High plasma ghrelin protects from coronary heart disease and Leu72Leu polymorphism of ghrelin gene from cancer in healthy adults during the 19 years follow-up study.

The aim of our investigation was to find out if ghrelin concentrations or polymorphisms predict the future risk for cardiovascular diseases and cancer in a population-based cohort initiated in 1991 (491 hypertensive and 513 control subjects). Total mortality and hospital events were followed up for 19 years. Fasting total ghrelin concentrations were determined and Arg51Gln, Leu72Met and -501 A > C polymorphisms identified. Cox regression analysis was performed. The mean value in the control cohort was 674 pg/ml whereas in the hypertensive cohort it was 661 pg/ml. The associations found suggest that in the controls the highest ghrelin quartile protected from CHD (coronary heart disease). The results were significant without or with adjustments for age, sex, smoking, systolic blood pressure and LDL cholesterol, BMI, type 2 diabetes or QUICK index. C/C variant of the promoter associated with the prevention of IHD (ischemic heart disease) in the hypertensive group (p<0.05). The controls with the Leu72Leu genotype had less cancer (p<0.05). In conclusion, high plasma ghrelin concentration was related to protection from CHD and Leu72Leu genotype to prevention of cancer in healthy adults during the 19 years follow-up. C/C promoter protects from IHD in the hypertensive subjects.

Detection rates of cancer, high grade PIN and atypical lesions suspicious for cancer in the European Randomized Study of Screening for Prostate Cancer.

THE AIM OF THE STUDY: This article presents the incidence of prostate cancer, isolated high grade prostatic intraepithelial neoplasia (PIN) and atypical lesions suspicious for prostate cancer (LSPC) during subsequent screening rounds in the centres of five of the countries participating in the European Randomized Study of Screening for Prostate Cancer (ERSPC). The incidence and predictive value of high grade PIN and LSPC for prostate cancer in subsequent biopsy following these diagnoses were evaluated. PATIENTS AND METHODS: Study group consisted of 56,653 screened men in the ERSPC centres of Finland, Italy, Netherlands, Sweden and Switzerland, who underwent 3-7 screening rounds at 2-4 year interval. Data for prostate cancer were obtained from the ERSPC central database. Data for high grade PIN and LSPC were gathered from each ERSPC centre. Detection rates of subsequent prostate cancer in the first re-biopsy after these diagnoses were determined. RESULTS: The average cancer detection rate was 3.5%, 3.2% and 3.5% for the completed rounds 1, 2 and 3, respectively, in all five centres. Incidence of high grade PIN increased from 1.5% in the first round to 5.0% in the third round, varying among centres in the first round between 0.8% and 7.6%. The cancer detection rate in the first re-biopsy after the diagnosis of high grade PIN was 12.9%. Incidence of LSPC was 2.4%, 2.7%, 2.2% and 2.6% in the first, second, third and fourth round, respectively. The cancer detection rate at the first re-biopsy after the diagnosis of LSPC was in average 33.8%. CONCLUSIONS: Cancer detection rate was stable during the three screening rounds. The wide variation in frequency in particular of high grade PIN among the ERSPC centres suggests a considerable inter-observer variation. The average comparatively low detection rate of isolated high grade PIN in the first screening round may be screening-related, while its consistent increase during three screening rounds could be the consequence of a.o. previous screening and ageing of the population. The observed low risk of prostate cancer after isolated high grade PIN in this screening setting is in line with the current recommendation to abstain from early repeat biopsies after this diagnosis. The association of LSPC with high incidence of prostate cancer in re-biopsies confirms the need for early repeat biopsies and follow-up of these men. The low percentage of LSPC (<3% of biopsies) throughout all rounds is reassuring as it limits the biopsy burden in a screening setting.

Magnetic field dependence of the distribution of NMR relaxation times in the living human brain.

OBJECTIVE: This study investigates the field dependence of the distribution of in vivo, whole-brain T1 values, and its usefulness for white matter/grey matter segmentation. Results on T1 values are presented on 12 healthy volunteers. T2 and T2* distributions and their field dependence have been measured on the same cohort of volunteers. In this paper, however, only the T2 and T2* results on a single volunteer are presented. The reported field dependence of T2 and T2* values should, therefore, be given less weight than that of T1 times. MATERIALS AND METHODS: Relaxation times were measured in vivo on 12 healthy volunteers, using three nearly identical whole-body scanners, operating at field strengths of 1.5, 3, and 4 T and employing nearly identical software platforms and very similar hardware. T1 mapping was performed using TAPIR, a sequence based on the Look-Locker method. T2* mapping was performed with a multi-slice, multi-echo, gradient echo sequence. A multi-slice, multi-echo T2 mapping sequence based on the Carr-Purcell-Meiboom-Gill (CPMG) method was used to map T2. For each volunteer, the global distribution of T1 relaxation times was described as the superposition of three Gaussian distributions. The field and age-dependence of the centroids and widths of the three Gaussians was investigated. The segmentation of the brain in white and grey matter was performed separately for each field strength. Using the T1 segmentation and the fact that all maps were coregistered, we investigated the distribution of T2 and T*(2) values separately for the white and grey matter and described them with a Gaussian distribution in each case. RESULTS: Multi-slice quantitative maps were produced for the relaxation parameters T1 (near whole-brain coverage with 41 slices), T2* (whole-brain coverage, 55 slices), and T2 (27 slices). A clear age dependence was identified for grey matter T1 values and correlated with similar behaviour observed in a separate study of the brain water content. The increase with field strength of the bulk white and grey matter T1 values was well reproduced by both Bottomley's [1] and Fischer's [2] formulae, with parameters taken from the literature. The separation between the centroids was, however, either overestimated or underestimated by the two formulae. The width of the T1 distributions was found to increase with increasing field. CONCLUSIONS: The study of the field dependence of the NMR relaxation times is expected to allow for better differentiation between regions which are structurally different, provide a better insight into the microscopic structure of the brain and the molecular substrate of its function.

Chromosomal changes in locally recurrent, hormone-refractory prostate carcinomas by karyotyping and comparative genomic hybridization.

The genetic mechanisms of prostate cancer recurrence during hormonal therapy are largely unknown. So far, data from conventional karyotype analysis on hormone-refractory prostate carcinomas have not been published, mainly because of the difficulties in obtaining fresh hormone-refractory prostate carcinoma samples and getting metaphases from them. Here, we have studied chromosomal changes in 12 locally recurrent, hormone-refractory prostate carcinomas using karyotyping and CGH that revealed genetic aberrations in all tumors. Loss of the Y chromosome was the most common (89%) finding, and tetraploidy or near-tetraploidy was detected in all tumors. Also non-random translocations were found in 56% of the tumors. The present study indicates that clonal chromosomal aberrations in hormone-refractory prostate carcinomas are more common than in untreated primary tumors, and also, further studies on the frequency and significance of translocations in prostate carcinoma progression during hormonal therapy are warranted.

Androgen receptor alterations in prostate cancer relapsed during a combined androgen blockade by orchiectomy and bicalutamide.

Mechanisms of prostate cancer (CaP) recurrence during a combined androgen blockade (CAB) are poorly understood. Previously, the role of androgen receptor (AR) gene mutations underlying the CAB therapy relapse has been raised. To investigate the hypothesis that AR gene aberrations are involved in CAB relapse, 11 locally recurrent CaP samples from patients treated with orchiectomy and bicalutamide were analyzed for copy number changes and DNA sequence alterations of the AR gene by fluorescence in situ hybridization and single-strand conformation polymorphism, respectively. Altogether, base changes were detected in four tumors (36%). Three of them were missense mutations (G166S, W741C, M749I) and two were silent polymorphisms. Interestingly, none of the tumors had AR amplification. These data suggest that different AR variants are developed and selected for during various types of hormonal treatments, and also, that CAB achieved by orchiectomy and bicalutamide does not act as a selective force for AR amplification.

Age dependence of bovine oocyte activation.

The ability of bovine oocytes to undergo parthenogenetic activation using either a Ca++-Mg++-H+ ionophore (A23187) or electric shock was investigated, as a prelude to understanding activation potential following nuclear transfer into ooplasm. Oocytes were collected from slaughterhouse ovaries by aspiration of 1-5-mm follicles. The time of placement into maturation medium was noted, and maturational age (time in culture) measured from that point. After exposure to activating conditions eggs were cultured for a further 12-16 hours, fixed, and stained with aceto-orcein. Oocytes that progressed to telophase or pronuclear formation were considered activated. Concentrations of A23187 ranging from 100 pM to 100 microM showed that 1-100 microM levels resulted in 94-100% activation at 30 hours maturation. Frequency of activation differed from controls (no ionophore) at 100 nM (49%; P less than 0.05). With A23187 maximum response occurred between 26 and 30 hours of maturation (77% and 92%, respectively). A short pulse electric shock, capable of causing oocyte membrane fusion, gave similar results relative to maturational age (82% and 90% activation for 26 and 30 hours, respectively). Therefore, maximum response to the two activating stimuli occurred in oocytes at similar maturational ages. Exposure to activating conditions prior to onset of activating ability (18 hours) followed by another exposure at 26 hours showed that the oocytes were still fully able to activate upon reaching maturational activation competence. Because cytochalasin B is present in the medium used for nuclear transfer, oocytes were incubated with cytochalasin B prior to exposure to an activating stimulus. Frequency of activation was similar to the control treatment (61% and 73%). The effect of mechanical stress of cytoplasm removal and replacement by electrofusion on activation was also not significant. Overall, maturational age of the oocyte was the main determinant of activation ability.