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Biomedical subjects

J A Thompson

Publications and source records attributed to J A Thompson.

At least 127 records · Page 7Linked to original sources
PubMed1996

Immunolocalization of FGF-1 and receptors in human renal allograft vasculopathy associated with chronic rejection.

Despite recognition of chronic vasculo-occlusive disease in solid organ transplantation, the exact pathophysiologic events resulting in neointima formation remain to be elucidated. Since acidic fibroblast growth factor (FGF-1) is an established modulator of vascular cell function, we examined the expression of this growth factor and its high affinity receptors in both relevant renal transplant controls (n = 5) and tissue from patients (n = 19) who underwent nephrectomy following graft loss secondary to chronic rejection. In situ hybridization and immunohistochemical studies demonstrated minimal vascular expression and distribution of FGF-1 and FGF high affinity receptors in the normal human kidney. In contrast, vascular lesions in kidney allografts experiencing chronic rejection demonstrated the exaggerated appearance of FGF-1 ligand and receptors. Immunoreactive FGF-1 readily was detected in medial smooth muscle cells and focal areas of intimal hyperplasia, particularly in association with the presence of inflammatory infiltrate. Enhanced staining for FGF-1 mRNA primarily was associated with the appearance of resident inflammatory cells. Medial smooth muscle cells of hyperplastic vascular structures demonstrated the greatest immunoappearance of FGF receptors-however, diffuse immunostaining also was observed in areas of intimal hyperplasia. The enhanced appearance of both FGF-1 and FGF receptors in the vascular wall suggests that this polypeptide mitogen may serve as an important mediator of growth responses associated with neointima development and angiogenesis during chronic rejection of human renal allografts.

Adult↗
PubMed1996

Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits.

Reactive oxygen species play a central role in vascular inflammation and atherogenesis, with enhanced superoxide (O2.-) production contributing significantly to impairment of nitric oxide (.NO)-dependent relaxation of vessels from cholesterol-fed rabbits. We investigated potential sources of O2.- production, which contribute to this loss of endothelium-dependent vascular responses. The vasorelaxation elicited by acetylcholine (ACh) in phenylephrine-contracted, aortic ring segments was impaired by cholesterol feeding. Pretreatment of aortic vessels with either heparin, which competes with xanthine oxidase (XO) for binding to sulfated glycosaminoglycans, or the XO inhibitor allopurinol resulted in a partial restoration (36-40% at 1 muM ACh) of ACh-dependent relaxation. Furthermore, O2.(-)-dependent lucigenin chemiluminescence, measured in intact ring segments from hypercholesterolemic rabbits, was decreased by addition of heparin, allopurinol or a chimeric, heparin-binding superoxide dismutase. XO activity was elevated more than two-fold in plasma of hypercholesterolemic rabbits. Incubation of vascular rings from rabbits on a normal diet with purified XO (10 milliunits/ml) also impaired .NO-dependent relaxation but only in the presence of purine substrate. As with vessels from hypercholesterolemic rabbits, this effect was prevented by heparin and allopurinol treatment. We hypothesize that increases in plasma cholesterol induce the release of XO into the circulation, where it binds to endothelial cell glycosaminoglycans. Only in hypercholesterolemic vessels is sufficient substrate available to sustain the production of O2.- and impair NO-dependent vasorelaxation. Chronically, the continued production of peroxynitrite, (ONOO-) which the simultaneous generation of NO and O2.- implies, may irreversibly impair vessel function.

Acetylcholine↗
PubMed1996

Immunolocalization of FGF-1 and receptors in glomerular lesions associated with chronic human renal allograft rejection.

Glomerular lesions are considered one of the more detrimental pathologic changes associated with chronic rejection of renal allografts. To elucidate potential pathophysiologic mechanisms associated with transplant glomerulopathy, we examined the expression of acidic fibroblast growth factor (FGF-1) and its high-affinity receptors (FGFR) in both relevant renal transplant controls (n=5) and tissue from patients (n=19) who underwent nephrectomy following graft loss secondary to chronic rejection. In situ immunohistochemical analyses demonstrated minimal staining and distribution of FGFR and FGF-1, which was localized to the mesangial matrix in glomeruli from normal human kidneys. In situ hybridization failed to detect the presence of FGF-1 mRNA in control tissue. In contrast, each stage of the developing glomerular lesion associated with chronic rejection demonstrated the exaggerated appearance of FGF-1 protein in visceral and parietal epithelial cells. Intense staining for FGF-1 protein did not correlate with the increased appearance of FGF-1 mRNA, which was restricted to circulating inflammatory cells. Glomeruli in kidneys with findings of chronic rejection also exhibited increased immunodetection of both FGFR and PCNA in mesangial and epithelial cells. Immunogold labeling of chronically rejected visceral epithelial cells revealed both cytoplasmic and nuclear/localization of FGF-1, thereby establishing mitogenic potential of the growth factor. The enhanced appearance of both biologically active FGF-1 and FGFR suggests that this polypeptide may serve as an important mediator of growth responses associated with glomerular lesion development during chronic rejection.

Adolescent↗
PubMed1996

Serum-starvation induces the extracellular appearance of FGF-1.

Autocrine/paracrine stimulation of cell growth by members of the fibroblast growth factor (FGF) family of polypeptides is dependent upon extracellular interactions with specific high affinity receptors at the cell surface. Acidic FGF (FGF-1) lacks a classical signal sequence for secretion, suggesting that intrinsic levels of this mitogen may not stimulate cell growth and utilizes a non-classical pathway to gain access to the extracellular compartment. To evaluate the biological potential of intracellular FGF-1 more rigorously, human cDNA sequences for the growth factor were introduced into primary murine embryonic fibroblasts using retrovirally mediated gene transfer. Heparin affinity, Western analysis, mitogenic assays, in situ immunohistochemical techniques, induction of tyrosine phosphorylation and antibody inhibition studies were used to demonstrate functionality of the FGF-1 transgene in this experimental model. Under normal culture conditions, cells constitutively expressing intracellular FGF-1 exhibited a slight growth advantage. In contrast, when maintained in reduced serum, these cells adopted a transformed phenotype and demonstrated an enhanced growth potential, induction of FGF-specific phosphotyrosyl proteins and the nuclear association of the growth factor. Analysis of the conditioned media from these stressed cells indicated that serum starvation induces the secretion of FGF-1 as latent high molecular mass complexes requiring reducing agents to activate its full biological potential.

Amino Acid Sequence↗
PubMed1996

Molecular conjugate-mediated gene transfer into isolated human kidneys.

Advances in systemic immunosuppressive therapy for solid organ transplantation have done little to decrease the percentage of allografts that eventually will develop chronic rejection. However, one of the promises of modern molecular biology includes the ability to introduce new genetic information into mammalian hosts. The ability to deliver genes and control their expression in the adult kidney has been described in appropriate animal models. Consequently, gene transfer technology represents a realistic therapeutic approach to modify the allogeneic kidney before engraftment in an effort to decrease the incidence of posttransplant dysfunction. To bridge the gap between animal studies and the clinical application of this technology, we report the first genetic transfection of isolated human kidneys under conditions of organ preservation. Polymerase chain reaction, reversed transcription polymerase chain reaction, and in situ hybridization techniques demonstrated that an adenovirus-polylysine-deoxyribonucleic acid (DNA) complex can be used to insert a complementary DNA expression vector encoding beta-galactosidase into the intact human kidney. Immunohistochemical and in situ enzymatic analyses determined further that gene delivery and expression were localized in proximal tubular epithelial cells. Consequently, targeting of genes to perturb mediators of the local inflammatory response may represent a rational therapeutic interventional strategy in chronic rejection of the kidney.

Adenoviridae↗
PubMed1996

Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia.

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.

Acute Disease↗
PubMed1996

Fibroblast growth factor-induced motor end plate regeneration in atrophic muscle.

OBJECTIVE: To determine whether fibroblast growth factor 1 implanted with viable nerve into atrophic muscle will stimulate formation of functional, acetylcholine producing motor end plates. DESIGN: Twelve male Lewis rats underwent predenervation of the hamstring muscle 8 weeks before implantation of the nerve at a site distant from the original motor end plate. Six animals underwent implantation of the tagged nerve ending into atrophic muscle with 50 microgram of fibroblast growth factor 1 in a fibrin adhesive carrier (group 1). Three animals underwent implantation with nerve, fibrin adhesive, and no fibroblast growth factor 1 (group 2); and three animals underwent implantation with fibroblast growth factor 1 and fibrin adhesive with no nerve (group 3). Animals were killed 9 weeks after implantation and nerve and muscle specimens were harvested. MAIN OUTCOME MEASURES: Histoenzymologic methods for acetylcholinesterase and silver impregnation of nerve fibers were performed 9 weeks after fibroblast growth factor 1-fibrin adhesive implantation. Variables included the number of motor end plates per highpower field and motor end plate length. RESULTS: Robust axonal sprouting and formation of multiple motor end plates were found arborized in serial fashion equidistant around the implanted nerve ending. Rare extrasynaptic staining occurred. End plate lengths were significantly shorter in the fibroblast growth factor 1-treated muscles (group 1) than in the specimens without fibroblast growth factor 1 (group 2) (31.2 vs 58.5 micron; P>001, paired t test). The arborization of motor end plates, rare extrasynaptic staining, and shorter end plate lengths seen in group 1 were all consistent with mature motor end plates. Controls (group 3) displayed limited motor end plate formation and extensive extrasynaptic staining typical of denervation. CONCLUSION: This study presents encouraging evidence that fibroblast growth factor 1 with fibrin adhesive carrier can facilitate the reinnervation of atrophied muscle by enhancing the formation or revitalization of motor end plates. Future studies will address muscle function and use of different carrier materials.

Animals↗
PubMed1996

Management of summer infertility in Texas Holstein dairy cattle.

The objectives of this study were to describe the impact of season on pregnancy odds and the effect of specific herd management practices to modify seasonal effects. Pregnancy odds were significantly associated with herd, season, days in milk, and milk production, and with 3 interactions: milk production-by-days in milk, milk production-by-parity, and season-by-days in milk. The estimate of relative risk for summer insemination resulting in pregnancy was 0.66 at 60 d post calving and 0.53 at 160 d post calving. Shade in the lounging area, holding pen or dry cow areas, and fans in the lounging area had positive effects on summer pregnancy odds. Fans in the dry cow area were associated with a reduced odds of pregnancy. Sprinklers did not significantly modify the effect of season on pregnancy odds. The strong seasonal decrease in pregnancy odds was less severe on farms that provided shade in the lounging areas, holding pens and dry cow areas and fans in lounging areas. Insemination strategies can also be adapted to increase the pregnancy odds.

Journal Article↗
PubMed1996

Alkylation of 2'-deoxynucleosides and DNA by quinone methides derived from 2,6-di-tert-butyl-4-methylphenol.

4-Alkylphenols, such as the antioxidant 2, 6-di-tert-butyl-4-methylphenol (BHT), exhibit toxicities that appear to be mediated by their oxidative metabolism to electrophilic quinone methides. Reactions of these Michael acceptors with simple nucleophiles and proteins have been reported, but little information is available on quinone methide binding to the competing nucleophilic sites in DNA. In the present investigation, 2'-deoxynucleoside adducts generated in vitro with two BHT-derived quinone methides, 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone and 6-tert-butyl-2- (2'-hydroxy-1',1'-dimethylethyl)-4-methylenecyclohexa-2,5-dieno ne (BHTOH-QM) were isolated and identified. Both quinone methides produced adducts at the 1- and N2-positions of deoxyguanosine (dG) and the N6-position of deoxyadenosine (dA). In addition, a labile adduct formed at the 7-position of dG, which degraded to the corresponding 7-alkylguanine derivative. Additional work was conducted with BHTOH-QM, the more reactive of the two quinone methides. This species also formed stable adducts at the N4-position of deoxycytosine (dC) and the 3-position of thymidine and formed a labile adduct at the 3-position of dC that underwent hydrolytic cleavage to regenerate dC. In mixtures of deoxynucleosides treated with [14C]BHTOH-QM, alkylation occurred primarily at the N2- and 7-positions of dG and the N6-position of dA and occurred secondarily at the 1-position of dG. Treatment of calf thymus DNA with this quinone methide yielded N6-dA and N2-dG adducts with the former predominating. The unstable 7-dG adduct was detected by analysis of the 7-alkylguanine product from depurination. These results demonstrate that quinone methides are most likely to damage DNA through alkylation of the exocyclic amino groups of purine residues and possibly also by attack at the 7-position of dG followed by depurination.

Alkylation↗
PubMed1996

Cognitive effects of flumazenil in patients with Alzheimer's disease.

Intravenous flumazenil was administered to two patients with probable Alzheimer's disease. Neuropsychological tests were administered at baseline, immediately after drug administration, and at washout 3 hours later. Cognitive function was observed to decline in both patients with eventual return to baseline, which indicates an adverse effect of flumazenil. Tests of vigilance were most severely affected, which may have been related to an inverse agonistic effect of flumazenil in producing symptoms of anxiety.

Aged↗
PubMed1996

Ways of coping with psychological distress after trauma.

One hundred and eight survivors of trauma attending a stress clinic were assessed on measures of coping, personality, control expectancies and psychological distress. The psychometric characteristics of these questionnaires are discussed, and the relationships between them investigated using correlational and regression techniques. Although cross-sectional studies can only be indicative, it would appear that most coping strategies, and particularly escape-avoidance, are consistently associated with high psychological distress, with the exception of positive reappraisal and distancing, which are the only strategies associated with better psychological outcome. It may be that deeply distressed survivors cannot find effective ways of obtaining relief, and therefore report many ways of trying to cope.

Adaptation, Psychological↗
PubMed1996

Detection of Helicobacter pylori infection by saliva IgG testing.

OBJECTIVES: Most currently available tests for the detection of Helicobacter pylori are invasive, time consuming, or impractical. We examined the test performance of a simple and rapidly administered salivary IgG assay kit in the diagnosis of Helicobacter pylori infection. METHODS: Patients referred to a tertiary care setting for upper gastrointestinal endoscopy were included in a prospective evaluation of the test performance of the Helisal Kit which uses an ELISA technique to determine IgG antibodies in saliva. The results of the salivary IgG assay were compared to those of the Helisal Serum Kit, and to gastric histology. Two by two contingency table analyses were performed, and 95% confidence intervals (CI) were determined. RESULTS: Upper gastrointestinal endoscopy was performed on 106 patients over a 3-month period. A statistically significant correlation was found between the blood and saliva IgG results (r = 0.60, p = 0.0001). When compared to serum IgG, the salivary assay test performance was: sensitivity 84% (CI: 70-93%), specificity 81% (CI: 69-90%), positive predictive value 76% (CI: 61-87%), negative predictive value 88% (CI: 76-95%), and diagnostic accuracy 88% (CI: 76-95%). Compared with gastric histology, the test performance of the salivary IgG assay decreased to: sensitivity 66% (CI: 52-79%), specificity 74% (CI: 60-85%), positive predictive value 71% (CI: 57-83%), negative predictive value 68% (CI: 55-80%), and diagnostic accuracy 70% (CI: 60-78%). More specifically, the salivary assay gave false-negative results in nine of 17 patients with duodenal ulcers. Results did not vary significantly when outcomes of the salivary and serum assays were combined. The incremental information obtained in the salivary test was greatest in the patient population exhibiting an intermediate pretest probability (30-70%) of being infected with Helicobacter. CONCLUSION: The salivary IgG results correlated significantly with the serum IgG titers but exhibited only modest test performance, compared with the results of gastric histology. This salivary test may be most useful in certain patient subpopulations or in specific clinical contexts.

Adult↗
PubMed1996

Close simulation of acute graft-versus-host disease by interleukin-2 administered after autologous bone marrow transplantation for hematologic malignancy.

The high relapse rate of hematologic malignancy treated with autologous bone marrow transplantation (ABMT) may reflect the absence of a graft-versus-leukemia (GVL) effect usually associated with graft-versus-host disease (GVHD). The purpose of this study was to determine whether administration of interleukin-2 (IL-2) early after ABMT might induce or exacerbate acute skin GVHD. Fourteen patients at high risk for post-transplant relapse, eight with NHL and six with AML > or = first relapse, were conditioned with chemotherapy and total body irradiation (13) or chemotherapy alone (1), and received purged (10) or unpurged (4) marrow. A median of 35 days (range 25-58) after ABMT, they received a 5-day induction course of Roche IL-2 (9 x 10(6) U/m2/day) followed by apheresis, reinfusion of LAK cells, and a 10-day maintenance course of IL-2 (0.9 x 10(6) U/m2/day), all by continuous i.v. infusion. Serial skin biopsies were obtained before and after IL-2 therapy and were read blindly. Patients were studied prospectively for the development of acute cutaneous GVHD as reflected by rash ( > or = 25% body surface area), skin biopsy ( > or = grade II histologic changes) and T cell infiltration as assessed by staining of the biopsy with antibodies UCHL-1 and TIA-1. No patient had a rash before IL-2 therapy, but 12 of 14 (85%) developed a rash during the IL-2 induction course. Before IL-2 therapy, biopsies from three of 10 patients (30%) revealed histologic GVHD; after induction IL-2, biopsies from 11 of 14 patients (79%) revealed grade II acute GVHD. Biopsies from all patients with histologic GVHD after IL-2 therapy contained TIA-1 positive T cells. HLA-DR was negative in the keratinocytes of these paraffin-embedded sections. One patient died early of sepsis, one patient required and responded to topical corticosteroids and 12 had spontaneous resolution of the rash. Six patients relapsed at 3-13 months, while seven remain in complete remission 32+ to 41+ months after ABMT. The results demonstrate that IL-2 therapy after ABMT can induce effects which histologically and clinically mimic cutaneous acute GVHD in most patients. Prospective, randomized trials of IL-2 vs observation after transplantation of autologous marrow or stem cells for high-risk NHL and AML have been initiated which may allow us to determine whether this phenomenon is associated with a clinical GVL effect as reflected by a decreased relapse rate.

Acute Disease↗
PubMed1996

In vivo gene transfer to the human biliary tract.

The human biliary tract offers an excellent model for gene transfer studies for a variety of diseases localized to the liver. The aim of this study was to determine if a viable liver might be employed to study viral transfection of the human biliary system in order to mimic in vivo human experiments. Using a normal human liver initially procured for transplantation, but subsequently found unsuitable, and with an intact biliary tree, the hepatic vascular supply was accessed for continuous perfusion. The common and left hepatic biliary system was isolated by balloon catheterization. A replication defective adenoviral vector containing the Escherichia coli beta-galactosidase (lac Z) reporter gene (AdCMVLacZ) was injected into the catheter-isolated left and common bile duct lumen. Viral exposure to the right duct system was prevented by ligation. The bile duct segments were excised and prepared for enzymatic (X-gal) staining. Intense staining was observed in the biliary epithelium exposed to the adenoviral vector. No evidence of beta-galactosidase staining was noted in the unexposed biliary mucosa. We report direct transfection of biliary epithelial cells from normal human liver with a recombinant adenovirus. Our data suggest potential therapeutic applications for gene therapy of hepatobiliary disorders.

Adenoviridae↗
PubMed1996

Paraneoplastic manifestations of renal cell carcinoma.

Paraneoplastic manifestations are present in up to 20% of patients with renal cell carcinoma (RCC). There is convincing evidence that RCC tumor cells elaborate proteins that serve as mediators of endocrine (eg, ectopic production of parathyroid hormone-related protein or erythropoietin) as well as nonendocrine paraneoplastic syndromes. A paraneoplastic syndrome may be the initial clinical presentation of RCC in a significant number of patients, and recognition of these syndromes may facilitate early diagnosis. Most paraneoplastic syndromes associated with RCC remit after resection of the primary RCC or treatment of metastatic sites. The natural history of metastatic RCC is extremely variable. A significant proportion of patients may survive several years with slowly progressing metastatic disease. In these patients, the accurate diagnosis and management of paraneoplastic syndromes may be important in palliative management. Except for hypercalcemia, conventional medical therapies are seldom helpful. Other paraneoplastic manifestations of RCC include cachexia, fever, hepatic dysfunction, anemia, and amyloidosis, although our understanding of the underlying pathophysiology remains incomplete.

Carcinoma, Renal Cell↗
PubMed1996

Molecular mechanisms of angiogenesis: experimental models define cellular trafficking of FGF-1.

Numerous studies have established that stimulation of cell growth by members of the fibroblast growth factor (FGF) family of polypeptides is dependent upon an extracellular pathway. Acidic FGF (FGF-1), however, lacks a classical signal sequence for secretion, thereby making it difficult to evaluate regulation of biological activity by this growth factor. Efforts in this laboratory have utilized molecular techniques of retrovirology and transgenic modeling to introduce cDNA sequences encoding either an intracellular or extracellular form of FGF-1 into primary diploid cells to examine trafficking and compartmentalization of FGF-1. Several lines of evidence obtained from these models provide a compelling argument that the stimulation of FGF-1-associated cellular transformation is restricted to an extracellular, receptor-mediated pathway, involving protein tyrosine phosphorylation and nuclear localization. In addition, an unconventional secretion pathway for intracellular FGF-1 has been identified that involves mechanisms associated with oxidative stress.

Animals↗
PubMed1995

Evaluation of the benefits of the timing of pregnancy testing by transrectal palpation in dairy cattle.

OBJECTIVE: To determine the benefits that were associated with pregnancy testing by use of transrectal palpation during the period 30 to 65 days after unsuccessful insemination of dairy cows. DESIGN: Nonconcurrent, cohort study. ANIMALS: Cows in 15 dairy herds in the United States and Canada. PROCEDURE: Reproductive records of cows (n = 713) that did not calve within 294 days of first-service insemination and that had been evaluated for pregnancy 30 to 65 days after first-service insemination were examined. Records were analyzed to determine the day of parturition or date of culling and to determine if the probability of a cow being culled or the interval to parturition was related to the number of days after insemination that pregnancy testing was performed. RESULTS: For cows that calved more than 294 days after first-service insemination, the interval from first-service insemination until parturition was associated significantly with herd, season, and treatment on the day of pregnancy testing with prostaglandin F2 alpha or one of its analogues. Cows treated with prostaglandin F2 alpha on the day of pregnancy testing were less likely to be culled than nontreated cows. For cows pregnancy tested 30 to 65 days after insemination, each additional day after day 30 before pregnancy testing was performed resulted in an increase of 1.09 days in the interval until parturition. CLINICAL IMPLICATIONS: Pregnancy testing by means of transrectal palpation as soon as possible after day 30 after insemination can result in shorter calving intervals.

Animals↗