Influence of Carisolv for resin adhesion to sound human primary dentin and young permanent dentin.

OBJECTIVE: This study evaluated the influence of Carisolv (Medi Team) for resin adhesion to sound human primary and young permanent dentin. METHOD: The buccal surfaces of 64 primary molars and 74 premolars were used. Two adhesive systems and resin composites were used; SD: Super-Bond D Liner DUAL (Sun Medical) and Clearfil Photo Anterior(Kuraray), and FB: Imperva Fluorobond and Lite-Fil IIA (Shofu). Ten groups were prepared. Groups 1-5 were primary dentin and Groups 6-10 were permanent dentin. Groups 1 and 6: Carisolv applied and agitated for 3min, SD was used. Groups 2 and 7: etched with 10-3 solution (Sun Medical) for 10s, SD was used. Groups 3 and 8: treated with Carisolv and then etched, SD was used. Groups 4 and 9: treated with Carisolv, FB was used. Groups 5 and 10: FB was used. The microstructural effects of Carisolv, 10-3 solution and Carisolv plus 10-3 solution applied to dentin were evaluated by SEM. In addition, the microstructure of the resin-dentin interfaces of each group were studied using SEM. Shear bond strengths (SBS) were tested, and the failed surfaces were observed using SEM. Data was statistically analyzed using ANOVA with subsequent application of post hoc Duncan's new multiple range test at p<0.05. RESULTS: The effect of Carisolv on primary dentin was stronger than that to permanent dentin. The mean SBS (unit:MPa) of Groups 1-10 were: 5.6, 15.8, 7.6, 17.5, 13.5, 8.1, 16.2, 18.2, 31.4 and 15.5. The SBS of Group 9 (Carisolv treated permanent dentin) was significantly higher than those of other groups. There was no significant difference of SBS among Groups 2, 4, 5, 7, 8 and 10, Groups 3, 5 and 6, and Groups 1, 3 and 6. SIGNIFICANCE: Carisolv treatment before etching significantly decreased the SBS to primary dentin in SD groups, but significantly increased the SBS to permanent dentin in FB groups.

GD3 synthase gene expression in PC12 cells results in the continuous activation of TrkA and ERK1/2 and enhanced proliferation.

A rat pheochromocytoma cell line (PC12) transfected with ganglioside GD3 synthase gene showed a marked change in the ganglioside profile and enhanced proliferation and no response of neurite extension to nerve growth factor (NGF) stimulation. In these transfectant cells, a continuous phosphorylation of TrkA and the activation of ERK1/2 without NGF treatment were observed. Proliferation inhibition experiments with kinase inhibitors such as herbimycin A, K-252a, and PD98059 revealed that the enhanced proliferation was actually due to the activation of the Ras/MEK/ERK pathway. A TrkA dimer was detected in the GD3 synthase transfectant cells regardless of NGF treatment by cross-linking and immunoblotting. The increased expression of GD1b and GT1b in these transfectant cells might induce the conformational change of TrkA to form a dimer and to be activated continuously. These results may indicate regulatory roles of gangliosides in cell proliferation under physiological and malignant processes.

Central selective acetylcholinesterase inhibitor with neurotrophic activity: structure-activity relationships of TAK-147 and related compounds.

A series of benzylamino inhibitors of acetylcholinesterase (AChE) have been designed based on a working hypothesis of the enzyme s active site. These compounds were tested for their inhibitory activities on AChE and potent inhibitors were further evaluated in terms of central selectivity. These studies led to a discovery of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4, 5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147). Pharmacokinetic study has shown that the compound has high central selectivity, as demonstrated by rapid elimination from plasma and long-term existence in the brain. As a consequence, TAK-147 ameliorates impairments of learning and memory in various animal models without producing peripheral side effects. TAK-147 also activates the monoaminergic systems and energy metabolism. Furthermore, TAK-147 was revealed to have NGF-like neurotrophic activity on central cholinergic neurons at concentrations where it inhibits AChE activity. Therefore, TAK-147 is expected not only to ameliorate the clinical symptoms in Alzheimer s disease via AChE inhibition but to prevent or slow the progression of the disease via its neurotrophic action. TAK-147 is now under clinical trial as a therapeutic drug for Alzheimer s disease. This article reviews design and structure-activity relationships of TAK-147 and related compounds. Preclinical pharmacology of TAK-147 is also summarized.

Synthesis of [11C] coenzyme Q-related compounds for in vivo estimation of mitochondrial electron transduction and redox state in brain.

We have studied the synthesis of [11C]2,3-dimethoxy-5-methyl-6-(10-hydroxy)-decyl-1,4-benzoquinone (idebenone) and [11C]2,3-dimethoxy-5-methyl-1,4-benzoquinone (CoQo) by methylation of their respective desmethyl precursors using [11C]CH3I for in vivo measurement of mitochondrial electron transfer and redox state. The [11C]idebenone was more lipophilic than [11C]CoQo; the latter became hydrophilic by reduction. Clearance of [11C]idebenone from mouse brain was more rapid than that of [11C]CoQo. The results indicated that modification of the isoprenoid side chain in [11C]CoQ is necessary to develop more suitable radiopharmaceuticals.

Expression cloning of mouse cDNA of CMP-NeuAc:Lactosylceramide alpha2,3-sialyltransferase, an enzyme that initiates the synthesis of gangliosides.

Expression cloning of a cDNA for the alpha2,3-sialyltransferase (GM3 synthase) (EC 2.4.99.-) gene was performed using a GM3-lacking mouse fibroblast line L cell and anti-GM3 monoclonal antibody. Plasmids from a cDNA library generated with poly(A)+ RNA of a mouse fibrosarcoma line CMS5j and pdl3027 (polyoma T antigen) were co-transfected into L cells. The isolated cDNA clone pM3T-7 predicted a type II membrane protein with 13 amino acids of cytoplasmic domain, 17 amino acids of transmembrane region, and a large catalytic domain with 329 amino acids. Introduction of the cDNA clone into L cells resulted in the neo-synthesis of GM3 and high activity of alpha2,3-sialyltransferase. Among glycosphingolipids, only lactosylceramide showed significant activity as an acceptor, indicating that this gene product is a sialyltransferase specific for the synthesis of GM3. An amino acid sequence deduced from the cloned cDNA showed the typical sialyl motif with common features among alpha2,3-sialyltransferases. Among various mouse tissues, brain, liver, and testis showed relatively high expression of a 2.3-kilobase mRNA, whereas all tissues, more or less, expressed this gene.

Transposition of mesial and distal aspects of maxillary first molars: case report.

Congenital absence of one or more teeth, hypodontia, is the most common developmental anomaly and is often accompanied by the presence of other tooth anomalies. In this case two Japanese sisters have several congenitally missing primary and permanent teeth and morphological abnormalities of maxillary first molars. One sister has transposition of mesial and distal aspects of a maxillary first molar, whose cusps display a normal shape. Another sister has maxillary first molars, which look like maxillary second molars. Mesio-distally shift of teeth is a very rare anomaly making this particular case important to analyze the teeth formation and development.

Goldenhar syndrome associated with various cardiovascular malformations.

This report presents a 54-year-old woman with Goldenhar syndrome featuring an epibulbar dermoid, left microtia and a left preauricular appendage, and synostosis of the vertebrae. Multiple cardiovascular malformations including Wolff-Parkinson-White syndrome, a partial anomalous pulmonary venous connection, patent ductus arteriosus, an anomalous origin of the coronary arteries, and a right-sided descending aorta were revealed by electrocardiography, echocardiography and cardiac catheterization. Goldenhar syndrome is very rare, but the frequency of cardiovascular malformations in this syndrome is 5-58%. It is necessary to perform a careful evaluation of general malformations, especially cardiovascular malformations.

Neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-b enzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase inhibitor, in rats.

We examined the neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzaze pin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase (AChE) inhibitor in vitro and in vivo. TAK-147 showed a potent and reversible inhibition of AChE activity in homogenates of the rat cerebral cortex (IC50 = 51.2 nM), and was 3.0- and 2.4-fold more potent than tacrine and physostigmine, respectively. By contrast, TAK-147 was the least potent inhibitor of butyrylcholinesterase activity in rat plasma (IC50 = 23,500 nM). Tacrine and physostigmine inhibited butyrylcholinesterase activity potently and nonselectively. TAK-147 showed a moderate inhibition of muscarinic M1 and M2 receptor binding with K(i) values of 234 and 340 nM, respectively. TAK-147 showed very weak or no inhibition of high-affinity choline uptake, nicotinic receptor binding and choline acetyltransferase activity. In ex vivo experiments, oral administration of TAK-147 at doses ranging from 1 to 10 mg/kg induced a statistically significant and dose-dependent decrease in AChE activity in the cerebral cortex. Of the monoaminergic systems, TAK-147 moderately inhibited uptake of noradrenaline and serotonin with IC50 values of 4020 and 1350 nM, respectively. TAK-147 also inhibited ligand binding at alpha-1, alpha-2 and serotonin 2 receptors with K(i) values of 324, 2330 and 3510 nM, respectively, whereas it showed only weak activities on D1, D2 and serotonin 1A receptor bindings. Oral administration of TAK-147 (3 mg/kg) significantly accelerated the turnover rates of dopamine, noradrenaline and serotonin in the rat brain. These results suggest that TAK-147 activates the central cholinergic system by specific inhibition of AChE activity without affecting peripheral butyrylcholinesterase activity, and that TAK-147 also moderately activates the monoaminergic systems.

Comparison of two dentin adhesives to primary vs. permanent bovine dentin.

The purpose of this study was to compare the shear bond strengths of two adhesive systems to the primary and permanent dentin. Labial surfaces of extracted and frozen bovine mandibular primary incisors and permanent incisors were ground with #600 grit SiC paper to expose dentin. Bisco Dental Products All Bond 2 (Group AB2) or Sunmedical Co. Superbond D Liner (Group SDL) tooth surface conditioner and adhesive were applied and bonded with resin composite. A shear bond strength (SBS) test was performed and the data were analyzed by an ANOVA (P < 0.05). After the SBS test, the test surfaces of the dentin and the resin were observed using SEM. SBS on the primary dentin were significantly higher than those on the permanent dentin, both in the nonthermal cycled groups and the thermal cycled groups with the exception of the thermal cycled group of Group SDL. In the thermal cycled group of Group SDL, there was no significant difference between SBS on the primary dentin and SBS on the permanent dentin. Bond strengths on the primary dentin were found to be significantly higher than those on the permanent dentin, when using All Bond 2 or Superbond D Liner adhesive systems.

Genetic remodeling of gangliosides resulted in the enhanced reactions to the foreign substances in skin.

Several lines of transgenic mice with gangliosides GM2/GD2 synthase gene were established, and the expression levels of the transgene in brain, liver, spleen and thymus were analyzed by comparing with those in their litter mates. Among four tissues, brain and skin showed markedly high expression levels of the transgene in Northern blotting. Particularly, transgenic mice skin showed about 10-fold higher expression of GM2/GD2 synthase gene than the wild type mice skin. Therefore, alterations in the morphology, glycolipid components, and responses to the exogenous stimulations in the transgenic mice skin were examined. Gangliosides in the transgenic skin were dramatically converted from GM3 to GM1, whereas no morphological changes were observed. However, when skin flap test was performed with insertion of nylon membranes under the skin flaps, much stronger inflammatory reactions consisting of edema, marked thickness, and cell infiltration were observed in the transgenic mice compared with the wild type. Similar enhanced inflammatory reaction was also observed in the skin injected by silicon gel, and in the peritoneal reaction to the injected casein. Main cell population in these inflammatory reactions consisted of neutrophils, suggesting an increased sensitivity of neutrophils to chemotactic factors in the transgenic mice.

Effect of TAK-147, a novel AChE inhibitor, on cerebral energy metabolism.

Effect of TAK-147, a novel acetylcholinesterase (AChE) inhibitor, on cerebral energy metabolism was investigated using an in vivo 31P-magnetic resonance spectroscopy (31P-MRS) technique and the autoradiographic 2-deoxy-[14C]-D-glucose method in aged Fischer 344 rats. We revealed that high-energy phosphate metabolites, phosphocreatine (PCr) and ATP, in the brain decreased gradually with aging and that significant decrement of cerebral PCr and ATP was observed from 13- and 8.5-month-old in comparison with those of 2.5-month-old rats, respectively. Daily oral administration of TAK-147 (1 mg/kg) for 40 days increased PCr and ATP levels in aged rats (29-month-old). To determine the site at which TAK-147 acts to increase high-energy phosphate metabolism, we investigated the rate of local cerebral glucose utilization (LCGU) in various brain regions. The rate of LCGU decreased in almost all brain regions in aged rats (28 months of age), and the decrease was significant in 29 out of the 35 regions. When TAK-147 was administered orally to the aged rats, the levels were dose dependently increased, especially in the auditory cortex. These results indicate that TAK-147 increases cerebral energy metabolism in aged rats.

Kinetic cavity preparation: protection of the cavo-surface enamel.

A significant defect of kinetic cavity preparation systems is damage to cavo-surface sound tooth enamel. The purpose of this study is to establish a protective method for cavo-surface sound tooth enamel during air-powder abrasive system cavity preparation, using protective varnish. A total of 39 extracted human primary teeth were used for this experiment. Protective varnish was applied to the tooth surface in single, double and triple coats. The kinetic instrument was used for cavity preparation. Class V cavities were prepared on the border area of varnish coated and intact tooth surface. After removal of varnish with a supersonic washer, specimens were dried and gold plated with ion-spatter, following which cavity margin enamel was observed through a SEM. Tooth surface enamel where coated with varnish appeared intact and the cavo-surface margin remained at a right angle form. However, tooth surface enamel without varnish coating appeared rough, and the cavo-surface margin exhibited a round shape. It seems likely that kinetic energy was absorbed by the soft varnish coating, thereby protecting the enamel. Protective varnish was found to provide a protective effect for cavo-surface sound enamel, and was also found to promote a sharp edge at the cavo-surface margin, during kinetic cavity preparation.

Effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1 -H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase inhibitor, on impaired learning and memory in animal models.

We examined the effects of p.o. administered 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-b enzazepin-8- yl)-1-propanone fumarate (TAK-147), a novel AChE inhibitor, on impaired learning and memory in animal models. At 1 to 3 mg/kg, TAK-147 ameliorated the passive avoidance deficit induced by diazepam. TAK-147 did not affect delayed-matching-to-position (DMTP) performance of normal rats at doses of 1 to 30 mg/kg assessed by using a three-lever operant chamber, but 9-amino-tetrahydroacridine disrupted the DMTP response at 5 to 20 mg/kg. Scopolamine (0.02-0.1 mg/kg s.c.) impaired DMTP performance, whereas methylscopolamine did not affect the DMTP task. TAK-147 ameliorated the impairment of DMTP performance induced by scopolamine without affecting the general behavior of the rats; however, 9-amino-tetrahydroacridine produced no significant amelioration of the impairment. The intraventricular injection of AF64A disrupted differential-reinforcement-of-low-rate 10-sec performance in rats, as demonstrated by marked decreases in reinforcement rate and response efficiency. TAK-147 slightly increased the reinforcement rate in AF64A-treated rats at a low dose of 1 mg/kg, but the effect was not significant statistically. TAK-147 had no significant effect on the duration of immobility in rats in a forced swimming test at doses of 2 to 10 mg/kg. 9-Amino-tetrahydroacridine prolonged the duration of immobility at 5 to 20 mg/kg. Furthermore, TAK-147 reversed reserpine-induced hypothermia and ptosis in mice at doses of 3 to 10 mg/kg, a result that implies an antidepressant-like action. These results indicate that TAK-147 ameliorates learning and memory impairment in animal models without affecting the general behavior or causing behavioral depression and suggest that TAK-147 may be useful for the treatment of Alzheimer's disease.

Study of cervical pulp horns in human primary molars.

This study confirmed that cervical pulp horns exist in human primary molars as the following results were found: 1. Fifteen cervical pulp horns were observed in the 40 extracted primary molars group (37.5%), 2. Ten cervical pulp horns were observed out of the 26 Indian primary molars group (38.5%), 3. Buccal extension of cervical pulp horns is 0.23 mm in the extracted primary molars group and 0.36 mm in the Indian primary molars group on average, 4. Cervical pulp horns of primary molars tend to be presented bilaterally in the same individual, 5. The percent of occurrence of cervical pulp horns in primary molars (37.6%, 38.5%) was lower than that of the permanent molar (77.1%).

Central cholinergic agents. 6. Synthesis and evaluation of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepi n-8-yl)-1-propanones and their analogs as central selective acetylcholinesterase inhibitors.

In an attempt to find central selective acetylcholinesterase (AChE) inhibitors, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1- benzazepin-8-yl)-1-propanones 9 and their analogs were designed on the basis of our working hypothesis of the enzyme's active site. These compounds were prepared by regioselective Friedel-Crafts acylation of 2,3,4,5-tetrahydro-1H-1-benzazepines and related nitrogen heterocycles as a key step. Most compounds showed potent inhibitory activities with IC50s in the 10-300 nM range. In order to estimate their central selectivities, we examined their effects on the apomorphine-induced circling behavior in rats with unilateral striatal lesions. Among compounds with potent AChE inhibition, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1- benzazepin-8-yl)-1-propanone fumarate (9a, TAK-147) (IC50 of AChE inhibition = 97.7 nM) inhibited the circling behavior at 3 mg/kg po, in which it had no significant effect on peripheral cholinergic effects. This demonstrates that 9a has favorable central selectivity. Furthermore, 9a significantly ameliorated diazepam-induced passive avoidance deficit at 1 mg/kg po. The benzazepine derivative 9a was selected as a candidate for clinical evaluation.

Central cholinergic agents. IV. Synthesis and acetylcholinesterase inhibitory activities of omega-[N-ethyl-N-(phenylmethyl)amino]-1-phenyl-1-alkanones and their analogues with partial conformational restriction.

Inhibitors of acetylcholinesterase (AChE) have been designed based on a working hypothesis of the enzyme's active site. These compounds were tested for their inhibitory activities on AChE and omega-[N-ethyl-N-(phenylmethyl)amino]-1-phenyl-1-alkanones (3) were found to be potent inhibitors. Various analogues of 3 were prepared to study the effect on AChE inhibition of partial restriction of conformation. Compounds with potent AChE inhibition were further evaluated in terms of central selectivity: the ratio of central action (ameliorating effect on scopolamine-induced memory impairment using a T-maze alternation task) to peripheral action.

Central cholinergic agents. III. Synthesis of 2-alkoxy-2,8- diazaspiro[4.5]decane-1,3-diones as muscarinic agonists.

A series of 2-alkoxy-2,8-diazaspiro[4.5]decane-1,3-diones and related compounds were synthesized and tested for muscarinic receptor binding affinity using [3H]pirenzepine and [3H]oxotremorine M as ligands. They were also evaluated for agonistic activities in the guinea pig ileum assay. 2-Methoxy- 2,8-diazaspiro[4.5]decane-1,3-dione (1i) was found to be a relatively M1 selective agonist. It reversed CO2-induced impairment of passive avoidance response with long duration of action, but also displayed peripheral effects at low doses. To minimize these side effects, we proposed the idea of conjugation of 1i with a muscarinic antagonist. The carbamate linked conjugate (1u) of 1i with methylatropine was therefore examined.

Resin adhesion to the ground primary enamel: influence of etching times and thermal cycling test.

The purpose of this study was to investigate the influence of etching times and thermal cycling on resin adhesion on ground primary enamel. Two hundred bovine mandibular primary incisors were used. Materials used in this study were 40% phospholic acid gel, Photo Bond and Photo Clearfil A (Kuraray Co., Kurashiki, Japan) in PCA groups and 37% phospholic acid gel, Scotch Bond and Silux (3M Co., St. Paul, MN) in the Silux groups. The etching times were 0, 10, 20, 30 and 60 seconds. Shear bond strengths were tested. After the shear bond strength test, the test surfaces of the enamel and the resin specimens were observed using the SEM. The etching times that showed the highest bond strengths were 30 seconds both in the PCA non-thermal cycled group (80.10 +/- 13.01 MPa) and the PCA thermal cycled group (78.99 +/- 10.93 MPa), 20 seconds in the Silux non-thermal cycled group (76.77 +/- 12.99 MPa) and 60 seconds in the Silux thermal cycled group (63.61 +/- 19.64 MPa). The influence of thermal cycling test to the enamel-resin adhesion is relatively slight both in the PCA group and the Silux group.