Interdisciplinary Global Health Forum: conference report.

In spring of 2012, students and staff at the First Faculty of Medicine at Charles University in Prague invited distinguished public health stakeholders and experts to engage in a Global Health Forum. The forum lasted an afternoon, was academically and clinically engaging and offered students and medical faculty a venue to discuss the most pressing global public health concerns. Main outcomes from the forum included describing outstanding public issues in public health policy and prevention, infectious disease and public health systems raised by the speakers, stakeholders and attendees. One major result of this forum is the establishment of the Prague Center for Global Health - an interdepartmental and interdisciplinary research collaborative to further the discussion and much needed field and academic research in global public health. The Prague Center for Global Health will include multiple international research centers and main function and results will include new courses at the university, publications based on best practices and research and a venue to learn, share and create in the academic space.

Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation.

Array comparative genomic hybridization was used to identify copy number alterations in clear cell renal cell carcinoma (ccRCC) patient tumors to identify associations with patient/clinical characteristics. Of 763 ccRCC patients, 412 (54%) provided frozen biopsies. Clones were analyzed for significant copy number differences, adjusting for multiple comparisons and covariates in multivariate analyses. Frequent alterations included losses on: 3p (92.2%), 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 9q (31.8%), 6q (30.8%), 3q (29.4%), 10q (25.7%), 13q (24.5%), 1p (23.5%) and gains on 5q (60.2%), 7q (39.6%), 7p (30.6%), 5p (26.5%), 20q (25.5%), 12q (24.8%), 12p (22.8%). Stage and grade were associated with 1p, 9p, 9q, 13q and 14q loss and 12q gain. Males had more alterations compared with females, independent of stage and grade. Significant differences in the number/types of alterations were observed by family cancer history, age at diagnosis and smoking status. Von Hippel-Lindau (VHL) gene inactivation was associated with 3p loss (P

Occupational exposure to dusts and risk of renal cell carcinoma.

BACKGROUND: Occupational exposures to dusts have generally been examined in relation to cancers of the respiratory system and have rarely been examined in relation to other cancers, such as renal cell carcinoma (RCC). Although previous epidemiological studies, though few, have shown certain dusts, such as asbestos, to increase renal cancer risk, the potential for other occupational dust exposures to cause kidney damage and/or cancer may exist. We investigated whether asbestos, as well as 20 other occupational dust exposures, were associated with RCC risk in a large European, multi-center, hospital-based renal case-control study. METHODS: General occupational histories and job-specific questionnaires were reviewed by occupational hygienists for subject-specific information. Odds ratios (ORs) and 95% confidence intervals (95% CIs) between RCC risk and exposures were calculated using unconditional logistic regression. RESULTS: Among participants ever exposed to dusts, significant associations were observed for glass fibres (OR: 2.1; 95% CI: 1.1-3.9), mineral wool fibres (OR: 2.5; 95% CI: 1.2-5.1), and brick dust (OR: 1.5; 95% CI: 1.0-2.4). Significant trends were also observed with exposure duration and cumulative exposure. No association between RCC risk and asbestos exposure was observed. CONCLUSION: Results suggest that increased RCC risk may be associated with occupational exposure to specific types of dusts. Additional studies are needed to replicate and extend findings.

Life course social mobility and risk of upper aerodigestive tract cancer in men.

The aim of this study was to explore associations between social mobility and tumours of the upper aero-digestive tract (UADT), focussing on life-course transitions in social prestige (SP) based on occupational history. 1,796 cases diagnosed between 1993 and 2005 in ten European countries were compared with 1585 controls. SP was classified by the Standard International Occupational Prestige Scale (SIOPS) based on job histories. SIOPS was categorised in high (H), medium (M) and low (L). Time weighted average achieved and transitions between SP with nine trajectories: H --> H, H --> M, H --> L, M --> H, M --> M, M --> L, L --> H, L --> M and L --> L were analysed. Odds ratios (ORs) and 95%-confidence intervals [95%-CIs] were estimated with logistic regression models including age, consumption of fruits/vegetables, study centre, smoking and alcohol consumption. The adjusted OR for the lowest versus the highest of three categories (time weighted average of SP) was 1.28 [1.04-1.56]. The distance of SP widened between cases and controls during working life. The downward trajectory H --> L gave an OR of 1.71 [0.75-3.87] as compared to H --> H. Subjects with M --> M and L --> L trajectories ORs were also elevated relative to subjects with H --> H trajectories. The association between SP and UADT is not fully explained by confounding factors. Downward social trajectory during the life course may be an independent risk factor for UADT cancers.

TP53, EGFR, and KRAS mutations in relation to VHL inactivation and lifestyle risk factors in renal-cell carcinoma from central and eastern Europe.

Renal-cell carcinomas (RCC) are frequent in central and eastern Europe and the reasons remain unclear. Molecular mechanisms, except for VHL, have not been much investigated. We analysed 361 RCCs (334 clear-cell carcinomas) from a multi-centre case-control study for mutations in TP53 (exons 5-9 in the whole series and exons 4 and 10 in a pilot subset of 60 tumours) and a pilot 50 tumours for mutations in EGFR (exons 18-21) or KRAS (codon 12) in relation to VHL status. TP53 mutations were detected in 4% of clear-cell cases, independently of VHL mutations. In non-clear-cell carcinomas, they were detected in 11% of VHL-wild-type tumours and in 0% of tumours with VHL functional mutations. No mutations were found in EGFR or KRAS. We conclude that mutations in TP53, KRAS, or EGFR are not major contributors to the RCC development even in the absence of VHL inactivation. The prevalence of TP53 mutations in relation to VHL status may differ between clear-cell and other renal carcinomas.

Vitamin d pathway genes, diet, and risk of renal cell carcinoma.

Mediated by binding to the high-affinity vitamin D receptor (VDR), vitamin D forms a heterodimer complex with the retinoid-X-receptor (RXR). Variation in both genes has been shown to modify renal cell carcinoma (RCC) risk. Therefore, we investigated whether VDR and RXRA polymorphisms modify associations between RCC risk and frequency of dietary intake of vitamin D and calcium rich foods, and occupational ultraviolet exposure among 777 RCC case and 1035 controls from Central and Eastern Europe. A positive association was observed in this population between increasing dietary intake frequency of yogurt, while an inverse association was observed with egg intake frequency. RXRA polymorphisms, located 3' of the coding sequence, modified associations between specific vitamin D rich foods and RCC risk, while RXRA polymorphisms, located in introns 1 and 4, modified associations with specific calcium rich foods. Results suggest that variants in the RXRA gene modified the associations observed between RCC risk and calcium and vitamin D intake.

Occupation and renal cell cancer in Central and Eastern Europe.

OBJECTIVE: Central and Eastern Europe has among the highest rates of renal cell cancer worldwide. Few studies have been conducted in these areas to investigate the possible role of occupational exposures in renal cell cancer aetiology. The purpose of this study was to examine the association of renal cell cancer with employment in specific occupations and industries. METHODS: From 1999 to 2003, we conducted a hospital-based case-control study in seven areas of the Czech Republic, Poland, Romania and Russia. A detailed occupational history was collected from renal cell cancer cases and controls, together with information on potential confounders. Odds ratios (ORs) and 95% CI of cancer risk were calculated for having ever been employed in selected jobs and industries, with follow-up analyses examining duration of employment. RESULTS: A total of 992 histologically confirmed incident renal cell cancer cases and 1459 controls were included in the analysis. An increased risk of renal cell cancer was observed for workers in agricultural labour and animal husbandry (OR 1.43; 95% CI 1.05 to 1.93), particularly among women employed as general farm workers (OR 2.73; 95% CI 1.05 to 7.13). Risk gradients for agricultural work increased with longer employment. An overall increased risk of renal cell cancer was seen among architects and engineers (OR 1.89; 95% CI 1.35 to 2.65), and mechanical engineers (OR 1.71; 95% CI 1.03 to 2.84). CONCLUSIONS: Our data suggest an association between renal cell cancer and agricultural work, particularly among female workers.

Socioeconomic factors associated with risk of upper aerodigestive tract cancer in Europe.

INTRODUCTION: In the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year--more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet. PATIENTS AND METHODS: A multicentre case-control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression. RESULTS: When controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR=1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators--comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR=1.60 (1.28, 2.00); and for unemployment OR=1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR=1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community). CONCLUSION: Socioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.

Human exposure to polyhalogenated hydrocarbons and incidence of selected malignancies -central European experience.

This paper describes results of two ecological studies design to analyze the incidence of selected malignancies in two populations exposed to polychlorinated hydrocarbons, mostly PCBs and TCDDs/Fs by comparing data available in the National Cancer Registry of the Slovak Republic and National Oncological Registry of the Czech Republic databases for the Slovak Republic (approximately 5M inhabitants) and the Czech Republic (10,3 M inhabitants) to the data relevant for the population of Michalovce District, the Slovak Republic (approximately 112,000 inhabitants) and Uherske Hradiste, the Czech Republic (146,000 inhabitants). Those districts are recognized as PCB-contaminated areas due to production and industrial use of PCBs. Data were analyzed for the 10-year period 1987-1996. The age adjusted world standard ratio (WSR) incidence of thyroid, pancreatic, breast, ovarian, bladder, and brain tumors in females and thyroid, pancreatic, breast, bladder, brain, prostate and testicular tumors in males were compared. Neither PCBs nor TCDDs/Fs appear to contribute to the observed significantly lower incidence of breast and prostate cancer in the Michalovce District and lower bladder cancer incidence in Uherske Hradiste District. However, anti-estrogenic and anti-androgenic properties have been described for hydroxylated and methylsulfonyl PCB metabolites. These properties could contribute to a mechanism through which these metabolites might modulate the development of breast, prostate and bladder cancer. The results of our analysis points to substantial potential problems of risk assessment for cancer incidence in populations exposed to xenobiotics, or more generally, as it relates to a wide spectrum of confoundings of cancer risk factors.

Renal cell carcinoma, occupational pesticide exposure and modification by glutathione S-transferase polymorphisms.

This study investigated associations between occupational pesticide exposure and renal cell carcinoma (RCC) risk. To follow-up on a previous report by Buzio et al., we also considered whether this association could be modified by glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) genotypes. About 1097 RCC cases and 1476 controls from Central and Eastern Europe were interviewed to collect data on lifetime occupational histories. Occupational information for jobs held for at least 12 months duration was coded for pesticide exposures and assessed for frequency and intensity of exposure. GSTM1 and GSTT1 gene deletions were analyzed using TaqMan assays. A significant increase in RCC risk was observed among subjects ever exposed to pesticides [odds ratio (OR): 1.60; 95% confidence interval (CI): 1.00-2.55]. After stratification by genotypes, increased risk was observed among exposed subjects with at least one GSTM1 active allele (OR: 4.00; 95% CI: 1.55-10.33) but not among exposed subjects with two GSTM1 inactive alleles compared with unexposed subjects with two inactive alleles (P-interaction: 0.04). Risk was highest among exposed subjects with both GSTM1 and GSTT1 active genotypes (OR: 6.47; 95% CI: 1.82-23.00; P-interaction: 0.02) compared with unexposed subjects with at least one GSTM1 or T1 inactive genotype. In the largest RCC case-control study with genotype information conducted to date, we observed that risk associated with pesticide exposure was exclusive to individuals with active GSTM1/T1 genotypes. These findings further support the hypothesis that glutathione S-transferase polymorphisms can modify RCC risk associated with occupational pesticide exposure.

Vitamin D receptor polymorphisms and renal cancer risk in Central and Eastern Europe.

Previous studies investigated the role of vitamin D intake and cancer risk. The kidney is a major organ for vitamin D metabolism, activity, and calcium homeostasis; therefore, it was hypothesized that dietary vitamin D intake and polymorphisms in the vitamin D receptor (VDR) gene may modify renal cell carcinoma (RCC) risk. Three common VDR gene polymorphisms (BsmI, FokI, TaqI) were evaluated among 925 RCC cases and 1192 controls enrolled in a hospital-based case-control study conducted in Central and Eastern Europe. Overall associations with RCC risk were not observed; however, subgroup analyses revealed associations after stratification by median age of diagnosis and family history of cancer. Among subjects over 60 yr, reduced risks were observed among carriers of the f alleles in the FokI single-nucleotide polymorphism (SNP) (odds ratio [OR] = 0.61 for Ff and OR = 0.74 for ff genotypes) compared to subjects with the FF genotype (P trend = 0.04; P interaction = 0.004). Subjects with the BB BsmI genotype and a positive family history of cancer had lower risk compared to subjects with the bb allele (OR = 0.60; 95% CI: 0.33-1.1; P trend = 0.05). Genotype associations with these subgroups were not modified when dietary sources of vitamin D or calcium were considered. Additional studies of genetic variation in the VDR gene are warranted.

The role of primary care in colorectal cancer screening: experience from Czech Republic.

Several programmes proven to be effective in the secondary prevention of colorectal cancer (CRC) have already been introduced in Europe, each varying involvement of general practitioners. This paper reviews current screening strategies for CRC from the primary care perspective, looking at the implementation of screening strategies in Europe, focusing on screening programmes based on the faecal occult blood testing (FOBT), and drawing from experiences in the Czech Republic. We used data on CRC screening from the survey The Burden of Gastrointestinal Diseases in Europe, which was undertaken by the Public Affairs Committee of the United European Gastroenterology Federation in 2003. The data were updated by members of European Society for Primary Care Gastroenterology in 2006. For a description of the Czech screening programme, data from General Health Insurance Fund were used. Specific primary care aspects were studied in the research network of 54 general practice settings in the Czech Republic. National screening programmes have been introduced in several countries, such as Germany, the Czech Republic, Slovakia and Poland. Several important aspects of screening require monitoring: target population adherence, GPs involvement, assessment of FOBT positive rate, interdisciplinary cooperation, patient compliance and the eligibility of patients for screening. The average population adherence to the screening programmes was low (about 20%). In the Czech Republic, 97 % of GPs participated in the programme, but only 20% of them have been able to screen at least 50 percent of the target population. The eligibility for screening declines with increasing age, co-morbidity and recently performed colonoscopy. In the age group of 50 to 75, approximately 15 % of patients are non-eligible for screening. Finally, the proportion of FOBT positive patients seem higher in established community programmes than the ratio reported from trials. CRC screening is experiencing a rapid expansion and effective programmes are now available. GPs should play a substantial role in CRC screening either by assessing the risk of their patients, explaining the screening options, or by deciding on the most individually-appropriate strategy within their local health care system. Implications of the population based screening for primary care should be considered and further studied.

The image analysis of colour changes of different human tissues in the relation to the age. Part 2: practical applicability.

The method of image analysis of intervertebral disc, Achilles tendon and rib cartilage was applied for assessment of colour changes of these tissues in the relation to the human age. It was proved that colour of tested tissues changes with age which is most obvious on rib cartilage and intervertebral disc, while Achilles tendon does not display important changes. The parameters MeanBlue, MeanSaturation and MeanBrightness are the best for age estimation based on colour analysis.

The image analysis of colour changes of different human tissues in the relation to the age. Part 1. Methodological approach.

The human age for medico-legal purposes is usually estimated from hard tissues like bones and teeth. Only little attention was paid to soft tissues most probably due to the lack of detectable age changes. This study deals with colour changes of human tissue from intervertebral discs, Achilles tendon and rib cartilage in the relation to the age. The image analysis of colour of investigated tissue samples was performed. The values of intensities of channels RGB (MeanRed, MeanGreen, and MeanBlue) and parameters from the IHS system (MeanSaturation, HueTypical, HueVariation, BrightVariation and MeanBrightness) were evaluated. The results confirm that colour changes of some tissues can be used for age estimation.

Glutathione S-transferase polymorphisms, cruciferous vegetable intake and cancer risk in the Central and Eastern European Kidney Cancer Study.

High consumption of cruciferous vegetables has been associated with reduced kidney cancer risk in many studies. Isothiocyanates, thought to be responsible for the chemopreventive properties of this food group, are conjugated to glutathione by glutathione S-transferases (GSTs) before urinary excretion. Modification of this relationship by host genetic factors is unknown. We investigated cruciferous vegetable intake in 1097 cases and 1555 controls enrolled in a multicentric case-control study from the Czech Republic, Poland, Romania and Russia. To assess possible gene-diet interactions, genotyped cases (N = 925) and controls (N = 1247) for selected functional or non-synonymous polymorphisms including the GSTM1 deletion, GSTM3 3 bp deletion (IVS6 + 22-AGG) and V224I G>A substitution, GSTT1 deletion and the GSTP1 I105V A>G substitution. The odds ratio (OR) for low (less than once per month) versus high (at least once per week) intake of cruciferous vegetables was 1.29 [95% confidence interval (CI): 1.02-1.62; P-trend = 0.03]. When low intake of cruciferous vegetables (less than once per month) was stratified by GST genotype, higher kidney cancer risks were observed among individuals with the GSTT1 null (OR = 1.86; 95% CI: 1.07-3.23; P-interaction = 0.05) or with both GSTM1/T1 null genotypes (OR = 2.49; 95% CI: 1.08-5.77; P-interaction = 0.05). These data provide additional evidence for the role of cruciferous vegetables in cancer prevention among individuals with common, functional genetic polymorphisms.

[Genotype-disease association and possibility to reveal environmentally modifiable disease causes: the use of mendelian randomization principle]. / Asociace genotypu s nemocí a odhalování jejich prostredím ovlivnitelných prícin: vyuzití principu mendelovské randomizace.

Though the methodology and designs of epidemiological studies and analyses of medical databases have improved, associations between modifiable exposures and the disease in observational epidemiological studies remain partly biased. Mendelian randomization principle, which is the random distribution of parental genes to offspring in meiosis during gametogeneis and at conception, represents a chance for methodology of evaluation of the causal relations between the external cause and the disease. The use of this principle assumes the association between the disease and the genetic polymorphism which reflects the biological relation between the suspected exposure and the disease, and is generally less prone to the phenomenon of confounding and reverse causation that can impair the interpretation of results in conventional observational studies. Authors describe explanatory options of the Mendelian randomization principle using examples in folic acid--homocysteine--coronary heart disease, and isothiocyanate versus lung carcinoma. Though the use of Mendelian randomization principle has its limitations, it offers new possibilities to test causal relations and clearly shows that means invested into the Human genome project can contribute to the understanding and prevention of adverse effects of modifiable exposure to the human health.

Contents of pentosidine in the tissue of the intervertebral disc as an indicator of the human age.

The study deals with the post-translational modifications of proteins - glycation of the tissue of the intervertebral disc and determination of one of advanced glycation end's products - pentosidine in the relation to the age. Pentosidine was detected in the hydrolysate of the intervertebral discs from persons between the ages of 16 and 95 years. 142 samples were analysed by high performance liquid chromatography, and the detected amounts of pentosidine were processed statistically. The coefficient of correlation of dependence of the amount of pentosidine on the age amounts to r = 0.92. The results of the work testify to the fact that it is possible to use the detection of pentosidine in the tissue of the intervertebral disc for the estimation of the age. Nevertheless subsequent experiments should be done under different conditions post-mortem decomposition.

Quality of Life, Sustainable Future and medical education.

Substantial social and environmental changes in a global world as well as a new paradigm of medicine emphasizing high technology and evidence based approach bring to the current medicine many paradoxes. Undoubtedly, new era creates many positive opportunities and challenges for medical professionals. On the other side, traditional concept of medicine as basically humanistic "helping profession" is rather threatened. In this context, there is a need for a re-defining of medical curricula and to offer to the medical students the concepts and ideas which reflect a current development. Traditional public health terms such as "Primary Prevention", "Health Promotion", "Health Protection", "Health Determinants" should be re-defined and the new ones such as "Quality of Life" and "Sustainable Future" must be introduced as an integral part of medical education. The relevant concepts are discussed in the context of specific situation of the health care transformation in Central and Eastern European Countries.

Some trace elements in coal of the Czech Republic, environment and health protection implications.

Mining for coal and its utilization have various impacts on the surrounding environment. Huge volumes of waste materials which are by-products of both the underground and open cast coal mining, pose one of the major environmental hazards in addition to air pollution caused by coal burning in power plants in the Czech Republic. Some of these risks could be reduced when having accurate and comprehensive data on coal quality. Statistical data processing of almost 35,000 coal samples from Late Paleozoic and Tertiary coal basins of the Czech Republic provided a unique information on the quality of lignite, sub-bituminous and bituminous coals and anthracites including the content of toxic trace elements (As, Be, Hg, Pb and Se). In this context related environment and health risks and protection implications are discussed.

[Relationship between the levels of toxic polychlorinated biphenyls in blood and follicular fluid of sterile women]. / Vztah mezi hladinami toxických polychlorovaných bifenylu v krvi a ve folikulární tekutine sterilních zen.

OBJECTIVE: The aim of this study was to confirm the possibility of detection of toxic polychlorinated biphenyls in blood and follicular fluid of infertile women undergoing IVF+ET program and determine the levels of some congeners. To confirm their cumulation in follicular fluid. DESIGN: Pilot study. SETTING: Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital, Prague, AXYS Varilab s.r.o., Vrané nad Vltavou, Institute of Hygieny and Epidemiology, 1st Faculty of Medicine Charles University and General Faculty Hospital, Prague, Euromise Centrum, Charles University, Prague. METHODS: We detected the level of polychlorinated biphenyls in blood and follicular fluid of infertile women undergoing IVF+ET program. We recieved the follicular fluid by transvaginal punction of follicles under ultrasonography control. The blood was taken before begining of anestezia. The follicular fluid and blood were frozen and transported to the laboratory. The samples were examined there by methods of gas chromatography and mass spectrometry. We were able to find all PCBs with 3-7 atoms of chlorine. RESULTS: We confirmed the possibility of detection of polychlorinated biphenyls (PCBs) in blood and follicular fluid of infertile women. We examineted the levels of PCB 77, 81, 105, 114, 118+123, 126, 156, 157, 167, 169, 189. The levels of PCBs were in ng/gram of fat. The levels of polychlorinated biphenyls differed from 0 to 400 ng/g of fat. Statistical analysis was made by t test a Wilcox test. All PCBs are cumulated in follicular fluid, except of PCB 126. CONCLUSION: The possibility of detection of PCBs in blood and follicular fluid of infertile women undergoing IVF+ET program was confirmed. The cumulation of these xenobiotics in follicular fluid was found. In the future we will analyse the relationship between the presence of these xenobiotics and achieving succesful pregnancy.