Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement

A new technetium-chelating agent based on a triamide monomercaptide tetradentate set of donor groups, mercaptoacetylglycylglycylglycine (MAG3), was synthesized and evaluated. Chelation with 99mTc resulted in a single radiochemical product as expected. Studies in mice of [99mTc]MAG3 indicated excretion rates faster than omicron-iodohippurate (OIH) both in normal and in probenecid treated animals. Specificity for renal excretion was essentially complete. Clearance studies in rats resulted in 2.84 ml/min/100 g for [99mTc]MAG3, 2.17 for OIH, and 1.29 for [125I]iothalamate. Extraction efficiencies were 85% for [99mTc]MAG3, 69% for OIH and 39% for [125I]iothalamate. Probenicid depressed the clearance both of [99mTc]MAG3 and OIH at 25 and 50 mg/kg/hr, but to a greater extent with [99mTc]MAG3. The greater effect is offset, however, by the larger fraction secreted by the renal tubular cells. The animal results suggest that [99mTc]MAG3 may be a useful alternative to [131I]OIH.     

Arterial complications of total knee replacement. The Australian experience

Arterial complications occurring in association with knee replacement surgery are rare, even though most patients having this operation are elderly and therefore more likely to have peripheral vascular disease. We report a patient who developed an arterial complication during the course of a knee replacement operation, as well as the results of a survey of Fellows of the Australian Orthopaedic Association. Recommendations to minimise this serious complication are proposed.     

Glomerular lesions in adolescents with gross hematuria or the nephrotic syndrome

We report clinical and pathological data in 56 adolescents presenting with gross hematuria (GH) and 65 presenting with idiopathic nephrotic syndrome (INS). IgA nephropathy (present in 52%) and other mesangial lesions were found in the majority of the 56 patients with GH. Many of these patients had complex urological procedures prior to consideration of a nephrological problem. This often led to significant delays in making the appropriate diagnosis. Pathological lesions in the 65 patients with INS included minimal change NS (MCNS) in 31%, membranous glomerulonephritis (MGN) and focal segmental glomerulosclerosis (FSGS) in 18.5% each, and membranoproliferative GN (MPGN) in 12%. In 47 of the patients with INS, in whom no specific treatment had been given prior to renal biopsy, MCNS and MGN were observed with a similar frequency (26% and 23%, respectively), with FSGS and MPGN being found in 21% and 11%. These results indicate that the pathological lesions in adolescents with INS who undergo a renal biopsy more closely resemble those in adults, and are usually more severe than those in young children. However, it should be noted that our study was retrospective. Hence, there were probably some adolescents with INS who had a successful response to therapy and therefore did not have a renal biopsy performed. Southwest Pediatric Nephrology Study Group (Central Office, Baylor University Medical Center at Dallas, Tex., USA). Director, Ronald J. Hogg; Associate Directors, Fred G. Silva and F. Bruder Stapleton; Statistician, Joan S. Reisch; Administrative Assistant, Kaye Green. Participating Centers—Baylor College of Medicine, Houston, Tex.: Phillip L. Berry, L. Leighton Hill, Sami A, Sanjad, Edith Hawkins; Baylor University Medical Center, Dallas, Tex.: Ronald J. Hogg, Kaye Green; Tulane University Medical Center, New Orleans, La.: Frank Boineau, John E. Lewy, Radhakrishna Baliga, Patrick Walker; University of Arkansas, Little Rock, Ark.: Watson Arnold, Eileen Ellis, Edward Uthman; University of Colorado Health Science Center, Denver, Colo.: Gary M. Lum, Wiliam Hammond; University of Oklahoma Medical Center, Oklahoma City, Okla.: James Wenzl, James Matson, Geoffrey Altshuler, Sarah Johnson; University of Tennessee, Memphis, Tenn.: F. Bruder Stapleton, Shane Roy, III, Robert J. Wyatt, Charles McKay, William Murphy; University of Texas Health Science Center at Dallas, Tex.: Billy S. Arant Jr, Michel Baum, Fred G. Silva, Arthur Weinberg, Craig Argyle, Joseph Rutledge, Ed Eigenbrodt; University of Texas Medical School, Houston, Tex.: Susan B. Conley, Jacques Lemine, Ron Portman, Ann Ince, Regina Verani; University of Texas Health Science Center at San Antonio, Tex.: Michael Foulds, Sudesh Makker, Kanwal Kher, Melanie Sweet, Victor Saldivar, Fermin Tio; University of Texas Medical Branch, Galveston, Tex.: Ben H. Brouhard, Alok Kalia, Luther B. Travis, Lisa Hollander, Tito Cavallo, Srinivasan Rajaraman; University of Utah Medical Center, Salt Lake City; Utah: Eileen Brewer, Richard Siegler, Elizabeth Hammond, Theodore Pysher. Note that this list reflects the investigators' addresses and positions during the period of this study and not necessarily their current situations.     

Structural Characterization of Variant Forms of Arylsulfatase A that Associate with Alcoholism

Several electrophoretic forms of human platelet arylsulfatase A (ASA), including variant type III_a and normal type IV_a, have been identified by nondenaturing polyacrylamide gel electrophoresis. An alcoholic population that we have analyzed is enriched in variant type III_a compared with nonalcoholic psychiatric and normal controls. Individuals with the III_a enzyme possess greatly reduced levels of ASA activity. To understand further the structural basis for the differences and their potential biological consequences, the nature of the ASA variant expressed by fibroblasts from different individuals was explored. The electrophoretic patterns of fibroblast ASA from the III_a and IV_a individuals differ in degree of phosphorylation. Furthermore, fibroblast ASA from III_a individuals lacks an N -linked glycan found in ASA from IV_a individuals. In addition, differences in peptide and/or posttranslational modification unrelated to the N -linked carbohydrate or phosphorylation exist between the fibroblast ASA from III_a and IV_a individuals. The finding that both fibroblasts and platelets exhibit related electrophoretic isoform patterns characteristic of the donor's ASA type allows for the use of fibroblasts to study the impact of ethanol on the metabolism of cells possessing different ASA types.     

Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine

The present set of experiments was designed to examine the effects of extension of the alpha-methyl of p-chloroamphetamine (PCA) to an alpha-ethyl. Therefore, the alpha-ethyl homologue of PCA, 1-(4-chlorophenyl)-2-aminobutane (CAB), was compared to PCA in a number of pharmacological assays. CAB was 2-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and 5-fold less potent at inhibiting uptake of [3H]dopamine ([3H]DA). In drug discrimination assays, CAB was approximately 3-fold less potent than PCA in animals trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or its alpha-ethyl homologue, S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-(+)-MBDB), from saline. Monitoring with in vivo microdialysis, 10 mg/kg of PCA caused a large increase in extracellular DA and a significant decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In contrast, 11 mg/kg CAB caused no increase and 22 mg/kg CAB caused only a slight increase in extracellular DA. Both doses of CAB caused a decrease in extracellular DOPAC. The potential 5-HT neurotoxicity of CAB was examined by measuring monoamine and metabolite levels and [3H]paroxetine binding at one week following acute doses. A 10 mg/kg dose of PCA caused an 80% decrease in cortical and hippocampal serotonergic markers, while an equimolar dose of CAB decreased only hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels. However, 22 mg/kg of CAB produced a 20-40% decrease in all serotonergic markers. Thus, extension of the alpha-alkyl significantly decreases the dopaminergic effects of PCA. The similar decrease in relative 5-HT neurotoxicity and the decreased ability to alter dopaminergic systems in vivo and in vitro supports the involvement of DA in the neurotoxicity of PCA.