Effects of comprehensive educational reforms on academic success in a diverse student body.

CONTEXT: Calls for medical curriculum reform and increased student diversity in the USA have seen mixed success: performance outcomes following curriculum revisions have been inconsistent and national matriculation of under-represented minority (URM) students has not met aspirations. Published innovations in curricula, academic support and pipeline programmes usually describe isolated interventions that fail to affect curriculum-level outcomes. METHODS: United States Medical Licensing Examination (USMLE) Step 1 performance and graduation rates were analysed for three classes of medical students before (matriculated 1995-1997, n=517) and after (matriculated 2003-2005, n=597) implementing broad-based reforms in our education system. The changes in pipeline recruitment and preparation programmes, instructional methods, assessment systems, academic support and board preparation were based on sound educational principles and best practices. RESULTS: Post-reform classes were diverse with respect to ethnicity (25.8% URM students), gender (51.8% female), and Medical College Admissions Test (MCAT) score (range 20-40; 24.1% scored ≤ 25). Mean±standard deviation MCAT scores were minimally changed (from 27.2±4.7 to 27.8±3.6). The Step 1 failure rate decreased by 69.3% and mean score increased by 14.0 points (effect size: d=0.67) overall. Improvements were greater among women (failure rate decreased by 78.9%, mean score increased by 15.6 points; d=0.76) and URM students (failure rate decreased by 76.5%, mean score increased by 14.6 points; d=0.74), especially African-American students (failure rate decreased by 93.6%, mean score increased by 20.8 points; d=1.12). Step 1 scores increased across the entire MCAT range. Four- and 5-year graduation rates increased by 7.1% and 5.8%, respectively. CONCLUSIONS: The effect sizes in these performance improvements surpassed those previously reported for isolated interventions in curriculum and student support. This success is likely to have resulted from the broad-based, mutually reinforcing nature of reforms in multiple components of the education system. The results suggest that a narrow reductionist view of educational programme reform is less likely to result in improved educational outcomes than a system perspective that addresses the coordinated functioning of multiple aspects of the academic enterprise.

A proteomics analysis of the effects of chronic hemiparetic stroke on troponin T expression in human vastus lateralis.

Stroke disability is attributed to upper motor neuron deficits resulting from ischemic brain injury. We have developed proteome maps of the Vastus lateralis to examine the effects of ischemic brain injury on paretic skeletal muscle myofilament proteins. Proteomics analyses from seven hemiparetic stroke patients have detected a decrease of three troponin T isoforms in the paretic muscle suggesting that myosin-actin interactions may be attenuated. We propose that ischemic brain injury may prevent troponin T participation in complex formation thereby affecting the protein interactions associated with excitation-contraction coupling. We have also detected a novel skeletal troponin T isoform that has a C-terminal variation. Our data suggest that the decreased slow troponin T isoform pools in the paretic limb may contribute to the gait deficit after stroke. The complexity of the neurological deficit on Vastus lateralis is suggested by the multiple changes in proteins detected by our proteomics mapping.

Oxidative modification and aggregation of creatine kinase from aged mouse skeletal muscle.

Creatine kinase catalyzes the reversible transfer of the gamma phosphate from ATP to creatine forming the high energy compound creatine phosphate. Muscle creatine kinase (CKm) activity maintains energetic homeostasis as variations in energy requirements dictate that ATP be readily available. Recent studies suggest that CKm activity is altered during aging. Proteomic analyses have shown that CKm is 3-nitrotyrosine (3-NT) modified and carbonylated in aged rodent skeletal muscle. However, it remains unknown if these modifications affect its structure and activity. To address this we characterized oxidatively modified CKm from the quadriceps of young, middle-aged, and aged mice. Our data indicate that 3-NT modified and carbonylated CKm are found predominantly in aged muscle and that it exists in high molecular weight oligomers and insoluble protein aggregates. CKm from middle-aged and aged mouse quadriceps also exhibits structural instability that may account for its reduction in function. These structural and functional changes correlate with the differential protein modifications. Interestingly, the majority of the age-related changes in enzyme activity and protein stability occurred by middle age. Our studies indicate that the age-associated oxidative and nitrative modification of CKm results in a decrease in its activity and may cause structural changes that promote oligomerization and aggregation.

Comprehensive changes in the learning environment: subsequent step 1 scores of academically at-risk students.

BACKGROUND: During the past 10 years at our institution, a number of changes have been instituted in the learning environment, including instructional techniques, assessment methods, academic support, and explicit board preparation. METHOD: The authors studied the Step 1 performance of students with MCAT scores of 20 to 25 in our former and current curricula. Effect sizes were calculated for score improvement using adjusted means from ANCOVA with covariates of MCAT and age. RESULTS: The overall effect size was 0.48, with larger effects seen for underrepresented minority students overall (d = 0.64) and African American students especially (d = 0.77), representing medium to large effects. Overall failure rates decreased by two thirds. CONCLUSIONS: Comprehensive changes in the learning environment were followed by substantial improvement in Step 1 performance among academically at-risk students.

Age-related increases in oxidatively damaged proteins of mouse kidney mitochondrial electron transport chain complexes.

Mitochondrial dysfunction generates reactive oxygen species (ROS) which damage essential macromolecules. Oxidative modification of proteins, DNA, and lipids has been implicated as a major causal factor in the age-associated decline in tissue function. Mitochondrial electron transport chain complexes I and III are the principal sites of ROS production, and oxidative modifications to the complex subunits inhibit their in vitro activity. Therefore, we hypothesize that mitochondrial complex subunits may be primary targets for oxidative damage by ROS which may impair normal complex activity by altering their structure/function leading to mitochondrial dysfunction associated with aging. This study of kidney mitochondria from young, middle-aged, and old mice reveals that there are functional decreases in complexes I, II, IV, and V between aged compared to young kidney mitochondria and these functional declines directly correlate with increased oxidative modification to particular complex subunits. We postulate that the electron leakage from complexes causes specific damage to their subunits and increased ROS generation as oxidative damage accumulates, leading to further mitochondrial dysfunction, a cyclical process that underlies the progressive decline in physiologic function seen in aged mouse kidney. In conclusion, increasing mitochondrial dysfunction may play a key role in the age-associated decline in tissue function.

Lower levels of F2-isoprostanes in serum and livers of long-lived Ames dwarf mice.

F2-isoprostanes (IsoPs), lipid peroxidation products, are markers that quantitatively measure levels of oxidative stress. IsoP levels increase in tissues and serum of aging animals suggesting an increase in oxidative stress. This supports the Free Radical Theory of Aging, which proposes that elevated levels of reactive oxygen species (ROS) cause macromolecular damage, and is a factor in the age-associated decline in tissue function. Numerous studies have shown that the longevity of long-lived mutant mice correlates with their resistance to oxidative stress. However, although the Ames dwarf (DW) mice show resistance to oxidative stress, it has not been shown that these mice have inherently lower levels of ROS. Our results show that the serum and liver IsoP levels in DW mice are lower at all ages suggesting that the lower levels of endogenous ROS production in DW mice may be a factor in their resistance to oxidative stress and longevity.

Carbonylation of ER chaperone proteins in aged mouse liver.

Progressive accumulation of oxidative damage to macromolecules in aged tissues is thought to contribute to the decline in tissue function characteristic of the aged phenotype. Mitochondria are a major intracellular source of reactive oxygen species (ROS); however, other organelles are also endogenous sources of oxyradicals and oxidants, which can damage macromolecules. We, therefore, sought to examine the relationship between aging and oxidative damage to ER resident proteins, which exist in a strongly oxidizing environment necessary for disulfide bond formation. In these studies, we have fractionated young and aged liver homogenates, resolved the proteins by 2D gel electrophoresis, assayed for oxidative damage as indicated by protein carbonylation, and identified BiP/Grp78, protein disulfide isomerase (PDI), and calreticulin as exhibiting an age-associated increase in oxidative damage. Increased carbonylation of these key proteins in aged liver suggests an age-associated impairment in protein folding, disulfide crosslinking, and glycosylation in the aged mouse liver.