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Biomedical subjects

S M Taylor

Publications and source records attributed to S M Taylor.

At least 37 records · Page 2Linked to original sources
PubMed2000

Thrombosis and shock induced by activating antiplatelet antibodies in human Fc gamma RIIA transgenic mice: the interplay among antibody, spleen, and Fc receptor.

Transgenic mouse lines were created that express Fc gamma RIIA on platelets and macrophages at human physiologic levels, and they were used to explore the consequences in vivo of activating antiplatelet antibodies. Anti-CD9 antibody activated platelets of Fc gamma RIIA transgenic (tg) mice and, following injection in vivo, caused more rapid severe thrombocytopenia than nonactivating antiplatelet antibody. Anti-CD9 injected into Fc gamma RIIA tg crossed with FcR gamma-chain knockout (gamma-KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. The shock depended on platelet Fc receptor density and antibody dose. On histologic examination, the lung vasculature of anti-CD9-treated Fc gamma RIIA tg x gamma-KO mice contained extensive platelet-fibrin thrombi. Thrombosis and shock in Fc gamma RIIA tg mice in the context of the FcR gamma-chain knockout suggested the importance of the interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically (splenectomy) or functionally (monoclonal antibody treatment) also facilitated anti-CD9-mediated shock in Fc gamma RIIA tg mice. The spleen, which clears nonactivating antibody-coated platelets leading to thrombocytopenia, appears to play a protective role in the thrombosis and shock observed with activating antiplatelet antibody. The data indicate that antibodies, which activate platelets in an Fc gamma RIIA-dependent manner, can lead to thrombosis, shock, and death. Furthermore, antibody titer, platelet Fc receptor density, and splenic clearance are likely important determinants of the outcome. (Blood. 2000;96:4254-4260)

Animals↗
PubMed2000

Expression patterns of the multiple transcripts from the folylpolyglutamate synthetase gene in human leukemias and normal differentiated tissues.

Folylpoly-gamma-glutamate synthetase (FPGS) catalyzes the activation of folate antimetabolites in mammalian tissues and tumors. We have determined the sequence, abundance, and function of human FPGS transcripts and found some striking differences to transcription of the mouse gene that allow production of FPGS isoforms in mouse liver and dividing tissues. Multiple human transcripts were identified, including the homolog of the mouse transcripts that initiate at two upstream exons. However, the human FPGS upstream promoter is infrequently used, and transcripts from this promoter include sequences homologous with only one of the upstream exons found in the mouse. The downstream promoter generates an array of transcripts, some of which do not produce active enzyme, a phenomenon not seen in the mouse. Hence, the dual promoter mechanism directing expression of FPGS isozymes in mouse tissues is not conserved in humans, and, unlike the mouse downstream promoter, the human downstream promoter is active in both dividing and differentiated tissues. This study raises questions about the differences in function served by the two mouse FPGS isozymes and how, or if, human tissues fulfill these functions. How humans and mice produce FPGS in only a subset of tissues using such different promoter structures also becomes a central issue.

Alternative Splicing↗
PubMed2000

Inhibition of C5a-induced neutrophil chemotaxis and macrophage cytokine production in vitro by a new C5a receptor antagonist.

A cyclic peptide, Phe-[Orn-Pro-D-Cyclohexylalanine-Trp-Arg] (F-[OPdChaWR]), was recently shown in vitro to antagonise the binding of C5a to its receptor (CD88) on human polymorphonuclear leukocytes (PMNs) and in vivo to inhibit the neutropenia associated with septic shock induced by lipopolysaccharide (LPS) in rats. The aim of this study was to investigate whether F-[OPdChaWR] inhibits C5a-mediated chemotaxis of human PMNs using a modified Boyden chamber and C5a-stimulated release of cytokines from human monocytes in vitro. Approximately 50% of the chemotactic activity induced by 10 nM C5a was inhibited by 76 nM F-[OPdChaWR]. This correlated with inhibition of C5a-induced polarisation of PMNs by F-[OPdChaWR]. C5a alone failed to induce release of the inflammatory cytokines interleukin(IL)-1beta, tumour necrosis factor (TNF)-alpha, and IL-6 from human monocytes at concentrations up to 100 nM. However, in the presence of low concentrations of LPS (50 ng/mL), both IL-1beta and TNF-alpha were stimulated by 1 nM C5a. This co-stimulation was inhibited by F-[OPdChaWR] with IC(50)s of 0.8 and 6.9 nM for release of TNF-alpha and IL-1beta, respectively. No agonist activity was detected for F-[OPdChaWR] in either the chemotaxis or cytokine release assays at concentrations up to 50 microM. These results show that F-[OPdChaWR] inhibits several important inflammatory activities of C5a and suggest that C5a receptor antagonists may be effective in the treatment of inflammatory diseases mediated by C5a.

Antigens, CD↗
PubMed2000

A new small molecule C5a receptor antagonist inhibits the reverse-passive Arthus reaction and endotoxic shock in rats.

C5a is implicated as a pathogenic factor in a wide range of immunoinflammatory diseases, including sepsis and immune complex disease. Agents that antagonize the effects of C5a could be useful in these diseases. We have developed some novel C5a antagonists and have determined the acute anti-inflammatory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as against some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS-induced neutropenia and elevated levels of circulating TNF-alpha, as well as polymorphonuclear leukocyte migration, increased TNF-alpha levels and vascular leakage at the site of immune complex deposition. These results indicate potent anti-inflammatory activities of a new C5a receptor antagonist and provide more evidence for a key early role for C5a in sepsis and the reverse Arthus reaction. The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.

Animals↗
PubMed2000

Induction of an antigen-specific CTL response by a conformationally biased agonist of human C5a anaphylatoxin as a molecular adjuvant.

A conformationally biased decapeptide agonist of human C5a anaphylatoxin (YSFKPMPLaR) was used as a molecular adjuvant in stimulating an Ag-specific CTL response against murine P815S target cells expressing an Ld-restricted CTL epitope of the hepatitis B surface Ag (HBsAg). Groups of BALB/c mice (H-2d) were immunized with aqueous solutions of the HBsAg CTL epitopes (IPQSLDSWWTSL and IPQSLDSWWTSLRR); the C5a agonist (YSFKPMPLaR); the C5a agonist and HBsAg CTL epitopes admixed (IPQSLDSWWTSL and IPQSLDSWWTSLRR + YSFKPMPLaR); the C5a-active, HBsAg CTL epitope-C5a agonist constructs (IPQSLDSWWTSLYSFKPMPLaR, IPQSLDSWWTSLRRYSFKPMPLaR, and IPQSLDSWWTSLRVRRYSFPMPLaR); a C5a-inactive, reverse-moiety construct (YSFKPMPLaRRRIPQSLDSWWTSL); and a C5a-attenuated, carboxyl-terminal-blocked construct (IPQSLDSWWTSLRRYSFKPMPLaRG). Ag-specific CD8+ CTL responses were observed after the secondary boost in the absence of any added adjuvant only in mice that were immunized with C5a-active contructs, IPQSLDSWWTSLRRYSFKPMPLaR and IPQSLDSWWTSLRVRRYSFKPMPLaR. These two C5a-active immunogens contained potential subtilisin-sensitive linker sequences between the HBsAg CTL epitope and the C5a agonist; i.e., a double-Arg (RR) and a furin protease sensitive sequence (RVRR). The introduction of these potentially cleavable sequences may be a method of increasing the likelihood of liberating the CTL epitope from the C5a agonist by intracellular proteases, thereby facilitating entry of the epitope into Ag-processing pathways via an exogenous route.

Adjuvants, Immunologic↗
PubMed2000

Induction of protective immunity to Dictyocaulus viviparus in calves while under treatment with endectocides.

Three groups of five parasite-naive calves were used. The treatments were: (a) Group 1 calves were weighed on Day 0 and injected with doramectin at 200 microg/kg. From Day 1 to 19 they were dosed orally with 2000 infective larvae of Dictyocaulus viviparus. On Day 28 they were again injected with doramectin, and infected with D. viviparus larvae from Days 33 to 41. They were then left untreated until Day 81 when they were infected with 20 infective larvae of D. viviparus per kg body weight. They were killed on Day 110 and lungworms were counted; (b) Group 2 calves were immunised with oral lungworm vaccine on Days 0 and 28, and infected and slaughtered as Group 1 on Days 81 and 110, respectively; (c) Group 3 calves acted as infection controls. Blood samples were taken at Days 0, 21, 49, 77 and 110 for antibody tests to D. viviparus. At autopsy there were no significant differences between the number of lungworms from Groups 1 and 2 (Means 17.4 and 31.3, respectively); Group 1 had significantly less value than Group 3 (Mean 228) (p < 0.05). Increased antibody titres to the larval sheath of the infective larvae were observed from Groups 1 and 2, showing that the larvae in Group 1 had penetrated the intestine before being killed by the circulating anthelmintic. This experiment shows that if calves are exposed to infective larvae while under systemic endectocide cover, an immune reaction is stimulated.

Animals↗
PubMed2000

Isolated arteriovenous dialysis access graft segment infection: the results of segmental bypass and partial graft excision.

Arteriovenous (AV) access graft infection results in disruption of dialysis and usually necessitates graft removal when the entire graft is involved. The management of an isolated infected segment of an otherwise noninfected AV access graft, however, remains controversial. To evaluate the utility of segmental bypass and partial graft excision for the treatment of an isolated infected AV access graft segment, 17 consecutive cases in 12 patients (7 females/5 males; 14 arm grafts/3 leg grafts; median age = 69 years) were analyzed on a vascular teaching service that performed 1244 total access procedures from January 1995 through February 1999. Infections presented as a draining sinus or a sinus with hemorrhage emanating from an area over the graft. At operation, the infected sinus was covered by a transparent occlusive dressing and the graft was explored through clean incisions proximal and distal to the infected segment. If the graft was incorporated and free of infection, a piece of expanded polytetrafluoroethylene (ePTFE) was anastomosed proximally end-to-end and tunneled through noninfected tissues around the infected sinus. After the distal anastomosis was performed, the skin incisions were closed and covered with occlusive dressings. The infected graft segment was then removed through the infected sinus wound. The technique of segmental bypass and partial graft excision results in predictable eradication of infection, graft salvage, and maintenance of uninterrupted dialysis in patients presenting with an isolated AV dialysis access infection.

Aged↗
PubMed2000

Frey's syndrome and parotidectomy flaps: A retrospective cohort study.

Gustatory sweating, also known as Frey's syndrome, is a recognized phenomenon after parotidectomy. The incidence of clinically significant gustatory sweating may be dependent on the thickness of the skin flap that is elevated at the time of surgery. Dissection in the subcutaneous level or the deeper sub-superficial musculoaponeurotic system level are 2 commonly used techniques in the operation. Twenty-eight patients were prospectively evaluated for Frey's syndrome after superficial parotidectomy. Thirteen patients underwent subcutaneous and 15 patients sub-superficial musculoaponeurotic system flap elevation. The overall incidence of gustatory sweating was determined, and a comparison of the two surgical techniques was assessed subjectively by patient interview-questionnaire and objectively evaluated with starch-iodine testing.

Cohort Studies↗
PubMed2000

Selected disorders of muscle and the neuromuscular junction.

A variety of disorders affect the muscles or the neuromuscular junction of dogs and cats, most often causing weakness, exercise intolerance, and muscular pain or atrophy. The myopathies are infectious, immune-mediated, inherited or acquired secondary to systemic disease. Acquired myasthenia gravis is a common disorder of the neuromuscular junction, which clinically resembles a myopathy. Reaching a specific diagnosis is essential to determine optimal therapy and prognosis for each of the commonly recognized disorders.

Animals↗
PubMed2000

A longitudinal study of the health impacts of a petroleum refinery.

Emissions from a petroleum refinery in Oakville, Ont., have been the source of longstanding health concerns among residents in the surrounding community. Between 1992 and 1997, the refinery implemented extensive odour reduction measures through improvements in waste water treatment, in sulphur recovery and combustion. In this paper, we present the main findings of a recent longitudinal analysis using data from community health surveys conducted in 1992 and 1997, before and after implementation of the odour reduction plan. The results show a decline in the frequency of odour perception and annoyance by residents whereas the reporting of cardinal and general symptoms among adults and children was virtually unchanged. Odour perception and annoyance were strongly related to symptom reporting in both years supporting the hypothesis that the effect of refinery emissions on residents' health is odour mediated. The findings extend our understanding of the psychosocial basis of symptom reporting in the vicinity of refineries.

Adult↗
PubMed2000

Cell phenotype as a target of drug therapy in chronic inflammatory diseases.

Many diseases share common pathological changes which could in principle be targets for new drugs. Vascular leakage of plasma and migration of cells into perivascular tissues are common to chronic inflammatory diseases such as asthma, atherosclerosis, arthritis, and proliferative nephropathy as well as some non-inflammatory proliferative disorders such as diabetes mellitus. Individual components of plasma have been shown to stimulate cellular proliferation, matrix deposition and phenotypic change, leading to tissue-damaging structural changes. Whereas most anti-inflammatory drugs either downregulate expression of inflammatory mediators or inhibit their actions on cells, there are alternate potential therapeutic strategies described here based on moderating vascular leakage or its consequences in chronic diseases. The hypothesis is that drugs that can modify a cell's phenotype could be used to limit structural changes which accompany inflammation and thus reduce permanent debility resulting from these diseases. Such drugs include the differentiating agents being developed for cancer therapy.

Animals↗
PubMed2000

Emphysematous cholecystitis in a Siberian husky.

A 6-year-old, intact male Siberian husky was evaluated for a 24-hour history of vomiting and lethargy. Diagnosis of emphysematous cholecystitis was achieved based on survey abdominal radiographs, a barium contrast gastrointestinal series, and abdominal ultrasound. Diagnosis and medical and surgical management of the condition are discussed.

Animals↗
PubMed2000

Concomitant renal revascularization with aortic surgery: are the risks of combined procedures justified?

Indications for concomitant renal revascularization during aortic surgery are not well established. Higher mortality and poorer results are often cited. To examine this, all combined aortic and renal revascularization procedures from August 1992 until May 1998 were reviewed. Of 2003 major arterial reconstructions performed on the Vascular Teaching Service, 45 patients (2%) underwent renal revascularization. Of these 31 patients (69%) had combined aortic and renal procedures. Aortic pathology in these 31 patients (54% male, 94% white, median age 64 years) included arterial occlusive disease (n = 21; 47%), abdominal aortic aneurysm (n = 6; 13%), and thoracoabdominal aortic aneurysm (n = 4; 9%). In all 31 cases the patient presented because of the aortic pathology. Indications for concomitant renal revascularization included renovascular hypertension (n = 21; 68%) and preservation of renal function (n = 10; 32%). Renal revascularization procedures included transaortic endarterectomy (n = 23; 74%), renal bypass (n = 7; 23%), and both bypass and endarterectomy (n = 1; 3%). Seven (22%) complications and two (6%) deaths (both patients operated on for renal salvage) occurred perioperatively. Complications included wound infection (n = 2; 6%), postoperative bleeding (n = 1; 3%), respiratory failure (n = 1; 3%), deep venous thrombosis (n = 1; 3%), cerebrovascular accident (n = 1; 3%), and pseudomembranous enterocolitis (n = 1; 3%). All patients either were cured of their hypertension (n = 5; 24%) or were improved (n = 16; 76%) at 3 months. No patient to date operated on for renal salvage progressed to chronic hemodialysis, but mortality was higher after renal revascularization for renal salvage versus hypertension (20% vs. 0; P = 0.034). There was no significant difference in mortality between the combined aortic/renal procedures versus aortic procedures alone. Despite adding complexity, renal revascularization in patients undergoing aortic surgery appears relatively safe and effective. These data favor an aggressive approach toward renal revascularization in selected patients needing aortic surgery.

Adult↗
PubMed2000

Ultrasound-guided thrombin injection of iatrogenic femoral pseudoaneurysms: a prospective analysis.

An adverse consequence of the use of the femoral artery for the endovascular evaluation and treatment of arterial disease is the increased incidence of iatrogenic femoral pseudoaneurysms. Although surgical repair has traditionally been used to treat such aneurysms, less invasive modalities have emerged. The purpose of this study is to prospectively evaluate ultrasound-guided thrombin injection (UGTI) for the treatment of iatrogenic femoral pseudoaneurysms. A treatment protocol was approved and 30 stable patients (21 female; age range 43-85 years; mean 67 years) were prospectively enrolled from December 1997 through June 1999 to undergo UGTI on 30 iatrogenic femoral pseudoaneurysms. Pseudoaneurysms occurred after cardiac intervention (n = 22, 73%), peripheral intervention (n = 7, 23%), and after a femoral line placement (n = 1, 3%). They ranged in size from one to 5 cm with a time interval from intervention until UGTI of one to 132 days (median 3 days). Eleven patients (37%) were systematically anticoagulated at the time of UGTI. All pseudoaneurysms were treated using sterile technique and local anesthesia with ultrasound-guided injection via a 20-gauge spinal needle of 0.1 to 2 cm3 (median 0.6 cm3) of 1000 units/cm3 topical thrombin solution administered by one of six physicians. A period of bedrest for 4 to 6 hours after injection was followed by repeat groin duplex scan at 24 hours and a clinical follow-up at 30 days. There were no procedural deaths or nonvascular complications. Twenty-seven (90%) UGTIs resulted in successful pseudoaneurysm ablation with no recurrences at 24 hours or 30 days. Two (7%) UGTIs failed and one (3%) femoral artery embolic complication occurred; all were successfully treated with surgery. Success appeared to be independent of anticoagulation status, pseudoaneurysm age, size, or operator experience. We conclude that UGTI is a safe, easy, well-tolerated and effective noninvasive method for treatment of iatrogenic femoral pseudoaneurysms and should be considered in all stable patients before operative repair.

Adult↗
PubMed1999

Tissue-specific expression of functional isoforms of mouse folypoly-gamma-glutamae synthetase: a basis for targeting folate antimetabolites.

Folates and folate antimetabolites are metabolically trapped in mammalian cells as polyglutamates, a process catalyzed by folylpoly-gamma-glutamate synthetase (FPGS). Using 5'-rapid amplification of cDNA ends, RNase protection assays, transfection of cDNAs into FPGS-deficient cells, and kinetic analysis of recombinant enzymes expressed in insect cells, it was determined that the species of active FPGS in mouse liver and kidney was different from that in mouse tumor cells, bone marrow, and intestine. The NH2-terminal peptide of hepatic enzyme contained 18 amino acids not found in enzyme from dividing tissues, and the specificity of the two isoforms for antifolates also differed, suggesting different architecture of the active sites. In most tissues, the expression of one isozyme or the other was an all-or-nothing event. The exclusive use of one of two alternative sets of initial coding exons in different tissues underlies this phenomenon, suggesting the design of antifolates specific for activation by individual FPGS isoforms and hence tissue-selective targeting of antifolate therapy for cancer, arthritis, or psoriasis.

Amino Acid Sequence↗
PubMed1999

Sheep scab--environmental considerations of treatment with doramectin.

The paper reviews the recent change in attitudes to dipping sheep and the proposed legal requirements to prevent and treat sheep scab. The implications of fulfillment of all the requirements of the European Groundwater Directive and the probable resultant increase of the use of injectable endectocides as an alternative to plunge dipping are discussed in relation to their likely frequency of use and potential ecological impact. In particular the properties of doramectin, one of the most recently introduced, are examined in relation to its use for the treatment of sheep scab.

Administration, Topical↗
PubMed1999

Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a.

Activation of the human complement system of plasma proteins during immunological host defense can result in overproduction of potent proinflammatory peptides such as the anaphylatoxin C5a. Excessive levels of C5a are associated with numerous immunoinflammatory diseases, but there is as yet no clinically available antagonist to regulate the effects of C5a. We now describe a series of small molecules derived from the C-terminus of C5a, some of which are the most potent low-molecular-weight C5a receptor antagonists reported to date for the human polymorphonuclear leukocyte (PMN) C5a receptor. 1H NMR spectroscopy was used to determine solution structures for two cyclic antagonists and to indicate that antagonism is related to a turn conformation, which can be stabilized in cyclic molecules that are preorganized for receptor binding. While several cyclic derivatives were of similar antagonistic potency, the most potent antagonist was a hexapeptide-derived macrocycle AcF[OPdChaWR] with an IC50 = 20 nM against a maximal concentration of C5a (100 nM) on intact human PMNs. Such potent C5a antagonists may be useful probes to investigate the role of C5a in host defenses and to develop therapeutic agents for the treatment of many currently intractable inflammatory conditions.

Antigens, CD↗