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Articles by R John
Total Records ( 2 ) for R John
  S. D Russell , J. G Rogers , C. A Milano , D. B Dyke , F. D Pagani , J. M Aranda , C. T Klodell , A. J Boyle , R John , L Chen , H. T Massey , D. J Farrar , J. V Conte and for the HeartMate II Clinical Investigators
 

Background— The effects of continuous blood flow and reduced pulsatility on major organ function have not been studied in detail.

Methods and Results— We evaluated renal (creatinine and blood urea nitrogen) and hepatic (aspartate transaminase, alanine transaminase, and total bilirubin) function in 309 (235 male, 74 female) advanced heart failure patients who had been supported with the HeartMate II continuous-flow left ventricular assist device for bridge to transplantation. To determine whether patients with impaired renal and hepatic function improve over time with continuous-flow left ventricular assist device support or whether there are any detrimental effects in patients with normal organ function, we divided patients into those with above-normal and normal laboratory values before implantation and measured blood chemistry over time during left ventricular assist device support. There were significant improvements over 6 months in all parameters in the above-normal groups, with values in the normal groups remaining in the normal range over time. Mean blood urea nitrogen and serum creatinine in the above-normal groups decreased significantly from 37±14 to 23±10 mg/dL (P<0.0001) and from 1.8±0.4 to 1.4±0.8 mg/dL (P<0.01), respectively. There were decreases in aspartate transaminase and alanine transaminase in the above-normal groups from 121±206 and 171±348 to 36±19 and 31±22 IU (P<0.001), respectively. Total bilirubin for the above-normal group was 2.1±0.9 mg/dL at baseline; after an acute increase at week 1, it decreased to 0.9±0.5 mg/dL by 6 months (P<0.0001). Both renal and liver values from patients in the normal groups remained normal during support with the left ventricular assist device.

Conclusions— The HeartMate II continuous-flow left ventricular assist device improves renal and hepatic function in advanced heart failure patients who are being bridged to transplantation, without evidence of detrimental effects from reduced pulsatility over a 6-month time period.

Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00121472.

  S. W Kong , Y. W Hu , J. W. K Ho , S Ikeda , S Polster , R John , J. L Hall , E Bisping , B Pieske , C. G dos Remedios and W. T. Pu
 

Background— Alternative mRNA splicing is an important mechanism for regulation of gene expression. Altered mRNA splicing occurs in association with several types of cancer, and a small number of disease-associated changes in splicing have been reported in heart disease. However, genome-wide approaches have not been used to study splicing changes in heart disease. We hypothesized that mRNA splicing is different in diseased hearts compared with control hearts.

Methods and Results— We used the Affymetrix Exon array to globally evaluate mRNA splicing in left ventricular myocardial RNA from controls (n=15) and patients with ischemic cardiomyopathy (n=15). We observed a broad and significant decrease in mRNA splicing efficiency in heart failure, which affected some introns to a greater extent than others. The profile of mRNA splicing separately clustered ischemic cardiomyopathy and control samples, suggesting distinct changes in mRNA splicing between groups. Reverse transcription–polymerase chain reaction validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that splicing of 4 key sarcomere genes, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), myosin heavy chain 7 (MYH7), and filamin C, gamma (FLNC), was significantly altered in ischemic cardiomyopathy and in dilated cardiomyopathy and aortic stenosis. In aortic stenosis samples, these differences preceded the onset of heart failure. Remarkably, the ratio of minor to major splice variants of TNNT2, MYH7, and FLNC classified independent test samples as control or disease with >98% accuracy.

Conclusions— Our data indicate that mRNA splicing is broadly altered in human heart disease and that patterns of aberrant RNA splicing accurately assign samples to control or disease classes.

 
 
 
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