Cultivating next generation leadership: preceptors' rating of competencies in post-graduate administrative residents and fellows

Substantial national attention is being directed at enhancing the competency levels of early careerists in healthcare management. In this study, we examined preceptors' ratings of administrative resident/fellow competencies in multiple domains, and we compared those to our previous results of self-rated competency by residents/fellows. In this national sample of preceptors (n=61) of administrative residency/fellowship program listed with the American College of Healthcare Executives, competency in the information management domain was ranked highest, with more than half of preceptors (55.7%) giving their residents/fellows an "A" rating. Fewer preceptors (between 30.0% and 39.2%) gave their residents/fellows an "A" rating in domains of interpersonal and emotional intelligence, analytic and conceptual reasoning, and clinical operations. Less than 20% of preceptors rated competencies as "A" level in the domains of human resources/marketing/public affairs, financial management, fund raising, and facilities management. There were significant differences in preceptor ratings compared with resident/fellow self-ratings, with preceptors often providing lower ratings than provided by resident/fellows. The findings highlight the need not only to enhance competency levels of graduates but also to address the potential mismatch in early careerists' and preceptors' views about required and attained competency levels.     

Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy

Caloric restriction extends life span in a variety of species, highlighting the importance of energy balance in aging. A new longevity gene, Indy (for I'm not dead yet), which doubles the average life span of flies without a loss of fertility or physical activity, was postulated to extend life by affecting intermediary metabolism. We report that functional studies in Xenopus oocytes show INDY is a metabolite transporter that mediates the high-affinity, disulfonic stilbene-sensitive flux of dicarboxylates and citrate across the plasma membrane by a mechanism that is not coupled to Na(+), K(+), or Cl(-). Immunocytochemical studies localize INDY to the plasma membrane with most prominent expression in adult fat body, oenocytes, and the basolateral region of midgut cells and show that life-extending mutations in Indy reduce INDY expression. We conclude that INDY functions as a novel sodium-independent mechanism for transporting Krebs and citric acid cycle intermediates through the epithelium of the gut and across the plasma membranes of organs involved in intermediary metabolism and storage. The life-extending effect of mutations in Indy is likely caused by an alteration in energy balance caused by a decrease in INDY transport function.     

In vitro antienterococcal activity explains associations between exposures to antimicrobial agents and risk of colonization by multiresistant enterococci

We compared ceftriaxone and piperacillin-tazobactam at doses ranging from 0.1 to 2 times the human equivalent daily dose (HEDD), to determine their impact on gastrointestinal colonization by ampicillin- and vancomycin-resistant Enterococcus faecium C68 in a mouse model. Ceftriaxone failed to promote colonization at doses up to 0.25 times the HEDD, whereas piperacillin-tazobactam promoted colonization at doses up to 0.5 times the HEDD. Ceftriaxone promoted colonization at doses at least 0.5 times the HEDD, whereas piperacillin-tazobactam inhibited colonization at doses at least 0.75 times the HEDD. Both piperacillin-tazobactam and ceftriaxone inhibited colonization by an enterococcal strain devoid of low-affinity penicillin-binding protein-5 (significantly increasing its susceptibility to these agents), at doses that promoted colonization by E. faecium C68. These results support a model in which the impact that different beta -lactam agents have on colonization by VRE is related to the level of the beta -lactam agent's intrinsic antienterococcal activity against the colonizing strain.     

A specific mechanism of nonspecific inhibition

Promiscuous small molecules plague screening libraries and hit lists. Previous work has found that several nonspecific compounds form submicrometer aggregates, and it has been suggested that this aggregate species is responsible for the inhibition of many different enzymes. It is not understood how aggregates inhibit their targets. To address this question, biophysical, kinetic, and microscopy methods were used to study the interaction of promiscuous, aggregate-forming inhibitors with model proteins. By use of centrifugation and gel electrophoresis, aggregates and protein were found to directly interact. This is consistent with a subsequent observation from confocal fluorescence microscopy that aggregates concentrate green fluorescent protein. beta-Lactamase mutants with increased or decreased thermodynamic stability relative to wild-type enzyme were equally inhibited by an aggregate-forming compound, suggesting that denaturation by unfolding was not the primary mechanism of interaction. Instead, visualization by electron microscopy revealed that enzyme associates with the surface of inhibitor aggregates. This association could be reversed or prevented by the addition of Triton X-100. These observations suggest that the aggregates formed by promiscuous compounds reversibly sequester enzyme, resulting in apparent inhibition. They also suggest a simple method to identify or reverse the action of aggregate-based inhibitors, which appear to be widespread.     

Enhancing antimelanoma immune responses through apoptosis

We examined the feasibility of using tumor apoptosis at accessible sites to enhance antimelanoma immune responses in a model of spontaneous canine melanoma. We show that priming peripheral blood mononuclear cells with apoptotic melanoma cells significantly enhanced autologous and allogeneic lymphokine-activated killing of tumor cells. Since various pathways required for intrinsic apoptosis are often inactivated in melanoma, we used Fas ligand (FasL) overexpression to promote extrinsic apoptosis. FasL induced apoptosis in five of six cell lines. Each of the susceptible lines, but not the resistant one, expressed Fas mRNA. In addition, direct intratumoral administration of FasL DNA to tumor-bearing dogs was safe, with no adverse events reported over 7 days of observation. A reduction of tumor burden was seen in three of five dogs treated. The reduction of tumor volume was correlated with Fas expression by the tumors, although one dog with a Fas-negative tumor survived for 82 weeks after treatment. Our data show that overexpression of FasL is suitable to promote apoptosis of Fas(+) melanomas, and support the notion that priming immune responder cells with apoptotic tumor cells may enhance antitumor responses. The results also suggest that intratumoral administration of FasL offers a safe route for therapeutic gene delivery.     

Evaluation of DNA repair inhibition by antitumor or antibiotic drugs using a chemiluminescence microplate assay

A recently derived in vitro chemiluminescence assay (Salles et al. [1995] Anal. Biochem., 232, 37-42) has been used to investigate the effects of a panel of twenty-two anticancer drugs and certain antibiotics on the excision repair activity of cell-free extracts from the human cell line, HeLa. This methodology, termed the 3D (Damaged DNA Detection) assay, based on the in vitro excision repair assay previously developed (Wood et al. [1988] Cell, 53, 97-106) has provided data indicating definite in vitro inhibition of DNA repair by actinomycin D, aphidicolin, doxorubicin, distamycin A and mithramycin A. This assay therefore offers the potential for identifying agents with the ability to inhibit DNA repair.