Biomedical subjects
J Lloyd
Publications and source records attributed to J Lloyd.
DNA testing: diagnostic role in single gene conditions.
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UK clinical research.
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Localisation of islet amyloid polypeptide and its carboxy terminal flanking peptide in islets of diabetic man and monkey.
Islet amyloid polypeptide is a normal constituent of islet Beta cells and is derived from a larger precursor by removal of flanking peptides at the carboxy (C) and amino (N) terminals. The role of these flanking peptides in the formation of amyloid in Type 2 (non-insulin-dependent) diabetes mellitus and in insulinomas is unknown. The C-terminal flanking peptide of islet amyloid polypeptide was localised by immunocytochemistry in human and monkey pancreatic islets from Type 2 diabetic and non-diabetic individuals by use of specific polyclonal antisera. Immunoreactivity for the C-terminal peptide was found in insulin-containing cells in both diabetic and non-diabetic tissue: no antibody binding was detected in islet amyloid of Type 2 diabetic man or of monkeys although a positive reaction occurred with antisera for islet amyloid polypeptide. The C-terminal peptide was localised by immunogold electron microscopy in the insulin granules in both diabetic and non-diabetic individuals but, unlike islet amyloid polypeptide, was not detected in lysosomes. The absence of immunoreactivity for the C-terminal peptide in amyloid suggests that incomplete cleavage of this flanking peptide from islet amyloid polypeptide is not a factor in the formation of islet amyloid.
A double-blind study of the speed of onset of analgesia following intramuscular administration of ketorolac tromethamine in comparison to intramuscular morphine and placebo.
A double-blind, randomised, parallel group, placebo-controlled study was performed in 85 patients to compare the speed of onset of analgesia following the intramuscular administration of a single dose of 30 mg of ketorolac tromethamine, 10 mg of morphine or placebo. A new, sensitive, method was used to measure the latency of analgesia. The onset of analgesia was defined by the time taken for the pain intensity score to reach a specified percentage of the baseline value. Twenty-five percent of patients achieving a 50% reduction in baseline pain intensity score appears to be the most appropriate parameter to assess the speed of onset of analgesia of ketorolac and morphine in the postoperative setting. Paired comparison demonstrated that ketorolac had a significantly faster onset of analgesia (p = 0.03) when compared to placebo, whilst comparison of morphine to placebo analgesic latency (p = 0.06) just failed to reach significance. There was no significant difference between the analgesic onset time of ketorolac and morphine (p = 0.73). Intramuscular ketorolac and intramuscular morphine have comparable analgesic onset times in the postoperative pain context. However, the sensitive method of measuring onset of analgesia described, highlights the slow onset of analgesia when analgesics of known efficacy are given by the intramuscular route in the postoperative period. More attention should be given to the speed of onset of analgesia in future assessments of analgesics.
Positron-labeled angiotensin-converting enzyme (ACE) inhibitor: fluorine-18-fluorocaptopril. Probing the ACE activity in vivo by positron emission tomography.
To evaluate the feasibility of probing the distribution of angiotensin-converting enzyme (ACE) in vivo using positron emission tomography (PET), 4-cis-[18F]fluorocaptopril (18FCAP) was prepared by the reaction of the triflate 2 with K18F/Kryptofix 222 in MeCN followed by hydrolysis (2 N NaOH). The synthesis time was 1 hr with an average radiochemical yield (EOS) of 12% and a specific activity of greater than 300 Ci/mmol. In vivo biodistribution in rats at 30 min after administration showed high uptakes into organs known to have high ACE concentration (lung, kidney and aorta) and faster clearance of 18FCAP for lung and kidney, compared to the clearance from the aorta. When different amounts of unlabeled 4-cis-fluorocaptopril (SQ 25750) were coinjected in rats, a dose of greater than 5 micrograms/kg decreased the lung uptake by one-half while only 1 microgram/kg decreased the kidney uptake by one-half. In general, the binding in the four tissues studied was saturable with the expected capacity. 18FCAP was administered to a human and displaceable uptake observed in the lung and kidney. The results demonstrate the feasibility of probing ACE in vivo using PET.
A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic.
The efficacy of a single dose of intramuscular ketorolac 10 mg or 90 mg was compared with pethidine 100 mg in a randomized double-blind study in 121 patients reporting at least moderate pain due to renal colic. Pain was assessed before drug administration, and then at 1 hour and 12 hours after the dose. Sedation was also assessed at these times, and additionally at the 12 hour assessment the time of the next analgesic dose was recorded. At 1 hour after dosing, pain scores had decreased in all groups; the largest decrease was seen in the ketorolac 90 mg group. The difference in the decrease was significant between the two ketorolac groups, but the differences between ketorolac and pethidine were not significant. Fewer patients in the ketorolac 90 mg group (17%) required a further dose of analgesic within 10 hours than in either the ketorolac 10 mg group (39%) or the pethidine 100 mg group (47%). The difference between ketorolac 90 mg and pethidine 100 mg was statistically significant. At both assessment times the proportion of patients with no sedation was higher in the two ketorolac groups than in the pethidine group. The overall incidence of adverse events was low with all drugs, notably so for the occurrence of vomiting after ketorolac. The results of the study show that intramuscular ketorolac is efficacious in the treatment of renal colic.
James Spence Medallist 1990. Professor Leonard B. Strang.
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Hemodynamic effects of two intravenous doses of ketorolac tromethamine compared with morphine.
The cardiovascular effects of intravenous administration of ketorolac tromethamine 10 and 90 mg were measured and compared with those of morphine sulfate 10 mg in 18 anesthetized patients after major vascular surgery. Morphine caused a significant reduction in mean arterial pressure, left cardiac work index, and left ventricular stroke work index. Stroke volume index, cardiac output, and pulmonary artery pressures decreased to a lesser extent. Ketorolac at either dose was not associated with any significant change in cardiac and hemodynamic parameters. The data suggest that even high doses of the drug may be safely administered in clinical situations where hypotension is disadvantageous or where reduction in afterload is not a specific therapeutic aim.
The reliability of EMG muscle scanning.
The reliability of a surface EMG scanning procedure was investigated for the right and left aspects of ten muscle sites using a large clinical sample of 102 chronic patients. Two neutral postures (sitting/standing) were systematically studied on three occasions approximately one hour apart on the same day. The multivariate analysis of RMS microvolts indicated no significant effects for Age, Gender, Muscle Site, Aspect, or Period. The range of the Pearson correlations was 0.41 to 0.94 when all muscle sites, aspects, postures, and periods were considered. The median correlation was found to be 0.64. The pattern of reliability was seen to be slightly higher in the lower back while standing. The results indicate that with adequate attention to skin preparation, EMG sensors held in place by hand with a light pressure produced reliable results.
Platelet function and exercise-induced myocardial ischaemia in coronary heart disease patients.
Divergent reports of the effects of exercise-induced myocardial ischaemia on platelet function require clarification. This study examines the relationship between exercise, exertional myocardial ischaemia, and in vivo and ex vivo platelet function in 27 male patients, aged 35 to 69, with stable coronary heart disease (CHD). All medications were ceased at least 5 days prior to a maximal exercise test. Blood was sampled before and after exercise to measure plasma and serum thromboxane B2 (TXB2), plasma beta-thromboglobulin (BTG), platelet count ratio (PCR), platelet count (PC), haemoglobin (Hb), haematocrit (Hct) and white cell count (WCC). The exercise test and blood measurements were repeated 5 weeks later, under the same conditions to confirm the reproducibility of any changes. Thirteen patients had a positive test for ischaemia and 14 a negative test. The PC, Hb, Hct and WCC increased in all patients after exercise, confirming earlier reports. The BTG level increased (25 +/- 9 to 30 +/- 15 ng/ml, p less than 0.05; and 24 +/- 9 to 32 +/- 8 ng/ml, p less than 0.004 in the repeat test) and was unrelated to exertional ischaemia. A decrease in the PCR only occurred in the non-ischaemic group in the initial test (0.84 +/- 0.14 to 0.78 +/- 0.13, p less than 0.02) but was not reproducible (0.84 +/- 0.10 to 0.82 +/- 0.13). No change occurred in plasma TXB2 levels. Serum TXB2 increased after exercise in the ischaemic group (255 +/- 150 to 314 +/- 190 ng/ml, and 240 +/- 139 to 370 +/- 169 ng/ml, p less than 0.05) but not in the negative test group (467 +/- 255 to 441 +/- 174 ng/ml, and 421 +/- 299 to 464 +/- 297 ng/ml, p greater than 0.1). Serum TXB2 discriminated poorly between individuals with positive and negative exercise tests. Thus, stable exertional ischaemia does not activate circulating platelets nor is it associated a priori with activated platelets. It may be associated with an increase in maximum thromboxane A2 production capability. Brief strenuous exercise may activate platelets in CHD patients independent of exertional ischaemia.
The excretion of ketorolac tromethamine into breast milk after multiple oral dosing.
We have studied the transfer of the analgesic ketorolac tromethamine into breast milk in ten women aged between 22 and 35 years. Ketorolac administration was started between 2 and 6 days after delivery. The breast milk was not fed to the infant because of maternal antibiotic use (6 patients) or because of jaundice of the baby. 10 mg of ketorolac was given four times daily for two days. Plasma and milk samples were collected on the two dosing days and on the first day after dosing. The plasma and milk were assayed for ketorolac concentrations by HPLC: the quantification limits were 10 ng.ml-1 and 5 ng.ml-1 respectively. The maternal plasma concentrations were within established ranges for ketorolac. In four patients the concentration of ketorolac in the milk was never above 5 ng.ml-1. At 2 h after dosing on both Days 1 and 2 there were quantifiable concentrations of ketorolac in the milk. The range was 5.2 ng.ml-1 to 7.9 ng.ml-1. The ratio of breast milk: plasma concentrations of ketorolac ranged from 0.015 to 0.037. The maximum potential amount of ketorolac that an infant may be exposed to daily could range from 3.16 mg to 7.9 mg, assuming a consumption of between 400 ml and 1 l of breast milk. On a weight-adjusted basis this is equivalent to between 0.16% and 0.40% of the total daily maternal dose.
Drosophila foldback elements, primate L1 elements, and transgenic mice.
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Growth and secretory responses of enriched populations of corticotropes.
The purpose of this study was to learn whether enriched populations of corticotropes could be grown without the other pituitary cell types. Corticotropes populations were enriched to 80-90% by counterflow centrifugation in an elutriator with the Sanderson chamber. After initial separation into small, medium, and large fractions, the cells were stimulated for 3 h with 0.5 nM corticotropin-releasing hormone (CRH) and then re-eluted to remove the enlarged corticotropes. More ACTH (6- to 10-fold) was released in media with 10% fetal bovine serum (FBS) than was released in media with no serum. The effects of FBS could not be mimicked by 0.3% BSA. Corticotropes grew in serum-containing media as long as they were plated at a density of at least 2500 cells per well. The corticotropes expanded in size and assumed two major morphological subtypes. Both stored ACTH and beta-endorphin. One subtype was flattened and pleomorphic. The other subtype was stellate with multiple processes. Cell counts showed a 2.5- to 3.8-fold increase in the number of labeled corticotropes during the first 21 days of culture. Then the numbers of cells declined rapidly. Basal secretion of ACTH rose 1.6-fold during the first week, plateaued after 14 days and then declined to less than 30% of first week levels. CRH stimulation produced dose-dependent increases in media ACTH. In 7 day cultures, both basal and stimulated levels of ACTH were similar to those in 7 day cultures of mixed pituitary cells (containing equivalent numbers of corticotropes). Stimulatory effects of CRH were evident for up to 42 days of culture. Arginine vasopressin enhanced CRH-mediated secretion in most cultures in the first week. Pretreatment with glucocorticoids (100 nM corticosterone) for 15 h blocked CRH-mediated secretion in all cultures. The studies showed that corticotropes do not need the other pituitary cell types for basic plating and basal and CRH-mediated secretory responses. Further tests of specific growth factors are needed to learn whether they will maintain function for longer periods.
Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers.
Ketorolac is a potent cyclo-oxygenase inhibitor used for the treatment of postoperative pain. It is known to have anti-platelet properties. The aim of this study was to determine the effect of ketorolac on haemostasis both alone and in combination with low dose heparin in 12 healthy male volunteers. Each volunteer received the following drug combinations in a double blind, placebo controlled, cross over manner: ketorolac placebo/heparin placebo, ketorolac active/heparin placebo, ketorolac active/heparin active and ketorolac placebo/heparin active. Ketorolac significantly prolonged bleeding time, inhibited platelet aggregation to arachidonic acid and collagen and platelet thromboxane production. Heparin had no effect on bleeding time or platelet function, but significantly prolonged the kaolin cephalin clotting time and increased anti-Xa levels. Ketorolac had no effect on the kaolin cephalin clotting time or anti-Xa levels and no interaction was found between ketorolac and heparin in any of the investigations. The prolongation of bleeding time seen with ketorolac is unlikely, to be of any major clinical significance as almost all subjects remained within the normal range; however, it should be used with caution in subjects with haemostatic problems.
The transfer of ketorolac tromethamine from maternal to foetal blood.
Thirty two women who were participating in an efficacy study comparing 10 mg ketorolac with 50 mg or 100 mg of pethidine in the relief of labour pain, underwent sampling of vein blood, for determination of plasma ketorolac concentrations. The sample was withdrawn at delivery and a sample of umbilical cord blood was withdrawn at the same time. The ratio of ketorolac concentrations in the cord blood sample: the maternal venous sample were calculated and plotted against the time elapsed between drug administration and sampling. Samples for one patient, withdrawn 24 min after dosing, had ketorolac concentrations below the quantification limit. The ratios in the remaining patients were all low and showed a tendency to increase with time. The mean ratio was 0.116 with a range of 0.04 in 2 patients, at 43 min and 1 h 6 min, to 0.25 at 6 h 34 min.
Phosphatidylcholine synthesis by peritoneal mesothelium: its implications for peritoneal dialysis.
This study investigated the possibility that the peritoneum is capable of synthesizing phosphatidylcholine (PC), a lubricant surfactant, in an amount similar to that produced by pulmonary alveoli. The synthesis of PC by rat lung (positive control), liver (negative control), and transparent mesentery (test tissue) was determined by in vitro incubation of these tissues in the presence of (methyl-14C) choline chloride for three hours at 37 degrees C in Warburg flasks. All lipid material present in tissue and incubation media was extracted by the Folch technique. Carrier egg PC was added to each sample and total PC was isolated using high performance thin-layer chromatography. The PC fractions were counted for total radioactivity. No statistically significant difference was observed between the mean radioactive value for mesenteric tissue compared with lung tissue. The mean radioactive value for liver when compared with mesenteric and lung tissue was significantly lower (P less than 0.001). Thus, under the conditions of the experiment, we have demonstrated for the first time that peritoneal tissue is capable of synthesizing PC in amounts similar to that produced by the lung. Electron microscopy of transparent mesentery (test tissue) showed that mesothelium constituted the bulk of the cell population. Therefore, it is most likely that the PC that has been detected in peritoneal fluid is produced by the mesothelial cell. These findings are of significant relevance to developing concepts on the role of surfactant phospholipids in the physiology of peritoneal dialysis.