Strategies for the preclinical and clinical characterization of immunogenicity.
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Animals↗
Biomedical subjects
S Swanson
Publications and source records attributed to S Swanson.
Single photon emission computerized tomography (SPECT) in detecting neurodegeneration in Huntington's disease.
Single photon emission computerized tomography (SPECT) studies were performed on 34 manifest Huntington's disease (HD) patients at various stages of clinical pathology ranging from early chorea to late dystonia with or without signs of dementia and 12 pre-symptomatic patients with abnormal terminal CAG expansions. Thirty HD patients with obvious clinical signs and seven pre-symptomatic patients without signs or symptoms of HD displayed selective caudate hypoperfusion by direct visual inspection. Such qualitative, selective striatal hypoperfusion patterns can be indicative of early and persistent metabolic changes in striatal neuropathology. SPECT studies can be useful in documenting early pre-clinical changes in patients with abnormal terminal CAG expansions and in confirming the presence of caudate pathology in patients with clinical signs of HD.
Adult↗
Stochastic regulation of cell migration from the efferent lymph to oxazolone-stimulated skin.
The systemic immune response is a dynamic process involving the trafficking of lymphocytes from the Ag-stimulated lymph node to the peripheral tissue. Studies in sheep have demonstrated several phases of cell output in the efferent lymph after Ag stimulation. When skin contact sensitizers are used as Ag, the efferent lymph cell output peaks approximately 96 h after Ag stimulation and is temporally associated with the recruitment of cells into the skin. To investigate the relative contribution of this high-output phase of efferent lymphocytes to lymphocytic inflammation in the skin, we used a common contact sensitizer 2-phenyl-4-ethoxymethylene-5-oxazolone (oxazolone) to stimulate the skin and draining prescapular lymph node of adult sheep. The efferent lymph ducts draining the Ag-stimulated and contralateral control lymph nodes were cannulated throughout the experimental period. The lymphocytes leaving the lymph nodes during the 72-h period before maximum infiltration were differentially labeled with fluorescent tracers, reinjected into the arterial circulation, and tracked to the site of Ag stimulation. Quantitative tissue cytometry of the skin at the conclusion of the injection period (96 h after Ag stimulation) demonstrated more migratory cells derived from the Ag-stimulated lymph node than the contralateral control (median 18.5 vs 15.5 per field; p < 0.05). However, when corrected for total cell output of the lymph node, the Ag-stimulated migratory cells were 3.8-fold more prevalent in the skin than the contralateral control cells. These results suggest that the in situ immune response generally mirrors the frequency of recruitable lymphocytes in the peripheral blood.
Adjuvants, Immunologic↗
Rho-A is critical for osteoclast podosome organization, motility, and bone resorption.
Rho plays a regulatory role in the formation of actin stress fibers and focal adhesions, and it is also involved in integrin-mediated signaling events. To study the role of Rho in alpha(v)beta(3)/gelsolin-dependent signaling, the HIV-Tat peptide, hemagglutinin (HA)-tagged Rho(Val-14) (constitutively active) and Rho(Asn-19) (dominant negative) were transduced into avian osteoclasts. Protein transduction by HA-Tat was highly efficient, and 90-100% of the cells were transduced with HA-tagged proteins. We demonstrate here that Rho(Val-14) transduction (100 nM) stimulated gelsolin-associated phosphatidylinositol 3-kinase activity, podosome assembly, stress fiber formation, osteoclast motility, and bone resorption, mimicking osteoclast stimulation by osteopontin/alpha(v)beta(3.) The effects of Rho(Val-14) transduction stimulation was time-dependent. C3 exoenzyme blocked the effects of Rho(Val-14) and induced podosome disassembly, loss of motility, and inhibition of bone resorption. Transduction of Rho(Asn-19) produced podosome disassembly, and blocked osteopontin stimulation. These data demonstrate that integrin-dependent activation of phosphoinositide synthesis, actin stress fiber formation, podosome reorganization for osteoclast motility, and bone resorption require Rho stimulation.
ADP Ribose Transferases↗
Ring avulsion injuries: a biomechanical study.
The biomechanics of ring avulsion injuries was studied in a cadaveric simulation model. Custom-fitted metal rings attached to a rigid frame were placed over the proximal phalanx of fresh or thawed fresh-frozen specimens. Ring avulsion injuries in 44 fingers were produced with a standardized force applied to the proximal ulna. The progress of injury was evaluated with simultaneous high-speed cinematography and continuous force measurements. The injured digits were x-rayed and categorized according to Urbaniak's classification. Continuous force measurements produced similar curves for all classes of injuries. The average maximum force resulting in class I injuries was 80 N. The average maximum force producing amputation in class III injuries was 154 N, a force much lower than expected. Force measurements for class II injuries were nearly identical to those of class III. This surprisingly minimal force resulting in digit amputation was explained by high-speed cinematography, which showed that the rings tilt on the digits concentrating disruption forces as a result of ring angulation on the finger. Incomplete amputations were due to loss of ring purchase by skin flap eversion. Finally, comparison of high-speed cinematography with force curves suggests that skin rupture rather than skeletal or tendon disruption accounted for the maximum force during ring avulsion injury.
Amputation, Traumatic↗
Evolutionary significance of isopreneemission from mosses.
Isoprene emission has been documented and characterized from species in all major groups of vascular plants. We report in our survey that isoprene emission is much more common in mosses and ferns than later divergent land plants but is absent in liverworts and hornworts. The light and temperature responses of isoprene emission from Sphagnum capillifolium (Ehrh.) Hedw. are similar to those of other land plants. Isoprene increases thermotolerance of S. capillifolium to the same extent seen in higher plants as measured by chlorophyll fluorescence. Sphagnum species in a northern Wisconsin bog experienced large temperature fluctuations similar to those reported in tree canopies. Since isoprene has been shown to help plants cope with large, rapid temperature fluctuations, we hypothesize the thermal and correlated dessication stress experienced by early land plants provided the selective pressure for the evolution of light-dependent isoprene emission in the ancestors of modern mosses. As plants radiated into different habitats, this capacity was lost multiple times in favor of other thermal protective mechanisms.
Journal Article↗
A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.
Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.
Adenoviridae↗
Ethyl-substituted erythromycin derivatives produced by directed metabolic engineering.
A previously unknown chemical structure, 6-desmethyl-6-ethylerythromycin A (6-ethylErA), was produced through directed genetic manipulation of the erythromycin (Er)-producing organism Saccharopolyspora erythraea. In an attempt to replace the methyl side chain at the C-6 position of the Er polyketide backbone with an ethyl moiety, the methylmalonate-specific acyltransferase (AT) domain of the Er polyketide synthase was replaced with an ethylmalonate-specific AT domain from the polyketide synthase involved in the synthesis of the 16-member macrolide niddamycin. The genetically altered strain was found to produce ErA, however, and not the ethyl-substituted derivative. When the strain was provided with precursors of ethylmalonate, a small quantity of a macrolide with the mass of 6-ethylErA was produced in addition to ErA. Because substrate for the heterologous AT seemed to be limiting, crotonyl-CoA reductase, a primary metabolic enzyme involved in butyryl-CoA production in streptomycetes, was expressed in the strain. The primary macrolide produced by the reengineered strain was 6-ethylErA.
Acyl Coenzyme A↗
Implementing the ISBT 128 labeling standard in a transfusion service.
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Blood Banks↗
Effusion cytology of esophageal carcinoma.
BACKGROUND: Effusions in patients with esophageal carcinoma have only been reported rarely, and the cytologic findings in these specimens have not been well described. METHODS: The authors reviewed 70 effusion specimens from 45 patients with known esophageal carcinoma, 37 of whom underwent resection. RESULTS: Seventeen specimens were from 10 patients with squamous cell carcinoma; only 1 specimen contained malignant cells. Fifty-three specimens were from 35 patients with adenocarcinoma. Twenty-one specimens from 10 patients with adenocarcinoma contained malignant cells; these included 17 pleural, 2 pericardial, and 2 peritoneal fluids. Lymph node involvement at the time of resection was a significant risk factor for the development of a malignant effusion. The cytologic features were similar to those of other adenocarcinomas, but >50% of the specimens were hypocellular and neoplastic cells were rare. Three of 48 negative specimens contained markedly atypical mesothelial cells that were misinterpreted as possibly malignant; in each case the findings resolved over time. These cells were smaller and the chromatin more smudgy than in the neoplastic cells. Patients with positive effusions were significantly more likely to die of disease than those with a negative effusion, and the average time to death was shorter (5.3 months vs. 17 months). CONCLUSIONS: Malignant effusions are more common in patients with esophageal adenocarcinoma than those with squamous cell carcinoma. Markedly atypical mesothelial cells are a diagnostic pitfall in patients who undergo resection.
Adenocarcinoma↗
Potent and selective 1,2,3-trisubstituted indole NPY Y-1 antagonists.
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Animals↗
Effusion cytology after extrapleural pneumonectomy for treatment of malignant mesothelioma.
Extrapleural pneumonectomy to treat malignant mesothelioma may offer a significant survival advantage for selected patients. The role of effusion cytology in these patients has not been previously examined. To evaluate this, cytology, pathology, and medical records of 26 cases in 21 patients who underwent extrapleural pneumonectomy because of malignant mesothelioma were reviewed. Positive cytologic results were noted on average 13 months later than negative results. Recurrence was most common in the peritoneum, followed by the ipsilateral thorax and contralateral thorax. Five of 11 true-negative results were secondary to infection; cytologic analysis revealed neutrophils in each case. Four of 5 false-negative cases were from the ipsilateral thorax, and no mesothelial cells were found. When these 4 cases are excluded, the sensitivity of cytologic examination in this setting was 91%, and specificity was 100%. Effusion cytology in patients after extrapleural pneumonectomy is an effective means of diagnosing recurrent malignant mesothelioma.
Adult↗
Flap closure of postpneumonectomy empyema.
Empyema continues to be an uncommon, frustrating, and potentially lethal complication of pneumonectomy. Between 1990 and 1994 we treated 16 cases of recalcitrant postpneumonectomy (partial or total) empyema with combinations of pulse lavage, sharp debridement, muscle flaps, myodermal flaps, and thoracoplasty. We performed 11 pectoralis muscle flaps, 6 serratus anterior muscle flaps, 9 latissimus dorsi muscle flaps, 6 rectus abdominis muscle flaps, and 1 trapezius muscle flap for an average of 2.1 muscle flaps per patient. There was 1 omental flap. Of these flaps, 2 were free and the rest pedicled. Ten of the muscle flaps carried deepithelialized cutaneous paddles, and 6 were larger than 150 cm3. Thoracoplasty was done in 11 patients to decrease the volume of the postpneumonectomy empyema cavity. Of 16 patients, 4 failed initially because of persistent bronchopleural fistula or infection but resolved after one additional procedure. There was 1 perioperative death, 3 reoperations for bleeding, 1 patient with upper extremity deep vein thromboses, 1 seroma, and 1 patient with significant postoperative pain syndrome. In order to determine the efficacy of different operative approaches, patients were retrospectively divided into two groups according to the number of operations using flaps needed to resolve their postpneumonectomy empyema. Group A required only one operation using flaps to eliminate the postpneumonectomy empyema. Group B required two operations using flaps to remedy the postpneumonectomy empyema. Group B operations were further classified into B1, for the first operation, and B2, for the second operation. No patient needed more than two operations using flaps. Three significant variables were identified, the number of muscle flaps, the number of ribs in any thoracoplasty, and the preoperative serum albumin level. The A and B2 groups had significantly more muscle flaps transposed (p = 0.006) and ribs resected (p = 0.0002) than the B1 group. These findings suggest that filling the postpneumonectomy empyema space with muscle and collapsing any remaining space by thoracoplasty were the most successful strategy. The B2 group's average albumin level was significantly higher (p = 0.03) than that in either the A or the B1 group, suggesting that improved nutrition may have played a role in the lack of recurrence. Our goals of single-stage closure and decontamination of empyema cavities were best achieved by following these principles: removal of infected and necrotic tissue using sharp debridement and pulsed lavage, repair of bronchopleural fistulas with muscle flaps, and minimization of the dead space with combinations of muscle flaps and thoracoplasty.
Adult↗
The AMPA antagonist LY293558 improves functional neurological outcome following reversible spinal cord ischemia in rabbits.
Glutamate (Glu) neurotoxicity is an important element of a number of neurological disorders including central nervous system (CNS) ischemia. We evaluated the effects of the novel AMPA Glu antagonist LY293558 on functional neurological outcome in two rabbit stroke models. In the reversible spinal cord ischemia model, ischemia of the caudal lumbar spinal cord was produced by temporary occlusion of the abdominal aorta. LY293558 was administered 5 min after recirculation as a 16 mg/kg i.v. bolus followed by 2.2 mg/kg infused over 1 h. Control animals received saline. LY293558 significantly increased the duration of ischemia required to produce paraplegia, from 30.5 +/- 15.8 min (mean +/- SD) controls to 50.1 +/- 11.5 in treated animals (p < 0.01). In an irreversible model of cerebral ischemia, 50 microns plastic microspheres were injected into the carotid artery and lodged in the cerebral microvasculature. LY293558 did not significantly reduce neurological damage in this model. These data suggest that LY293558 may have therapeutic benefit following some types of ischemic injury.
Animals↗
Client/server system cuts I/S costs in half.
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Community Networks↗
Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors.
Erysodine, an erythrina alkaloid related to dihydro-beta-erythroidine, was found to be a more potent inhibitor of [3H]cytisine binding at neuronal nicotinic acetylcholine receptors but a less potent inhibitor of [125I]alpha-bungarotoxin binding at muscle-type nicotinic acetylcholine receptors than dihydro-beta-erythroidine. Erysodine was a competitive, reversible antagonist of (-)-nicotine-induced dopamine release from striatal slices and inhibited (-)-nicotine-induced 86Rb+ efflux from IMR-32 cells. Erysodine was equipotent with dihydro-beta-erythroidine in the dopamine release assay but 10-fold more potent in the 86Rb+ efflux assay, suggesting differential subtype selectivity for these two antagonists. Erysodine, systemically administered to mice, entered the brain and significantly attentuated nicotine's hypothermic effects and its anxiolytic-like effects in the elevated plus-maze test. There was greater separation between antagonist and toxic doses for erysodine than for dihydro-beta-erythroidine, perhaps because of erysodine's greater selectivity for neuronal receptors. In rats, erysodine prevented both the early developing decrease and the late-developing increase in locomotor activity produced by (-)-nicotine. The potent and competitive nature of erysodine's antagonism together with its ability to enter the brain after systemic administration suggest that erysodine may be a useful tool in characterizing neuronal nicotinic acetylcholine receptors.
Alkaloids↗
Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat.
The effects of the glutamate alpha-amino-3-hydroxy 5-methyl-4-isoxazole propionate (AMPA) receptor antagonist LY-293558 in reducing ischemic brain damage have been assessed in halothane-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery, and the animals were killed 6 h later. The amount of early irreversible ischemic damage was assessed at 16 predetermined stereotactic planes by an observer blinded to treatment paradigm employed. Treatment with LY-293558 (15 mg/kg i.v., plus infusion of 7 mg/kg/h) initiated 30 min prior to middle cerebral artery occlusion reduced significantly (p < 0.02) the volume of ischemic damage (from 3,423 +/- 212 mm3 of the cerebral hemisphere in vehicle-treated cats to 2,822 +/- 569 mm3 in LY-293558-treated cats). The present data demonstrate that an AMPA receptor antagonist can reduce focal ischemic damage in a gyrencephalic species in which key physiological variables have been controlled and monitored throughout the postischemic period. These data provide additional support for the clinical evaluation of AMPA receptor antagonists in focal cerebral ischemia in humans.
Animals↗
Transfer of 210Po and 210Pb through the lichen-caribou-wolf food chain of northern Canada.
Natural background activity and food chain transfer of the uranium decay products, 210Po and 210Pb, were examined in the lichen-caribou-wolf food chain at two locations in the Northwest Territories of Canada. 210Po and 210Pb activities in lichens differed with species and location. Both 210Po and 210Pb were markedly higher in caribou bone than in wolf bone. 210Po activities in liver, kidney, and muscle were similar in both species. Caribou fetuses had lower activities of 210Po but higher activities of 210Pb than maternal muscle and placenta, suggesting greater placental transport of 210Pb than 210Po. Concentration ratios (CR = Bq kg-1 in consumer/Bq kg-1 in its food source) and ff values (ff in d kg-1 = Bq kg-1 in muscle/Bq d-1 ingested) showed that wolves retain more 210Po and less 210Pb from their diet than do caribou. 210Po CRs averaged 0.38 for caribou/lichens, 0.26 for caribou/rumen contents, and 0.40 for wolves/caribou. 210Pb CRs averaged 0.36 for caribou/lichens, 0.57 for caribou/rumen contents, and 0.13 for wolves/caribou.
Animals↗