Jun-ichi Nishimura

Clinical Manifestations of Paroxysmal Nocturnal Hemoglobinuria: Present State and Future Problems

The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.

Enhanced Responses of Glycosylphosphatidylinositol Anchor-Deficient T Lymphocytes

The functions of GPI-anchored proteins in T lymphocyte activation have been controversial. This issue was addressed by studying the responses of T lymphocytes from T lymphocyte-specific GPI anchor-deficient mice to different stimuli that normally allow coligation of TCR and GPI-anchored proteins. Stimulation of GPI anchor-deficient T lymphocytes with ConA induced 2-fold higher proliferative responses than did normal cells. In response to allogeneic stimulation, proliferation of GPI anchor-deficient T lymphocytes was enhanced 2- to 3-fold. The response to ConA of a GPI anchor-deficient anti-OVA T lymphocyte clone generated from these mice was ∼3-fold higher than that of cells from the same clone in which GPI anchor expression was restored by retroviral transduction. The response of the GPI anchor-deficient cloned anti-OVA T lymphocytes to antigenic stimulation was similar to that of the retrovirally restored cells. These results indicate that coligation with GPI-anchored proteins counteracts the response to TCR stimulation by ConA or alloantigen but not protein Ag.

Serial Analysis of Clonal Expansion in PNH by Flow Cytometry

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder caused by PIG-A mutations. To assess clonal expansion in PNH over time, patients with serial testing by flow cytometry (interval of at least one year) were analyzed. This study involved 164 patients with PNH from Duke (DP) and 151 patients from Japan (JP). The mean fraction of PMNs deficient in CD59 (mean±SE) was 75.2±4.2% in DP and 40.0 + 8.3% (n=21) in JP at the initial analysis, and were 74.1 ±4.7% and 50.7 + 8.6% at the latest analysis (P=NS). However, in individual cases, the proportion of affected PMNs varied considerably from -84% to +98%. Some DP and JP pts, however, had a diminution in their CD59-deficient PMNs over time, which was associated with the development of overall hematopoietic failure (P=.04 for DP, P=.05 for JP). These data illustrate the complexity of clonal expansion in PNH, and the marked variability over time. GPI-deficient populations vary considerably over time for individual patients, but a decreasing PNH clone indicates impending hematopoietic failure. Correlation between clonal expansion or diminution and the development or recovery from aplasia will help our understanding of the natural history of PNH.

Clinical usefulness of a perioperative bacteriological culture to treat patients with postoperative pneumonia after esophagectomy

The aim of the present study was to examine the usefulness of a perioperative bacteriological culture in predicting the pathogenic bacteria responsible for postoperative pneumonia after esophagectomy.

The Clinical Course of PNH in the USA and in JAPAN

PNH, which is characterized by intravascular hemolysis and venous thrombosis, is an uncommon disorder of hematopoietic stem cells with an acquired somatic mutation of PIG-A. An understanding of the natural history of PNH is essential to improve therapy. To determine and to directly compare the clinical courses of PNH patients from the USA and Japan, data were collected for 385 patients with PNH. There were 176 patients from Duke (DP) and 209 patients from Japan (JP). The mean age at diagnosis (mean ± SE) was 32.8 ±1.2 years (4-80) in DP, and 45.1 ±1.3 years (10-86) in JP. The incidence of various chnical events was analyzed. These analyses provide important diagnostic and long-term data on two large cohorts of PNH patients, and identify important differences between Caucasian and Asian patients with PNH. Caucasians tend to be younger and have classical symptoms of PNH including thrombosis, while Asians tend to be older and have symptoms of aplasia. Multivariate analysis of factors influencing survival was also undertaken. By this study, estimates of PNH prognostic factors may provide a better understanding of the complications of the disease so that therapeutic interventions may be sought. Further, by noting differences in the two populations, possible genetic modifiers of the course of the disease may be identified for further investigation.