A low-fat theory of anesthesia.
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Anesthesia, General↗
Biomedical subjects
R Matthews
Publications and source records attributed to R Matthews.
The role of hsp90 in fungal infection.
The immunodominant antigens of many microbial pathogens are heat shock proteins (hsps). In systemic candidal infections, a major target of protective antibody is an epitope shared with human hsp90. Here, Ruth Matthews and James Burnie suggest that fungal hsp90 plays a key pathogenic role in systemic infection by either binding to certain serum proteins, causing them to malfunction, or by mimicking the functional activity of other proteins.
Amino Acid Sequence↗
Acquired immunity to systemic candidiasis in immunodeficient mice: role of antibody to heat-shock protein 90.
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Animals↗
The in-vitro activity of two new quinolones: rufloxacin and MF 961.
The in-vitro activity of two new quinolone antimicrobials, rufloxacin and MF 961, together with the desmethylated metabolite of rufloxacin (MF 922) were compared with other orally administered agents against 622 bacterial strains. Against Enterobacteriaceae and Pseudomonas aeruginosa rufloxacin was generally active (MIC90 1-8 mg/L) with the exception of Klebsiella and Serratia spp. (MIC90 32 mg/L and Enterobacter spp. (MIC90) 64 mg/L. The respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis were susceptible to rufloxacin (MIC90 0.5 and 1 mg/L respectively) but Streptococcus pneumoniae was less susceptible (MIC90 32 mg/L). Staphylococcus aureus were susceptible to rufloxacin (MIC90 2 mg/L). The rufloxacin metabolite MF 922 was generally as active as its parent. MF 961 was usually two-fold more active than rufloxacin. All three compounds were four to 16 times less active than norfloxacin, but rufloxacin was as active or somewhat more active than norfloxacin against Staphylococcus spp. Any strains showing decreased susceptibility to other quinolones exhibited cross resistance to these new agents. The MBC of rufloxacin and MF 922 was within one dilution of the MIC and human serum had little effect upon the activity of both agents. The protein binding of rufloxacin and MF 922 at 1 and 10 mg/L were 55% and 63.8% and 30.3% and 32.6% respectively. The activity of rufloxacin against four strains of Chlamydia trachomatis and one strain of Chlamydia pneumoniae was determined. The MICs for C. trachomatis were 4-8 mg/L and 4 mg/L for C. pneumoniae.
Anti-Infective Agents↗
Balloon expandable stents to treat central venous stenoses in hemodialysis patients.
Vascular access failure in hemodialysis patients remains a significant problem. The use of thrombolytic agents and balloon angioplasty instead of or in conjunction with surgical revision, has been helpful in increasing the life span of vascular access in these patients. The application of newer endovascular therapies, such as vascular stents, may further improve the salvage rate of hemodialysis access sites. These stents may be particularly valuable in treating stenoses in large central veins. We present 2 cases in which a balloon-expandable Palmaz stent was used to treat a central venous stenosis causing signs of vascular access failure.
Aged↗
The application of epitope mapping in the development of a new serological test for systemic candidosis.
A new serological test for systemic candidosis was developed by raising a rabbit antiserum probe against a specific epitope on Candida albicans, hsp 90. A major fragment at the carboxy terminal end of this immunodominant candidal antigen was epitope mapped by Geysen's method. An epitope, recognised by all infected patients with antibody to the 47 kDa antigen, was synthesized and conjugated to keyhole limpet haemocyanin. A rabbit was successfully immunized against this synthesized peptide epitope and this antiserum was compared, in a dot-immunobinding assay, with unfractionated hyperimmune rabbit antiserum to C. albicans and an affinity-purified rabbit antiserum to the 47 kDa antigen. The epitope-specific antibody probe was more sensitive than the hyperimmune candidal antiserum but less sensitive than the affinity-purified antibody against the 47 kDa antigen, which recognised multiple epitopes. This probe is technically easy to prepare in large amounts and gives no false positives.
Amino Acid Sequence↗
Dental staff sexual behaviour.
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Adolescent↗
Flow support catheter for prolonged maintenance of coronary blood flow.
A newly designed flow support catheter with a supporting wire mesh cage which can be expanded into a tubular configuration and then readily reduced was evaluated in mongrel dogs. Regional myocardial blood flow (RMBF) was measured using the radioactive microsphere technique in the area of both balloon-denuded instrumented and control non-instrumented coronary arteries following placement of either a fixed-wire or a higher profile rapid exchange flow support catheter. At 5, 20, and 180 min following delivery and expansion of either device, RMBF was not significantly different in left ventricular subepicardium and subendocardium perfused by the instrumented vs. the control coronary arteries. Angiography demonstrated widely patent instrumented arteries in 15/18 dogs; in no dog was side branch occlusion observed. Significant cage thrombus deposition was seen angiographically in 3 animals causing temporary total coronary occlusion in 1. Following reduction and removal of the flow support catheter, vessel patency was present in all dogs. The flow support catheter is an effective endovascular stenting device capable of providing structural arterial support, while simultaneously maintaining distal coronary blood flow. It is envisioned that the primary application of this catheter will be to enable primary salvage of vessels acutely injured during coronary angioplasty, by "tacking up" intimal flaps for an extended period. It may also provide a bridge to emergency surgical revascularization.
Angioplasty, Balloon, Coronary↗
Identification of a gene encoding an HPr-like protein in Aspergillus fumigatus.
The gene encoding a histidine-containing protein (HPr)-like protein was identified in a cDNA library of Aspergillus fumigatus. The predicted amino acid sequence of the fungal HPr showed greater homology with HPr from Gram-positive bacteria than from Gram-negative bacteria. Since other components of the phosphoenolpyruvate: carbohydrate phosphotransferase system have not been identified in eukaryotes, this raises the question of what regulatory function the HPr-like protein might have evolved in this fungus.
Amino Acid Sequence↗
Differences in the pathological changes in dogs' hearts after defibrillation with extrapericardial paddles and implanted defibrillator electrodes.
A comparison was made between the pathological changes in the myocardium of eight dogs, each receiving about 90 joules of energy in a series of defibrillation discharges, delivered either between paddles placed against the pericardium (3 dogs) or between implanted Telectronics 040-105 defibrillation patch electrodes (5 dogs). The changes in the myocardium were most pronounced where the paddles had been applied to the pericardium. There was transmural damage beneath the left and right paddle positions and in the surrounding tissues. Extensive subepicardial and subendocardial myocyte damage was obvious histologically in the right ventricle of one of the patch dogs and in all of the paddle dogs. The percentage of damaged myocardial mass, both right ventricular and total involvement, was higher in the three paddle dogs compared with the five patch dogs. There was septal damage in the heart of one paddle dog. Necrosis of the right ventricular wall was observed in three of the patch dogs and in all the three paddle dogs. Scattered necrotic myocytes and some patches of mild necrosis up to 1-mm deep were observed in the left ventricle of the patch dogs (severity score 1-3). The necrosis was more extensive in the paddle dogs, ranging from mild necrosis less than 1-mm deep to marked necrosis incorporating half-to-whole ventricular wall thickness (severity score 3-5).
Animals↗
Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion.
BACKGROUND: There are several clinical situations in which large epicardial coronary arteries are deprived of blood flow, such as occurs when an obstructing thrombus or embolus lodges within a vessel or during coronary dissection. There is little information concerning the effect of flow deprivation on large epicardial coronary arteries. METHODS AND RESULTS: We studied a model in which a segment of a large epicardial coronary artery was deprived of blood flow using both proximal and distal clamps for 3 hours followed by reperfusion. On examination by light microscopy of cross sections of the arteries, 19 +/- 6 neutrophils were present in the intima of ischemic/reperfused vessels, whereas only a mean of 4 +/- 3 (SEM) were present in the intima of nonischemic vessels (p less than 0.02). On average, there were 17 +/- 9 neutrophils just under the elastic lamina in ischemic/reperfused vessels versus none in the nonischemic vessels (p less than 0.05); there were 16 +/- 10 neutrophils present within the media of ischemic/reperfused vessels, and none (p less than 0.05) in the nonischemic vessels. Electron microscopic analysis revealed that neutrophils in the ischemic/reperfused vessels were often "sandwiched" between the endothelial cells and the elastic lamina. Ultrastructural abnormalities within the myocardium also revealed damage to the microvasculature, including the presence of neutrophils within the vessels and erythrocyte stasis. To rule out the possibility that findings in the large epicardial arteries were due to toxic substances from static blood within the isolated arterial segment, a protocol was performed in which blood was removed from the isolated segment. Again, neutrophil infiltration into the vessel was observed. Resting mean epicardial coronary artery blood flow before coronary occlusion was 19 +/- 3 ml/min; mean coronary blood flow 2.5 hours after reperfusion was identical at 19 +/- 3 ml/min. Response to both endothelial-dependent vasodilation (acetylcholine) and endothelial-independent vasodilation (nitroglycerin) challenges was normal early after reperfusion but was depressed late after reperfusion, suggesting progressive vascular dysfunction and hence a form of vascular reperfusion injury in this model. CONCLUSIONS: When large epicardial coronary arteries are deprived of blood flow, followed by reperfusion in this model, neutrophils migrate into the vessel wall as well as into the microvasculature. These abnormalities are associated with reduced endothelial-dependent and endothelial-independent coronary vasodilator reserve.
Animals↗
Sjögren's syndrome in systemic sclerosis. A clinical study of 26 patients.
Features of Sjögren's syndrome were sought in 26 patients with systemic sclerosis and in age- and sex-matched control subjects. The assessments included a structured history to establish symptoms of dry eyes and dry mouth. Schirmer's I and II tear tests. Rose Bengal staining with slit lamp microscopy of the eyes, measurement of basal and stimulatory salivary secretion. We measured sweat secretion rates from the skin. Salivary scintigraphy and skin biopsies were performed on the patients. Only one patient showed the complete picture of Sjögren's syndrome with both clinical and investigational evidence of lacrimal and salivary gland involvement. A further patient had an abnormal Schirmer's II test and xerostomia with reduced salivary secretion and an abnormal scan, but no ocular symptoms and no keratoconjunctivitis sicca on ophthalmological examination. Two patients had reduced salivary flow and a dry mouth. A number of patients and control subjects showed various individual symptoms and signs of lacrimal and salivary disorders. These features alone are not sufficient for the diagnosis of Sjögren's syndrome. There is a clear need to adopt strict criteria for diagnosing the condition. The association of Sjögren's syndrome with systemic sclerosis seems doubtful and if it does occur it is very much less common than previously suggested.
Adult↗
Transvenous pacemaker leads in the dog: an experimental study.
Tined transvenous pacing leads were inserted into nine healthy large-breed dogs as part of an experimental study evaluating an implantable defibrillator. The pacing leads were used to induce ventricular fibrillation on the day of insertion, two and four weeks after insertion and then monthly. Despite daily running exercise on and off a leash, the tined leads remained firmly anchored to the right ventricular apex for the full experimental period of up to 12 months. Apart from mechanical endocarditis of the tricuspid valve, and partial penetration of the ventricular wall in one dog, problems associated with the pacing leads were not encountered. The use of tined leads and careful technique may minimise the likelihood of transvenous lead displacement.
Animals↗
Effects of distal point-site mutations on the binding and catalysis of dihydrofolate reductase from Escherichia coli.
The importance of salt bridge interactions at the NADPH binding site of dihydrofolate reductase has been studied by using site-directed mutagenesis. The mutations R44L and H45Q respectively disrupt the ionic contacts made between the 2'-phosphate and pyrophosphoryl moiety of the coenzyme and the N-terminal region of helix C. Equilibrium fluorescence experiments indicate that while the overall binding of NADPH to both free mutants is weakened by 1.1 and 1.5 kcal/mol (H45Q and R44L, respectively), the binding of dihydrofolate and tetrahydrofolate is unaffected. Despite the similar binding energies for both mutants, the transition state for the chemical hydride step is differentially destabilized relative to wild type (0.6 and 1.8 kcal/mol for H45Q and R44L, respectively). Both stopped-flow and pre-steady-state experiments suggest that the root of this effect may lie in multiple conformations for the E-NADPH complex of R44L. The ability of both mutants to transmit their effects beyond the local environment of the NADPH pocket is manifested in several details: (1) the pKa of Asp-27 (25 A away from the sites of mutation) is elevated from 6.5 in the wild type to 7.5 and 8.4 in H45Q and R44L, respectively; (2) NADPH elevates the off rates for tetrahydrofolate from 12 s-1 in the wild type to greater than 45 s-1 in R44L; and (3) bound tetrahydrofolate decreases the affinity of the enzymes for NADPH as reflected in the Km from 2 to 40 microM for H45Q (similar to wild type) but from 8 to 5000 microM for R44L.
Binding Sites↗
Cloning of a DNA sequence encoding a major fragment of the 47 kilodalton stress protein homologue of Candida albicans.
Part of the gene coding for the immunodominant 47 kDa antigen of the human fungal pathogen Candida albicans was cloned and sequenced. The predicted amino acid sequence was homologous to stress proteins, the most extensive similarity being with the heat shock protein hsp 90 of Saccharomyces cerevisiae. The 47 kDa antigen has diagnostic and therapeutic potential and is the first candidal antigen to be cloned and sequenced.
Amino Acid Sequence↗
Effects of intravenous metoprolol on global and regional left ventricular function after coronary arterial reperfusion in acute myocardial infarction.
Coronary reperfusion in myocardial infarction improves infarct zone motion, but its effect on the global ejection fraction has been less consistent. The directional movement of the ejection fraction is determined by the opposing influences of improved infarct zone motion and diminishing hyperkinesia in the noninfarct zone. Noninfarct zone hyperkinesia has been attributed to catecholamine stimulation, the Frank-Starling mechanism or intraventricular interactions that unload noninfarcted segments. To investigate the influence of catecholamine stimulation, 9 men presenting with a first myocardial infarction (mean age 53 +/- 13 years) were studied. Coronary reperfusion was accomplished less than 4 hours after the onset of myocardial infarction. Radionuclide ventriculography was then performed before and immediately after the intravenous administration of 15 mg of metoprolol. End-diastolic volume did not change, but end-systolic volume increased 28% after metoprolol (p = 0.041). The ejection fraction decreased from 55 +/- 13% before metoprolol to 45 +/- 14% after its administration (p = 0.002). There was no effect of intravenous metoprolol on infarct zone motion, whereas motion in the noninfarcted segment decreased (p = 0.002). The patients underwent repeat ventriculography after receiving metoprolol, 100 mg orally twice a day for 9 days. Infarct zone motion improved (p less than 0.002) and the ejection fraction increased to 55 +/- 12% (p less than 0.02). Normal zone motion did not change. Thus, compensatory hyperkinesia is at least in part caused by catecholamine stimulation. Conclusions regarding the effects of reperfusion on global ventricular performance can be influenced by the timing of ejection fraction determinations relative to metoprolol therapy.
Adult↗
Assessment of DNA fingerprinting for rapid identification of outbreaks of systemic candidiasis.
DNA fingerprinting was assessed as an improved typing system for Candida albicans aimed at speeding the implementation of cross infection control measures in outbreaks of systemic candidiasis. The study was carried out with 45 previously characterised isolates from five different outbreaks and with 96 unrelated isolates from a mixed control population. Sixteen different genotypes were produced. Results were obtainable within days, reproducibility was high, and there was good discrimination among different outbreaks. Compared with existing typing systems DNA fingerprinting provides a robust system that may be used rapidly to identify outbreaks of nosocomial candidiasis in laboratories with no specialist skill in typing C albicans.
Candida albicans↗
Anionic salivary proteins associated with connective tissue disorders: sialated tissue kallikreins.
Parotid saliva was collected from 32 patients with rheumatoid arthritis, 10 with systemic lupus erythematosus, three with mixed connective tissue disease, 12 with progressive systemic sclerosis, two with primary Sjögren's syndrome, and four with Raynaud's syndrome. Tissue kallikreins were measured by radioimmunoassay, and saliva samples were subjected to isoelectric focusing followed by immunoblotting or silver staining. The results showed that the saliva of patients with connective tissue diseases contained increased amounts of immunoreactive tissue kallikrein. In addition, there was an increase in the multiple forms of anionic tissue kallikreins, resulting mainly from a shift in their distribution towards that of higher sialic acid content and lower isoelectric point. These changes were most obvious in patients with systemic lupus erythematosus. Novel or unusual glycosylation may explain the occurrence of increased amounts of anionic salivary proteins in connective tissue diseases.
Adolescent↗