Biomedical subjects
Publications and source records attributed to W F Coulson.
A case of gastric teratoma in a newborn is presented. Ten months after removal of the teratoma, peritoneal gliomatosis was discovered incidentally in inguinal hernia sacs. This is the first report of an association between peritoneal gliomatosis and a teratoma other than ovarian.
The brain metabolism of glutamate and gamma-aminobutyrate (GABA) was investigated in thiamin-deficient and pair-fed control rats, in order to determine whether the GABA shunt may provide an important alternative to 2-oxo-glutarate dehydrogenase (EC 1.2.4.2) in energy-yielding metabolism in thiamin deficiency. Brains from thiamin-deficient animals contained less glutamate, 2-oxo-glutarate and GABA than those from control animals. The brain content of ATP was unaffected by thiamin deficiency. After intracerebroventricular injection of [14C]glutamate, the specific radioactivity of GABA in the brains from deficient animals was 45-50% higher than that in controls, suggesting a considerable increase in the metabolic flux through the GABA shunt in thiamin deficiency. Brain GABA showed a marked circumannual variation, with a peak in mid-summer and a minimum value in mid-winter.
Explore the source record for details and available documents.
The staging and histologic cell type of patients in the Lung Cancer Study Group (LCSG) clinical trials program are reviewed and confirmed or resolved at the reference center for anatomic and pathologic classification of lung cancer. A high level of consistency in classification has been achieved through the use of criteria that minimize intraobserver variability. The data obtained from the review project have been used to characterize the relationship of disease extent and cell type to survival in the clinical trials population. Survival characteristics were generated for 1,121 patients who underwent apparent complete resection of nonsmall cell lung cancer and were subsequently entered into various protocols to receive either adjuvant treatment or no further therapy. The end results study provides some insight regarding the biological behavior of squamous cell carcinoma and adenocarcinoma of the lung in terms of the anatomic extent of disease at the time of apparent complete resection. Patients with squamous cell carcinoma had an outcome superior to that of patients with adenocarcinoma in every TNM subset. The differences in survival according to these major cell types were significant overall and in the T1 N0, T1 N1, and T2 N1 subsets but not in the TNM subsets in stage III disease. Histologic cell type and extent of disease are important factors in survival expectations; thus the accuracy and reproducibility of these classifications plays a significant role in the evaluation of differing modalities of treatment.
Vitamin B6 deficient female rats showed a significantly earlier, greater and more prolonged uptake of a tracer dose of [3H]oestradiol into the uterus, with increased nuclear accumulation, compared with vitamin B6 supplemented animals. This was most marked at oestrus, with little difference at anoestrus. The responses to low doses of ethynyl-oestradiol were greater in ovariectomized deficient animals than in those receiving the supplemented diet, with an increased uterotrophic response and greater induction of peroxidase. In the deficient animals there was virtually complete suppression of LH secretion at doses of ethynyl-oestradiol that had no effect in controls. At high doses of ethynyl-oestradiol there was no difference between the two groups of animals. The results suggest that increased uterine uptake and accumulation of [3H]oestradiol in vitamin B6 deficiency is associated with enhanced end-organ responsiveness to sub-maximal oestrogen stimulation, and that pyridoxal phosphate may have a coenzyme role in oestrogen action.
The chemical synthesis and characterization, including 1H NMR, of 16 alpha-iodo-androstenedione and 16 alpha-iodo-testosterone are described. Each has been synthesized with 125I and tested in rats in vivo for accumulation in androgen dependent tissues over a 24 hr time course. Neither compound was accumulated in prostate against the blood gradient of normal or 24 hr castrate animals. The metabolism, subcellular distribution and binding of 16 alpha-[125I]iodo-testosterone to protein in prostate has also been examined. By comparison with data obtained after the administration of [3H]testosterone we conclude that the failure of this iodinated androgen to accumulate in androgen dependent tissues arises because of its low binding affinity for receptor protein.
16 alpha-Iodo-oestradiol binds with high affinity to the oestrogen receptor and has been shown to accumulate in oestrogen sensitive tissues in many test systems. We have prepared the compound labelled with 131I at four specific activities. Using these preparations we have attempted to image human primary and metastatic breast cancer deposits at various times from 15 min to 24 h post injection by external gamma scintigraphy. Clinical studies were conducted on 10 post-menopausal patients. The receptor status was determined in seven cases, four were positive and three negative. The imaging results were very poor, in only two cases were images obtained, these were very faint and only of the primary, never of the metastatic deposits. The oestrogen receptor status was only available in one of these cases, it was positive. Dynamic studies in vivo revealed that the compound is cleared rapidly from the circulation during the first 5 min and thereafter undergoes extensive enterohepatic recycling. Studies of the radiochemical identity of the circulating species revealed that the injected compound was extensively metabolised. Neither an increase in specific activity of injected radiotracer nor imaging at shorter times after injection improved the results.
Female strain A/J mice were exposed to 0.31 ppm (608 micrograms/m3) ozone continuously for 103 h every other week for 6 mth. Following an additional period of 5 mth in a filtered air environment, animals were killed and examined for evidence of altered spleen weight. It was observed that animals exposed to ozone had a greater spleen weight, and spleen to body weight ratio than air-breathing controls. In some of the ozone-exposed mice, pronounced splenomegaly was noted. Increased spleen weight appears to be another example of an extrapulmonary effect of ozone inhalation.
Inbred strain A/J mice, responsive to the chemical induction of pulmonary adenomas, were used to assess any of several roles that the photochemical air pollutant ozone might play in lung carcinogenesis. In separate experiments, animals were exposed to two concentrations of ozone (0.31 +/- 0.01 and 0.50 +/- 0.02 ppm) intermittently for a 6-month period, to evaluate the potential of ozone to act as either a pulmonary carcinogen, a tumor promoter, or an inhalant capable of increasing lung tumor yield when exposure was in conjunction with a pulmonary carcinogen, urethane. Statistical analyses of results indicated that ozone exposure at both concentrations caused an increase in lung tumor number relative to clean air controls, but that ozone was not an effective tumor promoter under the conditions of our protocol. When ozone exposure immediately preceded treatment with urethane (CAS: 51-79-6), animals were at increased risk for the development of lung adenomas.
An intrinsic defect in the aortic media in six patients with Marfan's syndrome, who died of cardiovascular complications of the disease at an average age of 32 years, has been delineated by correlated morphologic, biochemical, and mechanical studies. The findings in the Marfan aortas have been compared with those in age- and sex-matched controls, who died of unrelated diseases without significant aortic lesions, and in three patients with dissecting aneurysms of non-Marfan origin. The results showed that there was a significant reduction in the tensile strength of the aorta in Marfan's syndrome. This finding was correlated by scanning electron microscopy with structural alterations of the medial elastic fibers, including enlarged interlaminar spaces and loss of interlaminar elastic fibrils. No structural alterations were identified in collagen fibers. Biochemical analyses of the aortic media revealed a substantial reduction in aortic elastin content. Furthermore, the desmosine content of the isolated elastin was reduced by approximately 50%. No changes were detected in the composition or solubility of the medial collagen. In contrast to Marfan aortas, the elastin and collagen contents of the dissecting aneurysms of non-Marfan origin were similar to those of the controls. These findings suggest that the vascular complications in Marfan's syndrome may be based on a genetic abnormality affecting elastin fibrillogenesis.
Six-week old male rats were maintained for 4 weeks on a vitamin B6-free diet to cause a moderately severe degree of vitamin B6 depletion. This led to a significant reduction in the circulating concentration of testosterone in plasma (control = 8.36 +/- 1.68, deficient = 2.13 +/- 0.54 nmol/l), but had no effect on circulating concentrations of luteinizing hormone, or, in intact males, on the weight of the prostate relative to body weight. In both intact and 24-h castrated animals vitamin B6 deficiency resulted in a significant increase in the uptake of [3H]testosterone into the prostate, and both increased and prolonged the specific nuclear retention of the steroid, as assessed by the ratio of radioactivity in the nuclear pellet: the high speed supernatant fraction. The results suggest that vitamin B6 has a function in the action of testosterone (and other steroid hormones), possibly in the recycling of receptors from the nucleus back into the cytosol after initial translocation. Vitamin B6 deficient animals have either a reduced rate of synthesis of testosterone or an increased rate of metabolic clearance compared with vitamin B6 supplemented controls, and this appears to be associated with enhanced target organ response to the hormone.
Explore the source record for details and available documents.
Clinical and histological correlates of survival in patients undergoing complete resection of pulmonary metastases from nonseminomatous testicular carcinoma were determined in 25 Stage C patients aged 17-38 years treated from 1969-1978. All patients had orchiectomy and retroperitoneal lymphadenectomy. Nineteen patients received combination chemotherapy before resection, and all received chemotherapy after resection. Three patients had four additional thoracotomies for pulmonary recurrence. Survival was measured from time of first thoracotomy to time of last followup or death. Actuarial survival for the entire group at one, two, and five years was 80, 63, and 59%, respectively. Median follow-up of the survivors was 3.5 years. Patients in low tumor burden groups such as those with no tumor in retroperitoneal nodes, with unilateral metastases, or with single metastases had better prognosis, as did patients whose primary tumors were moderately well differentiated. Characteristics of pulmonary metastases that favorably influenced the prognosis were the presence of mature teratoma, presence of few mitoses, lack of mononuclear infiltrate, and lack of desmoplastic response. These findings confirm the effectiveness of multimodality therapy which includes the resection of pulmonary metastases for Stage C nonseminomatous carcinoma of the testes. In addition, they suggest that consideration should be given to the stratification of prospective clinical trials on the basis of tumor burden and histologic characteristics of the primary and metastatic lesions.
Rats were depleted of vitamin B6 by treatment with isoniazid, and then maintained on diets providing: no vitamin B6, an adequate amount (1.2 mg/kg diet) or a very large amount (120 mg/kg) for 5 weeks. The uptake of a tracer dose of [3H]-oestradiol into the nuclei of liver and uterus was significantly greater in deficient animals than in those receiving an adequate or greater than adequate amount of the vitamin. Similarly the accumulation of oestradiol in the region of the brain corresponding to the hypothalamus, pre-optic area and septum (the major oestradiol-sensitive regions of the central nervous system) was higher in deficient animals than in other groups. There were significant inverse correlations between the uptake of oestradiol into target tissues and vitamin B6 nutritional status as determined by the concentrations of pyridoxal phosphate in plasma and liver. Uteri from deficient animals were significantly smaller than those from animals receiving an adequate or greater amount of vitamin B6, and the induction of uterine peroxidase by oestradiol was impaired. It therefore seems likely that despite the greater net accumulation of steroid in target tissues, vitamin B6 deficiency impairs biological responsiveness to oestrogens. It is suggested that this may be due to a failure of the recycling of oestradiol receptors from the nucleus.
Antisera for the radioimmunoassay of pregnanediol glucuronide have in the past been raised against immunogens in which the carboxyl group of the glucuronide has been attached to the protein. Such antisera do not discriminate well between the glucuronide and the unconjugated steroid. In order to increase this discrimination we have synthesized an immunogen in which the triacetoxy methyl ester of pregnanediol glucuronide is attached to the protein by a 6 beta-hemisuccinoxy bridge. This immunogen was then deprotected to expose the glucuronide. In one group of rabbits deprotection was achieved in vivo simply by injecting the immunogen. In a second group the immunogen was selectively hydrolysed prior to immunization. The antisera raised against these immunogens possessed high affinity and discriminated well between the free steroid and the steroid glucuronide.
The benign to malignant ratio (B:M ratio) among breast biopsies (number of benign breast lesions divided by number of breast cancers) is widely believed to be around 4:1 or 5:1. This belief appears to be based upon experience from the 1950's and 1960's. We investigated possible reasons for the current wide variability of the B:M ratio. A straight line relationship between the log B:M ratio and age exists in our data. The B:M ratio is sensitive to racial differences between patient groups but in only minimally affected by varied histologic inclusion criteria. The overall B:M ratio should not be used to counsel women about their breast cancer risk at the time of biopsy. Age-specific B:M ratios provide a more realistic risk assessment.
Monoclonal and rabbit antibodies raised against estrone-3-glucuronide and pregnanediol-3 alpha-glucuronide have been studied with respect to their ability to bind free estrone and its conjugates or free pregnanediol and its conjugates, respectively. High titre and high specificity were observed with monoclonal antibodies produced against pregnanediol-3 alpha-glucuronide, whereas the monoclonal antibodies produced against estrone-3-glucuronide were not so specific when compared with the corresponding rabbit antibodies. Both monoclonal and rabbit antibodies had affinity constants in the range of 10(9)--10(10) liter/mole.
Explore the source record for details and available documents.