This study tested the hypothesis that age-related changes in the dystrophin-glycoprotein complex (DGC) may precede age-associated alterations in muscle morphology and function. Compared to those in adult (6 month) rats, extensor digitorum longus (EDL) and soleus muscle mass was decreased in old (30 month) and very old (36 month) Fischer 344/NNiaHSD x Brown Norway/BiNia rats. The amount of dystrophin, beta-dystroglycan, and alpha-sarcoglycan increased with aging in the EDL and decreased with aging in the soleus. alpha-Dystroglycan levels were increased with aging in both muscles and displayed evidence of altered glycosylation. Immunostaining for the presence of antibody infiltration and dystrophin following increased muscle stretch suggested that the aging in the soleus was characterized by diminished membrane integrity. Together, these data suggest that aging is associated with alterations in EDL and soleus DGC protein content and localization. These results may implicate the DGC as playing a role in age-associated skeletal muscle remodeling.

Here, we determine the influence of aging on multiple markers of oxidative stress in the aorta of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSdxBrown Norway/BiNia (F344/NxBN) rats. Compared to adults, increases in as determined by oxidation of hydroethidine (HE) to ethidium (Et) were increased 79.7+/-7.0% in 36-month aortae and this finding was highly correlated with increases in medal thickness (r=0.773, p<0.01) and total protein nitration (r=0.706, p<0.01) but not Ki67, a marker for cell proliferation. Regression analysis showed that increases in aortic superoxide anion (O.-2) with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in metabolic (AMPK-alpha), signaling (mitogen activated protein kinases (MAPKs) along with c-Src), apoptotic (Bax, Bcl-2, Traf-2) and transcriptional (NF-kappaB) activities. These results suggest that the aging F344/NxBN aorta may be highly suited for unraveling the molecular events that lead to age-associated alterations in aortic oxidative stress.

A reversed association between Hp and EoE was found in a cohort of West Virginia children. The possible explanations for these findings are discussed.

The positive predictive value of tissue transglutaminase titers at ≥3× upper limit of normal or higher was too low to predict celiac disease in children. Our data suggested that in routine clinical practice, high titers of tissue transglutaminase are not sufficient to diagnose celiac disease in North American children without intestinal biopsies.

Objective We describe the Clickbusters initiative implemented at Vanderbilt University Medical Center (VUMC), which was designed to improve safety and quality and reduce burnout through the optimization of clinical decision support (CDS) alerts. Materials and Methods We developed a 10-step Clickbusting process and implemented a program that included a curriculum, CDS alert inventory, oversight process, and gamification. We carried out two 3-month rounds of the Clickbusters program at VUMC. We completed descriptive analyses of the changes made to alerts during the process, and of alert firing rates before and after the program. Results Prior to Clickbusters, VUMC had 419 CDS alerts in production, with 488 425 firings (42 982 interruptive) each week. After 2 rounds, the Clickbusters program resulted in detailed, comprehensive reviews of 84 CDS alerts and reduced the number of weekly alert firings by more than 70 000 (15.43%). In addition to the direct improvements in CDS, the initiative also increased user engagement and involvement in CDS. Conclusions At VUMC, the Clickbusters program was successful in optimizing CDS alerts by reducing alert firings and resulting clicks. The program also involved more users in the process of evaluating and improving CDS and helped build a culture of continuous evaluation and improvement of clinical content in the electronic health record.

Background: Diabetes mellitus is an important risk factor for increased vein graft failure after bypass surgery. However, the cellular and molecular mechanism(s) underlying vessel attrition in this population remain largely unexplored. Recent reports have suggested that the pathological remodeling of vein grafts may be mediated by mechanically-induced activation of the mitogen activated protein kinase (MAPK) signaling pathways and the MAPK-related induction of caspase-3 activity. On the basis of these findings, we hypothesized that diabetes may be associated with alterations in how veins "sense" and "respond" to altered mechanical loading.

Among the mono- and dichloroanilines, 3,5-Dichloroaniline (3,5-DCA) is the most potent nephrotoxicant in vivo and in vitro. However, the role of renal biotransformation in 3,5-DCA induced nephrotoxicity is unknown. The current study was designed to determine the in vitro nephrotoxic potential of 3,5-DCA in isolated renal cortical cells (IRCC) obtained from male Fischer 344 rats, and the role of renal bioactivation and oxidative stress in 3,5-DCA nephrotoxicity. IRCC (~4 million cells/ml) from male rats were exposed to 3,5-DCA (0-1.0 mM) for up to 120 min. In IRCC, 3,5-DCA was cytotoxic at 1.0 mM by 60 min as evidenced by the increased release of lactate dehydrogenase (LDH), but 120 min was required for 3,5-DCA 0.5 mM to increase LDH release. In subsequent studies, IRCC were exposed to a pretreatment (antioxidant or enzyme inhibitor) prior to exposure to 3,5-DCA (1.0 mM) for 90 min. Cytotoxicity induced by 3,5-DCA was attenuated by pretreatment with inhibitors of flavin-containing monooxygenase (FMO; methimazole, N-octylamine), cytochrome P450 (CYP; piperonyl butoxide, metyrapone), or peroxidase (indomethacin, mercaptosuccinate) enzymes. Use of more selective CYP inhibitors suggested that the CYP 2C family contributed to 3,5-DCA bioactivation. Antioxidants (glutathione, N-acetyl-L-cysteine, α-tocopherol, ascorbate, pyruvate) also attenuated 3,5-DCA nephrotoxicity, but oxidized glutathione levels and the oxidized/reduced glutathione ratios were not increased. These results indicate that 3,5-DCA may be activated via several renal enzyme systems to toxic metabolites, and that free radicals, but not oxidative stress, contribute to 3,5-DCA induced nephrotoxicity in vitro.

The effects of ageing on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signalling molecules that may be of particular importance in mediating numerous cellular responses, including control of cell growth, differentiation and adaptation, are the proteins associated with the mitogen-activated protein kinase (MAPK) signalling systems. The MAPKs, in conjunction with the p70 S6k signalling cascade, have emerged as critical components for regulating numerous mechanotransduction-related cellular responses. Here we investigate the ability of uniaxial stretch to activate the MAPK and p70 S6k pathways in adult (6-monthold), aged (30-month-old) and very aged (36-month-old) Fischer 344/NNiaHSd × Brown Norway/BiNia (FBN) rats. Western blotting of the MAPK family proteins extracellular signalregulated kinase (Erk) 1/2, p38-and c-Jun NH 2 -terminal kinase (Jnk)-MAPKs showed differential expression and activation between these proteins with age. An acute 15 min interval of 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of Erk1/2, p38-and Jnk-MAPK. However, ageing altered uniaxial induced p70 S6k pathway signalling. These observations confirm previous data demonstrating that MAPK proteins are mechanically regulated and also suggest that p70 S6k signalling expression and activation are controlled differently with ageing. Taken together, these data may help to explain, in part, the age-related changes in vascular morphology, function and response to injury.