Intercontinental fetal surgical consultation with image transmission via Internet.
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Computer Communication Networks↗
Biomedical subjects
R Wootton
Publications and source records attributed to R Wootton.
The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a potential anti-sickling agent, following oral administration to healthy subjects.
1. Tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid) interacts stoichiometrically with haemoglobin to increase oxygen affinity. By decreasing the proportion of insoluble deoxy sickle haemoglobin at capillary oxygen concentrations, tucaresol may be of therapeutic benefit in sickle cell anaemia. 2. In this study, which involved the first administration to man, the pharmacokinetics and pharmacodynamics of tucaresol were studied in healthy male volunteers following oral doses of 200-3600 mg. 3. Peak drug concentrations in plasma and erythrocytes were linearly related to dose; mean (s.d.) values were 95.8 (26.1) and 1035 (67) micrograms ml-1, respectively, at the highest dose. Median tmax in plasma was 6.5 h and in erythrocytes 24.5 h, when approximately 60% of the administered dose was in the target tissue. Plasma drug concentrations fell biexponentially with commencement of the apparent terminal elimination phase at approximately 24 h. The terminal elimination half-life from plasma increased with dose (r = 0.77; P < 0.0001) from 133-190 h at 400 mg to a mean (s.d.) of 289 (30) h at 3600 mg. Erythrocyte drug concentrations declined mono-exponentially with a half-life that was always shorter than the apparent terminal half-life in plasma: overall mean (95% CI) of t1/2 erythrocyte/t1/2 plasma ratio was 0.57 (0.53, 0.61). The erythrocyte AUC/plasma AUC ratio increased with dose (r = 0.67; P < 0.001). 4. The proportion of haemoglobin modified to a form with high oxygen affinity (%MOD) increased in a dose-related manner above doses of 800 mg reaching 19-26% after the 3600 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Radiation safety in the animal house.
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Animals↗
Retinal vessel circulation patterns visualized from a sequence of computer-aligned angiograms.
PURPOSE: To present a computer method that can be used to combine the images from a sequence of fluorescein angiograms of the retinal microcirculation so that a composite image can be generated and a color image illustrating circulation at all points in the vascular network can be computed. This should enable more accurate comparison of retinal vascular occlusions that occur during cardiopulmonary bypass surgery. METHODS: Photographic negatives of the macular region from two angiographic sequences, one taken before surgery and the other taken just before the end of bypass, were digitized, background shade corrected, and registered. Composite images were generated as minimum projection images and the filling images generated from parameters of a smooth curve fit to the filling data at every point. RESULTS: The composite images showed a filling pattern that more accurately reflected the maximum fluorescence at every point than any single image. The images generated from the filling data provide a new way to visualize and quantify changes in the retinal circulation. CONCLUSIONS: The technique demonstrates that problems arising from selection of a single frame from a filling sequence can be overcome by combining images. The technique used to generate the color-coded filling image should prove useful for any image sequence in which differential filling is of interest.
Blood Flow Velocity↗
High-level stable expression of recombinant 5-HT1A 5-hydroxytryptamine receptors in Chinese hamster ovary cells.
The human 5-hydroxytryptamine 5-HT1A receptor gene was transfected into Chinese hamster ovary cells. A series of recombinant monoclonal cell lines expressing the receptor were isolated and the properties of one cell line that expressed receptors at a high level (2.8 pmol/mg) were studied in detail. In ligand binding assays with the selective 5-HT1A receptor agonist 2-(NN-di[3H]propylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene ([3H]8-OH-DPAT) only a single class of saturable high-affinity binding sites was detected, with a pharmacological profile in competition experiments essentially identical to that of the 5-HT1A receptor of bovine hippocampus. [3H]8-OH-DPAT binding to the recombinant cell membranes was inhibited by GTP, showing that the receptors in the transfected cells couple to G-proteins. A series of 5-hydroxytryptamine agonists inhibited forskolin-stimulated adenylate cyclase activity in the cells and, despite the high level of receptor expression, their apparent efficacies were similar to those observed for inhibition of adenylate cyclase in brain. This recombinant cell line provides a complete model system for studying the 5-HT1A receptor and its transmembrane signalling system. The recombinant cells can also be grown in suspension culture for long periods but, whereas 5-HT1A receptor numbers and receptor regulation by guanine nucleotides are maintained in suspension-grown cells, the inhibition of adenylate cyclase by the 5-HT1A receptor is gradually lost.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Phase I study of BW12C in combination with mitomycin C in patients with advanced gastrointestinal cancer.
The effect of combining the oxyhemoglobin-modifying drug BW12C with mitomycin C was investigated in a Phase I study of 18 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 50 mg/kg to modify the hemoglobin-oxygen saturation curve by up to 48%. The period of maximum modification was then prolonged for up to 3 hr by a maintenance infusion of 4-6 mg/kg/hr. Pharmacokinetics of BW12C and mitomycin C were performed in all patients. Peak levels of BW12C increased from 139 micrograms/ml to 378 micrograms/ml. Plasma half life was independent of dose, with an average of 3.3 hr. BW12C was well tolerated with no severe side effects. Three patients had objective tumour responses.
Adenocarcinoma↗
A new system for cotside display and analysis of the preterm neonatal electroencephalogram.
Continuous EEG monitoring is considered to be a sensitive indicator of changes in cerebral function. This paper describes a system for cotside display and analysis of EEG discontinuity and amplitude in one-minute epochs, with provision for simultaneous recording of the EEG. It has been successfully used to monitor continuously the EEGs of more than 30 babies in a neonatal intensive care unit for periods of up to nine days. This system rapidly provides indications of changes in cerebral function, which can allow early intervention and possible prevention of morbidity.
Brain Damage, Chronic↗
The POPUMET regulations: careless radiology costs lives.
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Humans↗
Glycyl-L-proline transport in rabbit enterocyte basolateral-membrane vesicles.
The properties of a peptide-transport system in rabbit enterocyte basolateral membrane were examined with glycyl-L-proline as the substrate. Basolateral-membrane vesicles prepared from rabbit proximal intestine were characterized in terms of both purity and orientation. Marker-enzyme assays show that the basolateral-membrane marker, ouabain-sensitive K(+)-activated phosphatase, is enriched 17-fold with respect to the initial homogenate. The activities of enzymes used as markers for other membranes and organelles are low, and contamination of the final membrane fraction with these is minimal. The use of immunoblotting techniques further confirms the absence of brush-border-membrane contamination. Proteins in the basolateral-membrane vesicle preparation gave no cross-reaction with antibodies against the 140 kDa antigen and the Na+/glucose-symport protein, markers specific to the brush-border membrane of the enterocyte. Conversely, antibodies raised against the classical basolateral-membrane marker, the RLA class I histocompatibility complex, reacted strongly with a 43 kDa basolateral-membrane protein. The orientation of the basolateral-membrane vesicles was shown to be predominantly inside-out on determination by two independent criteria. The uptake of [1-14C]glycyl-L-proline by these vesicles is stimulated by the presence of an inwardly directed pH gradient, and this stimulation can be abolished by the proton ionophores carbonyl cyanide p-trichloromethoxyphenylhydrazone (CCCP) and tetrachlorotrifluoromethylbenzimidazole (TTFB). Transport is also inhibited by HgCl2, thimerosal, Na+ and other glycyl dipeptides.
Amino Acids↗
The effect of intermittent local heating on fracture healing in the distal tibia of the rabbit.
Two series of controlled experiments were carried out to investigate the effect of intermittent local heating on fracture healing in the distal tibia of the rabbit. In the first series, the distal tibia was fractured in a reproducible manner and then treated by compression plate fixation. Nine animals received intermittent local heating around the fracture site for 6 weeks postoperatively in comparison with 5 control animals. The mechanical strength of the healed tibia was then measured in a standardized 3-point bend test. Intermittent local heating produced stronger bones than the untreated controls in 6 of the 9 cases, a result which was marginally significant (P = 0.055). In the second series of experiments, a reproducible bone defect was created by drilling a 2 mm diameter hole through the distal tibia; compression plate stabilization was not required. Fourteen animals received intermittent local heating around the fracture site for 3 weeks postoperatively in comparison with 7 control animals. Intermittent local heating produced stronger bones than the untreated controls in 8 of the 14 cases, a result which was not significant (P greater than 0.1). It is concluded that intermittent local heating of the type studied has too small an effect on accelerating the rate of fracture repair to be clinically useful.
Animals↗
Automatic geometrical registration of fluorescein retinal angiograms.
Changes in retinal microvascular perfusion revealed by fluorescein angiography have been reported in patients undergoing coronary artery surgery. Quantification of these changes is important and current techniques depend on careful visual inspection of the angiograms by humans. Computer image processing methods can be used to identify and highlight differences, but geometrical registration of the images is a prerequisite to the comparisons. Automatic methods for locating and matching reference points have therefore been developed. In combination with an iterative process which used least-squares error to calculate the transformation coefficients, subsets of reference points were selected and used to register successfully 20 image pairs.
Coronary Artery Bypass↗
High indices of remodelling in iliac trabecular bone predict reduced forearm cortical bone mass indices in patients with proximal femoral fractures.
To investigate whether high bone turnover could be a predictor of cortical bone loss and a candidate risk factor for fractures of the proximal femur, 33 7.5-mm transiliac biopsies taken at fracture fixation from 48 patients who participated in a study of potential risk factors have been quantitated. Twenty-four of the 33 patients made good recoveries and about 6 weeks postoperatively consented to bone densitometry of the forearm midshaft. Forearm bone density correlated negatively (r = 0.77, P = 0.001) with the surface of trabecular bone covered with osteoid, which in osteoporotic patients with crush fractures of the vertebrae was previously shown to relate both to rates of bone formation and resorption. An important minority of these femoral fracture patients appeared to be suffering from high rates of iliac trabecular bone resorption. Thus, high bone remodelling activity could lead to excessive cortical thinning. This has pathogenetic implications which may be clinically important.
Aged↗
Metabolic studies of radioiodinated serum amyloid P component in normal subjects and patients with systemic amyloidosis.
125I-Serum amyloid P component (SAP), injected intravenously into 10 normal subjects, remained predominantly intravascular with mean (SD) T1/2 (half time) in plasma of 24.5 (5.9) h. The fractional catabolic rate of 68 (19)% of the plasma pool per day was more rapid than other reported human plasma proteins. All radioactivity was excreted in the urine by 14 d. In 16 patients with monoclonal gammopathy or chronic inflammatory diseases, but without amyloidosis, 125I-SAP metabolism was normal. However, among 45 patients with biopsy-proven systemic amyloidosis (25, amyloid A type; 20, amyloid L type), 125I-SAP was cleared from the plasma more rapidly, accumulated in the amyloid deposits, and persisted there. The T1/2 in amyloid, measured directly with 131I-SAP, was 24 d. Repeat studies after 6-18 mo were notably consistent in normals but changed significantly in amyloid patients, generally correlating with clinical signs of disease progression. Measurements of 125I-SAP turnover may thus be of value for diagnosis and monitoring of amyloidosis. Analysis of SAP metabolism in amyloidosis suggests that plasma SAP is in dynamic equilibrium with a very large amyloid pool, and in two autopsies the total mass of SAP in the amyloid deposits was 2,100 and 21,000 mg, respectively.
Adult↗
Demonstration of cerebral microemboli occurring during coronary artery bypass graft surgery using fluorescein angiography.
Coronary artery bypass graft surgery is associated with an unacceptably high incidence of neurological and neuropsychological complications (Breur et al., 1981; Smith, 1988). The main cause of cerebral dysfunction following this type of surgery is probably cerebral microembolism (Dutton et al., 1974; Taylor, 1986). The eye is an outgrowth of the brain and therefore is uniquely suitable for the study of cerebral microcirculation. Retinal fluorescein angiography has been employed during this surgical procedure to demonstrate the changes which occur in the cerebral microcirculation during operation.
Cardiopulmonary Bypass↗
Influence of oxygenator type on the prevalence and extent of microembolic retinal ischemia during cardiopulmonary bypass. Assessment by digital image analysis.
We have previously reported the occurrence of microembolic ischemia in the retina during cardiopulmonary bypass, as revealed by fluorescein angiography. This method has been extended by digital image analysis to include quantification of the extent of retinal ischemia and has been applied to a prospective comparative study of 64 patients undergoing elective coronary operations with either a bubble or a membrane oxygenator. Patients with diabetes or clinically evident cerebrovascular disease were excluded. Bypass procedures were standardized in all cases with pulsatile flow and a 40 microns arterial line filter (Pall EC Plus). Thirty patients had bypass with a bubble oxygenator (Harvey H1700) and 34 patients had bypass with a flat sheet membrane oxygenator (COBE CML). In each case retinal fluorescein angiograms were obtained preoperatively and 5 minutes before the end of bypass and were processed with a digital image analyzer (Context Vision GOP-302). Microembolic perfusion defects were identified by digital subtraction of preoperative and end-bypass angiograms and their total area was computed. Results. In the bubble oxygenator group retinal perfusion defects indicative of microembolism occurred in all 30 (100%) patients. In contrast, over half the patients in the membrane oxygenator group had normal retinal perfusion, and the prevalence of perfusion defects (44%; 70% confidence limits 34% to 54%) was significantly less than in the bubble group (p less than 0.001). In addition, those patients in the membrane group had significantly fewer lesions (median 0; 70% confidence limits 0 to 1) than patients in the bubble group (median 2; 70% confidence limits 2 to 2; p less than 0.001) and also had significantly smaller total areas of retinal ischemia (median 0 mm2; 70% confidence limits 0 to 0.16 mm2) than the bubble group (median 0.22 mm2; 70% confidence limits 0.21 to 0.27 mm2; p less than 0.001). There was no relationship between the extent of retinal ischemia and bypass time, arterial blood gas concentrations, volume of cardiotomy suction or donor blood returned to the pump, or recent medication with aspirin. Inferences. Digital image analysis of retinal fluorescein angiograms may provide a method of quantifying microembolic ischemia in the central nervous system during cardiopulmonary bypass. Flat sheet membrane oxygenation appears to provide significantly better protection against microembolic ischemia than bubble oxygenation.
Blood Gas Analysis↗
Relationships of plasma lipoprotein concentrations to unbound, albumin-bound and sex hormone-binding globulin-bound fractions of gonadal steroids in men.
Most epidemiologic studies of plasma lipoproteins and gonadal steroids have measured total hormone concentrations only. Gonadal steroids are transported in plasma in unbound, albumin-bound and sex hormone-binding globulin (SHBG)-bound forms, only the first two of which are biologically active. In the present study the associations of plasma lipoproteins with the different fractions of testosterone, oestradiol and 5 alpha-dihydrotestosterone (5 alpha DHT) were explored by multiple regression in 70 men aged 52-67 years (mean, 59 years). The principal finding was that the distribution of cholesterol between the two major subclasses of high density lipoprotein (HDL) was correlated with the concentrations of unbound and albumin-bound oestradiol, but not with SHBG-bound oestradiol or any fraction of testosterone or 5 alpha DHT. These associations were independent of plasma triglyceride. Apoproteins A-I and A-II were not correlated with any hormone fraction. Thus, in middle-aged/elderly men HDL subclasses appear to be influenced by circulating estrogenic activity, but not by androgenic activity, through a mechanism that is unrelated to triglyceride transport or HDL apoprotein metabolism.
Aged↗
Cerebral blood flow and metabolism in fasting neonatal piglets.
Cerebral blood flow and cerebral metabolism were studied in 8 fasting neonatal piglets. Cerebral blood flow was not significantly different (p greater than 0.1) at 24 h (75.0 +/- 30.7 ml/min/100 g) and 48 h (74.2 +/- 32.3 ml/min/100 g) of age. Blood glucose concentration was lower in 48-hour-old fasted piglets (1.27 +/- 0.60 mmol/l) in comparison with 24-hour-old fasted animals (2.90 +/- 0.52 mmol/l), and cerebral glucose utilisation rate was also reduced in the 48-hour-old piglets (17.6 +/- 6.0 mumol/min/100 g at 48 h, 34.2 +/- 12.2 mumol/min/100 g at 24 h). Blood lactate concentration and cerebral lactate utilisation rate were not significantly different at 24 and 48 h of age. Brain lactate utilisation accounted for approximately 10% of cerebral oxygen utilisation at 48 h in fasted piglets. Cerebral glucose and lactate utilisation at 48 h accounted for approximately 66% of cerebral oxygen uptake, indicating that other substrates make a major contribution to cerebral metabolic requirements in fasting neonatal piglets.
Animals↗
Reversal of fentanyl/fluanisone neuroleptanalgesia in the rabbit using mixed agonist/antagonist opioids.
The reversal of the neuroleptanalgesic combination of fentanyl/fluanisone using mixed agonist/antagonist opioids has been investigated in the rabbit. All of the compounds studied (naloxone, nalbuphine, meptazinol, butorphanol, buprenorphine, pentazocine, doxapram) reversed the respiratory depression and sedation produced by fentanyl/fluanisone. Fentanyl/fluanisone produced profound analgesia for 180 min, which was rapidly and completely antagonized by naloxone. The mixed agonist/antagonist opioids produced a reduction in the degree of analgesia but, in contrast to naloxone, analgesic activity persisted from 120 min (meptazinol) to 420 min (buprenorphine). Administration of buprenorphine to rabbits anaesthetized with fentanyl/fluanisone and midazolam confirmed that the reversal of respiratory depression was accompanied by the return of arterial pH, PCO2 and PCO2 to preanaesthetic values. The use of neuroleptanalgesic anaesthetic regimens, which have been shown to provide effective surgical anaesthesia, combined with reversal using a mixed agonist/antagonist opioid to provide postoperative analgesia, appears to be a valuable refinement of current laboratory animal anaesthetic practice.
Analgesics↗