Role of implant configurations supporting three-unit fixed partial denture on mandibular bone response: biological-data-based finite element study.

Implant-supported fixed partial denture with cantilever extension can transfer the excessive load to the bone around implants and stress/strain concentration potentially leading to bone resorption. This study investigated the effects of implant configurations supporting three-unit fixed partial denture (FPD) on the stress and strain distribution in the peri-implant bone by combining clinically measured time-dependent loading data and finite element (FE) analysis. A 3-dimensional mandibular model was constructed based on computed tomography (CT) images. Four different configurations of implants supporting 3-unit FPDs, namely three implant-supported FPD, conventional three-unit bridge FPD, distal cantilever FPD and mesial cantilever FPD, were modelled. The FPDs were virtually inserted to the molar area in the mandibular FE models. The FPDs were loaded according to time-dependent in vivo-measured 3-dimensional loading data during chewing. The von Mises stress (VMS) and equivalent strain (EQS) in peri-implant bone regions were evaluated as mechanical stimuli. During the chewing cycles, the regions near implant necks and bottom apexes experienced high VMS and EQS than the middle regions in all implant-supported FPD configurations. Higher VMS and EQS values were also observed at the implant neck region adjacent to the cantilever extension in the cantilevered configurations. The patient-specific dynamic loading data and CT-based reconstruction of full 3D mandibular allowed us to model the biomechanical responses more realistically. The results provided data for clinical assessment of implant configuration to improve longevity and reliability of the implant-supported FPD restoration.

Structure-activity relationships for mitomycins. Application of the distance and charge analysis method.

Molecular orbital calculations based on coordinates from X-ray analysis have been performed for a set of 24 mitomycins, of which eight compounds have not been isolated so far. To prioritize the order of synthesis of these missing compounds, a new method named DISCA (distance and charge analysis) has been developed. DISCA screens correlations between spatial distribution of charge in molecules and their biological activity. The spatial distribution of charge is represented by several indexes in DISCA. LD50 and ED50 were used as measures of biological activity. DISCA has successfully extracted indexes which have significantly high correlation coefficients. The indexes with the highest correlation coefficient were common to both LD50 and ED50. By use of the correlation functions with high correlation coefficients DISCA has predicted that 9-epi-1a-N-demethylmitomycin D should have the best ED50 and a modest LD50 among the missing mitomycins.

5-HT3 receptor antagonists. 1. New quinoline derivatives.

A series of esters and amides of 1-alkyl-2-oxo-1,2-dihydroquinoline-4- carboxylic acid or 2-alkoxy-quinoline-4-carboxylic acid containing a basic azabicycloalkyl moiety has been synthesized and evaluated for affinity for the [3H]quipazine-labeled 5-HT3 receptors. Most of the esters exhibited 10-fold more potent activity than that of ondansetron (1; Ki = 7.6 nM). Lipophilic substituents at the 1- or 2-position of the quinoline ring enhanced affinity for the receptors. Compounds 21 and 37 showed the highest affinity (Ki = 0.32 and 0.31 nM, respectively) among them. On the other hand, most of the amides showed 100-fold lower affinity than that of the esters. Molecular modeling studies indicated that the carbonyl moiety in 19 (ester) or 31 (amide) was not coplanar to the plane of an aromatic ring (over 20 degrees deviation). Although some of the selected compounds exhibited potent activity in the Bezold-Jarisch (B-J) reflex test, good correlation was not observed between the affinity for the 5-HT3 receptors and the activity in the B-J reflex test (in vivo). From these data, it was suggested that our quinoline derivatives might interact with the 5-HT3 receptors in a different way from that of the reported 5-HT3 receptor antagonists presumably due to the presence of the heterogeneity of the 5-HT3 receptors between brain and heart.

Design and synthesis of potent antitumor 5,4'-diaminoflavone derivatives based on metabolic considerations.

Recently, we reported that 5,4'-diaminoflavone (1) exhibits potent and specific growth-inhibitory activity against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7. However, when compound 1 was incubated with S-9 mix, its metabolites were observed. Moreover, addition of S-9 mix to the medium caused the drastic decrease in activity of compound 1. Since the 6-, 8-, and 3'-positions were considered to be metabolized oxidatively in vivo from MO calculations, a series of 5,4'-diaminoflavone derivatives substituted at such putative metabolic positions with various functional groups were synthesized aiming at the metabolically stable derivatives. Among them, 5,4'-diamino-6,8,3'-trifluoroflavone (14d) exhibited strong growth-inhibitory activity against MCF-7 cells even in the presence of S-9 mix. Moreover, orally administered compound 14d completely suppressed the growth of MCF-7 inoculated into nude mice, and the effect was more potent than that of compound 1. In addition to ER-positive breast cancer cells, compound 14d exhibited growth-inhibitory activity against a panel of human cancer cell lines including a part of ER-negative breast, endometrial, ovarian, and liver cancers. From these results, fluorine introduction to the putative metabolic positions of compound 1 was elucidated to be effective in the enhancement of the in vivo antitumor activity, probably due to the block of the metabolic deactivation.

5-HT3 receptor antagonists. 2. 4-Hydroxy-3-quinolinecarboxylic acid derivatives.

A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromatic ring, but in 7 there was a 30 degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3- quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.1 micrograms/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: Ki = 0.48 nM) for the 5-HT3 receptors than ondansetron (Ki = 7.6 nM) or granisetron (Ki = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 micrograms/kg, iv) more potently than ondansetron (ED50 = 210 micrograms/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.

Behaviours of three-dimensional compressive and tensile forces exerted on a tooth during function.

The 3-D tensile and compressive forces exerted on a tooth were measured in vivo during function using a force-measuring device including a piezoelectric transducer. The device was mounted on the maxillary left second molar of a healthy male subject; the subject tooth had been endodontically treated and prepared for metal abutment and a crown. The 3-D forces were expressed as a vector of the coordinates based on the Frankfort horizontal (x-y) and sagittal (y-z) planes. The device captured the sequential changes in the forces. The directions of the forces changed during not only chewing a caramel or a peanut but also maximum voluntary clenching (MVC). As the magnitudes of the force increased during both MVC and caramel chewing (CaC), the force vector tended to correspond to the direction of the palatal root, medially and posteriorly. The compressive forces during MVC and caramel and peanut chewing were 173.29+/-15.32, 146.3+/-14.7 and 57.7+/-35.7 N, respectively. The force vector during MVC was directed from the crown to the root medially at an angle of 10.27+/-1.00 degrees from the y-z plane and posteriorly at an angle of 3.18+/-0.85 degrees from the x-z plane to the perpendicular line of the F-H plane. There were significant differences in the behaviour of the compressive forces between clenching and chewing. The tensile force was recorded during CaC, not peanut chewing.

Establishment of a rat hepatoma-derived cell line proliferating in D-phenylalanine medium and expressing D-amino-acid oxidase.

A cell line (R-Y121B.DF) has been established from a cell line (R-Y121B) derived from a rat hepatoma line (H4-II-E). The R-Y121B.DF cells have been continuously cultured in a serum-free modified Eagle's minimum essential medium in which L-phenylalanine was replaced by D-phenylalanine. They had D-amino-acid oxidase (DAO) activity which is essential for the growth in the medium containing D-amino acids. The enzyme activity of the R-Y121B.DF cells was approximately one-fourth of that of the rat liver. Northern hybridization using a DAO cDNA probe detected a hybridizing signal in the R-Y121B.DF cells and the rat liver but not in the parental R-Y121B and H4-II-E cells. Reverse transcription-polymerase chain reaction using DAO-specific primers amplified a DNA fragment of the expected size in the R-Y121B.DF cells but not in the R-Y121B and H4-II-E cells. This fragment was confirmed to be DAO cDNA by nucleotide sequencing. Western blotting showed that DAO protein was present in the R-Y121B.DF cells and the rat liver but not in the R-Y121B and H4-II-E cells. Southern hybridization showed that the DAO gene structure was not different among the R-Y121B.DF cells, R-Y121B cells, H4-II-E cells, and the rat liver. These results indicate that the R-Y121B.DF is a unique cell line which proliferates in the medium containing D-phenylalanine and explicitly expresses DAO. This line is useful for the study of DAO in vitro.

DNA strand scission by neocarzinostatin: molecular recognition process responsible for site-specificity.

A series of hexanucleotides possessing A-T, G-C, inosine (I)-C and 2-aminoadenine (ANH2)-T base pairs at 5'-side of the target thymine were prepared and their selectivity for C-5' and C4' oxidation in the NCS-mediated degradation was investigated. Quantitative product analysis indicated that preferential C5' oxidation of deoxyribose moiety of the target T occurs at -5'-AT- and 5'-IT- sites, whereas C5' and C4' oxidation occurs competitively at T of -5'-GT- and -5'-ANH2T- sites. Based on the experimental results, an intercalation model that permits competitive hydrogen abstraction from C5' and C4' of deoxyribose moiety has been proposed.

Bullous pemphigoid associated with silicosis.

Bullous pemphigoid (BP) has never before been reported to associate with silicosis, although there are numerous reports of silicosis accompanied by different autoimmune diseases, such as systemic sclerosis, systemic lupus erythematosus, dermatomyositis or rheumatoid arthritis. We report on a 63-year-old Japanese patient with silicosis who developed tensed bullae, erosions and macular pigmentation on the trunk and extremities. Indirect immunofluorescence revealed anti-basement-membrane-zone antibodies; immunoblotting analysis demonstrated that the patient's serum reacted with the 230-kD BP antigen in the epidermal extracts, as well as a recombinant protein of the NC16a domain of 180-kD BP antigen. Clinical symptoms improved after treatment with systemic steroids. To the best of our knowledge, this is the first reported case of BP associated with silicosis.