Basophilic blast crisis in chronic myeloid leukemia

Acute nonoliguric renal failure developed in a 13-year-old girl, 1 month after the institution of isoniazid therapy because of a positive tuberculin test at school screening. A renal biopsy demonstrated severe crescentic glomerulonephritis with focal interstitial changes. Discontinuation of isoniazid and a short course of steroids and cyclophosphamide therapy were followed by complete recovery. Whereas isoniazid has been shown to induce a lupus-like syndrome and antihistone antinuclear antibodies, our patient displayed none of the clinical or immunological features that are characteristic of drug-induced lupus. Furthermore, none of the identifiable causes for crescentic glomerulonephritis was evident in this girl. To the best of our knowledge this is the first report suggesting a possible association of crescentic glomerulonephritis to isoniazid treatment.     

Natural Abundance Carbon Isotopic Analysis Indicates the Equal Contribution of Local Synthesis and Plasma Uptake to Palmitate Levels in the Mouse Brain

Saturated fatty acids are the most abundant fatty acids in the brain, however, there has been some debate regarding the ability of intact dietary saturated fatty acids to be incorporated into the brain. In the present study, we use compound specific isotope analysis to measure the natural abundance carbon isotopic signature of brain, liver, and blood palmitic acid (PAM) and compare it to the dietary PAM and sugar isotopic signatures to calculate the relative contribution of both the incorporation of intact and endogenously synthesized PAM to these pools. Mice were equilibrated to the study diet, and extracted fatty acids were analyzed with gas chromatography isotope ratio mass spectrometry to determine the carbon isotopic signature of PAM (δ¹³C_PAM). Liver, serum total, and serum unesterified fatty acid δ¹³C_PAM ranged between ?20.6 and ?21.1 mUr and were approximately 8.5 mUr more enriched in ¹³C when compared to the dietary PAM signature. Brain δ¹³C_PAM was found to be more enriched than liver or blood pools (?16.7 ± 0.2 mUr, mean ± SD). Two end‐member‐mixed modeling using the carbon isotopic signature of dietary PAM and dietary sugars determined the contribution of synthesis to the total tissue PAM pool to range between 44% and 48%. This suggests that endogenous synthesis and dietary PAM are near equal contributors to brain, liver, and blood PAM pools. In conclusion, our data provide evidence that brain PAM levels are maintained by both local endogenous synthesis and through the uptake of intact PAM from the blood.     

Differential immediate early gene expression in conditional hepatitis B virus pX-transforming versus nontransforming hepatocyte cell lines

We report construction and characterization of tetracycline-controlled hepatitis B virus pX-expressing hepatocyte (AML12) cell lines. These cell lines were constructed in AML12 clonal isolates (clones 3 and 4), which express constitutively the tetracycline-controlled transactivator. Since pX is implicated in HCC, this immortalized hepatocyte model system was used to investigate the mechanism of pX in transformation. Clonal isolates of 3pX and 4pX lineages display conditional synthesis of pX mRNA and protein and a 2-fold increase in growth saturation density following tetracycline removal, implicating pX in monolayer overgrowth. Interestingly, only 3pX clones display pX-dependent anchorage independence. Clone 3 lineages express hepatocyte nuclear factor-1alpha and hepatocyte-specific marker genes; clone 4 lineages express hepatocyte nuclear factor-1beta and reduced levels of hepatocyte-specific marker genes, suggesting the importance of the differentiated hepatocyte in pX-mediated oncogenic transformation. Importantly, 3pX and 4pX lineages display differential expression of immediate early genes c-fos and ATF3. The pX-transforming 3pX lineage displays early, pX-dependent induction of ATF3 and prolonged induction of c-fos. The nontransforming 4pX cells display an absence of pX-dependent ATF3 induction and transient induction of c-fos. Our results support the direct link of pX expression to oncogenic transformation in 3pX lineage clones and underscore the advantage of this conditional cellular model system for studying mechanisms of pX-mediated oncogenesis.