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Objective: Annual program evaluations are important activities of all graduate medical education programs. Although the Accreditation Council for Graduate Medical Education provides general guidelines, there is substantial scope for educational innovation. Strengths, opportunities, aspirations, and results (SOAR) is a strengths-based framework for strategic planning. Because SOAR emphasizes positivity and engagement, it is an appealing framework for evaluating graduate medical education programs. Our objective was to demonstrate the feasibility and acceptability of SOAR in a program evaluation committee of a fellowship program to generate strategic initiatives., Methods: The authors used the four steps of SOAR within the program evaluation committee in 2022. Interviewers collected positive stories to understand program strengths. Then, rapid ideation was used to translate strengths into opportunities. These opportunities were condensed and refined for fellows to assess how well they align with aspirations. The ones that aligned best with aspirations were prioritized for implementation. Results were monitored through a scorecard based on specific, measurable, achievable, relevant, and time-bound (SMART) goals every month., Results: Of 15 divisional members, 11 participated (73.3%). Five major strengths were identified: supportive environment, variety of cases, scheduling flexibility, integration with larger networks, and multidisciplinary collaboration. These 5 yielded 15 opportunities, which were refined and condensed to 9. Four were selected for implementation: scholarly works accountability group, hybrid-flex curriculum, fellowship weekly huddles, and structured electives. Scorecards have shown successful implementation during a 4-month period., Conclusions: SOAR is an innovative and feasible approach to program evaluation that uses trainee engagement to translate and synergize existing program strengths into actionable program improvement.

Extracellular ATP regulates many important cellular functions in the liver by stimulating purinergic receptors. Recent studies have shown that rapid exocytosis of ATP-enriched vesicles contributes to ATP release from liver cells. However, this rapid ATP release is transient, and ceases in ~30 s after the exposure to hypotonic solution. The purpose of these studies was to assess the role of vesicular exocytosis in sustained ATP release. An exposure to hypotonic solution evoked sustained ATP release that persisted for more than 15 min after the exposure. Using FM1-43 (N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl)pyridinium dibromide) fluorescence to measure exocytosis, we found that hypotonic solution stimulated a transient increase in FM1-43 fluorescence that lasted ~2 min. Notably, the rate of FM1-43 fluorescence and the magnitude of ATP release were not correlated, indicating that vesicular exocytosis may not mediate sustained ATP release from liver cells. Interestingly, mefloquine potently inhibited sustained ATP release, but did not inhibit an increase in FM1-43 fluorescence evoked by hypotonic solution. Consistent with these findings, when exocytosis of ATP-enriched vesicles was specifically stimulated by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), mefloquine failed to inhibit ATP release evoked by NPPB. Thus, mefloquine can pharmacologically dissociate sustained ATP release and vesicular exocytosis. These results suggest that a distinct mefloquine-sensitive membrane ATP transport may contribute to sustained ATP release from liver cells. This novel mechanism of membrane ATP transport may play an important role in the regulation of purinergic signaling in liver cells.

Purinergic P2Y(2) G-protein coupled receptors play a key role in the regulation of hepatic Ca(2+) signaling by extracellular ATP. The concentration of copper in serum is about 20muM. Since copper accumulates in the liver in certain disease states, the purpose of these studies was to assess the effects of copper on P2Y(2) receptors in a model liver cell line. Exposure to a P2Y(2) agonist UTP increased [Ca(2+)](i) by stimulating Ca(2+) release from thapsigargin-sensitive Ca(2+) stores. Pretreatment of HTC cells for several minutes with copper did not affect cell viability, but potently inhibited increases in [Ca(2+)](i) evoked by UTP and thapsigargin. During this pretreatment, copper was not transported into the cytosol, and inhibited P2Y(2) receptors in a concentration-dependent manner with the IC(50) of about 15muM. These results suggest that copper inhibits P2Y(2) receptors through the effects on thapsigargin-sensitive Ca(2+) stores by acting from an extracellular side. Further experiments indicated that these effect of copper may lead to inhibition of regulatory volume decrease (RVD) evoked by hypotonic solution. Thus, copper may contribute to defective regulation of purinergic signaling and liver cell volume in diseases associated with the increased serum copper concentration., (Copyright 2010 Elsevier Inc. All rights reserved.)

Cells release ATP in response to physiologic stimuli. Extracellular ATP regulates a broad range of important cellular functions by activation of the purinergic receptors in the plasma membrane. The purpose of these studies was to assess the role of vesicular exocytosis in cellular ATP release. FM1-43 fluorescence was used to measure exocytosis and bioluminescence to measure ATP release in HTC rat hepatoma and Mz-Cha-1 human cholangiocarcinoma cells. Exposure to a Cl(-) channel inhibitor 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) (50-300 microM) stimulated a 5-100-fold increase in extracellular ATP levels within minutes of the exposure. This rapid response was not a result of changes in cell viability or Cl(-) channel activity. NPPB also potently stimulated ATP release in HEK293 cells and HEK293 cells expressing a rat P2X7 receptor indicating that P2X7 receptors are not involved in stimulation of ATP release by NPPB. In all cells studied, NPPB rapidly stimulated vesicular exocytosis that persisted many minutes after the exposure. The kinetics of NPPB-evoked exocytosis and ATP release were similar. Furthermore, the magnitudes of NPPB-evoked exocytosis and ATP release were correlated (correlation coefficient 0.77), indicating that NPPB may stimulate exocytosis of a pool of ATP-enriched vesicles. These findings provide further support for the concept that vesicular exocytosis plays an important role in cellular ATP release and suggest that NPPB can be used as a biochemical tool to specifically stimulate ATP release through exocytic mechanisms.

5'-AMP-activated kinase (AMPK) plays a key role in the regulation of cellular lipid metabolism. The contribution of vesicular exocytosis to this regulation is not known. Accordingly, we studied the effects of AMPK on exocytosis and intracellular lipid content in a model liver cell line. Activation of AMPK by metformin or 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) increased the rates of constitutive exocytosis by about 2-fold. Stimulation of exocytosis by AMPK occurred within minutes, and persisted after overnight exposure to metformin or AICAR. Activation of AMPK also increased the amount of triacylglycerol (TG) and apolipoprotein B (apoB) secreted from lipid-loaded cells. These effects were accompanied by a decrease in the intracellular lipid content indicating that exocytosis of lipoproteins was involved in these lipid-lowering effects. While AMPK increased the rates of fatty acid oxidation (FAO), the lipid-lowering effects were quantitatively significant even after inhibition of FAO with R-etomoxir. These results suggest that hepatic AMPK stimulates constitutive exocytosis of lipoproteins, which may function in parallel with FAO to regulate intracellular lipid content.

Unlabelled: Ionotrophic purinergic (P2X) receptors function as receptor-gated cation channels, where agonist binding leads to opening of a nonselective cation pore permeable to both Na(+) and Ca(2+). Based on evidence that extracellular adenosine 5'-triphosphate (ATP) stimulates glucose release from liver, these studies evaluate whether P2X receptors are expressed by hepatocytes and contribute to ATP-dependent calcium signaling and glucose release. Studies were performed in isolated hepatocytes from rats and mice and hepatoma cells from humans and rats. Transcripts and protein for both P2X4 and P2X7 were detectable, and immunohistochemistry of intact liver revealed P2X4 in the basolateral and canalicular domains. In whole cell patch clamp studies, exposure to the P2X4/P2X7 receptor agonist 2'3'-O-(4-benzoyl-benzoyl)-adenosine 5'-triphosphate (BzATP; 10 microM) caused a rapid increase in membrane Na(+) conductance. Similarly, with Fluo-3 fluorescence, BzATP induced an increase in intracellular [Ca(2+)]. P2X4 receptors are likely involved because the calcium response to BzATP was inhibited by Cu(2+), and the P2X4 modulators Zn(2+) and ivermectin (0.3-3 microM) each increased intracellular [Ca(2+)]. Exposure to BzATP decreased cellular glycogen content; and P2X4 receptor messenger RNA increased in glycogen-rich liver samples., Conclusion: These studies provide evidence that P2X4 receptors are functionally important in hepatocyte Na(+) and Ca(2+) transport, are regulated by extracellular ATP and divalent cation concentrations, and may constitute a mechanism for autocrine regulation of hepatic glycogen metabolism.

Aim: To assess the academic performance of students who transferred to the Zagreb School of Medicine from other three medical schools in Croatia., Methods: Academic performance of medical students who moved from Rijeka, Osijek, or Split University Medical Schools to the Zagreb University School of Medicine at the second or third year was compared with academic performance of students enrolled at the Zagreb University School of Medicine. Using the Zagreb Medical School's registry, we made a list of 57 transfer students to Zagreb Medical School in the 1985-1994 period. Control group was formed of students enrolled at the Zagreb School of Medicine in the same period, whose names followed in alphabetical order after the names of transfer students. Students' performance was analyzed according to their grade average before transfer, grade average in the first year after transfer, total grade average after transfer, overall grade average, and duration of studies. We also analyzed the proportion of students in each group who did not pass the admission test at the Zagreb School of Medicine in the year before the enrollment in Zagreb, Osijek, Rijeka, and Split Medical Schools. Nineteen transfer students, transferred between 1985 and 1988, and their controls were excluded from the analysis because of incomplete data., Results: Transfer students had significantly lower grade average before transfer (3.2-/+0.6 vs 3.5-/+0.7, p=0.03, Student t-test), lower grade average in the first year after transfer (3.2-/+0.6 vs 3.5-/+0.7, p=0.03), lower total grade average after transfer (3.6-/+0.5 vs 4.0-/+0.6, p<0.001), and lower overall grade average (3.5-/+0.5 vs 3.9-/+0.6, p<0.001) than control students. Median time to graduate for transfer students was 7 years (range, 5-9) and 6 years (range, 5-9) for control students (p=0.375, Mann-Whitney test). There were significantly more students among transfer students who did not pass the admission test at the Zagreb School of Medicine in the year before the final enrollment than their controls (15/38 vs 4/38, p=0.009, chi-square test)., Conclusion: Transfer students had poorer academic performance than students who passed the admission test and were enrolled at the Zagreb School of Medicine from the first year of studies.