 (47%) positive both for HBsAg and antibodies to HCV. The present data support the view that hepatitis B and C virus have an interacting role in the origin of hepatocellular carcinoma.

It is frequently assumed that the risk of hepatocellular carcinoma related to hepatitis B virus is higher when chronic hepatitis B virus infection is acquired early in life. This hypothesis has never been directly evaluated. However, firstborn and secondborn children are exposed to common infections after their school enrollment, whereas later-born children are exposed much earlier, through their older siblings. The authors analyzed sibship size and birth order data from a large case-control study of patients admitted to Athens, Greece, hospitals between April 1976 and October 1984. The analyses included 185 patients with hepatocellular carcinoma 35 patients with metastatic liver cancer, and 432 other hospital controls. There was a tendency for cases of hepatocellular carcinoma to concentrate at higher birth orders. When the analysis was restricted to cases and controls who were positive for hepatitis B surface antigen, this tendency was even more notable. These results are compatible with the hypothesis that establishment of chronic hepatitis B virus infection at an early age increases the risk of hepatocellular carcinoma substantially more than does chronic infection with this virus established at a later age.

The phagocytic activity of mononuclear phagocytes of A/J mice and Wistar rats was estimated by the carbon clearance test following injection of Mycoplasma arthritidis. In mice, the overall phagocytic activity was significantly increased at the end of the first week (P < 0.0001), but the increase was marginal by the third and fourth weeks after injection. A significant increase in the relative weight of liver and spleen was observed even when phagocytic activity had returned to levels similar to those of controls (P < 0.001). In rats, the overall phagocytic activity was significantly increased until the fourth week (P < 0.00001). There was not, however, an increase in the relative weight of liver and spleen as observed for the mice. The results are discussed in the context of factors contributing to the pathogenic mechanisms responsible for differences in the patterns of arthritis due to mycoplasma observed in mice and rats.

Serum taken from patients in a case-control study in Athens, Greece, was used to examine the interactive roles of hepatitis B virus (HBV) and hepatitis C virus (HCV) in the origin of hepatocellular carcinoma (HCC). An enzyme immunoassay for anti-HCV was used to test serum taken from 185 cases with HCC, 35 cases with metastatic liver cancer (MLC), and 432 hospital controls. Weakly positive anti-HCV results were more strongly related to MLC than to HCC, implying that these anti-HCV results are false positive. By contrast, strongly positive anti-HCV results were significantly related to HCC (relative risk [RR], 6.3), whereas no significant association was evident for MLC (RR, 0.6). The association of anti-HCV with HCC was substantially higher among subjects whose radioimmunoassay was positive for hepatitis B surface antigen (RR, 20.0) than among those whose radioimmunoassay was negative for this marker (RR, 4.8). These findings indicate that HCV infection has an interactive role in the origin of HCC.

A recently introduced enzyme immunoassay procedure for antibodies against the hepatitis-C virus (HCV) was used to test samples from 185 cases with hepatocellular carcinoma (HCC) and 432 hospital controls. The anti-HCV results were examined in conjunction with previously reported data from this study concerning hepatitis-B virus (HBV) serology, hepatitis-D virus (HDV) antibodies, presence of cirrhosis and tobacco smoking. There was evidence for interaction between HBV and HCV in the causation of HCC: as previously reported, the rate ratio (RR) linking the presence of anti-HCV to HCC among subjects positive for hepatitis-B surface antigen (HBsAg) was substantially higher than the corresponding RR among those negative for this marker; furthermore, among HCC patients positive for HBsAg, a high proportion (33/61) of those who were positive for hepatitis-Be antigen (HBeAg) or its antibody were positive for anti-HCV, whereas among HBsAg-positive controls who were also positive for HBeAg or its antibody, none was positive for anti-HCV (0/18; p < 10(-4)). The anti-HCV-related RR for HCC was also higher among HCC patients with cirrhosis than among those without evidence of co-existing cirrhosis (RR 11.4 vs. 4.4; p = 0.06). In addition, there was some evidence of interaction between tobacco smoking and HCV in the origin of HCC; after controlling for age, sex and HBsAg status, the RR for subjects positive for anti-HCV was 6.8 among smokers but only 3.2 among non-smokers (p = 0.26). By contrast, there was no suggestion of an interaction between anti-HCV and anti-HDV, in agreement with the presumed minimal role, if any, of HDV in HCC etiology. These results support the notion that HCV is involved in the etiology of HCC by advancing, through a chronic liver disease process, carcinogenesis initiated by other factors.

To investigate the effect of long term hashish use on T-lymphocytes we have measured the incorporation of14C-thymidine by peripheral blood lymphocytes, unstimulated and stimulated by phytohemagglutinin, as well as the proportion and number of E-rosettes in 12 healthy male chronic users of the drug before and after a smoking session, and in 15 control subjects. The results show that hashish smoking does not impair the response of lymphocytes to PHA, at least at the concentration of PHA used. Furthermore there is a possibility that among chronic users a hashish smoking session may have a slight stimulatory effect. © 1978 Springer-Verlag.