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Biomedical subjects

D Clarke

Publications and source records attributed to D Clarke.

At least 145 records · Page 8Linked to original sources
PubMed1994

Creatine kinase isoform electrophoresis for the early confirmation of myocardial infarction detected by timed sequential CK slope analysis.

Creatine kinase (CK)-MM and -MB isoforms were evaluated for the early diagnosis of myocardial infarction in patients aged over 65 years admitted to a district general hospital with acute chest pain. Samples were collected for standard cardiac enzymes, timed CK slope analysis, and CKMM and CKMB isoform analysis from 48 patients admitted with acute chest pain. CKMM and CKMB isoform analyses were conducted using a Helena Rep electrophoresis system under standard conditions supplied by the company. In addition to the results of the biochemical tests the discharge diagnosis of the patients were also recorded. CKMM isoform analysis resulted in three false-negative classifications of patients and one false-positive. The predictive value of this test was 100% for a positive result and 94% for a negative result. CKMB isoform analysis was less accurate and there were six false-negative results and five false-positive results. The predictive value of a positive result was 75% and 85% for a negative result. CK isoform analysis became unreliable when mean total CK levels in serum were 210 IU/l (+/- 171). CK isoform analysis may be of use in the investigation of patients whose samples have a total CK concentration greater than the reference range but was no better than timed CK slope analysis for the detection of myocardial infarction in patients aged more than 65 years.

Aged↗
PubMed1994

Use of cloned and expressed human liver UDP-glucuronosyltransferases for analysis of drug glucuronide formation and assessment of drug toxicity.

Five cloned human hepatic UDP-glucuronosyltransferase (UGT) cDNAs were stably expressed in tissue culture cell lines. More than 100 drugs and xenobiotics were used as substrates for glucuronidation catalyzed by the cloned human transferases to determine the chemical structures accepted as substrates. UGT-HP1 exhibited a limited substrate specificity for planar phenolic compounds, whereas UGT-HP4 was more accepting of nonplanar phenols, anthraquinones, flavones, alphatic alcohols, aromatic carboxylic acids, steroids and many drugs of varied structure. UGT-HP3 (bilirubin UGT) catalyzed the glucuronidation of ethinylestradiol. UGT-H6 and UGT-H25 (steroid/bile acid UGTs) also catalyzed the glucuronidation of some xenobiotics. Levels of UGT-HP4 activity towards some substrates were sufficient to allow determination of kinetic parameters for the enzyme reaction. Further, metabolism of drugs could be studied by addition to the recombinant cell lines in culture and extraction of the media allowed analysis of glucuronide formation. The protection afforded against cytotoxic drugs was observed. The data presented here demonstrate the potential of using these recombinant cell lines for investigation of phase II metabolism by human UGTs and subtle differences in protein structure which affect their specificity.

Cell Line↗
PubMed1994

The radiology of sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology. The role of radiology is not only to support the clinical diagnosis but also as an adjunct to monitor the course and progression of the disease. The cornerstone of radiological assessment is the plain radiograph, however newer imaging methods are producing more information in relation to the anatomical distribution and pathophysiology which may ultimately have a profound effect on the management of this protean disease.

Female↗
PubMed1994

Family studies in Prader-Willi syndrome.

Clinical, cytogenetic and molecular studies have been undertaken in the families of 52 probands with Prader-Willi syndrome. The maternal age at the birth of a proband with a deletion in 15p11q13 was on average 8 years less than that of the mothers of probands with uniparental disomy (UPD), the paternal age was on average 7 years less. Seven probands with UPD were all female, as were 7 patients who had neither a detectable chromosomal abnormality nor UPD. Cytogenetic and molecular polymorphisms in proximal chromosome 15 indicated that for probands with a 15q11q13 deletion, inheritance of both the maternal and the intact paternal homologue is random in their unaffected sublings. Pigmentation studies suggest that probands who have a deletion in 15q11q13 have lighter colouring than other family members implying that D15S12 may not be imprinted.

Adult↗
PubMed1993

Drug and xenobiotic glucuronidation catalysed by cloned human liver UDP-Glucuronosyltransferases stably expressed in tissue culture cell lines.

Two human UDP-Glucuronosyltransferase (UGT) cDNA clones were stably integrated into V79 chinese hamster fibroblast cells and the functional enzymes were expressed in this heterologous environment. More than 100 drugs and xenobiotics were used as substrates for glucuronidation, catalysed by the cloned UGTs to determine the chemical structures accepted as substrates. UGT HP1 exhibited a limited specificity for planar phenolic compounds, whereas UGT HP4 was more promiscuous in acceptance of non-planar phenols, anthraquinones, flavones, aliphatic alcohols, aromatic carboxylic acids, steroids and many drugs of varied structure. These conclusions are illustrated here by using a series of alkyl- and halophenols. This work indicates the considerable potential value in use of these recombinant cell lines to study human drug glucuronidation.

Animals↗
PubMed1993

Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis.

Diclofenac is a frequently prescribed nonsteroidal antiinflammatory drug (NSAID). Significant hepatotoxicity related to diclofenac may be more common than previously recognized, as three patients with diclofenac-associated hepatitis were seen by one clinician in a single year. All patients were ANA positive during the hepatitis and had histologic features of chronic active hepatitis. Two had been inappropriately treated with corticosteroids. The third patient presented more acutely with jaundice and symptoms of hepatitis. Two of the patients developed the same hepatic reaction when rechallenged with diclofenac. The third patient was changed to tiaprofenic acid, a NSAID of the same family, and redeveloped evidence of hepatotoxicity. All three were subsequently able to take naproxen without liver dysfunction. Diclofenac-induced liver disease may be misdiagnosed. Twenty-six cases of significant hepatic reactions to diclofenac have been previously reported in the literature and are reviewed. Such hepatic reactions to diclofenac and related NSAIDs may be commoner than realized. Introduction of a NSAID of another class appears to be safe.

Aged↗
PubMed1993

Pharmacokinetics of dapsone in children.

We studied dapsone pharmacokinetics in eight children with compromised immune function who were receiving three different preparations. Peak serum concentration was less than 0.25 microgram/ml after doses of an extemporaneous liquid preparation but ranged from 0.72 to 1.33 micrograms/ml after initial tablet or proprietary liquid doses and 1.48 to 2.48 microgram/ml during long-term proprietary liquid administration. Elimination followed first-order kinetics; the mean elimination half-life was 15.1 hours.

Biological Availability↗
PubMed1993

Organising unrestricted open access gastroscopy in South Tees.

Increasing demand for upper gastrointestinal endoscopy has forced many clinicians to reconsider the policy of seeing all patients in a specialist clinic before gastroscopy. The following are considered essential in setting up an open access gastroscopy service. (1) Assessment of the need by examination of waiting times for the outpatient clinic and the proportion of patients requiring upper gastrointestinal endoscopy, and consultation with colleagues in general practice. During the first 2 years of the service the average waiting time for a medical gastrointestinal outpatient appointment has fallen from over 120 days to 37 days in this area. (2) An adequately staffed and equipped gastrointestinal unit with well motivated nurses (the workload will increase) and sufficient clinical support to allocate patients to the next available gastroscopy list is vital. A safe mechanism for relaying information back to the GP (including histology reports) is essential otherwise medicolegal problems could arise. Open access gastroscopy now accounts for 29% of the total endoscopy workload in South Tees. (3) Close cooperation between medical and surgical gastroenterologists must be achieved to ensure a uniform approach to the provision of this service and equal distribution of the endoscopy workload. This will require close examination of the potential numbers and may necessitate appointment of a clinical assistant or additional consultant. Clinical assistants perform just over 50% of the open access gastroscopies in South Tees and the waiting time has been kept short (average 17 days). (4) A comprehensive request form with guidelines for GPs and a specific box identifying whether the GP requires a report and brief advice only or follow up at the discretion of the endoscopist (often a clinical assistant) is required. (5) Management must be involved in identifying adequate resources. (6) Methods of monitoring requests and outcome measures to ensure effective audit must be established.

Endoscopy, Gastrointestinal↗
PubMed1993

Endothelium dependent and independent responses in coronary artery disease measured at angioplasty.

OBJECTIVE--To investigate the effects of substance P and papaverine, two drugs that increase coronary blood flow by different mechanisms, on vasomotion in stenotic coronary arteries at percutaneous transluminal coronary angioplasty (PTCA). DESIGN--Coronary blood flow responses to substance P and papaverine were measured in stenotic coronary arteries at the time of PTCA with quantitative angiography and a Doppler flow probe. SETTING--A cardiothoracic referral centre. PATIENTS--15 patients undergoing elective PTCA of a discrete epicardial coronary artery stenosis. INTERVENTIONS--Pharmacological coronary flow reserve was determined with papaverine 5-10 minutes before and after successful PTCA. Endothelium dependent responses to 2 minute infusions of substance P (10-15 pmol.min-1) were assessed immediately before PTCA. MAIN OUTCOME MEASURES--Coronary blood flow responses and changes in epicardial coronary artery area at stenotic, proximal, and distal sites with papaverine and substance P. RESULTS--Stenotic sites dilated with papaverine before PTCA (17.7%(6.9%) (mean (SEM)) area increase, p < 0.05 v baseline). Substance P dilated stenotic sites (16.8%(5.7%) area increase, p < 0.05) and proximal (14.3%(5.4%), p < 0.05) and distal sites (41.7%(9.3%), p < 0.005). Coronary flow reserve increased but did not reach normal values after PTCA (2.3(0.4) before PTCA v 3.0(0.4) after PTCA, p < 0.05) and was associated with an increase in peak flow with papaverine. Angioplasty did not alter baseline flow. After PTCA papaverine caused significant vasoconstriction at the stenotic site (-13.6%(4.3%) area decrease, p < 0.05). There was a negative correlation (r = -0.68, p < 0.05) between the dilator response with papaverine before PTCA and the constrictor response after PTCA. CONCLUSIONS--Substance P causes endothelium dependent dilatation in atheromatous coronary arteries, even at sites of overt atheroma. The cause of the paradoxical constrictor response to papaverine after PTCA is uncertain, but unopposed flow mediated vasoconstriction (the myogenic response) after balloon induced endothelial denudation may be one of several contributory factors.

Angioplasty, Balloon, Coronary↗
PubMed1993

Coronary flow reserve in patients with chest pain and normal coronary arteries.

BACKGROUND: Many studies have shown that coronary flow reserve is reduced in patients with chest pain and angiographically normal coronary arteries. The methods used to assess coronary blood flow have varied, but in nearly all reports dipyridamole has been used to bring about vasodilatation. This study was designed to assess whether the apparent impairment of coronary flow reserve seen with dipyridamole could be reproduced with either papaverine or adenosine, which induce maximum coronary blood flow by different mechanisms. METHODS: 25 patients with chest pain and angiographically normal coronary arteries were studied with an intracoronary Doppler flow probe and quantitative angiography to determine epicardial coronary artery area, coronary blood flow velocity, coronary flow reserve, and coronary vascular resistance index (CVRI, the ratio of resistance after intervention to basal resistance). All patients received papaverine 8 mg. Eight patients with positive exercise tests received intracoronary papaverine (8 and 10 mg), intracoronary adenosine (6, 20, 60 micrograms), and high-dose intravenous dipyridamole (0.84 mg/kg). RESULTS: The velocity ratio (peak after intervention: baseline) (mean (SEM)) after 8 mg papaverine was 3.3 (0.2) (n = 25) and the coronary flow reserve was 4.1 (0.3) (n = 25). There were no differences between patients with a positive (n = 16) or negative (n = 9) exercise test. In eight patients coronary flow reserve was measured after increasing doses of papaverine, adenosine, and dipyridamole. Coronary flow reserve was 4.5 (0.3) with papaverine, 4.8 (0.3) with adenosine, and 3.5 (0.4) with dipyridamole (p = 0.08 v papaverine and adenosine). CVRI was 0.22 (0.01) with papaverine, 0.21 (0.02) with adenosine, and 0.29 (0.03) with dipyridamole (p < 0.05 v papaverine, p = 0.09 v adenosine). CONCLUSIONS: These results indicate that measurement of coronary flow reserve and CVRI in patients with chest pain and normal coronary arteries depends on the pharmacological stimulus. Normal values were obtained with papaverine in all patients, irrespective of the exercise test response. In patients with a positive exercise test significantly lower values were obtained with dipyridamole than with papaverine, or adenosine. The reported impairment of coronary flow reserve in patients with angina and normal coronary arteries may reflect the variability in response to different pharmacological agents. The mechanism underlying this variability is unknown, but may involve an abnormality of adenosine metabolism in the myocardium.

Adenosine↗
PubMed1993

Alpha-2 adrenergic receptors in inner medullary collecting duct cells of the rabbit kidney.

The stimulation of alpha-2 adrenergic receptors in the kidney produces diuresis. In this study, alpha-2 adrenergic receptors were examined in inner medullary collecting duct (IMCD) cells isolated from the rabbit kidney. The equilibrium binding of [3H] rauwolscine to IMCD cell homogenate was measured after incubation for 45 min at 25 degrees C in the absence (total binding) and presence (nonspecific binding) of 100 microM phentolamine. The specific binding of [3H]rauwolscine was saturable with a Bmax of 170 fmol/mg of protein and Kd of 4.18 nM. The displacement of [3H]rauwolscine binding to IMCD cells by adrenergic antagonists and agonists displayed the following order of potency: phentolamine > yohimbine > clonidine > oxymetazoline > azepexole > propranolol > prazosin > alpha-methyl norepinephrine > epinephrine. Activation of alpha-2 adrenergic receptors by azepexole decreased vasopressin- and forskolin-stimulated cAMP formation in the IMCD cells. Because IMCD cells in the kidney have a hypertonic environment made up of urea and NaCl, we also determined the effects of a mixture of NaCl and urea (1200 mOsm/kg water) on the binding of [3H]rauwolscine and cAMP formation in the IMCD cells. The hypertonicity increased the Kd and Bmax of [3H]rauwolscine binding to 15.2 nM and 240 fmol/mg of protein, respectively. In addition, hypertonicity decreased forskolin-stimulated cAMP formation in IMCD cells. It is concluded that: 1) high-affinity specific alpha-2 adrenergic receptors are present in the rabbit IMCD; 2) selective alpha-2 agonists inhibit vasopressin- and forskolin-stimulated cAMP formation in rabbit IMCD and 3) the effects of adrenergic drugs on the IMCD in vivo will depend on the renal medullary osmolality that itself depends on the state of the hydration of the animal.

Animals↗
PubMed1992

Binding of primitive hematopoietic progenitor cells to marrow stromal cells involves heparan sulfate.

Blast colony-forming cells (BI-CFC) and pre-colony-forming unit-granulocyte, monocyte (CFU-GM) in human bone marrow bind to marrow-derived stromal layers grown in the presence of methylprednisolone (MP+), but do not bind to stroma grown without MP (MP-). The BI-CFC bind to stroma and form colonies when overlaid with agar; the pre-CFU-GM bind to stroma and release CFU-GM into the supernatant culture medium (delta assay). These two classes of progenitor may represent similar stages of hematopoietic cell development. Their binding to stroma depends on the presence of heparan sulfate proteoglycan (HS-PG) in the extracellular matrix secreted by the stromal cells. Here, we have analyzed the functional and biochemical properties of HS-PG isolated from MP+ and MP- stromal cultures. HS-PG or isolated HS glycosaminoglycan (GAG) side chains partially blocked progenitor cell binding when they were added to the 2-hour binding phase of the BI-CFC or delta assays. Gel electrophoresis of HS-PG resolved more bands in matrix preparations from MP+ cultures than in preparations from MP- cultures. The blocking activity of the eluted MP+ HS-PG bands depended partly on the amount of GAG attached to the protein core and presumably partly on the structure of the core itself. Time course studies demonstrated that the HS-dependent phase of the binding interaction was limited to the first 30 to 60 minutes of the 2-hour binding phase. The different blocking effects of MP+ and MP- HS indicate that they have different biochemical properties. The HS-GAG in MP+ stroma has a higher degree of sulfation and a greater negative charge to mass ratio compared with MP- HS-GAG. Variations in HS may determine specific binding by hematopoietic progenitor cells and a heparan sulfate receptor is envisaged as acting in concert with further cell adhesion molecules (CAMs) on the progenitor cell surface.

Adult↗
PubMed1992

Rapid fitness losses in mammalian RNA virus clones due to Muller's ratchet.

Muller's ratchet is an important concept in population genetics. It predicts that when mutation rates are high and a significant proportion of mutations are deleterious, a kind of irreversible ratchet mechanism will gradually decrease the mean fitness of small populations of asexual organisms. In contrast, sexual recombination may stop or reverse this mutational ratchet by recombinational repair of genetic damage. Experimental support for Muller's ratchet has previously been obtained in protozoa and in a tripartite RNA bacteriophage. We now show clear evidence that Muller's ratchet can operate on a nonsegmented nonrecombining pathogenic RNA virus of animals and humans. We did genetic bottleneck passages (plaque-to-plaque transfers) of vesicular somatitis virus (VSV) and then quantitated relative fitness of the bottleneck clones by allowing direct replication competition in mixed infections in cell culture. We document variable fitness drops (some severe) following only 20 plaque-to-plaque transfers of VSV. In some clones no fitness changes (or only insignificant changes) were observed. Surprisingly, the most regular and severe fitness losses occurred during virus passages on a new host cell type. These results again demonstrate the extreme genetic and biological variability of RNA virus populations. Muller's ratchet could have significant implications for variability of disease severity during virus outbreaks, since genetic bottlenecks must often occur during respiratory droplet transmissions and during spread of low-yield RNA viruses from one body site to another (as with human immunodeficiency virus). Likewise, the lower-probability generation of increased-fitness clones during repeated genetic bottleneck transfers of RNA viruses in nature might also affect disease pathogenesis in infected individuals and in host populations. Whenever genetic bottlenecks of RNA viruses occur, enhanced biological differences among viral subpopulations may result.

Animals↗
PubMed1992

Contrast variation studies of clathrin coated vesicles by small-angle neutron scattering.

Structural information on clathrin coated vesicles has been obtained by small angle neutron scattering using contrast variation. A characteristic peak in the neutron scattering profile, which is apparent in 75% D2O, as well as in H2O, disappears when contrast matching the protein component of the coated vesicles in 42% D2O. Neutron, as well as dynamic, light scattering give a coated vesicle size of about 900 A in H2O and D2O, but for neutron scattering the diameter decreases when matching out the protein coat of the clathrin coated vesicles. From the match point for the clathrin coated vesicles it is demonstrated that the clathrin cages do contain internal membrane. The mass of 34 MD and composition of 75% protein and 25% lipid found from the analysis of the small-angle scattering data are both in good agreement with the values reported in the literature. Electron microscopy gives an average outer diameter of 880 A for the coated vesicles and an average diameter of 460 A for the vesicle itself.

Biophysical Phenomena↗
PubMed1992

The treatment of pelvic soft tissue radiation necrosis with hyperbaric oxygen.

OBJECTIVE: The purpose of this study was to examine the therapeutic effects of hyperbaric oxygen on radiation-induced soft tissue necrosis in patients who previously received treatment for a gynecologic malignancy. STUDY DESIGN: Fourteen patients whose necrotic wounds failed to heal after 3 months of conservative therapy were enrolled in a prospective observational study. Outcome of hyperbaric oxygen treatment was measured by resolution of necrosis. RESULTS: Fourteen patients underwent 15 courses of hyperbaric oxygen treatments. All those with radiation necrosis of the vagina alone or in association with rectovaginal fistula had complete resolution of necrosis with hyperbaric oxygen. Only one treatment failure occurred. CONCLUSION: Hyperbaric oxygen is a safe, effective, and well-tolerated treatment for radiation-induced soft tissue necrosis.

Adult↗
PubMed1992

Vibration white finger and Dupuytren's contracture: are they related?

Between 1988 and 1990, 500 claimants were assessed and considered to have vibration white finger (VWF). Of these, 137 were under 45 years of age and none had Dupuytren's contracture of the remaining 363, 311 were aged 50-85 years, and of these 62 (19.9 per cent) had Dupuytren's contracture. Statistically, this prevalence was significantly higher than that in a control group of 150 men of similar age distribution (10.7 per cent). As far as can be ascertained, this is the first study to indicate that there may be a causal relationship between VWF and Dupuytren's contracture, and the possible theoretical reasons for this are discussed. It is suggested that further studies are required to confirm or refute the findings.

Adult↗