Retionic acid and its receptors are required for expression of aryl hydrocarbon receptor mRNA and embryonic development of blood vessel and bone in the medaka fish, Oryzias latipes.

Retinoic acid (RA), the active derivative of vitamin A, is essential for normal embryonic development of vertebrates because both the lack and excess of RA result in developmental malformations. We previously reported that aryl hydrocarbon receptor (AHR) is also required for vascular and bone formation by regulating cytochrome P450 expression. However, little is known about the roles of retinoic acid receptors (RAR) and retinoid X receptors (RXR) in the embryonic development of blood vessels and molecular cross-talk between RAR/RXR and AHR. We report for the first time that RA and RAR/RXR are required for expression of AHR mRNA and the embryonic development of blood vessel and bone. The embryonic organogenesis of medaka fish was specifically inhibited by an inhibitor of RA synthesis (diethylaminobenzaldehyde), antagonists of RAR (Ro41-5253) and RXR (Ro71-4595), agonist (beta-naphthoflavone) and antagonist (alpha-naphthoflavone) of AHR, and excess RA. These reagents are useful for future studies to elucidate molecular mechanisms for vascular and bone formation in the medaka embryogenesis. Our results also show that medaka embryos may be useful for screening inhibitors of vascular formation for anti-cancer drugs.

The effects of combination therapy with niceritrol and pravastatin on hyperlipidaemia.

In the present study, we evaluated the effects of combination therapy with niceritrol and pravastatin in patients with hyperlipidaemia. A total of 62 patients with hyperlipidaemia, defined as total cholesterol levels above 220 mg/dl or triglyceride levels above 150 mg/dl, were recruited. Patients were divided into two groups: Group N received initial therapy with niceritrol 750-1500 mg/day, and those in Group P, pravastatin 10 mg/day. After 8 weeks, pravastatin 10 mg/day was added to the Group N treatment regimen for a further 8 weeks, while patients in Group P were given niceritrol 750-1500 mg/day in addition to pravastatin for 8 weeks. After the 8-week combination therapy study period, total cholesterol levels were 209.6 mg/dl in Group N and 220.7 mg/dl in Group P. Decreased triglyceride and lipoprotein(a) levels and increased high-density lipoprotein cholesterol levels, neither of which were achieved by pravastatin administration alone, were achieved with the combination of pravastatin and niceritrol. We conclude that when a single lipid-lowering drug fails to show therapeutic value, attempting combination therapy with a nicotinic acid preparation and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) is worthwhile.

Estrogen inhibits development of yolk veins and causes blood clotting in transgenic medaka fish overexpressing estrogen receptor.

We established three transgenic medaka fish lines overexpressing the medaka estrogen receptor under the constitutive medaka beta-actin promoter. The transgenic embryos became hypersensitive to estrogens (17 beta-estradiol and 17alpha-ethinylestradiol), and failed to develop yolk veins while blood clots formed in the blood island within 3 days after exposure to the estrogens. The embryos developed normally if exposed to estrogen after an early neurula stage, suggesting that the sensitive stage is before neurulation. The developmental defects were recovered by incubation with an anti-estrogen, tamoxifen. These results indicate that activation of estrogen receptor caused the estrogen-induced developmental defects. Our results show that the transgenic embryos can be used to assay the blood clotting activity of estrogenic compounds in vivo.

Doxazosin, an alpha1-adrenergic antihypertensive agent, decreases serum oxidized LDL.

Oxidized low-density lipoprotein (ox-LDL) is well known to play an important role in atherogenesis through the recruitment of monocytes into vessel walls and the deposition of cholesterol ester in the macrophages, which leads to the formation of lipid-rich plaque. It was assumed that only trace amounts of ox-LDL were present in plasma because the half-life of ox-LDL was only a few minutes. Recently, through the use of a monoclonal antibody against ox-LDL, a quantitative method to measure serum ox-LDL concentration has been developed. Metabolites of doxazosin, an alpha1-adrenergic antihypertensive agent, have been reported to inhibit oxidation of LDL in vitro. In this study, we investigated the in vivo effect of doxazosin on LDL oxidation using this new method to measure serum ox-LDL concentration. After the administration of doxazosin for 1 to 2 months, serum concentration of ox-LDL decreased significantly (P < .05). Although the reduction of ox-LDL concentration does not strictly indicate doxazosin's antiatherosclerotic effect, it may constitute one of doxazosin's additional weapons beside lowering blood pressure and serum lipid values in the prevention of atherosclerosis.

[Proliferative vitreoretinopathy treated with daunorubicin].

Nine eyes with severe proliferative vitreoretinopathy underwent vitrectomy and infusion of Daunorubicin to prevent reproliferation. In 5 eyes (56%) the retina was reattached. In 4 eyes redetachment occurred because of reproliferation or incomplete sealing of the break. After a second vitrectomy, complete reattachment of the retina was obtained eventually in all eyes including one eye with silicone oil tamponade. As postoperative complications, conjunctival dehiscience occurred in 3 eyes. In two of the 3 eyes scleral buckling occurred, and orbital cellulitis occurred in one eye. Daunorubicin seemed to be effective to suppress reproliferation, but care should be taken to avoid postoperative complications.