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Biomedical subjects

D Thomas

Publications and source records attributed to D Thomas.

At least 289 records · Page 16Linked to original sources
PubMed1998

Control of murine cytomegalovirus in the lungs: relative but not absolute immunodominance of the immediate-early 1 nonapeptide during the antiviral cytolytic T-lymphocyte response in pulmonary infiltrates.

The lungs are a major organ site of cytomegalovirus (CMV) infection, pathogenesis, and latency. Interstitial CMV pneumonia represents a critical manifestation of CMV disease, in particular in recipients of bone marrow transplantation (BMT). We have employed a murine model for studying the immune response to CMV in the lungs in the specific scenario of immune reconstitution after syngeneic BMT. Control of pulmonary infection was associated with a vigorous infiltration of the lungs, which was characterized by a preferential recruitment and massive expansion of the CD8 subset of alpha/beta T cells. The infiltrate provided a microenvironment in which the CD8 T cells differentiated into mature effector cells, that is, into functionally active cytolytic T lymphocytes (CTL). This gave us the opportunity for an ex vivo testing of the antigen specificities of CTL present at a relevant organ site of viral pathogenesis. The contribution of the previously identified immediate-early 1 (IE1) nonapeptide of murine CMV was evaluated by comparison with the CD3epsilon-redirected cytolytic activity used as a measure of the overall CTL response in the lungs. The IE1 peptide was detected by pulmonary CTL, but it accounted for a minor part of the response. Interestingly, no additional viral or virus-induced antigenic peptides were detectable among naturally processed peptides derived from infected lungs, even though infected fibroblasts were recognized in a major histocompatibility complex-restricted manner. We conclude that the antiviral pulmonary immune response is a collaborative function that involves many antigenic peptides, among which the IE1 peptide is immunodominant in a relative sense.

Animals↗
PubMed1998

Synaptophysin immunoreactivity in the rat pituitary: alterations after 6-hydroxydopamine treatment.

Synaptophysin (SN) is a synaptic-vesicle-associated membrane protein whose presence is indicative of intact, functional synapses. This study examines the presence of SN in pituitary gland innervation after neurotoxin-induced denervation followed by reinnervation. Immunostaining of rat pituitary neurointermediate lobe tissue for SN reveals a pattern of dot-like densities in the intermediate lobe and intensely stained dispersed regions in the neural lobe of normal animals. In rats treated with 6-hydroxydopamine (6-OHDA), a catecholamine neurotoxin, by peripheral injection, there is a significant depletion of the SN immunostaining in the intermediate lobe, as well as a significant reduction of SN immunoreactivity in the neural lobe, in animals studied 1 wk after drug treatment, with computer analysis of the tissue sections. At 3 wk after 6-OHDA, there is a partial recovery of immunoreactivity for SN in the neural lobe in many tissue sections, and the intermediate lobe also contains only relatively sparse staining for the synaptic protein. Computer analysis revealed that at 3 wk after 6-OHDA, both lobes still had reduced SN immunoreactivity, but the difference in levels measured did not achieve statistical significance. These results contrast with the prior finding of significant recovery of immunoreactivity for GAP-43, a growth and regeneration-associated protein, in intermediate lobe innervation of rats treated with the same drug regimen. We suggest that 6-OHDA treatment damages synaptic vesicle integrity in both the intermediate and neural lobes of the pituitary, and that recovery is in progress, but not complete at 3 wk after the drug is administered.

Animals↗
PubMed1998

Acute toxicity of selected pesticides to the Pacific blue-eye, Pseudomugil signifer (Pisces).

Because the larvivorous fish Pseudomugil signifer is native to southeastern Queensland and is abundant in shallow estuarine habitats, intertidal marshes, wetland habitats, and freshwater streams, it was chosen as an indicator species for toxicologic studies with pesticides. Acute toxicity studies with 2 organophosphorus pesticides (pirimiphos-methyl and temephos) and 3 alternate compounds under evaluation for registration in Australia (Bacillus thuringiensis var. israelensis, s-methoprene, and pyriproxyfen), were tested in 96-h laboratory trials. Pirimiphos-methyl was the most toxic compound, with a median lethal concentration (LC50) of 0.091 ppm (0.3 times the estimated field concentration [EFC] for a 15-cm-deep pool). Temephos had an LC50 value of 0.594 ppm (9.9 times the EFC). Bacillus thuringiensis var. israelensis and pyriproxyfen produced LC50 values of 6.1 x 10(11) International Toxic Units (477 times the EFC) and 0.854 ppm (106 times the EFC), respectively. s-Methoprene was the least toxic compound, with no mortality recorded at 500 times the EFC.

Animals↗
PubMed1998

Roles of sphingosine-1-phosphate in cell growth, differentiation, and death.

Recent evidence suggests that branching pathways of sphingolipid metabolism may mediate either apoptotic or mitogenic responses depending on the cell type and the nature of the stimulus. While ceramide has been shown to be an important regulatory component of apoptosis induced by tumor necrosis factor alpha and the Fas ligand, sphingosine-1-phosphate (SPP), a further metabolite of ceramide, has been implicated as a second messenger in cellular proliferation and survival induced by platelet-derived growth factor, neuronal growth factor, and serum. SPP protects cells from apoptosis resulting from elevations of ceramide. Inflammatory cytokines stimulate sphingomyelinase, but not ceramidase, leading to accumulation of ceramide, whereas growth signals also stimulate ceramidase and sphingosine kinase leading to increased SPP levels. We propose that the dynamic balance between levels of sphingolipid metabolites, ceramide, and SPP and consequent regulation of different members of the mitogen-activated protein kinases (JNK versus ERK) family is an important factor that determines whether a cell survives or dies.

Animals↗
PubMed1998

Laboratory and field evaluation of efficacy of VectoBac 12AS against Culex sitiens (Diptera: Culicidae) larvae.

Laboratory bioassay studies of the efficacy of VectoBac 12AS (active ingredient: 1,200 International Toxic Units [ITU]/mg Bacillus thuringiensis var. israelensis) against field-collected late 3rd/early 4th-instar larvae of Culex sitiens indicated excellent control potential. A 95% lethal concentration (LC95) value of 1.381 x 10(7) ITU was calculated, which equated to a dosage of 0.011 liters/ha. This dosage represented 1.8% of the recommended lowest dosage rate for the product. A field trial of VectoBac 12AS against late 3rd/early 4th-instar field specimens of Cx. sitiens in floating mesh cylinders was then conducted in salt-marsh pools near Coomera Marina, southeast Queensland, Australia. At a rate of 0.5 liters/ha, 100% mortality of Cx. sitiens larvae was recorded at 24 h posttreatment.

Animals↗
PubMed1998

Pharmacokinetics/dynamics of 5c8, a monoclonal antibody to CD154 (CD40 ligand) suppression of an immune response in monkeys.

The pharmacokinetics and pharmacodynamics (PK/PD) of chimeric (Ch5c8) and humanized (Hu5c8) 5c8, a monoclonal antibody that binds CD154 (CD40 ligand), thus blocking the interaction between CD40 and CD154, were investigated in cynomolgus monkeys. Single-dose groups (n = 3 animals per dose) received saline, 0.2, 1, 5 or 20 mg/kg i.v. doses of Hu5c8. The repeat-dose groups (n = 4 animals) received 0 or 5 mg/kg i.v. doses of Ch5c8 or Hu5c8 on days 1, 2, 3, 5, 7 and 9. The single-dose PK parameters showed dose proportionality, with a terminal half-life of 300 h, a volume of distribution at steady state of 73 ml/kg and clearance of 0.2 ml.h-1.kg-1. The repeat-dose regimen produced a longer terminal half-life (500 h) and lower clearance (0.13 ml.h-1.kg-1) than in the single-dose groups. The antibody titer to tetanus toxoid (ATT) challenge served as the immunodynamic marker. The primary ATT response consisted of a latent phase of approximately 10 days, during which the immune system was processing antigen but not yet producing antibody, a rise to an antibody maximum titer at approximately 18 days and a decline toward baseline by approximately 40 days in controls. The 5c8 produced a log(dose)-proportional reduction in the area under the curve of ATT. An indirect PK/PD model based on the kinetics of tetanus toxoid exposure and inhibition of ATT production in relation to 5c8 concentrations was developed. A median inhibitory concentration of 0.84 microg/ml and a efficacy of 0.84 reflected marked inhibition of ATT response by 5c8. The model provides quantitation of reduced ATT responses after 5c8 and was applicable to primary and secondary immune responses and to both single-dose and multiple-dose treatments. The monoclonal antibody 5c8 blocks the CD40 and CD154 interaction, producing consistent and substantive reduction in antibody formation after administration of tetanus toxoid, which can be characterized with PK/PD modeling. It is anticipated that 5c8 may have utility in the treatment of antibody-mediated autoimmune disease.

Animals↗
PubMed1998

Fibrinogen as a risk factor for coronary heart disease.

An elevated plasma fibrinogen level is associated with increased frequency of coronary heart disease and stoke. Although fibrinogen is also associated with other well-known risk factors such as smoking, age and diet, this paper discusses fibrinogen as an independent and modifiable risk factor for cardiovascular disease. There are several pathways by which acute or chronic increase in fibrinogen levels can lead to a cardiovascular event, especially and atherosclerotic event, including infiltration of the vessel wall by fibrinogen, rheological effects due to increase blood viscosity, increased platelet aggregation and thrombus formation, and increased fibrin formation. Elevated fibrinogen is a strong primary risk factor for cardiovascular disease in healthy individuals. It is also a risk factor for death or recurrence of myocardial ischaemia in patients with a previous coronary event, and a predictor of accelerated coronary atherosclerosis. Indeed, studies confirm that the positive association between plasma fibrinogen levels and cardiovascular events is a predictive as elevated cholesterol levels.

Cholesterol↗
PubMed1998

[Cardiac abscess in infectious endocarditis. A multicenter study apropos of 233 cases. The Working Group on Valvulopathy of the French Society of Cardiology].

The aim of this retrospective multicenter study was to determine present characteristics of infectious endocarditis complicated by abscess and to identifying predictive factors of mortality. The files of 233 patients with infectious endocarditis complicated by perivalvular abscesses between January 1989 and December 1993 were analysed. Two hundred and thirteen patients underwent medico-surgical treatment (175 aortic and 38 mitral abscesses) and 20 patients underwent medical treatment alone (17 aortic and 3 mitral abscesses). The abscess was observed on native valves in 156 cases and valve prostheses in 77 cases. The causative organism was identified in 69% of cases : the commonest organism was the staphylococcus. The diagnostic sensitivity of transthoracic and transoesophageal echocardiography was 36 and 80% respectively. The operative mortality at one month was 16%. Patients over 65 years of age, staphylococcal infection, renal failure and fistulisation of the abscess, were identified as independent predictive factors of mortality at one month. The survival rate three months after surgery was 75 +/- 10% and 59 +/- 11% at 27 months. An age over 65, staphylococcal infection, uncontrolled infection, circumferential abscess and fistulisation were independent predictive factors of global mortality (the first month and after). The mortality rate in unoperated patients was 40%: cardiac failure and fistulisation of the abscess detected by echocardiography were predictive factors of mortality on univariate analysis.

Abscess↗
PubMed1998

Modifiable templates facilitate customization of physician order entry.

Physician order entry is a key factor in improving the quality of healthcare, while simultaneously reducing its cost. This paper describes an editor, a database, and a run-time system for creating and executing highly customized, user modifiable, order entry templates. The system allows non-programmers to create new order entry templates rapidly. Over the past 18 months, the templates have been used on over 2500 patients to enter over 40,000 separate orders.

Database Management Systems↗
PubMed1997

Nuclear calcium signalling by individual cytoplasmic calcium puffs.

It is known that the nucleoplasmic ionised calcium concentration (Can) controls nuclear functions such as transcription, although the source and nature of the signals which modulate Can are unclear. Using confocal imaging, we investigated the subcellular origin of Can signals in Fluo-3-loaded HeLa cells. Our data indicate that all signals which increased Can were of cytoplasmic origin. Can was elevated during the propagation of global Ca waves within cells. More strikingly, we found that individual cytoplasmic elementary release events e.g. Ca puffs, evoked by physiological levels of stimulation, caused transient Can increases. Significantly, >70% of all Ca puffs originated within a 2-3 micron perinuclear zone and propagated anisotropically across the entire nucleus. Due to the relatively slow relaxation of Can transients compared with those in the cytoplasm, repetitive perinuclear Ca puffs were integrated into a 'staircase' of increasing Can. Due to the effective diffusion of Ca in the nucleoplasm, the nucleus served as a 'Ca tunnel', distributing Ca to parts of the cytosol which were otherwise not within the cytoplasmic diffusion radii of Ca puffs. Given the close proximity of the majority of puff sites to the nucleus, it seems that the elementary Ca release system is designed to facilitate nuclear Ca signalling. Consequently, Ca-dependent regulation of nuclear function must be considered at the microscopic elementary level.

Biological Transport↗
PubMed1997

Indium-111 antimyosin scintigraphy before and after coronary bypass surgery: unexpected preoperative myocardial uptakes.

The present study was designed to evaluate 111In-antimyosin scintigraphy in detecting pre- and post-operative myocardial infarction in patients undergoing coronary artery bypass surgery. Fab antimyosin scintigraphy has been shown to be sensitive and specific in detecting myocardial necrosis and to be potentially valuable in situations where other criteria are not reliable. In a previous study, postoperative antimyosin uptakes occurred in 82% of the studied patients. Sixteen consecutive patients with an indication of coronary artery surgery were assessed by preoperative coronary angiography, serial electrocardiograms, and myocardial scanning with 111Indium-labeled antimyosin antibodies performed before and after operation. In four patients, a recent myocardial infarction (1 to 3 months) was detected with an accurate localization when compared to the classic criteria of myocardial infarction. One more patient with a 21-year old myocardial infarction showed an intense uptake whereas there was no recent acute coronary event. Four other patients had an unexpected preoperative uptake, since there were no acute coronary events in their medical history. All preoperative scintigraphic uptakes were still present on the second scan performed postoperatively in these nine patients. Only one patient showed a new postoperative uptake when compared to the preoperative scan which was normal; this postoperative septal infarct was confirmed by a postoperative coronary angiography. Extracardiac uptakes (sternum and ribs) were frequently observed after operation and might hamper the interpretation of postoperative scintigrams. Unexpected preoperative uptakes may be related to non diagnosed small necrosis. A preoperative reference scan is required for an accurate interpretation of a postoperative 111In-antimyosin uptake. Moreover, extracardiac uptakes may limit the interpretation of perioperative cardiac damage.

Aged↗
PubMed1997

The carboxy-terminus of I kappaB alpha determines susceptibility to degradation by the catalytic core of the proteasome.

The Rel/NF-kappaB family of transcription factors controls the expression of a wide variety of genes that are implicated in immune and inflammatory responses and cellular proliferation. Disregulation of NF-kappaB is associated with cellular transformation and the maintenance of a high anti-apoptotic threshold in transformed cells. NF-kappaB activity is in turn regulated by its sequestration in the cytoplasm by the inhibitor I kappaB. I kappaB alpha, the most abundant and well-characterized member of the I kappaB multiprotein family, is rapidly degraded in response to multiple physiologic stimuli. In the present study we show that not only the amino-terminus, but also the carboxy-terminus of I kappaB alpha contain transferable signals that must be simultaneously present in an unrelated protein to render it susceptible to activation-induced, proteasome-mediated degradation. We show here that I kappaB alpha amino-terminal modifications occur independently of the carboxy-terminus. Moreover, we present evidence indicating a critical role for the carboxy-terminal region in facilitating proteolysis by the catalytic core of the proteasome. When incubated with 20S proteasome extracted from rat liver, I kappaB alpha was quickly degraded while a deletion mutant lacking the carboxy-terminus was resistant to proteolysis. Likewise, chimeric proteins of beta-galactosidase with the I kappaB alpha carboxy-terminus were degraded in vitro independently of the presence of the I kappaB alpha amino-terminus, whereas chimeric proteins lacking the I kappaB alpha carboxy-terminus were stable. Our results identify the carboxy-terminus of I kappaB alpha as a domain critical for degradation through interaction with an as yet unidentified component of the proteasome.

Animals↗
PubMed1997

Differential utilization of ShcA tyrosine residues and functional domains in the transduction of epidermal growth factor-induced mitogen-activated protein kinase activation in 293T cells and nerve growth factor-induced neurite outgrowth in PC12 cells. Identification of a new Grb2.Sos1 binding site.

By transient expression of both truncated forms of p52(SHCA) and those with point mutations in 293T cells, it has been shown that, in addition to Tyr-317, Tyr-239/240 is a major site of phosphorylation that serves as a docking site for Grb2.Sos1 complexes. In addition, analysis of epidermal growth factor (EGF)-induced activation of mitogen-activated protein kinase in 293T cells showed that the overexpression Shc SH2 or phosphotyrosine binding (PTB) domains of ShcA alone has a more potent negative effect than the overexpression of the forms of ShcA lacking Tyr-317 or Tyr 239/240 or both. In transiently transfected PC12 cells, the ShcA PTB domain and tyrosine phosphorylation in the CH1 domain, especially on Tyr-239/240, are crucial for mediating nerve growth factor (NGF)-induced neurite outgrowth. These findings suggest that the EGF and NGF (TrkA) receptor can utilize Shc in different ways to promote their activity. For EGF-induced mitogen-activated protein kinase activation in 293T cells, both Shc PTB and SH2 domains are essential for optimal activation, indicating that a mechanism independent of Grb2 engagement with Shc may exist. For NGF-induced neurite outgrowth in PC12 cells, Shc PTB plays an essential role, and phosphorylation on Tyr-239/240, but not on Tyr-317, is required.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease.

Homocysteine is a graded risk factor for the incidence of stroke and for the degree of carotid atherosclerosis. Homocysteine is also a graded risk factor for the incidence of myocardial infarction but we do not know its precise relations to the severity of atherosclerosis in coronary patients. Seventy five symptomatic coronary patients were recruited for the study. Fifty of these patients had coronary artery disease only and were compared in a case-control manner to 50 healthy controls matched for age and sex. The 25 other coronary patients had also symptoms in another atherosclerotic territory (cerebral, peripheral or both) and were also compared to 25 matched controls. Mean plasma homocysteine level was significantly higher in coronary patients than in controls (11.7 +/- 0.7 mumol l-1, n = 50 versus 9.9 +/- 0.5 mumol l-1, n = 50, p < 0.05). Homocysteine in patients with symptomatic atherosclerosis in two or three arterial sites was 15.7 +/- 1.5 mumol l-1 which differed significantly from matched controls and from patients with coronary artery disease only (p = 0.01). The extent of coronary atherosclerosis evaluated by an angiographic coronary score correlated weakly to plasma homocysteine levels (r = 0.25, p < 0.05). The patients with both hypertension and high levels of homocysteine (> 11.3 mumol l-1, median value) had more severe coronary atherosclerosis (coronary score of 16.3 +/- 2.3 versus 11.9 +/- 0.9, p < 0.05) and more diffuse atherosclerosis (number of atherosclerotic territories of 1.5 +/- 0.2 versus 1.2 +/- 0.7, p = 0.08) than the coronary patients without this association. There were no other high risk association when considering the other classical risk factors. Thus, the highest levels of homocysteine were present in patients with coronary disease and another symptomatic localisation of atherosclerosis. A small gradient in the extent of coronary atherosclerosis was found with increasing levels of homocysteine. The presence of both hypertension and hyperhomocysteinemia was associated with more severe coronary atherosclerosis.

Biomarkers↗
PubMed1997

CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates.

Selective inhibition of T cell costimulation using the B7-specific fusion protein CTLA4-Ig has been shown to induce long-term allograft survival in rodents. Antibodies preventing the interaction between CD40 and its T cell-based ligand CD154 (CD40L) have been shown in rodents to act synergistically with CTLA4-Ig. It has thus been hypothesized that these agents might be capable of inducing long-term acceptance of allografted tissues in primates. To test this hypothesis in a relevant preclinical model, CTLA4-Ig and the CD40L-specific monoclonal antibody 5C8 were tested in rhesus monkeys. Both agents effectively inhibited rhesus mixed lymphocyte reactions, but the combination was 100 times more effective than either drug alone. Renal allografts were transplanted into nephectomized rhesus monkeys shown to be disparate at major histocompatibility complex class I and class II loci. Control animals rejected in 5-8 days. Brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days). Two of four animals treated with both agents experienced extended (>150 days) rejection-free allograft survival. Two animals treated with 5C8 alone and one animal treated with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection, but a repeat course of their induction regimen successfully restored normal graft function. Neither drug affected peripheral T cell or B cell counts. There were no clinically evident side effects or rejections during treatment. We conclude that CTLA4-Ig and 5C8 can both prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.

Abatacept↗