Rapid effects of phytoestrogens on human colonic smooth muscle are mediated by oestrogen receptor beta.

Epidemiological studies have correlated consumption of dietary phytoestrogens with beneficial effects on colon, breast and prostate cancers. Genomic and non-genomic mechanisms are responsible for anti-carcinogenic effects but, until now, the effect on human colon was assumed to be passive and remote. No direct effect on human colonic smooth muscle has previously been described. Institutional research board approval was granted. Histologically normal colon was obtained from the proximal resection margin of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended under 1g of tension in organ baths containing oxygenated Krebs solution at 37 degrees C. After an equilibration period, tissues were exposed to diarylpropionitrile (DPN) (ER beta agonist) and 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) (ER alpha agonist) or to the synthetic phytoestrogen compounds genistein (n=8), daidzein (n=8), fisetin (n=8) and quercetin (n=8) in the presence or absence of fulvestrant (oestrogen receptor antagonist). Mechanism of action was investigated by inhibition of downstream pathways. The cholinergic agonist carbachol was used to induce contractile activity. Tension was recorded isometrically. Phytoestrogens inhibit carbachol-induced colonic contractility. In keeping with a non-genomic, rapid onset direct action, the effect was within minutes, reversible and similar to previously described actions of 17 beta oestradiol. No effect was seen in the presence of fulvestrant indicating receptor modulation. While the DPN exerted inhibitory effects, PPT did not. The effect appears to be reliant on a p38/mitogen activated protein kinase mediated induction of nitric oxide production in colonic smooth muscle. The present data set provides the first description of a direct effect of genistein, daidzein, fisetin and quercetin on human colonic smooth muscle. The presence of ER in colonic smooth muscle has been functionally proven and the beta isoform appears to play a predominant role in exerting non-genomic effects.

Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging.

Evidence concerning anatomical connectivities in the human brain is sparse and based largely on limited post-mortem observations. Diffusion tensor imaging has previously been used to define large white-matter tracts in the living human brain, but this technique has had limited success in tracing pathways into gray matter. Here we identified specific connections between human thalamus and cortex using a novel probabilistic tractography algorithm with diffusion imaging data. Classification of thalamic gray matter based on cortical connectivity patterns revealed distinct subregions whose locations correspond to nuclei described previously in histological studies. The connections that we found between thalamus and cortex were similar to those reported for non-human primates and were reproducible between individuals. Our results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.

Evidence for increased dopaminergic and opioid activity in patients with hypothalamic hypogonadotropic amenorrhea.

PIP: The functional activity of endogenous opioids and dopamine (DA) was assessed by analyzing gonadotropin and prolactin responses to DA receptor antagonist (metoclopramide) and the opioid receptor antagonist (naloxone) in selected patients with hypothalamic hypogonadotropic amenorrhea and in normal cycling women. 8 amenorrheic and 9 normal women during the low estrogen (early follicular) phase of menstrual cycle were studied. Simultaneous blood sampling and agent infusion was performed via 2 indwelling catheters after an overnight fast. Those receiving metoclopramide (10 mg intravenous bolus) and those receiving naloxone (1.6 mg/h for 4 hours) had blood samples withdrawn at various intervals. The 8 amenorrheic patients weighed significantly less (P .01) and had significantly lower mean basal serum luteinizing hormone (LH) (P .0001) and prolactin (P .01) than normal women. Metoclopramide administered to normal women induced no significant changes in pituitary gonadotropin levels. In contrast, 4 of 8 hypogonadotropic amenorrhea patients responded to metoclopramide with a significant mean net change of LH (P .05); a concomitant rise in follicle stimulating hormone (FSH) was also seen but was not statistically significant. The other 4 showed no response, as in normal women. Prolactin response to metoclopramide was reduced uniformly in all 8 patients, independent of LH responders or nonresponders. Naloxone in normal women showed no response. However, a clear increment of mean LH in response to naloxone was observed in the same 4 hypogonadotropic amenorrhea patients who also responded to metoclopramide. Mean LH nearly doubled; FSH levels showed no significant changes. Those other 4 patients who had no response to metoclopramide also had no response to naloxone. The 4 LH nonresponders with significantly (P .01) lower mean basal prolactin levels compared with normal women showed greater than l00% increase in prolactin levels by Hour 3 of naloxone infusion; in contrast, the LH responders showed no changes in prolactin levels in response to naloxone infusion.^ieng