Publications

The DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) causes cardiomyocyte death as a result of energy loss from excessive activation of poly-(ADP) ribose polymerase-1 (PARP-1) resulting in depletion of its substrates nicotinamide adenine dinucleotide (NAD) and ATP. Previously we showed that the chemotherapeutic agent vincristine (VCR) is cardioprotective. Here we tested the hypothesis that VCR inhibits MNNG-induced PARP activation. Adult mouse cardiomyocytes were incubated with 100 micromol/L MNNG with or without concurrent VCR (20 micromol/L) for 2 to 4 hours. Cardiomyocyte survival was measured using the trypan blue exclusion assay. Western blots were used to measure signaling responses. MNNG-induced cardiomyocyte damage was time- and concentration-dependent. MNNG activated PARP-1 and depleted NAD and ATP. VCR completely protected cardiomyocytes from MNNG-induced cell damage and maintained intracellular levels of NAD and ATP. VCR increased phosphorylation of the prosurvival signals Akt, GSK-3beta, Erk1/2, and p70S6 kinase. VCR delayed PARP activation as evidenced by Western blot and by immunofluorescence staining of poly (ADP)-ribose, but without directly inhibiting PARP-1 itself. Known PARP-1 inhibitors also protected cardiomyocytes from MNNG-induced death. Repletion of ATP, NAD, pyruvate, and glutamine had effects similar to PARP-1 inhibitors. We conclude that VCR protects cardiomyocytes from MNNG toxicity by regulating PARP-1 activation, intracellular energy metabolism, and prosurvival signaling.

BACKGROUND

Although residency programs must prepare physicians who can analyze and improve their practice, practice improvement (PI) is new for many faculty preceptors. We describe the pilot of a PI curriculum incorporating a practice improvement module (PIM) from the American Board of Internal Medicine for residents and their faculty preceptors.

METHODS

Residents attended PI didactics and completed a PIM during continuity clinic and outpatient months working in groups under committed faculty.

RESULTS

All residents participated in PI group projects. Residents agreed or strongly agreed that the projects and the curriculum benefited their learning and patient care. A self-assessment revealed significant improvement in PI competencies, but residents were just reaching a "somewhat confident" level.

CONCLUSION

A PI curriculum incorporating PIMs is an effective way to teach PI to both residents and faculty preceptors. We recommend the team approach and use of the PIM tutorial approach especially for faculty.

BACKGROUND

Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.

METHODS

We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.

RESULTS

The prevalence of moderate to severe kidney disease (eGFR 15-59 mL/min/1.73 m(2)) among anaemic persons was 15-16% when based on serum creatinine alone (eGFR(SCR)) or combined with cystatin C (eGFR(SCR) (+) (CYSC)); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFR(CYSC)). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFR(CYSC) than eGFR(SCR) and eGFR(SCR) (+) (CYSC) in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98-27.36).

CONCLUSIONS

Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFR(CYSC) may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.

Multistate modeling methods are well-suited for analysis of some chronic diseases that move through distinct stages. The memoryless or Markov assumptions typically made, however, may be suspect for some diseases, such as hepatitis C, where there is interest in whether prognosis depends on history. This paper describes methods for multistate modeling where transition risk can depend on any property of past progression history, including time spent in the current stage and the time taken to reach the current stage. Analysis of 901 measurements of fibrosis in 401 patients following liver transplantation found decreasing risk of progression as time in the current stage increased, even when controlled for several fixed covariates. Longer time to reach the current stage did not appear associated with lower progression risk. Analysis of simulation scenarios based on the transplant study showed that greater misclassification of fibrosis produced more technical difficulties in fitting the models and poorer estimation of covariate effects than did less misclassification or error-free fibrosis measurement. The higher risk of progression when less time has been spent in the current stage could be due to varying disease activity over time, with recent progression indicating an "active" period and consequent higher risk of further progression.

PURPOSE

The purpose of this study was to compare the biomechanical properties of transosseous versus suture anchor repair of the subscapularis tendon. We also performed real-time measurement of contact area and pressure of the repair site under rotational loads.

METHODS

Six paired human cadaveric shoulders were subjected to rotational loading after repair of the subscapularis tendon. Both shoulders were randomized to transosseous or suture anchor repairs. Real-time pressure sensors were placed between the subscapularis tendon and lesser tuberosity. The repair was subjected to cyclical rotational loading and load-to-failure testing.

RESULTS

No significant difference was detected in initial pressurized contact area between transosseous repairs (1.70 +/- 0.99 cm(2), 57.88 +/- 30.02% footprint) and suture anchor repairs (1.08 +/- 0.58 cm(2), 34.26% +/- 17.32% footprint). Under cyclical loading, the conditioning elongation of transosseous repairs (0.64 +/- 0.40 mm) was significantly lower (P < .05) than that of suture anchor repairs (2.38 +/- 1.58 mm). No significant difference was found in mean pressurized contact area between the transosseous repairs (2.72 +/- 1.25 cm(2), 94.2% +/- 37.4% footprint) and suture anchor repairs (2.01 +/- 0.89 cm(2), 65.9% +/- 27.9% footprint). For suture anchor repairs, repair-site contact area was significantly (P < .05) smaller than the area of corresponding native insertional footprints; for transosseous repairs, no significant difference was detected. There were no significant differences in peak pressures between the 2 repairs. In the load-to-failure tensile test, there was no significant difference between transosseous repairs (453.2 +/- 66.1 N) and suture anchor repairs (392.6 +/- 78.0 N).

CONCLUSIONS

Transosseous and suture anchor repairs of the subscapularis tendon have comparable biomechanical properties. Despite increased conditioning elongation in suture anchor repairs, we found no significant differences in mean contact area between the 2 repairs under cyclical loading. The suture anchor repairs do have a smaller contact area than the native insertional area. Real-time pressure and contact area measurements enabled mapping of the repair site throughout cyclical loading.

CLINICAL RELEVANCE

Rotational loading of the subscapularis tendon may provide a more accurate representation of subscapularis tendon injuries. Both techniques showed adequate repair strength; however, neither surgical technique exhibited normal insertional behavior in this time-zero biomechanical study.