Type 1 and type 2 diabetes are ultimately characterized by depleted b-cell mass. Characterization of the molecular pathways that control b-cell proliferation could be harnessed to restore these cells. The homeobox b-cell transcription factor Nkx6.1 induces b-cell proliferation by activating the orphan nuclear receptors Nr4a1 and Nr4a3. Here, we demonstrate that Nkx6.1 localizes to the promoter of the mitotic kinase AURKA (Aurora Kinase A) and induces its expression. Adenovirus mediated overexpression of AURKA is sufficient to induce proliferation in primary rat islets while maintaining glucose stimulated insulin secretion. Furthermore, AURKA is necessary for Nkx6.1 mediated b-cell proliferation as demonstrated by shRNA mediated knock down and pharmacological inhibition of AURKA kinase activity. AURKA preferentially induces DNA replication in b-cells as measured by BrdU incorporation, and enhances the rate of histone H3 phosphorylation in primary b-cells, demonstrating that AURKA induces the replicative and mitotic cell cycle phases in rat b-cells. Finally, overexpression of AURKA results in phosphorylation of the cell cycle regulator p53, which targets p53 for degradation and permits cell cycle progression. These studies define a pathway by which AURKA upregulation by Nkx6.1 results in phosphorylation and degradation of p53, thus removing a key inhibitory factor and permitting engagement of the b-cell proliferation pathway.

Postoperative wound infection, most often with, is of ubiquitous concern in surgical practice, occurring in an average of 1.5 to 5 percent of all procedures. The antimicrobial properties of local anesthetics have been documented over the past 25 years by in vitro studies. This study evaluates the effects of lidocaine preparations on in an in vivo setting. In a wound infection model using live albino guinea pigs, inoculum was introduced for the reproducible bacterial colonization of clean surgical wounds. One of two sites on the dorsum of each animal was infiltrated with a commercial lidocaine preparation (with and without epinephrine) prior to inoculation with (10 cfu/ml). The other site, inoculated with without preinfiltration with lidocaine, served as the control. Cultures from the sites treated with lidocaine were then compared with cultures from the control sites. All control sites had a consistent presence >or=10 cfu/ml, the threshold for bacterial inhibition of wound healing. Infiltration of the wound with 2 ml of 2% lidocaine prior to inoculation was associated with an average decrease in bacterial count of >70 percent ( n= 19). On the other hand, the addition of epinephrine (1:100,000) to lidocaine was associated with a 20-fold in bacterial counts compared with control values ( n= 10). This is the first study to demonstrate inhibition of by a local anesthetic agent in an in vivo model of a surgical wound. This information suggests a possible role for local anesthetics in prophylaxis against surgical wound infection.

Postoperative wound infection, most often with, is of ubiquitous concern in surgical practice, occurring in an average of 1.5 to 5 percent of all procedures. The antimicrobial properties of local anesthetics have been documented over the past 25 years by in vitro studies. This study evaluates the effects of lidocaine preparations on in an in vivo setting. In a wound infection model using live albino guinea pigs, inoculum was introduced for the reproducible bacterial colonization of clean surgical wounds. One of two sites on the dorsum of each animal was infiltrated with a commercial lidocaine preparation (with and without epinephrine) prior to inoculation with (10 cfu/ml). The other site, inoculated with without preinfiltration with lidocaine, served as the control. Cultures from the sites treated with lidocaine were then compared with cultures from the control sites. All control sites had a consistent presence >or=10 cfu/ml, the threshold for bacterial inhibition of wound healing. Infiltration of the wound with 2 ml of 2% lidocaine prior to inoculation was associated with an average decrease in bacterial count of >70 percent ( n= 19). On the other hand, the addition of epinephrine (1:100,000) to lidocaine was associated with a 20-fold in bacterial counts compared with control values ( n= 10). This is the first study to demonstrate inhibition of by a local anesthetic agent in an in vivo model of a surgical wound. This information suggests a possible role for local anesthetics in prophylaxis against surgical wound infection.