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Epithelial proliferation of the ventral prostate in rodents peaks between 2 and 4 weeks of age, and by week 8, proliferating cells are rare. We have used ER␤ ؊/؊ and CYP7B1 ؊/؊ mice to investigate the role of ER␤ and one of its ligands, 5␣-androstane-3␤,17␤-diol (3␤Adiol), in growth of the ventral prostate. Before puberty, ER␤ was found in quiescent but not in proliferating cells, and proliferating cells occurred more frequently in ventral prostates of ER␤ ؊/؊ mice than in wild-type littermates. Treatment with 3␤Adiol decreased proliferation in wild-type but not in ER␤ ؊/؊ mice. In rats, treatment with 3␤Adiol from postnatal day 2 to 28 resulted in reduction in growth of ventral prostates. The prostates of CYP7B1 ؊/؊ mice were hypoproliferative before puberty and smaller than those of their wild-type littermates after puberty. Because CYP7B1 represents the major pathway for inactivating 3␤Adiol in the prostate, we suggest that ER␤, 3␤Adiol, and CYP7B1 are the components of a pathway that regulates growth of the rodent ventral prostate. In this pathway, ER␤ is an antiproliferative receptor, 3␤Adiol is an ER␤ ligand, and CYP7B1 is the enzyme that regulates ER␤ function by regulating the level of 3␤Adiol.

We describe a metabolic defect in bile acid synthesis involving a deficiency in 7 ␣ -hydroxylation due to a mutation in the gene for the microsomal oxysterol 7 ␣ -hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3 ␤ -hydroxy-5-cholenoic and 3 ␤ -hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were Ͼ 4,500 times normal. The biochemical findings were consistent with a deficiency in 7 ␣ -hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7 ␣ -hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon.

The human pS2 gene is specifically expressed under estrogen transcriptional control in a subclass of estrogen receptor-containing human breast cancer cells. The pS2 gene encodes an 84-amino acid protein that is secreted after signal peptide cleavage. The distribution of pS2 protein in normal human tissues was studied with antibodies to pS2; pS2 was specifically expressed and secreted by mucosa cells of the normal stomach antrum and body of both female and male individuals. Moreover, no estrogen receptor could be detected in these cells, indicating that pS2 gene expression is estrogen-independent in the stomach. The function of the pS2 protein in the gastrointestinal tract is unknown. However, the pS2 protein is similar in sequence to a porcine pancreatic protein that has been shown to inhibit gastrointestinal motility and gastric secretion.

Rabies is one of the oldest diseases know to man, but its successful control has remained elusive. Although effective vaccines of tissue culture origin against rabies do exist, such preparations are expensive. Live vaccinia virus (VV) recombinants expressing influenza or hepatitis B antigens have recently been used to immunize against these diseases. We have now used this approach to produce a novel rabies vaccine. We first altered the rabies glycoprotein cDNA by site-directed mutagenesis and removed the poly(dG) tail. We then aligned the modified cDNA with an early VV promoter sequence inserted within a cloned copy of the vaccinia thymidine kinase gene and transfected this plasmid into VV-infected cells. Recombination between the virus and the plasmid resulted in a recombinant virus harbouring the rabies glycoprotein cDNA. Inoculation of rabbits with the live recombinant virus induced high titres of rabies virus-neutralizing antibodies, and scarification with the recombinant VV protected mice against challenge with street rabies virus.

Hippocampal lesions produce memory deficits, but the exact function of the hippocampus remains obscure. Evidence is presented that its role in memory may be ancillary to physiological regulation. Molecular studies demonstrate that the hippocampus is a primary target for ligands that reflect body physiology, including ion balance and blood pressure, immunity, pain, reproductive status, satiety and stress. Hippocampal receptors are functional, probably accessible to their ligands, and mediate physiological and cognitive changes. This argues that an early role of the hippocampus may have been in sensing soluble molecules (termed here 'enteroception') in blood and cerebrospinal fluid, perhaps reflecting a common evolutionary origin with the olfactory system ('exteroception').Functionally, hippocampal enteroception may reflect feedback control; evidence is reviewed that the hippocampus modulates body physiology, including the activity of the hypothalamus-pituitary-adrenal axis, blood pressure, immunity, and reproductive function. It is suggested that the hippocampus operates, in parallel with the amygdala, to modulate body physiology in response to cognitive stimuli. Hippocampal outputs are predominantly inhibitory on downstream neuroendocrine activity; increased synaptic efficacy in the hippocampus (e.g. long-term potentiation) could facilitate throughput inhibition. This may have implications for the role of the hippocampus and long-term potentiation in memory. Journal of Endocrinology (2001) 169, 205-231The hippocampus and memory Attention has focused on the hippocampus in view of its likely role in memory encoding and its dysfunction in Alzheimer's disease. The hippocampal formation undoubtedly contributes to the encoding of long-term memories, but an exclusive focus on memory would be a mistake. The present review emphasises an important aspect of hippocampal function: that of responding to and governing body physiology. What follows briefly revisits the role of the hippocampus in learning and memory, and the electrophysiological correlates of memory processes, before considering how the spectrum of genes expressed in the hippocampal formation may cast light on the involvement of the hippocampus in other processes. (In this paper, 'hippocampus' and 'hippocampal formation' are used interchangably to denote the juxtaposition of the fields of the cornu ammonis with the dentate gyrus.) Memory and the hippocampusThe hippocampus, located beneath the cerebral hemispheres, resembles a large 'wishbone' (the curved Y-shaped bone in the chicken neck), but takes its name from the appearance of its arms in cross-section -the interlocking double-U formed by the tightly aligned cell bodies of ammon's horn (cornu ammonis) and the dentate gyrus -reminiscent of the shape of Hippocampus spp. ( Fig. 1; for detailed reviews of hippocampal structure see Amaral 1987, Amaral & Witter 1989. Memory problems in a patient with limbic damage (i.e. at the edge of the forebrain) were first recorded in 1898; another 60 years elapsed be...

Steroids produced locally in brain (neurosteroids), including dehydroepiandrosterone (DHEA), inf luence cognition and behavior. We previously described a novel cytochrome P450, Cyp7b, strongly expressed in rat and mouse brain, particularly in hippocampus. Cyp7b is most similar to steroidogenic P450s and potentially could play a role in neurosteroid metabolism. To examine the catalytic activity of the enzyme mouse Cyp7b cDNA was introduced into a vaccinia virus vector. Extracts from cells infected with the recombinant showed NADPH-dependent conversion of DHEA (K m , 13.6 M) and pregnenolone (K m , 4.0 M) to slower migrating forms on thin layer chromatography. The expressed enzyme was less active against 25-hydroxycholesterol, 17␤-estradiol and 5␣-androstane-3␤,17␤-diol, with low to undetectable activity against progesterone, corticosterone, and testosterone. On gas chromatography and mass spectrometry of the Cyp7b metabolite of DHEA the retention time and fragmentation patterns were identical to those obtained with authentic 7␣-hydroxy DHEA. The reaction product also comigrated on thin layer chromatography with 7␣-hydroxy DHEA but not with 7␤-hydroxy DHEA; when [7␣-3 H]pregnenolone was incubated with Cyp7b extracts the extent of release of radioactivity into the medium suggested that hydroxylation was preferentially at the 7␣ position. Brain extracts also efficiently liberated tritium from [7␣-3 H]pregnenolone and converted DHEA to a product with a chromatographic mobility indistinguishable from 7␣-hydroxy DHEA. We conclude that Cyp7b is a 7␣-hydroxylase participating in the synthesis, in brain, of neurosteroids 7␣-hydroxy DHEA, and 7␣-hydroxy pregnenolone.