Biomedical subjects

G D Thomas

Publications and source records attributed to G D Thomas.

At least 19 recordsLinked to original sources

PubMed1991

Optimal tumor targeting by antibodies: development of a mathematical model.

A mathematical model has been developed to optimize tumor targeting with labeled antibodies. The model is compartmental and nonlinear, incorporating saturable binding. Published parameter values have been used in the model, and the resulting stiff differential equations have been solved using FACSIMILE, a computer package that can simulate very stiff differential systems. Results show that successful tumor targeting depends on an optimal combination of antibody dose, affinity, and molecular size. The model has allowed an assessment to be made of the complicated and interrelated dynamic relationships that these factors have on tumor targeting. It has also offered an explanation for previously unsatisfactory results from tumor targeting with labeled antibodies. The structural identifiability of the model parameters is also analyzed and it is shown that, with the prior knowledge of some parameters which is likely in practice, the remaining model parameters are uniquely identifiable.

Algorithms↗

PubMed1991

Developmental sites and relative abundance of immature stages of the stable fly (Diptera: Muscidae) in beef cattle feedlot pens in eastern Nebraska.

A 3-yr study was done to determine where and at what relative frequency stable fly, Stomoxys calcitrans (L.), immatures develop in beef cattle feedlot pens and the relationship of stable fly immature versus adult sample densities. Pens within feedlots were divided into five areas (the feed apron, back fence, side fences, mound, and the general lot); from each area, three core samples were randomly taken weekly. In 1986 and 1987, the feed apron yielded the most immature stable flies (62.5%). The mound and side fences yielded a significant percentage of flies (24.6 and 8.4%, respectively). There was a strong correlation (overall r = 0.86) between numbers of immatures and numbers of adults 2 wk later. In 1988, a drought year, low numbers of immatures were collected, and only one correlation between numbers of immatures and adults was significant. In all 3 yr, sample densities of stable fly immatures peaked and began to decline by midseason. Waste management along the feed apron and mound areas could significantly reduce stable fly populations. Sampling immatures from these areas could permit prediction of adult numbers.

Animals↗

PubMed1991

Chemical sympathectomy alters the development of hypertension in miniature swine.

To determine if the neurotoxin 6-hydroxydopamine could be used to chemically sympathectomize neonatal miniature swine, eight newborn swine were treated with 6-hydroxydopamine beginning on the first day after birth and continuing at regular intervals for the next 6 months. Six littermates served as controls and received vehicle injections. A significant reduction in the pressor response to intravenous tyramine (95%) and in the tissue norepinephrine content of the kidneys, left ventricle, and gastrocnemius muscle (more than 93%) provided evidence for an effective long-term sympathectomy in the 6-hydroxydopamine-treated animals. In addition, the blood pressure response of these young, chemically sympathectomized swine to chronic deoxycorticosterone acetate treatment was evaluated. Mean arterial pressure before deoxycorticosterone was similar in the 6-hydroxydopamine-treated (116 +/- 2 mm Hg) and control (125 +/- 5 mm Hg) groups. One week after deoxycorticosterone, mean arterial pressure had risen significantly by 20-22 mm Hg in both groups. Blood pressure continued to increase in the control group, reaching a value of 163 +/- 6 mm Hg by the third week after treatment. In contrast, mean arterial pressure in the 6-hydroxydopamine group did not increase further during weeks 2 and 3 after deoxycorticosterone. In conclusion, chronic treatment of neonatal swine with 6-hydroxydopamine produced an animal model with an effective, general, peripheral sympathectomy. The significant attenuation of the hypertensive response in these sympathectomized animals lends further support to the hypothesis that an intact sympathetic nervous system is necessary for the full expression of deoxycorticosterone hypertension in miniature swine.

Animals↗

PubMed1991

Acute renal function in chronically sympathectomized deoxycorticosterone acetate-treated miniature swine.

We recently validated a swine model in which chronic treatment with 6-hydroxydopamine (6-OHDA) produced an effective sympathectomy. These sympathectomized swine demonstrated a significantly attenuated hypertensive response when treated with deoxycorticosterone acetate (DOCA). Because renal nerve activity is elevated and important in controlling renal function and blood pressure in the DOCA swine model, we wanted to study the effect of chronic sympathectomy on acute renal hemodynamics and tubular function. Kidney function was assessed in 14 DOCA-treated miniature swine, 8 of which were sympathectomized by chronic treatment with 6-OHDA, while 6 served as controls. Effective renal sympathectomy in this model has been previously confirmed by a significant reduction (97%) of norepinephrine in renal cortical tissue. When anesthetized, mean arterial pressure and renal blood flow were similar between the two groups. Glomerular filtration rate was lower by 43%, urine flow rate by 71%, sodium excretion by 66%, and potassium excretion by 48% in the 6-OHDA DOCA animals. All of these parameters were significantly different from the intact DOCA controls. These results indicate that anesthetized, chronically sympathectomized swine exhibit decreased renal excretory function. The changes in renal function may have been due to the development of a tubular or glomerular supersensitivity to circulating antinatriuretic factors, since the 6-OHDA group had a 28% greater pressor response to the alpha-agonist phenylephrine and a significantly greater fall in mean arterial pressure in response to alpha-blockade with prazosin when compared with the controls. These changes in renal function may also explain why the 6-OHDA animals demonstrated a slight increase in mean arterial pressure in response to DOCA. Because acute renal denervation in DOCA-treated swine produces a diuresis and natriuresis, this study affirms that there may be important functional differences in acutely versus chronically denervated kidneys for which the implications under normal physiologic conditions are unknown.

Animals↗

PubMed1990

Renal denervation decreases blood pressure in DOCA-treated miniature swine with established hypertension.

The role of renal sympathetic nerve activity (RSNA) in the maintenance phase of essential hypertension has not yet been clearly defined. Renal function and mean arterial pressure (MAP) were studied in four Yucatan miniature swine (YMS) with established DOCA hypertension prior to and for 3 weeks after surgical renal denervation (RDX). During the first week post-RDX, MAP decreased from 141 /+- 6 to 121 +/- 3 mm Hg (P less than .05), while sodium balance increased from 0.32 +/- 0.05 to 0.95 +/- 0.14 mEq/kg/day (P less than .05). By 3 weeks post-RDX, MAP remained below normotensive levels while sodium balance returned to the pre-RDX value. There was no significant change in potassium or water balance after RDX. Thus, in DOCA-YMS the renal nerves are important in the maintenance of hypertension. The reduction in MAP with RDX in the absence of a natriuresis suggests a role for renal afferent nerve activity.

Analysis of Variance↗

PubMed1990

Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts.

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

Adenosine Triphosphate↗

PubMed1990

Effects of 6-hydroxydopamine in hypertensive adult miniature swine.

To validate a miniature swine model of sympathectomy, six swine that had chronic high blood pressures for unknown reasons and five DOCA hypertensive swine were treated with a single dose of the neurotoxin 6-hydroxydopamine (6-OHDA) (50 mg/kg i.v.). One week after 6-OHDA, conscious mean arterial pressure (MAP) had fallen by 47-49 mmHg and the pressor response to tyramine was attenuated in both groups. Norepinephrine content was significantly decreased in the kidneys (greater than 85%) and left ventricle (greater than 94%) in both 6-OHDA treated groups. These results indicate that 6-OHDA can be used to effectively sympathectomize adult swine. Chemical sympathectomy of swine with either unexplained high blood pressure or experimentally induced DOCA hypertension resulted in an equivalent fall in MAP in both of these populations. Further studies using 6-OHDA in miniature swine may help to elucidate the mechanisms involved in maintaining hypertension in this animal model.

Animals↗

PubMed1990

Theoretical considerations for improving tumour targeting.

To determine the relative importance of factors influencing tumour uptake of antibodies, we used a mathematical model to simulate intravenous injection of substances of varying molecular sizes and tumour-binding affinities at several dose levels. The FACSIMILE program was used to simulate the time course of tumour uptake of the tumour-binding substance by calculating the instantaneous tumour content (TC) and tumour:background uptake ratios (UR). Relative total doses to tumour and normal tissue were calculated by integration of TC/time curves. The model was used to make theoretical predictions on the effects of altering different parameters. The size of the injected dose in relation to the number of tumour receptors was crucial:if too low, uptake could not be improved by manipulating other variables, and if too high, the UR for large binding molecules was reduced. Using the standard scanning dose of labelled antibody, absolute numbers of labelled molecules binding to tumour could be increased by injection of a large excess of unlabelled molecules. Given an adequate dose, peak tumour content increased with increasing affinity up to receptor saturation. The peak uptake ratio rose progressively with affinity for a small ligand, but reached a relatively low plateau for antibody due to constant high background levels. At low doses such as those currently administered for diagnostic scanning with antibody, no effect of increasing affinity was predicted.

Antibodies, Monoclonal↗

PubMed1989

Effect of dose, molecular size, affinity, and protein binding on tumor uptake of antibody or ligand: a biomathematical model.

A mathematical model has been developed to determine the best approach to improving tumor targeting with antibody. The amount of antibody in the tumor (tumor content) and the tumor:normal tissue antibody concentration ratio (uptake ratio) were calculated over 12 days from injection, using the computer program FACSIMILE to solve the stiff nonlinear differential equations describing the system. Results indicate that success requires an optimal combination of dose, size, and binding affinity of antibody. Increasing the dose to 100 times that presently used for scanning increased both the percentage of injected antibody in the tumor and the uptake ratio by up to 2 orders of magnitude to maximal values determined by affinity. This result could be achieved by coinjecting unlabeled antibody. Increasing affinity from Keq = 10(9) to 10(13)M-1 increased the uptake ratio from 5 to 100 for whole antibody and to 550 for a small ligand, at the calculated optimal dose, but had no effect at the current scanning dose. With decreasing molecular size at average affinity, the same maximum tumor content and uptake ratio were achieved but progressively earlier. At high affinity there was a substantial advantage for a small ligand compared with whole antibody in terms of uptake ratio (550 versus 100) and tumor:normal tissue integral dose ratio (330 versus 60). The uptake of a small ligand was not increased by binding to plasma protein but with increasing time the tumor content was higher than without protein binding.

Animals↗

PubMed1988

Response rates and survival in patients with head and neck cancer treated with a combination of cisplatin and 5-fluorouracil prior to radiotherapy.

Fifty-three previously untreated patients with advanced head and neck cancer were given courses of cisplatin and 5-fluorouracil prior to radical radiotherapy. The overall response rate to chemotherapy alone was 66% but only two cases achieved a complete response. After radiotherapy, 62% were in complete remission but there was no evidence for improved overall survival when compared to historical data. Patients who responded to chemotherapy had a significantly better chance of achieving a complete remission after radiotherapy, and had a significantly improved survival when compared to non responders to chemotherapy, including those whose disease disappeared after radiotherapy. The survival data compare favourably with other series claiming higher complete and partial responses to the same combination of drugs.

Adolescent↗

PubMed1988

Quality assessment in cervical cytology: a pilot study.

A pilot study of an external quality assessment scheme was run between February 1985 and September 1986 to (i) assess the feasibility of running one from a district general hospital; (ii) to estimate the time required to organise and run it with a computer; (iii) to provide sound statistical results with which future schemes could be compared. Seven laboratories participated, and the 20 smears selected from each laboratory were circulated in three rounds in batches of seven, seven, and six according to a prearranged order. Results analysed using the kappa statistic showed moderate levels of interlaboratory agreement, with complete agreement emerging only on a small proportion of cases.

Computers↗

PubMed1987