Biomedical subjects
Publications and source records attributed to K D Williams.
Four infants with congenital or acquired tracheobronchial stenosis were successfully treated with angioplasty balloon catheter dilation. The technical details and complications of these procedures are described. The authors believe balloon dilation therapy should be considered as the initial form of therapy for tracheal stenosis in infants, even in the presence of complex stenotic lesions.
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Pancreas divisum is a congenital anomaly in which the ventral and dorsal pancreas drain separately into the duodenum. It is the most common congenital variant of pancreatic ductal fusion and drainage anomalies. With widespread use of endoscopic retrograde cholangiopancreatography, pancreas divisum is being detected with increasing frequency. Ten cases of pancreas divisum detected among 500 endoscopic retrograde cholangiopancreatography examinations performed between 1979 and 1985 at our institution were critically analyzed. Patients with symptomatic pancreas divisum (group 1) were typically young (mean age 29 yr), usually female, and had no history of significant alcohol abuse. Those with incidental detection of pancreas divisum (group 2) were older (mean age 62 yr), usually male with hepatobiliary disease, and had a history of significant alcohol ingestion. The radiological feature of pancreas divisum is characterized by a short (1-6 cm) and thin (2 mm diameter) pancreatic duct (duct of Wirsung) that branches off into regular arborization and drains only the posterior part of the head of the pancreas. This appearance is quite typical; however, this may be simulated by other conditions such as previous pancreatic trauma, partial pancreatectomy, or pancreatitis with irreversible damage to the duct, pseudocyst, and pancreatic carcinoma. The differentiation between true and false pancreas divisum is important because of its clinical implications.
Effects of 2,4-dithiobiuret (DTB) treatment in rats on neuromuscular transmission and the disposition of cholinergic substances, acetylcholine (ACh) and choline (Ch), were examined in a combined electrophysiological/biochemical study using an in vitro extensor digitorum longus (EDL) muscle-peroneal nerve preparation. EDL muscle preparations isolated from rats treated with DTB (1 mg/kg/day X 5 days, ip) displayed a 49% depression in the frequency of miniature end-plate potentials (MEPPs) and a 21% depression in mean MEPP amplitude. Statistical analysis of evoked end-plate potentials (EPPs) measured in curarized preparations indicated that the mean quantal content (m) was significantly depressed in EDL muscles from DTB-treated rats. At stimulation rates of 1, 10, 20, and 50 Hz the estimated values of m in EDL preparations from DTB-treated rats were, respectively, 21, 25, 45, and 51% of that in control preparations. Biochemical determinations of ACh and Ch revealed a significant DTB-induced increase in endogenous ACh and Ch content in EDL preparations fixed for extraction of ACh and Ch immediately after dissection from the treated rats. In vitro, however, there were negligible changes in overall ACh synthesis since the total (tissue and medium) tracer ACh (2H4-ACh) synthesized from tracer Ch (2H4-Ch; 10 microM) supplied in the perfusion medium was similar in EDL preparations from DTB-treated and control rats. Also, in EDL muscles from DTB-treated rats the resting release of ACh was not affected, but when exogenous Ch (2H4-Ch) was not supplemented in the medium the evoked release (via peroneal nerve stimulation) of ACh was depressed. Thus, decreases in spontaneous quantal ACh release, as detected in the electrophysiological experiments, were not reflected by changes in the biochemically determined ACh resting release. The biochemical determination of evoked ACh release, however, correlated with the decrease in quantal content detected in the electrophysiological analysis of evoked EPPs when exogenous Ch was not supplemented in the perfusion medium. Significant and consistent increases (two to three times) in both Ch content and efflux occurred in the EDL muscles from DTB-intoxicated rats. These results indicate that DTB induces a prejunctional impairment of neuromuscular transmission that is not specifically directed at ACh synthesis. Rather those processes by which ACh is incorporated into or released from vesicles appear to be altered.
Daily administration of dithiobiuret (DTB, 1 mg/kg X 6 days, ip) produced delayed onset muscle weakness in rats as indicated by failure in a treadmill test. In nerve-muscle preparations from DTB-intoxicated rats neuromuscular toxicity was manifested as contractile fatigue during tetanic nerve stimulation. As muscle weakness developed, feed intake decreased and the animals lost body weight. Water intake was not altered during this time, but urine output was increased concomitant with the development of muscle weakness and resulted in a state of negative water balance. Daily administration of d-penicillamine (d-PEN) antagonized DTB-induced treadmill failure in a dose-dependent fashion. A daily dose of d-PEN (1 mMol/kg, ip) that completely antagonized treadmill failure also antagonized the contractile fatigue, reduced feed intake, weight loss and negative water balance caused by DTB administration. In rats already intoxicated with DTB, initiating daily d-PEN treatment or discontinuing further DTB administration, caused the animals to recover normal treadmill performance after a latent period of five days. A single dose of d-PEN (1 mMol/kg, iv) was not effective in reversing treadmill failure or contractile fatigue in rats already intoxicated with DTB. Thus, continuous daily administration of d-PEN was necessary for it to be effective. A single dose of d-PEN (1 m Mol/kg, ip) administered one hr after [14C]-DTB (1 mg/kg, ip) did not affect the plasma and tissue concentrations of DTB-derived radioactivity or their corresponding elimination kinetics. Cumulative urinary and fecal excretion of DTB-derived radioactivity were also unaffected by d-PEN administration as were the relative proportions of DTB and two of its metabolites, monothiobiuret and thiuret, in urine. Other agents that produced dose-dependent antagonism of DTB toxicity were diethyldithiocarbamate, disulfiram, cysteamine and 2,2'-dipyridyl. Considering the chemical and biological properties of DTB and its antagonists, a mechanism of antagonism involving an alteration of the thiol-disulfide and/or divalent metal cation status of motor axon terminals is postulated.
Dietary exposure of rats to three different concentrations of zinc pyridinethione (ZPT; 166, 332, 498 ppm) caused delayed onset failure in a treadmill test and, at the higher concentrations (332 and 498 ppm), death. Daily treatment with d-penicillamine (d-PEN) increased the latency period for treadmill failure and lethality. Comparable levels of toxicity were achieved only after d-PEN treated rats had consumed 2-3 times more ZPT than rats not treated with d-PEN. In contrast to ZPT, administration of d-PEN did not affect the onset of treadmill failure associated with acrylamide, p-bromophenylacetylurea or 2,5-hexanedione. Thus, d-PEN provided protection which was selective for ZPT.
Our main objective was to describe the metabolism of dithiobiuret (DTB) in the adult, male rat. Based on the thin-layer chromatographic analysis of urine from animals treated ip with 1 mg/kg of [14C] or [35S] labeled DTB, two pathways for metabolism are proposed. One pathway is reversible and involves the oxidation of DTB to thiuret and the reduction of thiuret back to DTB. The other pathway consists of the desulfuration of DTB to monothiobiuret. The liver appears to desulfurate DTB because DTB-derived [35S] was eliminated from the liver more rapidly (T1/2 = 10 hr) than [14C] (T1/2 = 15 hr). The liver was the only tissue where the elimination kinetics of [35S] and [14C] DTB were different. For all extrahepatic tissues examined and plasma, the elimination of DTB-derived [35S] paralleled that of [14C]. The T1/2 for plasma disappearance of both radiolabeled forms of DTB was approximately 10 hr and the cumulative urinary excretion of DTB-derived [35S] and [14C] was parallel and amounted to about 60% of the dose in 24 hr. DTB-derived radioactivity in urine that co-chromatographed with DTB, monothiobiuret, thiuret and sulfate was quantitated along with that of three uncharacterized metabolites. The presence of these unknown metabolites suggests that DTB metabolism is complex. The present study is the first description of the metabolic fate of DTB in the rat and serves as a starting point for determining whether DTB neurotoxicity is caused by the parent compound or a metabolite.
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The objective of this study was to characterize the renal toxicity and carcinogenicity of p-nitrobenzoic acid in F344 rats. Dose levels in 13-week and 2-year studies ranged from 630-10,000 ppm and 1,250-5,000 ppm, respectively. At 13 weeks, renal lesions included minimal to mild hyaline droplet accumulation in male rats and karyomegaly in male and female rats. At 2 years, renal lesions included proximal tubule epithelial cell hyperplasia in male rats and oncocytic hyperplasia in high-dose male and female rats, and a decreased severity of nephropathy in males and females. The hvaline droplets in renal tubular epithelial cells of male rats at 13 weeks were morphologically similar to those described in alpha2u-globulin nephropathy. Using immunohistochemical methods, alpha2u-globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistry was significantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with alpha2U-globulin nephropathy such as single-cell necrosis of the P2 segment epithelium or accumulation of granular casts in the outer medulla did not occur in the 13-week study. In addition, chronic treatment related nephrotoxic lesions attributed to accumulation of alpha2u-globulin such as linear foci of mineralization within the renal papilla, hyperplasia of the renal pelvis urothelium and kidney tumors were not observed. Although there was histologic evidence of alpha2u-globulin accumulation in male rats at 13 weeks, the minimal severity of nephropathy suggests that the degree of cytotoxicity was below the threshold, which would contribute to the development of renal tumors at 2 years.
The performance of a new quality control dose monitor for radiation therapy with respect to precision, stability, temperature coefficient, and radiation damage has been extensively evaluated. The results of routine use at several centers are reported.
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Intraspinal synovial or ganglion cysts are uncommon lesions associated with degenerative lumbosacral spine disease. CT usually reveals cystic lesions adjacent to a facet joint, and they may show calcification. MR imaging of four surgically confirmed cases of intraspinal synovial cysts revealed subtle signal changes compared with CSF. Short TR/TE images showed the lesions to be slightly hyperintense in three cases and isointense in one case. Long TR/TE sequences revealed a hyperintense appearance in two cases and a hypointense appearance in the others. A peripheral rim of decreased signal on long TR/TE images probably reflects fine calcification or hemorrhage in the margins of the cysts. The multiplanar and contrast characteristics of MR make this technique well suited to the diagnosis of herniated disk, degenerative facet disease, and synovial cyst.
The paranasal sinuses were prospectively evaluated by CT, clinical history, and physical examination in infants and children having cranial CT for indications unrelated to upper respiratory inflammation (URI). One hundred and one CT scans were studied, and sinus abnormalities were detected in 18% of patients older than 1 year and without signs or symptoms of URI. When signs and/or symptoms of recent URI were present, the incidence of abnormalities was 31%. Maxillary antral were not identifiable or were opacified in 72% of all infants under 1 year old. Because of the high incidence of sinus abnormalities on CT in children with and without evidence of recent URI, abnormalities should not be ascribed to sinusitis without close clinical correlation.