Abstract-Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min Ϫ1) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation attenuated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2001;89:e32-e38.) Key Words: atrial fibrillation Ⅲ antioxidant Ⅲ ascorbate Ⅲ oxidative stress Ⅲ cardiac surgery A trial fibrillation (AF) is self-perpetuating 1 because of the combined effects of rate-induced electrophysiological and structural remodeling. 2 The earliest observed change in AF is an abbreviation of the atrial effective refractory period (ERP). The mechanisms by which high-rate activity results in electrophysiological remodeling are poorly understood. AF is also a frequent postoperative complication of cardiac surgery, with a reported incidence of 20% to 50%, increasing the risk of stroke. 3 Before arrhythmia onset, patients who experience postoperative AF exhibit increased atrial ectopy, abbreviation of monophasic action potential duration, and increased heart rate. 4 Evidence from animal models of atrial fibrillation, 5-7 as well as our studies of patients with postoperative AF, 8 supports a prominent role for myocyte calcium overload in initiating the process of atrial electrophysiological remodeling. We have documented both significant electrophysiological remodeling 8,9 and biochemical evidence of oxidative stress...

AMP-activated protein kinase (AMPK) is an important energy sensor that may be critical in regulating renal lipid accumulation. To evaluate the role of AMPK in mediating renal lipid accumulation, C57BL/6J mice were randomized to a standard diet, a high-fat diet, or a high-fat diet plus AICAR (an AMPK activator) for 14 weeks. Renal functional and structural studies along with electron microscopy were performed. Mice given the high-fat diet had proximal tubule injury with the presence of enlarged clear vacuoles, and multilaminar inclusions concurrent with an increase of tissue lipid and overloading of the lysosomal system. The margins of the clear vacuoles were positive for the endolysosomal marker, LAMP1, suggesting lysosome accumulation. Characterization of vesicles by special stains (Oil Red O, Nile Red, Luxol Fast Blue) and by electron microscopy showed they contained onion skin-like accumulations consistent with phospholipids. Moreover, cholesteryl esters and phosphatidylcholine-containing phospholipids were significantly increased in the kidneys of mice on a high-fat diet. AMPK activation with chronic AICAR treatment prevented the clinical and structural effects of high-fat diet. Thus, high-fat diet contributes to a dysfunction of the lysosomal system and altered lipid metabolism characterized by cholesterol and phospholipid accumulation in the kidney. AMPK NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript activation normalizes the changes in renal lipid content despite chronic exposure to lipid challenge. KeywordsAMPK; chronic kidney disease; lipid accumulation; lysosomal dysfunction; obesityThe growing epidemic of obesity particularly in the western world is considered a serious health and economic burden. Central obesity is a major risk factor for diabetes and hypertension that together account for ~ 70% of all cases of end-stage renal disease 1 that will lead to expensive renal replacement therapy. Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses in targeted organs. However, a full understanding of the mechanisms involved in progressive renal disease is still absent. Obesity-and diabetes-related kidney disease are associated with renal hemodynamic abnormalities, endothelial and podocyte dysfunction, glomerular basement membrane thickening and mesangial expansion, tubular atrophy, interstitial fibrosis, and a progressive decrease in renal function (increased albuminuria and decreased glomerular filtration rate) leading to end-stage renal disease. [2][3][4][5] There are marked lipid vacuoles present in human and experimental obesity-associated kidney disease; however, the composition and pathways related to their formation is unclear.In a recent study, our group highlighted the appearance of many of these features in high-fat diet (HFD)-induced obesity-related kidney disease model. 6 There was a beneficial effect of the specific central energy sensor AMP-activated protein kinase (AMPK) in regulating the initial inflammatory...

Stent fracture was likely to be affected by mechanical stress provoked by rigid structures and hinge points. Stent fracture might be associated with the high incidence of target lesion revascularization.

Toy Poodles with grade 4 MPL had significant femoral varus deformity, medial displacement of the tibial tuberosity, internal torsion of the proximal tibia, and hypoplasia of the patella.

BackgroundAutism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders.Objectives and MethodsWe used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice.ResultsWe found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.ConclusionsHyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.

Purpose:To elucidate whether apparent diffusion coefficient (ADC) values calculated from echo-planar diffusionweighted MR imaging (EPDWI) are useful in the differential diagnosis of ovarian cystic masses. Materials and Methods: EPDWI was performed in 131patients with ovarian cystic masses (54 mature cystic teratomas, 35 endometrial cysts, four other benign cysts, 14 benign neoplasms, and 24 malignant neoplasms). The areas of the highest signal intensity on EPDWI (b ϭ 1000 seconds/mm 2 ) and the lowest ADC values within the cystic component were evaluated. Results:On qualitative and quantitative analyses, mature cystic teratomas tended to show higher signal intensity and had areas of lower ADC values than endometrial cysts and other benign and malignant neoplasms (P Ͻ .005). In vitro scanning of the cystic contents of mature cystic teratomas confirmed that high signal on DWI or low ADC value was attributable to the keratinoid substance within the tumors. The difference in ADC between malignant and benign lesions were significant when mature cystic teratomas and endometrial cysts were included, but was not significant when they were excluded. Conclusion:The ADC value may add useful information to the differential diagnosis of ovarian cystic masses in limited populations, such as those with mature cystic teratomas with a small amount of fat. DIFFUSION-WEIGHTED IMAGING (DWI) and the calculated apparent diffusion coefficient (ADC) were originally used to demonstrate early ischemic change in brain tissue by depicting cytoplasmic edema (1). They have also been applied to differentiate brain tumors, particularly in the diagnosis of epidermoid and lymphoma (2-6). A high signal on DWI or a low ADC value of these tumors have been attributed to intratumoral keratinoid substance in the former, and high cellularity and a high nuclear-to-cytoplasm (NC) ratio without interstitial edematous change in the latter (2-6). Both of these conditions restrict Brownian movement of the free water molecules within the tumor. The ability of high-speed echo-planar imaging (EPI) to minimize artifacts due to respiratory motion has extended the application of DWI and ADC to the diagnosis of breast lesions (7-10) and prostate carcinomas (11,12), and promising preliminary results have been reported. However, there is controversy regarding the usefulness of this technique in cystic ovarian tumors (13-16), particularly as applied to differentiating benign from malignant lesions.In this study we applied echo-planar DWI (EPDWI) and ADC values to 131 cystic ovarian masses and assessed their potential usefulness in the differential diagnosis. MATERIALS AND METHODS SubjectsBetween September 2000 and December 2003, 322 consecutive women underwent MRI for evaluation of known ovarian lesions. Of these patients, 131 (11-75 years old, mean ϭ 33.9 years) underwent surgical resection within 2 weeks after the MRI was performed. Of the 131 patients, 102 had a lateral lesion and 29 had bilateral lesions. In the bilateral cases, the largest lesion was selected for...

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