No abstract

We have utilized Caenorhabditis elegans to study human methylmalonic acidemia. Using bioinformatics, a full complement of mammalian homologues for the conversion of propionyl-CoA to succinyl-CoA in the genome of C. elegans, including propionyl-CoA carboxylase subunits A and B (pcca-1, pccb-1), methylmalonic acidemia cobalamin A complementation group (mmaa-1), co(I) balamin adenosyltransferase (mmab-1), MMACHC (cblc-1), methylmalonyl-CoA epimerase (mce-1) and methylmalonyl-CoA mutase (mmcm-1) were identified. To verify predictions that the entire intracellular adenosylcobalamin metabolic pathway existed and was functional, the kinetic properties of the C. elegans mmcm-1 were examined. RNA interference against mmcm-1, mmab-1, mmaa-1 in the presence of propionic acid revealed a chemical phenotype of increased methylmalonic acid; deletion mutants of mmcm-1, mmab-1 and mce-1 displayed reduced 1-[ 14 C]-propionate incorporation into macromolecules. The mutants produced increased amounts of methylmalonic acid in the culture medium, proving that a functional block in the pathway caused metabolite accumulation. Lentiviral delivery of the C. elegans mmcm-1 into fibroblasts derived from a patient with mut o class methylmalonic acidemia could partially restore propionate flux. The C. elegans mce-1 deletion mutant demonstrates for the first time that a lesion at the racemase step of methylmalonyl-CoA metabolism can functionally impair flux through the methylmalonyl-CoA mutase pathway and suggests that malfunction of MCEE may cause methylmalonic acidemia in humans. The C. elegans system we describe represents the first lower metazoan model organism of mammalian propionate spectrum disorders and demonstrates that mass spectrometry can be employed to study a small molecule chemical phenotype in C. elegans RNAi and deletion mutants.

Purpose To evaluate the value of multiparametric quantitative ultrasound imaging (QUI) in assessing chronic kidney disease (CKD) using kidney biopsy pathology as the reference standard. Methods We prospectively measured multiparametric QUI markers with grayscale, spectral Doppler, and acoustic radiation force impulse imaging in 25 patients with CKD prior to their kidney biopsies and in 10 healthy volunteers. Based on all pathology (glomerulosclerosis, IF/TA, arteriosclerosis, and edema) scores, the 25 CKD patients were classified into mild (no grade 3 and < 2 of grade 2) and moderate to severe (at least 2 of grade 2 or 1 of grade 3) CKD groups. Multiparametric QUI in the study included kidney length, cortical thickness, pixel-intensity, parenchymal shear wave velocity (SWV), intrarenal artery peak systolic velocity (PSV), end diastolic velocity (EDV), and resistive index (RI). We tested the difference in QUI parameters among mild CKD, moderate to severe CKD, and healthy controls using ANOVA, analyzed correlations of QUI parameters to kidney pathology scores and to eGFR using the Pearson correlation coefficient, and examined the diagnostic performance of QUI parameters in determining moderate CKD and eGFR <60 using ROC curve analysis. Results There were significant differences in cortical thickness, pixel-intensity, PSV, and EDV among the 3 groups (all p< 0.01). Among QUI parameters, the top AUROCs of PSV and EDV for determining pathologic moderate to severe CKD were 0.88 and 0.97, and for eGFR <60 were 0.76 and 0.86, respectively. Moderate to good correlations were found for PSV, EDV, and pixel-intensity to pathology score and eGFR. Conclusion PSV, EDV, and pixel-intensity are valuable in determining moderate to severe CKD. The value of SWV in assessing CKD needs further investigation.

Among cirrhotic patients who underwent evaluation for HCC with MR imaging, the revised OPTN/UNOS policy led to increased detection of 1-2-cm HCCs, decreased detection of 2-5-cm HCCs, and fewer patients who met criteria for increased transplant priority.

No abstract