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Articles by J. A Johnson
Total Records ( 3 ) for J. A Johnson
  F. M Clement , S Klarenbach , M Tonelli , J. A Johnson and B. J. Manns
 

Background  Treatment of anemia in chronic kidney disease (CKD) with erythropoietin-stimulating agents (ESAs) is commonplace. The optimal hemoglobin treatment target has not been established. A clearer understanding of the health-related quality of life (HQOL) impact of hemoglobin target levels is needed. We systematically reviewed the randomized controlled trial (RCT) data on HQOL for patients treated with low to intermediate (9.0-12.0 g/dL) and high hemoglobin target levels (>12.0 g/dL) and performed a meta-analysis of all available 36-item short-form (SF-36) RCT data.

Methods  We conducted a search to identify all RCTs of ESA therapy in patients with anemia associated with CKD (1966–December 2006). Inclusion criteria were (1) 30 or more participants, (2) anemic adults with CKD, (3) epoetin (alfa and beta) or darbepoetin used, (4) a control arm, and (5) reported HQOL using a validated measure. All available SF-36 data underwent meta-analysis using the weighted mean difference.

Results  Of 231 full texts screened, 11 eligible studies were identified. The SF-36 was used in 9 trials. Reporting of these data was generally incomplete. Data from each domain of the SF-36 were summarized. Statistically significant changes were noted in the physical function (weighted mean difference [WMD], 2.9; 95% confidence interval [CI], 1.3 to 4.5), general health (WMD, 2.7; 95% CI, 1.3 to 4.2), social function (WMD, 1.3; 95% CI, –0.8 to 3.4), and mental health (WMD, 0.4; 95% CI, 0.1 to 0.8) domains. None of the changes would be considered clinically significant.

Conclusions  Our study suggests that targeting hemoglobin levels in excess of 12.0 g/dL leads to small and not clinically meaningful improvements in HQOL. This, in addition to significant safety concerns, suggests that targeting treatment to hemoglobin levels that are in the range of 9.0 to 12.0 g/dL is preferred.

  M Schafer , S Dutsch , U auf dem Keller , F Navid , A Schwarz , D. A Johnson , J. A Johnson and S. Werner
 

Ultraviolet (UV) B irradiation can severely damage the skin and even induce tumorigenesis. It exerts its effects by direct DNA modification and by formation of reactive oxygen species (ROS). We developed a strategy to genetically activate target gene expression of the transcription factor NF-E2-related factor 2 (Nrf2) in keratinocytes in vivo based on expression of a constitutively active Nrf2 mutant. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS detoxification. Remarkably, the protective effect was extended to neighboring cells. Using different combinations of genetically modified mice, we demonstrate that Nrf2 activates the production, recycling, and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. Most importantly, we found that endogenous Nrf2 controls selective protection of suprabasal keratinocytes from UVB-induced apoptosis through activation of cytoprotective genes. This finding explains the preferential UVB-induced apoptosis of basal cells, which is important for elimination of mutated stem cells as well as for preservation of skin integrity. Taken together, our results identify Nrf2 as a key regulator in the UV response of the skin.

  L Liu , J Hou , J Du , R. S Chumanov , Q Xu , Y Ge , J. A Johnson and R. M. Murphy
 

Tg2576 mice produce high levels of beta-amyloid (Aβ) and develop amyloid deposits, but lack neurofibrillary tangles and do not suffer the extensive neuronal cell loss characteristic of Alzheimer's disease. Protection from Aβ toxicity has been attributed to up-regulation of transthyretin (TTR), a normal component of plasma and cerebrospinal fluid. We compared the effect of TTR purified from human plasma (pTTR) with that produced recombinantly (rTTR) on Aβ aggregation and toxicity. pTTR slowed Aβ aggregation but failed to protect primary cortical neurons from Aβ toxicity. In contrast, rTTR accelerated aggregation, while effectively protecting neurons. This inverse correlation between Aβ aggregation kinetics and toxicity is consistent with the hypothesis that soluble intermediates rather than insoluble fibrils are the most toxic Aβ species. We carried out a detailed comparison of pTTR with rTTR to ascertain the probable cause of these different effects. No differences in secondary, tertiary or quaternary structure were detected. However, pTTR differed from rTTR in the extent and nature of modification at Cys10. We hypothesize that differential modification at Cys10 regulates TTR's effect on Aβ aggregation and toxicity.

 
 
 
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