LY294002 Inhibits Intermediate Conductance Calcium-Activated Potassium (KCa3.1) Current in Human Glioblastoma Cells.

Glioblastomas (GBs) are among the most common tumors with high malignancy and invasiveness of the central nervous system. Several alterations in protein kinase and ion channel activity are involved to maintain the malignancy. Among them, phosphatidylinositol 3-kinase (PI3K) activity and intermediate conductance calcium-activated potassium (KCa3.1) current are involved in several aspects of GB biology. By using the electrophysiological approach and noise analysis, we observed that KCa3.1 channel activity is LY294002-sensitive and Wortmannin-resistant in accordance with the involvement of PI3K class IIß (PI3KC2ß). This modulation was observed also during the endogenous activation of KCa3.1 current with histamine. The principal action of PI3KC2ß regulation was the reduction of open probability in intracellular free calcium saturating concentration. An explanation based on the "three-gate" model of the KCa3.1 channel by PI3KC2ß was proposed. Based on the roles of KCa3.1 and PI3KC2ß in GB biology, a therapeutic implication was suggested to prevent chemo- and radioresistance mechanisms.

In vitro activity of ceftaroline and ceftobiprole against methicillin-resistant Staphylococcus aureus with decreased susceptibility to vancomycin isolated in paediatric patients.

Minimal inhibitory concentrations (MIC, mg/l) of ceftaroline and ceftobiprole were evaluated over 70 methicillin-resistant Staphylococcus aureus (MRSA) strains with vancomycin MIC ≥1 isolated in a paediatric hospital. The proportion of non-wild-type strains (MIC > epidemiological cut off) was 18% for ceftobiprole and 64% for ceftaroline. Only 1.4% of strains was resistant to ceftobiprole, and none to ceftaroline. These results are worrisome, since show the presence of non-negligible proportions of MRSA strains with high MIC values for ceftaroline and ceftobiprole in a setting where both drugs were never used.

Characterization of Staphylococcus aureus small colony variant strains isolated from Italian patients attending a regional cystic fibrosis care centre.

Small colony variant (SCV) Staphylococcus aureus are a subpopulation of auxotroph, slow-growing strains causing persisting and relapsing infections in cystic fibrosis (CF) patients. Twenty-eight SCV and 29 normal S. aureus strains were isolated from 42 out of 222 Italian CF patients. The isolates were characterized for: susceptibility to antibiotics, methicillin-resistance (MR), Panton Valentine leukocidin, auxotrophy, hypermutability and biofilm formation. Clonal identity of SCV and normal strains was determined by pulsed-field gel electrophoresis. We found that 27 out of 28 SCVs were thymidine-dependent. Furthermore, in contrast to normal phenotype, SCVs were characterized by antibiotic resistance. We also found that 39.3% SCV vs 20.7% normal strains were strong mutators. Moreover, SCVs showed a higher capability to form biofilm compared to normal strains (100% vs 59%). Importantly, we found evidence of clonal spread of SCV strain among CF patients. Using molecular typing, we found that five patients shared the same type A and five out of seven MR-SCV belonged to the same clone (Clone C). The particular virulence and spreading ability of MR-SCV observed highlights the importance of accurate identification and susceptibility testing of these strains. It is important to adopt the optimal approach to treat patients and to prevent cross-infection in CF centres.