Methotrexate in psoriasis: revised guidelines.
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Biomedical subjects
Publications and source records attributed to R Auerbach.
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Adult splenocytes from BALB/c mice, labeled with a monoclonal antibody directed against the L3T4 (CD-4) differentiation antigen, were sorted to obtain pure suspensions of this T-cell subset. When inoculated intradermally into irradiated, semi-allogeneic adult animals these cells were found to be the effector cells responsible for the lymphocyte-induced angiogenesis. The experiments demonstrate that the CD-4 lymphocyte subset is primarily or entirely responsible for this immune-mediated elicitation of the host neovascular reaction.
Ovarian neoplasms of the pure neuroectodermal type, although quite rare, have recently been described. Lesions of similar histology in the central nervous system have previously been shown to contain estrogen and progestin receptors. A patient with a pure ovarian ependymoma is presented. The tissue was rich in estrogen and progestin receptor protein, containing 17 femtomoles of estrogen receptor per milligram cytosol protein and 80 femtomoles of progestin receptor per milligram cytosol protein. The case is used to illustrate the possible influence of hormonal manipulation in the management of this rare gynecologic neoplasm.
More than a century ago, Fuchs recognized that although tumors varied in their propensity for metastasis, there was, as well, discrimination in the different organs of the body, some providing a more fertile soil for growth for specific tumors than others. Paget dramatized this clear distinction between the intrinsic properties of the cancer cell and the properties of the host when he expanded on the analogy between tumors and plants: "When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil." Paget is almost apologetic as he contrasts the work of those that study the 'seed' to his own work on the 'soil': "The best work in the pathology of cancer is done by those who...are studying the nature of the seed. They are like scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observations of the properties of the soil may also be useful." In a time where the primary emphasis in cancer research is at the level of gene expression, of regulation and of epigenetic modification of the "seed," those individuals, such as Pauli and Lee, who study the properties of the host environment should not be ignored. Not only are the observations of the 'soil' useful, they provide essential information without which we will not be able to understand the nature of the metastatic process.
We have compared the rate and extent of adhesion of various types of mouse tumor cells to endothelial cells derived from different organ sources. Our panel of tumors has included sarcoma, bladder carcinoma, glioma, teratoma, hepatoma, endothelioma, mammary adenocarcinoma, and lymphoma cells. Endothelial cell monolayers have included murine microvascular endothelial cells from ovary, brain, lung, and liver as well as large vessel endothelium from thoracic duct and dorsal aorta. Tumor cells differ both in the adhesive propensity and adhesive preference for different endothelial cells. Some, but not all, of the adhesive preferences correlate with the known in vivo metastatic behavior of these tumors. Our results support the hypothesis that endothelial cell surface-associated specificities may play a significant role in determining the pattern of metastasis.
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The embryonic yolk sac is the first site in the mammalian embryo in which cells are found that can carry out cell-mediated immune functions, yet the relation of cells of this primitive hematopoietic organ to the development of the mature immune system has not been established. We have initiated a series of experiments to determine the potential of cells of the mouse yolk sac to differentiate in vitro, in order to get an insight into the development of immunocompetence in this primary population of hematopoietic stem cells. The present paper describes the conditions promoting stem-cell differentiation and provides an initial characterization of cell surface phenotypes of the cell lineages established in vitro. Yolk sac cells obtained from 10- to 13-day mouse embryos were maintained in culture for more than 18 months, giving rise to a variety of cell types belonging to the hematopoietic lineages and culminating in the establishment of long-term cell lines. Supernatants of secondary mixed leukocyte cultures were found to be an effective source of growth factors promoting the initial differentiation as well as the maintenance of these cells. Flow-cytometric analysis showed that, in contrast to freshly obtained yolk sac cells, which had no detectable Thy 1 antigen, cells expressing significant levels of Thy 1 were obtained after 1 week or more of culture. Ly1 and Lyt 2 antigens were detected only rarely and the L3T4 (GK 1.5) antigen was never expressed.(ABSTRACT TRUNCATED AT 250 WORDS)
Microvascular endothelial cell cultures have been established from mouse lung, liver, brain, heart, placenta, kidney, urinary bladder, mammary gland, ovary and epididymal fat pad. In addition, large vessel endothelial cells have been obtained from the mouse aorta and thoracic duct. The heterogeneity of these cells has been shown by flow cytometric determination of angiotensin-converting enzyme, by differential presence of the acetyl low density lipoprotein receptor, by the variable expression of cell surface antigens, and by differential binding of various plant lectins. The endothelial cell lines we have developed provide the means to examine in the mouse, long a key species for biomedical research, a wide range of biological functions and properties of the vascular endothelium.
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Supernatants from secondary mixed leukocyte cultures (MLC) are capable of stimulating both endothelial cell proliferation and endothelial cell chemokinesis. The proliferation factor(s) has been subject to further biochemical characterization. At least one factor is precipitable by 30% ammonium sulfate, a procedure that separates this factor from the chemokinesis-inducing factor(s) and most other growth-stimulating lymphokines. The partially purified lymphokine preparation can stimulate growth of microvascular endothelial cells, yet fails to induce proliferation of large vessel endothelium and a variety of other cell types. Addition of indomethacin to the MLC medium leads to an increase in endothelial cell mitogenic activity. Chromatography on S-200 Sephacryl suggests a m.w. greater than 200,000 when eluted in isotonic saline, whereas the apparent m.w. is less than 30,000 when the material is eluted from the same column with 0.5 M ammonium acetate. The proliferative activity is stable to acid (pH 2) but not to heat treatment at 50 degrees C. Although the factor is resistant to trypsin digestion, it is sensitive to digestion with pronase, suggesting that it is a protein. The potential importance of endothelial cell-specific lymphokines in the vascular responses accompanying inflammation and disease-associated neovascular reactions is discussed.
Our central thesis is that the endothelial cells which line capillaries of various organs are not all alike. Using monoclonal and conventional antibodies we demonstrate that capillary endothelial cells express on their cell surface an array of antigens that manifest organ selectivity. Brain-derived endothelial cells possess brain-associated antigens, ovary-derived endothelial cells share antigenic markers with other ovarian cells, and lung-derived endothelium possesses antigens that are primarily expressed on cells of the lung. Our experiments lead us to suggest that organ-associated determinants on the endothelial cell surface may play a role in the selective adhesion of tumor cells during metastasis, in site-limited vascular pathology, and in the regionally limited release of angiogenesis-induced factors.
Hitherto voice changes have been regarded as an infrequent complication of thyroidectomy and damage to the recurrent laryngeal nerve has been given as their major cause. Voice function was assessed in 325 patients after thyroidectomy. Permanent changes occurred in 35 (25%) after subtotal thyroidectomy and in 19 (11%) after lobectomy. The commonest cause of voice change appeared to be injury to the external laryngeal nerves on one or both sides. Damage to the recurrent laryngeal nerve, which was routinely identified and protected, was rarely a cause. When the external laryngeal nerves were identified and preserved, permanent voice changes occurred in only 5% of cases; this was similar to the incidence of 3% in controls after endotracheal intubation alone. The course of the external laryngeal nerve is variable, and consequently mass ligation of the vessels at the top of the upper pole will damage it in a high proportion of cases. To minimise this serious complication these nerves should be identified and protected as well as the recurrent nerves and voice function should be assessed early in the postoperative period by laryngoscopy and by a speech therapist.
In this paper we describe a new and simple technique for studying cell movement in vitro. This method is based upon the migration of endothelial cells on polystyrene bead monolayers. It permits the rapid preparation and screening of multiple 96-well plates for effects on migration, requires fewer samples per test and has the potential for precise quantitation by digital image analysis. The locomotive response of endothelial cells in response to different protein matrices (fibrin, collagen, albumin, gelatin), as used by this technique, is also described. Experiments in progress have shown that this technique can be used to study the effect of different factors (monoclonal antibodies, lymphokines, etc.) on cell migration, and that it may be used with other cell types which exhibit cell migration on substrates in vitro.
Adhesion studies were carried out to determine the relative ability of glioma cells and ovary-derived teratoma cells to adhere to endothelial cells obtained from mouse brain capillaries (designated MBE cell line) or mouse ovaries (designated MOE cell line). The teratoma cells showed preferential adhesion to MOE cells, whereas the glioma cells showed preferential adhesion to the MBE cell line. In contrast, the glioma and teratoma cells adhered equally to L929 and 3T3 fibroblasts. A testicular teratoma with ovary-seeking properties in vivo also adhered preferentially to MOE cells, while the preference for MBE cells was shared by glioma cells with an endothelioma and a bladder tumor line. The endothelioma, interestingly, showed a marked preferential adhesion to 3T3 cells, thus distinguishing it from the glioma. The experiments demonstrate that capillary endothelial cells derived from different sources are not alike and that differences expressed at the cell surface of these cells can be distinguished by tumor cells.
The nature of hypothyroxinemia in sick very low-birth-weight (VLBW) infants was evaluated by assessment of the hypothalamic-pituitary axis and by the clinical response to thyroxine (T4) therapy. Twenty-three very low-birth-weight infants of gestational age 26 to 28 weeks, whose serum T4 concentrations were 4 micrograms/dL on two occasions, and thyrotropin less than 20 microU/mL, were included in a double-blind study. Following a thyrotropin-releasing hormone stimulation test, babies were given either T4 or placebo. Nine babies were thyrotropin-releasing hormone tested prior to therapy; four babies, two from each group, were tested 1 to 2 weeks after therapy. In 11 untreated babies, mean base line serum thyrotropin of 7.0 +/- 1.4 rose to 23.7 +/- 4.1 microU/mL in 30 minutes. This response was not significantly greater than the observed response in full-term babies, 23.7 +/- 4.1 v 16.6 +/- 0.97 microU/mL, respectively, P greater than .05. In two babies treated with T4 the thyrotropin response to thyrotropin-releasing hormone was completely suppressed. Serial serum T4 determinations showed normalization in both groups after a similar time interval. There was no beneficial effect of T4 therapy on growth of head circumference, length, or weight. Developmental data revealed no significant differences in the mental, motor, or gross neurologic outcome in the treated and nontreated infants after 1 year of follow-up. These observations imply that hypothyroxinemia in sick preterm infants is not a direct consequence of hypothyroidism. Despite the lack of demonstrable short-term beneficial effects of T4 therapy, follow-up studies are necessary to resolve the question of long-term benefits.
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The source of stem cells within the early mammalian embryo has not been identified. The yolk sac, once thought to provide the early stem cells in birds, is now seen more as a primitive effector organ capable of allorecognition, natural cytotoxic reactions and elaboration of cytokines. In lower vertebrates the source appears to be within a region delineated by the anterior limbs, foregut and mesonephros. That region defines the boundaries of the developing omentum, a fold in the peritoneum. As the omentum is known to develop lymphoid cells postnatally we have now examined the omental rudiment for the presence of lymphoid cell precursors. Our experiments provide evidence that the presumptive omentum of the 13-day mouse embryo is capable of histiotypic differentiation into a reticular organ containing a significant number of Thy 1+ lymphocytes, which suggests that the omentum may represent a new primary lymphoid organ in the mouse.