Structural organization of the mouse metabotropic glutamate receptor subtype 3 gene and its regulation by growth factors in cultured cortical astrocytes.

Metabotropic glutamate receptors (mGluRs) belong to the class of G protein-coupled receptors and consist of eight different subtypes. We have characterized the structural organization of the mouse mGluR3 gene by genomic cloning in combination with rapid amplification of 5'- and 3'-cDNA ends and examined regulatory expression of mGluR3 mRNA in cultured cortical astrocytes. The mGluR3 gene consists of six exons and spans over 95 kb. Exon 1 and its preceding putative promoter are located distantly from the following protein-coding region. In the mGluR family, mGluR3 and mGluR5 are both expressed in neuronal and glial cells and are upregulated during the early postnatal period. They are, however, coupled to two distinct signaling cascades and have been shown to exert opposite influences on some functions of cultured astrocytes. In cultured astrocytes, mGluR3 and mGluR5 mRNA levels were significantly increased by exposure to epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or transforming growth factor-alpha; and EGF was more efficacious than bFGF in producing this increase. Hence, mGluR3 and mGluR5 mRNAs are concertedly upregulated in cultured astrocytes by specific growth factors. This finding suggests that the two mGluR subtypes may play an important role in maintaining the proper balance of astrocyte functions via two distinct signal transduction mechanisms.

[Report of three cases of emergency operation for acute pulmonary embolism].

Three successful surgical cases of acute pulmonary embolism with severe cardiopulmonary impairment were reported. Currently, thrombolysis is widely accepted as the front-line treatment for most patients with pulmonary embolism. However, treatment failure is high and can lead to death in the most severe cases. If these patients have severe cardiopulmonary impairment, pulmonary embolectomy should be done immediately.

Potent inhibitors of acyl-CoA:cholesterol acyltransferase. 2. Structure-activity relationships of novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amides.

Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compounds, N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent ACAT inhibitory activity. The synthesis and structure-activity relationships of these compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl) amides, lipophilicity of the acyl moiety was necessary for the potent ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2- dimethyldodecanamide (10) and 6-(4-chlorophenoxy)-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-y l)-2,2-dimethyloctanamide (50) showed potent activity. Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety resulted in highly potent activity. The most potent compound, N-[5-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl ]-2,2-dimethyldodecanamide (13, TEI-6620), showed highly potent ACAT inhibitory activity (rabbit small intestine IC50 = 0.020 microM, rabbit liver IC50 = 0.009 microM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 0.030 microM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (Cmax = 2.68 microg/mL at 1 h, 10 mg/kg po).

The effect of a synthetic 7-thiaprostaglandin E1 derivative, TEI-6122, on monocyte chemoattractant protein-1 induced chemotaxis in THP-1 cells.

1 The ability of various prostaglandins (PGs) to inhibit monocyte chemotaxis induced by monocyte chemoattractant protein-1 (MCP-1) was investigated with a human monocytic leukaemia cell line, THP-1. Moreover, to investigate the mechanism of the inhibitory action of PGs the involvement of either intracellular adenosine 3': 5'-cyclic monosphosphate (cyclic AMP) accumulation or intracellular Ca2+ mobilization was studied. 2 TEI-6122, a synthetic 7-thia-PGE1 derivative, inhibited chemotaxis of THP-1 cells induced by MCP-1 with an IC50 of 1.5 pM. Its inhibitory activity was 1000 fold more than that of PGE1 and PGE2 (IC50 = 2.8 nM and 0.9 nM, respectively), which were more potent than other PGs such as PGA1, PGA2, PGF2 alpha and PGI2 (IC50 > or = 1 microM). 3 With respect to the effect on intracellular cyclic AMP accumulation in THP-1 cells, TEI-6122 was as potent as PGE1 and PGE2, which were approximately 100 to 1000 fold more potent than the other PGs such as PGA1, PGA2 and PGI2. The minimum concentration of TEI-6122 required to increase intracellular cyclic AMP accumulation in THP-1 cells was 1 nM. 4 TEI-6122 and PGE1 (4 microM) transiently increased intracellular calcium levels in THP-1 cells. When added prior to MCP-1, both PGs partially suppressed the increased in Ca2+ caused by this cytokine. There were no significant differences between the activity of TEI-6122 and PGE1 in either respect. 5 It is concluded that TEI-6122, a synthetic 7-thia-PGE1 derivative is a much more potent inhibitor of MCP-1-induced THP-1 cell chemotaxis than PGEI and PGE2 which are the best inhibitors among the natural PGs tested, while neither intracellular cyclic AMP accumulation nor effects on Ca2+ mobilization account for the extremely potent inhibitory activity of TEI-6122. Thus, either a novel PGE2 receptor (EPreceptor) or a novel intracellular signal transduction system may be involved in the extremely potent chemotaxis inhibitory activity of TEI-6122.

Spontaneous non-traumatic rupture of the thoracic aorta.

Spontaneous non-traumatic rupture of the aorta is a very rare condition that requires immediate surgery. However, correct preoperative diagnosis is difficult or impossible to establish. We report a case of spontaneous aortic rupture which was successfully treated by emergency surgical exploration following a transesophageal echographic diagnosis of hemopericardium. This case, as well as other reports, suggests that hemopericardium along with symptoms which suggest aortic dissection or rupture (e.g., acute chest or back pain) should raise a strong suspicion of spontaneous aortic rupture even in the absence of intimal flap or aortic dilatation, and the emergency surgery may be life-saving.

Tooth-based age estimation of an adipocerated cadaver using the amino acid racemization method.

We attempted to estimate the age of a completely adipocerated unidentified body using the aspartic acid racemization reaction (racemization method). The material used to make the estimate consisted of two teeth, the right and left lower first premolars, and for comparison five lower first premolars from persons of known age were used. From testing of the specimen teeth, it was estimated that age at the time of death was 39 +/- 3 years. Later, the body was identified as that of a woman who had been murdered 6 years before at the age of 41 years, and it was possible to estimate almost precisely her age at the time of death. It was clarified that the dentin racemization reaction hardly proceeds even when the body adipocerates, under conditions in which normal tooth color and hardness are maintained.