A twin study of dental dimension. II. Independent genetic determinants

To demonstrate the presence of independent genetic determinants of multiple correlated tooth dimensions from twin data, a multivariate analysis was performed on the covariance matrices of monozygotic and dizygotic within-pair differences for mesiodistal and buccolingual dimensions of 28 teeth of the secondary dentition. The results provided strong evidences that the correlation among tooth dimensions is primarily genetic in origin, probably attributable to the pleiotropic action of either independent genes or groups of genes. Among the genetic factors that were identified, one appeared to affect the maxillary teeth in general while a second influenced primarily the anterior mandibular teeth. There was a striking tendency for homologous measurements on the right and left sides to be associated with the same genetic factor. In contrast, genetic determination of the maxillary and mandibular dentition seemed to be independent of each other, and a wider range of genetic factors were found to influence the mandibular than the maxillary teeth, suggesting that a differential degree of evolutionary stability may have been achieved in the teeth of the two jaws.     

The plasma protein binding and distribution of etomidate in dog, rat and human blood

The interactions of etomidate and its major metabolite (R 28 141) with plasma proteins were studied by equilibrium dialysis with a multiple cell system. A 4% human serum albumin solution was able to bind 78.5% of the etomidate, and 60.5% of R 25 141, whereas a 1.5% human gamma globulin solution bound etomidate for not more than 3% and did not bind R 28 141 at all. The association constants and free binding energies for the binding of etomidate and R 28 141 to human serum albumin were determined. Plasma protein binding of etomidate was 75.4% in the dog and 76.5% in man; in rat plasma 79.5% of the radioactivity was bound to the plasma proteins, however the etomidate was partly hydrolyzed, even in the presence of sodium fluoride. In the rat 29.7% was distributed to the blood cells, 55.9% bound to plasma proteins and 14.4% was present in plasma water; in the dog the distribution percentages were 42.1%, 43.7% and 14.2% respectively, and in man 37.7%, 47.6% and 14.7% respectively. The major metabolite of etomidate was distributed for 26.3% to the human blood cells, 47.4% was bound to plasma proteins and 26.2% was present in the plasma water; its plasma protein binding amounted to 64.3%. Etomidate was bound at or in the blood cells, whereas R 28 141 was not.     

In-vitro metabolism of etomidate by rat liver fractions

(R)-(+)-etomidate and (S)-(-)-etomidate were found to be metabolized in-vitro by various rat liver homogenization fractions: the 16,000 g supernatant fraction caused a more intensive metabolic breakdown than the microsomal fraction; the 100,000 g supernatant fraction was only slightly active. The metabolism was somewhat more rapid and more extensive for the (R)-(+)-etomidate than for the (S)-(-)-isomer. For both isomers, a dose-dependence was observed: the smaller the substrate concentration, the smaller the relative amount of unmetabolized drug, and the more the rate of metabolic breakdown after a certain incubation time slowed down. Only minor qualitative differences between the metabolic pathways of the two isomers were observed. The main metabolic pathway for the in-vitro metabolism was the hydrolysis of the ethyl ester. Decarboxylation and oxidative N-dealkylation were also observed.     

The intermolecular cross-links in uterine collagens of guinea pig, pig, cow, and human beings

The intermolecular cross-links have been studied in the uterine insoluble collagen of guinea pig, pig, cow, and human beings with a single given procedure. After NaB3H4 reduction, there are three intermolecular cross-links; namely, dihydroxylysinonorleucine, hydroxylysinonorleucine, and histidinohydroxymerodesmosine. In human uterine collagen samples these reduced cross-links are present in equal amounts. The reduced intermolecular collagen cross-links of uterine leiomyoma are very similar to those of the normal uterine tissue. Dihydroxylysinonorleucine is the principal reduced cross-link in uterine collagen of guinea pig, pig, and cow. Alkaline hydrolysis reveals that dehydrodihydroxylysinonorleucine and dehydrohydroxylysinonorleucine occur in vivo as glycosylated derivatives.     

Trigeminal neuralgia: retrolabyrinthine selective posterior root section

Experience gained from the treatment of 41 patients with 42 operations for the relief of Vth nerve pain over the past 5 years is reported. For the selective section of the posterior root of the trigeminal nerve 28 retrolabyrinthine procedures were performed for typical tic douloureux with complete lasting relief in 25; 1 was relieved with the addition of aspirin; and 2 were relieved by Tegratol even though it was ineffective before surgery. There were no deaths and no serious complications. None had facial paralysis or anesthesia dolorosa. The retrolabyrinthine approach to the posterior root of the trigeminal nerve is ideally suited for those patients with refractory tic douloureux or patients with facial pain secondary to other causes such as tumor. Because of its effectiveness and low morbidity, this procedure offers advantages over other surgical techniques.     

Expression of a rat glutathione-S-transferase complementary DNA in rat mammary carcinoma cells: impact upon alkylator-induced toxicity

The role of glutathione-S-transferase (GST) in alkylator drug resistance has been studied in MatB rat mammary carcinoma cells. A series of GST transfectant cell lines was established by using an expression vector containing the complementary DNA for the rat GST Yc gene under regulation of the SV40 early region promoter and the antibiotic resistance plasmid pSV2neo. Transfectant cell lines expressing up to 4-fold higher total GST activity than in the parental wild type cell line were identified. Southern blot analysis confirmed a DNA fragment corresponding in size to the transfected GST Yc complementary DNA. Wild type MatB cells contain very low levels of Yc protein, whereas the Yc+ clones showed greatly increased amounts of the Yc subunit. The effect of increased GST Yc activity on the sensitivity of the transfected clones to various cytotoxic agents was assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell survival assay. The clones expressing recombinant GST Yc were more resistant to melphalan (6- to 12-fold), mechlorethamine (10- to 16-fold), and chlorambucil (7- to 30-fold). In late passage populations of the GST Yc+ clones that had been grown over a period of 14 months under continuous selection in G418, GST activity was decreased and it was paralleled by a decrease in Yc protein. These late passage clones with diminished GST Yc content also demonstrate a partial reversion toward the wild type phenotype as determined by cytotoxicity assays using melphalan, mustargen, and chlorambucil. Interstrand DNA cross-links induced by mechlorethamine were significantly lower at 0, 2, and 20 h posttreatment in one of the GST Yc+ clones when compared to wild type MatB cells. These studies indicate that GST Yc overexpression can confer resistance to alkylating agents and that this correlates with inhibition of DNA cross-link formation.     

The influence of medium formulation on phosphomonoester and UDP-hexose levels in cultured human colon tumor cells as observed by 31P NMR spectroscopy

High-resolution 31P NMR spectroscopy at 11.7 T was used to examine the influence of medium formulation (medium and serum type, and concentrations of glucose and inositol) on the cellular phosphate metabolism of CX-1 cells, a human colon cancer cell line derived from HT-29 cells. Striking differences in the 31P spectra of harvested CX-1 cells were observed. The largest variation was seen in the phosphocholine and UDP-hexose levels (up to seven-fold changes), with smaller differences in the levels of other phosphate metabolites. The major UDP-hexose species were found to be UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine (ca 2:1 ratio), which have been proposed in the literature to be markers of cell differentiation status. Medium-induced alterations in metabolite levels were much greater than the normal variations seen in CX-1 control samples grown under identical conditions. They even exceeded the characteristic differences observed between different human tumor cell lines grown under one set of culture conditions. The remarkable sensitivity of CX-1 cellular phosphate metabolism to the culture environment has implications for the comparison of in vitro vs in vivo spectra, and for the interpretation of effects due to growth and therapy.     

Anti-retroviral therapy and antiepileptics. Case report and discussion]

Therapy of HIV infection is changing rapidly as new drugs are introduced. Many patients with HIV infection require anticonvulsants for therapy or prophylaxis of seizures. Antiretroviral drugs, above all protease inhibitors, and anticonvulsants may cause interactions since they are metabolised through common hepatic pathways and may substantially modulate the activity of numerous cytochrome P450 isoenzymes. We describe known interactions between anticonvulsants and antiretroviral drugs and advise on possible combinations.