Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain

Metformin is treatment of choice for the metabolic consequences seen in polycystic ovary syndrome for its insulin-sensitizing and androgen-lowering properties. Yet, the mechanism of action remains unclear. Two potential targets for metformin regulating steroid and glucose metabolism are AMP-activated protein kinase (AMPK) signaling and the complex I of the mitochondrial respiratory chain. Androgen biosynthesis requires steroid enzymes 17α-Hydroxylase/17,20 lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which are overexpressed in ovarian cells of polycystic ovary syndrome women. Therefore, we aimed to understand how metformin modulates androgen production using NCI-H295R cells as an established model of steroidogenesis. Similar to in vivo situation, metformin inhibited androgen production in NCI cells by decreasing HSD3B2 expression and CYP17A1 and HSD3B2 activities. The effect of metformin on androgen production was dose dependent and subject to the presence of organic cation transporters, establishing an important role of organic cation transporters for metformin's action. Metformin did not affect AMPK, ERK1/2, or atypical protein kinase C signaling. By contrast, metformin inhibited complex I of the respiratory chain in mitochondria. Similar to metformin, direct inhibition of complex I by rotenone also inhibited HSD3B2 activity. In conclusion, metformin inhibits androgen production by mechanisms targeting HSD3B2 and CYP17-lyase. This regulation involves inhibition of mitochondrial complex I but appears to be independent of AMPK signaling.

Comparisons of bacterial patterns present at implant and tooth sites in subjects on supportive periodontal therapy. I. Impact of clinical variables, gender and smoking

OBJECTIVE: (I) To compare the oral microflora at implant and tooth sites in subjects participating in a periodontal recall program, (II) to test whether the microflora at implant and tooth sites differ as an effect of gingival bleeding (bleeding on probing (BOP)), or pocket probing depth (PPD), and (III) to test whether smoking and gender had an impact on the microflora. MATERIAL AND METHODS: Data were collected from 127 implants and all teeth in 56 subjects. Microbiological data were identified by the DNA-DNA checkerboard hybridization. RESULTS: PPD> or =4 mm were found in 16.9% of tooth, and at 26.6% of implant sites (P<0.01). Tooth sites with PPD> or =4 mm had a 3.1-fold higher bacterial load than implant sites (mean difference: 66%, 95% confidence interval (CI): 40.7-91.3, P<0.001). No differences were found for the red, orange, green, and yellow complexes. A higher total bacterial load was found at implant sites with PPD> or =4 mm (mean difference 35.7 x 10(5), 95% CI: 5.2 (10(5)) to 66.1 (10(5)), P<0.02 with equal variance not assumed). At implant sites, BOP had no impact on bacterial load but influenced the load at tooth sites (P<0.01). CONCLUSION: BOP, and smoking had no impact on bacteria at implant sites but influenced the bacterial load at tooth sites. Tooth sites harbored more bacteria than implant sites with comparable PPD. The 4 mm PPD cutoff level influenced the distribution and amounts of bacterial loads. The subject factor is explanatory to bacterial load at both tooth and implant sites.

Model to describe the mode I fracture of steel fiber reinforced ultra-high performance concrete

Ultra-high performance fiber reinforced concrete (UHPFRC) has arisen from the implementation of a variety of concrete engineering and materials science concepts developed over the last century. This material offers superior strength, serviceability, and durability over its conventional counterparts. One of the most important differences for UHPFRC over other concrete materials is its ability to resist fracture through the use of randomly dispersed discontinuous fibers and improvements to the fiber-matrix bond. Of particular interest is the materials ability to achieve higher loads after first crack, as well as its high fracture toughness. In this research, a study of the fracture behavior of UHPFRC with steel fibers was conducted to look at the effect of several parameters related to the fracture behavior and to develop a fracture model based on a non-linear curve fit of the data. To determine this, a series of three-point bending tests were performed on various single edge notched prisms (SENPs). Compression tests were also performed for quality assurance. Testing was conducted on specimens of different cross-sections, span/depth (S/D) ratios, curing regimes, ages, and fiber contents. By comparing the results from prisms of different sizes this study examines the weakening mechanism due to the size effect. Furthermore, by employing the concept of fracture energy it was possible to obtain a comparison of the fracture toughness and ductility. The model was determined based on a fit to P-w fracture curves, which was cross referenced for comparability to the results. Once obtained the model was then compared to the models proposed by the AFGC in the 2003 and to the ACI 544 model for conventional fiber reinforced concretes.

Book review of “Germany in Transit: Nation and Migration, 1955-2005”. 588 pages, University of California Press, 2007, by Deniz Göktürk, David Gramling and Anton Kaes (eds.)

Though migration is an age-old feature of human activity, driven by various circumstances, its current place in the midst of global dynamics and the phenomenon of globalization is becoming increasingly critical. International immigration and its regulation have been largely shaped by the policies in the receiving countries, often determining preferences for nationality cohorts and work skills to satisfy their labor and human capital requirements. When immigration has been necessitated by political strife, host countries have displayed immense magnanimity as well. However, the growing realization of resource limitations and the strange quirks of cultural pluralism are in turn creating waves of dissonance. Literature and the media are now replete with an in depth look into the immigration debate in various nations of the world in trying to seek new directions and satisfactory solutions.

The Basic Law (Grundgesetz) 2012: The Constitution of the Federal Republic of Germany – Introduction and Translation

This introduction and translation is part of the research project International Constitutional Law. All amendments up to and including the 59th Amendment of 11th July 2012 have been translated and included into a consolidated edition. There have been no more amendments until today (8th October 2013).

The HeartQoL: Part I. Development of a new core health-related quality of life questionnaire for patients with ischemic heart disease

Background: Evaluation of health-related quality of life (HRQL) is important in improving the quality of patient care. Methods: The HeartQoL Project, with cross-sectional and longitudinal phases, was designed to develop a core ischemic heart disease (IHD) specific HRQL questionnaire, to be called the HeartQoL, for patients with angina, myocardial infarction (MI), or ischemic heart failure. Patients completed a battery of questionnaires and Mokken scaling analysis was used to identify items in the HeartQoL questionnaire. Results: We enrolled 6384 patients (angina, n = 2111, 33.1%; MI, n = 2351, 36.8%; heart failure, n = 1922, 30.1%) across 22 countries and 15 languages. The HeartQoL questionnaire comprises 14-items with 10-item physical and 4-item emotional subscales which are scored from 0 (poor HRQL) to 3 (better HRQL) with a global score if needed. The mean baseline HeartQoL global score was 2.2 (±0.5) in the total group and was different (p < 0.001) by diagnosis (MI, 2.4 ± 0.5; angina, 2.2 ± 0.6; and heart failure, 2.1 ± 0.6). Conclusion: The HeartQoL questionnaire, with global and subscale scores, has the potential to allow clinicians and researchers to (a) assess baseline HRQL, (b) make between-diagnosis comparisons of HRQL, and (c) evaluate change in HRQL in patients with angina, MI, or heart failure with a single IHD-specific HRQL instrument.

Educational Expansion and Persistent Inequalities of Education: Utilizing the Subjective Expected Utility Theory to Explain the Increasing Participation Rates in Upper Secondary School in the Federal Republic Of Germany

This investigation attempts to answer the question why more and more parents have chosen the Gymnasium for their children's secondary school education in post‐war West Germany. Based on the theory of subjective expected utility, the crucial mechanisms of parental educational decisions have been emphasized. From this perspective it is assumed that increasing educational motivation coupled with changes in the subjective evaluation of the cost–benefit of education were important conditions for an increasing participation in upper secondary schools. These were, however, in turn, the result of educational expansion. The empirical analyses for three time‐periods in the 1960s, 1970s, and 1980s confirm these assumptions to a large degree. Additionally, empirical evidence was found to suggest that in addition to the intentions of parents and the educational career of their children, structural moments of educational expansion and their own inertia played an important role in the pupils' transition from one educational level to the next. Finally, evidence was found that persistent class‐specific educational inequality stems from a constant balance in the relative cost–benefit advantages between social classes as well as from an increasing difference of primary origin effect between social classes in the realization of their educational choice.

Cohort-specific effects of the expansion of the welfare state on job opportunities: a longitudinal analysis of three birth cohorts in the Federal Republic of Germany

Ziel der Untersuchung war es, Einflüsse auf den Arbeitsmarkt der Bundesrepublik durch das Anwachsen des Wohlfahrtsstaates zu ermitteln. Zu diesem Zweck wurden zwischen 1981 und 1983 2.171 Männer und Frauen der Geburtskohorten 1929-31, 1939-41 und 1949-51 mit standardisierten Interviews befragt zu ihrem Lebensverlauf, speziell unter den Gesichtspunkten: Soziale Herkunft, Ausbildung, Beschäftigung, Familie, Mobilität. Insbesondere interessierte die Frage nach der Beschäftigung im öffentlichen Dienst oder in der Privatwirtschaft bzw. ob und wann ein Wechsel von einem in den anderen Bereich stattgefunden hat. Einige Ergebnisse: Die Bildungsexpansion in den 70er Jahren führte dazu, daß eine steigende Anzahl von Universitätsabsolventen im öffentlichen Dienst Beschäftigung fand; seit der Stagnation des Wohlfahrtsstaates ab ca. 1980 sind die Beschäftigungschancen für hochqualifizierte Berufsanfänger dort wieder gesunken. In der Privatwirtschaft wird unqualifizierte Beschäftigung durch höher qualifizierte ersetzt, während im öffentlichen Dienst bei geringerem Arbeitsplatzangebot weniger hochqualifizierte Berufsanfänger nachgefragt werden.