The effect of azathioprine (Imuran) on the kinetics of monocytes and macrophages during the normal steady state and an acute inflammatory reaction

The effect of azathioprine on the kinetics of peripheral blood monocytes and peritoneal macrophages was studied in normal mice and in mice in which an inflammatory reaction was provoked. Two dosage levels were used: a high dose of 200mg/kg which is the maximum tolerated daily dose in mice, and low dose of 3 mg/kg which is about equivalent to a nontoxic, immunosuppressive, anti-inflammatory dose in man. The number of peripheral blood monocytes decreases gradually during azathioprine treatment of normal mice, the extent and duration being dependent on the dose and duration of administered over a period of 9 days gives an almost complete reduction, and a low dose (3 mg/kg) given for the same period results in a reduction of about 50%. This effect seems to be reversible, because when treatment is stopped the number of monocytes starts to increase 24-48 hr later. The number of peritoneal macrophages is only affected when a high dose (200 mg/kg) is given over a long period; a low dose has virtually no effect. In mice in which an inflammatory reaction was prevoked in the peritoneal cavity, the normally occurring increase in the numbers of both peripheral blood monocytes and peritoneal macrophages was suppressed, the extent being dependent on the dose of azathioprine administered. Labeling studies with 3H-thymidine indicated that the reduction of peripheral blood monocytes and peritoneal macrophages in the inflammatory exudate is due to a diminished monocyte production.     

Systematic review of efficacy of dose-dense versus non-dose-dense chemotherapy in breast cancer, non-Hodgkin lymphoma, and non-small cell lung cancer

Randomized controlled trials (RCTs) have suggested a potential advantage of dose-dense chemotherapy in improving disease-free and overall survival in patients with certain malignancies. This systematic review summarizes the literature on the efficacy of dose-dense chemotherapy across various cancers (breast cancer, non-Hodgkin lymphoma [NHL], and non-small cell lung cancer) and chemotherapy regimens. Among the 17 trials identified, few reported statistically significant differences between dose-dense and standard chemotherapy, and most were small with limited statistical power. Statistically significant differences in overall survival favoring dose-dense schedules were apparent among large RCTs in potentially curative settings such as early-stage breast cancer and NHL. Clinical and treatment heterogeneity demonstrated the flexibility of the dose-dense paradigm but also precluded quantitative meta-analysis of results. Further study of dose-dense schedules based on large RCTs is needed to demonstrate the consistency and generalizability of these findings.     

Effects of supervised daily dental plaque removal by children after 3 years

The benefits of a school-based plaque removal program are presented. Children in grades 5-8 were included in a study which was designed to determine the effect on oral hygiene, gingival inflammation and dental caries of removing dental plaque through supervised daily flossing and toothbrushing in school. A fluoride-free dentifrice was used. Controls did not receive instruction in plaque removal procedures nor did they engage in plaque removal activities at school. For three school years the students in the treatment group practiced daily plaque removal, supervised by trained personnel. All participants were examined initially for plaque (PHP), gingival inflammation (DHC) and dental caries (DMFS). Girls in the treatment group showed a significant reduction (28%) in mean plaque scores and, for girls and boys, the mean changes in gingivitis scores were significantly reduced (40% and 17%, respectively). Adjusted mean incremental DMF surface scores were 13 % lower in the treatment group than in the control group. The difference between groups was not statistically significant and was accounted for entirely by the findings in mesial and distal surfaces (26%). This difference approached statistical significance (P= 0.07).     

Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis

Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC. MICs of fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, /=64 microgram/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied. FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P < 0.001) and tissue burden of C. albicans in tongue, soft palate, and esophagus (P < 0.001). In comparison, rabbits infected with FR isolates were unresponsive to fluconazole and had no reduction in oral mucosal quantitative cultures or tissue burden of C. albicans versus untreated controls. We conclude that there is a strong correlation between in vitro fluconazole susceptibility by NCCLS methods and in vivo response to fluconazole therapy of OPEC due to C. albicans.     

Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis

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