Objective-Cross-sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON).Methods-Patients underwent OCT measurement of RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at three centers. Low-contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed.Results-Among 299 patients (593 eyes) with ≥6 months follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: p<0.001; VA: p=0.005). RNFL thinning increased over time, with average losses of 2.9 μm at 2-3 years and 6.1 μm at 3-4.5 years (p<0.001 vs. 0.5-1-year follow-up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test-retest variability (≥6.6 μm) increased from 11% at 0-1 year to 44% at 3-4.5 years (p<0.001).Interpretation-Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with sub-clinical axonal loss in the anterior visual pathway in MS and support the use of OCT and low-contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols.Address all correspondence to: Dr. Laura J. Balcer, Department of Neurology, 3 E. Gates, 3400 Spruce Street, Philadelphia, PA 19104, 215-349-8072, Fax 215-349-5579, lbalcer@mail.med.upenn.edu. NIH Public Access Author ManuscriptAnn Neurol. Author manuscript; available in PMC 2011 June 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptVisual dysfunction is a common cause of disability and reduced quality of life in multiple sclerosis (MS). 1 The anterior visual pathway is a frequent site for inflammation and demyelination, and axonal degeneration is likely to be a final common pathway to permanent visual loss. [2][3][4][5] Recognized by MS experts as a critical dimension for outcomes assessment, 6 vision has been an important area of investigation. The findings of many studies have supported low-contrast letter acuity as a candidate clinical trial outcome measure. It can capture subtle visual impairment, treatment effects, MRI lesion burden, prolonged visual evoked potential latencies, and quality of life. 1,[7][8][9][10][11][12][13] Many ongoing MS trials have incorporated low-contrast acuity as a tertiary outcome.The emergence of optical coherence tomography (OCT) in MS has brought the anterior visual pathway to the forefront as a model for measuring therapeutic efficacy, particularly for trials involving neuroprotection. 14-32 A reliable marker for axonal loss in MS, 24 retina...

ABSTRACT:Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V max was 8.0 and 17.0 nmol/min/nmol enzyme and K m,u was 0.21 and 0.21 M, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 ؎ 9.8 ml/min/mg protein and 6.1 ؎ 3.6 ml/ min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.

Blood vessels are lined by endothelial cells engaged in distinct organ-specific functions but little is known about their characteristic gene expression profiles. RNA-Sequencing of the brain, lung, and heart endothelial translatome identified specific pathways, transporters and cell-surface markers expressed in the endothelium of each organ, which can be visualized at http://www.rehmanlab.org/ribo. We found that endothelial cells express genes typically found in the surrounding tissues such as synaptic vesicle genes in the brain endothelium and cardiac contractile genes in the heart endothelium. Complementary analysis of endothelial single cell RNA-Seq data identified the molecular signatures shared across the endothelial translatome and single cell transcriptomes. The tissue-specific heterogeneity of the endothelium is maintained during systemic in vivo inflammatory injury as evidenced by the distinct responses to inflammatory stimulation. Our study defines endothelial heterogeneity and plasticity and provides a molecular framework to understand organ-specific vascular disease mechanisms and therapeutic targeting of individual vascular beds.

No abstract

BackgroundCardiovascular disease is the leading cause of death in patients with chronic kidney disease. A body of evidence suggests that p-cresyl sulfate (PCS), a uremic toxin, is associated with the cardiovascular mortality rate of patients with chronic kidney disease; however, the molecular mechanisms underlying this feature have not yet been fully elucidated.Methods and ResultsWe aimed to determine whether PCS accumulation could adversely affect cardiac dysfunction via direct cytotoxicity to cardiomyocytes. In mice that underwent 5/6 nephrectomy, PCS promoted cardiac apoptosis and affected the ratio of left ventricular transmitral early peak flow velocity to left ventricular transmitral late peak flow velocity (the E/A ratio) observed by echocardiography (n=8 in each group). Apocynin, an inhibitor of NADPH oxidase activity, attenuates this alteration of the E/A ratio (n=6 in each group). PCS also exhibited proapoptotic properties in H9c2 cells by upregulating the expression of p22phox and p47phox, NADPH oxidase subunits, and the production of reactive oxygen species. Apocynin and N-acetylcysteine were both able to suppress the effect of PCS, underscoring the importance of NADPH oxidase activation for the mechanism of action.ConclusionsThis study demonstrated that the cardiac toxicity of PCS is at least partially attributed to induced NADPH oxidase activity and reactive oxygen species production facilitating cardiac apoptosis and resulting in diastolic dysfunction.