Flucytosine resistance is restricted to a single genetic clade of Candida albicans

Population studies have revealed that Candida albicans can be separated into five major clades, groups I, II, III, SA, and E. Groups SA and E are highly prevalent in South Africa and Europe, respectively, while group II is excluded from the southwestern portion of the United State. In each geographical locale, several clades exist side by side, suggesting little interclade recombination. These results suggest clade-specific phenotypes. In the present study we demonstrate that resistance to flucytosine (5FC MIC >/= 32 micro g/ml), an antifungal used for the treatment of systemic C. albicans infections, is restricted to clade I. In addition, while 97% of all strains for which 5FC MICs were >/=0.5 micro g per ml were members of group I, only 3% were members of the other groups. 5FC MICs were >/=0.5 micro g per ml for 72% of all group I isolates, while 5FC MICs were >/=0.5 micro g per ml for only 2% of all non-group I isolates. These results demonstrate for the first time the clade specificity of a clinically relevant trait (5FC resistance) and suggest that while intraclade recombination may be common, interclade recombination is rare.     

Invasion of Rous sarcoma virus-transformed retinal cells: role of cell motility.

Transformation of retinal neuro-epithelial cells by Rous sarcoma virus (RSV) leads to many alterations in cell phenotype, including changes in cell movement, cell-cell adhesion and protease secretion. To define and quantitate the alterations in cell movement, we analyzed video recordings of cultured cells using the computer-assisted Dynamic Morphology System (DMS). Control neuro-epithelial cells showed very low levels of translocation and membrane activity. After transformation, neuro-epithelial cells exhibited increased membrane activity, although directed cell translocation remained low. Developing retinas also contain a small proportion of Müller glial cells, which were purified by repeated passaging of control cultures. In contrast to neuro-epithelial cells, both control and RSV-transformed glial cells showed high levels of translocation and membrane activity. To analyze how different kinds of cell movement affect invasive behavior, we compared the ability of control and RSV-transformed cells to invade the chorio-allantoic membrane of developing chicken embryos. Control neuro-epithelial cells were not invasive. RSV-transformed neuro-epithelial cells, which showed low levels of translocation as revealed by DMS, were invasive. Similarly, RSV-transformed glial cells were invasive while control glial cells, which translocated, were not invasive. These results suggest that high levels of cell translocation are not necessary for invasion. In addition, the results suggest that elevated membrane activity in neuro-epithelial cells may be important for their invasion.     

Current surfactant use in premature infants

Exogenous surfactant therapy has been a significant advance in the management of preterm infants with RDS. It has become established as a standard part of the management of such infants. Both natural and synthetic surfactants lead to clinical improvement and decreased mortality, with natural surfactants having additional advantages over currently available synthetic surfactants. The use of prophylactic surfactant administered after initial stabilization at birth to infants at risk for RDS has benefits compared with rescue surfactant given to treat infants with established RDS. In infants who do not receive prophylaxis, earlier treatment (before 2 hours) has benefits over later treatment. The use of multiple doses of surfactant is a superior strategy to the use of a single dose, whereas the use of a higher threshold for retreatment seems to be as effective as a low threshold. Adverse effects of surfactant therapy are infrequent and usually not serious. Long-term follow-up of infants treated with surfactant in the neonatal period is reassuring. In the future we are likely to see the development of new types of surfactants. Further research is required to determine the optimal use of surfactant in conjunction with other respiratory interventions.     

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera

We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5.