Acute management of the burned patient.
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Algorithms↗
Biomedical subjects
B F Burns
Publications and source records attributed to B F Burns.
Leukocytosis in mice following long-term reconstitution with genetically-modified bone marrow cells constitutively expressing interleukin 1 alpha or interleukin 6.
Leukemic cells of patients with acute myeloid leukemia have recently been shown to spontaneously produce autostimulatory IL-1 and IL-6. In order to investigate the effects of systemic production of these cytokines on normal hematopoietic cells, mice were engrafted with bone marrow cells infected with high-titer retroviral vectors carrying the murine IL-1 alpha or IL-6 genes and the neomycin phosphotransferase gene. Sustained expression of the introduced IL-1 alpha and IL-6 genes was documented by Northern-blot analysis of RNA from G418-resistant mast cells and T cells, derived from bone marrow and spleen, respectively, of successfully reconstituted mice 6-10 months after transplantation. A single mouse engrafted with IL-1 alpha-infected cells which presented with a dramatic neutrophilic granulocytosis (54-fold elevation in circulating neutrophils) was sacrificed for health concerns 2 months post-transplant. Modest changes in peripheral leukocyte counts (at most a 2-fold rise) were observed in all of the other mice, and they remained healthy throughout the observation period. The majority displayed increased hematopoietic activity in bone marrow and spleen, predominantly granulopoiesis, with moderate lymphoid hyperplasia seen in the spleens of mice constitutively expressing IL-1 alpha. These mouse models provide the opportunity to evaluate the potential of persistent IL-1 alpha and IL-6 expression to contribute to leukemogenic transformation.
Animals↗
Expression of retrovirally transduced IL-1 alpha in IL-6-dependent B cells: a murine model of aggressive multiple myeloma.
Retroviral-mediated gene transfer was employed to introduce an IL-1 alpha cDNA into an IL-6-dependent murine B-cell line. Bone marrow metastases and bone lesions were frequently observed following intravenous injection of these B cells into syngeneic mice. Because the retroviral vector also contained the neomycin phosphotransferase gene, metastatic cells could be easily recovered from bone marrow by addition of G418 to the culture medium. Interestingly, the metastatic B cells were found to retain their IL-6 dependency through several transplant generations. By comparison, intravenous injection of autonomously-growing B-cell lines generated in vitro by retroviral introduction of an IL-6 cDNA rarely resulted in bone marrow metastases. These results demonstrate that abrogation of growth factor dependency is neither necessary nor sufficient for the in vivo growth and dissemination of tumor cells in this experimental system. It is proposed that the increased metastasis of the IL-1 alpha-producing B-cells to bone marrow is due to alterations in cell adhesion molecules. The B-cell bone marrow metastasis model described here may be useful for studies of bone marrow homing and for evaluation of therapeutic regimens for multiple myeloma.
Animals↗
Ki-1-positive non-Hodgkin's lymphomas. An immunophenotypic, ultrastructural, and morphometric study.
The authors studied four cases of diffuse, large cell non-Hodgkin's lymphomas with strong Ki-1 expression to determine if they shared characteristic ultrastructural or morphometric features in common. The tumor cells in these lymphomas all had very abundant cytoplasm, which often showed a concentration of organelles, especially mitochondria and Golgi apparatus, in regions next to nuclear concavities. One case had very complex cytoplasmic membrane projections resembling a "microvillous" lymphoma. These ultrastructural features combined with the frequent reniform nuclei and scattered lysosomes suggested histiocyte differentiation. However the immunophenotype was variable, more often showing "activation" markers and abnormal T-cell marker patterns. The mean nuclear area for all cases was between 38.3 +/- 12.7 to 42.3 +/- 16.2 microns2, roughly twice the size of the small lymphocyte population. The nuclear contour index, a measure of irregularity of the nuclear membrane, ranged from 4.75 +/- 0.86 to 6.36 +/- 1.89 (a circle is 3.54). These nuclear parameters are comparable in size to those of previously measured large cell lymphomas but exhibit more nuclear irregularity than most. Ki-1 lymphomas appear to represent a somewhat diverse group of tumors of lymphoid origin that exhibit some hybrid features of histiocytes.
Adult↗
An ultrastructural morphometric study of follicular center lymphocytes: III. The control of lymphocyte nuclear size in reactive hyperplasia and non-Hodgkin's lymphoma.
Since lymphocyte nuclear size and shape play such a key role in the classification of non-Hodgkin's lymphoma (NHL), the mechanisms and nuclear compartments responsible for the control of nuclear size are of fundamental importance to pathologists. To assess the role of condensed chromatin and the interchromatinic region of the nucleus in determining the size of this organelle, morphometric image analysis of total nuclear area and the area occupied by these two compartments was performed on electron micrographs of nuclear profiles from lymphocytes in lymph node biopsies of four cases of reactive lymphoid hyperplasia and ten examples of NHL. Using bivariate linear regression analysis, it was clear that, whether in normal mantle zone and follicular center lymphocytes or in the neoplastic lymphocytes of various NHLs, there is an extremely high correlation (R = 0.96) between the size of the interchromatinic region and the area of nuclear profiles. In contrast, there is a poorer correlation (R = 0.63) between the area occupied by condensed chromatin and nuclear area. The results demonstrate for the first time that even in NHL, where some nuclear features clearly vary from the normal counterpart, the control of nuclear size continues to be largely dependent on a particular subcompartment of the nucleus, the interchromatinic region. How this fact influences the categorization of subtypes of NHL for therapeutic and prognostic purposes will be an essential avenue for further investigation.
Cell Nucleus↗
Salivary gland myoepithelioma variants. Histological, ultrastructural, and immunocytological features.
The histological and ultrastructural features of five major salivary gland tumours, which have little or no evidence of duct- or gland-type differentiation in routine sections, are described. Four of the cases have the tumour cells organized as narrow, anastomosing cords of cells separated by a myxoid and vascularized stroma; we have designated such lesions as reticular-type myoepitheliomas. The fifth case has a solid growth pattern and is largely composed of hyaline cells, that is, a plasmacytoid myoepithelioma. Ultrastructurally, one reticular myoepithelioma reveals myoepithelial cell differentiation with microfilament aggregates, while the other three examples are composed of modified myoepithelial cells displaying widened intercellular spaces, prominent synthesis of extracellular glycosaminoglycans, distinct basal lamina development, and obvious accumulations of cytoplasmic intermediate filaments. In electron micrographs, the modified myoepithelial cells of the plasmacytoid variant closely resemble the tumour cells in the reticular form. Three cases had expression of both glial fibrillary acid protein (GFAP) and vimentin, but only one of the myoepitheliomas contained muscle-specific actin. At least focally, each of the cases exhibited a considerable spectrum of cytokeratin filaments. Using double-labeled immunofluorescent microscopy of one reticular variant and the plasmacytoid myoepithelioma, there was individual tumour cell co-expression of GFAP and vimentin focally in the plasmacytoid myoepithelioma, but co-expression of cytokeratins 13, 16 and GFAP were not noted in either case. As expected, co-expression of high- and low-molecular weight cytokeratin filaments was widespread in both myoepitheliomas. Most described myoepitheliomas have a solid growth pattern and are composed of spindle and plasmacytoid cells, but based on cytological features and growth patterns in this series, it is apparent that polygonal-shaped cells with novel architecture can occur in myoepitheliomas. The results also indicate the close relationship between pleomorphic adenoma and such variants of myoepithelioma.
Actins↗
A case of a Ki-1 large cell anaplastic lymphoma with ultrastructural features.
A 29-year-old woman first presented in 1982 with a large cell lymphoma, initially thought to be of histiocytic origin on the basis of prominent sinus infiltration. She had a complete response to chemotherapy, but relapsed in 1987. Histologically, a repeat biopsy was identical to the first. Immunocytochemically, there was strong reactivity with Ki-1 antibody and histiocyte lineage markers, but all specific T cell markers were negative. Southern blot hybridization demonstrated a clonally rearranged band with the T cell receptor (T beta) probe. Ultrastructurally, the cells showed sparse organelles except for prominent paranuclear Golgi apparatus, frequent reniform nuclear indentations, and ruffled cytoplasmic membranes. This case appears to represent a Ki-1-positive lymphoma with the hybrid features of an activated T lymphocyte and a histiocyte.
Adult↗
Molecular genetic markers in lymphoproliferative disorders.
The elucidation of the genetic mechanisms involved in the generation of antibody diversity is little more than a decade old, but the impact has already been felt in many areas of biology and medicine. In order for a B or T cell to become a functional antigen recognizing cell it must produce a unique protein to act as a membrane receptor. In the case of the B cell this is an immunoglobulin molecule while in the T cell it is an analogous dimeric protein, the T cell receptor. Diversity in these proteins is generated by a shuffling of the genes responsible for these respective proteins and is unique to each cell. Using Southern blot hybridization to exploit this, it is possible to determine whether a group of lymphocytes is derived from a single progenitor cell, i.e., clonal, and also whether they are of B or T cell origin. Oncogene activity and chromosomal translocations are believed to be responsible for a variety of lymphomas and leukemias. The association of established oncogenes, such as c-myc, with translocations to regions near immunoglobulin enhancers in some lymphomas has prompted successful searches for novel proto-oncogenes in other forms of lymphomas that also have characteristic, but different, translocations.
Blotting, Southern↗
Observer variation in the pathologic diagnosis of malignant lymphoma in Canada.
Biopsies from "poor prognosis" non-Hodgkin's lymphomas were studied to assess diagnostic variations among pathologists. The original diagnosis and the diagnoses of a nationwide panel of local reference pathologists (LRPs) from 104 cases were reviewed and the technical quality of each biopsy evaluated. Using a modified Rappaport classification, there was agreement in 57% of cases among the panel. This increased to 84% when diagnoses were grouped according to Working Formulation grades. Of the 90 cases in which a comparison of the contributing pathologist's diagnosis and the most common panel diagnosis was possible, there was exact agreement in 51% (kappa = 0.311) of cases and agreement regarding WF grade in 68% (kappa = 0.318). Major panel disagreements occurred in 26 (25%) cases, involving the distinction of metastatic anaplastic carcinoma or Hodgkin's disease from non-Hodgkin's lymphoma in 17 cases and follicular versus diffuse architecture in 16 (overlap present). The contributing pathologist had a major disagreement with the panel in 18 cases (20%), of type and frequency similar to those within the panel itself. Poor fixation (complete or partial) was present in 49 cases (47%); this resulted in significantly fewer majority agreements than in the well-fixed group (25% versus 60%, P = 0.020) and also increased rates of disagreement in the diagnosis of lymphoma versus anaplastic carcinoma. Thus improvements in the technical quality of biopsy material could further improve the diagnostic accuracy of lymphoma diagnosis.
Female↗
Intermediate filament expression in normal parotid glands and pleomorphic adenomas.
A comparative immunohistochemical study of intermediate filament expression in normal parotid glands and pleomorphic adenomas (PA) was performed using material fixed in a modified methacarn fixative. The normal myoepithelial cells of acini stained only with monoclonal antibodies 312C8-1 (cytokeratin (CK) 14) and 4.62 (CK 19) while myoepithelial/basal cells of ducts also reacted with antibodies 8.12 (CK 13, 16), 8.60 (CK 10, 11, +/- 1), and PKK1 (CK 7, 8, 17, 18). Normal duct luminal cells showed a different CK profile, reacting consistently with ECK, a polyclonal antibody to epidermal prekeratin (CK 3,6), and monoclonal antibodies 4.62, PKK1 and 8.60. In PA, tumour cells at the periphery of ducts, in solid areas, and at the edge of myxoid regions all had CK profiles similar to normal myoepithelial/basal cells except that antibody 4.62 was generally negative. Vimentin and glial fibrillary acidic protein (GFAP) were uniformly negative in normal parotids but showed variable (often strong) reactivity with some cells in chondroid, myxoid and solid areas of PA. A surprising feature of most PA was the variability of CK subtype expression not only from one case to another but also within morphologically similar areas of the same specimen. These results suggest that the morphology of PA is the result of diversity of tumour cell differentiation rather than the processes implicit in a reserve cell histogenetic model.
Adenoma↗
Fatal post-transfusion acquired immunodeficiency in a heterosexual man: quantitative lymph node immunopathology.
Employing a novel panel of monoclonal antibodies, we characterized in detail the quantitative immunopathologic alterations of lymph nodes in a 69-year-old heterosexual man who died of acquired immunodeficiency 1.5 years after transfusion of blood products. Absolute decreases were evident in total T cell, helper T cell, cytotoxic T cell, and Leu 8+ cell counts. Suppressor T cells and histiocytes were absolutely increased. There were relative increases in B cells and Leu 7+ cells. B-cell follicles were sparse and exhibited small, burned-out germinal centers composed predominantly of R4/23+ dendritic reticulum cells. These findings closely paralleled those described previously for homosexual men with acquired immunodeficiency syndrome (AIDS). They suggest that AIDS occurring among diverse clinical groups, such as homosexual men and blood donor--recipient pairs, involves similar immunopathologic alterations within lymph node microenvironments.
Acquired Immunodeficiency Syndrome↗
Warthin's tumor: an ultrastructural and immunohistochemical study of basilar epithelium.
The cellular characteristics of the basilar epithelium in Warthin's tumor have had limited investigation. Ultrastructural examination of basal cells in 9 Warthin's tumors reveals that in addition to numerous mitochondria these cells possess a rich complement of tonofilaments. However, in three examples there are a proportion of these tonofilament-rich cells that have a narrow band of microfilaments in the peripheral cytoplasm adjacent to the basal lamina. Frozen sections of Warthin's tumor and normal salivary glands, doubly labeled with rhodamine-phalloidin for actin and monoclonal antibody 312C8-1 for cytokeratin 14, show that normal myoepithelial cells of acini and intercalated ducts have both of these filaments, as do a proportion of basal cells in the tumor. There are distinct differences in the cytokeratin polypeptide complement between normal luminal and myoepithelial cells as well as between luminal and basal cells in Warthin's tumor. Differences occur in the cytokeratin profiles between the luminal and basal cells of Warthin's tumor and comparable cells in the normal gland; however, there continue to be some similarities in the cytokeratin polypeptides of myoepithelium and the basal cells of normal salivary ducts and the basal cells of Warthin's tumor. These findings show that basal cells in Warthin's tumor are a mixed population with some capable of differentiating as myoepithelial-like cells, and that this tumor could arise from any level of the normal salivary gland duct system.
Adenolymphoma↗
The effects of fixative type and fixation time on the quantity and quality of extractable DNA for hybridization studies on lymphoid tissue.
Encouraged by recent reports of extraction of diagnostically useful DNA from formalin-fixed tissues, we devised a study to determine which fixatives are suitable for DNA hybridization studies. Seven lymph node specimens (6 lymphomas and one reactive hyperplasia) were studied. Specimens were divided into portions, each of which was processed separately. Processing protocols followed were: 1) snap freezing; 2) immersion in formalin, ethanol, glutaraldehyde, B5 and methanol acetic acid (MAA) Michel's transport medium or phosphate buffered saline for 2, 24, 48 and 120 hrs.; 3) paraffin embedding following fixation. DNA was obtained by proteinase K digestion followed by phenolchloroform extraction. DNA was cleaved with restriction endonucleases (Eco RI and Bam HI), separated by agarose gel electrophoresis, after which Southern blot hybridization with radio-labelled probes for J-heavy and T-beta genes was performed. Fixation with formalin, glutaraldehyde and B5 resulted in poor yields of DNA. MAA produced degradation of DNA and Michel's medium and PBS gave low quantities and purity of extracted DNA. Ethanol fixation consistently permitted extraction of large amounts of high molecular weight DNA suitable for hybridization studies and compared favourably with the fresh-frozen 'gold standard'. We conclude that ethanol may be the fixative of choice when transport or storage conditions limit the availability of fresh frozen tissue for DNA hybridization studies.
Acetates↗
In vivo induction of tumor variants by phorbol 12-myristate 13-acetate.
Malignant cells within solid tumors commonly exhibit phenotypic changes such as alterations in karyotype and acquisition of the ability to invade and to metastasize. We have used a fibrosarcoma, grown subcutaneously in C57BL/6 mice, to study the mechanisms underlying this phenotypic instability. Tumor-bearing animals were injected with phorbol myristate acetate (PMA) and then the tumors were transplanted to animals without further PMA treatment. These tumor cells were tum+, that is, unlike the parental tumors, they were able to grow in animals immunized against the parental tumors. This property was maintained for at least 6 tumor passages after the initial PMA injections. Thus, PMA appears to be able to induce an unstable tum+ phenotype in these cells at relatively high frequency.
Animals↗
Histiocytosis X of the thymus in association with myasthenia gravis.
A patient with myasthenia gravis underwent thymectomy following the failure of medical treatment. The thymus was normal except for four nodules, which, on histologic and electron microscopic examination, were found to consist of proliferative clusters of Langerhans' cells characteristic of histiocytosis X. This patient therefore had two disease processes in which thymic abnormalities are frequently encountered, but their simultaneous occurrence in the same patient has not hitherto been documented. The case is briefly discussed in the context of current concepts of the pathogenesis of histiocytosis X and myasthenia gravis.
Adult↗
In situ quantitation of lymph node helper, suppressor, and cytotoxic T cell subsets in AIDS.
We have used the novel monoclonal antibodies 9.3 and anti-Leu-8 in conjunction with other T cell markers to quantify T cell subpopulations in the paracortex, mantle, and germinal center compartments of frozen sections of lymph nodes from seven homosexual men with acquired immunodeficiency syndrome (AIDS) and five heterosexual controls. Antibody 9.3 allows dissection of the Leu-2+ cytotoxic/suppressor subset (Tcs) into 9.3+ cytotoxic cells (Tc) and 9.3- suppressor cells (Ts). Anti-Leu-8 allows dissection of the Leu-3+ helper subset (TH) into functionally distinct subpopulations. The data indicate that the T cells in patients with AIDS exhibit normal antigen expression but altered subset ratios. In this series, the data suggested that the reversal of the paracortical TH-Tcs ratio was due to an increase in Ts with a concomitant decrease in TH and Tc. These changes were also reflected in a reversal of the normal paracortical Tc-Ts ratio (3.0) to less than 1.0. Furthermore, the data suggested a marked decrease in paracortical Leu-3+8+TH, which are known to have inducer function in cellular immune reactions and exert feedback inhibition of immunoglobulin production through a suppressor T cell intermediary. In contrast, there was preservation of the Leu-3+8-TH population within the germinal center. This T cell subset is known to help B cell differentiation. This microenvironmentally specific constellation of T cell subset alterations within lymph nodes may in part explain several of the immunologic findings associated with AIDS.
Acquired Immunodeficiency Syndrome↗
Unusual thymic seminomas.
Although most thymic seminomas have a histologic appearance similar to those arising in the testis, some seminomas undergo pronounced secondary changes that may obscure the diagnosis. We found three cases that showed a combination of reactive follicular hyperplasia (three cases), large cysts (three cases), epithelioid granulomas (two cases), and fibrosis (two cases), to such a degree that the seminoma component was indistinct. Immunoperoxidase staining for keratin in one case highlighted the intimate association of the positively staining thymic epithelial cells with the nonstaining seminoma cells. The seminoma cells in this case were reactive with placental alkaline phosphatase. No other group of thymic or mediastinal tumors, including those of Hodgkin's disease, exhibited this combination of secondary reactive changes to a similar degree. Because of the favorable prognosis of thymic seminomas, these variants should not be confused with other mediastinal tumors.
Adolescent↗
The varied histopathology of lymphadenopathy in the homosexual male.
We review the clinical features and histopathologic changes observed in 69 cases of lymphadenopathy in homosexual men. The most common pattern seen was that of florid reactive follicular hyperplasia (43 cases). A peculiar and distinctive lysis of the germinal centers, a phenomenon we have termed "follicle lysis," was noted in 25 cases. Eighteen of these lymph nodes also contained sinusal collections of "monocytoid" cells and neutrophils and six showed focal dermatopathic changes. Seven cases were characterized by a lymphocyte-depleted pattern with only occasional regressively transformed germinal centers. Nine patients were found to have involvement of their lymph nodes by Kaposi's sarcoma; malignant lymphomas were encountered in 10 patients (eight with Hodgkin's disease and two with non-Hodgkin's lymphomas). Polykaryocytes (multinucleated giant cells) were observed in germinal centers or interfollicular areas within the lymph nodes of four patients. Limited clinical follow-up was available but the lymphocyte-depleted group appeared to have a more aggressive clinical course (three patients in this group developed pneumocystis pneumonia, two had mycobacterial infections and one cutaneous Kaposi's sarcoma). The diverse nature of these findings and the potential for treatment of certain patients (i.e., those with malignant lymphomas and mycobacterial infections) underlines the importance of lymph node biopsy in all cases of unexplained lymphadenopathy in homosexuals and other individuals susceptible to the acquired immunodeficiency syndrome (AIDS). The histopathologic findings may also serve to identify a subgroup of these patients at increased risk to develop more severe AIDS-related complications.
Adult↗