Motoo Kikuchi

MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies.

MUM1/IRF4 is a myeloma-associated oncogene transcriptionally activated as a result of t(6;14)(p25,q32) chromosomal translocation and by virtue of its juxtaposition to the immunoglobulin heavy chain gene (IgH) locus. When this oncogene becomes non-functional, no activated B/T lymphocytes and Ig secreting plasma cells are observed, suggesting that MUM1/IRF4 is crucial for lymphoid development. Its expression was analyzed in both reactive lymphoid and lymphoma tissues by means of an immunohistochemical technique using specific goat antiserum against MUM1/IRF4. This analysis detected a 50 kDa MUM1product whose localization was restricted to the nuclei of the lymphocytes. The MUM1+ cells in reactive lymph nodes were found to consist of plasma cells and a small fraction (approximately 7.9%) of B cells harboring CD20+CD38+, which were located in the light zone of the germinal center. MUM1 expression in peripheral blood B/T lymphocytes was upregulated by mitogenic stimuli, suggesting that MUM1 positivity represents the activated state of the B/T cells. In B cell non-Hodgkins lymphoma (NHL), MUM1 expression was observed in 73.2% (30/41) of diffuse large B cell lymphoma (DLBCL), 20% (1/5) of marginal zone lymphoma (MZL) and 43% (3/7) of small lymphocytic lymphoma (SLL) cases, whereas it was not seen in any cases of mantle cell lymphoma (MCL) or follicle center lymphoma (FCL). Also, MUM1 was stained at high intensity in various types of T cell lymphomas including adult T cell leukemia/lymphoma (ATL/L) and anaplastic large cell lymphoma (ALCL) and in the majority of Hodgkins diseases. Our results suggest that a major proportion of lymphomas comprise either physiologically or aberrantly activated neoplastic lymphocytes expressing the MUM1 protein.

Five-year survival of older people with anemia: variation with hemoglobin concentration.

OBJECTIVES: To investigate the significance of low hemoglobin concentration and longevity in older people.

Atrial natriuretic peptide in aged patients with iron deficiency anemia

Anemia is a common disease in elderly people. However, since hemoglobin concentration often decreases subclinically with aging because of nutritional impairment, its pathological significance is unclear. To investigate the pathological significance of low hemoglobin concentration, we studied the relation between hemoglobin levels and arrhythmia, as well as circulatory parameters. Arrhythmia was detected by Holter type ambulatory electrocardiography in 42 elderly people (aged 60 or over) living in a nursing home. Plasma concentrations of human atrial natriuretic peptide (hANP) after iron therapy were determined by immunoradiometric assay. Changes in circulatory parameters in elderly people with iron deficiency anemia were examined. Supraventricular and ventricular premature contractions significantly increased in elderly people with low hemoglobin concentrations or hematocrit. hANP increased significantly as the hemoglobin concentration decreased in 22 elderly people. Of these 22 subjects, 11 showed a low serum concentration of iron, and were administered ferrous salts. No side effects, such as nausea, occurred. After iron supplementation, the average hemoglobin level increased from 9.0 to 10.5 g/dl, and the average hANP level was reduced from 58.3+/-23.5 to 41.2+/-27.9 pg/ml, which was statistically significant by Wilcoxons signed rank sum test. The increase in the hemoglobin level inversely correlated with the hANP level. Heart rate, blood pressure and body weight of subjects decreased significantly after iron supplementation therapy. Although hemoglobin levels were increased by iron supplementation therapy after a long period of anemia, the duration of the period with low hemoglobin levels showed no significant relation to initial hANP concentration. In conclusion, low hemoglobin levels induced secretion of hANP, and treatment of iron deficiency might exert favorable effects on the circulatory system.

Clinical significance of the soluble interleukin-2 receptor as a putative systemic nutritional index in the elderly*

Background:  The clinical significance of a slight increase in serum soluble interleukin‐2 receptor (sIL2R) concentration in the stable elderly was investigated.

Clonality Assay of Hematopoietic Disorders: Significance of the Buccal Epithelium as Non-hematopoietic Control and of 95% Rejection Limit as a Novel Criterion for Monoclonality

In clonality assays using × chromosome inactivation patterns (XCIPs), several factors such as constitutive and acquired XCIP skewing, lack of appropriate controls for hematopoietic diseases including multilineage disorders, and ambiguous criteria for monoclonality, have complicated determination of clonality. To address these issues, we studied the significance of the buccal epithelium as a non‐hematopoietic control and the usefulness of the 95% rejection limit as a criterion for monoclonality. Sixty‐nine females informative for human androgen receptor gene (HUMARA) were divided into “young,”“middle‐aged” and “elderly” groups. When XCIP correlation between the buccal epithelium, peripheral granulocytes, and peripheral lymphocytes was analyzed, the buccal epithelium showed a good correlation with granulocytes and lymphocytes in “young” and “middle‐aged” groups, whereas the correlation was poor for the “elderly” group. For all age groups, there was an excellent correlation between granulocytes and lymphocytes. When we performed clonality assay for seven “young” and “middle‐aged” patients with various leukemic phases using buccal epithelium as a non‐hematopoietic control, all cases were accurately evaluated with the aid of a novel criterion, the 95% rejection limit. Our findings suggest that the buccal epithelium may constitute an effective control, especially when a non‐hematopoietic control is required, and that the 95% rejection limit may serve as a statistically‐defined criterion for monoclonality.

Risk factors of disseminated intravascular coagulation in septic systemic inflammatory response syndrome in nursing home residents

Aims:  Disseminated intravascular coagulation syndrome (DIC) is a serious complication in elderly patients with systemic inflammatory response syndrome (SIRS). We investigated whether the clinically relevant parameters of atherosclerosis, nutrition and cellular immunity are determining factors for DIC in septic SIRS patients or not.

Effect of copper and zinc supplementation on peripheral leukocytes in neutropenia due to copper deficiency

Background:  Recent quantitative and qualitative studies in animals suggest that copper deficiency causes immunological impairment and a decrease in leukocytes. We investigated the effect of copper supplementation in remedying these effects of its deficiency and whether zinc, a trace element that is significant to the immune status modifies such effects.

Multiple myeloma with infiltration into skeletal muscle after injections of granulocyte-colony stimulating factors

Multiple myelomas often occur in elderly people with age‐related complications as they age further. A 54‐year‐old man was first admitted with cerebral infarction and multiple myeloma (IgG kappa, stage IIIA) in November 1989. There was partial remission following chemotherapy. The karyotype of the marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single‐strand conformation polymorphism analysis. In February 1999, chemotherapy (melphalan, vindesine, ranimustine, prednisolone) was administered as a result of aggravation of the myeloma. Later, after daily subcutaneous injection of 50 µg of nartograstim for 6 days to treat febrile neutropenia, the soft tissues around the right eye swelled gradually, but without redness accompanied by an elevation of the serum creatine‐kinase concentration. When nartograstim was discontinued, however, the swelling disappeared and the creatine‐kinase level normalized. Then in July, on the sixth day of daily subcutaneous injections of 75 µg of filgrastim following the same chemotherapy regimen, similar swelling of the soft tissues occurred around the left eye, and was again reversed by withdrawal of the drug. In July 2000, infusion of dexamethasone was conducted, and following daily subcutaneous‐injection of 75 µg of filgrastim for 5 days, the right subclavicular soft tissue became swollen. The patient later died of myocardial infarction and an autopsy revealed an infiltration of myeloma cells into the right subclavicular muscle and bone marrow that was packed with myeloma cells. This case suggests that exposure to granulocyte‐colony stimulating factors enables myeloma cells to proliferate and infiltrate into soft tissues.

[Clinical significance of soluble interleukin-2 receptor as a putative systemic nutritional index in the elderly].

急性疾患や悪性腫瘍を罹患していない高齢者に認められる, 軽度に上昇したsIL2R値の臨床医学的な意義ついて検討した. 脳梗塞後遺症のために特別養護老人ホームで生活している高齢者で発熱や明らかな感染症, 急性炎症症状や疼痛などの自覚的臨床症状のあるものや, 免疫学的に影響する治療を受けているものは除外した35例を対象にして, 既往歴・現病歴より悪性腫瘍またはその疑いのない高齢者24名 (NC群) と, 悪性腫瘍はあるが安定している高齢者11名 (CA群) に群別した. 血清学的な一般検査, CD4およびCD8陽性リンパ球数, 血清可溶性IL-2受容体濃度 (sIL2R値) を測定し, NC群をsIL2R値が883U/mL以下 (15例, Control 群), 884U/mL以上 (9例, NH群) にわけ追跡した. Control 群とNH群との間で性・年齢差は無く, ADL score, Alb, BUN, T. Chol, Pettigrew の prognostic nutritional index (PNI) は有意差を認めた. sIL2R値に関する共通因子の解析では, NC群で Cre, BUNで正の相関関係を認め, Alb, T. Chol, ADL score, PNIで負の相関関係を認めた. CA群では Control 群と比較してsIL2R, Alb, TP, T. Chol, β-Lipo, PNIは有意差を認めたが, sIL2値に関する共通因子や相関関係は無かった. 生存率は Control 群の24カ月間の予後がNH群より有意に良好であったが, CA群との有意差は無かった. 軽度に増加しているsIL2R値は悪性腫瘍を罹患していない慢性期の安定している高齢者において, 栄養状態など不顕性に悪化している全身状態と密接な関係があり, 短期的な予後とも関連しうることが示唆された.