Seasonal trends in the prevalence of hypospadias: Aetiological implications.

The aim of the present study was to examine the seasonality of hypospadias in Greece in an attempt to elucidate the aetiology. All boys born between 1991-1998, who underwent hypospadias repair at 'Aghia Sophia' Children's Hospital, Athens (n=542) were analysed. All Greek live-born males during the same period (population at risk; m=421,175) served as the controls. Seasonality by month of birth was evaluated with specific statistical tools. Meteorological parameters were also analysed. All tests yielded significant results, suggesting a simple harmonic prevalence pattern (highest/lowest: autumn, peak in October/spring, trough in April). Therefore, the first trimester of hypospadiac gestations coincides more frequently with winter. Meteorological parameters varied seasonally (maximal sunlight; air temperature in summer/minimal in winter, maximal rainfall in winter/minimal in summer) and were strongly associated pairwise. Hypospadiac birth prevalence follows a simple harmonic seasonal pattern and is associated with that of cryptorchidism in Greece. The coincidence of the first or third trimester of a potentially genetically influenced gestation with winter could lead to the phenotypic expression of hypospadias or cryptorchidism, respectively. The potential role of a cyclic-varied androgen-production stimulator, such as human chorionic gonadotrophin may be speculated. The seasonality of a common environmental factor acting directly/indirectly may contribute to these patterns, and possibly to the common pathogenesis of these congenital malformations.

Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitis infection.

BACKGROUND: Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are of paramount etiologic importance for hepatocellular carcinoma (HCC), but other factors are likely to be important. The association of diabetes mellitus and obesity with HCC raises the possibility that dietary glycemic load (GL) may interact with chronic hepatitis infection in the causation of HCC. PATIENTS AND METHODS: We conducted a case-control study of 333 HCC patients and 360 controls in Athens, Greece. Third-generation assays were used to determine chronic HBV and HCV infection and information from a semiquantitative food frequency questionnaire to estimate dietary GL. RESULTS: After adjustment for possible confounding factors through multiple logistic regression, we found a nonsignificant positive association between GL and HCC, which was exclusively accounted for by a positive association between GL and HCC cases with chronic infection with hepatitis B and/or C. For the latter group of patients, the odds ratio at the highest compared with the lowest GL quintile was 1.95 (95% confidence interval 1.09-3.48). The association was strengthened after exclusion of subjects with diabetes. CONCLUSION: Our results indicate that, among patients with chronic infection with HBV and/or HCV, reduction of dietary GL could reduce risk or delay development of HCC.

Behçet's disease associated with malignancies. Report of two cases and review of the literature.

OBJECTIVE: To investigate the incidence of malignancies in a cohort of Behçet's disease patients and review the world literature. METHODS: Our database of 128 patients was searched and the age standardized rate (ASR) for cancer was calculated. Furthermore, we performed a MEDLINE search from 1970 through 2003, as well as, a search in the proceedings of international conferences for cases of malignancies associated with Behçet's disease. RESULTS: Two of our 128 patients with Behçet's disease were found to have solid tumors. One male had lung cancer and the other female had kidney cancer. The ASR for cancer cases in our population was investigated and it was found to be 1,600 per 100,000 in 10 years. The ASR for cancer cases in Greece according to WHO is 272.51 per 100,000 per year and therefore 2,725 per 100,000 in 10 years. In the world literature 112 cases of malignancies associated with Behçet's disease were found: Sixty five cases were of male patients and 46 of female with 1 case of unknown gender. The solid malignancies associated with Behçet's disease included cases of bladder, breast, uterus, thyroid and stomach cancer, whereas haematological malignancies included leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma, Hodgkin's disease and lymphosarcoma. The treatment administered in these patients with their disease is also reported. CONCLUSION: The age standardized rate of cancer in our population was lower than that of the general population in Greece, although the difference was not statistically significant. However, there is discrepancy in the world literature and the possibility of development of malignancies in Behçet's disease patients should not be ignored.

Breast arterial calcifications as an indicator of systemic vascular disease.

PURPOSE: To evaluate the association between mammographically detected arterial calcifications and systemic vascular disease. MATERIAL AND METHODS: The medical records of 77 women who had either breast arterial calcifications or underwent surgery for carotid stenosis, abdominal aortic aneurysm, or femoropopliteal bypass (study groups A and B) were evaluated and compared with 33 women without breast arterial calcifications (group C). Patients in both arms of the study underwent additional vascular tests or mammography. RESULTS: Currently available data indicate that there is a statistically significant correlation between the presence of arterial calcifications on the mammogram and atheromatosis of the carotid or femoral arteries. CONCLUSION: Screening mammograms might be useful in the detection of women at risk for systemic vascular disease.

Intake of specific flavonoid classes and coronary heart disease--a case-control study in Greece.

OBJECTIVE: Dietary intake of flavonoids has been reported to protect against coronary heart disease (CHD) risk, but associations of specific classes of flavonoids with CHD have not been adequately studied. DESIGN: Hospital-based case-control study relying on interviewer administered questionnaires. SETTING: Cardiology Department of the University of Athens Medical School in the Hippokrateion General Hospital (1990-1991). SUBJECTS: Cases were 329 patients with electrocardiographically confirmed first coronary infarct or a first positive coronary arteriogram, or both (participation fraction 93%). Controls were 570 patients admitted to the same hospital for minor conditions unrelated to nutrition (participation fraction 95%). All cases and controls were interviewed in the hospital wards by experienced interviewers, and a 110-item food frequency questionnaire was administered. RESULTS: There was statistically significant evidence (P approximately 0.03) for an inverse association between intake of flavan-3-ols and CHD risk, an increase of about 21 mg per day corresponding to a 24% decrease in CHD risk. The inverse association between flavan-3-ols and CHD risk was largely accounted for by the intake of wine and to a lesser extent tea. For none of the other flavonoid classes was there statistically significant evidence of an association. CONCLUSION: Flavan-3-ols, which are largely found in wine and tea, are inversely associated with, and may be protective against, coronary heart disease.

Flavonoids, vitamin C and adenocarcinoma of the stomach.

OBJECTIVE: To examine the role of six flavonoid classes (flavanones, flavan-3-ols, flavonols, flavones, anthocyanidins and isoflavones) and vitamin C in the aetiology of stomach cancer. METHODS: Case-control study undertaken in Greece in the 1980s. Dietary information was obtained from 110 patients with incident stomach adenocarcinoma and 100 control patients. Flavonoid estimates were based on the recently released database of the US Department of Agriculture. RESULTS: In models including sociodemographic variables, energy intake, vegetables, fruits and, alternatively, vitamin C the six flavonoid classes, only flavanones and vegetables remained significantly inversely associated with stomach cancer risk. The odds ratio (95% confidence intervals) per one standard deviation increase of intake of flavanones was 0.55 (0.31-0.96) whereas for vitamin C it was 1.05 (0.46-2.41). When fruits and vegetables were not adjusted for, both vitamin C and several flavonoid categories were inversely associated with stomach cancer risk, but these associations could be attributed to other compounds in these foods. CONCLUSIONS: Among the major flavonoid classes studied, only flavanone intake is inversely associated with stomach cancer risk and could account for the apparent protective effect of fruit intake against this form of cancer. Additional factors, however, are likely to be involved in the consistent protection conveyed by vegetables.

Mortality among pilots and cabin crew in Greece, 1960-1997.

BACKGROUND: Specific health hazards, among them radiation of cosmic origin, have caused some concern among aircrew in civil aviation in recent years. Several cohort studies in Northern countries have investigated mortality and cancer incidence among aircrew. Our goal was to study the pattern of mortality among Greek commercial airline cockpit and cabin crew. METHODS: We performed a retrospective cohort study including 843 Olympic Airways cockpit crew and 1835 cabin attendants. Standardized mortality ratios (SMR) were calculated based on death rates of the Greek population. Duration of employment as a proxy for occupational exposure was used to stratify the cohort. RESULTS: For cockpit crew, the overall SMR was 0.7 (n = 65, 95% CI: 0.5-0.9). The SMR for all cancers was also significantly decreased (n = 17; SMR = 0.6; 95% CI: 0.3-0.9). Most of this reduction was due to a large deficit in lung cancer deaths (SMR = 0.1; 95% CI: 0.0-0.5). Slight but non-significant increases were noted for brain and liver cancer. The SMR for cardiovascular death was close to unity. Among female cabin attendants the SMR for all causes was 0.8 (95% CI: 0.4-1.3). The SMR for all cancers was 0.8 (95% CI: 0.3-1.7). Mortality from breast cancer was not increased. Among male cabin crew, SMR for all causes was 0.5 (95% CI: 0.3-0.9). Analyses according to duration of employment showed no pattern. CONCLUSIONS: In this first-ever occupational cohort study in Greece, Greek aircrew had a low overall and cancer mortality. Due to the small number of events, the strength of our study is limited. The Greek data will be included in a pooled analysis of European studies.

Cryptorchidism: seasonal variations in Greece do not support the theory of light.

To examine seasonal trends of cryptorchidism in Greece, 583 males with true isolated cryptorchidism were analyzed. All 208 912 live-born boys born during the same period were used as a comparison group. Seasonality by month of birth was evaluated using both Edwards' model with adjusted frequencies and exact theta(i), and Walter-Elwood method with exact theta(i). Both tests resulted in consistent findings. The incidence of cryptorchid births in Greece follows a documented cyclic pattern of simple harmonic type with spring being the season of statistical predominance (peak in March with a second, almost equivalent, peak in May). In contrast, in autumn the incidence of cryptorchid births was considerably lower (trough in September). Given the fact that no significant differences in daylight length are found among seasons in Greece, the detection of a significant seasonal variation suggests that factors other than light are involved in the pathogenesis of cryptorchidism. Low environmental temperature is proposed as a causative factor negatively influencing the maternal hCG profiles and the inguinoscrotal phase of testicular descent. This is further supported by: (i) the similarity of our results to those reported by other European countries of different longitude and geographical width and (ii) our data showing significantly smaller maternal hCG profiles at the 26th week of gestation during winter compared with summer.

Diabetes and the risk of prostate cancer.

The relation between diabetes and prostate cancer risk was investigated in a combined analysis of two hospital-based case-control studies conducted in Italy and Greece, between 1985 and 1997. Cases were 608 men with incident prostate cancer, and controls were 1008 men admitted to hospital for acute non-neoplastic diseases. No material association between diabetes and prostate cancer was observed, with a multivariate odds ratio (OR) of 1.07 (95% confidence interval (CI) 0.68-1.66). Compared with men without diabetes, there was a non-significant increased risk of prostate cancer in those diagnosed with diabetes within the last 5 years (OR 2.04), while the ORs were 0.96 and 0.78 respectively for a diagnosis of diabetes 5-9 years and > or = 10 years ago.

The contribution of cigarette smoking to bladder cancer in women (pooled European data).

BACKGROUND: Using a combined analysis of 11 case-control studies from Europe, we have investigated the relationship between cigarette smoking and bladder cancer in women. METHODS: Available smoking information on 685 female bladder cancer cases and 2416 female controls included duration of smoking habit, number of cigarettes smoked per day, and time since cessation of smoking habit for ex-smokers. RESULTS: There was an increasing risk of bladder cancer with increasing duration of smoking, ranging from approximately a two-fold increased risk for a duration of less than 10 years (odds ratio (OR) = 1.9, 95% confidence interval (CI) 1.1-3.1) to over a four-fold increased risk for a duration of greater than 40 years (OR = 4.1, 95% CI 3.0-5.5). A dose-response relationship was observed between number of cigarettes smoked per day and bladder cancer up to a threshold limit of 15-20 cigarettes per day, OR = 3.8 (95% CI 2.7-5.4), after which no increased risk was observed. An immediate decrease in risk of bladder cancer was observed for those who gave up smoking. This decrease was over 30% in the immediate 1-4 years after cessation, OR = 0.68 (95% CI 0.38-1.2). However, even after 25 years the decrease in risk did not reach the level of the never-smokers, OR = 0.27 (95% CI 0.21-0.35). CONCLUSION: The proportion of bladder cancer cases among women attributable to ever smoking was 0.30, (0.25-0.35) and to current smoking was 0.18 (0.14-0.22). These attributable proportions are less than those observed among men, although they are likely to increase in the future as the smoking-related disease epidemic among women matures.

Estrogens, testosterone and sex hormone binding globulin in relation to liver cancer in men.

OBJECTIVE: Liver disease in men has been associated with an imbalance of serum estradiol and testosterone. We have evaluated whether serum estradiol and testosterone levels are altered in male liver cancer patients as a result of a specific effect of the disease or because of the associated liver damage. METHODS: We have performed a hospital-based case-control study in Greece. The study subjects were all men; 73 patients with hepatocellular carcinoma (HCC), 25 with metastatic liver cancer (MLC) patients and 111 control subjects. Serum estradiol, testosterone and sex hormone binding globulin (SHBG) levels were measured for each subject. Data were analyzed by multiple linear regression. RESULTS: Mean serum estradiol levels were significantly higher among HCC patients as well as among patients with MLC compared to controls. Mean serum testosterone levels were significantly lower among HCC patients as well as among patients with MLC compared to controls. The mean SHBG levels did not differ significantly between the groups. After controlling for the degree of liver damage, the elevated serum estradiol and reduced serum testosterone levels among HCC and MLC patients were no longer significant. CONCLUSIONS: Changes in sex steroid levels among patients with liver damage are due to the liver damage per se and not to specific disease processes.

Peripheral neuropathy does not invariably coexist with autonomic neuropathy in diabetes mellitus.

Background: Peripheral somatic and autonomic neuropathies are the most common types of diabetic polyneuropathy. Although duration and degree of hyperglycemia are considered to be risk factors for both autonomic and peripheral neuropathy, recent studies have raised the question of a different development and natural history of these neuropathies in diabetes. In addition, a few studies have investigated the relationship between chronic painful and autonomic neuropathy. The aim of this study was to investigate to what extent autonomic and peripheral neuropathy coexist, as well as whether painful neuropathy is more common in diabetic patients with autonomic neuropathy. Methods: Subjects with type 1 (n=52; mean age 31.7 years) and type 2 diabetes (n=53; mean age 54.5 years) were studied. Evaluation of peripheral neuropathy was based on clinical symptoms (neuropathic symptom score), signs (neuropathy disability score), and quantitative sensory testing (vibration perception threshold). Assessment of autonomic neuropathy was based on the battery of standardized cardiovascular autonomic function tests. Results: Prevalence rates of pure autonomic and of pure peripheral neuropathy in patients with type 1diabetes were 28.8 and 13.5%, respectively. The respective rates in patients with type 2 diabetes were 20.7% (P=0.33 vs. type 1 diabetes) and 20.7% (P=0.32). Peripheral and autonomic neuropathy coexisted in 28.8% of type 1 and in 45.3% of type 2 diabetic subjects (P=0.08). Prevalence rates of chronic painful neuropathy in subjects with type 1 diabetes, with and without autonomic neuropathy, were 16.6 and 22.7%, respectively (P=0.85) and in type 2 diabetic subjects 20 and 22.2%, respectively (P=0.58). Multivariate analysis after adjustment for age, sex, blood pressure, duration of diabetes, HBA(1c), and presence of retinopathy or microalbuminuria showed that neither the indices of peripheral nerve function (neuropathic symptom score, neuropathy disability score, vibration perception threshold) nor the presence of peripheral neuropathy or chronic painful neuropathy are associated with the presence of autonomic neuropathy in individuals with either type 1 or type 2 diabetes. Conclusions: Peripheral and autonomic neuropathies do not invariably coexist in diabetes. In addition, chronic painful neuropathy may be present irrespective of the presence of autonomic neuropathy.

Are there age-dependent effects of diet on prostate cancer risk?

OBJECTIVES: To examine whether there are age-dependent effects of diet on prostate cancer risk. METHODS: We have postulated that nutritional factors that may affect the risk of initiation would be more likely to be identified among younger patients, whereas those that may affect the risk of progression would be more clearly identifiable among older patients. Study subjects were 320 patients with prostate cancer and 246 controls with no systematic disease, hospitalised in six major hospitals in Athens, Greece. Logistic regression models were fitted separately for men under 70 years and 70 years or older. RESULTS: Polyunsaturated lipids substantially increased the risk among younger subjects, but played little role among older ones (p for interaction 0.21). Cooked tomatoes had a strong protective effect among older persons, but not among younger subjects (p for interaction 0.009). Last, vitamin E was strongly inversely related to prostate cancer risk among younger subjects, but not among older subjects (p for interaction 0.15). CONCLUSIONS: Even a simple straight forward interpretation of the data, i.e., that older cases of prostate cancer have a different dietary risk profile than younger ones, has potentially useful implications.

Echocardiographic and signal averaged ECG indices associated with non-sustained ventricular tachycardia after repair of tetralogy of fallot.

OBJECTIVE: To identify any possible association between different readily available non-invasive indices and potential malignant ventricular arrhythmias in patients with repaired tetralogy of Fallot. DESIGN: 27 consecutive patients, mean (SD) age 27.3 (11.7) years, were studied 15.7 (6.7) years after corrective surgery for tetralogy of Fallot, using 12 lead ECG, 24 hour Holter recordings, signal averaged ECG, and echocardiography. The following variables were measured: standard QRS duration, filtered QRS duration (fltQRS), low amplitude signal duration, and root mean square voltage of the last 40 ms of the fltQRS (RMS-40), as well as right ventricular systolic pressure, right ventricular ejection fraction, and the ratio of the maximum short axis diameters of the right and left ventricles (RD:LD). RESULTS: All patients had right bundle branch block, with a mean QRS duration of 137.1 (14.9) ms. There were no patients with sustained arrhythmia. Five patients had runs of non-sustained ventricular tachycardia (group A) and the other 22 patients did not (group B). Univariate analysis showed that fltQRS and RD:LD ratio were significantly associated with non-sustained ventricular tachycardia. In addition, a fltQRS >/= 148 ms, low amplitude signal >/= 32.5 ms, RMS-40 /= 1.05 were cut off points with a high sensitivity for detecting patients with non-sustained ventricular tachycardia. CONCLUSIONS: Abnormal signal averaged ECG and echocardiographic variables are associated with potentially malignant ventricular arrhythmias on the Holter recordings in asymptomatic patients with repaired tetralogy of Fallot.

Birth order, as a proxy for age at infection, in the etiology of hepatocellular carcinoma.

First-born and second-born children are exposed to common infections after enrollment at school, whereas later-born children are exposed to these infections earlier through their older siblings. We have evaluated whether birth order is a risk factor for hepatitis B virus (HBV)-related, hepatitis C virus (HCV)-related, and apparently virus-unrelated hepatocellular carcinoma (HCC) in a large case-control study that included 333 HCC cases and 632 controls. In comparison with controls who were carriers of hepatitis B surface antigen (HBsAg), HBsAg-positive HCC cases were more likely to have been later-born children (odds ratio per increase in birth order = 2.0; 95% confidence interval = 1.2-3.6). There was no such evidence for anti-HCV-positive cases compared with anti-HCV-positive controls or for virus-negative HCC cases compared with virus-negative controls. We conclude that early infection with HBV increases the risk of HBV carriers to develop HCC, over and beyond its role in facilitating the establishment of a carrier state.

Fraction of prostate cancer incidence attributed to diet in Athens, Greece.

Diet appears to be a major determinant in the incidence of prostate cancer. In a case-control study conducted in Athens, Greece, we found that dairy products, butter and seed oils were positively associated with risk of prostate cancer, whereas cooked and raw tomatoes were inversely associated. We utilized the data from this study to calculate the population attributable fractions under alternative assumptions of feasible dietary changes. For each subject, a dietary score was calculated and categorized into approximately quintiles, representing increasing levels of prostate cancer risk as a function of the intake of the five discriminatory food groups or items. Population attributable fractions in terms of this dietary score were calculated taking into account multivariate adjustment. We observed that, if all individuals were shifted to the baseline category, the incidence of prostate cancer in this study population would be reduced by 41% (95% confidence interval 23-59%). However, if all individuals were shifted to the adjacent lower risk quintile, the expected incidence reduction would be a more modest 19%. The incidence of prostate cancer in Greece could be reduced by about two-fifths if the population increased the consumption of tomatoes and reduced the intake of dairy products, and substituted olive oil for other added lipids.

Insulin-like growth factor 1 in hepatocellular carcinoma and metastatic liver cancer in men.

The insulin-like growth factor (IGF) axis has important autocrine, paracrine, and endocrine roles in the promotion of growth. Alterations of the IGF system have recently been implicated in the pathogenesis of several malignancies, but the relation to hepatocellular carcinoma (HCC) risk is unclear. To address this issue, we used an immunoradiometric assay to quantify IGF-1 levels in serum samples in a hospital-based, case-control study in Greece. The study subjects were all men and included 53 patients with HCC positive for hepatitis B and/or hepatitis C virus infections, 20 virus-negative HCC patients, 25 virus-negative patients with metastatic liver cancer (MLC), and 111 virus-negative control subjects. Data were analyzed by multiple linear regression, using IGF-1 as the dependent variable. The mean value of IGF-1 was 65.9 ng/ml among virus-positive HCC patients, 79.5 ng/ml among virus-negative HCC patients, 110.8 ng/ml among patients with MLC, and 174.7 ng/ml among hospital controls. After controlling for the degree of liver damage, as assessed by prothrombin time and serum albumin level, the reduction in IGF-1 level among HCC patients was found to be more than could be attributed to liver damage alone. This finding may have both diagnostic and pathophysiological implications.

Changes of the infrarenal aortic segment after conventional abdominal aortic aneurysm repair.

OBJECTIVES: to delineate the natural history of the residual infrarenal aortic segment after conventional abdominal aortic aneurysm (AAA) repair. DESIGN: open prospective study. PATIENTS AND METHODS: between 1990 and 1997, 100 patients, who underwent conventional infrarenal AAA repair at our department, were followed annually by means of colour duplex ultrasonography. Data from 76 patients who had at least 3 scans were analysed. RESULTS: mean duration of follow-up was 4.7 years (range: 3-8 years). The residual infrarenal aorta dilated a mean of 0.57 mm annually. No patient required reoperation. There was no significant correlation between dilatation and any of the recorded risk factors except for the initial neck diameter (p=0.03). CONCLUSIONS: conventional AAA surgery is durable so that surveillance, during the first 5 postoperative years, is not justified in terms of cost-effectiveness. The impact of such a dilatation on endovascular AAA repair requires further investigation.

Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies.

The primary risk factor for bladder cancer is cigarette smoking. Using a combined analysis of 11 case-control studies, we have accurately measured the relationship between cigarette smoking and bladder cancer in men. Available smoking information on 2,600 male bladder cancer cases and 5,524 male controls included duration of smoking habit, number of cigarettes smoked per day and time since cessation of smoking habit for ex-smokers. There was a linear increasing risk of bladder cancer with increasing duration of smoking, ranging from an odds ratio (OR) of 1.96 after 20 years of smoking (95% confidence interval [CI] 1.48-2.61) to 5.57 after 60 years (CI 4.18-7.44). A dose relationship was observed between number of cigarettes smoked per day and bladder cancer up to a threshold limit of 15-20 cigarettes per day, OR = 4.50 (CI 3.81-5. 33), after which no increased risk was observed. An immediate decrease in risk of bladder cancer was observed for those who gave up smoking. This decrease was over 30% after 1-4 years, OR = 0.65 (0. 53-0.79), and was over 60% after 25 years of cessation, OR = 0.37 (0. 30-0.45). However, even after 25 years, the decrease in risk did not reach the level of the never-smokers, OR = 0.20. (0.17-0.24). The proportion of bladder cancer cases attributable to ever-smoking was 0.66 (0.61-0.70) for all men and 0.73 (0.66-0.79) for men younger than 60. These estimates are higher than previously calculated.