We present a review of the epidemiological evidence for relations of prostate cancer risk to circulating total and bioavailable androgens, to alterations in the metabolism of insulin-like growth factor-1 (IGF-1), and to anthropometric indices of longitudinal growth (body stature) and overweight. In addition, we review the physiological inter-relationships between insulin, growth hormone/IGF-1 axis, and sex steroid metabolism, as well as the associations of bioavailable sex steroid levels with overweight and obesity. A ®rst conclusion of this review is that, taken together, epidemiological studies have provided little support for the hypothesis that prostate cancer risk is increased in men with elevated total or biovailable testosterone (T). Although one prospective study showed an increased risk in men with low plasma sex hormone-binding globulin (SHBG) and with elevated plasma T for given levels of SHBG, this was not con®rmed by results from other cohort studies. A second conclusion is that overweight, which is generally associated with moderate reductions in both total and bioavailable plasma T, appears to be unrelated to any signi®cant increase or decrease in prostate cancer risk. However, signi®cant increases in risk have been observed for men with a taller body stature, or with elevated plasma IGF-1. IGF-1 may directly enhance prostate tumorigenesis by inhibiting apoptosis and by stimulating cell proliferation. In addition, IGF-1 downregulates the synthesis of SHBG, and enhances sex steroid synthesis. Therefore, we do not entirely rule out that due to an elevation of plasma IGF-1 levels, men at increased risk of prostate cancer also have mildly elevated plasma bioavailable T, which epidemiological studies may have failed to demonstrate because of methodological problems. Prostate Cancer and Prostatic Diseases (2000) 3, 157±172.

Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in psychiatric diseases. This gene encodes the protein LG72 that has been discussed to function as a putative activator of the peroxisomal enzyme D-aminoacid-oxidase (DAO) and as a mitochondrial protein. We recently generated 'humanized' bacterial artificial chromosome transgenic mice (G72Tg) expressing G72 transcripts in cells throughout the brain. These mice exhibit several behavioral phenotypes related to psychiatric diseases. Here we show that G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species. Affected neurons display deficits in short-term plasticity and an impaired capability to sustain synaptic activity. These deficits lead to an impairment in spatial memory, which can be rescued by pharmacological treatment with the glutathione precursor N-acetyl cysteine. Our results implicate LG72-induced mitochondrial and synaptic defects as a possible pathomechanism of psychiatric disorders.

Follicle-stimulating hormone is the major regulator of growth and development of antral follicles in the ovary. Granulosa cells (GCs) in these follicles are coupled via gap junctions (GJs) consisting of connexin 43 (Cx 43). Because we and others have found that Cx 43 and GJs, respectively, are more abundant in large antral follicles compared with small antral and preantral follicles, we hypothesized that FSH may control Cx 43 gene expression, GJ formation, and intercellular communication. To directly address these points, we chose a rat GC line (GFSHR-17) expressing the FSH receptor and the Cx 43 gene. The functionality of FSH receptors was shown by the effects of porcine FSH, namely cell rounding, reduced cellular proliferation, and stimulation of progesterone production of GFSHR-17 cells, which are effects that were detectable within hours. Treatment with FSH also statistically significantly increased Cx 43 mRNA levels, as shown after 6 to 9 h in Northern blots. These effects were antedated by altered GJ communication, which was observed within seconds. Using a single-cell/whole-cell patch clamp technique, we showed that FSH rapidly and reversibly enhanced electrical cell coupling of GFSHR-17 cells. Increased GJ communication was associated with statistically significantly decreased phosphorylation of Cx 43, which was observed within 10 min after FSH addition, during immunoprecipitation experiments. Our results demonstrate, to our knowledge for the first time, that the gonadotropin FSH acutely and directly stimulates intercellular communication of GFSHR-17 cells through existing GJs. Moreover, FSH also increases levels of Cx 43 mRNA. These changes are associated with reduced proliferation and enhanced differentiation of GFSHR-17 cells. In vivo factors in addition to FSH may be involved in the regulation of GJ/GJ communication between GCs in the follicle, but our results suggest that improved cell-to-cell coupling, enhanced Cx 43 gene expression, and possibly, formation of new GJs are direct consequences of FSH receptor activation and may antedate and/or initiate the pivotal effects of FSH on GCs.

Virtually all CNS synapses display the potential for activity-dependent long-term potentiation (LTP) and/or long-term depression (LTD).Intriguingly, the potential to exhibit LTP or LTD at many central synapses itself is powerfully modulated by previous synaptic activity. This higher-order form of plasticity has been termed metaplasticity. Here, we show that inhibitory autophosphorylation of Ca 2ϩ / calmodulin-dependent kinase II (CaMKII) is required for hippocampal metaplasticity at the lateral perforant path-dentate granule cell synapse. Brief 10 Hz priming, which does not affect basal synaptic transmission, caused a dramatic, pathway-specific and long-lasting (up to 18 h) reduction in subsequently evoked LTP at lateral perforant path synapses. In contrast, LTD was unaffected by priming. The induction of lateral perforant path metaplasticity required the activation of NMDA receptors during priming. In addition, metaplasticity was absent in knock-in mice expressing ␣CaMKII that cannot undergo inhibitory phosphorylation, indicating that inhibitory autophosphorylation of ␣CaMKII at threonines 305/306 is required for metaplasticity. Metaplasticity was not observed in the medial perforant pathway, consistent with the observation that CaMKII activity was not required for the induction of LTP at this synapse. Thus, modulation of ␣CaMKII activity via autophosphorylation at Thr305/Thr306 is a key mechanism for metaplasticity that may be of importance in the integration of temporally separated episodes of activity.

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Gesellschaften stellen sich vor Überschrift 0 Deutsche Kinderkrebsstiftung: Damit krebskranke Kinder gesund werden Jedes Jahr erkranken in Deutschland rund 2000 Kinder an Krebs. Die Diagnose bedeutet für jede Familie einen Schock. Denn obwohl die Überlebenschancen dank der medizinischen Fortschritte von 30 % in den 1960er-Jahren auf heute mehr als 80 % gesteigert werden konnten, ist die heimtückische Krankheit noch immer lebensbedrohlich. Sie bringt einschneidende Veränderungen für die Betroffenen und ihre Familien mit sich. Auch Spät-oder Langzeitfolgen können vorkommen.