Antagonistic roles of Notch and p63 in controlling mammary epithelial cell fates.

The breast epithelium has two major compartments, luminal and basal cells, that are established and maintained by poorly understood mechanisms. The p53 homolog, p63, is required for the formation of mammary buds, but its function in the breast after birth is unknown. We show that in primary human breast epithelial cells, maintenance of basal cell characteristics depends on continued expression of the p63 isoform, ΔNp63, which is expressed in the basal compartment. Forced expression of ΔNp63 in purified luminal cells confers a basal phenotype. Notch signaling downmodulates ΔNp63 expression and mimics ΔNp63 depletion, whereas forced expression of ΔNp63 partially counteracts the effects of Notch. Consistent with Notch activation specifying luminal cell fate in the mammary gland, Notch signaling activity is specifically detected in mice at sites of pubertal ductal morphogenesis where luminal cell fate is determined. Basal cells in which Notch signaling is active show decreased p63 expression. Both constitutive expression of ΔNp63 and ablation of Notch signaling are incompatible with luminal cell fate. Thus, the balance between basal and luminal cell compartments of the breast is regulated by antagonistic functions of ΔNp63 and Notch.

The effect of moxifloxacin on QTc and implications for the design of thorough QT studies.

A number of issues have remained unanswered in the design of "thorough QT"(TQT) studies. In this randomized, placebo-controlled, two-period crossover study in 20 healthy subjects, replicate electrocardiograms (ECGs) were recorded on a digital 12-lead Holter recorder, extracted in a core ECG laboratory, and interpreted manually by a cardiologist. The observed within-subject variability was slightly greater when time-matched baselines were employed than when predose baselines were employed, whereas the magnitude of the increase in QTc was similar for both. Moxifloxacin 400 mg was associated with an observed 7.5-12.5 ms increase in the mean placebo- and baseline-corrected QTc interval. A PK-QTc model estimated a 3.9 ms increase in the QTc interval for every 1,000 ng/ml increase in moxifloxacin concentration. The QTc increases associated with moxifloxacin support the appropriateness of its use as a positive control in TQT studies. This crossover study failed to justify the use of time-matched baselines rather than the less resource-intensive predose definition of baseline.

Liver pathology in children with AIDS: a comparison between the South American and North American population.

Liver tissue from autopsies of twenty-nine cases of children with AIDS were collected from three major South America (S.4) pediatric hospitals. The hepatopathologic findings were classified in the same fashion as in a series of sixty-one children with AIDS from North America (NA): inflammation, non-specific, lymphoproliferative disorders, and giant cell transformation. By comparing both groups. we noted that the SA children were Younger at time of death consistent with a more rapid progression of the disease. Opportunistic infections varied with a higher prevalence of Cytomegalovirus (CMV) infection in SA children. The histopathologic features of CMV in the liter of SA children were associated with a conspicuous inflammation absent in the NA group. Finally, different non-specific hepatic changes were found in SA children, including one case of peliosis hepatis.

Variation in the sequence of Epstein Barr virus nuclear antigen 1 in normal peripheral blood lymphocytes and in Burkitt's lymphomas.

We have examined sequence variations in the EBNA-1 protein of EBV in normal peripheral blood lymphocytes (PBL) and Burkitt's lymphomas (BL). We find two EBNA-1 strains P (prototype) and V (variant) which differ by 15 amino acids. Each strain has two subtypes defined by the amino acid at position 487 (P-ala, P-thr, V-pro and V-leu). In PBLs from 32 normal individuals, up to three of these subtypes were found in each sample, but the V strain did not occur in the absence of P strain viruses, nor was the V-leu subtype ever observed in normal PBL. In BLs only a single subtype was observed in each tumor. The P-thr and V-leu subtypes were more frequently seen than the P-ala and V-pro subtypes, which occurred in only two and one of the 36 tumor samples respectively. The P-thr was the most commonly observed subtype in peripheral blood of both American and African lymphocytes as well as in African tumors. However, in 11 of 12 American tumors, the EBNA-1 subtype was V-leu. These data indicate that some EBNA-1 subtypes are more likely to lead to oncogenesis, and one subtype, V-leu, appears only to occur in tumors.

Single daily dose amikacin in paediatric patients with severe gram-negative infections.

Twenty-five children with serious Gram-negative infections were treated in a prospective study with amikacin 20 mg/kg administered in a single daily dose as a 30 min iv infusion for 4 to 12 days. In nine cases the amikacin was combined with beta-lactam antibiotics. Escherichia coli were the most frequent bacteria isolated followed by K. pneumoniae, Providencia and Enterobacter spp. and Pseudomonas aeruginosa with MICs ranging from 1 to 16 mg/l. Mean (+/- S.D.) peak and trough concentrations of days 1 and 4 of therapy ranged from 49 +/- 13.5 to 53.6 +/- 13.4 mg/l and 6 + 1.4 to 7.7 +/- 4.1 mg/l respectively. All patients were clinically and bacteriologically cured. No significant adverse reactions were observed. The results suggest that administration of a single daily dose of 20 mg/kg amikacin should be considered practical and safe in children. Further studies are needed.