Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.

Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.     

Associations among circulating sex hormones, insulin-like growth factor, lipids, and mammographic density in postmenopausal women.

OBJECTIVE: Hormone therapy use has been positively associated with mammographic density in several studies. However, few studies have examined the association between endogenous hormone levels and mammographic density. Therefore, we evaluated the relationship of endogenous sex hormones, insulin-like growth factor (IGF), and lipids with mammographic density in 88 overweight, postmenopausal women not taking hormone therapy. METHODS: Percent density and dense area were evaluated as continuous measures using a computer-assisted program. We used multiple linear regression to evaluate the associations of sex hormones, IGF, and cholesterol with mammographic density, adjusting for confounders, including adiposity. We evaluated stratification by history of hormone therapy use (former versus never) and hormone therapy latency (<5 versus > or = 5 years). RESULTS: Among former hormone therapy users, mammographic density was inversely associated with circulating levels of estrone (P = 0.01), estradiol (P = 0.003), free estradiol (P = 0.004), testosterone (P = 0.04), free testosterone (P = 0.02), androstenedione (P < 0.001), dehydroepiandrosterone (P = 0.01), and the ratio of IGF-I to its binding protein (IGF-I/IGFBP-3; P = 0.04). We found similar associations when we limited the analyses to women who had used hormone therapy within the past 5 years. We also noted positive associations of mammographic density with total cholesterol (P = 0.03) and low-density lipoprotein (P = 0.03) among former hormone therapy users. No associations were noted among women who had never used hormone therapy. CONCLUSIONS: These results suggest that there is an inverse relationship between endogenous sex hormones and mammographic density in postmenopausal women among former users of hormone therapy. This is not consistent with the hormone therapy literature and should be confirmed in larger studies.     

Distinguishing true from false positives in genomic studies: p values

Distinguishing true from false positive findings is a major challenge in human genetic epidemiology. Several strategies have been devised to facilitate this, including the positive predictive value (PPV) and a set of epidemiological criteria, known as the “Venice” criteria. The PPV measures the probability of a true association, given a statistically significant finding, while the Venice criteria grade the credibility based on the amount of evidence, consistency of replication and protection from bias. A vast majority of journals use significance thresholds to identify the true positive findings. We studied the effect of p value thresholds on the PPV and used the PPV and Venice criteria to define usable thresholds of statistical significance. Theoretical and empirical analyses of data published on AlzGene show that at a nominal p value threshold of 0.05 most “positive” findings will turn out to be false if the prior probability of association is below 0.10 even if the statistical power of the study is higher than 0.80. However, in underpowered studies (0.25) with a low prior probability of 1 × 10^?3, a p value of 1 × 10^?5 yields a high PPV (>96 %). Here we have shown that the p value threshold of 1 × 10^?5 gives a very strong evidence of association in almost all studies. However, in the case of a very high prior probability of association (0.50) a p value threshold of 0.05 may be sufficient, while for studies with very low prior probability of association (1 × 10^?4; genome-wide association studies for instance) 1 × 10^?7 may serve as a useful threshold to declare significance.     

Alte Forderung,neuer Biss

Der Freie Zahnarzt - FVDZ-Landesversammlung in Sachsen Über die Gebührenordnung für Zahnärzte (GOZ) lässt sich immer wieder trefflich diskutieren. Deshalb wählte die...     

On the Connection Between Affective Evaluation of Recollected Relationship Experiences and the Severity of the Psychic Impairment

This study, carried out at three different university centers contributes to validating the valence dimension of the CCRT-method. Working on the state of the CCRT-research on affective evaluation of relationship narratives, the connection between the valence dimension of the responses from others (RO), responses of the self (RS) and the severity of the psychological disorder has been analyzed with the help of a sample taken from 266 female patients. Both therapists as well as patients themselves evaluate the severity of the impairment similarly. The more the patients are impaired, the more negatively they describe both their own reactions and those of their interaction partners as shown in the relationship episodes. Die vorliegende multizentrizch Studie stellt einen Beitrag zur Vaidierungder Valenzdimension der ZBKT-Methode dar. Ausgehend vom Stand der ZBKT-Forschung bezüglich der affektiven Bewertung der Beziehungsschilderungen wurde an einer Stichprobe von 266 Patientinnen der Zusammenhang zwischen der Valenzdimension der Reaktionskomponenten und der Schwere der psychischen Störung untersucht. Für die Einschätzung der krankheitsschwere sowohldurch die therapeuten wie auch durch die patientinnen selbst Gilt: je schwerer gestört patientinnen sind, um so negativer beschreiben sie die eigenen Reaktionen und die ihrer Interaktionspartner in den Beziehungsepisoden. Cette étude menée dans trois centres universitaires contribue à la validation de la dimension positivité/négativité («valence») du CCRT. Dans notre travail sur la situation dela recherche concernant le CCRT et l'évaluation affective des épisodes relationnels, nous avons analysé, sur base d'un échantillon de 266 patientes, le lien entre ladimension «valence» des réponses de l'autre, de la réaction du sujet, et la gravité du trouble psychique. les thérapeutes et les patientes elles-mêmes arrivent à une jugement comparable de la Sévérité de l'atteinte. Plus les patientes sont atteintes, et plus le récit des réactions des autres et d'elles-mêmes dans les épisodes relationnels est négatif. Este estudio, llevado a cabo en tres centros universitarios diferentes, contribuye a validar la dimensión valencia del método CCRT. Trabajando sobre el estado actual de la investigació del CCRT en la evaluación afectiva de las narrativas relacionales, se analizó, en una muestra de 266 pacientes mujeres, la conexión entre la dimensión valencia en las respuestas de otros (Ro), las respuestas del self (RS) y la severidad del desorden psíquico.Los terapeuttas evaluaron la severidad de las perturbaciones en forma similar a las pacientes mismas. Como se ve en los episodios relacionales, cuanto màs perturbadas estàn las pacientes, mà negativamene describen sus propias reacciones y las de sus interlocutores.