In vitro and in vivo antipseudomonal activity, acute toxicity, and mode of action of a newly synthesized fluoroquinolonyl ampicillin derivative

Compounds N-(6,7-difluoroquinolonyl)-ampicillin (AU-1) and N-(6-fluoroquinolonyl)-ampicillin (FQ-1), synthesized by coupling of the carboxyl group of 6,7-difluoroquinolone (FP-3) and 6-fluoroquinolone (FP4), respectively, with the alpha-amino-group of ampicillin side chain, exhibit antipseudomonal activity similar to and lower acute toxicity than that of norfloxacin, whereas neither ampicillin nor the fluoroquinolone moieties, compound FP-3 or FP4, alone have such activity. Also, AU-1 and FQ-1 are active against tested clinical isolates of Pseudomonas aeruginosa that are highly resistant to norfloxacin, gentamicin, or both. The therapeutic efficacies of FQ-1 and norfloxacin were assessed and compared in neutropenic mice infected with a 90% lethal dose of P aeruginosa. Mice intraperitoneally administered FQ-1 (10 mg/kg) 4, 8, 24, and 48 hours after infection had survival rates as high as 80%, comparable to those of mice treated with norfloxacin at the same dosage and dosing schedule. The study of protoplast formation revealed that FQ-1 did not inhibit cell-wall biosynthesis but did induce cell filamentation of Bacillus subtilis at a level close to its minimal inhibition concentration. Both AU-1 and FQ-1 were able to intercalate into the double-stranded DNA. However, that FQ-1 lost such activity after it was treated with penicillinase suggests that the lactam-ring structure in ampicillin moiety of FQ-1 was hydrolyzed by penicillinase and that the hydrolyzed structure of FQ-1 does not own DNA-intercalation activity.     

Veterinary physiology and community development: are they compatible in a new South Africa?

One of the most complex and troubling issues facing society and health care professionals is physician-assisted suicide (PAS). The convergence of significant trends in legislation, judicial decisions, research, and public sentiment has highlighted its importance. A broad spectrum of societal opinion and philosophical, religious, legal, and professional debate surrounds PAS.     

Predicting soft tissue changes in mandibular advancement surgery: a comparison of two video imaging systems

BACKGROUND: The Asymptomatic Carotid Atherosclerosis Study (ACAS) showed that carotid endarterectomy was beneficial for symptom-free patients with carotid stenosis of 60% or more. This finding raises the question of whether widespread screening to identify cases of asymptomatic carotid stenosis should be implemented. OBJECTIVE: To determine whether a screening program to identify cases of asymptomatic carotid stenosis would be a cost-effective strategy for stroke prevention. DESIGN: Cost-effectiveness analysis using published data from clinical trials. SETTING: General population of asymptomatic 65-year-old men. INTERVENTION: Patients who were screened for carotid disease with duplex Doppler ultrasonography were compared with patients who were not screened. If ultrasonography found significant carotid stenosis (> or = 60%), disease was confirmed by angiography before carotid endarterectomy was done. MEASUREMENTS: Quality-adjusted life-years, costs, and marginal cost-effectiveness ratios. RESULTS: When the conditions and results of ACAS were modeled and it was assumed that the survival advantage produced by endarterectomy would last for 30 years, the lifetime marginal cost-effectiveness of screening relative to no screening was $120,000 per quality-adjusted life-year. Sensitivity analysis showed that marginal cost-effectiveness decreased to $50,000 or less per quality-adjusted life-year only under implausible conditions (for example, if a free screening instrument with perfect test characteristics was used or an asymptomatic population with a 40% prevalence of carotid stenosis was found). CONCLUSIONS: Surgery offers a real but modest absolute reduction in the rate of stroke at a substantial cost. A program to identify candidates for endarterectomy by screening asymptomatic populations for carotid stenosis costs more per quality-adjusted life-year than is usually considered acceptable.     

Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production

An in vitro model of folate-deficient erythropoiesis has been developed using proerythroblasts isolated from the spleens of Friend virus-infected mice fed an amino acid-based, folate-free diet. Control proerythroblasts were obtained from Friend virus-infected mice fed the same diet plus 2 mg folic acid/kg diet. Our previous studies showed that, after 20 to 32 hours of culture in folate-deficient medium with 4 U/mL of erythropoietin, the folate-deficient proerythroblasts underwent apoptosis, whereas control erythroblasts survived and differentiated into reticulocytes over a period of 48 hours. The addition of folic acid or thymidine to the folate-deficient medium prevented the apoptosis of the folate-deficient erythroblasts, thereby implicating decreased thymidylate synthesis as the main cause of apoptosis in the folate-deficient erythroblasts. In the study reported here, we examined intracellular folate levels, uracil misincorporation into DNA, p53 and p21 proteins, and reticulocyte formation in erythroblasts cultured in folate-deficient or control medium. In all experiments, the folate-deficient erythroblasts cultured in folate-deficient medium gave results that varied significantly from folate-deficient erythroblasts cultured in control medium or control erythroblasts cultured in either folate-deficient or control media. Folate-deficient erythroblasts cultured in folate-deficient medium had marked decreases in all coenzyme forms of folate that persisted throughout culture, increased uracil misincorporation into DNA, persistent accumulations of p53 and p21, and decreased reticulocyte production but increased size of individual reticulocytes. A model of folate-deficient erythropoiesis based on apoptosis of late stage erythroblasts is presented. This model provides explanations for the clinical findings in megaloblastic anemia.