Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis

OBJECTIVE: To evaluate aspects of the natural history of AA amyloidosis complicating juvenile rheumatoid arthritis (JRA), and its response to therapy with chlorambucil. METHODS: Scintigraphy and 7-day turnover studies were performed in JRA patients with histologically proven (n = 35) or clinically suspected (n = 30) AA amyloidosis, following intravenous injection of 123I and 125I-labeled serum amyloid P component (SAP). Prospective monitoring studies were performed over 2-3 years in 20 patients with amyloidosis. All but 2 amyloidosis patients were treated with chlorambucil. RESULTS: Positive scanning results were obtained in all patients in whom imaging was performed within 12 years of positive biopsy findings of amyloid and in 5 patients with clinically suspected amyloidosis. Negative scanning results with normal SAP metabolism, indicating regression of amyloid, were obtained in 4 patients whose amyloidosis had been in full clinical remission for more than 12 years. Prospective monitoring studies in patients whose JRA-associated inflammatory activity was in remission demonstrated regression of amyloid in 8 patients and no substantial changes in 8 others; however, in 4 further patients with active inflammation, there was accumulation of amyloid. There was a very poor correlation between the amount of amyloid present at a particular site and the resultant organ dysfunction. CONCLUSION: Radiolabeled SAP scintigraphy and turnover studies are useful complementary tools in the diagnosis, screening, and quantitative monitoring of type AA amyloidosis in JRA. The amyloid deposits may progress and/or regress at different rates in different anatomic sites over short periods.     

Internal mammary vein to coronary artery anastomotic fistula

Two patients are presented where internal mammary artery grafting was performed for the relief of symptomatic coronary artery disease. At follow-up the internal mammary artery was occluded and a communication between the internal mammary vein and the native coronary artery was demonstrated. These patients were characterised by the early recurrence of angina or the appearance of a continuous murmur. Both patients were treated by re-operation with ligation of the arterio-venous fistula and saphenous vein grafting.     

Motion patterns of Nabesna Glacier (Alaska) revealed by interferometric SAR techniques

Nabesna Glacier is one of the longest land-terminus mountain glaciers in North America. However, its flow has never been studied. We derived detailed motion patterns of Nabesna Glacier in winter and spring 1994–1996 from the synthetic aperture radar (SAR) images acquired by the European Remote Sensing satellites (ERS-1 and ERS-2) using interferometric SAR (InSAR) techniques. Special effort was made to assess the accuracy of the motion estimates, and remove data points with high uncertainty from the motion profiles, enabling us to obtain reliable glacier flow patterns along the highly curved main course of Nabesna Glacier. The results, covering 80 km of the 87 km main course of the glacier, were used to delineate four distinctive sections in terms of spatial and temporal variability of the glacier speed: (1) the upper section where glacier flow was apparently random both temporally and spatially presumably due to development of crevasses; (2) the upper-middle section with relatively steady flow around 0.27 to 0.4 m/day; (3) the middle section with a stable pattern of acceleration from 0.27–0.3 m/day to the maximum about 0.67–0.73 m/day, followed by a general deceleration to 0.17–0.33 m/day before reaching (4) the lower section where the glacier motion was generally slow yet highly variable although uncertainty in the estimation is high. Occurrence of the flow maximum, as well as many local maxima and minima at consistent locations over different periods suggests that the valley geometry affect the overall flow pattern. On top of this general trend, many small-scale temporal/spatial variations in the glacier flow patterns were observed along the glacier, especially in the lower sections. On average, the flow speeds were in the range of 0.3 to 0.7 m/day; however this lacks any measurements of summer flow speeds which are expected to be significantly higher.     

Observers for stabilization of systems with matched uncertainty

In this article, we study the design of observer-based robust linear feedback controllers. The uncertainty, which can enterA, and either theB orC matrices, is assumed to satisfy certain matching conditions. Lyapunov techniques are used to establish sufficient conditions for stability, given an uncertainty bound. In particular, sufficient conditions are obtained that, if met, result in stabilizing controllers regardless of the size of the uncertainty entering the system matrix, as long as the standard constraints on the uncertainty entering the input or output matrices are met. As with the case of more general forms of uncertainty, the resulting observers often have high gains. To study performance, the problem of disturbance rejection is considered. Sufficient conditions are presented for obtaining control laws that stabilize the closed loop system, regardless of the size of the uncertainty entering the system matrix, while simultaneously guaranteeing arbitrarily small infinity norm for the transfer function from the plant disturbances to the outputs.     

Bone marrow and renal injury associated with haloalkene cysteine conjugates in calves

Almost 40 years ago, it was reported that cattle-feed which had been extracted with hot trichloroethylene and then fed to calves produced renal injury and a fatal aplastic anaemia. The toxic factor was subsequently identified as S-(1,2-dichlorovinyl)-L-cysteine (DCVC). These original findings have been confirmed, a single intravenous dose of DCVC at 4 mg/kg, or 0.4 mg/kg intravenously per day administered for 10 days to calves produced aplastic anaemia, and renal injury after a single dose of 4 mg/kg. The toxicity to calves of a number of other haloalkene cysteine conjugates has been examined to ascertain whether, like DCVC, they produce bone marrow and renal injury. Intravenous administration of the N-acetyl cysteine conjugate of DCVC produced renal but not bone marrow injury at a molar equivalent dose to DCVC, indicating that the calf can deacetylate the mercapturic acid and further that sufficient chemical had reached the kidney to be a substrate for the enzyme cysteine conjugate beta-lyase. However, intravenous administration of the alpha-methyl analogue of DCVC, which cannot undergo metabolism via the enzyme cysteine conjugate beta-lyase, was without toxicity at doses about five-fold higher than DCVC. These latter findings provide strong evidence that metabolism of DCVC via the enzyme beta-lyase is necessary for bone marrow and renal injury to occur. The cysteine conjugates of perchloroethylene and hexachloro-1,3-butadiene(HCBD) when given intravenously to calves at molar equivalent doses to DCVC, or above, did not produce either bone marrow or renal injury. In contrast, intravenous administration of the cysteine conjugate of tetrafluoroethylene (TFEC) produced severe renal tubular injury in calves without affecting the bone marrow. In vitro studies with these haloalkene cysteine conjugates showed, like DCVC, that they were good substrates for calf renal cysteine conjugate beta-lyase and toxic to renal cells as judged by their ability to reduce organic anion and cation transport by slices of calf renal cortex and inhibit the renal enzyme glutathione reductase. Calves were also dosed either orally or intravenously with HCBD to assess its toxicity. HCBD at higher molar equivalent doses than DCVC produced mid-zonal necrosis in the liver, renal tubular necrosis but no bone marrow injury in calves. The key findings emerging from these studies are (1) that none of the other cysteine conjugates, at molar equivalent doses to DCVC and above, produce bone marrow injury in calves, (2) TFEC produced only renal injury, suggesting that sufficient of the other conjugates had not reached the kidney for metabolism by beta-lyase to produce cytotoxicity and (3) that HCBD itself is more toxic than its cysteine or mercapturic acid conjugate, suggesting that pharmaco-kinetics and disposition are important factors in determining the toxicity of these conjugates to calves. Further studies are needed to understand the basis for the selective toxicity of DCVC to the bone marrow of calves.     

Laser therapy of Barrett''s mucosa

Midden and Dahl, in a recent paper, have presented important data on the inactivation of bacteria by singlet oxygen. In analyzing the data, use was made of a theory published earlier by the present author. The purpose of this paper is to point out that theory and experiment can be brought into better agreement by assuming that the interaction of singlet oxygen with the bacteria takes place in an essentially lipid environment rather than aqueous.     

Structure-function relationships in membrane segment 5 of the yeast Pma1 H+-ATPase

Membrane segment 5 (M5) is thought to play a direct role in cation transport by the sarcoplasmic reticulum Ca2+-ATPase and the Na+, K+-ATPase of animal cells. In this study, we have examined M5 of the yeast plasma membrane H+-ATPase by alanine-scanning mutagenesis. Mutant enzymes were expressed behind an inducible heat-shock promoter in yeast secretory vesicles as described previously (Nakamoto, R. K., Rao, R., and Slayman, C. W. (1991) J. Biol. Chem. 266, 7940-7949). Three substitutions (R695A, H701A, and L706A) led to misfolding of the H+-ATPase as evidenced by extreme sensitivity to trypsin; the altered proteins were arrested in biogenesis, and the mutations behaved genetically as dominant lethals. The remaining mutants reached the secretory vesicles in sufficient amounts to be characterized in detail. One of them (Y691A) had no detectable ATPase activity and appeared, based on trypsinolysis in the presence and absence of ligands, to be blocked in the E1-to-E2 step of the reaction cycle. Alanine substitution at an adjacent position (V692A) had substantial ATPase activity (54%), but was likewise affected in the E1-to-E2 step, as evidenced by shifts in its apparent affinity for ATP, H+, and orthovanadate. Among the mutants that were sufficiently active to be assayed for ATP-dependent H+ transport by acridine orange fluorescence quenching, none showed an appreciable defect in the coupling of transport to ATP hydrolysis. The only residue for which the data pointed to a possible role in cation liganding was Ser-699, where removal of the hydroxyl group (S699A and S699C) led to a modest acid shift in the pH dependence of the ATPase. This change was substantially smaller than the 13-30-fold decrease in K+ affinity seen in corresponding mutants of the Na+, K+-ATPase (Arguello, J. M., and Lingrel, J. B (1995) J. Biol. Chem. 270, 22764-22771). Taken together, the results do not give firm evidence for a transport site in M5 of the yeast H+-ATPase, but indicate a critical role for this membrane segment in protein folding and in the conformational changes that accompany the reaction cycle. It is therefore worth noting that the mutationally sensitive residues lie along one face of a putative alpha-helix.