Study comparing the effect of pioglitazone in combination with either metformin or sulphonylureas on lipid profile and glycaemic control in patients with type 2 diabetes (ECLA).

OBJECTIVE: To explore whether the improvement of lipid profile and glycaemic control observed in randomized control trials with pioglitazone (PIO) is replicated under conditions of general clinical practice. RESEARCH DESIGN AND METHODS: We studied 2388 patients with type 2 diabetes (T2DM) not adequately controlled by monotherapy on either metformin (MET) or sulphonylurea (SU). Addition of a second drug, according to the treating physician's choice, resulted in three groups, PIO + MET, PIO + SU and MET + SU, followed for twelve months, while efficacy and safety parameters were measured at baseline, at six and at twelve months. RESULTS: A total of 2116 (88.6%) patients completed the study. Diabetic control and lipid profile improved in all three groups, but the improvement was always greater in the two PIO groups. At 12 months PIO + SU and PIO + MET groups compared to SU + MET showed greater increase in HDL cholesterol (8.3% and 9.2 versus 4.3% p < 0.001) and greater decrease in HbA1c (1.53% and 1.46% versus 0.97%, p < 0.001 for both), in triglycerides (20.7% and 21.5% versus 15.2%, p < 0.001) and in LDL cholesterol (15.2% and 14.6% versus 11.3%, p < 0.001 and p < 0.01, respectively). All changes were greater in patients already taking hypolipidaemic drugs. As ECLA was an observational study, the major limitation is the introduction of confounding bias which, however, was accounted for in the statistical analysis. CONCLUSIONS: Since improvement of both glycaemic control and lipid profile are considered main targets in the management of the diabetic patient, the results of the present study, conducted under conditions of everyday clinical practice, show that pioglitazone may be considered a potential choice for the treatment of type 2 diabetes, when lifestyle and metformin fail.

Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.

OBJECTIVES: The aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection. METHODS: 14 patients with chronic HBV infection, 19 HBV-vaccinated patients and 19 patients with resolved HBV infection were included in the study. All HBV-infected patients received combination therapy with oral antivirals and anti-TNF agents. During treatment the levels of hepatitis B surface antibodies (anti-HBs) in HBV-vaccinated patients and of serum HBV DNA in patients with chronic or resolved HBV infection were monitored. RESULTS: No viral reactivation was observed in patients with resolved HBV infection while anti-HBs titres decreased during anti-TNF treatment in vaccinated patients, similarly to patients treated with methotrexate alone. None of the HBV-infected patients developed liver decompensation or a significant increase in alanine aminotransferase levels. One patient (7%) treated with lamivudine and etanercept showed viral reactivation due to the emergence of a lamivudine-resistant mutant strain. CONCLUSIONS: Anti-TNF agents represent a safe option for patients with chronic HBV infection when combined with antiviral therapy, as well as in patients previously exposed to HBV receiving no HBV prophylaxis. Resistant HBV strains may arise in patients with chronic hepatitis B, necessitating the initial use of anti-HBV agents with a low risk of resistance.

Survivin expression in colorectal carcinomas: correlations with clinicopathological parameters and survival.

BACKGROUND: Survivin is a new member of the Inhibitor of apoptosis protein family that has a dual function as a mitotic regulator and apoptosis inhibitor. Survivin is prominently expressed in transformed cell lines and in many human cancers, including colorectal carcinoma. The aim of this study is to investigate the expression of survivin in colorectal carcinomas and its possible associations with clinicopathological parameters and patient survival. MATERIALS AND METHODS: Sections of formalin-fixed paraffin-embedded tissues from 77 colorectal carcinomas were immunohistochemistry stained for survivin. RESULTS: Survivin was mainly detected in the bottom of the glands of normal mucosa with mainly cytoplasmic localization. No survivin expression was found in infiltrating lymphocytes, fibroblasts, smooth muscle cells or neural tissue. Survivin staining was detected in 68/77 (88.3%) colorectal carcinomas. Survivin expression was found to be significantly associated with tumor differentiation (P = 0.02) but not with gender, age or Dukes stage. Survival did not differ according to survivin expression. CONCLUSION: Survivin was found in the majority of colorectal carcinomas, suggesting that its expression is an early event in colorectal carcinogenesis. Its expression is statistically significantly associated with tumor differentiation but not with patient survival.

Serum hepcidin levels are related to the severity of liver histological lesions in chronic hepatitis C.

Hepcidin is synthesized in the liver and has a crucial role in iron homoeostasis. Its synthesis is up-regulated in chronic inflammation and iron excess. We examined the determinants of serum hepcidin and liver hepcidin mRNA levels and their association with histological lesions in patients with chronic hepatitis C (CHC) and healthy controls. We studied 96 patients with CHC and 30 controls. Serum hepcidin levels were measured by an in-house competitive ELISA. Hepcidin mRNA levels were determined by a one-step qRT-PCR in total RNA extracted from liver biopsy specimens of 27 patients with CHC and six disease controls. Histological lesions were evaluated according to Ishak's classification. Serum hepcidin was significantly lower in patients with CHC than healthy controls (14.6 ± 7.3 vs 34.6 ± 17.3 ng/mL, P < 0.001). In patients with CHC, serum hepcidin correlated positively with aspartate aminotransferase (r = 0.334, P = 0.001) and insulin resistance (r = 0.27, P = 0.016) and had a trend for correlation with alanine aminotransferase (r = 0.197, P = 0.057) and serum haemoglobin (r = 0.188, P = 0.067) but not with ferritin. A significant positive correlation was also found between serum hepcidin levels and both necroinflammation (r = 0.259, P = 0.011) and fibrosis (r = 0.214, P = 0.036). Serum hepcidin was among others an independent predictor of cirrhosis (odds ratio: 1.145, P = 0.039). Liver hepcidin mRNA levels did not differ between patients and controls and were relatively lower in patients with than without cirrhosis (19.3 ± 21.7 vs 38.3 ± 26.0, P = 0.067). Patients with CHC have reduced serum hepcidin levels, which correlate with worse necroinflammation and fibrosis. The previously mentioned observations suggest a viral effect on hepatic hepcidin production, but might also support its involvement in the inflammatory process.

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study.

BACKGROUND: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes. AIM: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR. METHODS: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006). CONCLUSIONS: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.

Evidence that even "normal" albuminuria may denote incipient GFR reduction in patients with type 2 diabetes mellitus.

AIMS: In patients with diabetes and microalbuminuria, small changes of GFR could have been missed, due to the lack of sensitive methodology for GFR determination in clinical practice (creatinine based calculations). Therefore we explored the relation of the degree of albumin excretion with Cystatin C, which has been recently proved to be a better marker of GFR, compared to serum creatinine. METHODS: We studied 179 patients with type 2 diabetes, in whom renal function and microalbuminuria were evaluated. RESULTS: In patients with normal renal function, GFR/MDRD>or=60 ml/min/1.73 m(2), (n=79), urinary albumin concentration (UAC) was significantly correlated with Cystatin C, both in patients with normoalbuminuria (r=0.547, p<0.023) or microalbuminuria (r=0.305, p<0.035), while it was not correlated either with serum creatinine or calculated creatinine clearance. In patients with GFR/MDRD<60 ml/min/1.73 m(2), (n=100), UAC was significantly correlated with Cystatin C, also both in patients with normoalbuminuria (r=0.536, p<0.032) or microalbuminuria (r=0.340, p<0.016), while it was significantly correlated with serum creatinine and calculated creatinine clearance only in those with microalbuminuria. CONCLUSIONS: Subtle changes in renal function, as judged by Cystatin C concentration, may parallel the degree of albuminuria, even in the normoalbuminuric stage. This finding needs further confirmation by more appropriate methodology in prospective follow up studies.

Prevalence of glucose intolerance in patients with chronic hepatitis B or C: a prospective case-control study.

Despite several studies, the association of glucose intolerance with chronic hepatitis B (CHB) or C (CHC) virus infection remains controversial. We evaluated the prevalence of glucose intolerance by oral glucose tolerance test (OGTT) in patients with CHB or CHC in comparison with matched controls. In total, 189 consecutive outpatients with CHB or CHC and 189 subjects individually matched for age, sex and body mass index (BMI) were included. OGTT was performed in all cases, except in known diabetics, and glucose intolerance was defined as impaired glucose tolerance (IGT), OGTT-diabetes or known diabetes. Most patients with abnormal OGTT had normal fasting glucose (IGT: 69.8%, OGTT-diabetes: 54.5%). Compared with their own controls, CHB patients had a higher prevalence of IGT (13.6% vs 2.5%, P = 0.018) and family history of diabetes (34.6% vs 16.0%, P = 0.011), while CHC patents had higher prevalence of glucose intolerance (37.0% vs 15.7%, Rho = 0.001), mostly because of more frequent IGT (21.3% vs 6.5%, Rho = 0.003). After age and BMI adjustment, patients with CHC compared with those with CHB had significantly higher prevalence of glucose intolerance (37.0% vs 29.6%, P = 0.037). In conclusion, increased prevalence of glucose intolerance is documented by OGTT both in CHC and CHB patients compared with age, sex and BMI matched controls. Glucose intolerance is more frequent in CHC than CHB patients, regardless of known risk factors. An OGTT might be necessary at the baseline work-up of CHB or CHC patients, as a normal fasting glucose value does not exclude IGT or OGTT-diabetes.

Severe rhabdomyolysis with hypoglycemia in an adult patient with carnitine palmitoyltransferase II deficiency.

Carnitine palmitoyltransferase II (CPT2) deficiency is an inherited disorder associated with rhabdomyolysis. The adult form of CPT2 deficiency is usually "benign", characterized by episodes of rhabdomyolysis without extramuscular manifestations and with a good outcome, while the infantile type characteristically presents with severe metabolic symptoms such as hypoketotic hypoglycemia. We present here a case of severe rhabdomyolysis with acute renal failure and hypoglycemia in an adult patient with CPT2 deficiency.

Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis.

BACKGROUND: The prevalence of metabolic syndrome and its possible impact on the severity of liver histological lesions have not been studied prospectively in chronic liver diseases. AIM: To investigate the prevalence of metabolic syndrome in patients with chronic viral hepatitis or non-alcoholic steatohepatitis, and to determine its associations with histological severity. METHODS: We prospectively included 317 patients (hepatitis B e antigen-negative chronic hepatitis B: 95, chronic hepatitis C: 176, non-alcoholic steatohepatitis: 46) with liver biopsy. Metabolic syndrome was defined using the Adult Treatment Panel III criteria. Histological lesions were evaluated according to Ishak's or Brunt's classification. RESULTS: Metabolic syndrome was present in 10.4% of patients being significantly more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis (41.3% vs. 5.1%, P < 0.001). In chronic viral hepatitis, cirrhosis (stages 5-6) was independently associated with increasing age, higher aspartate aminotransferase and gamma-glutamyl-transpeptidase levels, severe necroinflammation and metabolic syndrome (P = 0.016). In non-alcoholic steatohepatitis, severe fibrosis (stages 3-4) was independently associated with severe necroinflammation and metabolic syndrome (P = 0.033). Presence of metabolic syndrome was not associated with presence or severity of steatosis both in chronic viral hepatitis and in non-alcoholic steatohepatitis. CONCLUSION: Metabolic syndrome is more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis; it is associated independently with more severe fibrosis but not with the severity of steatosis, both in chronic viral hepatitis and in non-alcoholic steatohepatitis.

Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection.

BACKGROUND AND AIMS: In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early liver injury. An investigation was carried out into whether the serum levels of caspase-generated fragments of cytokeratin-18 (CK-18) are associated with the severity of liver lesions in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection. Patients/ METHODS: CK-18 fragment serum levels were determined in 115 treatment-naive, consecutive HBV patients and 30 healthy controls. Hepatic-expression of CK-18 fragments was evaluated by immunocytochemistry in chronic hepatitis B patients. RESULTS: CK-18 fragment levels (U/l) were significantly lower in healthy controls (mean (SD), 154 (31)) than in 53 inactive carriers (172 (24), p = 0.003) and in 62 chronic hepatitis B patients (474 (488), p<0.001). The receiver operating characteristic curve showed excellent diagnostic accuracy (c-statistic: 0.87) for differentiating inactive carriers from chronic hepatitis B patients. A CK-18 fragment cut-off level of 240 U/l gave a sensitivity of 60%, and a specificity and positive predictive value of 100% for chronic hepatitis B diagnosis. CK-18 fragment levels were also lower in inactive carriers than in 16 chronic hepatitis B patients with transiently normal alanine aminotransferase (ALT; 327 (256), p = 0.001), offering good accuracy for such a differentiation (c-statistic: 0.78). In chronic hepatitis B patients, serum CK-18 fragments correlated positively with ALT/aspartate aminotransferase (AST), viraemia, grading score and their immunohistochemical hepatic expression, and negatively with platelet counts, but not with fibrosis or steatosis severity. CONCLUSIONS: Serum apoptotic caspase activity is strongly associated with the presence of liver injury in patients with HBeAg-negative chronic HBV infection. CK-18 fragment levels seem to be a very useful marker for differentiation between the inactive HBV carrier state and HBeAg-negative chronic hepatitis B, but not for estimation of the severity of liver histological lesions among HBeAg-negative chronic hepatitis B patients.

Correlation of NK T-like CD3+CD56+ cells and CD4+CD25+(hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: Association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy.

BACKGROUND: Several cytokines have been associated with immune regulation and prognosis in ovarian cancer. CD4+CD25+ Tregs and CD3+CD56+ NK-like T cells are involved in the immune response against the tumor. We have investigated the association of cytokines in the ascites from patients with ovarian cancer with these populations, the platinum resistance and the prognosis of these patients. PATIENTS AND METHODS: Ascites from 64 patients with ovarian cancer was analysed. Forty-two patients were studied at diagnosis (FIGO stage III in 40 cases) and were treated with cytoreductive surgery and platinum-based chemotherapy. Ascites from 9 patients with cirrhosis was used as control. Vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), interleukin-10 (IL10) and interleukin-12 (IL12) in ascites and serum were measured by enzyme-linked immunosorbent assay (ELISA), while lymphocytic populations were studied with three-colour flow cytometry. RESULTS: VEGF ascites levels were inversely correlated with CD3+CD56+ cells (rho=-0.316, p=0.012), while a similar correlation was observed between TNFalpha ascites levels and CD4+CD25+(hi) cells (rho=-0.332, p=0.041). Among patients receiving first-line chemotherapy, VEGF levels <1900 pg/ml and TNFalpha levels >35 pg/ml were associated with platinum sensitivity (p=0.021 and p=0.028, respectively) and improved progression-free survival (PFS) (p=0.007 and p=0.045, respectively). Low VEGF levels were also associated with improved overall survival (p=0.026). CONCLUSION: VEGF and TNFalpha ascites levels are associated with prognosis in advanced ovarian cancer. Their prognostic significance may be due to their association with immunologically important populations, namely the NK T-like CD3+CD56+ cells and the Tregs CD4+CD25+(hi) cells.

Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C.

BACKGROUND/AIMS: Hepatic steatosis has not been adequately studied in chronic hepatitis B, while it is considered to be a cardinal feature in chronic hepatitis C and to be mainly metabolically induced in patients infected with genotype 1. We investigated the prevalence of and the parameters associated with steatosis in HBeAg-negative chronic hepatitis B. METHODS: We studied 213 patients with HBeAg-negative chronic hepatitis B and compared them with 163 patients with genotype-1 chronic hepatitis C. Steatosis was semi-quantitatively graded. RESULTS: Steatosis was significantly less frequent in chronic hepatitis B than chronic hepatitis C (60% versus 72%, P=0.016), but there was no difference in the prevalence of moderate/severe steatosis. In chronic hepatitis B, steatosis was associated only with higher body mass index (P=0.002), while moderate/severe steatosis was associated only with higher body mass index (P=0.043) and diabetes (P=0.031). Steatosis was relatively less frequent in chronic hepatitis B than chronic hepatitis C non-diabetic, normal-weight patients (45.6% versus 62.5%, P=0.063), but it did not differ in diabetic and/or overweight/obese patients with chronic hepatitis B or chronic hepatitis C. CONCLUSIONS: Hepatic steatosis in HBeAg-negative chronic hepatitis B (a) is less frequent than in genotype-1 chronic hepatitis C, (b) is mainly associated with presence of host metabolic factors, such as high body mass index and diabetes and (c) does not seem to be associated with the severity of liver histological lesions.

Liver transplantation in Greek patients: epidemiological data, morbidity, and mortality of 71 patients from a single center with 6 years of mean follow-up.

Liver transplantation remains an underdeveloped technique in Greece; currently there is no information on outcomes in Greek patients. In this study, data were provided on the outcomes of liver transplantation in 71 patients with a mean follow-up of 6 (0.1 to 16) years in our center. Mean age at transplantation was 46 +/- 13 years, while the main cause for transplantation was hepatitis B (16 patients, 23%) or C (six patients, 8%) virus. In the first posttransplantation year, three patients died, while 18 (25%) required at least one hospitalization with a median stay of 30 days. At the end of follow-up, 56 patients (79%) are alive. The leading cause of death was de novo malignancies (40%), appearing at a mean of 5.2 +/- 3.3 years. Late adverse effects of immunosuppressive therapy included hypertension (42%), hyperlipidemia (24%), chronic renal failure (21%), and diabetes mellitus (24%). With the exception of diabetes, all the above abnormalities were significantly associated with cyclosporine-based but not with tacrolimus-based immunosuppressive regimens. Relapse of primary disease in liver transplants occurred in 21 (29.6%) patients at a mean time of 1.5 +/- 1.4 years, of whom 67% were related to viral hepatitis. The quality of life (Karnofsky scale 1 to 6) was excellent in 64% of surviving patients, affordable in 21%, and poor in 15%. In conclusion, after 6 mean years, the majority of Greek liver transplant recipients conduct a normal life, although metabolic abnormalities are often observed. A national registry is needed to provide more solid evidence of outcomes.

Significant differences of lymphocytes isolated from ascites of patients with ovarian cancer compared to blood and tumor lymphocytes. Association of CD3+CD56+ cells with platinum resistance.

OBJECTIVES: Tumor infiltrating lymphocytes (TILs) and T regulatory cells (Tregs) have been associated with prognosis in ovarian cancer, but their prognostic significance in ascites has not been studied. We performed a prospective study of T lymphocytes isolated from ascites from patients with ovarian carcinoma and we compared them with the respective populations in blood and tumors. METHODS: Mononuclear cells from ascites (n=71) and blood were isolated by Ficoll, while tumor lymphocytes (n=20) were obtained upon mechanical dissociation. Phenotypic analysis was performed with flow cytometry. Ascites from 10 patients with cirrhosis was used as control. RESULTS: Tregs containing CD4(+)CD25(+) cells, NK-T containing CD3(+)CD56(+) cells and CD69 and HLADR expression of CD4 and CD8 lymphocytes were significantly increased in tumor ascites compared to blood and control ascites. A selective accumulation of these populations in the ascites of cancer patients, was suggested by the significantly higher ascites/blood (A/B) ratios in cancer patients but not controls. Cancer cell content in ascites was correlated with CD4(+)CD25(+), CD4(+)CD69(+), CD4(+)HLADR(+) and CD8(+)CD69(+) cells. There was no correlation of lymphocyte populations between ascites and samples from peritoneal metastases. Higher tumor grade was associated with increased A/B CD4(+)CD25(+) ratio and reduced CD3(+)CD56(+) cells, while platinum resistance was associated with reduced A/B CD3(+)CD56(+) ratio. CONCLUSIONS: There are significant differences of CD3(+)CD56(+) and CD25(+)CD4(+) lymphocytes and increase in lymphocyte activation between blood, ascites and peritoneal metastases from patients with ovarian cancer. The selective accumulation of CD3(+)CD56(+) population in ascites may be a predictive factor for platinum resistance.

Severe hepatitis C virus-related cryoglobulinaemic sensory-motor polyneuropathy treated with pegylated interferon-a2b and ribavirin: clinical, laboratory and neurophysiological study.

BACKGROUND/AIMS: Severe involvement of central and/or peripheral nervous system is a rare complication of hepatitis C virus (HCV)-related cryoglobulinaemia. METHOD: Four patients with HCV-related type II/III cryoglobulinaemia (three males with genotype 1, one female with genotype 3) who presented with severe sensory-motor polyneuropathy, one with central nervous system involvement as well, were treated with pegylated IFNa-2b 1.5 microg/kg/week and ribavirin 10.6 mg/kg/daily for 48 weeks. Neurological evaluation involved detailed clinical motor and sensory scores/scales and neurophysiological studies before and after treatment. RESULTS/CONCLUSION: Three out of four patients had undetectable serum HCV-RNA, normal levels of aminotransferases and substantially lower or undetectable levels of cryoglobulins at the end of treatment and at 24 weeks follow-up period. Treatment was well tolerated and all patients exhibited significant improvement of neuropathy based on solid clinical and laboratory criteria that was associated with the virological response.

Prophylactic and therapeutic use of recombinant activated factor VII in patients with cirrhosis and coagulation impairment.

Patients with cirrhosis and impaired coagulation often pose major therapeutic problems during bleeding episodes or invasive procedures. Recombinant activated factor VII (rFVIIa), which has been licensed for the treatment of haemophilia patients with factor VIII or IX inhibitors, has been occasionally used in cirrhotic patients. We present five patients with cirrhosis and coagulopathy who received 1-4 recombinant activated factor VII infusions either prophylactically in order to safely undergo an invasive procedure or therapeutically in order to control a severe bleeding episode which did not respond to standard supportive care. In particular, recombinant activated factor VII infusions were given in two patients before a percutaneous liver biopsy, in one patient before teeth extraction and in two patients with haemoperitoneum after an invasive procedure. Infusions of recombinant activated factor VII achieved rapid correction of prothrombin time in all cases allowing the safe performance of invasive procedures or resulting in efficient control of the bleeding episode. In conclusion, recombinant activated factor VII seems to be a rather promising agent for the prevention or treatment of complications of haemostasis impairment in cirrhotic patients. However, its exact role in this setting needs to be evaluated within well-designed, controlled clinical trials.

Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations.

Hepatitis B virus (HBV) strains carrying the precore stop-codon mutation (A1896) have been considered among the predisposing factors for reactivation during chemotherapy for malignancies. The role of the T1762/A1764 basic core promoter (BCP) mutations has not been fully evaluated. We aimed to record any changes in HBV serological markers after reactivation, detect the presence of A1896 and BCP mutations and evaluate the type of cytotoxic drugs involved. We retrospectively screened eight patients presenting with HBV reactivation following chemotherapy for malignancies. The chemotherapy regimens used included corticosteroids (CSs), fludarabine and cyclophosphamide/adriamycine. The INNO-LiPA HBV PreCore kit was used for the detection of the A1896 and BCP mutations. Six patients who were hepatitis B surface antigen (HBsAg)-(+)/hepatitis B e antigen (HBeAg)-(-) before chemotherapy, had disease reactivation following a mean of four cycles of chemotherapy. Four survived and two died of hepatic failure. At the time of reactivation, all six patients carried the A1896 and five of them the BCP mutations. The remaining two patients were HBsAg-(-)/anti-HBs-(+)/anti-hepatitis B core (HBc)-(+)/HBeAg-(-) before chemotherapy. One of them reverted to HBeAg-(+) status but remained HBsAg-(-), while the other became HBsAg-(+)/HBeAg-(+), following three and eight cycles of fludarabine treatment, respectively. The former carried the A1896 and the latter the wild-type virus. Both died from causes associated with their haematological disease. All but one of our patients with HBV reactivation during chemotherapy carried the precore stop-codon and BCP mutations. Whether this occurs more frequently in such patients than those carrying the wild-type virus needs further investigation. Fludarabine should be added to the list of drugs inducing HBV reactivation. HBV reactivation following fludarabine treatment occurred in HBsAg-(-) patients who had been anti-HBs-(+).

Epidemiological evidence for the non-random clustering of the components of the metabolic syndrome: multicentre study of the Mediterranean Group for the Study of Diabetes.

OBJECTIVE: To determine: (a) whether the components of metabolic syndrome (MetS) cluster more frequently than predicted by chance alone and (b) whether increased risk for MetS is associated also with values of each component below, but close to the cutoff points defining MetS. RESEARCH DESIGN AND METHODS: Anthropometrical and biochemical measurements were performed and a dietary questionnaire was filled-in in 1833 randomly selected non-diabetic subjects, 916 men and 917 women, 20-74 years old, in nine centres in five Mediterranean countries. The prevalence of MetS and of possible combinations of its individual components was measured. The expected frequencies of the above combinations were calculated according to the mathematical formula of probabilities. RESULTS: The overall prevalence of MetS was 27.2%, but varied greatly among countries, from 5.8% in Algeria to 37.3% in Greece. The observed prevalence of each combination diagnostic of MetS was higher than the expected by chance. Thus, the observed overall prevalence of MetS was also higher than the expected, 27.2 vs 24.0%, P=0.03. Furthermore, for each individual component (except high-density lipoprotein), as values in the normal range, approached the cutoff point, the risk of having MetS (i.e. clustering of the other components) increased significantly (odds ratio 2.2-4.6, P<0.001). CONCLUSIONS: The MetS is not related to the Mediterranean type of diet and its prevalence varies greatly among five Mediterranean countries. The clustering of the components defining the MetS is not due to chance and moreover even 'high normal' levels of each component confer increased risk for the syndrome.