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Biomedical subjects

J S Marshall

Publications and source records attributed to J S Marshall.

18 recordsLinked to original sources
PubMed1992

Dexamethasone induces a down regulation of rat mast cell protease II content in rat basophilic leukaemia cells.

Corticosteroids are widely used to treat severe allergic and inflammatory disease in which mast cells have been implicated as playing an important role. It has been previously shown that in vivo treatment with large bolus doses of corticosteroid can induce a down regulation of the number of IMMC in the rat. Previous in vitro studies of the RBL cell line have shown that culture in the presence of high doses of dexamethasone can induce an increase in cellular histamine content similar to that induced by other agents known to reduce the rate of cell division such as 5-hydroxyurea or sodium butyrate. In our studies the rat mucosal mast cell like cell line RBL-2H3 was cultured in the continuous presence of dexamethasone for periods of up to 4 weeks. Cell-associated histamine levels were found not to increase significantly at the doses of the corticosteroid we used. Of greater interest was the observation that levels of the mucosal mast cell specific protease RMCPII were dramatically reduced in these dexamethasone-treated cultures even at doses that might be considered to be physiologically relevant. This effect could be observed at 3 days after dexamethasone treatment and a continued reduction of RMCPII content was noted up to 4 weeks, at which time RMCPII levels were less than 5% of the control values in 10(-7) M dexamethasone treated cells. 5-Hydroxyurea did not reduce cellular RMCPII content even at a concentration which substantially reduced the rate of cell division and significantly increased cell associated histamine content.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Increased limb salvage with intraoperative and postoperative ankle level urokinase infusion in acute lower extremity ischemia.

Over a 30-month period (May 1988 to November 1990) 143 acutely ischemic lower extremities (126 patients) were treated with an aggressive surgical approach that included ankle level tibial-peroneal artery thromboembolectomy. Twelve lower extremities in 10 patients that remained ischemic were further treated with adjuvant ankle level urokinase infusion. Sixteen ankle level arteries in 12 extremities were infused with an intraoperative bolus (1 to 2) of urokinase (50,000 to 100,000 units). Continuous postoperative urokinase (25,000 to 50,000 units per catheter per hour x 1 to 5 days) was infused through ankle level arteriotomies in 10 extremities (14 arteries) that did not improve with the initial intraoperative bolus. Concomitant bypass grafting was necessary in four extremities. With adequate inflow established, adjuvant ankle level urokinase salvaged all 12 extremities. The mean increase in ankle/brachial pressure index was 0.84. During continuous postoperative urokinase infusion, lower extremity bleeding requiring blood transfusion occurred in four patients (50%). No deaths occurred in the operative period. Although rhabdomyolysis occurred in 90% of patients, no patients had renal insufficiency. The addition of ankle level urokinase delivery increased the potential limb salvage from 90% of the entire 143 extremities treated during this period to an actual limb salvage of 98%. A mean follow up of 13 months (6 to 36 months) identified one late amputation. Despite the demanding postoperative management required in these patients and the frequent need for early reoperation, the limb salvage obtained justifies this aggressive adjuvant technique in the management of the acutely ischemic lower extremity.

Aged↗
PubMed1992

Expression of nerve growth factor receptor immunoreactivity on follicular dendritic cells from human mucosa associated lymphoid tissues.

Nerve growth factor (NGF) was originally considered as a trophic factor for peripheral sympathetic and sensory neurones; however, recent reports indicate that NGF may induce proliferation of immune and haematopoietic cells. Histochemical studies conducted in human spleen and lymph nodes have suggested the presence of NGF receptor (NGF-R) immunoreactive elements in secondary follicles; however the nature of the cells bearing the NGF-R in lymphoid tissue has not been determined. In this paper we report the results of an immunohistochemical study conducted on mucosa associated lymphoid tissue. Using a specific monoclonal antibody to human NGF-R (mAb 20.4) we observed an NGF-R-immunoreactive population in all secondary lymphoid follicles examined. Double immunostaining revealed that this population was composed of follicular dendritic cells (FDC); lymphoid cells within the germinal centres did not appear to be 20.4 immunoreactive. Cell suspensions from tonsillar follicles also contained NGF-R immunopositive dendritic cells which were enriched by a 20.4 labelled magnetic bead procedure, revealing cells with the morphological characteristics of FDC. Mononuclear cells from human peripheral blood did not contain any NGF-R-immunoreactive elements using our techniques.

Adolescent↗
PubMed1979

Antihormone treatment of stage IV breast cancer.

The antiestrogen Tamoxifen (T), given orally to 113 patients with stage IV breast cancer, induced objective remission in 50%. Duration of remission in the first 39 patients, with minimum 27 months follow up, is 18 + months; these results are equal to those of surgical hypophysectomy. T prolonged survival in responders. Older age, previous response to endocrine therapy and positive estrogen receptors predicted response to T. T was effective in hypophysectomized patients in whom serum growth hormone and prolactin were undetectable, but serum ostrogens were present in low amount, suggesting a direct stimulatory effect of estrogens at the tumor level. Hypophysectomy induced further palliation after treatment with T, indicating that pituitary hormones may also play a role in the growth of some human breast cancers. Side effects from T were minimal. T is the initial treatment of choice for postmenopausal women with hormone responsive stage IV breast cancer.

Breast Neoplasms↗
PubMed1979

Transsphenoidal hypophysectomy in breast cancer: evidence for an individual role of pituitary and gonadal hormones in supporting tumor growth.

Transsphenoidal hypophysectomy was performed in 212 consecutive patients with metastatic breast cancer: 11 died within 30 days, two of surgical complications and nine of advanced metastatic disease. Two patients were unevaluable because of inadequate follow-up in one and simultaneous radiation treatment in the other. Of 199 evaluable patients 42% had an objective remission. Duration of remission averaged 18+ months with 10 out of 84 patients still in remission. Presence of estrogen receptors in the tumor significantly predicted response to hypophysectomy. Of 156 patients in whom completeness of hypophysectomy was assessed, 128 were thought to have a complete removal as shown by the fact that their growth hormone and prolactin were undetectable after stimulation with arginine or chlorpromazine, respectively. Of 26 patients in whom TRH test was performed, TSH and prolactin were undetectable in 20. Of 23 patients where autopsy was performed only six had microscopic pituitary tissue remaining. Hypophysectomy induced remission in eight of 15 patients who had previously responded and then relapsed to the antiestrogen Tamoxifen and in four of 17 who had failed. Conversely, antiestrogen therapy induced remission in six of 26 patients who had previously responded to hypophysectomy and in whom serum estrogens were present in small amount. These data indicate that both gonadal and pituitary hormones play a role in the growth of some human breast cancers.

Adult↗
PubMed1978

Preparation of glycopeptides and oligosaccharides from thyroxine-binding globulin.

Over 99% of thyroxine (T4), the major form of thyroid hormone in plasma, is bound to the plasma glycoprotein thyroxine-binding globulin (TBG). The carbohydrate composition of TBG (14.6% by weight) consists of mannose, galactose, N-acetylglucosamine, and N-acetylneuraminic acid in the molar ratios of 11:9:16:10 per mol of glycoprotein. No fucose or N-acetylgalactosamine were detected. Amino acid analyses were performed. Glycopeptides, prepared by exhaustive pronase treatment of the glycoprotein, were separated by gel filtration and ion exchange chromatography. All glycopeptides contained the four sugars present in the native glycoprotein. One-fourth of the glycopeptide fraction was resolved into a discrete component, glycopeptide I. The remaining glycopeptides were a mixture termed glycopeptides II and III. Glycopeptides II and III were resolved into two discrete carbohydrate units, termed oligosaccharides A and B, by alkaline-borohydride treatment and DEAE-cellulose chromatography. We propose that TBG contains four oligosaccharide chains as calculated from the molecular weights of the glycopeptides and from compositional data assuming 1 asparagine residue/glycopeptide. The carbohydrate structures of the glycopeptides and relative affinities of TBG, glycopeptides and oligosaccharides for hepatocyte plasma membrane binding are presented in the accompanying paper (Zinn, A.B., Marshall, J.S., and Carlson, D.M. (1978) J. Biol. Chem. 253, 6768-6773.

Amino Acids↗
PubMed1978

Serum inhibitors of desialylated glycoprotein binding to hepatocyte membranes.

Identification of the material present in human serum which is responsible for inhibition of binding of desialylated glycoproteins to rat hepatocyte membranes was accomplished by means of affinity chromatography using Sephadex to which the galactose-specific lectin, Ricinus Communis Agglutinin (RCAI) was covalently bound. RCAI-Sephadex was capable of extraction of virtually all of the inhibitory activity from cirrhotic serum. The RCA I-bound inhibitory activity could be eluted with 0.05 M D-galactose. The D-galactose eluate when subjected to radioimmunoelectrophoresis against a number of specific antibodies to human serum glycoproteins produced arcs corresponding to alpha 1-acid glycoprotein, alpha2-macroglobulin, IgG, IgA, and IgM. In another experiment putative terminal galactosyl groups of desialylated glycoproteins in the D-galactose eluate from cirrhotic serum exposed to RCAI-Sephadex were labelled with tritiated borohydride after treatment with galactose oxidase. Subsequent gel electrophoresis showed peaks of radioactivity throughout the area of the gel corresponding to protein molecular weights of the 19 S, 7 S, and 4 S classes. It thus appears that a heterogeneous population of desialylated serum glycoproteins accounts for the inhibition of binding of desialylated glycoprotein to the hepatocyte membrane and that these desialylated glycoproteins are present in small amounts in normal human serum and in greatly increased quantities in serum from patients with cirrhosis.

Animals↗
PubMed1978

Role of pituitary hormones in the growth of human breast cancer.

Hypophysectomy was performed in 28 women with Stage IV breast cancer who were treated initially with antiestrogens. Six of 13 patients who responded to tamoxifen and 2 of 12 who failed to benefit from tamoxifen obtained remissions from hypophysectomy. The remissions average 11+ months. Three of 8 patients treated initially with antiestrogens have responded to androgen therapy. The results suggest that hormones other than estrogen, which appears to play a major role, may be involved in stimulating the growth of some human breast cancers. Prolactin receptors were detectable in 51% of human breast cancers and were detected in both estrogen receptor-positive and -negative tumors. Preliminary clinical correlations suggest that prolactin receptors will not be useful in predicting response to antiestrogen therapy.

Breast Neoplasms↗
PubMed1977

Cell surface changes in diabetic rats. Studies of lectin binding to liver cell plasma membranes.

We have previously reported changes in the chemical composition of cell surface membranes in diabetic rats (Chandramoulis, V. and Carter, Jr., J. R. (1975) Diabetes 24, 257-262 [1]). To examine the possible implications of these changes for cell surface structures, we have measured the binding of labeled lectins and desialylated glycoproteins to plasma membranes prepared from the livers of streptozotocin--diabetic and control rats. Lectins were chosen which have affinities for different carbohydrate moieties. The binding of ricin and concanavalin A to liver cell membranes from the diabetic rats was significantly reduced, but no change in the binding of wheat germ agglutinin was noted. Binding of desialylated thyrozine--binding globulin, previously shown to be dependent on membrane sialic acid residues, ws strongly suggest that insulin deficiency leads to generalized changes in cell surfaced glycoproteins, at least in this animal model of diabetes.

Animals↗
PubMed1977

Treatment of breast cancer with antiestrogen: approach to medical hypophysectomy?

Tamoxifen (ICI 46474), an antiestrogen, was given to 89 selected patients with stage IV breast cancer at a dose of 20 mg orally every 12 hours. Forty-seven percent of the patients had objective tumor regression averaging 11+ months with 25 of 42 women still in remission. In the first 39 patients where the minimum follow-up period is 16 months the average duration of remission is more than 15 months with 8 of 19 patients still in remission. These results are approaching those of surgical hypophysectomy, where, in our experience the average remission lasts about 18 months. Thus, Tamoxifen is a highly effective antitumor agent and is probably the initial treatment of choice for women with hormone responsive breast cancer. Antiestrogen induced objective remissions in 5 of 19 patients who had previously responded to surgical hypophysectomy, and 5 additional patients showed no progression of disease lasting 15+ months. Estradiol and estrone were detectable in the serum of these patients whereas, prolactin and growth hormone were not detectable. Thus, antiestrogen can induce remissions in some patients in the absence of the pituitary gland, and this constitutes additional palliation and provides evidence that estrogens can directly stimulate tumor growth. Four of 7 patients who obtained remissions from Tamoxifen obtained further improvement from hypophysectomy, and 1 of 8 patients who failed to benefit from antiestrogen improved after hypophysectomy. These results suggest that prolactin and growth hormone may also play a role in stimulating tumor growth in some patients.

Animals↗
PubMed1976

Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.

It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility. Human TBG was purified by affinity chromatography, labeled under sterile conditions with 131I or 125I,, and mixed with [125I]thyroxine (T4) or [131I]T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +/-SD for TBG and T4 respectively, were as follows: Half time (t1/2) 5.3 +/- 0.4 and 7.0 +/- 0.6 days; distribution space (DS) 7.2 +/- 1.0 and 10.8 +/- 1.2 liters; and total daily degradation (D) 0.211 +/- 0.053 and 0.088 +/- 0.011 mumol/day. In all subjects, t1/2 of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the t1/2 and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration. A striking decrease in the t1/2 of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction. TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG t1/2 was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG. These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.

Adult↗
PubMed1976

Antiestrogen-induced remissions in stage IV breast cancer.

Tamoxifen (NSC-180973, ICI-46474), an antiestrogen, was administered to 39 women with stage IV breast cancer at a dose of 20 mg orally every 12 hours. Patients were selected as eligible for endocrine ablative treatment and with disease not so aggressive as to jeopardize further treatment in case the experimental drug failed. Objective remission was obtained in 19 patients (49%) with a mean duration of 11+ months and ten patients are still in remission. No progression was seen in seven patients (18%) lasting 13+ months with only one patient in relapse. Thirteen patients (33%) have failed. Objective remission was obtained in two premenopausal women even though menstrual cycles were not suppressed; bilateral oophorectomy in one of these patients induced a second remission after relapse from tamoxifen. Objective remissions were obtained in two women with proven complete hypophysectomy a direct action of antiestrogens at the tumor level. Positive estrogen receptors were suggestive of being a good predictor of response. Menopausal status and dominant site of metastasis did not affect the response to tamoxifen in this small series. Tamoxifen did not alter prolactin secretion, and side effects from the drug were usually mild and transient in nature. We conclude that tamoxifen is an effective antitumor agent in patients with stage IV breast cancer; further studies are necessary to determine whether it will equal the therapeutic effect of oophorectomy, adrenalectomy, and hypophysectomy.

Adrenalectomy↗
PubMed1975

Studies on human thyroxine-binding globulin (TBG). IX. Some physical, chemical, and biological properties of radioiodinated TBG and partially desialylated TBG.

Thyroxine-binding globulin (TBG) and partially desialylated or slow TBG (STBG) were purified from human serum by affinity chromatography. Purified TBG was identical to TBG present in serum by the criteria of electrophoretic mobility, affinity for thyroxine (T4), and heat-inactivation response. Purified STBG had slower electrophoretic mobility and lower affinity for T4. Both bound T4 in an equimolar ratio, were immunoprecipitable, and had similar inactivation t1/2 at 61 degrees C. TBG and STBG were iodinated by the chloramine-T-catalyzed reaction. An average of from 0.02 to 6 atoms I could be incorporated per molecule of the protein by adjusting the conditions of the reaction (time, protein and iodide concentrations). 125-I, 131-I, and 127-I were used. Iodination increased the anodal mobility of TBG but did not affect the reversible T4-binding, precipitation by antiserum, or the heat-inactivation properties. "Heavily" and "lightly" iodinated TBG had identical disappearance half-times from serum in the rabbit. 15 min after the intravenous administration of [131-I]-STBG and [125-I]TBG mixture to rats, more than 90% of the injected 131-I dose was in the liver, and the liver 131-I/125-I ratio was 32-fold that of serum. Selective uptake of STBG by the liver was also observed in the rabbit and in man. The serum [125-I]STBG/[131-I]TBG ratio declined from 1 to 0.2 in 10 min in the intact rabbit but remained unchanged for 1 h in the acutely hepatectomized animal. In the rabbit, t 1/2 was approximately 3 min for STBG and 0.8-3.4 days for TBG. The radioiodine derived from the iodinated proteins is partly excreted in bile but the bulk was precipitable with specific antibodies. Some isotope in the form of iodide appeared in blood and was excreted in the urine. Since radioiodinated TBG and STBG preserve their biologic and immunologic properties they are useful as tracer materials for metabolic studies. In rat, rabbit, and man STBG is rapidly cleared from serum by the liver. Conversion of TBG to STBG may be the limiting step in the regulation of TBG metabolism.

Animals↗