Biomedical subjects
Publications and source records attributed to S C Brooks.
One hundred consecutive patients treated in the resuscitation room of the Accident and Emergency Department at the Royal Infirmary of Edinburgh were studied and the results were compared with earlier surveys. Half the cases were medical emergencies, which suggests that this should be reflected in the training for specialists in accident and emergency medicine.
The effects of ionizing irradiation on the sedimentation coefficients of both estrogen receptor (ER) and progesterone receptor (PgR) have been examined in comparison to the effects of proteolysis. DMBA-induced rat mammary tumors were subjected to a treatment of 20 Gy and the ER and PgR concentrations were determined at different time intervals after irradiation. On a 5-20% sucrose gradient the ER sedimented as 9-11 and 4-5 S molecular forms, while PgR sedimented as a small 8-9 S peak and a major 4-5 S peak. Radiotherapy particularly reduced the 4-5 S sedimentation peaks of both receptors but did not initiate any new sedimentation forms. Although the 4-5 S ER receptor concentrations remained low, both progesterone receptor forms appeared to recover by 60 days after treatment. As these effects could be due to the release of proteolytic enzymes following irradiation of tumors, the receptors from untreated tumors were exposed to different concentrations of trypsin. The effects of trypsin were identical for ER and for PgR, and proved to be dependent on the trypsin concentration. Only concentrations of trypsin up to 30 micrograms/ml resulted in a reduction of 9-11 S ER or 8-9 S PgR forms which was accompanied by a simultaneous increase in the 4-5 S peaks, resulting in no change in total binding sites. Still higher trypsinization (300-3000 micrograms/ml) also reduced the 4-5 S ER and PgR fractions. In the presence or the absence of sodium molybdate, a stabilizer of the faster sedimenting forms of the receptor, no alterations were observed in the position of, or the total number of binding sites of, the sucrose gradient fractions from control or irradiated tumors. The irradiation effects appear to be due either to damage of the cytosolic ER receptor, thereby preventing its participation in the induction of de novo synthesis of ER and PgR, or to the non-specific damage of transcription and/or translation systems.
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Studies have been carried out which were designed to examine the hormonal requirement for the appearance of estrogen sulfotransferase activity in porcine uteri. Mature, ovariectomized (OVX) gilts were housed for 3 weeks before being treated with various regimens of estradiol-17 beta (E2) and progesterone (P). Uteri were then removed, minced, incubated for 2 h with [3H] E2 (10(-8) M) and Na2 35SO4 (10(-4) M) and the labeled metabolic products were extracted and analyzed. Endometrial samples were also taken for the determination of E2 and P cytoplasmic and nuclear receptors (R). It was found that 4 daily injections of 250 micrograms of E2 was sufficient to bring plasma E2 concentrations to that representative of a normal estrous cycle (approx. 30 pg/ml) and to induce cytoplasmic PR to high levels (7000--19000 fmol/mg DNA). Estrogen sulfotransferase activity, which was negligible in OVX and E2-treated pigs, increased to near normal secretory levels (4 pmol product/h per 0.4 g tissue) only in pigs primed with E2 and subsequently treated with E2 and P (25--250 mg/day, 3 days). This treatment also brought about the translocation of PR to the nuclear compartment. The steroid alcohol sulfotransferase activity in these tissues decreased upon ovariectomy and remained unaffected by the hormone treatments. Endometria from treated and untreated pigs were cultured for a period up to 7 days. During this time E2 (10(-8) M) induced and/or maintained PR and P (10(-6) M) was shown to stimulate estrogen sulfurylation concomitant with the translocation of PR to the nucleus. These studies have demonstrated that, in OVX pigs and endometrial cultures, P stimulated uterine estrogen sulfotransferase activity to a level normally found in secretory uteri. In order for P to bring about elevated levels of estrogen sulfurylation it was necessary that the endometrium contain adequate concentrations of cytoplasmic PR (which required E2 priming of the system) and the P receptor complex must display nuclear translocation.
A man with resistant lithium-induced nephrogenic diabetes insipidus and affective psychosis was successfully treated with carbamazepine. Carbamazepine may be appropriate for concurrently treating lithium-induced renal dysfunction and manic-depression in patients whose prognosis may be jeopardized by lithium discontinuation.
4-Nitroestrone 3-methyl ether has been shown to be an effective growth inhibitor of certain dimethylbenz(a)anthracene-induced rat mammary tumors in intact or ovariectomized rats. When administered at optimum levels (24 mg/kg daily), this A-ring-substituted estrone displayed no toxicity, slight estrogenicity, and an antitumor activity which was comparable to that of tamoxifen and nafoxidine and was surpassed only by ovariectomy or pharmacological doses of 17 beta-estradiol 3-benzoate. In addition, the appearance of mammary tumors was prevented when this estrogen derivative was administered to rats just prior to or after dimethylbenz(a)anthracene intubation. Unique to the action of the methyl ether of 4-nitroestrone on mammary tumors was the destruction of adenocarcinomas while permitting the appearance of fibroadenomas. Systemically, 4-nitroestrone 3-methyl ether brought about focal atrophy within the pituitary and ovaries while causing moderate hypertrophy of the uterus. Plasma prolactin was unaffected.
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Human breast cancer cells (MCF-7, maintained in long-term culture) contain separate estrogen receptors specific for either 17 beta-estradiol or estrone. Utilizing optimum conditions for the protamine sulfate assay, it has been possible to demonstrate both receptors in the 0.6 M KCl extract of nuclei and in the cytosol. Similarly, in the exchange assay, high-affinity low-capacity binding sites for 17 beta-estradiol and estrone have been found in the salt-extracted nuclear residue. Dissociation constants and binding capacities were determined for either receptor in the absence of the other [e.g., estrone receptor (E1R) in the cytosol or nuclear residue from 17 beta-estradiol-stimulated cells] or, when both receptors were present, a saturating amount of the other estrogen (unlabeled) was added to the assay mixture (e.g., the salt-extractable nuclear receptors). Specificity was demonstrated by the inability of estrone to compete with 17 beta-[2,4,6,7-3H]estradiol for the 17 beta-estradiol receptor (E2R) at molar excesses less than 10-fold. Likewise, there was no inhibition of [6,7-3H]estrone binding to its receptor by molar excesses of 17 beta-estradiol below 100-fold. Other steroid hormones were very weak competitors of [6,7-3H]estrone, even at 1000-fold molar excesses. The quantitative relationships of these two estrogen receptors were shown to fluctuate in the various cellular compartments following incubation (37 degrees) of MCF-7 cells with 10(-8) M 17 beta-estradiol. This level of 17 beta-estradiol elicited the translocation of all detectable cytosolic E2R to the nucleus, where, after an incubation of 1 hr, the salt-resistant 17 beta-estradiol disappeared and 40% of the extractable 17 beta-estradiol-binding capacity was lost (processed). Simultaneously, the E1R which remained in the nuclear residue appeared in the nuclear extract, and ultimately this receptor accumulated in the cytosol. The estrone-binding capacity (0.78 pmol/mg DNA) which appeared following the processing of E2R nearly equalled the loss of 17 beta-estradiol binding sites per cell (0.85 pmol/mg DNA). Concentrations of 17 beta-estradiol which elicited the greatest processing of E2R in these incubations brought about the appearance of maximum levels of E1R in MCF-7 cells. Considering these results in the light of data previously reported from this laboratory concerning the metabolic and ligand fate of 17 beta-[3H]estradiol in MCF-7 cells, processing would appear to involve the formation of E1R in the salt-resistant nuclear compartment followed by the accumulation of E1R in the cytosol.
There is debate about the most appropriate form of treatment for partial tears of the lateral ligament of the ankle, which are common after inversion injuries. A prospective trial of four forms of treatment was carried out. The forms of treatment used were: no treatment with only a minimal bandage, Tubigrip support, immobilisation in plaster-of-Paris, and physiotherapy. The end point was taken when the patient returned to work or had a low score on an objective clinical scale. Early mobilisation, with or without physiotherapy, was found to offer the most rapid return to functional activity. Patients who had had their ankle immobilised in plaster-of-Paris required more days off work and longer attendance at a follow-up clinic. Inversion injuries are common and cause absence from work and discomfort for the patient. These findings suggest that mobilisation with physiotherapy, although not practical for all patients, is the most satisfactory course of treatment.
Inversion injuries of the ankle are a common cause of referral and presentation to accident units. They impose a load on radiographic services. A prospective trial was carried out to determine the accuracy of clinical examination. All patients were assessed clinically then examined radiographically, the clinical assessment missed 5% of the fractures. These, however, were all minor avulsion fractures or crush fractures and Tubigrip support was sufficient. Clinical examinations is, therefore, accurate and the need for most x-ray examination is questionable. X-ray examination should be reserved for patients with continuing pain or those who clinically have a fracture requiring immobilisation. This would produce a large saving in NHS resources.
The levels of estrogen (E2R) and progesterone (PgR) receptors in 165 breast tumor biopsies have been determined. Seventy-seven percent of the specimens contained significant levels of E2R; 38.2% were positive for both receptors. Only four tumors displayed the unusual E2R=/PgR+ pattern. Tumors from pre- and postmenopausal patients had similar receptor characteristics. Two-thirds of the six patients with E2R+PgR+ tumors responded to hormonal therapy, whereas only 28.7% of the E2R+/PgR- tumors regressed after similar treatment. These data from a limited number of patients indicate that the presence of E2R and PgR in breast tumor biopsies is of higher prognostic value for response of the patient than in the presence of E2R alone.
Patients with estrogen receptor (E2R)-positive breast cancers experience a longer disease-free interval and longer survival following primary surgery than do patients with E2R-negative tumors. The presence of E2R is correlated with patient age at diagnosis and tumor grade but not with the presence of metastatic foci in axillary lymph nodes. The difference in the rates of recurrence between E2R-positive and negative tumors is greater in pre- and perimenopausal patients than in postmenopausal patients.
We reviewed 89 patients with disseminated breast cancer who had at least one valid estrogen receptor (ER) assay and who underwent one or several trials of chemotherapy. The responses were assessed by two independent extramural reviewers. Of the 89 patients, 81 were evaluable; 28 of 36 (77.8) ER-positive (ER+) and 28 of 45 (60.7%) ER-negative (ER-) tumors reached at least one remission. Of patients who had received Adriamycin-containing therapy, 13/20 (65%) ER+ and 12/34 (35.3%) ER-tumors experienced a remission . ER+ breast cancer tends to respond better to Adriamycin-containing combinations than ER-negative tumors. This study does not support the thesis that lack of estrogen receptor in breast cancer predicts favorable for response to chemotherapy.
Patients with ER positive primary tumors usually have initial metastases at the more favorable sites. Twelve out of 14 patients with ER positive had first site of metastases in either bone or soft tissue. In contrast, 13 of 17 patients with negative ER developed first metastases in viscera. ER positive patients respond better to endocrine therapy and survived twice as long as negative ER patients from the onset of recurrent cancer until death. ER content is not a sufficient criterion for the prediction of the response to endocrine manipulation but serves as useful supplementary information to clinical judgement in to selection of systemic therapy. Prior employment of radiation therapy or the administration of hormones or antihormones, as well as inadequate tumor cells in the specimen and poor procurement of the tumor, can produce spuriously low ER. A protocol to study simultaneous endocrine and chemotherapy in comparison to the sequential approach of endocrine treatment followed by chemotherapy in ER positive patients is desirable.
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Estrogen receptors (ER) were present in tumor specimens from 29 of 34 cases of male breast cancer. There was a significant negative correlation of ER concentration with age. The quantity of ER tended to correlate directly with progesterone receptor levels, disease-free interval, and response duration among responders, but not to a statistically significant extent. In 13 patients for whom response data were available, no significant correlation was observed between ER levels and either frequency or duration of orchiectomy response. Among the six patients with tumor ER levels of less than 30 fmol per mg of protein, however, only two brief responses to orchiectomy occurred that were of little clinical benefit, while three of seven patients with higher ER responded more favorably. Thus, although this suggests that a relationship between low ER and unfavorable orchiectomy response may emerge as more patients are studied, currently available data do not justify basing therapeutic intervention on ER status of a biopsy in a manner analogous to that used for female breast cancer. Nine of 14 male breast cancer patients had positive progesterone receptor assays and several had androgen or glucocorticoid receptors. Tissue from only three of ten men with gynecomastia had measurable ER, and these were limited to the 4S component on sucrose gradients.
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