William L. Gitomer

Recent Advances in the Biochemical and Molecular Biological Basis of Cystinuria

PURPOSE We reviewed the literature describing recent advances in the understanding of the nature of the transport proteins involved in the renal transport of cystine, properties of the solute carrier family 3, member 1 (SLC3A1) gene, which is involved in renal cystine transport, and the mutations reported in this gene, which have been shown to be the causative factor in approximately half of the cases of type I cystinuria studied. MATERIALS AND METHODS The MEDLINE data base from 1966 to date and the internet online mendelian inheritance in man were searched using cystinuria, cystine crossed with biological transporters and cystine transporter as key words. Selected citations within these references were also reviewed. RESULTS The SLC3A1 gene has been shown to code for a protein that, when expressed in Xenopus oocytes, confers on these cells the ability to transport cystine, arginine, lysine and ornithine. To date 21 different mutations and 9 polymorphisms have been reported in the SLC3A1 gene isolated from cystinuric patients. CONCLUSIONS Type I cystinuria appears to be due to mutations in the SLC3A1 gene, while the molecular genetic determinants of types II and III cystinuria remain to be delineated.

In vivo effects of lipopolysaccharide on hepatic free-NAD(P)+-linked redox states and cytosolic phosphorylation potential in 48-hour-fasted rats

This study was performed to determine the magnitude and time of onset of in vivo changes in hepatic bioenergetics in response to a sublethal dose of lipopolysaccharide (LPS), a bacterial endotoxin. Male rats (48-hour-fasted) were administered an intraperitoneal injection of LPS (5 mg/kg body weight) or vehicle alone, and the livers were freeze-clamped 5, 30, or 180 minutes or 24 hours later. Liver tissue was extracted with perchloric acid, and the metabolites necessary to calculate NAD(+)- and NADP(+)-linked redox states and the cytosolic phosphorylation potential were measured. There was no significant difference in hepatic cytosolic phosphorylation potential between LPS and control groups at any of the times investigated. This indicated that the ability of the liver to synthesize adenosine triphosphate (ATP) was not compromised under the conditions of the study. No changes in hepatic redox states were observed 5 or 30 minutes after LPS treatment. Three hours after LPS treatment, hepatic cytosolic and mitochondrial free-[NAD+]/[NADH] redox states and the cytosolic free-[NADP+]/[NADPH] redox state were more oxidized. By 24 hours, only NAD(+)-linked redox states were more oxidized than the time-matched controls. Hepatic urea content was elevated at both 3 and 24 hours, compatible with an increased rate of urea synthesis as a consequence of increased amino acid metabolism, whereas hepatic beta-hydroxybutyrate and total ketone bodies were decreased 24 hours after LPS treatment, indicating decreased hepatic ketogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

The Genetics of Stone Disease

The lifetime risk of stone formation is estimated at 5–10%; hence, stone disease represents one of the most frequent causes of hospitalization in the United States (1). Various intrinsic and extrinsic factors are associated with risk for stone formation. Among intrinsic factors are race, sex, and genetics (2,3). Over the past decade significant advances have occurred in our understanding of the underlying genetic lesions that are associated with many forms of stone disease. However, it is interesting to note that most advances in the identification of genetic defects have been made in the rarer forms of stone disease. Progress toward understanding the genetic contribution in the more common forms of calcium oxalate stone disease has been impeded by the fact that many forms of this disease are complex, associated with phenotypic variability, and further compounded by multifactorial inheritance. A recent review of the literature indicates that 27 individual chromosomal loci have been associated with various forms of urolithiasis (4). All modes of inheritance are represented among the various genetic stone diseases.

A Comparison of Fluoride Bioavailability from a Sustained-Release NaF Preparation (Neosten) and Other Fluoride Preparations

Twelve normal subjects completed a crossover study with sustained‐release sodium fluoride (Neosten, 11.3 mg F), monofluorophosphate (MFP, 10 mg F), and plain sodium fluoride (P‐NaF, 11.3 mg F). After each preparation was given with 400 mg calcium, serum fluoride (Fser was measured for 24 hours, and pharmacokinetic data were calculated. Fluoride absorption in the Neosten group, as measured by change in the area under the curve (ΔAUC] of Fser, was less than 33% of that in the MFP and P‐NaF treated groups. Both peak Fser (Cmax) and peak‐basal variation in the Neosten group were 25% that found in the other groups. t1/2 was nearly twofold greater after Neosten. MFP and P‐NaF showed greater bioavailability than Neosten and much higher Cmax that exceeded the toxic threshold of Fser (190 ng/ml). These findings could explain the ineffectiveness of MFP and P‐NaF observed in recent clinical trials.