C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption

1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.     

Experience in using at a polyclinic the Siberia low-dose digital X-ray unit

Application interactive CLASS software for stimulating productive binocular cooperation based on random-dot patterns and stereograms was used for treating strabismus and amblyopia in 105 children during a standard course of treatment. The children were divided into 3 groups treated by the CLASS alone (1), Class + two other application programs (2), and CLASS + traditional methods. General positive changes (improvement of visual acuity, decrease of eye deviation, etc.) were similar in these 3 groups. Positive effect of CLASS exercises on binocular visual mechanisms was significant. Due to precise evaluation of binocular interaction provided by CLASS, positive changes in binocular cooperation and stereovision were attained in 93% of children.     

Co-amplification of the amelogenin and HLA DQ alpha genes: optimization and validation

An optimized PCR-based system allowing the co-amplification of the HLA DQ alpha and the amelogenin genes has been developed and validated, enabling simultaneous identity testing and sex determination. Sensitivities below 100 pg of human DNA were obtained, using a convenient, high resolution agarose gel system and ethidium bromide staining. Comparison of several co-amplification methods revealed that the best sensitivities and most consistent results were obtained using a hotstart technique employing an inactivating antibody to Taq polymerase. HLA DQ alpha typing results were reliably obtained using the co-amplification process. The sensitivity and ease of this system rendered it directly applicable to forensic analyses. The optimized techniques described here have been validated and successfully applied to forensic cases including People vs. Trujillo, in which the California Superior Court accepted these techniques as scientifically reliable and admissible. Work currently in progress has demonstrated that the described protocol may also be used to co-amplify the amelogenin gene with the AmpliType PM (polymarker) system, allowing identity testing at six loci in addition to sex determination.     

Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth

BACKGROUND: Studies have shown that nitric oxide (NO) and NO synthase (NOS) inhibitors injure and protect organs after endotoxin (lipopolysaccharide [LPS]) challenge. OBJECTIVE: To test the hypothesis that LPS-induced gut injury and bacterial translocation (BT) are mediated through activation of inducible NOS (iNOS). DESIGN: A randomized, controlled study using genetically altered, iNOS gene knockout mice. SETTING: University research laboratory. METHODS: Forty-five wild-type (iNOS+/+) or homozygous mutant (iNOS-/-) mice weighing 25 to 35 g were challenged with Escherichia coli LPS or saline (10 mg/ kg) intraperitoneally (n = 8/group). In a second set of experiments, a bacterial overgrowth model of BT (E coli monoassociation) was tested (n = 6-7/group). The mesenteric lymph nodes and cecums were cultured, and liver, ileal, and blood nitrite and nitrate levels measured 24 hours after LPS or E coli monoassociation. RESULTS: After LPS challenge, 87.5% of the iNOS+/+ mice but 0% of the iNOS-/- mice had BT to their mesenteric lymph nodes (P < .01; chi 2 analysis). Nitrite and nitrate levels of the liver, ileum, and blood were higher in the iNOS+/+ mice (P < .05). In the E coli overgrowth model, BT to mesenteric lymph nodes occurred in 100% of iNOS-/- and iNOS+/+ mice. CONCLUSIONS: In this limited study, LPS-induced BT did not occur in iNOS-deficient mice, suggesting that LPS induction of increased iNOS activity is necessary for LPS-induced BT to occur. In contrast, iNOS activation does not seem to be necessary in a bacterial overgrowth model of BT.     

Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity

OBJECTIVE: To estimate the efficacy and toxicity of typhoid fever vaccines. DESIGN: Meta-analysis of randomised efficacy trials and both randomised and non-randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. SUBJECTS: 1,866,951 subjects in 17 efficacy trials; 11,204 subjects in 20 toxicity studies. MAIN OUTCOME MEASURES: Pooled estimates of three year cumulative efficacy, year specific efficacy, and incidence of adverse events. RESULTS: Three year cumulative efficacy was 73% (95% confidence interval 65% to 80%) for two doses of whole cell vaccines (based on seven trials); 51% (35% to 63%) for three doses of Ty21a vaccine (four trials); and 55% (30% to 71%) for one dose of Vi vaccine (one trial). For whole cell and Ty21a vaccines, regimens of fewer doses were less effective. Efficacy was shown to be significant for five years for whole cell vaccines, four years for Ty21a vaccine, and two years for Vi vaccine. Neither the age of vaccine recipient nor the incidence of typhoid fever in the control group (varying from 6 to 810 cases per 100,000 person years) affected the efficacy of the whole cell or Ty21a vaccines. After vaccination, fever occurred in 15.7% (11.5% to 21.2%) of whole cell vaccine recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine recipients, and 1.1% (0.1% to 12.3%) of Vi vaccine recipients. CONCLUSIONS: Whole cell vaccines are more effective than the Ty21a and Vi vaccines but are more frequently associated with adverse events. Whether the added efficacy of the whole cell vaccines outweighs their toxicity will depend on the setting in which vaccination is used.     

An anti-invasive concentration of the alkyl-lysophospholipid ET-18-OCH3 enhances the motility of embryonal chick heart cells cultured on solid substrate

Pretreatment of embryonal chick heart fragments with ET-18-OCH3 is known to induce resistance to invasion by several malignant cell lines. Embryonal chick heart fragments or cell suspensions prepared from such fragments were explanted on solid substrate and treated in medium with 10 micrograms/ml ET-18-OCH3 or with drug-free medium (control) for 48 h. This medium was washed away and replaced by drug-free fresh medium. Twenty-four to 48 h later the fast plasma membrane movements (involved in ruffling, blebbing, fast shape change and fast translocation) were quantified using a simple method based on subtracting two video images taken with an interval of 28 s. The ET-18-OCH3-treated cells showed a higher intensity of fast plasma membrane movements than control cells. Cells around a treated explant did not show the same radial alignment as in controls, suggesting loss of contact inhibition of movement. Cells from a cell suspension derived from a treated fragment showed faster translocation on solid substrate and faster shape change. We speculate that increased motility of host cells may be involved in resistance to invasion.     

Control of the vertical dimension in Class II correction using a cervical headgear and lower utility arch in growing patients. Part I

A retrospective cephalometric study was performed comparing three groups of 30 growing patients with Class II, Division 1 malocclusions. Group 1 was treated with a cervical headgear/lower utility arch combination (CHG/LUA), group 2 was treated with a cervical headgear alone (CHG), and the third group was untreated. The average treatment time was 1 year, 6 months. No other appliances were used during this period. Maxillary and mandibular dental and skeletal treatment responses were compared with an analysis of variance (ANOVA) and a Scheffe's test. In addition, a multiple stepwise regression was performed to determine whether pretreatment measures of facial pattern were accurate predictors of mandibular rotational response. Both treatment groups demonstrated significant reduction in maxillary protrusion. The CHG-only group showed significantly greater anterior descent of the palatal plane as compared with the untreated group. The maxillary molars showed significant distal movement in both treatment groups without any extrusion beyond that seen with normal growth. The maxillary incisor demonstrated significant retroclination in the CHG-only group. There was no statistical difference among the groups for variables commonly used for measuring mandibular rotation or protrusion. The change in vertical position of the lower molar was not significantly different among the groups. A CHG as used in this study produced maxillary orthopedic and orthodontic changes without upper molar extrusion beyond that seen with normal eruption and in the absence of an opening rotation of the mandible, even in subjects with dolicocephalic facial patterns. The LUA did not appear to influence lower molar eruption or mandibular rotational response. None of the commonly used predictors of facial pattern, such as the Y-axis, XY-axis, or MP angle, accurately predicted mandibular rotational response. Further study would be necessary to ascertain whether this was a result of their invalidation as predictors, or a result of the treatment strategy employed.     

High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically

OBJECTIVE: To determine changes in the incidence of candidemia in a neonatal intensive care unit (NICU) during a 15-year period (1981 to 1995) and to compare the prevalence and case fatality rates of Candida albicans and Candida parapsilosis infections. METHODS: A retrospective study was conducted of candidemia occurring in infants in a NICU between January 1, 1981, and December 31, 1995. Cases were identified through computerized searching of a microbiology blood culture database. Candidemia was considered contributory to mortality if death occurred within 3 days of positive blood cultures or if there was autopsy evidence of disseminated candidiasis. RESULTS: One hundred eleven cases of candidemia occurred in 107 infants, representing 1% of all NICU patients during the study period. The rate of candidemia in the NICU increased from 2.5 cases per 1000 admissions in 1981 to 1985, to 4.6 per 1000 admissions in 1986 to 1990 and to 28.5 per 1000 in 1991 to 1995 (P = 0.001). C. albicans was the predominant cause of candidemia between 1981 and 1990. C. parapsilosis was the most prevalent species between 1991 and 1995, causing 53 of 89 cases (60%). The mortality from C. albicans, 13 of 50 cases (26%), was significantly higher than the mortality from C. parapsilosis, 2 of 54 (4%) (P = 0.002; relative risk, 7; 95% confidence interval, 1.7 to 30). CONCLUSIONS: The rate of candidemia in our neonatal intensive care unit increased >11-fold in the 15 years from 1981 to 1995; the prevalent Candida species shifted from C. albicans to C. parapsilosis; and candidemia associated with C. albicans has significantly higher mortality than with C. parapsilosis.