Chromosomal aberrations in benign and malignant Bilharzia-associated bladder lesions analyzed by comparative genomic hybridization

Background

Bilharzia-associated bladder cancer (BAC) is a major health problem in countries where urinary schistosomiasis is endemic. Characterization of the genetic alterations in this cancer might enhance our understanding of the pathogenic mechanisms of the disease but, in contrast to nonbilharzia bladder cancer, BAC has rarely been the object of such scrutiny. In the present study, we aimed to characterize chromosomal imbalances in benign and malignant post-bilharzial lesions, and to determine whether their unique etiology yields a distinct cytogenetic profile as compared to chemically induced bladder tumors.

Methods

DNAs from 20 archival paraffin-embedded post-bilharzial bladder lesions (6 benign and 14 malignant) obtained from Sudanese patients (12 males and 8 females) with a history of urinary bilharziasis were investigated for chromosomal imbalances using comparative genomic hybridization (CGH). Subsequent FISH analysis with pericentromeric probes was performed on paraffin sections of the same cases to confirm the CGH results.

Results

Seven of the 20 lesions (6 carcinomas and one granuloma) showed chromosomal imbalances varying from 1 to 6 changes. The most common chromosomal imbalances detected were losses of 1p21-31, 8p21-pter, and 9p and gain of 19p material, seen in three cases each, including the benign lesion.

Conclusion

Most of the detected imbalances have been repeatedly reported in non-bilharzial bladder carcinomas, suggesting that the cytogenetic profiles of chemical- and bilharzia-induced carcinomas are largely similar. However, loss of 9p seems to be more ubiquitous in BAC than in bladder cancer in industrialized countries.

     

Breast cancer screening, outside the population-screening program, of women from breast cancer families without proven BRCA1/BRCA2 mutations: a simulation study.

PURPOSE: We assessed the cost-effectiveness of mammography screening for women under the age of 50, from breast cancer families without proven BRCA1/BRCA2 mutations, because current criteria for screening healthy women from breast cancer families are not evidence-based. METHODS: We did simulation studies with mathematical models on the cost-effectiveness of mammography screening of women under the age of 50 with breast cancer family histories. Breast cancer screening was simulated with varying screening intervals (6, 12, 18, and 24 months) and screening cohorts (starting at ages 30, 35, 40, and 45, and continuing to age 50). Incremental costs of screening were compared with those of women ages 50 to 52 years, the youngest age group currently routinely screened in the nationwide screening program of the Netherlands, to determine cost-effectiveness. Sensitivity analyses were done to explore the effects of model assumptions. The cost-effectiveness of breast cancer screening for women over the age of 50 was not debated. RESULTS: The most effective screening interval was found to be 12 months, which, however, seems only to be cost-effective in a small group of women under the age of 50 with at least two affected relatives, including at least one affected in the first degree diagnosed under the age of 50. Significantly, early breast cancer screening never seemed to be cost-effective in women with only one affected first-degree or second-degree relative. CONCLUSION: Annual breast cancer screening with mammography for women under the age of 50 seems to be cost-effective in women with strong family histories of breast cancer, even when no BRCA1/BRCA2 mutation was found in affected family members.     

Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer – A retrospective analysis

BACKGROUND: Brain metastases have evolved from a rare to a frequently encountered event in advanced breast cancer due to advances in palliative systemic treatment. PATIENTS AND METHODS: All Patients treated at our centre from 1994 to 2004 with WBRT for brain metastases from breast cancer were included. We performed a multivariate analysis (Cox regression) to explore which factors are able to influence significantly cerebral time to progression (TTP) and overall survival (metastatic sites [visceral versus non-visceral], Karnofsky performance score [KPS], age, intensified local treatment [boost irradiation, neuro-surgical resection] further systemic treatment). RESULTS: Overall 174 patients, median age 51 years, range 27-76 years, were included. Median TTP was 3 months (m), range 1-33+ m. Median overall survival was 7 m, range 1-44 m. Factors significantly influencing TTP were KPS (p = 0.002), intensified local treatment (p < 0.001), and palliative systemic treatment (p = 0.001). Factors significantly influencing survival were intensified local treatment (p = 0.004), metastatic sites (p = 0.008), KPS (p = 0.006), and palliative systemic treatment (p < 0.001). CONCLUSION: As shown by the significant influence of metastatic sites, some patients die from their advanced systemic tumour situation before they would die from cerebral progression. In other individuals however, intensified local treatment and systemic treatment appear to influence cerebral time to progression and overall survival.     

Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytomas and abdominal paragangliomas

Pheochromocytomas and abdominal paragangliomas are rare catecholamine-producing tumours arising from neural crest-derived chromaffin cells. Frequent deletions of several distinct regions on the short arm of chromosome 1 suggest their involvement in the tumourigenesis process. The RIZ1 tumour suppressor encoded by the RIZ gene in 1p36.21 represents an attractive candidate target for the distal 1p deletions in these tumours. A panel of 18 pheochromocytomas (14 benign, and 4 malignant) and 11 abdominal paragangliomas (4 benign, and 7 malignant) were characterised for somatic deletions and mRNA expression status of RIZ1 using loss of heterozygosity (LOH) analysis and real-time quantitative PCR, respectively. Furthermore, we evaluated the methylation status of the RIZ1 promoter utilising methylation-specific PCR (MSP). Intragenic LOH at the RIZ locus was detected in 10 of 16 informative cases (62%), including 8 of 12 pheochromocytomas (67%) and 2 of 4 paragangliomas (50%). RIZ1 mRNA appeared to be significantly under-expressed in the tumour samples compared to normal adrenal controls (mean 0.6 vs. 1.0, p<0.001). This was not associated with RIZ1 promoter methylation in any of the samples, indicating that promoter hypermethylation is unlikely to be the underlying cause of the frequent expressional silencing. The recurrent inactivation of the tumour suppressor RIZ1 suggests that this event may be a significant contributing factor to tumour development in pheochromocytomas and abdominal paragangliomas.     

Assessment of pesticide exposure in the agricultural population of Costa Rica

We describe a model for the retrospective assessment of parental exposure to 26 pesticides, selected by toxicity-based prioritization, in a population-based case-control study of childhood leukaemia in Costa Rica (301 cases, 582 controls). The model was applied to a subset of 227 parents who had been employed or self-employed in agriculture or livestock breeding. It combines external data on pesticide use for 14 crops, 21 calendar years and 14 regions, and individual interview data on determinants (task and technology, personal protective equipment, field reentry, storing of pesticides, personal hygiene) of exposure. Recall was enhanced by use of checklists of pesticides in the interview. An external database provided information on the application rate (proxy for intensity of potential exposure) for each pesticide. The calendar time was individually converted to five time windows (year before conception, first, second and third trimester, and first year of the child). Time-windowed individual data on determinants of exposure and their expert-based general weights and their category-specific hazard values jointly provided an individual determinant score. This score was multiplied by the application rate to obtain an individual index of exposure intensity during application. Finally, average exposure intensity during entire time windows was estimated by incorporating in the model the individual time fraction of exposure during application. Estimates of exposure intensities were proxies assumed to be proportional to dermal exposure intensity, which represents the major pathway of occupational exposure to pesticides. A simulated sensitivity analysis resulted in a correlation coefficient of 0.91 between two sets of 10 000 values of individual exposure indices, based on two different but realistic sets expert-assigned weights. Lack of measurement data on concurrent exposures in comparable circumstances precluded direct validation of the model.     

The Structure of Maladaptive Schemas: A Confirmatory Factor Analysis and a Psychometric Evaluation of Factor-Derived Scales

One thousand and thirty-seven psychiatric patients and non-patients from six different sites completed the 205-item Young Schema Questionnaire or its shortended form, the 75-item Young Schema Questionnaire-S. Among 888 of the subjects, who all were patients, a confirmatory factor analysis (CFA) of the 75 items included in both forms of the questionnaire clearly yielded the 15 Early Maladaptive Schema (EMS) factors rationally developed by J. E. Young (1990). Confirmatory factor analyses, testing three models of the higher-order structure of the 15 EMSs, indicated that a four-factor model was the best alternative. The results slightly favored a correlated four second-order factor model over one also including a third-order global factor. The four factors or schema domains were Disconnection, Impaired Autonomy, Exaggerated Standards, and Impaired Limits. Scales derived from the four higher-order factors had good internal and test–retest reliabilities and were related to DSM-IV Cluster C personality traits, agoraphobic avoidance behavior, and depressive symptoms.     

Evaluation of doctoral nursing programs - a review and a strategy for follow up

Enhancing and assuring the quality of doctoral nursing programs is currently of major concern to promote growth in quality and quantity of research in nursing. The aims of the paper were to review the literature about evaluation of higher education with focus on doctoral programs in nursing, and to present a strategy to evaluate a doctoral nursing program. A search of literature in relevant databases was done using the keywords doctoral program, evaluation, nursing, program evaluation and higher education. From the review it is concluded that more systematic evaluations are necessary to guide the development of quality in nursing. Attention must be given to the curricula, competence in the faculty, the research activity and to the students' involvement in courses and research. Therefore, a strategy for evaluation should be ongoing, flexible, systematic and comprehensive. It should involve students, graduates, employers and faculty members in evaluation, include process and outcome data and give possibility for comparison to internal and external standards. The strategy developed aims to facilitate ongoing and future improvement of the doctoral nursing program. This process is dependent on a methodological pluralism of evaluation to detect what is of most weight for growth in the process of research and education.     

Enhanced c-Fos in periaqueductal grey GABAergic neurons during opioid withdrawal

The ventrolateral subdivision of periaqueductal grey is crucial for expression of opioid withdrawal signs. Previous investigations suggest that interneurons rather than the medullary projecting output neurons in this midbrain region are hyperexcited during opioid withdrawal. In the present study, transgenic mice with glutamic acid decarboxylase-containing neurons coupled to enhanced green fluorescent protein expression were used as a marker for GABAergic neurons and for studying opioid withdrawal. We found that these transgenic mice exhibited a full range of opioid withdrawal signs on abrupt cessation of chronic opioid action. Consistent with previous studies, c-Fos expression was also robustly enhanced (two-fold) in the ventrolateral periaqueductal grey. Furthermore, about one third (30%) of glutamic acid decarboxylase-containing neurons coupled to enhanced green fluorescent protein in the ventrolateral periaqueductal grey were stained c-Fos positive (i.e. a four-fold increase from control mice). These results indicate hyperexcitation of GABAergic neurons in the ventrolateral periaqueductal grey during opioid withdrawal.     

Effects of statins on microglia

High serum cholesterol level has been shown as one of the risk factors for Alzheimer's disease (AD), and epidemiological studies indicate that treatment with cholesterol-lowering substances, statins, may provide protection against AD. An acute-phase reaction and inflammation, with increased levels of proinflammatory cytokines, are well known in the AD brain. Notably, there is evidence for antiinflammatory activities of statins, such as reduction in proinflammatory cytokines. Consequently, it is of interest to analyze the effects of statins on microglia, the main source of inflammatory factors in the brain, such as in AD. The aims of this study were to determine the effects of statins (atorvastatin and simvastatin) on microglial cells with regard to the secretion of the inflammatory cytokine interleukin-6 (IL-6) and cell viability after activation of the cells with bacterial lipopolysaccharides (LPS) or beta-amyloid1-40 (Abeta1-40) and in unstimulated cells. Cells of the human microglial cell line CHME-3 and primary cultures of rat neonatal cortical microglia were used. Incubation with LPS or Abeta1-40 induced secretion of IL-6, and Abeta1-40, but not LPS, reduced cell viability. Both atorvastatin and simvastatin reduced the basal secretion of IL-6 and the cell viability of the microglia, but only atorvastatin reduced LPS- and Abeta1-40-induced IL-6 secretion. Both statins potentiated the Abeta1-40-induced reduction in cell viability. The data indicate the importance of also considering the microglial responses to statins in evaluation of their effects in AD and other neurodegenerative disorders with an inflammatory component.     

Psychiatric and neuropsychological signs and symptoms in patients with fabry disease: literature review

Fabry Disease (FD) is an X-linked lysosomal storage disorder (prevalence about 1 : 100 000) caused by a genetic defect associated with a lack of alpha-galactosidase A (alpha-GAL) enzyme activity. As a consequence, neutral glycosphingolipides can not be cleaved and metabolized, and accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. The most prominent symptoms comprise pain attacks and acroparesthesia, angiokeratoma, corneal opacity, renal and cardiac dysfunction, hypo- and anhidrosis, gastrointestinal symptoms, and cerebrovascular dysfunction with vertigo, headache, and cerebral ischemia. Characteristic symptoms of FD can occur in male and female patients with the same prevalence, while females with FD seem to be less severely affected. The course of untreated illness is progressive with considerable interindividual variability. Since 2001 two enzyme replacement therapies are approved which can possibly stop the disease progress and alleviate symptoms. The very few reports and clinical observations have shown that a very high proportion of FD patients develop neuropsychiatric symptoms. However, accurate data are lacking. Although the pathophysiologic mechanisms are quite unknown, it is surmised that sphingolipid deposits in the endothelium of small cerebral vessels lead to regional cerebral ischemia accompanied by neuropsychiatric symptoms and deficits. Furthermore, patients with FD are chronically distressed by pain attacks and additional somatic and psychological impairment. Frequently, pain attacks are triggered by psychosocial stress. The high interindividual variability can, thus, also be interpreted on the basis of existing stress and coping models. The present paper will review the presently available psychiatric and neuropsychological findings in FD and will discuss difficulties associated with classification and differential diagnosis of psychiatric disorders occurring in patients with FD.