Is it time to reevaluate the airway management of tracheoesophageal fistula?
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Bronchoscopy↗
Biomedical subjects
C D Smith
Publications and source records attributed to C D Smith.
Hippocampal volume measurements using magnetic resonance imaging in normal young adults.
Volumetric analysis of brain magnetic resonance images (MRIs) measures structural changes associated with neurological and neuropsychiatric disorders. Several studies investigated the hippocampus specifically, reporting degrees of atrophy in such disorders. However, the range of normal hippocampal volumes must be known to assess atrophy. In tracings of T1 oblique slice and three-dimensional MRIs in 24 normal subjects reported here, the average volume of right and left hippocampus was 2.90 cm3 and 2.78 cm3, respectively. On paired analysis, this difference was significant. The literature indicated these volumes are in the middle of a wide range of hippocampal volumes (1.73-5.68 cm3) in both MRI-based and histology-based studies. This wide variation can be explained by differing hippocampal boundary definitions; technical factors of image processing, segmentation, and display; sample heterogeneity; and interoperator differences.
Adult↗
Protection against nerve agent-induced neuropathology, but not cardiac pathology, is associated with the anticonvulsant action of drug treatment.
Brain and cardiac tissue was examined for pathological changes from rats that survived 24 hrs following exposure to a convulsant dose of the nerve agent soman. The animals had been treated following varying durations of seizure activity (2.5 - 40 min) with a number of different compounds that did or did not terminate the seizure. Moderate to severe neuropathology was evident in virtually all animals (98%) in which drug treatment did not terminate seizures. All animals that experienced up to 10 min of seizure activity before drug treatment successfully terminated the seizure were free of neuropathology. There was an increasing frequency in the incidence of neuropathology in animals that experienced 20 (10%) or 40 min (79%) of seizure activity before drug treatment terminated the seizure, but the degree of neuropathology in these groups was significantly less than that observed in animals where seizure activity was not terminated. Cardiac lesions occurred at a much higher frequency (88%) than neuropathological changes (57%) and were not consistently associated with the anticonvulsant effectiveness. Early treatment (< or = 10 min) with anticholinergic drugs, however, was associated with protection from cardiac damage. The results strongly support the hypothesis that nerve agent-induced brain damage is linked to epileptiform activity. The minimal amount of seizure activity necessary for irreversible neural damage to become evident under these conditions is approximately 20 min, and the process accelerates greatly after this minimal time has elapsed. Successful termination of seizure activity, regardless of the type of drug used, protected either totally or relatively against brain damage depending upon how long the seizure had progressed. The mechanisms responsible for cardiac lesion formation occur more rapidly and may have a cholinergic component.
Animals↗
Inhibition of ileal sodium-dependent bile acid transport by 2164U90.
Inhibition of the ileal bile acid active transport system, previously shown to be mechanism underlying the hypocholesterolemic activity of 2164U90 in rodents, was further characterized in isolated intestinal preparations from three species. 2164U90 inhibited sodium-dependent transport of taurocholic acid by Caco-2 cells and by monkey and human ileal brush border membrane vesicles in a concentration-dependent manner with IC50s of 7 microM, 5 microM, and 2 microM, respectively. In rat ileal brush border membrane vesicles, 2164U90 was a competitive inhibitor of sodium-dependent taurocholic acid uptake with an estimated Ki of 1.8 +/- 0.2 microM. In anesthetized rats, 5 microM 2164U90 placed in the isolated distal ileum with 3 mM [3H]taurocholic acid decreased ileal uptake, transport into the bile, and transport rate of taurocholic acid by 31-35%. Stereospecificity of inhibition by 2164U90 was demonstrated by the relative inactivity of three other possible stereoisomers in rat ileal sacs and brush border membrane vesicles. 2164U90 did not inhibit sodium-dependent glucose transport by monkey jejunal brush border membrane vesicles, indicating that 2164U90 may be specific for the bile acid transporter. These results suggest that 2164U90 is a potent, selective, stereospecific, competitive inhibitor of the sodium-dependent bile acid transporter in the ileal mucosal cell brush border membrane.
Animals↗
Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance.
Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga Hapalosiphon welwitschii as a part of our effort to identify new compounds that overcome multiple drug resistance. The abilities of three structurally similar members of this family to interact with P-glycoprotein have been compared. Similarly to the effects of verapamil, N-methylwelwitindolinone C isothiocyanate (compound 1) attenuated the resistance of MCF-7/ADR cells to natural product anticancer drugs, including vinblastine, taxol, actinomycin D, daunomycin, and colchicine, without affecting the cytotoxicity of cisplatin. These effects of compound 1 were apparent at doses as low as 0.1 microM, indicating that it is considerably more potent than verapamil for reversal of resistance. Welwitindolinone C isothiocyanate (compound 3) demonstrated weaker reversing activity, whereas an analogue of compound 1 in which the isothiocyanate group is replaced by an isonitrile group (compound 2) was inactive. The accumulation of [3H]vinblastine in SK-VLB-1 cells was increased by compound 1 > compound 3 > verapamil >> compound 2. Interestingly, only compound 1 and verapamil enhanced [3H]taxol accumulation by these cells. Photoaffinity labeling of P-glycoprotein with [3H]azidopine in membranes from SK-VLB-1 cells was inhibited by compounds 1 and 3, but not by compound 2. Therefore, the differences in the size and/or the electronegativity of the isothiocyanate and isonitrile moieties appear to dramatically affect the abilities of the compounds to interact with P-glycoprotein.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Differential interactions of cytochalasins with P-glycoprotein.
Cytochalasins are a family of structurally related natural product cytotoxins that selectively depolymerize microfilaments. In this study, the interaction between several cytochalasins and the drug transporter P-glycoprotein was investigated. Dihydrocytochalasin B and cytochalasin E consistently sensitized P-glycoprotein-overexpressing human breast carcinoma cells (MCF-7/ADR) to daunomycin, vinblastine, and actinomycin D without affecting the cytotoxicity of cisplatin. These compounds did not affect the sensitivities of the parental MCF-7 cells to anticancer drugs, indicating that their effects are due to P-glycoprotein inhibition. Effects of dihydrocytochalasin B and cytochalasin E were observed at concentrations as low as 2.5 and 5 microM, respectively. In contrast, cytochalasins A, B, C, D, H, and J did not sensitize MCF-7/ADR cells to any of the drugs. The accumulation of [3H]-vinblastine by MCF-7/ADR cells and by drug-resistant human ovarian carcinoma cells (SKVLB1) was increased to the greatest extent by verapamil, followed by dihydrocytochalasin B > cytochalasin E > cytochalasin B, whereas cytochalasins A, C, D, H, and J did not alter intracellular accumulation of the drug. Similarly to verapamil, dihydrocytochalasin B significantly stimulated the ATPase activity of P-glycoprotein, while other cytochalasins were ineffective. These results demonstrate that very closely related compounds can differentially interact with P-glycoprotein. For example, the only difference between cytochalasin B and dihydrocytochalasin B is the saturation of a carbon-carbon double bond in dihydrocytochalasin B. These structural differences may provide important insight into chemical determinants for drug interaction with P-glycoprotein.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Aging- and oxygen-induced modifications in brain biochemistry and behavior.
In summary, the work presented here has shown accumulation of oxidized protein with age in an animal aging model. In gerbil brain, this accumulation is associated with (1) decreased activity of oxidatively sensitive enzymes creatine kinase and glutamine synthetase; (2) decreased function of particular cytoskeletal proteins; and (3) decreased performance in a radial-arm maze task. Manipulations shown to increase the presence of reactive oxygen species in the brain increase oxidized protein, decrease the index enzyme activities and cytoskeletal protein defects, and worsen performance deficits. Moreover, intervention designed to quench ROS-mediated reactions decrease oxidized protein levels, and nearly normalize index enzyme activities and associated behavioral deficits. The precise connections between the performance deficits and protein measures are probably highly complex and likely to remain obscure for now. Currently, the behavioral measures serve as a marker for the functional consequences of the protein alterations. Our studies in humans have shown oxidized protein accumulation with age and a differential decrease of glutamine synthetase activity in the frontal lobe in AD. Further preliminary results in AD autopsy material show a striking correlation between the distribution of index enzyme inactivation and the known intensity distribution of AD pathology. These findings support the hypothesis that inability to restrain age- or pathology-related increases in local ROS activity can result in AD.
Aging↗
Cryptophycin: a new antimicrotubule agent active against drug-resistant cells.
Cryptophycin is a cytotoxic dioxadiazacyclohexadecenetetrone isolated from cyanobacteria of the genus Nostoc. Incubation of L1210 leukemia cells with cryptophycin resulted in dose-dependent inhibition of cell proliferation in parallel with increases in the percentage of cells in mitosis (half-maximal effects at < 10 pM). Indirect immunofluorescence studies demonstrated that treatment of A-10 vascular smooth muscle cells with cryptophycin results in marked depletion of cellular microtubules and reorganization of vimentin intermediate filaments, similar to the effects of vinblastine. Cytochalasin B caused the depolymerization of microfilaments in these cells, while neither vinblastine nor cryptophycin affected this cytoskeletal component. Pretreatment of cells with taxol prevented microtubule depolymerization in response to either vinblastine or cryptophycin. While microtubule depolymerization in response to vinblastine was rapidly reversed by removal of the drug, cells treated with cryptophycin remained microtubule depleted for at least 24 h after removal of the compound. Combinational treatments with vinblastine and cryptophycin resulted in additive cytotoxicity. Ovarian carcinoma and breast carcinoma cells which are multiply drug resistant due to overexpression of P-glycoprotein are markedly less resistant to cryptophycin than they are to vinblastine, colchicine, and taxol. Therefore, cryptophycin is a new antimicrotubule compound which appears to be a poorer substrate for P-glycoprotein than are the Vinca alkaloids. This property may confer an advantage to cryptophycin in the chemotherapy of drug-resistant tumors.
Animals↗
A sensitive assay for taxol and other microtubule-stabilizing agent.
The ability of taxol to protect microtubules in cultured human ovarian carcinoma cells from drug- and cold-induced depolymerization was characterized as a functional assay for microtubule stabilizing agents. Treatment of the cells with concentrations of vinblastine or colchicine of 50 nM or greater, or incubation at 4 degrees C resulted in complete depolymerization of cytoplasmic microtubules. Pretreatment with taxol for 3 h enabled the cells to maintain substantial numbers of microtubules following the application of vinblastine or colchicine. This protective effect was easily observed at 50 nM taxol, whereas taxol-induced microtubule bundling was observed only at concentrations of 500 nM or greater. Concentrations of taxol as low as 10 nM stabilized microtubules against cold-induced depolymerization. Therefore, protection of microtubules from drug- and cold-induced depolymerization provides a sensitive functional assay for taxol. These systems should be similarly effective in identifying novel compounds which stabilize microtubules.
Cell Division↗
P-glycoprotein binding and modulation of the multidrug-resistant phenotype by estramustine.
BACKGROUND: Previous preclinical studies of combinations of estramustine and vinblastine or paclitaxel (Taxol) have shown that it is possible to achieve a greater than additive cytotoxicity with these antimicrotubule drug combinations. Phase II studies in hormone-refractory prostate cancer have demonstrated clinical antitumor activity of sufficient magnitude to stimulate further laboratory and clinical studies of these drugs combinations. PURPOSE: Our purpose was to characterize the interactions of estramustine with P-glycoprotein and to determine its effects. METHODS: Standard laboratory techniques were used to study the effects of estramustine on intracellular drug concentrations, cytotoxicity, and induction of messenger RNA (mRNA) for the MDR1 (also known as PGY1) gene. Using a photoaffinity analogue of estramustine 17-0-[[2-[3-(4-azido-3-[125I]-iodophenyl) propionamido]ethyl]-carbamyl]estradiol-3-N-bis(2-chloroethyl)ca rba mate ([125I]AIPP-estramustine), binding to the membrane proteins of human ovarian (SKOV3) and their multidrug-resistant counterpart SKVLB1 cells was studied. Southern-blot analysis was performed on DNA extracted from human prostate carcinoma wild-type DU145, estramustine-resistant cell line (E4), and SKVLB1 cells. RESULTS: Membrane fractions from SKOV3 and SKVLB1 cells were analyzed for proteins that could be photoaffinity labeled with [125I]AIPP-estramustine. Competitive inhibition of this binding was achieved with excess concentrations of (in order of efficacy) estramustine, vinblastine, verapamil, progesterone, and to a lesser degree, by paclitaxel but not with estramustine phosphate, estradiol, and estriol. SKVLB1 cells accumulated much less [3H]vinblastine and [3H]paclitaxel than did SKOV3 cells. Estramustine caused a concentration-dependent enhancement of drug accumulation in the SKVLB1 cells to a maximum of approximately 12-fold. No effect of estramustine was apparent for the wild-type SKOV3 cells. In comparison with verapamil, estramustine was less effective as a modulator; however estramustine demonstrated good chemosensitizing activity in combination with actinomycin D and vinblastine. Neither short-term, low-dose no longer-term, higher concentration were found to produce measurable transcript (mRNA for the MDR1 gene levels. Such data suggest that, at least levels. Such data suggest that, at least for two distinct human cell line (SKOV3 and DU145), estramustine does not induce the overexpression of the MDR1 gene. CONCLUSION: It is apparent from the P-glycoprotein data that estramustine interacts with this efflux pump, altering intracellular drug accumulation. Overall, the nonempiric basis for including estramustine in clinical protocols that contain other multidrug-resistant drugs is strengthened by the present data.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Radical pancreatoduodenectomy for misdiagnosed pancreatic mass.
Occasionally pancreatoduodenectomy is performed for clinically suspected pancreatic malignancy only for the surgeon to find that a benign aetiology accounts for the pancreatic mass. The aim of this study was twofold: to determine the incidence of pancreatoduodenectomy performed for a misdiagnosis of pancreatoduodenal malignancy and to identify potentially avoidable errors in preoperative and intraoperative judgement. Between 1956 and 1990, radical pancreatoduodenectomy was performed in 603 patients at the Mayo Clinic; 29 (5 per cent) underwent pancreatoduodenectomy for a diagnosis made before and during surgery of primary pancreatic or periampullary malignancy that was later proven histopathologically to be either unsuspected subacute or chronic pancreatitis (22 patients), benign fibrous common bile duct stricture (two), and penetrating duodenal ulcer, metastatic melanoma, ampullary adenoma, intrahepatic drug-induced cholestasis and pseudocyst (one each). No patient had a preoperative diagnosis of chronic pancreatitis. Weight loss, pain and/or jaundice were present in 27 of the 29 patients. Objective imaging tests, such as computed tomography, ultrasonography and/or endoscopic retrograde cholangiopancreatography, were performed in 25 patients. Potential errors in judgement may be avoided by a more aggressive attempt at biopsy in selected patients; in others, resection for presumed malignancy may be unavoidable.
Aged↗
Malaria-induced increase of splenic gamma delta T cells in humans, monkeys, and mice.
The number and distribution of gamma delta T cells in spleens from patients who died of cerebral malaria and from rhesus monkeys severely infected with Plasmodium coatneyi were examined by immunocytochemistry. gamma delta T cells were significantly increased in these spleens. In a rodent malaria model using Plasmodium chabaudi adami, an avirulent strain of murine malaria parasites, the degree of parasitemia appears to be modulated by the number of gamma delta T cells in the spleen. As parasitemia increases, these T cells increase in number. At some critical point, gamma delta T cells in collaboration with macrophages and alpha beta T cells apparently start to clear parasitized erythrocytes from the blood, leading to an abatement of the parasitemia, which is followed by a reduction in the number of gamma delta T cells. This gamma delta T cell phenomenon may be responsible for the self-limiting infection in mice.
Animals↗
Prospective evaluation of gastric acid secretion and cobalamin absorption following gastric bypass for clinically severe obesity.
The pathophysiologic mechanism(s) responsible for cobalamin deficiency after Roux-en-Y gastric bypass for clinically severe obesity remains unexplained. Inadequate secretion of intrinsic factor has been postulated, but decreased gastric acid secretion resulting in maldigestion and inadequate liberation of free cobalamin from its native protein-bound form is also possible. The aim of this study was to determine prospectively secretion of gastric acid and absorption of crystalline (free) and protein-bound cobalamin before and after gastric bypass. Eight patients (two men, six women) underwent orogastric intubation of the intact stomach preoperatively and the proximal gastric pouch postoperatively. Gastric acid secretion in the basal and stimulated (pentagastrin, 6 micrograms/kg) states was determined by a perfused, nonabsorbable marker technique to quantitate recovery of gastric secretion. Absorption of radiolabeled (57Co) crystalline and protein-bound cobalamin was assessed on separate days by 24-hr urinary excretion. After gastric bypass, acid secretion (mean +/- SEM) was markedly reduced in basal (9.1 +/- 3.6 vs 0.005 +/- 0.003 meq/hr; P = 0.04) and stimulated (12.8 +/- 1.8 vs 0.008 +/- 0.003 meq/30 min; P = 0.002) states. Absorption of crystalline cobalamin was decreased (15.8 +/- 2.5 vs 9.4 +/- 1.4%; P = 0.08) to a lesser extent than was protein-bound cobalamin (5.9 +/- 1.0 vs 1.1 +/- 0.3%; P = 0.004). In summary, gastric acid secretion from the gastric pouch is negligible after gastric bypass, and food-bound cobalamin is maldigested and subsequently malabsorbed presumably due to pouch achlorhydria. Decreased absorption of free cobalamin suggests decreased cobalamin-intrinsic factor complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Paired box gene expression in Wilms' tumor.
Wilms' tumor (WT) is an embryonal renal neoplasm with features resembling fetal kidney development. A family of genes potentially involved in WT induction is called the paired box (PAX) gene family. In this study we examined by Northern blot analysis the expression of several PAX genes in a variety of WTs and other childhood neoplasms. RNA was isolated from four primary WTs and 12 WTs propagated in nude mice (heterotransplant), as well as from a variety of other childhood renal and nonrenal embryonal tumors. RNA samples were electrophoretically separated in 1.2% agarose gels, transferred to nylon membranes, and hybridized to random primer-labeled PAX2, PAX8, and WT1 probes. Membranes were then exposed to x-ray films at -70 degrees C with intensifying screens. PAX2 and WT-1 expression were seen in all four primary WTs; PAX8 was seen in three of the four primary WTs. Of the 12 heterotransplant Wilms' tumors, PAX2, PAX8, and WT1 were concomitantly expressed in seven tumors. Another heterotransplant WT expressed WT1 alone. Expression of these three genes, with one exception, was not seen in the other childhood renal and nonrenal solid tumors. The PAX genes are transcriptional regulators; their protein products bind to specific DNA segments and control gene expression. Their role in the pathogenesis of Wilms' tumor and their interaction with WT1 are unclear. Elucidation of the functional significance of the PAX genes will provide important insights into not only the pathogenesis of WT but also the molecular control of the developing kidney.
Animals↗
Impact of laparoscopic cholecystectomy on the management of cholelithiasis in children with sickle cell disease.
Children with sickle cell disease, well known to have a high incidence of cholelithiasis, are frequently admitted to the hospital for episodes of abdominal pain. Before the advent of laparoscopy, few children with sickle cell and cholelithiasis underwent cholecystectomy unless absolutely necessary, because of the high morbidity of an open cholecystectomy (OC). We reviewed our records of all children with sickle cell disease and cholelithiasis treated from 1985 to 1992 to investigate the impact of laparoscopic cholecystectomy (LC). During that period, 32 children underwent cholecystectomy: 10 OC and 22 LC (all since December 1990). Before December 1990, all children had either classic biliary tract symptoms or abdominal pain of unknown etiology. However, of the 22 LC children, five had asymptomatic cholelithiasis. Only three of the 32 patients had choledocholithiasis, although 30 of 32 had elevated total bilirubins. Two LC children presented with choledocholithiasis and were initially treated with endoscopic sphincterotomy and stent placement. A standard intraoperative cholangiogram (IOC) through the cystic duct was performed in all OC cases. In 19 of 22 LC cases, an IOC through the gallbladder was performed before any dissection; unsuspected choledocholithiasis was not found, but the IOC did allow visualization of the course of the cystic duct, facilitating its subsequent dissection. Total operative length was comparable between the two groups, but the LC patients' postoperative length of stay was half that of the OC patients (2.1 v 4.6 days). Postoperative complications in the OC group included three children who had severe pain, atelectasis, fever, and hypoxemia (30%).
Adolescent↗
Tracheoesophageal compression from aortic arch anomalies: analysis of 30 operatively treated children.
During a 16-year period (1976 to 1992), 30 children underwent surgery for tracheoesophageal compression caused by aortic arch anomalies. The age range was 3 days to 12 years (median, 3 months); 19 (63%) were male, and 20 (67%) were white. Of the 30 patients, 10 had a double aortic arch (the left was atretic in 6), 5 had a left-sided arch with an aberrant right subclavian artery (4) or innominate artery (1), and 15 had a right-sided arch with an aberrant left subclavian artery (14) or with mirror-image branching (1). There was no mortality during hospitalization or within 30 days of surgery. The left ductus arteriosus was divided in 26 of the 30 patients. Among the 10 patients with a double aortic arch, division of the atretic left arch (6), the lesser left arch (3), or the lesser right arch (1) was carried out. All 4 patients with a left arch and aberrant right subclavian artery had division of the artery. Of 14 patients with a right arch and aberrant left subclavian artery, only 3 underwent division of the artery. Of the 30 patients, anterior arteriopexy was performed in 9 (30%), and reoperation for persistent symptoms was necessary in 4 (13%). The second operation usually consisted of aortopexy or tracheopexy. Of the 4 patients with associated cardiac anomalies, 2 underwent simultaneous cardiac repair. The duration of hospital stay for the 30 patients ranged from 4 to 148 days (median, 6 days). Excluded from this series are patients with vascular rings who were asymptomatic and patients with the pulmonary vascular sling syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
Aorta, Thoracic↗
On the pH-dependent yield of hydroxyl radical products from peroxynitrite.
Nitric oxide reacts rapidly with superoxide to give the strongly oxidizing peroxynitrite anion (ONOO-), which undergoes spontaneous first-order decomposition when protonated. The oxidative chemistry of peroxynitrite (ONOO-) is highly pH-dependent. At acidic pH, peroxynitrous acid (ONOOH) oxidizes dimethylsulfoxide to formaldehyde and 2,2'-azino-bis-(3-ethyl-1,2- dihydrobenzothiazoline 6-sulfonate) (ABTS) to the greenish-colored ABTS+ radical cation. The product yield from dimethylsulfoxide and ABTS decreased at more alkaline pH with apparent pK(a)s of 7.9 and 8.2, respectively. Decreasing yield with increasing pH could not be explained by the oxidation of either formaldehyde or ABTS+ by peroxynitrite. In the presence of 50 mM dimethylsulfoxide, nitrogen dioxide was formed in approximately equimolar amounts to the other reaction product, formaldehyde. The yield of nitrogen dioxide also decreased with an apparent pK(a) of 8.0. We propose that the complex oxidative chemistry of peroxynitrite is controlled by the pH-dependent isomerization of the relatively stable cis-configuration (predominant at high pH) to the trans-configuration. Trans-peroxynitrous acid can form a vibrationally excited intermediate capable of reacting like hydroxyl radical. The vibrationally excited intermediate can also directly rearrange to nitric acid, reducing the apparent hydroxyl radical yield to less than 30%. The loss of hydroxyl radical-like reactivity can be explained on the basis of ionization of trans-peroxynitrous acid to the trans-anion, which in turn undergoes internal rearrangement to nitrate without forming a strong oxidant.(ABSTRACT TRUNCATED AT 250 WORDS)
Benzothiazoles↗
Proposed AORN position statement on perioperative care of patients with do-not-resuscitate (DNR) orders. Association of Operating Room Nurses.
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Humans↗