[Selection and properties of mutant yeast Pichia guilliermondii strains resistant to chromium (VI)].

Yeast Pichia guilliermondii strains L3 and L2, exposed to UV mutagenesis, produced over 80 mutants capable of growing on media containing 1.5 mM bichromate (Cr(VI)). The mutations making the strains resistant to Cr(VI) were dominant or semidominant. The mutants varied in Cr(VI) resistance, the degree of chromium accumulation in the cells (from 0.1 to 11.6 mg/g dry cells), and the degree of Cr(VI) reduction (from 50% to complete disappearance of bichromate from the culture liquid). Chromium accumulation in mutant cells depended on medium composition, Cr(VI) concentration, and the time of exposure to Cr(VI). The resistance to bichromate can be caused by various reasons: decrease in chromium absorption, altered ability to reduce Nr(VI), or damage of sulfate transport mechanisms.

Radical D2 surgery for patients with gastric cancer.

UNLABELLED: The authors analyzed and prepared a report concerning 18 radical surgeries for gastric cancer that were performed between 1999-2001. Overall, 55 operation were performed, 32 radical, 18 palliative and 5 explorative laparatomies. D2 resections were performed 18 times, while D1 type 14 times. The group undergoing D2 surgery comprised of 10 men and 8 women with average age of 64.3. D2 resection included partial (8 times), or total (10) gastrectomy and lymfadenectomy of perigastric nodes, supra and infrapyloric nodes and nodes along common hepatic artery, truncus coeliacus, lienal artery, left paracardial nodes and removing capsula of pancreas. Splenectomy was performed twice. On average, 37.5 lymphnodes were removed for every operation (25-69). Operative mortality was none (0%) and morbidity was 22%. As of January 1, 2002 relaps was noted in six patients, and 5 patients died. CONCLUSION: D2 resection surgeries performed by an experienced surgeon show low morbidity as well as better outcome and higher perspective for long-term survival in patients with gastric cancer. (Tab. 1, Ref. 19.).

[Radical treatment of rectal cancer]. / Radikálna liecba rakoviny konecníka.

The authors present an account on radical resections of the rectum in 73 patients during 1991-1995. A radical operation with excision of the mesorectum was performed 69 times, local excisions 4 times. Five-year survival was recorded in 57.90% patients, local relapses were recorded in 10.14% patients. Remote metastases or generalization of the disease was found in 18.84% patients. Adjuvant treatment was administered to 74% patients.

A multinational investigation of the impact of subcutaneous sumatriptan. IV: Patient satisfaction.

This report describes the patient satisfaction results from a prospective, sequential, multinational study. The study was conducted to concurrently evaluate the effects of sumatriptan, compared with customary therapy, on clinical parameters, health-related quality of life, productivity and patient satisfaction in adult patients with moderate to severe migraine. Patients treated migraine attacks for 12 weeks with their customary therapy, followed by 24 weeks' treatment with subcutaneous sumatriptan 6 mg. A questionnaire was conducted at the end of each study phase, or retrospectively at the end of the study, to assess patient satisfaction with customary therapy and sumatriptan. Sumatriptan was considered by most patients (67 to 85%) to be dependable and fast-acting, and to have a long duration of effect, allowing a quick return to normal activities. By comparison, 15 to 32% of patients considered that their customary therapy possessed the same attributes. However, customary therapy was considered to be easy/very easy to use by 82% of patients compared with 62% for subcutaneous sumatriptan. 89% of patients indicated that they would use sumatriptan again in the future. This study demonstrates that treatment of migraine attacks with subcutaneous sumatriptan for 24 weeks is associated with greater patient satisfaction as regards specific drug attributes than customary therapy.

The effect of a single oral dose of ethanol on hepatic blood flow in man.

The magnitude and time course of changes in hepatic blood flow following oral ingestion of a single (0.6 g/kg) dose of ethanol was studied using the model compound indocyanine green (ICG). Hepatic blood flow was not significantly different at 40, 90, 150 and 210 minutes following ethanol as compared to baseline values measured 20 and 70 min prior to alcohol ingestion. These results suggest that ethanol, at concentrations commonly associated with social drinking, has minimal effects on liver blood flow and would be expected to contribute little to changes in either the bioavailability or clearance of drugs highly extracted by the liver.

Hematological effects associated with beta-lactam use.

Beta-lactam antibiotics have continued to be the mainstay of antiinfective treatment. Newer agents, such as the third-generation cephalosporins or ureidopenicillins, have the advantage of a broader antimicrobial spectrum and improved pharmacokinetics. The beta-lactams are often promoted as alternatives to more toxic antibiotic regimens. However, several of the beta-lactams have been shown to produce hematological effects, some of which can be life threatening. The primary hematological effects appear to be inhibition of normal platelet function and the coagulation cascade, which is reflected by changes in bleeding times and increases in prothrombin time and activated partial thromboplastin time, respectively. Although not all patients will develop bleeding problems associated with these agents, close monitoring of patients with risk factors for bleeding and dosage adjustments may help to avert these drug-induced hematological problems.

[Genetic control of riboflavin biosynthesis in Pichia guilliermondii yeasts. The detection of a new regulator gene RIB81]. / Geneticheskii kontrol' biosinteza riboflavina u drozhzhei Pichia guilliermondii. Obnaruzhenie novogo reguliatornogo gena RIN81.

The properties of mutants resistant to 7-methyl-8-trifluoromethyl-10-(1'-D-ribityl)-isoalloxazine (MTRY) were studied. The mutants were isolated from a genetic line of Pichia guilliermondii. Several of them were riboflavin overproducers and had derepressed flavinogenesis enzymes (GTP cyclohydrolase, 6.7-dimethyl-8-ribityllumazine synthase) in iron-rich medium. An additional derepression of these enzymes as well as derepression of riboflavin synthase occurred in iron-deficient medium. The characters "riboflavin oversynthesis" and "derepression of enzymes" were recessive in mutants of the 1st class, or dominant in those of the 2nd class. The hybrids of analogue-resistant strains of the 1st class with previously isolated regulatory mutants ribR (novel designation rib80) possessed the wild-type phenotype and were only capable of riboflavin overproduction under iron deficiency. Complementation analysis of the MTRY-resistant mutants showed that vitamin B2 oversynthesis and enzymes' derepression in these mutants are caused by impairment of a novel regulatory gene, RIB81. Thus, riboflavin biosynthesis in P. guilliermondii yeast is regulated at least by two genes of the negative action: RIB80 and RIB81. The meiotic segregants which contained rib80 and rib81 mutations did not show additivity in the action of the above regulatory genes. The hybrids of rib81 mutants with natural nonflavinogenic strain P. guilliermondii NF1453-1 were not capable of riboflavin oversythesis in the iron-rich medium. Apparently, the strain NF1453-1 contains an unaltered gene RIB81.

Kinetics of meperidine N-demethylation in the perfused rat liver preparation.

Meperidine and normeperidine elimination was studied in the once-through perfused rat liver preparation. Biliary excretion of these bases was minimal, and nonlinear metabolism of meperidine (extraction ratio of 1.0 to 0.89 at 1 to 19 micrograms/ml) and normeperidine (extraction ratio of 0.6 to 0.1 at 1 to 25 micrograms/ml) was observed when input concentration was increased. The rate of efflux of normeperidine in hepatic venous blood represented an increasing proportion of the rate of presentation and the rate of loss of meperidine (34 to 92%) at increasing meperidine input concentration. But when the data were corrected for the nonlinear sequential metabolism of normeperidine, the rate of N-demethylation accounted completely for the rate of metabolism of meperidine. These N-demethylation rates obeyed Michaelis-Menten behavior, and appeared to be saturated at input meperidine concentration greater than 5 micrograms/ml.

[Effect of riboflavin analogs on Pichia guilliermondii growth]. / Vliianie analogov riboflavina na rost Pichia guilliermondii.

The work was aimed at studying the biological activity of 32 structural riboflavin (RF) analogs substituted at positions 7, 8 and 10 as well as with a modified structure of the isoalloxazine cycle and the side D-ribityl chain. An RF-dependent mutant of the yeast Pichia guilliermondii MS1 was used as a test organism. The strain could grow in a medium without the vitamin in the presence of 2-thio-RF and analogs with esterified hydroxyls in the side chain, viz. tetraacetate and tetrabutyrate of RF. The antagonistic properties were distinctly displayed only by D-ribityl derivatives of vitamin B2 with a substitution of CF3, Cl, H, NH2 and N(CH3)2 for one or the both methyl groups. The inhibition indices for such analogs varied from 0.52 to 10.8. The action of the antivitamins on the yeast growth was competitively eliminated by adding RF to the growth medium. The antivitamin activity of an analog abruptly decreased or disappeared if (i) a bulky substituent such as N-piperidyl or hydroxyethylamine was incorporated at position 8 of an antimetabolite molecule, (ii) the D-ribityl side chain was substituted by a D-galactyl, D-sorbityl, L-ramnityl, 2-hydroxyethyl or methyl group and (iii) the structure of isoalloxazine cycle was modified. The analogs which were phosphorylated by RF kinase (ATP: RF-5'-phosphotransferase, EC 2.7.1.26) from P. guilliermondii were shown to be effective antivitamins. Therefore, the antagonistic effect of vitamin B2 analogs in yeast cells is realized at the level of coenzyme forms.

[Substrate and inhibitory specificity of riboflavin kinase from Pichia guilliermondii yeast]. / Issledovanie substratnoi i ingibitornoi spetsifichnosti riboflavinkinazy iz drozhzhei Pichia guilliermondii.

The interaction of purified riboflavin kinase (EC 2.7.1.26) from Pichia guilliermondii with 44 structural vitamin B2 analogues is studied. The presence of D-ribityl lateral chain in an analogue structure is found to be necessary for the substrate activity. The substitution of CH3 groups in the 7 and 8 positions of isoalloxazine ring in the riboflavin molecule for CF3, Cl, H, NH2 and N(CH3)2 resulted in the decrease of the analogue affinity to riboflavin kinase as compared with the natural substrate, vitamin B2. The most efficient enzyme inhibitors of analogues without substrate properties turned to be trifluoromethylisoalloxazines, containing 2'-hydroxyethyl group at N10. The elongation of D-ribityl lateral chain, the elimination of change of CH3-groups in the 7 and 8 positions for CF3- Cl-, COOH-substitutors resulted in the decrease of the inhibitory effect of flavines. Modifications in the structure of isoalloxazine ring, etherification of OH-groups in the lateral D-ribityl chain, and the introduction of volume substitutors (N-piperidyl, D-ribitylamine, hydroxyethylamine) prevented the interaction of the analogue with riboflavin kinase. Flavin nucleotides (FMN and FAD) did not affect the rate of vitamin B2 phosphorylation.