Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.

Six new ellagitannins, phyllanemblinins A-F (1-6), were isolated from Phyllanthus emblica, along with 30 known tannins and related compounds. Their structures were determined by spectral and chemical methods. Phyllanemblinins A (1) and B (2) were confirmed to be ellagitannins having a tetrahydroxybenzofuran dicarboxyl group and a hexahydroxydiphenoyl group, respectively, by chemical synthesis from furosin (8). Phyllanemblinin C (3) has a new acyl group at the glucose 2,4-positions and is structurally related to chebulagic acid. Phyllanemblinins D (4), E (5), and F (6) were found to be positional isomers of neochebuloyl 1(beta)-O-galloylglucose.

The recurrent nerve nodes and perigastric nodes are the principal proximal regional lymph nodes involved in superficial carcinoma of the thoracic oesophagus. Systematic lymph node dissection, which included these nodes, yielded an acceptable and favourable outcome in patients with node-positive superficial carcinoma.

CS-023 (RO4908463, formerly R-115685) is a novel 1␤-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), ␤-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa. CS-023 showed the most potent activity among the compounds tested against P. aeruginosa and MRSA, with MICs at which 90% of isolates tested were inhibited of 4 g/ml and 8 g/ml, respectively. CS-023 was stable against hydrolysis by the ␤-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum ␤-lactamase-producing Escherichia coli. The in vivo efficacy of CS-023 was evaluated with a murine systemic infection model induced by 13 strains of gram-positive and -negative pathogens and a lung infection model induced by 2 strains of PRSP (serotypes 6 and 19). Against the systemic infections with PRSP, MRSA, and P. aeruginosa and the lung infections, the efficacy of CS-023 was comparable to those of imipenem/cilastatin and vancomycin (tested against lung infections only) and superior to those of meropenem, ceftriaxone, and ceftazidime (tested against P. aeruginosa infections only). These results suggest that CS-023 has potential for the treatment of nosocomial bacterial infections by gram-positive and -negative pathogens, including MRSA and P. aeruginosa.

Menkes' disease is an X-linked recessive disorder charaaerized by accumulation of copper in various organs and cells, such as the intestine, kidney, and cultured fibroblasts. Light and electron microscopic localization of Cu was investigated in the intestine and kidney ofmacular mice, an animal model of Menkes' disease, by a modified dide-silver method. Cu was accumulated in the cytoplasm of the absorptive epithelial cells, the vascular endothelium, and secretory granules of the Paneth cells. In kidney the distal tubule cells and glomeruli of both macular and control mice stained faintly, whereas the organelle-free cytoplasm in the proximal tubule

Phyllanthus emblica L. (Euphorbiaceae) is a shrub or tree native to subtropical and tropical areas of China, India, Indonesia and the Malay Peninsula. The fruit has been widely used for antiinflammatory and antipyretic treatment. The root, leaves and bark are also used for the treatment of indigestion, diarrhea or dysentery, eczema and wart. As a continuation of investigation on the constituents of this plant,

Neuropeptide B/W receptor 1 (NPBWR1) is a G-protein coupled receptor, which was initially reported as an orphan receptor, and whose ligands were identified by this and other groups in 2002 and 2003. To examine the physiological roles of NPBWR1, we examined phenotype of Npbwr1 −/− mice. When presented with an intruder mouse, Npbwr1 −/− mice showed impulsive contact with the strange mice, produced more intense approaches toward them, and had longer contact and chasing time along with greater and sustained elevation of heart rate and blood pressure compared to wild type mice. Npbwr1 −/− mice also showed increased autonomic and neuroendocrine responses to physical stress, suggesting that impairment of NPBWR1 leads to stress vulnerability. We also observed that these mice show abnormality in the contextual fear conditioning test. These data suggest that NPBWR1 plays a critical role in limbic system function and stress responses. Histological and electrophysiological studies showed that NPBWR1 acts as an inhibitory regulator on a subpopulation of GABAergic neurons in the lateral division of the CeA and terminates stress responses. These findings suggest important roles of NPBWR1 in regulating amygdala function during physical and social stress.

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