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Biomedical subjects

D Kilpatrick

Publications and source records attributed to D Kilpatrick.

At least 37 records · Page 2Linked to original sources
PubMed1996

Transfusion-related acute lung injury due to HLA-A2-specific antibodies in recipient and NB1-specific antibodies in donor blood.

Transfusion-related acute lung injury (TRALI) is a hazardous but little-known complication of blood transfusion, characterized by non-cardiogenic lung oedema after blood transfusion. Leucoagglutinating antibodies in the donor plasma are considered to play a central role in the pathogenesis of TRALI but no recommended procedure currently exists for their detection, and most of them have not yet been well characterized. Serum samples of two patients who have developed TRALI within 30 min of blood transfusion and the sera of the involved blood donors were investigated for leucocyte antibodies by granulocyte immunofluorescence, granulocyte agglutination and lymphocytotoxicity assays using typed test cells. Suspected specificities of the detected antibodies were confirmed by a luminoimmunoblot assay and the antigen capture assay MAIGA. One case was associated with granulocyte agglutinating anti-HLA-A2 antibodies in the recipient's (i.e. patient's) own blood and the other with donor-related non-agglutinating antibodies directed against the granulocyte-specific antigen NB1. Leucocyte incompatibility between donor and recipient was shown in both cases by crossmatching and typing of the incompatible cells for the appropriate antigen. The results show that TRALI is associated not only with donor- but also with recipient-related leucocyte antibodies. In addition to leucoagglutinating antibodies, non-agglutinating granulocyte-specific antibodies can be also involved. For immunodiagnosis, sera from both must be investigated by a combination of granulocyte and lymphocyte (HLA) antibody screening tests and leucocyte incompatibility verified by crossmatching.

GPI-Linked Proteins↗
PubMed1996

Validation of a subendocardial ischaemic sheep model by intracoronary fluorescent microspheres.

1. We evaluated the use of non-radioactive fluorescent-labelled microspheres (FM) for the measurement of regional myocardial blood flow (RMBF) in an ischaemic sheep model. 2. Injection of FM directly into the coronary artery was compared with left atrial injection. There was a good correlation in the measurement of RMBF between these two injection methods (r = 0.92; n = 107 data points). Injection into the coronary artery requires less FM (one twentieth of that required by atrial injection) and is more economical. 3. The use of a fluorescent technique without filtering myocardial tissue was investigated. Calibration curves from the fluorescence plus myocardial tissue samples were similar to those of the pure fluorescence samples and both showed a linear relationship between fluorescent intensity and the number of microspheres (r >0.97). These results indicate that the extraction of six fluorescent dyes (blue-green, yellow-green, green, orange, red and crimson) directly from the aqueous solution using ethyl acetate is effective. 4. A subendocardial ischaemic model was produced by partially occluding the circumflex artery (CxA) with concomitant left atrium (LA) pacing. During ischaemia, the endocardium/epicardium (Endo/Epi) flow ratios in the ischaemic area changed from 1.04 +/- 0.12 to 0.47 +/- 0.17 (P <0.05; CxA injection) and from 1.08 +/- 0.12 to 0.51+/- 0.05 (P <0.05; LA injection). The ratio in the non-ischaemic area remained unchanged (1.12 +/- 0.26 to 1.01 +/- 0.22; not significant). 5. RMBF calculation using coronary inflow as the reference flow was also compared with that using the traditional method. We found that, in this study in which a non-filtering technique was applied, using coronary inflow as the reference flow was superior to the conventional distal sampling method.

Animals↗
PubMed1996

Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.

PURPOSE AND METHODS: Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. RESULTS: The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively. CONCLUSION: A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.

Adult↗
PubMed1996

Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Adult↗
PubMed1996

Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel.

In a clinical trial of paclitaxel (Taxol) and carboplatin in combination, the severity of thrombocytopenia was less than would be expected with an equivalent dose of carboplatin alone. To determine whether a pharmacokinetic interaction was responsible for this observation, the effect of pretreatment with Taxol on the pharmacokinetics of carboplatin was examined in 11 patients. Each patient was randomized to one of two treatment groups that determined the order of drug treatments. The treatments were carboplatin as a 30-min infusion alone or immediately following 175 mg/m2 Taxol administered as a 3-h i.v. infusion. The treatments were separated by 1 week. The carboplatin dose was chosen to produce a target area under the concentration-time curve (AUC) of 3.75 mg-min/ml according to a previously published formula (A. H. Calvert et al., J. Clin Oncol., 7: 1748-1756, 1989). The mean administered dose of carboplatin was 338 mg. Serial blood samples were collected over 24 h and analyzed for total and free platinum, and, in some patients, Taxol. The pharmacokinetics of carboplatin (i.e., total clearance and volume of distribution at steady state), was not significantly affected by pretreatment with Taxol. Total clearances of carboplatin were 67.2 +/- 28.8 ml/min and 64.6 +/- 27.9 ml/min in the absence and presence of Taxol, respectively (P = 0.56). The AUC of free carboplatin (3.45 mg-min/ml) obtained in the absence of Taxol was not significantly different from that measured in the presence of Taxol (3.27 mg-min/ml). The AUC of carboplatin in both the absence and presence of Taxol agreed with the projected target AUC of 3.75 mg-min/ml. In conclusion, the application of an individualized dosing strategy is valid for the calculation of the carboplatin dose in this combination. The pharmacokinetics of carboplatin is not altered by pretreatment with Taxol at a standard dose, and a pharmacokinetic interaction is not responsible for the altered toxicity of the combination.

Adult↗
PubMed1995

The inverse problem of electrocardiology: the performance of inversion techniques as a function of patient anatomy.

Sixteen anatomically correct bodies have been studied to determine the performance of the inversion techniques of zero-order Tikhonov regularization and singular value decomposition. The bodies have varying heart height and diameter, thickness of subcutaneous fat layer, and distance of the heart from the left wall of the chest. Comparisons are made in terms of trade-off curves for noise amplification factor and spread of epicardial potentials. It was found that regularization performs better than singular value decomposition on all bodies; the larger the heart size, the more reliable the results; and for a given heart size, the thinner the subcutaneous fat layer, the more reliable the results. The distance of the heart from left wall of the chest was found to be a less significant factor for a given heart size.

Adipose Tissue↗
PubMed1994

Inverse electrocardiographic transformations: dependence on the number of epicardial regions and body surface data points.

The inverse problem of electrocardiography, the computation of epicardial potentials from body surface potentials, is influenced by the desired resolution on the epicardium, the number of recording points on the body surface, and the method of limiting the inversion process. To examine the role of these variables in the computation of the inverse transform, Tikhonov's zero-order regularization and singular value decomposition (SVD) have been used to invert the forward transfer matrix. The inverses have been compared in a data-independent manner using the resolution and the noise amplification as endpoints. Sets of 32, 50, 192, and 384 leads were chosen as sets of body surface data, and 26, 50, 74, and 98 regions were chosen to represent the epicardium. The resolution and noise were both improved by using a greater number of electrodes on the body surface. When 60% of the singular values are retained, the results show a trade-off between noise and resolution, with typical maximal epicardial noise levels of less than 0.5% of maximum epicardial potentials for 26 epicardial regions, 2.5% for 50 epicardial regions, 7.5% for 74 epicardial regions, and 50% for 98 epicardial regions. As the number of epicardial regions is increased, the regularization technique effectively fixes the noise amplification but markedly decreases the resolution, whereas SVD results in an increase in noise and a moderate decrease in resolution. Overall the regularization technique performs slightly better than SVD in the noise-resolution relationship. There is a region at the posterior of the heart that was poorly resolved regardless of the number of regions chosen. The variance of the resolution was such as to suggest the use of variable-size epicardial regions based on the resolution.

Adult↗
PubMed1994

Ifosfamide, carboplatin, and etoposide plus granulocyte-macrophage colony-stimulating factor: a phase I study with apparent activity in non-small-cell lung cancer.

PURPOSE: A phase I trial was performed to evaluate the feasibility of escalating the dose of etoposide in dose-intensive ifosfamide, carboplatin, and etoposide (ICE) with granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS: Twenty-four patients were entered between November 1990 and November 1991. Patients received ifosfamide 5 g/m2 by continuous infusion over 48 hours, carboplatin 400 mg/m2 by intravenous bolus, and GM-CSF 5 micrograms/kg/d subcutaneously from day 4 until neutrophil recovery. The etoposide dose was escalated, with six patients receiving 300 mg/m2 total dose (level 1), six receiving 600 mg/m2 (level 2), three receiving 900 mg/m2 (level 3), and five receiving 1,200 mg/m2 (level 4). Level 4B consisted of three patients who received etoposide 1,200 mg/m2 and GM-CSF 10 micrograms/kg/d. Cycles were repeated every 21 days. The maximum-tolerated dose (MTD) was prospectively defined as the dose level at which the next higher level produced greater than 7 days of grade 4 myelosuppression in two or more of six patients. RESULTS: Twenty-three patients were assessable. The median duration of neutropenia was < or = 7 days on cycle 1 at all dose levels. The initial criteria for determination of the MTD was never achieved. However, seven of eight patients treated at levels 4 and 4B required hospitalization for neutropenic fever on cycle 1 of therapy, with three of four septic events occurring at these levels. Cumulative thrombocytopenia occurred at all dose levels, with > or = 50% of patients requiring platelet transfusions on cycle 3. This became the dose-limiting toxicity above level 3. The overall response rate was 48%, with 11 of 23 objective responses, including two complete responses (CRs). Seven of 11 (64%) patients with non-small-cell lung cancer (NSCLC) responded, including one CR. Two of four (50%) heavily pretreated non-Hodgkin's lymphoma (NHL) patients responded, with one CR. CONCLUSION: The addition of GM-CSF to a dose-intensive ICE regimen permitted dose escalation of etoposide to 900 mg/m2, with cumulative thrombocytopenia as the dose-limiting toxicity. Carboplatin dosing by the area under the curve (AUC) may minimize thrombocytopenia. This appears to be an active regimen for patients with NSCLC and refractory NHL.

Adult↗
PubMed1993

Observations on the effects of long-term withdrawal on carcass composition and residue concentrations in clenbuterol-medicated cattle.

The detection of the illegal use of clenbuterol (CBL) as a growth promoter has relied on detecting residual concentrations of the drug in body fluids or tissues. Analysis of retinal extracts has recently been shown to considerably extend the detection period following withdrawal. The withdrawal periods required to eliminate residues from the liver and retina were investigated by medicating 20 cattle with CBL for 30 days; 6 control animals remained unmedicated. Residual concentrations were monitored throughout this period and for the subsequent 140 days. Concurrent changes in muscle areas and backfat thicknesses were recorded by ultrasound. CBL was detectable in liver up to the 56th day of withdrawal (0.35 ng/g, SD = 0.5), but retinal concentrations remained well above detectable concentrations throughout the withdrawal period (22.5 ng/g, SD = 6.5). There were small gains (3-4%) in the muscle areas of treated cattle during medication as compared to controls (p > 0.05). These comparative gains remained during withdrawal. Backfat thicknesses in treated animals were 40% lower than in controls at the end of medication (p < 0.01). However, by 70 days after withdrawal this difference had disappeared (p > 0.05) owing to accelerated fat deposition in the treated group. The retina has been shown to be a highly effective target matrix for detecting CBL administration after long withdrawal periods.

Adipose Tissue↗
PubMed1993

Relationship of ST-segment elevation to eventual QRS loss in acute anterior wall myocardial infarction.

The position of electrocardiographic ST-segment elevation in acute myocardial infarction (MI) is related to the region of infarction, but the relationship between the initial ST-segment elevation and the eventual loss of QRS voltage remains uncertain. The authors examined body surface map data in 76 patients with acute anterior wall MI to clarify this relationship. The patients had no evidence of previous MI, no subsequent MI, and did not receive thrombolytic therapy or other acute interventions. Maps were recorded on admission to the hospital, every 24 hours during the hospital stay, and again at follow-up examinations 6-48 months after the index MI. The region of ST-segment elevation on the initial body surface map was compared to the region of developed voltage loss in the QRS complex as measured by the integral 0-30, 0-40, 0-80, and 30-80 ms body surface maps subsequently recorded 24 hours, 48 hours, and over 6 months after the initial body surface map. There was a relationship between the position of the ST-segment elevation and the loss of the QRS segment voltages, which was pronounced early after acute MI and diminished months after the MI. The region of ST-segment elevation in the initial body surface map predicts the QRS loss. In the integral QRS0-30 map versus the initial ST-segment map the mean correlation coefficient was -0.54 +/- 0.33 with a median value of -0.67. The integral QRS0-40 map and ST-segment map had a mean correlation coefficient of 0.60 +/- 0.29 and median of 0.66. The mean correlation coefficient is less for the integral QRS0-80 map and nonexistent in the integral QRS30-80 map. This method may be useful for monitoring acute interventions in acute MI.

Electrocardiography↗
PubMed1993

Assessment of reperfusion in myocardial infarction by body surface electrocardiographic mapping.

To determine the efficacy of body surface potential mapping to detect and quantify reperfusion in acute infarction, 66 patients were studied by repeated body surface potential mapping before and after administration of the thrombolytic agent. The QRS and ST-segment were analyzed and compared to the arterial patency as assessed by arteriography within 10 days. The infarct-related vessel was patent in 50 patients and occluded in the remaining 16. In 6 of the 15 patients in whom thrombolytic therapy was started within 2 hours of the onset of chest pain the ST-segment changed from that of an acute infarction pattern to that of a normal pattern, and the QRS pattern either remained normal or recovered prior to discharge. In two additional patients the QRS pattern returned to normal prior to discharge from the hospital. In the 51 patients with later thrombolytic therapy (> or = 2 hours) the degree of ST elevation and depression decreased more than either the control infarction group (36 inferior and 73 anterior patients) or the group in whom reperfusion attempts were unsuccessful, but the pattern of the map remained that of an infarction. The QRS maps showed that in the first 48 hours recovery of potential was insufficient to distinguish those with successful thrombolysis. Early reperfusion could be detected by body surface potential mapping and the eventual damage predicted from the degree of change in the QRS map. Later reperfusion could be surmised but not quantified.

Electrocardiography↗
PubMed1993

Electrical current paths in acute pericarditis.

The electrocardiographic changes accompanying pericarditis consist of ST elevation in most of the leads of the 12-lead electrocardiogram. The source of this ST elevation is thought to be local inflammatory changes in the epicardium underlying the inflamed pericardium. The current from this area of ST elevation must return to some unaffected region of the heart and this should be associated with a region of ST depression. This current path from the external epicardial surface has been postulated to flow back into the endocardium through the great vessels and atria. To test this hypothesis, 18 patients with pericarditis were studied by body surface potential mapping and inverse epicardial potential distributions were computed. The resultant maps were compared to those of normal people and patients with acute anterior infraction. Epicardial maps from patients with pericarditis showed a region of current flow into the heart over the great vessels and atria in all 18 patients. This pattern was not seen in normal patients or infarction patients and was consistent with the mechanism resulting in ST elevation in pericarditis being one of current flowing from the epicardium out into the thorax and back into the heart through the great vessels and atria.

Acute Disease↗
PubMed1991

Mathematical modelling of flow through an irregular arterial stenosis.

A mathematical model of flow through an irregular arterial stenosis is developed. The model is two-dimensional and axi-symmetric with the stenosis outline obtained from a three-dimensional casting of a mildly stenosed artery. Agreement between modelled and experimental pressure drops (obtained from an axi-symmetric machined stenosis with the same profile) is excellent. Results are also obtained for a smooth stenosis model, similar to that used for most mathematical modelling studies. This model overestimates the pressure drop across the stenosis, as well as the wall shear stress and separation Reynolds number. Also, the smooth model predicts one instead of three recirculation zones present in the irregular model. The original stenosis is modified to increase the severity from 48 and 87% areal occlusion, while maintaining the same general shape. This has the effect of increasing the pressure drop by an order of magnitude and decreasing the number of recirculation zones to one, with a lower separation Reynolds number.

Arterial Occlusive Diseases↗
PubMed1990

Importance of the great vessels in the genesis of the electrocardiogram.

The electrocardiogram is the graphic representation against time of the difference in potential between points of the body caused by the current field of the heart. To examine the origin of this current field, a method of transforming body surface electrocardiographic data to the epicardial surface has been developed. The computed epicardial current density distributions in 219 patients with acute inferior myocardial infarction showed that, in 89% of patients, the current flow out of the heart during the ST segment came from two regions, not only from the infarction region but also from a region over the great vessels. This findings suggests that current flows from the ischemic region, through the low-resistance pathway provided by the intracavity blood, out the great vessels, and back to the epicardium. A similar pathway has been hypothesized when ischemia caused endocardial ST elevation, such as during a stress test or with unstable angina. To test this hypothesis, a group of patients with ST depression on the 12-lead electrocardiogram, not associated with ST elevation, was examined with body surface mapping. Ninety-four percent of patients had epicardial current density distributions that showed a region of current flow out of the heart and over the great vessels that was consistent with this hypothesis. This could explain the poor localization of coronary artery disease by electrocardiographic techniques when there is ST depression on the body surface.

Aorta↗
PubMed1990

The vascular resistance of arterial stenoses in series.

The vascular resistance of stenoses in series has been studied in vitro by use of fiber optic laser Doppler anemometry to measure the cross-sectional areas of the stenoses. Pressure gradients across each of the stenoses were measured while both the severity and the separation of the stenoses were altered. The individual resistances were compared with the combined resistance. Resistance at a stenosis is a nonlinear function of the severity of the stenosis. The resistance is a complex function of the perfusion pressure and the cross-sectional area of the stenosis and cannot be accurately predicted from a single plane angiographic image. With multiple stenoses an approximate assessment of the combined effect can be obtained by summing the value of the resistance for each stenosis but not the degree of the stenoses. The nonlinear relationship of resistance to stenosis severity means that if one stenosis is more severe than the other, the combined effect can be regarded as the same as the effect of the more severe stenosis acting by itself. The distance between the stenoses does not change their combined effect.

Arteries↗
PubMed1989

Prognostic significance of ST potentials determined by body surface mapping in inferior wall acute myocardial infarction.

Electrocardiographic body surface mapping on admission to coronary care has been shown to predict prognosis in a previous study of 100 patients with inferior wall acute myocardial infarction (AMI). A further 98 patients with first inferior wall AMI were now studied by body surface mapping on admission to coronary care to confirm that both the spatial distribution or map pattern of ST-segment potentials and the precise measurement of the maxima and minima are of prognostic significance. Each ST-segment map was compared by correlation coefficient to the average map pattern of the 4 groups derived in a previous study and placed in the group with the highest correlation coefficient. Analysis of these groups against outcome confirmed that the group dominated by a large area of marked anterior ST depression was associated with a high rate of complications and a significantly lower survival free of coronary artery bypass grafting (p less than 0.01). Patients in this group had more extensive and severe coronary artery disease than patients in the other groups. Increasing values of maximal ST depression correlated with mortality and complication rates. The extent by which the magnitude of ST-segment depression exceeded the magnitude of ST-segment elevation correlated with mortality and incidence of left ventricular failure. The results confirm the findings of the original study. Body surface mapping is of prognostic significance in inferior wall AMI.

Adult↗