Structural aspects of airway remodeling in asthma

Airway remodeling in asthma is a complex process that involves structural changes in virtually all tissues of the airway wall. The histologic changes to the airways consist of epithelial proliferation and goblet cell differentiation, subepithelial fibrosis, airway smooth muscle (ASM) growth, angiogenesis, matrix protein deposition, gland hyperplasia and hypertrophy, and nerve proliferation. Cytokines, chemokines, and growth factors from inflammatory cells and structural cells contribute to remodeling. There are complex interactions among the various signaling pathways involving matrix metalloproteinases that are required for growth factor release. The physiologic consequences of remodeling are airway hyperresponsiveness from ASM growth and mucus hypersecretion from gland and goblet cell hyperplasia. Airway stiffening is a probable contributor to airway hyperresponsiveness through attenuation of the transmission of potently bronchodilating cyclical stress to the ASM during breathing. The epidermal growth factor receptor’s role in remodeling and its interaction with other potential causes of remodeling are discussed.     

Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

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Suppression of amiodarone-induced torsade de pointes by landiolol in a patient with atrial fibrillation-mediated cardiomyopathy

An elderly Japanese woman developed acute decompensated heart failure caused by persistent atrial fibrillation (AF) and left ventricular systolic dysfunction. Approximately 6 days after starting intravenous administration of amiodarone (600 mg/day) for maintaining sinus rhythm after cardioversion of AF, electrocardiograms revealed a prolonged QT interval associated with torsade de pointes (TdP). The amiodarone-induced TdP disappeared after intravenous administration of landiolol plus magnesium and potassium, without discontinuation of amiodarone or overdrive cardiac pacing, although the prolonged QT interval persisted. To the best of our knowledge, this is the first report that landiolol could be effective for amiodarone-induced TdP.     

The Wistar Furth rat: an animal model of hereditary macrothrombocytopenia

The mechanisms that determine and regulate platelet size are unknown. By phase microscopy, we observed that Wistar Furth (WF) rats had macrothrombocytopenia. In this study, we have characterized and compared platelets and megakaryocytes of WF rats with those of Wistar, Long-Evans hooded (LE), and Sprague-Dawley rats. In addition, we have examined the mode of inheritance of this WF rat platelet abnormality. The average platelet count of WF rats was only one-third that of the other three rat strains. In contrast, the mean platelet volume (MPV) of adult WF rats was twice that of the other rat strains; however, the average megakaryocyte diameter and DNA content distribution of WF rats were not significantly different from those of LE rats. The average megakaryocyte concentration was 30% lower in the WF strain compared with that of LE rats. Mazelike membrane formations were observed in WF platelets and megakaryocytes by electron microscopy. Reciprocal crosses of WF and LE rats resulted in offspring with MPVs and platelet counts like those of LE rats, indicating that the macrothrombocytopenic trait is recessive in its inheritance. Reciprocal marrow transplants between the WF and LE strains resulted in MPVs like those of the donor strain, demonstrating that the macrothrombocytopenia is an intrinsic marrow abnormality of the WF strain. Splenectomy did not alter the MPV of WF rats. The response of WF megakaryocytes and platelets to severe, acute thrombocytopenia was similar to that of LE rats except that the shift to higher megakaryocyte DNA contents was muted and platelet recovery was slower in the WF rats. In summary, the WF rat has a hereditary macrothrombocytopenia that is recessive in nature and not due to differences in megakaryocyte size or DNA content. These results suggest that the macrothrombocytopenia of WF rats results from the formation of fewer platelets per megakaryocyte, possibly resulting from a qualitative or quantitative defect in some component necessary for proper subdivision of megakaryocyte cytoplasm into platelets.     

High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells

Mitoxantrone has been shown in vitro to exhibit a steep dose-response relationship with respect to the clonogenic survival of acute myeloid leukemia cells. In this report, we show that 1-hour exposure of human myeloid leukemia HL-60 and KG-1 cells to mitoxantrone concentrations ranging between 0.1 and 10.0 mumol/L induced internucleosomal DNA fragmentation of approximately 200-bp integer multiples, characteristic of cells undergoing programmed cell death (PCD) or apoptosis. Mitoxantrone-mediated PCD was associated with a steep inhibition of the clonogenic survival of the leukemic cells. In addition, intracellularly, mitoxantrone-induced PCD was associated with a marked induction of c-jun and significant repression of c-myc and BCL-2 oncogenes. Pretreatment with the protein kinase C stimulator phorbol myristate acetate enhanced mitoxantrone-induced internucleosomal DNA fragmentation, whereas protein kinase C inhibitors staurosporine and H7 had no effect. These findings suggest that PCD is a potential mechanism underlying the steep dose-response relationship of mitoxantrone to the inhibition of clonogenic survival of acute myeloid leukemia cells.     

Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes

We describe additional nonrandom chromosome abnormalities in 18 cases of intermediate- to high-grade non-Hodgkin's lymphoma (NHL) bearing t(14;18) that were ascertained in a prospective cytogenetic study of all lymphomas seen at Memorial Hospital during the period January 1, 1984, to December 31, 1986. These included seven cases that had histological evidence of transformation from a lower grade and 11 that lacked such evidence. The most common of the additional changes seen in both groups affected chromosomes 6 and 7 and comprised the loss of chromosome 6 or del(6q) and the presence of more than two copies of chromosome 7 or duplication of 7q. Changes affecting these two chromosomes were less frequent in low-grade lymphomas with t(14;18) as well as in lymphomas lacking the translocation. These data suggest that common cytogenetic mechanisms underlie expression of high-grade histologies by lymphomas carrying t(14;18). In addition, they may serve as indicators of transformation when encountered in low-grade lymphomas with t(14;18).     

Cellular ras oncogene expression and cell cycle measured by flow cytometry in hematopoietic cell lines

Human hematopoietic malignancies provide an excellent model for the study of the activity of cellular oncogenes in a context of known defects in cell proliferation and differentiation. A flow cytometric immunofluorescence assay was developed to quantitate the expression of the cellular ras oncogenes in relation to the cell cycle in individual leukemic cells. Specific binding of a monoclonal antibody to the 21-kd protein (p21ras) encoded by the Ha-ras, Ki-ras, and N-ras genes was measured by flow cytometry and confirmed by fluorescence microscopy. P21ras was detected in 416B, a murine hematopoietic precursor cell characterized by a high level of Ki-ras expression, and in the human leukemic cell lines P-12 and KG-1. The presence of p21ras in the cell lines was also shown by immunoprecipitation. Cellular DNA content was determined simultaneously to define cell cycle phases. There was an equal distribution of p21ras in G1, S, and G2M, with considerable heterogeneity of ras gene expression in the G1 compartment. The assay allows oncogene expression to be studied in populations of intact single cells in which cell heterogeneity is maintained, requires very few cells per sample, and directly correlates oncogene expression to cell kinetic data.     

In vitro tumor cell cytolysis mediated by peptide defensins of human and rabbit granulocytes

We examined the activity of defensins, cysteine-rich cationic peptides that are abundant in the cytoplasmic granules of human and rabbit granulocytes, against various tumor targets. The three human defensins, HNP-1, HNP-2, and HNP-3, lysed human and murine targets in chromium release and dye exclusion assays. Defensin-mediated tumor cell lysis was concentration-dependent, inhibited by serum, and dependent on temperature-sensitive events. Lysis was first detected by three hours of incubation and it reached a plateau between eight and 14 hours. In vitro exposure of murine teratocarcinoma cells to HNP 1-3 abrogated their oncogenicity in vivo. Nonmalignant target cells were also susceptible to defensin-mediated lysis. Four rabbit granulocyte defensins exerted marked (NP-1, NP-2) or moderate (NP-3a, NP-3b) cytotoxic activity, whereas defensin NP-5 was not cytotoxic. When tumor cells were incubated with human defensins in combination with hydrogen peroxide, synergistic cytotoxicity was detected. As defensins are released from granulocytes by various stimuli, their release could contribute to extracellular cytotoxicity which is independent of reactive oxygen intermediates.     

Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate

The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.