Quaternary heterocyclylamino beta-lactams. V. L-640,876 treatment of induced enterotoxigenic colibacillosis (scours) in calves and piglets

A new semisynthetic cephalosporin antibiotic designated L-640,876, 7-beta-(1-benzylpyridinium-4-yl)amino-3-[( (1-methyl-1H-tetrazol-5-yl)thio] methyl)ceph-3-em-4-carboxylate, was highly active in vitro against 110 enteropathogenic strains of Escherichia coli and Salmonella species of animal origin. The MIC90 was 0.125 microgram/ml for the E. coli strains, 2 micrograms/ml for the S. choleraesuis strains and 4 micrograms/ml for the S. typhimurium strains. In colostrum-fed calves infected with E. coli strain B44, L-640,876 administered by gavage at 30 mg/calf (0.67 mg/kg) twice a day for 3 days, starting at 20-hour post-inoculation, eliminated the diarrhea and reduced the mortality from 82% in the infected, nonmedicated calves to 11% in the infected, medicated calves (P less than 0.05). In colostrum-fed piglets infected with E. coli strain P155, L-640,876 administered by gavage at 12.5 or 20 mg/piglet (10 or 16 mg/kg) twice a day for 3 days, starting at 6-hour post-inoculation, eliminated the diarrhea and reduced the mortality from 79% in the infected, nonmedicated to 25% in the infected, medicated piglets (P less than 0.05). Thus, L-640,876 was highly effective in restoring the calves and piglets to good health by eliminating diarrhea and reducing mortality.     

Pulse sequence optimization for MR imaging using a paramagnetic hepatobiliary contrast agent

Paramagnetic agents enhance contrast between tissues in magnetic resonance (MR) imaging by altering tissue relaxation times. The effect of these changes on MR image intensity depends in part on the choice of operator-controlled pulse sequence parameters. With the newly described paramagnetic hepatobiliary contrast agent, iron(III) ethylenebis-(2-hydroxyphenylglycine), Fe(EHPG)-, an in vivo experimental analysis of pulse sequence optimization was performed on the rat. We compared the enhancement of the liver divided by background noise, EL/N, of standard inversion-recovery (IR) and spin-echo (SE) T1-weighted pulse sequences and several pulse sequences theoretically predicted to have improved EL/N. Optimization of the echo time (TE = TEmin) gave a substantial (greater than 60%) increase in EL/N over the standard IR and SE pulse sequences. Images obtained with optimized repetition rate and inversion time gave only a slight additional improvement. Within the uncertainties of our relaxation measurements, the measured changes in EL/N with pulse sequence optimization corresponded well with theoretical predictions. With the experimental and theoretical data, the importance of using a short echo time to obtain maximal T1 contrast in contrast-enhanced MR imaging and the relative merits of optimized SE versus IR pulse sequences for contrast-enhanced MR imaging are discussed.     

Chronic oral inflammation and the progression of periodontal pathology in the third molar region.

PURPOSE: To assess the association between risk markers of chronic oral inflammation and changes over time in periodontal probing depth (PD) in the third molar region, the distal of a second molar, or around a third molar. SUBJECTS AND METHODS: The data from these analyses are part of a study of subjects enrolled with 4 asymptomatic third molars with adjacent second molars in an institutional review board-approved longitudinal trial. Full-mouth periodontal probing was conducted at enrollment and follow-up. Enrollment levels of periodontal pathogens and gingival crevicular fluid inflammatory mediators were assayed as indicators of the degree of oral inflammation. Subjects were categorized as those who had at least a 2 mm change in periodontal PD between baseline and follow-up in the third molar region and those who did not. The relationship between aggregated subject baseline PD, levels of periodontal pathogens, and gingival crevicular fluid IL-1 beta, and the proportion of subjects with changes in PD >or=2 mm versus those with PD <2 mm were compared with Cochran-Mantel-Haenzsel statistics. Level of significance was set at 0.05. Risk assessment models for a change in PD >or=2 mm were developed using logistic regression analysis. RESULTS: Twenty-four percent of 254 subjects exhibited a change in PD from baseline to follow-up of >or=2 mm in the third molar region. Of these, 95% had a baseline PD of >or=4 mm. Both high (>or=10(5)) "orange" and "red" complex bacteria and PD of >or=4 mm detected at enrollment were significantly associated with a change in PD >or=2 mm. Odds of a change in PD >or=2 mm were increased if baseline pathogen levels were >or=10(5) or a PD of >or=4 mm was detected at enrollment. CONCLUSION: Our findings are consistent with chronic oral inflammation leading to a progression of periodontal disease in the third molar region.     

Reconstruction of a mandibular critical-sized defect using iliac graft in rats

OBJECTIVE: To evaluate, histologically and by optical densitometry of radiographs, the healing of a critical-sized defect in the rat mandible filled with iliac graft. MATERIALS: The study was conducted on 25 adult Wistar rats. With the rats under general anesthesia, a bicortical critical-sized osseous defect was created in the right mandibular ramus and filled with autogenous iliac crest graft. The animals were divided into 5 groups, with 5 rats in each. They were sacrificed after 1, 7, and 14 days, and 1 and 3 months. The mandibles were removed, fixed in formalin, and radiographed. The right hemi-mandibles were decalcified, and sections were cut and stained with hematoxylin and eosin. RESULTS: Initially, an acute inflammatory process was noted along the graft that was tightly fitted to the defect. Subsequently, intense bone neoformation from external corticals and in the inner spaces of the graft was observed, while medullar spaces were occupied by granulation tissue and osteoblasts. There was remodelation of the receptor site, with a decrease in the graft volume and medullary space, as well as cancellous bone replaced by compact bone. Later, the receptor site was similar to the normal mandible, and only devitalized remnants of corticals of the graft were found. Optical densitometry of radiographs revealed statistically significant differences between experimental and control sites. CONCLUSIONS: This experimental model is valuable in the study of bone healing. The study showed that autogenous iliac graft promoted healing of the critical-sized defect of the mandible with complete bony remodeling.     

Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress

Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-ras(G12D) allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras-expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras-driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.