MaryBugbee2LynnFairbanks2 YongKe1 ThomasOshiro1 Paul Martin3 FawzyFawzy2
OBJECTIVE.Our objective was to assess the metabolite levels (myo-inositol
SUBJECTS AND METHODS.A stimulated-echo sequence was used to localize a sin gle voxel in the parietal region. Seventeenpatients and 13 healthy volunteers were investi gated. Nine of the 17 patients also were investigated after liver transplantation. A battery of neuropsychologic tests also was administered to patients to assessfrontal, memory, and mo tor functions.RESULTS. Before liver transplantation, significant reductions in mI:Cr (5 1%) and Cho:Cr (I I%) and a significant increase in Glx:Cr (20%) were observed in patients compared with the respective ratios in healthy subjects. Patients also were significantly impaired on neuro psychologic tests measuring frontal and motor performance, but not memory. Impairment on the frontal index showed a significant correlation with mI:Cr levels; likewise, performance on the motor index showed a significant correlation with serum ammonia levels before transplan tation. MR spectroscopy after liver transplantation showed changes in the metabolite ratios compared with the pretransplantation status. Even though the Glx:Cr ratios decreased after transplantation, the mI:Cr ratio remained lower than those of healthy subjects.
CONCLUSION.The relationship of changes in the metabolite ratios recorded from a voxel in the posteromedial parietal lobe to the neuropsychologic findings before and after liver transplantation is a major finding.
Background and aims: Barrier dysfunction is an important feature contributing to inflammation and diarrhoea in Crohn's disease (CD). Recently, tumour necrosis factor a (TNF-a) antibodies were recognised as effective in steroid refractory CD. The aim of this study was to characterise the effects of this therapy on the epithelial barrier. Patients and methods: Forceps biopsies were obtained from the sigmoid colon before and 14 days after TNF-a antibody therapy in 11 patients treated for chronic active CD (Crohn's disease activity index .150). Epithelial apoptoses were measured after terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL) and 49,6-diamidino-2-phenylindole staining. Epithelial resistance was determined by alternating current impedance analysis in miniaturised Ussing chambers. Occludin, claudin 1, and claudin 4 expression was quantified in immunoblots. Results: The epithelial apoptotic ratio was 2.1 (0.2)% in controls and increased to 5.3 (1.0)% in CD. TNF-a antibody therapy decreased the apoptotic ratio to 2.9 (1.0)% (normalised in 10 of 11 patients). In parallel, epithelial resistance was lower in CD than in controls (24 (3) v 42 (3) V6cm2 ) and improved to 34 (3) V6cm 2 after therapy. Occludin, claudin 1, and claudin 4 were not affected by TNF-a antibody therapy. In support of a functional role of epithelial apoptoses in CD, a similar decrease in resistance of 240% was observed when the apoptotic rate was selectively upregulated from 2.6% to 5.4% with camptothecin in HT-29/B6 cells. Conclusions: Epithelial apoptoses were upregulated in the colon in CD and restored to normal in 10 of 11 patients by TNF-a antibody therapy. This is the structural correlate of epithelial barrier dysfunction measured as epithelial resistance while expression of tight junction proteins did not contribute to this therapeutic effect.
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