Afferent connections of the corpus cerebelli in holocentrid teleosts

The holocentrid corpus cerebelli (CC) is composed of the dorsal (CCd) and ventral (CCv) lobes. In the present study, afferent connections of the CCd and CCv in holocentrid teleosts (Sargocentron rubrum and S. diadema) were examined by means of tract-tracing methods. Tracer injections into either lobe of the CC labeled neurons in the ipsilateral area pretectalis pars anterior et posterior, nucleus paracommissuralis (NPC), nucleus accessorius opticus and nucleus tegmentocerebellaris. Labeled neurons were also present in the bilateral nucleus lateralis valvulae (NLV), nucleus raphes, nucleus reticularis lateralis and inferior reticular formation, and in the contralateral inferior olive. Injections into the CCd labeled only a few neurons in the area pretectalis pars anterior et posterior, nucleus accessorius opticus and nucleus tegmentocerebellaris, whereas many labeled cells were seen in these nuclei after CCv injections. Injections into the CCv also revealed afferent connections that were not observed after CCd injections. The CCv injections labeled additional neurons in the ipsilateral torus longitudinalis and nucleus subeminentialis and in the bilateral nucleus subvalvularis and nucleus of the commissure of Wallenberg. These differences in afferent connections suggest functional differences between the CCd and CCv. After injections into the CCd, labeled neurons in the NPC were restricted to a medial portion of the nucleus. On the other hand, after injections into the CCv, labeled neurons were found throughout the NPC. Labeled neurons in the NLV were mainly located in its rostral portion following CCd injections, whereas labeled neurons were mainly distributed in the medial portion following CCv injections. These observations suggest topographical organizations of the NPC-CC and NLV-CC projections.     

Fiber connections of the lateral valvular nucleus in a percomorph teleost, tilapia (Oreochromis niloticus)

Fiber connections of the lateral valvular nucleus were investigated in a percomorph teleost, the tilapia (Oreochromis niloticus), by tract-tracing methods. Following tracer injections into the lateral valvular nucleus, neurons were labeled in the ipsilateral dorsal part of dorsal telencephalic area, corpus glomerulosum pars anterior, dorsomedial thalamic nucleus, central nucleus of the inferior lobe, mammillary body, semicircular torus, valvular and cerebellar corpus, in the bilateral rostral regions of the central part of dorsal telencephalic area, dorsal region of the medial part of dorsal telencephalic area, habenula, anterior tuberal nucleus, posterior tuberal nucleus, and spinal cord, and in the contralateral lateral funicular nucleus. Labeled fibers and terminals were found in the ipsilateral cerebellar corpus and bilateral valvula of the cerebellum. Tracers were injected into portions of the telencephalon, pretectum, inferior lobe, and cerebellum to confirm reciprocally connections with the lateral valvular nucleus and to determine afferent terminal morphology in the lateral valvular nucleus. Telencephalic fibers terminated mainly in a dorsolateral portion of the lateral valvular nucleus. Terminals from the corpus glomerulosum pars anterior, central nucleus of the inferior lobe, and mammillary body showed more diffuse distributions and were not confined to particular portions of the lateral valvular nucleus. Labeled terminals in the lateral valvular nucleus were cup-shaped or of beaded morphology. These results indicate that the lateral valvular nucleus receives projections from various sources including the telencephalon, pretectum, and inferior lobe to relay information to the valvular and cerebellar corpus. In addition, the corpus glomerulosum pars anterior in tilapia is considered to be homologous to the magnocellular part of superficial pretectal nucleus in cyprinids.     

Lipid-lowering properties of TAK-475, a squalene synthase inhibitor,in vivo and in vitro

1. Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. 2. TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED(50), 2.9 mg kg(-1)) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3. In marmosets, TAK-475 (30, 100 mg kg(-1), p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg(-1), p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. 4. TAK-475 (60 mg kg(-1), p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. 5. In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of (125)I-low-density lipoprotein (LDL) to LDL receptors. 6. These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia.     

Lipid-lowering effects of TAK-475, a squalene synthase inhibitor,in animal models of familial hypercholesterolemia

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.     

Neo-adjuvant chemotherapy with UFT and adriamycin in head and neck cancer

Thirty-one patients with head and neck cancer were administered pretreatment induction chemotherapy (so-called neo-adjuvant chemotherapy) consisting of a UFT and ADM combination. The chemotherapy consisted of ADM (0.5 mg/kg b.w.) once a week up to 3 times, and UFT (600 mg/day) every day for 20 days. Overall response rate was 37.9% (11/31), and 1 CR and 10 PR were obtained. After definitive treatment, the primary control rate was 80.6% (25/31). Sixteen primary lesions in the 31 patients were classified according to Shimosato's grading system into 1 grade IV, 5 grade III and 10 grade II b a-I. Lymph-node metastases in 5 cases were also classified. The grading of lymph-node metastases was lower than that of the primary lesions.     

A case of tracheal benign mixed tumor]

A 44-year-old male was admitted because of dyspnea. Bronchoscopy revealed a tumor obstructing 85% of the tracheal lumen, at the site of the membranous portion, 3 cm below the vocal cords. The tumor was removed by sleeve tracheal resection with end to end anastomosis. Histological findings showed benign mixed tumor (pleomorphic adenoma) arising from the tracheal wall. Postoperative course was uneventful. Only 5 tracheal mixed tumors have been found in the Japanese literatures. Therapeutic approach to this tracheal tumor is discussed in this paper.     

Effect of brain natriuretic peptide on cyclic GMP accumulation in a kidney epithelial cell line (LLC-PK1)

The effect of porcine brain natriuretic peptide (pBNP) on cyclic GMP accumulation was studied in the kidney epithelial cell line, LLC-PK1. The addition of pBNP to the LLC-PK1 cells produced a time- and concentration-dependent increase in cyclic GMP accumulation and this effect was equipotent to that of alpha-human atrial natriuretic peptide (alpha-hANP). The simultaneous addition of pBNP and alpha-hANP at the maximal effective concentration of 10(-6) M did not have an additive effect on the cyclic GMP contents. The findings suggest that pBNP and alpha-hANP may share the same receptor in the LLC-PK1 cells.