[The measurement of erythrocyte zinc protoporphyrin/heme ratio in various anemias in childhood]. The measurement of erythrocyte zinc protoporphyrin (ZPP) with a hematofluorometer is known to be a simple and cost-effective method to screen iron deficiency and lead poisoning. We measured ZPP on blood samples from 201 children suffering from various diseases, which revealed that ZPP has better sensitivity and specificity for identifying iron deficiency than serum ferritin and percent transferrin saturation. ZPP levels in various anemias were also measured. ZPP rose markedly (> 200 mumol/mol heme) in untreated iron deficiency anemia and returned to normal in 3-4 months since the initiation of iron therapy. Moderate elevation of ZPP was observed in acute leukemia (at onset and during induction therapy), MDS, aplastic anemia and some other anemic conditions. These findings suggest that erythrocyte ferrochelatase may be unexpectedly affected in anemias even except lead poisoning.


[Idiopathic thrombocytopenic purpura associated with pregnancy]. We examined 14 patients (18 cases) with idiopathic thrombocytopenic purpura (ITP) during pregnancy at our department. ITP, which had improved, recurred during pregnancy in 4 cases while it developed for the first time during pregnancy in 10 cases. In the other 4 cases, pregnancy occurred in the course of ITP. Although a normal infant was born in 14 cases, 3 stillbirth and a premature infant was observed in 4 cases. Six deliveries had some toxemia of pregnancy. A transient decrease in neonatal platelets was observed in 4 of 14 cases and mother's platelets count was less than 40 X 10(3)/microliters in the 4 cases. Although antinuclear antibody, Coomb's test and antiphospholipid antibody were positive in some cases, these were not markedly related to clinical course or neonatal platelets count. Eleven cases were treated with glucocorticoids, high dose gamma globulin or platelets transfusion, but 11 cases were not treated. Since ITP is frequently observed during pregnancy and may be some risk factor for pregnancy, treatment of ITP is important during pregnancy.


[Cyclic thrombocytopenia with chronic thyroiditis and ankylosing spondylitis]. A 58-year-old man with cyclic thrombocytopenia who was initially diagnosed as idiopathic thrombocytopenic purpura (ITP), concomitant with chronic thyroiditis and ankylosing spondylitis, was reported. Serum level of T 3 (0.48 ng/ml) and T 4 (2.1 micrograms/ml) were both subnormal and that of TSH (257.1 microU/ml) was markedly elevated. Thyroid test (6400X) and microsome test (6400X) was both positive, but anti-nuclear antibodies were negative. Radiographic findings of lumbar spine showed the typical "bamboo spine" and HLA B 27 was positive. Therapies for ITP, such as adrenocorticosteroids including steroid pulse therapy, high-dose intravenous gamma-globulin, danazol, slow infusion of vinca alkaloids and splenectomy, were only effective transiently. After these therapies platelet counts began to fluctuate from 0.4 X 10(10)/L to 34.4 X 10(10/L, therefore the diagnosis of cyclic thrombocytopenia was done. Interestingly low-dose methotrexate (MTX) was effective, and the cyclic fluctuation of platelet counts disappeared. These observations in this case were very suggestive of the pathogenesis of cyclic thrombocytopenia and mechanisms of cyclic change of platelet counts.


[A case report of childhood acute lymphoblastic leukemia with leukoencephalopathy that responded to oxygenation under hyperbaric pressure therapy]. In this report, we described a case of acute lymphoblastic leukemia with leukoencephalopathy that responded to oxygenation under hyperbaric pressure (OHP) therapy. The patient was 6 year-old female who was diagnosed as acute lymphoblastic leukemia (ALL) one year and 9 months earlier. After the first relapse of the central nervous system (CNS) leukemia, intrathecal administration of methotrexate (MTX) and skull irradiation induced CNS remission. The patient was readmitted because of second CNS relapse. After the third administration of weekly intrathecal MTX injection, apathy and finger tremor were observed. Her conscious disturbance continued for two weeks and magnetic resonance imaging (MRI) revealed abnormal findings in the white matter of her brain. Subsequently OHP therapy was commenced, and the conscious disturbance was improved gradually. One month later, neuro-disturbance resolved completely and the findings of MRI were improved. We could not find any case of leukoencephalopathy which was treated with OHP in the literature. But our case suggested that OHP therapy is valuable in patient with leukoencephalopathy in the early stage.


[Disappearance of Philadelphia chromosomes after remission induction in lymphoid crisis of chronic myelogenous leukemia]. The authors report a rare case of chronic myelogenous leukemia (CML) in which the Ph1 clone disappeared after remission induction of lymphoid crisis. A 58-year-old man was admitted to our hospital because of fever in July 1988. The white cell count was elevated. Bone marrow aspirate showed hypercellularity with myeloid hyperplasia. In the chromosomal analysis, Ph1 chromosomes were detected in 100% of bone marrow cells analysed. Diagnosis of CML was made and treatment was initiated with recombinant interferon-alpha 2a. Hematological remission without cytogenetic improvement was achieved. In March 1990 he developed lymphoid crisis with proliferation of CD10-positive cells. The chromosomal analysis revealed additional abnormalities including, 45, X, -Y, t(9;22) (q34;q11), +1, -8. With vincristine 0.6 mgX4, pirarubicin 15 mgX4, dexamethasone 40 mgX4 therapy complete remission was obtained. In December 1990 the Ph1 positive clone completely disappeared judging from normal karyotypes in the chromosomal analysis and the disappearance of M-bcr gene rearrangement.


[Effective treatment of CMMoL with F-COP (epirubicine, cyclophosphamide, vincristine, prednisolone) therapy]. A 66-year-old female was admitted with high fever and loss of consciousness. For the past one year, she has experienced recurrent febrile episodes. On admission, the presence of monocytosis, thrombocytopenia of the peripheral blood and dysplastic findings of the bone marrow cells indicated chronic myelomonocytic leukemia (CMMoL). The high fever persisted in spite of treatment with antibiotics. Although she was treated by pulse therapy with methyl-prednisolone, her clinical symptoms did not improve. Pleural effusion and ascites were also noted. Treatment with F-COP (epirubicine, cyclophosphamide, vincristine, prednisolone) therapy, resulted in a dramatic improvement of her condition. The F-COP therapy was given monthly for the next 7 months. This case suggests that F-COP therapy may be effective for some patients with CMMoL.


[Hodgkin's disease presenting with fever of unknown origin associated with granulomas of the bone marrow]. A 73-year-old man was admitted to our hospital on April 30, 1990, because of fever persisting for 18 months. Bone marrow puncture and biopsy were performed, because examination on admission revealed an elevated leukocyte count and anemia while his superficial lymph nodes, liver and spleen were not palpable. The results of the bone marrow biopsy revealed evidence of granuloma. Around May 10, the patient developed hepatosplenomegaly and enlargement of left cervical lymph nodes. Based on the results lymph node biopsy, a diagnosis of Hodgkin's disease was made, and CHOP therapy was instituted on May 20. However, the patient developed interstitial pneumonia and died on July 3. This patient's disease was manifested by fever of unknown origin. Bone marrow biopsy revealed granuloma with histiocytes predominating, and the patient subsequently developed lymph node enlargement. His disease was then diagnosed as Hodgkin's disease on the basis of a biopsy. Malignant lymphomas associated with granulomas in the bone marrow, liver or spleen are for the most part found in the advanced stage of the disease. It should be borne in mind, however, that some patients may exhibit granuloma formation in their bone marrow prior to lymph node enlargement or hepatosplenomegaly, as in the present case.


[Isolated cerebellar tumor formation in a patient with blastic crisis of chronic myelogenous leukemia]. A 42-year-old male was diagnosed as having Ph-positive chronic myelogenous leukemia (CML) in 1988. He had been treated with ranimustine and interferon alpha. In April 1990, he was admitted to our hospital because of hemorrhagic diathesis. Blood counts revealed a white blood cell count of 319,200/microliters with 12 per cent blasts, a hemoglobin level of 9.2 g/dl, and a platelet count of 48,000/microliters. The bone marrow aspiration revealed hypercellularity with 68.2 per cent blasts, and chromosomal analysis showed 48, XY, +8, double Ph. A combination chemotherapy containing vindesine, cytarabine and prednisolone was administered. Four days later, he suddenly complained of headache and vertigo. CT scan of the brain showed a high density area at the cerebellar vermis. He was then treated with intensive combination chemotherapy including enocitabine, daunomycin, 6-mercaptopurine and prednisolone. He attained a hematological response and clinical improvement temporarily, as the cerebellar tumor regressed. In September he had headache and vertigo again, and CT scan revealed a rapid increase in size of the cerebellar tumor. Local irradiation with total doses of 19 Gy brought about a partial resolution of the lesion, and relief from the symptoms. In November, his hematological conditions deteriorated gradually and he died of brain hemorrhage on November 22, 1990. Post-mortem examination disclosed a 1 x 1 cm sized mass in the cerebellar vermis which showed a fibrous change surrounded with hemosiderin-laden macrophages microscopically. We reviewed the eight reported cases of CML with intracranial tumors, and discussed the factors which had contributed to the prolongation of survival in our patient.


[Treatment of CML with blastic crisis by the combination therapy of VP and low-dose Ara-C]. Forty-three-year-old man with schizophrenia, who had been diagnosed as chronic myelogenous leukemia (CML) and had been treated with hydroxyurea for 3 months, developed blastic crisis. The cytochemical study of the blastic cells showed POX (+), SBB (+) and TdT (+). The surface marker analysis revealed that the blastic cells expressed both myeloid (CD13, 33) and lymphoid (CD10, 19) markers. In the chromosomal analysis, additional chromosomal abnormality (11q+) was detected in all cells analysed (20/20) in addition to the standard type Ph1 chromosome. He was diagnosed as bi-phenotypic blastic crisis, and vincristine-prednisolone therapy was started. Initially, he responded to VP therapy well, but gradually became refractory to the therapy after 5 courses of VP. As many myeloblasts containing azurophilic granules were seen in the bone marrow after VP therapy, low dose Ara-C therapy was combined to VP. After 21 days of low dose Ara-C and VP, the percentage of the blast in the BM was significantly decreased and normal myeloid differentiation was observed after transient BM suppression. The chromosomal analysis showed the partial reappearance of standard Ph1 chromosome in 55% of the cells analyzed (11/20). Taken together, our data suggested that the combination of VP and low-dose Ara-C therapy might have some therapeutic benefit for the treatment of the CML with blastic crisis.


[Successful interferon-alpha treatment of hepatitis B developing during chemotherapy of malignant lymphoma]. In a 47-year-old male patient a tonsillar swelling was pointed out in May, 1991. Lymph node biopsy revealed that he had malignant lymphoma (diffuse large cell type). He had no hepatic dysfunction on admission, but because of positive hepatitis B (HB) antigen and negative HB antibody, he was diagnosed as an asymptomatic HB carrier. The staging examination showed that he had stage IIA lymphoma. Treatment with the COP-BLAM regimen was initiated on June 8. But the level of serum GOT and GPT increased to 286 IU/l and 392 IU/l, respectively. Serum DNA polymerase also increased to 9492 cpm. Interferon-alpha (3 x 10(6) units daily) was administered intramuscularly from June 8. Serum DNA polymerase decreased to zero on September 2, and his HBe antibody became positive indicating seroconversion. COP-BLAM chemotherapy without prednisolone was initiated from September 9 and complete remission was achieved. He was discharged from our hospital on September 25. It has been frequently reported that asymptomatic HB antigen carriers developed fulminant hepatitis during the course of chemotherapy. Our case suggests that it is necessary to continue chemotherapy in order to attain seroconversion by early use of interferon-alpha, when lymphoma patients display aggravated hepatic dysfunction and increased DNA polymerase levels.


[HIV-1 seropositive hemophilia A complicated by disseminated intravascular coagulation syndrome and acute pancreatitis during treatment of Pneumocystis carinii pneumonia]. Pneumocystis carinii pneumonia (PCP) is a major opportunistic infection in acquired immunodeficiency syndrome (AIDS) and is treated with co-trimoxazole, pentamidine and others. The severe adverse reactions, including bone marrow suppression, by these therapeutic agents often preclude their continued use. A 14-year-old male HIV-positive hemophilia A patient, who was complicated by disseminated intravascular coagulation syndrome (DIC) following acute pancreatitis during treatment for PCP, was treated with proteinase inhibitors and anticoagulant agents. He was improved and discharged. As pentamidine may cause pancreatitis and develop DIC, it is important that pancreatic enzymes should be carefully followed when this agent administrated. In this case, granulocyte colony-stimulating factor and erythropoietin were effective for the bone marrow suppression, suggesting that importance of these agents for the prophylaxis of other secondary infections during the treatment.


[Clinicopathological review of Japanese cases with neoplastic angioendotheliosis]. The patient was a 76-year-old female who had been referred to our hospital because of fever of unknown origin on October 15, 1987. On admission, the body temperature was 38.6 degrees C and atonic palsy of the left upper limb was noted. Abnormal laboratory findings included CRP5+, an increase in LDH, Hb 7.9 g/dl. The cause of the fever could not be identified. The fever did not respond to various treatment. The patient developed DIC in late October and died on November 5. In autopsy histological examination revealed tumor cells in the vessels of the generalized organs. A diagnosis of neoplastic angioendotheliosis (NAE) and immunohistologically B lymphoma was made. We reviewed the literature on 37 Japanese cases of NAE. The cases, consisting of 19 males and 18 females, were aged 37-87 years with a median value of 60 years. The symptoms observed during the course were most frequently mental or neurological symptoms and fever, and rash was uncommon. Laboratory findings were non-specific and biopsy was needed for definitive diagnosis. By autopsy, lesions were noted more frequently in the brain, kidneys, and lungs, and the findings in the skin were indeterminate. These observations suggest that when NAE should be considered, kidney, lung or skin biopsy should be performed for definitive diagnosis.


[Lumbago as a presentation of B-cell lymphoma invading psoas muscle]. A 73-year-old male had severe lumbago and right inguinal lymphadenopathy. A CT scanning of his abdomen showed marked enlargement of right psoas and erector spinae muscles. The biopsies of the lymph node and the muscles revealed non-Hodgkin's lymphoma of follicular mixed type with muscle invasion. THP-COPE therapy was begun. The swelling of the muscles diminished and the lumbago resolved rapidly. It was reported that clinically prominent infiltration of of lymphoma in skeletal muscle was rarely and psoas muscle was for the most part. We have to consider that psoas muscle invasion of lymphoma cause hard to cure lumbago.


[Mechanism of cytokine pleiotropy and mutual regulation]. Cytokines manifest overlapping effects on many cell types and their production is regulated by a cytokine network. This minireview summarizes the current understanding of how affinity converter molecules, shared by several cytokines, is related to cytokine pleiotropy, and how Th1/Th2 are differentially developed and regulated through a cytokine network, especially, negative loop. Finally, the importance of the temporal expression of cytokines, in relation to the physiological relevance of the network, is pointed out.


[Regulation of proliferation and differentiation of hematopoietic cells by cytokines]. Recent studies on the hematopoietic system have revealed that both constitutive and inducible hematopoiesis are regulated by complicated networks composed of various kinds of cytokines and that there are some general rules for hematopoietic cytokine biology. Further accumulation of knowledge about the regulation of proliferation and differentiation of hematopoietic cells by cytokines will serve to clarify the pathophysiology of hematological diseases, resulting in the development of therapeutic strategy for these diseases.


[Regulation of immune response by cytokine network]. Cytokines are a highly diverse group of intracellular messages. Many cDNAs that encode the cytokines have been cloned in 1980's and the structure of the molecules have been determined. The main function of the cytokines is to amplify the immune and inflammatory responses, keeping them under control at the same time. They orchestrate the response and maintain a proper balance among the various cell types. In this chapter, we summarized the immunoregulation by cytokine network, focussing on the control of antibody production and immunoglobulin class switch by various cytokines produced by helper T cell subsets.


[Inflammation and pro-inflammatory cytokine]. The main pathological feature of inflammation consists of leukocyte infiltration and exudation of plasma into the lesion in the early stage followed by proliferation of connective tissue including fibroblasts, which leads to the formation of granulation tissue. Systemic manifestations include elevation of body temperature and increase of serum acute phase reactants such as C-reactive protein and serum amyloid A. Most of these reactions are presumed to be caused by mediators which are produced by a various kinds of cells and tissues upon contact with inflammatory stimuli, such as bacteria, helminths, viruses, etc. Recently, it has become known that most of inflammatory stimuli induce the production of large amounts of several cytokines including interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF) alpha and that these cytokines exert a wide variety of effects to accelerate inflammation. Hence, these cytokines are called "pro-inflammatory cytokines". These cytokines have overlapping biological functions and induce the production of each other, thus forming a complicated cytokine network. Here, in order to review the roles of these cytokines in the progression of inflammation, the effects on the body temperature, leukocyte infiltration and production of serum acute phase reactants, in particular, will be discussed.


[Membrane receptors and cell transformation]. Here I discuss quantitative and qualitative activation of several receptor-type molecules in tumor cells. Recently we have shown that EGF-R gene is frequently mutated in human glioblastoma. Mutant EGF-R had a 801-bp deletion within the ligand binding domain, and showed a ligand-independent, constitutive elevation of tyrosine kinase activity. This EGF-R mutation is detected only in glioma and associated with gene amplification, suggesting a relationship in the molecular mechanism between deletion mutation and initiation of gene amplification in these cases. Secondly I have shown an activation of mouse CD43 gene by amplification and rearrangement in erythroleukemia cell lines. Intracellular domain of CD43 has no kinase domain but a highly conserved structure among mammals, probably interacting with intracellular signal transducers. Recently CD43 has been demonstrated to be specifically associated with a cell-adhesion molecule ICAM-1. Thus, CD43-ICAM-1 system might be a new type of cytokine system which regulate cell-proliferation through cell-cell interaction. In addition, activation of EpoR and v-mpl is also discussed.


[Antitumor cytokines].

[Antitumor cytokines]. Cytokines have various kinds of functions, including immunoregulation, host defense system, induction of inflammation and pathogenesis of many diseases. One of the characteristics of cytokines is the interaction among cytokines, and they further play an important role in the defense against tumor development, although its mechanism is highly complicated. In this paper, cytokines possessing antitumor activity, are described. These are 2 categories of antitumor cytokines, immunological and non-immunological ones. As immunological cytokines, interferons, interleukin 1, 2, 4, 5, 6, 8 and 12, tumor necrosis factor and lymphotoxin, have been investigated. On the other hand, tumor-degenerating factor, tumor regressing factor, glial maturation factor, glial growth inhibitory factor, neuroblastoma growth inhibitory factor, neonatal brain derived carcinostatic factor, chondromodulin and gliostatin have been characterized as non-immunological antitumor cytokines. These cytokines interact, and the complicated network of immunological and non-immunological antitumor cytokines is formed.


[New cytokines for negative growth regulation]. Considerable evidence has accumulated indicating that proliferation of animal cells is regulated by a balance between positive and negative growth stimuli. To clarify molecular species and physiological roles of growth inhibitors, we have been studying cytostatic or cytotoxic proteins present in different sources, such as sera and conditioned media of cultured cells. One cytostatic and two cytotoxic factors were recently purified from normal rabbit serum and characterized. Other groups also have reported various kinds of growth-inhibitory factors. The properties of these recently reported growth-inhibitory factors and their possible significance are summarized in this article.


[Growth regulation of vascular cells by cytokines]. Cytokines with stimulatory or inhibitory activities for vascular cells are reviewed. Directly or via humoral factors, vascular endothelial cells interact with blood cells, such as lymphocytes, neutrophils and platelets, while smooth muscle cells do so with inflammatory cells. Various cytokines, including IL-1, 6, 7, 8, GM-, G-, M-CSF, a, b-FGF, PDGF, TGF beta, PAF, PA, PAI-1, cell adhesion molecules and endothelin are produced by endothelial cells and/or smooth muscle cells, and in turn they and cytokines produced by blood cells, act as modulators of growth or function of the vascular cells under some physico-pathological states. Vascular cells, especially, endothelial cells might thus be involved in cytokine network.


[Structural similarity and signal transduction of cytokine receptors]. The advent of expression cloning has established a new group of membrane glycoproteins, called the cytokine receptor superfamily. Members of this family have common structural similarities in the extracellular region and no intrinsic tyrosine kinase activity is seen in the intracellular region. A combination of two distinct subunits (alpha and beta) in the family has been shown to generate high-affinity receptors in which the alpha subunits specify the binding and the beta subunits function as transducers that are presumably associated with tyrosine kinases. The high-affinity receptors for IL-3, IL-5 and GM-CSF all share the same beta subunit. The high-affinity receptor for IL-2 is however unique in that it requires a third component, notably, the gamma subunit, whose gene we have recently cloned.


[Studies of physiological functions of cytokines by generating mutant mice through the transgenic and the gene-targeting technology]. Molecular cloning of gene coding for cytokines, growth factors and their receptors have facilitated an accumulation of findings regarding the function of their products. So far, many kinds of functions of such molecules in vitro have been identified. To clarify the physiological roles of such molecules in vivo a variety of cytokine-transgenic mice and a few cytokine-gene targeted mice have been generated. Many of the phenotypes expressed by these animals are as expected from the in vitro assay data, but some are unexpected. In this short article, some of the phenotypes reported are introduced and their significance is discussed.


[Function, molecular structure and gene expression of interleukin-1]. Recent cloning of human and murine IL-1 receptor (IL-1R) has revealed that there are at least two type of IL-1R: type I IL-1R is detected on T cells and fibroblasts and consists of 552 AAs with a cytoplasmic domain of 213 AAs, while type II is detected on B cells and monocytic cell lines and consists of 398 AAs with a short stretch intracytoplasmic domain of 29 AAs. Extracytoplasmic portion of IL-1R has some homology with vaccinia virus B15 Ag or fibroblast protein ST-2, while cytoplasmic portion has considerable similarity with Drosophila toll gene. By transfecting murine type I IL-1R cDNA into a human Jurkat cell line, structural and functional potion required for the IL-1 signal transduction is determined. At least broad portion of cytoplasmic domain including 364-474 AAs from N-terminus are found to be essential, while PKC acceptor site (Ser-431 and Ser-509), and PKA acceptor site (Ser-528) are not essential for the IL-8 gene expression.


[Function, molecular structure and gene expression of IL-2 and the receptors]. The Interleukin 2 receptor is now assumed to be composed of three chains, the L (alpha or Tac), H (beta) chain and p56. The L chain binds IL-2 with low affinity, whereas intermediate-affinity binding of IL-2 is achieved by an association of p56 and the H chain. The high-affinity IL-2R is therefore believed to be a quaternary complex composed of the L chain, the H chain, p56 and IL-2. A larger number of L chains enhances the association rate of IL-2 to form the high-affinity IL-2R in agreement with the stepwise binding model. The signal transduction-competent H chain has been shown to associate with p56lck upon IL-2 stimulation.


[IL-3 gene, receptor and signal transduction]. Interleukin 3 (IL-3) plays a critical role in growth and differentiation of myeloid cells. The human IL-3 gene, located on chromosome 5 contains several cis-acting DNA sequences, i.e. CLE (conserved lymphokine element) and a GC rich region, similar to the GM-CSF gene. The expression of the GM-CSF and IL-3 genes in activated T cells may be regulated coordinately through these cis-regulatory elements. Recently, reconstitution experiments using isolated cDNA clones for receptor subunits have revealed that two distinct proteins are required for the high affinity receptors for GM-CSF, IL-3 and IL-5; the alpha subunits bind with the corresponding ligands with low affinity, and the beta subunit is shared in common. Tyrosine kinase activity appears to be involved in the signal transduction of the IL-3 and GM-CSF receptors.


[Function, molecular structure and gene expression of IL-4]. Interleukin-4 (IL-4) is a T-lymphocyte-derived 20-kDa glycoprotein that has a broad spectrum of biological activity including growth and differentiation of T cells, B cells, mast cells, hematopoietic cells and non-hematopoietic cells. The biological effects of IL-4 are induced by binding to specific membrane receptors (IL-4R) on target cells. Molecular cloning of IL-4R revealed a novel cytokine receptor family, but not clues as to the signalling mechanism. The biochemical mechanism of IL-4 signal, induced by its specific binding, remains to be clarified. Recent studies on the physiological function of IL-4 are presented here.


[IL-5-and its receptor--the role of IL-5 in the development of hematopoietic cells in the long-term bone marrow cultures]. IL-5 is a T-cell-derived glycoprotein that acts on B cells and eosinophils to induce their growth and differentiation. We clarified using in vitro long-term bone marrow culture that IL-5 supports the growth and survival of Ly-1+ common progenitor cells which can differentiate into Ly-1+ B cells and Ly-1+ macrophages. The functional IL-5 receptor (IL-5R) consists of alpha and beta heterodimers. The 60 kDa alpha chain binds to IL-5 with low affinity, while the 130 kDa beta chain does not bind with IL-5 by itself, but converts low affinity IL-5R to high affinity IL-5R together with the alpha chain. The beta chain is shared with GM-CSFR and IL-3R.


[The interleukin-6 signal transducer, gp130, functioning in immune, hematopoietic, and neural systems]. Functional pleiotropy and redundancy are characteristic features of cytokines. To understand the signaling mechanisms of such cytokines, we have proposed a two-chain interleukin-6 receptor (IL-6-R) model: IL-6 triggers the association of a ligand-binding chain (IL-6-R) and a non-binding signal transducer (gp130) to form a high-affinity receptor complex, causing transmission of the signal by the cytoplasmic portion of gp130. This model would explain the functional redundancy of cytokines if we were to assume that gp130 interacts with several different receptor chains. Here we present data indicating that gp130 functions as a common signal transducer for IL-6, oncostatin M (OM), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF). We show that anti-gp130 monoclonal antibodies completely block the biological responses induced by all of these factors. Since LIF functions as a cholinergic differentiation factor in nerve cells as does CNTF, these results suggest that gp130 may also play a role in the neural system.


[Molecular aspects of IL-7-IL-7 receptor system]. IL-7 is a multifunctional cytokine which acts on cells such as B cells, T cells and macrophages. As the IL-7 clearly plays many important roles the in control of growth and differentiation, it is important to understand how IL-7 and IL-7 receptor (IL-7R) are expressed. Recently, to understand the transcriptional regulation of IL-7 and IL-7R genes, a detailed analysis of the 5' flanking region of the IL-7 and IL-7R genes has been done. In this review recent progress on these topics is introduced and discussed.


[Function, molecular structure and gene expression of IL-8]. Interleukin-8 (IL-8) is a potent chemotactic factor for neutrophils and T lymphocytes. Various reagents such as lectins, mitogens, IL-1, TNF, induce IL-8 production in a wide range of cells and tissues. The IL-8 gene is known to be activated by AP-1, NF-kB like factor and C/EBP like factor, but the relative importance of these transcriptional factors varies from cell to cell. Two types of human IL-8 receptor cDNA have recently been cloned. Both are G-protein coupled receptors and the amino acid sequences are highly homologous. Other members of the IL-8 family, such as GRO/MGSA and MIP2, bind to IL-8 receptors, and the receptors of other chemoattractants such as fMLP and C5a, show high homology to the IL-8 receptors.


[Function, molecular structure and gene expression regulation of interleukin 9 (IL-9)]. Interleukin-9 (IL-9)/P40 is a recently reported murine growth factor for helper T-cell clones. It is produced by ConA stimulated CD4+ T-cells or several T-cell lines such as TUC 2.15 derived from C57Bl/6 mouse. In the murine system, IL-9/P40 directly supported proliferation of mucosal type mast cells, and also induced erythroid burst formation, indirectly. On the other hand, human IL-9, which is a homologue to murine P40, was cloned from a cDNA library prepared with mRNA isolated from PHA-induced T-cell line (C5MJ2). Analysis of the sequence of cDNA revealed a striking similarity between murine and human IL-9/P40. Human IL-9 supported formation of a subpopulation of erythroid bursts that are responsive to IL-3. In this communication, identification, cloning of cDNA, and biological activities of murine and human IL-9/P40 are discussed.


[Function, molecular structure and gene expression regulation of interleukin-10 (IL-10)]. Interleukin-10 has a variety of biological activities. Murine interleukin-10 inhibits cytokine production by Th2 cells in the presence of macrophages, enhances T cell proliferation, sustains the viability of B cells in vitro, induces class II MHC antigen expression on B cells, enhances mast cell proliferation in the presence of IL-3 and/or IL-4, and inhibits cytokine production by macrophages. Human interleukin-10 inhibits cytokine production by human T cells and reduces antigen-specific human T cell proliferation by downregulation of class II MHC antigen expression on monocytes. cDNA clones encoding murine and human interleukin-10 exhibit a strong homology to BCRFI in Epstein-Barr virus. BCRFI conserves only a part of interleukin-10 activities.


[Function, molecular structure and gene expression of interleukin-11 (IL-11/AGIF)]. Interleukin-11 (IL-11) is a novel cytokine that was identified in a medium conditioned by the primate bone marrow-derived stromal cell line PU-34. It was originally identified as a growth factor for the IL-6-dependent plasmacytoma cell line T1165. Adipogenesis inhibitory factor (AGIF) was cloned from the human bone marrow-derived cell line KM-102. The AGIF cDNA sequence was revealed to be identical to that of the IL-11 cDNA. AGIF inhibits the process of adipogenesis of the bone marrow-derived preadipocyte cell line H-1/A. Other biological activities of IL-11/AGIF, megakaryocytopoiesis, stem-cell proliferation, hepatic acute phase responses and antigen-specific antibody responses are also summarized.


[Function,molecular structure and gene expression of macrophage colony-stimulating factor]. Human urinary macrophage colony-stimulating factor (hM-CSF) is a glycoprotein with a molecular weight of 85 kDa which consists of two homologous subunits with a molecular weight of 43 kDa. It stimulates monocyte production through the stimulation of progenitor cells to differentiate to mature monocytes as well as neutrophil production through the stimulation of mature monocytes to produce granulocyte-macrophage and granulocyte CSF. It also enhances platelet production through the production of megakaryocyte potentiator (Meg-POT). Recently, proteoglycan type M-CSF has been found by our group. This type of M-CSF has a molecular weight of greater than 200 kDa and consists of a 43 kDa subunit and a 150-200 kDa subunit, the latter of which contains chondroitin sulfate glycosaminoglycan. This proteoglycan type M-CSF binds to extra-cellular matrix at the part of glycosaminoglycan. In addition to hematopoiesis-stimulating activity, M-CSF has a promoting activity on monocyte tumor-killing, osteoclast production and differentiation of cytotrophoblasts to syncytiotrophoblasts which secrete gonadotropin. M-CSF receptor (M-CSF-R) was found as a product of proto-oncogene, c-fms which consists of 972 amino acids. Mutations at Tyr 969 and Ser 301 of M-CSF-R has been found in patients with myelodysplastic syndrome and monocytic leukemia.


[Function, molecular structure and gene expression of granulocyte-macrophage colony stimulating factor]. Granulocyte-macrophage colony stimulating factor (GM-CSF), a 22 kDa glycoprotein secreted from activated T cells and stroma cells, plays an important role, both in the constructive and inducible hemopoiesis, by stimulating a wide range of hemopoietic cells. After the cloning of receptor genes, the high affinity GM-CSF receptor was reconstituted by the combination of cloned 80 kDa molecule (alpha chain) and 120 kDa molecule (beta chain). This human GM-CSF receptor beta chain also works as a beta chain of IL-3 or IL-5 high affinity receptor. The fact that the alpha chains of GM-CSF, IL-3 and IL-5 share the same beta chain may define a biological interaction among these three cytokines.


[Function, molecular structure and gene expression regulation of erythropoietin]. Erythropoietin (EPO) is a glycoprotein hormone which enhances red blood cell production by stimulating growth and differentiation of erythroid progenitor cells. Recombinant human EPO (huEPO), expressed in CHO cells, is highly similar to urinary huEPO with respect to both structural and functional properties. EPO production is primarily localized to peritubular interstitial cells in the cortex of the kidney. Increased EPO production due to anemia seems to be correlated with increased numbers of EPO-producing cells rather than with increased production by the individual EPO-producing cells. A heme protein is proposed to be the oxygen sensor. Tissue-specific and hypoxia-inducible expression of EPO gene is governed by multiple regulatory elements. Murine CFU-E from the spleens of mice, infected with the anemia-inducing strain of Friend virus, differentiate into reticulocytes in response to EPO. EPO appears to prevent CFU-E from programmed death (apoptosis). The gene for mouse EPO receptor produces 65 Kd protein on the cell surface. This protein seems to be specifically associated with another 100 Kd and/or 85 Kd proteins. The gene for human EPO receptor was also cloned, based on its similarity to murine counterpart. EPO receptor belongs to a novel class of receptors termed the cytokine receptor superfamily.


[Epidermal growth factor and its receptor: the structure and function]. Epidermal growth factor (EGF) binds to the specific membrane receptor and subsequently activates the signal transduction pathway through intrinsic tyrosine kinase activity. To elucidate the mechanism in which structural alteration of the EGF may affect functional properties including its receptor binding ability, site-directed mutagenesis has been employed. The functional significance of structural characteristics of the EGF receptor has been studied also by mutant receptor constructs in the transfected cells. Recent progress on the studies of the EGF and EGF receptor interaction are reviewed.


[Function, molecular structure and gene expression of fibroblast growth factor (FGF/HBGF)]. The structure and function of members of the fibroblast growth factor (FGF) gene family and their receptors are reviewed. All the member of this gene family bind heparin, and therefore, are also called the as heparin-binding growth factor (HBGF). In this review, the structural features of FGF/HBGF are summarized first, and general features of the structure and function of their receptors are then described briefly. After biological effects of FGF/HBGF on adult-type tissues and cultured cells are reviewed, effects of FGF on the mesodermal induction in amphibian (Xenopus laevis) embryonic system are reviewed in more detail. Emphasis is given on the experiments with Xenopus animal cap assay system and also on the injection into Xenopus fertilized eggs of mRNA of dominant defect mutant of FGF receptor, which leads to the formation of embryos with abnormal axial mesoderm.


[Function, molecular structure and gene expression regulation of Platelet-derived growth factor]. Platelet-derived growth factor (PDGF) is a cationic glycoprotein of approximately 30 kDa, composed of two subunits. These subunit chains are termed A (18 kDa) and B (12-14 kDa) with high homology of the peptide sequences, including 8 cysteine residues at identical positions. Three isoforms of PDGF, AA, BB homodimers and AB heterodimer are distributed in the different tissues and cell lines suggesting that these isoforms have different functions. Two types of PDGF receptors alpha, and beta with Mr of 160-180 kDa are seen on the cell surface. PDGFR alpha can bind to both A and B subunits of the PDGD, while PDGFR beta, only B subunit. PDGF (AA) combines alpha alpha, PDGF (AB) makes dimers of alpha alpha and alpha beta, and PDGF (BB) can make three types of dimers, alpha alpha, alpha beta, and beta beta. These dimeric PDGFRs are active forms and phosphorylate its own domain and other neighbor specific proteins. The substrates of the receptor kinase are phospholipase C-gamma, GTPase activating protein (GAP), serine/threonine kinase Raf-1 and others. These molecules are thought to transfer information of the PDGFs on its receptors to the nucleus.


[Function, molecular structure and gene expression regulation of nerve growth factor]. Nerve growth factor (NGF) is the initially discovered and best characterized target-derived neurotrophic factor. The NGF gene family includes NGF, brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, NT-4, and NT-5. The members of this family can interact with the members of trk family of receptor-like protein-tyrosine kinases (trk, trk B and trk C), suggesting that the different trk protein serves as receptor subunits for the different neurotrophins. Meanwhile, some recent reports have shown that exogenous administration of NGF itself or a stimulator of NGF synthesis to damaged neurons have beneficial effects. These findings open the possibility of new therapy for nervous diseases, such as Alzheimer's disease.


[Function, molecular structure and gene expression of insulin-like growth factors ]. In this short review, gene structure, transcriptional pattern, biological activity, specific receptors and binding proteins for insulin-like growth factors (IGF: IGF I and IGF II) are explained. In spite of their close similarity in both gene and peptide structures, their receptors are completely distinct from each other in molecular structure and in signal transduction. Expression of IGF function in vivo is strongly restricted by plasma binding proteins.


[Function, molecular structure and gene expression regulation of transforming growth factor-beta (TGF-beta)]. Transforming growth factor-beta (TGF-beta) is a multifunctional peptide growth factor widely distributed in vertebrates and represents a prototype of a large family of structurally related factors that regulate various cellular functions, ranging from amphibian embryonal development to hormone production in the human pituitary. TGF-beta is a disulfide-bonded homodimer of a subunit of 12.5 kD that is derived from a much larger precursor. The amino acid sequences of TGF-betas are highly conserved among species, suggesting their physiological importance. TGF-beta was originally isolated from human platelets as a factor that induces anchorage-independent growth of normal fibroblasts. However, later studies have revealed that its major biological activities include inhibition of cell proliferation, and regulation of differentiation, cell adhesion and extracellular matrix deposition. There are three types of cellular receptors that bind TGF-beta. Type II receptor, of which cDNA was recently cloned, is a functional serine/threonine kinase and is thought to be involved in the TGF-beta-mediated signal transduction pathway. The importance of TGF-beta in clinical medicine will increase not only as it is a promising therapeutic drug, but also as its excessive activity can be the cause of various human fibrotic diseases.


[Function, molecular structure and gene expression regulation of LD78]. LD78 is a member of a new cytokine superfamily, consisting of at least twelve small proteins, which are involved in inflammation and cell growth. Depending on their primary structure, these cytokines can be divided into two families, one of which contains LD78 and is known as the CC family. The protein and gene structures and the physiological functions of LD78 in comparison with the other CC family members are summarized here. Furthermore, the generation mechanism of the three LD78 genes and their expression are discussed.


[Function, molecular structure and gene expression regulation of receptor for D-factor/LIF]. Differentiation-stimulating factor (D-factor)/leukemia inhibitory factor (LIF) is a cytokine inducing differentiation of mouse myeloid leukemic M1 cells. IL-6, oncostatin M (OSM) and G-CSF also induce differentiation of M1 cells. These four cytokines are suggested to be members of a single cytokine family. The LIF receptor is structurally related to the gp130 signal-transducing component of the IL-6 receptor and to the G-CSF receptor. The high-affinity receptors for LIF, OSM and IL-6 share the common subunit, gp130. This provides an explanation for the functional redundancy of those cytokines.


[Structure and biological property of fibroblast-derived tumor cytotoxic factor (F-TCF)]. Fibroblast-derived tumor cytotoxic factor (F-TCF), isolated from human embryonic lung fibroblasts, is cytotoxic against various human and mouse tumor cells. Physicochemical and biological properties indicate that F-TCF is closely similar to hepatocyte growth factors (HGFs), cDNAs of which are isolated from human liver and placenta. Isolation and expression of F-TCF cDNA revealed that F-TCF was identical to the placenta type HGFs, including a variant with a deletion of 15 base pairs in the coding region. The deleted form of recombinant HGF (rHGF) had slightly lower heparin binding affinity than the intact form. Specific activities of rHGFs were almost the same in tumor cytotoxic activity, but different in hepatocyte growth stimulating activity. These results indicate that deletion of five amino acids results in conformational change which alter biological activity.


[Therapy with interleukin 2 for chronic viral hepatitis]. We administered 250-10,000 u of recombinant interleukin 2 (r-IL2) for 1-4 weeks intravenously or intramuscularly to patients with chronic hepatitis B positive for serum HBe antigen as immunostimulants and studied the effect of r-IL2 for antiviral system. Serum ALT levels increased during the therapy and then decreased after the treatment. Activities of DNA-P were gradually reduced and became negative in 6 of 11 cases. Serum HBeAg decreased and anti-HBe increased during and after the therapy. Peripheral lymphocytes and eosinocytes increased during the therapy but returned to the pretreatment level after the therapy. TSI (%) increased rapidly and TS (%) decreased during infusion of r-IL2. However, TH/TS ratio increased after the infusion since TH (%) decreased gradually during the infusion of r-IL2. The r-IL2 therapy was useful for chronic hepatitis with serum HBe antigen as therapy with immunostimulant or treatment with biological response modifier (BRM).


[Acid-base regulation: a general introduction]. Acid-base homeostasis of the body fluid in all the animal species including humans is now recognized to be kept at 0.6-0.7 unit higher than neutral pH (pN). This concept is called relative constant alkalinity. It has also found that intracellular pH is approximately kept at pN, so that the difference between extracellular (pHo) and intracellular pH (pHi) is again 0.6-0.7. Since pN increases about 0.016 unit/1 degree C with decreasing temperature, normal blood pH at 20 degrees C is about 7.7 in cold-blooded animals as well as in humans with low temperature e.g. during special operative procedure. The main physiological significance for maintaining pHi at pN is that ionized small molecules in the cell are held within the intracellular space and metabolic process can be proceeded smoothly.


[Measurement of intracellular pH].

[Measurement of intracellular pH]. Since various cellular processes depend on changes in pH, the regulation of intracellular pH (pHi) is important both for the individual cell and for the organism. The mechanisms of the regulation of pHi can be investigated by monitoring pHi. In this report, we discuss the four major techniques available for measuring pHi, which are 1) Distribution of weak acids and bases, 2) pH-sensitive microelectrodes, 3) pH-sensitive dyes, and 4) Nuclear magnetic resonance. Among four techniques, the advantage of the microelectrode approach is that it can monitor membrane potential at the same time and be applied to a single cell. The dye technique is a relative new developing technique, which has lots of advantages. It is easy to use, and is capable of monitoring rapid pHi changes, and being applied to a smaller cell, or a single cell.


[Band 3 protein, anion exchange protein of the erythrocyte membrane]. Band 3 protein is the major transmembrane protein of the erythrocyte membrane, comprising 25% of the total membrane protein and existing at 10(6) copies per cell, and mediates the rapid exchange of anions across the membrane. The exchange of Cl- for HCO3- anions plays an important role on the regulation of oxygen and bicarbonate delivary to or from peripheral tissues. Band 3 protein has functionally distinct two domains. The membrane-spanning domain, 55K domain, is believed to span the membrane bilayer 14 times and mediates the rapid anion exchange. The complementary cytosolic domain, 40K domain, is an anchor for the cytoskeletal proteins and regulates the cell deformability and the cell life span. The purpose of this paper is to review the physiological functions of band 3 protein and the anion exchange mechanisms.


[Respiratory regulation system].

[Respiratory regulation system]. In 1874, Kussmaul described "featiful terminal dyspnea" in a case of severe diabetic coma. Probably, this was the first sign of respiratory regulation for metabolic acidosis. After this first case, about 40 years has been needed to establish the theory of acid-base equiribration, namely Henderson-Hasselbalch's equation. pH = 6.1 + log [HCO3-]/[H2CO3] This equation indicates that plasma pH is determined by the ratio of HCO3 concentration and H2CO3 concentration. Because of linear relationship between H2CO3 and PaCO2, pH depend on the ratio of HCO3- and PaCO2. In the state of metabolic acidosis, increase of [H+] stimulates ventilation and decreases the PaCO2. Inversely, in the state of metabolic alkalosis, increase of PaCO2 occurs. These reactions are called "respiratory compensation" or "respiratory regulation". The respiratory regulation system will not retern pH to normal (7.4), but compensation has some limitation which is shown as "SIGNIFICANCE BAND". In this paper, physiological and clinical importance of respiratory regulation and significance band is discussed.


[Acid-base equilibrium control system--red cell function]. The physiological functions of the red cell are oxygen transport, facilitation of carbon dioxide transport and control of acid-base equilibrium in the blood. The last function is closely related to the first two, which are cooperative to each other. The oxygen transport by red cells is characterized by high efficiency and regulation, which depend on allosteric properties of hemoglobin. The CO2 transport in the form of bicarbonate is also facilitated by the buffer action and the Haldane effect of hemoglobin. Hemoglobin is the major buffer system in the red cell. Its buffer power is strengthen through the Haldane effect. Carbonic anhydrase in red cell, together with band 3 protein in the membrane which facilitates the Cl-/HCO3- exchange across membrane, allows the conversion between CO2 and HCO3- and the buffering of carbonic acid to occur in a time scale of blood circulation.


[Urinary acidification].

[Urinary acidification]. Current understanding of the features and mechanisms of renal acidification along the nephron segments is summarized. Emphasis is placed on recent approaches to the "structure and function" of H/HCO3 transport proteins by molecular techniques. The amount of renal acidification is strictly matched to the endogenous production of non-volantile acids. This regulation is handled by many factors, including blood acid-base parameters, aldosteron, distal delivery of Na and accompanying anions, extracellular fluid volume, and PTH. Cellular mechanisms of these regulatory factors are summarized.


[The interaction between neural activity and intracellular pH]. The regulation of intracellular pH (pH(i)) in the nervous system has been vigorously studied using a variety of animal cells in the last decade, through advances in techniques for measuring pH(i) accurately in living cells. These studies have elucidated the mechanisms of pH(i) regulation, such as intracellular buffering and acid transport across the cell membrane, in neurons and glial cells. Following an outline of pH(i) regulation, the interaction between neural activity and acid-base balance is discussed. The dynamic change of pH(i), produced by neural activity, and the effect of pH(i) on the electrical properties of neurons and other excitable cells is emphasized.


[Acid-base balance and contraction of the cardiac muscle]. In cardiac muscle, intracelular pH (pHi) is regulated to close to 7.1, both by membrane transport systems (Na-H and Cl-HCO3 exchange) and intracellular H+ buffers. Internal acidosis depresses the contraction, while alkalosis increases it. Internal proton depresses the contraction even without altering the internal concentration of Ca (Cai). The proton blocks the Ca channels. However, as it releases membrane-bound Ca and the influx of Na via Na-H exchange increases Ca influx through Na-Ca exchange, pHi decrease is often accompanied by the Cai increases. The internal proton also affects the uptake and release of sarcoplasmic reticulum, Ca binding to troponin, actomyosin dynamics and variable catalytic processes.


[Effects of pH on vascular smooth muscle contraction]. Effects of pH on vascular smooth muscle contractility were reviewed. Basic effect of acidosis seems to be the inhibition of K channels and L-type Ca channels. Inhibition of K channels results in a membrane depolarization, opening of L-type Ca channels, increase in Ca influx and muscle contraction. Inhibition of Ca channels results in an opposit effect. Thus, the effect of acidosis is determined by the relative potency of these two contradictory effects. This may be the reason why acidosis induces contraction in polarized muscle whereas it slightly inhibits contraction in depolarized muscle. In addition, measurements of cytosolic Ca level simultaneously with muscle tension suggest that acidosis increases Ca sensitivity of contractile elements, and this effect also helps acidosis to induce contraction in vascular smooth muscle.


[Effect of pH on blood cells].

[Effect of pH on blood cells]. Intracellular pH of blood cells is controlled by the Na+/H+ exchanger and anion channels. The Na+/H+ exchanger plays a major role in elevating intracellular pH in activated platelets, lymphocytes and neutrophils. In lymphocytes, intracellular alkalinization is associated with proliferation and differentiation. In platelets, protein kinase appears to increase the turnover rate of Na+/H+ exchange, thus accelerating the process of alkalinization. Intracellular alkalinization serves to increase the energy supply by glycolysis, and to activate the production of thromboxane A2, a potent activator of platelets. Clinically an increased activity of the Na+/H+ exchanger has been demonstrated with platelets from hypertensive patients.


[Renal adaptations to acid-base disorders]. Alterations in acid-base status affect renal hemodynamics and tubular function. GFR is reduced both in acute acidosis and alkalosis. Tubular functional adaptation to acute acidosis includes an acceleration in proximal acidification, induced by the increase in Pco2 and luminal bicarbonate concentration and a stimulated ammonia production, induced by low pH. Alteration in distal bicarbonate reabsorption is also an important determinant of the net acid excretion. Renal functional alterations in acute alkalosis include a reduction in GFR and a stimulated bicarbonate secretion in the cortical collecting duct. Proximal acidification is almost unchanged during acute alkalosis but reportedly accelerates after at least 3 weeks of maintained alkalosis. Renal adaptation during chronic phase of acid-base disorders differs from that during the acute phase.


[Effects of pH on the endocrine system and metabolism]. Changes in extra- and intracellular pH affect metabolic states and hormone responses. In general, alkalosis stimulates and acidosis inhibits glycolysis although the relationship is not a simple one. 6-phosphofructo-1-kinase, a rate limiting enzyme in glycolysis, seems to be activated directly by a rise in pH. Alkalosis stimulates the production of pyruvic acid and lactic acid. Citric acid cycle is stimulated in alkalosis and hexose monophosphate shunt pathway is facilitated in acidosis. Acid-base disorders affect the insulin secretion and insulin action. In acidosis, insulin action in the target tissues is reduced. Other hormones, including parathormone, renin-angiotensin-aldosterone system, and adrenocorticotropine, respond to the changes in pH.


[Clinical aspects of acid-base disorders]. Acid-base disorders are frequently recognized in a wide variety of clinical settings such as severe systemic hospitalized patients. The principal object is to assessment of acid-base equilibrium and to obtain an appropriate guide to therapy. The approach is centered to a systemic analysis of blood gas evaluation. To establish this complex matter is followed. Is an acid-base disorder present? Is the disorder a simple or a mixed abnormality? What is the primary cause? These evaluations should be obtained by accurate history taking, physical examination, and routine laboratory tests. In addition, the supporting analysises such as anion gap (AG) calculation, urine AG assessment, urine chloride concentration and so on are also useful for correct diagnosis. In view of the complexty and difficult expression of acid-base disorders, it is desirable that clinicians must have full knowledges of systemic approach to the blood gas analysis and its evaluation.


[Diagnosis, countermeasure and classification of acidosis]. Acidosis is the result of the net addition of hydrogen ion to the extracellular space or loss of bicarbonate from that space. Hydrogen ion may be added by the increased production of strong acids, an increase in CO2 concentration, or the addition of exogenous acids. The common approach to the differential diagnosis of metabolic acidosis is to divide the patients into two categories based on whether the anion gap in plasma is increased or not. Metabolic acidosis with normal anion gap (hyperchloremic) suggests that bicarbonate has been effectively replaced by chloride. In contrast, metabolic acidosis with an increased anion gap suggests addition to the body fluids of an acid other than hydrochloric acids or its equivalent.


[Diagnosis, therapy and classification of alkalosis]. The pathogenesis, classification, diagnosis and treatment of alkalosis are described. Alkalemia is defined as an elevation in the blood pH and alkalosis refers to processes that tend to raise the pH, and divided into two types; metabolic alkalosis (a primary increase in plasma HCO3- concentration) and respiratory alkalosis (a primary decrease in PCO2). These disorders are most frequently observed in the hospitalized patients. As the critically ill-patients with severe alkalemia are often associated with high mortality, treatment should be directed to the underlying diseases and severe alkalemia should be corrected promptly.


[Mixed acid-base disorders].

[Mixed acid-base disorders]. Maintenance of the acid-base balance is critical for keeping cellular and whole body integrity, and acid-base disturbances are commonly encountered in critically ill patients. In this chapter, the classification and the pathogenesis of mixed acid-base disorders are reviewed in order to understand and manage these abnormalities. First of all, the compensatory reactions to the primary acid-base state must be evaluated. Careful examination of the physical findings and medical history are also essential for making a correct diagnosis and to treat the patients effectively.


[Graphic evaluation of the significance band for hypercapnia in pulmonary disorders]. Alveolar hypoventilation due to the chronic obstruction of the airway such as pulmonary emphysema, or severe restrictive dysfunction due to sequela of pulmonary tuberculosis causes chronic hypercapnia (chronic respiratory acidosis). Ninety-five percentile of significance band of chronic and acute hypercapnia of both experimental and clinical setting is introduced in the graphic display of the acid-base balance. On acute exacerbation of these disorders, examination of arterial blood gas in series are usually plotted along the significance band of hypercapnia. With clinical improvement, the plot will gradually drop down to the chronic stable area of the band. Although cases with metabolic disorders complicate the interpretation, evaluation of the acid-base status using the graphic display will be of help at bedside assessment.


[Acid-base disturbances in heart failure]. Disturbance in acid-base balance is commonly observed in patients with heart failure. The most common disturbance is metabolic alkalosis combined with hypokalemia, as a result of the excessive use of loop diuretics. Occasionary, hypoxia due to pulmonary edema stimulates ventilation, resulting in respiratory alkalosis. When pulmonary edema develops, carbon dioxide retention occurs, resulting in respiratory acidosis. Decreased tissue oxygen delivery may also produce lethal lactic acidosis. Compensatory mechanisms, coexistence of independent acid-base disorders and changes in electrolytes complicate acid-base balance in the individual patients. As acid-base disturbances have harmful effects on the cardiovascular system, precise diagnosis and proper treatment are highly important.


[Impairment of acid-base balance in renal failure]. It is very critical for the living organism to maintain homeostasis of body fluid volume and its electrolyte composition by renal regulation, including acid-base balance. In renal failure, impaired acid-base balance is inescapable because of disturbed urinary acidification, one of the major renal functions. Among all types of acid-base imbalance, metabolic acidosis is a major one in renal failure. For better understanding of this issue, several fundamental items for the renal mechanisms of urinary acidification must be discussed first, and the pathophysiological features and their relevant treatment for acid-base imbalances in renal failure, next. Moreover, some comments on the practical aspects, in long-term dialyze uremic patients, is also provided.


[Disorders of acid-base balance in liver disease]. Disorders of acid-base balance are frequently encountered in fulminant hepatic failure, liver cirrhosis and autoimmune liver diseases. The disorders per se except lactic acidosis rarely poses serious clinical problems. However metabolic alkalosis induced by administration of diuretics and hypokalemia in renal tubular acidosis are risk factors for hepatic encephalopathy.


[Acid-base disturbance in adrenal and parathyroid diseases]. Aldosterone stimulates sodium absorption in the collecting tubule, which makes the potential more lumen-negative, and secondarily stimulates proton and potassium secretion. Potassium depletion stimulates ammonia synthesis, which increases distal buffer delivery, increases luminal pH in the collecting tubule, and secondarily stimulates proton secretion. This stimulation of the distal nephron acidification by aldosterone can result in metabolic alkalosis. Inversely, aldosterone deficiency can produce characteristic metabolic acidosis with hyperkalemia (type IV renal tubular acidosis). Acute administration of parathyroidhormone (PTH) decreases renal bicarbonate reabsorption in the proximal tubule. Since the effect of PTH is overridden by other factors, such as PTH-induced base release from bone, hyperparathyroidism does not uniformly cause metabolic acidosis.


[Renal tubular acidosis].

[Renal tubular acidosis]. Renal tubular acidosis (RTA) can be separated into three main types: distal RTA (the defect in the excretion of hydrogen ion), proximal RTA (the defect in the reabsorption of bicarbonate), and hyperkalemic RTA. Some patients present combined types of proximal and distal RTA. Most of the pediatric patients with RTA manifest failure to thrive. They have hyperchloremic metabolic acidosis and normal plasma anion gap. Fractional excretion of bicarbonate is below 5% in dRTA and over 15% in pRTA. Renal complications of dRTA are nephrocalcinosis, renal calculi, renal cysts and reversible low molecular weight proteinuria. The patient with isolated pRTA is very rare.


[Acid-base balance disorder in various diseases--diabetes mellitus]. Metabolic acidosis is the serious acid-base balance disorder complicated in diabetes mellitus. The pathogenesis and treatment of various type of metabolic acidosis (Keto-acidosis, lactic acidosis, hyperchloremic acidosis and type IV renal tubular acidosis) are discussed. Metabolic acidosis in the diabetic patient is associated with an increased anion-gap caused by the presence of organic anion (beta-hydroxybutyrate, acetoacetate, and lactate). The rise in anion-gap usually equals the fall in plasma bicarbonate. With appropriate therapy, progressive decline in the anion-gap is one of the best indications of successful treatment. If hyperchloremic acidosis is established, appropriate infusion of hypochloremic rehydration fluid may be useful.


[Acid-base disturbances in hematologic diseases]. In this article, the acid-base disturbances encountered in hematologic diseases are discussed. Occurrence of lactic acidosis (LA) without obvious clinical tissue hypoxia has been reported in patients with leukemia and lymphoma. Most of the patients with LA had liver involvement and clinical evidence of impaired hepatic function, suggesting that both increased production and decreased lactate metabolism are necessary for the development of LA in leukemia and lymphoma. Acute tumor lysis syndrome consists of hyperuricemia, hyperpotassemia, and hyperphosphatemia with hypocalcemia following neoplastic cell lysis, particularly in lymphoproliferative disorders. In patients with multiple myeloma (MM), proximal renal tubular acidosis (Fanconi syndrome) associated with Bence Jones proteinuria has been reported. In addition, MM is one of the first conditions recognized to be associated with lower anion gap.


[Acid-base disorders in anesthesiology and in related fields]. Acid-Base disorders in anesthesia and in related fields were discussed. Four topics were chosen because they are relatively new and attracting attentions. They are 1) Monitoring Petco2 in anesthesia and in Intensive Care, 2) Relationships between newly established laparoscopic surgery and ventilatory impairment/elevation of Paco2, 3) Surgery in which large amount of chloride ion is absorbed, and 4) High venous Pco2 in resuscitation.


[Drug-induced acid-base disorders].

[Drug-induced acid-base disorders]. Drug-induced acid-base disorders may be classified into four categories with respect to the mechanism. 1. Metabolic acidosis is induced by a large acid loads incurred from exogenous sources (e.g. NH4Cl, or toxin ingestion) or endogenous acid production (e.g. generation of ketoacids or lactic acids by alcohol or phenformin) or base loss (e.g. abuse of laxatives). 2. Metabolic alkalosis results from exogenous bicarbonate loads (e.g. milk-alkali syndrome) or effective extracellular fluid contraction, potassium depletion plus hyperaldosteronism (e.g. vomiting, diuretics, or licorice). 3. Renal tubular acidosis is induced by the drugs which mainly impair proximal and/or distal tubules (e.g. vitamin D, NSAID, acetazolamide or amphotericin B). 4. Respiratory acidosis or alkalosis results from drug-induced respiratory center depression or neuromuscular impairment (e.g. anesthetic, sedative overdosage or curare) or hyperventilation (salicylates, paraldehyde, epinephrine, or nicotine).


[Acid-base disturbances in surgical operation]. Metabolic acidosis immediately after surgical operation is followed by metabolic alkalosis. Hormonal change by surgical stress and anaerobic glucolysis due to tissue ischemia cause initial lactic acidosis. Later alkalosis may be caused by secondary aldosteronism and bicarbonate production from lactate and citrate supplied by massive infusion and transfusion. Postoperative complications, such as respiratory insufficiency, renal failure and hypovolemic or septic shock, cause acidosis. In the gastrointestinal surgery, acidosis can be caused by starvation and loss of bicarbonate contained in bile, pancreatic juice or intestinal fluid, and alkalosis can be caused by loss of HCl in gastric juice. Severe acidosis can be caused by extracorporeal circulation, hypothermia, low output syndrome or declamping shock in cardioaortic surgery.


[Acid-base disturbances in pediatrics].

[Acid-base disturbances in pediatrics]. Acid-base balance is regulated by respiratory and metabolic factors and also by the compensatory mechanisms of the body. This balance is often disturbed by various diseases or conditions in children. These diseases or conditions which cause acidosis or alkalosis in pediatric practice are presented and discussed in this paper with special interest in their age at presentation.


[Abnormalities in acid-base balance in the elderly]. Physiological decline in the ability to adjust acid-base balance and increase the incidence of diseases with aging, modifies pathophysiological and clinical features of acid-base disturbance in the elderly. Regulation of pH ultimately depends on the kidney and lung, however, the ability of the two organs is decreased with physiological aging. Moreover, the elderly are more prone to suffer from renal insufficiency and/or chronic obstructive pulmonary disease. Furthermore, medication with various drugs, such as diuretics, often affect the acid-base balance in the elderly. This paper describes the characteristics of the abnormalities in acid-base balance in the elderly, including metabolic acidosis and alkalosis, and respiratory acidosis and alkalosis.


[Acid-base balance during exercise].

[Acid-base balance during exercise]. The required energy may be produced almost exclusively by aerobic processes during light exercise. Anaerobic energy-yielding metabolic processes however, play a greater role as the severity of the exercise increases. This process produces endoproducts, such as lactate, which are related to acid-base regulation. During exhaustive exercise, large amounts of lactate accumulate in both muscle and blood, and the corresponding accumulation of proton ions produces metabolic acidosis. Three mechanisms control the acid-base quality of the internal environment; intramuscle buffers, blood buffers and physiologic buffers. In healthy male, the change in blood pH after heavy exercise is one which is expected in conditions of metabolic acidosis, and this change is consistently related to the lactate content. Finally, the effect of exercise on acid-base status in patients with several conditions is discussed.


[Transgenic mouse and gene targeting].

[Transgenic mouse and gene targeting]. Transgenic mouse technology has proved to be a powerful tool for medical research. So far, a large number of transgenic mice have been generated expressing, e.g. oncogenes, viral genes, immunoglobulins, lymphokines and MHC antigens, and have provided much valuable information. Furthermore, gene targeting technology (homologous recombination between specific chromosomal DNA sequences and exogenously introduced DNA sequences) has been improved and applied to pluripotent, mouse embryonic stem (ES) cells, providing the means to create mice of specifically altered genotype. In this review, some of the background and recent advances of transgenic mouse technology and gene targeting in mouse ES cells are described.


[Mutations of amyloid precursor protein in early-onset familial Alzheimer's disease]. Genetic linkage studies of familial Alzheimer's disease (FAD) have suggested that some form of early-onset FAD is linked to proximal long arm of chromosome 21. It has been also suggested that some form of late-onset FAD is linked to long arm of chromosome 19. Goate et al have identified a mis-sense mutation (Val to Ile) in exon 17 of the amyloid precursor protein (APP) gene in 2 of 16 early-onset FAD families, and have shown that the FAD locus in an FAD family is tightly linked to the mis-sense mutation. To determine if the mis-sense mutation is observed in different ethnic origine, we have studied some early-onset FAD families. Two early-onset FAD families showed the existence of the mutation. As the mutation has been identified in different ethnic origine and the mutation has not been observed in normal individuals, it strengthen hypothesis that the mutation is pathogenic. Recently, Val to Phe and Val to Gly mutations have been also identified at the same codon (Codon 717) of the APP gene.


[Acid base balance in the digestive system]. The mechanisms of acid base balance in digestive organs, including stomach, intestine as well as liver, have been described in the present paper. The stomach secrets large amount of acid as well as sodium bicarbonate, so that hydrogen ion would be lost in the severe vomiting state such as pyloric stenosis, resulting in metabolic alkalosis and hypokalemia. In the diarrheal condition, sodium bicarbonate would be lost in large amount, causing metabolic acidosis and hypokalemia. Hepatic failure induces the respiratory alkalosis of which mechanisms have not been clarified yet. In any case, urgent correction of acid base imbalnce would be crucial. It is, however, obscure to date how the systemic acid base imbalnce affects the function of the digestive system. This issue would be promising field in the investigation of digestive diseases.


Dysplasia in the human esophagus: clinicopathological study on 500 esophagi at autopsy. To clarify the relation between esophageal carcinoma and dysplasia, the pathology and epidemiology of 500 cases where clinically overt esophageal carcinoma had not been the direct cause of death were studied at autopsy. There were 297 men and 203 women. Four hundred and eighty-five patients had had malignant disease, of which 91 fulfilled the criteria for multiple primary malignancies. For all cases, cigarette and drinking habits were examined in patient records. All the esophagi were examined at autopsy by microscopy. Carcinoma in situ was found in six cases (1.2%). Dysplasia was observed in 73 (14.6%) and was graded mild in 58, moderate in 25 and severe in seven. The incidence of dysplasia was frequent in men than in women. Carcinoma in situ and severe dysplasia were more frequent where there was a history of habitual smoking and drinking, and were often associated with multiple primary cancers, mainly in the head and neck region. Predisposing factors for high grade dysplasia of the esophagus are gender, smoking, drinking, head and neck cancer and multiple primary cancers, corresponding to those of clinical esophageal carcinoma.


The role of socioeconomic factors in the survival of patients with gastrointestinal cancers. The relations between type of occupation, marital status and residential area and survival from gastrointestinal cancers were examined among 4485 cases of stomach cancer and 2618 cases of colorectal cancer diagnosed between 1983 and 1988 and recorded in the Aichi Cancer Registry. In univariate analyses, the cumulative five-year survival rates of both cancers were highest among professionals and managers and lowest among service workers, in males. They were highest among professionals, managers and clerical workers and lowest among housewives, in females. For both men and women, single people had a lower survival rate than married, and patients living in a metropolis had a higher survival rate than those living in other areas. Multivariate analyses, based on Cox's proportional hazards model, revealed occupation to have a statistically significant effect on prognosis for both sexes, although the effect of extent of disease was definitive. The analyses also confirmed the unfavorable effect of a single marital status and the favorable effect of residing in a metropolis, in women. The results suggest that socioeconomic factors may have a role to play in the survival of patients with gastrointestinal cancers.


A multi-institute case-control study on the risk factors of developing pancreatic cancer. A multi-institute, hospital-based, case-control study on pancreatic cancer was carried out to examine its association with preceding diseases, cigarette smoking, alcohol drinking and dietary factors. Analyses were based on 124 newly diagnosed exocrine pancreatic cancer cases and sex-, age- and institute-matched hospital controls in seven hospitals in Japan. Cigarette smoking showed a positive association with the risk of developing pancreatic cancer. Especially among smokers, a risk enhancing effect of involuntary/passive smoking prior to twenty years of age was observed (P < 0.05). No consistent associations were found with coffee, black tea or alcohol consumption. Among dietary factors, favoring food of a salty taste and drinking green tea five cups per day or more were positively associated with the risk. Drinking milk and eating fish everyday were inversely associated with the risk.


Penile metastasis from lung cancer.

Penile metastasis from lung cancer. A case of metastatic tumor of the penis from lung cancer is reported. The patient, who had received a right pneumonectomy 17 months previously for a squamous cell carcinoma of the lung, complained of urinary retention and painful erection of the penis. He underwent an emergency suprapubic cystostomy. Twenty days after the procedure, he died of disseminated lung carcinoma. The autopsy demonstrated massive metastasis to the penis from squamous cell carcinoma of the lung. Penile metastasis from lung cancer is a very rare condition and only 14 cases of this secondary carcinoma have been reported.


[Analysis of circulating thyroid-stimulating activities in pregnant women with Graves' disease: differential measurement of activities induced by TSH receptor antibody and hCG]. Thyrotoxicosis in Graves' disease is often aggravated in early pregnancy and this aggravation is associated with postpartum relapse of thyrotoxicosis. To examine whether thyroid-stimulating TSH receptor antibody (TSAb) or human chorionic gonadotropin (hCG), which also has thyroid-stimulating activity (TSA), is responsible for this early aggravation, the respective TSA due to TSAb or hCG were evaluated with a sensitive cAMP accumulation assay using FRTL-5 cells. TSA, which was detectable in all of 11 women in normal early pregnancy, correlated positively with serum hCG level, but was abolished completely by the pretreatment of serum samples with the solid-phase hCG antibody coupled with Sepharose-4B. Total TSA in the model samples of mixture of Graves' and pregnant sera (Gr + Preg), was reduced by the pretreatment with the solid-phase antibody, just corresponding with the reduction in hCG-induced TSA. Total TSA in early pregnant sera in 15 patients with Graves' disease, decreased significantly but was still positive even by the pretreatment with the hCG antibody. Pregnancy-associated changes in TSA was examined serially in a patient with Graves' disease, and hCG-induced TSA increased predominantly along with the serum thyroid hormone in early aggravation period. These data indicate that (1) the respective TSA due to TSAb or hCG can be differentially measured by using the solid-phase hCG antibody and (2) hCG plays an important role for aggravation of Graves' thyrotoxicosis in early pregnancy.


[Study for the nature of interfering substances responsible for non-specific reactive phenomena occurred occasionally in EIA determination of CA125]. We studied the nature of IgM-like protein responsible for non-specific reactive phenomena occurred occasionally in EIA determination of CA125. We isolated highly purified IgM-like protein from two patients with non-specifically high CA125 serum values in affinity high performance liquid chromatography (HPLC) using anti-human IgM antibody-TSKgel Tresy15PW column. The isolated IgM-like protein possessed CA125 activity determined in EIA method. SDS-PAGE profiles of this isolated IgM-like protein were compatible with that of normal human IgM, and were distinct from those of CA125 antigen. Moreover, we ruled out the possibility that the Fc region of anti-CA125 monoclonal antibody might be responsible for the non-specific reactive phenomena. Thus, the data obtained from the present study indicate that the IgM-like protein is an anti-idiotypic antibody against the anti-CA125 monoclonal antibody (OC125).


[Detection of dystrophin with anti-peptide antibodies]. The analysis of dystrophin in skeletal muscles was performed to identify Duchenne and Becker muscular dystrophy (DMD and BMD) by means of immunohistochemical stain and Western blotting with antisera against synthetic dystrophin peptides. The control muscle specimens derived from normal healthy persons, and patients without DMD and BMD revealed clearly continuous stains of dystrophin at surface membrane. A band with 400 kDa of molecular size by Western blotting was positively stained by anti-dystrophin antibodies. The muscle specimens from eleven DMD patients showed no observation both in the band on Western blotting and in the immunohistochemical staining of dystrophin on frozen-thin sections. BMD muscle specimens showed patchy and faint stains, but no detection of any band on Western blotting except a 380 kDa minor band with anti-peptide IX antibody in one patient muscle. The immunohistochemical procedure was found to be more sensitive than Western blotting for the detection of dystrophin. These results indicate that the dystrophin analysis by both methods is an useful tool for the differential diagnosis of patients with DMD and BMD.


[Expansion of CD4+CD8+ T lymphocytes in the peripheral blood of a patient with pulmonary tuberculosis]. We detected a high level of CD4+CD8+ double marker cells in the peripheral blood of a male patient with pulmonary tuberculosis (TB), ranging from 10% to 12%. Three color staining was useful for the further examination of surface markers of these abnormal lymphocytes. Three color staining of his CD4+CD8+ cells demonstrated that his CD4+CD8+ cells expressed CD2, CD3 and TCR alpha beta. Stimulation of his PBMC with OKT3 (or rIL-2) for 4 days resulted in the increase of up to about 50% (20%) of CD4+CD8+ cells. His PBMC had a normal proliferative response to mitogen. Although we could not evaluate the significance of the presence of an expanded CD4+CD8+ cells, it was not correlate with the disease of TB or the activity of the disease at least.


[Comparison of different methods for anti-HTLV-I assay]. In 130 patients, who were considered to be anti-HTLV-I positive or negative by the PA method, we compared the anti-HTLV-I detection rates and the specificity of the following three EIA methods: the Ei-test ATL and two new EIA methods using different recombinant antigens which recognize different sites. The results from the three EIA methods were consistent with the results from the PA method at a rate over 96.9%. The specificity and sensitivity of the three methods were excellent. In 8 (0.6%) of the 130 cases, however, the results from the four methods were not in agreement. All of these 8 cases had been classified (by the PA method) as weakly positive (low antibody titer). The use of the Ei-test ATL produced some false positive cases and some false negative cases (no false negative cases have been reported in tests for anti-HTLV-I antibody before). In 3 patients, the results of the two new EIA methods were not in agreement. Because all of these three patients had a low antibody titer, the discrepancy was difficult to explain based on the difference in the antigens used. Although the four methods had similar anti-HTLV-I detection rates, the results indicate a need to carefully evaluate the data in patients with low antibody titers. Therefore, it is recommended that a combination of multiple tests be used or that the results from one test be checked against those from another test.


[Studies on a serum factor inhibiting lactate dehydrogenase (LDH) activity in a patient's serum]. We found extremely low activity of serum lactate dehydrogenase (LDH, EC. 1.1.1.27) in a 70-year-old female patient. The decrease of LDH activity was observed when the normal serum was incubated with the patient's serum. Inhibition rate of LDH activity by the patient's serum was higher at 4 degrees C than at 37 degrees C. The patient's serum inhibited both subunits of LDH, and inhibited more strongly the M-subunit than the H-subunit LDH isoenzymes. IgG (lambda type) in the patient's serum was found to be responsible for the inhibition of LDH activity. The mechanism why IgG inhibiting LDH activity developed in the patient's serum remain undetermined.


[Clinical significance of the measurement of serum pepsinogen group I and II by enzyme-linked immunosorbent assay]. We have developed enzyme-linked immunosorbent assay (ELISA) for pepsinogen group I and II (PG I.II) in human serum, and clinical significance of serum pepsinogen measurement was evaluated. Serum PG I.II levels in patients with gastric and duodenal ulcer were higher than those in normal healthy subjects. On the other hand, serum PG I levels in patients with pernicious anemia were significantly low levels. In both gastric ulcer and duodenal ulcer, serum PG I.II levels at active stage were higher than healing stage. These results suggested that the measurement of PG I.II levels was useful for screening or monitoring test for the injury of gastric and duodenal mucosa.


[Development of automated lactate analyzer with continuous blood sampling for monitoring blood lactate and its application for the testing of physical exercise]. The anaerobic threshold is useful for estimating the intensity of physical exercise. It is shown as either an increase in blood concentrations of lactate or a disproportionate increase in ventilation. We developed a lactate analyzer based on an electroenzymatic method with a continuous blood sampling system through a double-lumen catheter. Ascorbic acid, bilirubin, hemoglobin, creatinine, uric acid, and glucose did not interfere the results. The lactate concentrations in blood samples from healthy subjects during physical exercise correlated well (r = 0.993) with results measured by the conventional enzymatic method. We measured the concentrations of blood lactate with a use of this lactate analyzer to see the anaerobic threshold in nine healthy volunteers during exercise on a treadmill with an increasing workload. The point at which lactate concentrations started to increase was detected easily. The anaerobic threshold identified as a disproportionate increase in ventilation was seen at almost the same time. We conclude that the lactate analyzer, with a continuous blood sampling system, can measure precisely concentrations of lactate in blood and can detect the anaerobic threshold during physical exercise.


[Immunological detection of fecal occult blood-follow up study on patients with positive testing]. To evaluate its clinical utility in the early detection of colorectal diseases, we carried out the immunological fecal occult blood test in 922 patients and monitored the clinical course of the 87 patients in whom it was positive. Thirty-five (40.2%) of these patients underwent subsequent X-ray and colonoscopy, and colorectal cancer was detected in 8 (20%). Our findings confirm the clinical usefulness of this test.


[Decrease of CD16 antigen density on granulocytes in chronic myeloid leukemia]. We examined the fluorescence intensity of CD16 antigen, which represents the density of CD16 antigen, on granulocytes by flow cytometry in 15 healthy subjects and 15 patients with neutrophilia due to inflammatory diseases and 10 patients with chronic myeloid leukemia (CML). The fluorescence intensity of CD16 antigen was significantly lower in patients with CML than in healthy subjects and also than in patients with neutrophilia. These data indicate that 1) density of CD16 antigen on granulocytes decrease in CML, and 2) analysis on the density of granulocyte CD16 antigen is useful for differential diagnosis of CML from inflammatory diseases with neutrophilia.


[A case of hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity]. A 68-year-old male patient with benign hypertension shows high levels of high density lipoprotein cholesterol (HDL-C) of 171 mg/dl. The serum total cholesterol was 240 mg/dl. An abnormal slow alpha band and polydisperse low density lipoprotein (LDL) bands were detected by agarose gel and polyacrylamide gel electrophoresis. The slow alpha band was considered as an apo E-rich HDL. A peak of large HDL particle and a peak of abnormal high-molecular-LDL particle were observed in the patient's serum by gel permeation high performance liquid chromatography. Cholesteryl ester transfer activity (CETA) of the patient's serum was completely deficient (0.0%/10 microliters/18 hr). From these results, it is strongly suggested that patient's hyper-HDL-cholesterolemia caused by a complete deficiency of CETA.


The measurement of fibronectin concentrations in human aqueous humor. The concentrations of fibronectin in aqueous humor, measured by ELISA which was developed to detect fibronectin, ranged from 5 ng/ml to 100 ng/ml. Aqueous humor was aspirated from human eyes with cataracts and glaucomas using a 26 gauge needle through the peripheral cornea before making the limbal incision into the anterior chamber during surgery. The results of the study show that the average concentration and standard deviation of fibronectin was 0.136 +/- 0.192 microgram/ml in cataract eyes, and 0.962 +/- 0.918 microgram/ml in glaucoma eyes respectively. There was a statistically significant difference between both groups (p = 0.000). However, no significant differences according to age and sex were noted. There was no influence due to preoperative intravenous mannitol injection on fibronectin concentration. The source of aqueous fibronectin is still not clearly known and the mechanism of the higher concentration of fibronectin in glaucoma has not been clearly disclosed, however it is thought that normally present fibronectin is accumulated in the anterior chamber because it can not pass the aqueous outflow pathway, or that fibronectin production may be increased in glaucoma.


Clinical efficacy of topical homologous fibronectin in persistent corneal epithelial disorders. The clinical efficacy was investigated of topical homologous fibronectin on persistent corneal epithelial defects of various etiologies. Fibronectin was purified from blood bank homologous plasma by gelatin-Sepharose 4B affinity chromatography. Twenty eight eyes of twenty five patients with persistent corneal epithelial defects and sterile corneal ulcers that failed to improve with standard therapy were treated by the instillation of homologous fibronectin eyedrops 5 times a day (500 micrograms/ml). Complete reepithelialization was achieved in all patients except two eyes due to uncontrolled glaucoma and the taking of steroids. The healing time tended to be different depending on the duration of persistent corneal epithelial defects and the severity of underlying diseases. The mean +/- standard deviation duration of epithelial defect was 68.18 +/- 77.80 days. Average healing time was 42.07 +/- 17.47 days. Ocular symptoms were relieved significantly and no side effects were observed. Over an average follow-up period of about 8 months, two cases of recurrences were noted. These results show that homologous fibronectin was also effective in patients with persistent corneal epithelial defects and corneal ulcers.


Ocular dimensions with aging in normal eyes. To quantify the dynamic changes taking place in the anterior segment, we measured the anterior chamber depth (ACD), lens thickness (LT) and their difference between sexes and age groups in normal eyes using contact ultrasonography and anterior chamber photography. There were 141 women (241 eyes) and 76 men (130 eyes) between the ages of 10 and 70 years. In normal eyes, the lens thickness was increased and the anterior chamber depth was decreased with aging in both sexes. The anterior chamber depth showed an accelerated decrease between the 4th and 5th decades in females and the ratio of anterior chamber depth to axial length was smaller in females than in males after the 5th decade. The results suggested that the prevalence of angle closure glaucoma will be increased in females after middle age.


Optic disc of the myopic eye: relationship between refractive errors and morphometric characteristics. Because the optic disc in myopic eyes is different from a normal optic disc, there are many difficulties in examining the optic discs of myopic eyes. To study optic disc change due to myopia, we performed a morphometrical study of stereophotographs of 61 men, 109 eyes, who had no glaucoma history. The range of refractive error was from +0.75 diopter to -12.75 diopter, and all subjects had intraocular pressure below or equal to 21 mmHg. According to the increase in the myopic degree, the temporal slope of the disc cup was significantly decreased, but the ratio of the vertical disc diameter (VDD) to the horizontal disc diameter and the ratio of the width of peripapillary atrophy (PPA) to the VDD were significantly increased. The above results suggests that in high myopia the optic disc was tilted and the rim-cup border was indistinct and there are some problems in the estimation of the morphometric parameters. Also in evaluation of the PPA of myopic glaucoma patients, there may be some difficulty in deciding whether it is due to myopic change or glaucomatous damage.


The components of the proliferative membranes in retinopathy of prematurity: an electron microscopic study. Electron microscopic examination of proliferative membranes in retinopathy of prematurity (ROP) was performed in order to evaluate the components of the membranes. The proliferative membranes were obtained from nine patients with ROP stage 5 during pars plicata lensectomy, vitrectomy, and delamination of membrane. Fibrous astrocytes, myofibroblasts, lymphocytes, macrophages, and calcification were found respectively in two cases, and fibroblast-like cells were found in one case. Varying amounts of collagen tissues were found in eight cases and vascular tissues in four cases. Most of membranes were hypocellular and composed mainly of collagen matrix. It is considered that fibrous astrocytes, myofibroblasts, fibroblasts, and vascular structures are involved in the formation of proliferative membranes of ROP, and that later these cells degenerate and disappear, and that finally only collagen matrix remains in the membranes.


Myopia in premature infants at the age of 6 months. The authors performed cycloplegic refractions in 180 eyes of 99 premature infants at the age of 6 months to evaluate the incidence and the degree of myopia according to the development and disease course of retinopathy of prematurity (ROP) and to investigate the effect of cryotherapy on the refractive error. The incidences of myopia were not different between premature infants without ROP and premature infants with spontaneously and totally regressed ROP (36.3%, 25.5%), and the degrees of myopia were low in both groups (-1.76 D, -2.25 D). In premature infants with totally regressed ROP after cryotherapy, the incidence of myopia was high (75.5%) but the degree of myopia was low (-3.03 D). In premature infants with cicatricial ROP, cryotreated or not, both the incidence and the degree of myopia were high (93.9%, -5.50 D). It is suggested that cryotherapy increases the incidence of myopia but the degree of myopia induced by cryotherapy is low.


Unilateral congenital ocular motor apraxia: a case report. Congenital ocular motor apraxia (COA), first described by Cogan in 1953, is a rare disorder which shows characteristic defects of the horizontal voluntary saccades, and compensatory head thrust. Until now, most cases have showed a presumably congenital origin, bilaterality, and a tendency to various stages of recovery with aging. But the cause and mechanism of COA are not completely known. Occasionally, it combines with other neurologic abnormalities and metabolic diseases such as Gaucher's disease exhibit similar clinical characteristics to COA. We recently experienced a case of a 3-year-old girl who showed the clinical features of unilateral congenital ocular motor apraxia.


Effects of aqueous humor on filtering bleb in rabbits. Preoperative aqueous humor, known to inhibit the growth of fibroblasts in tissue culture assay, was used as an adjunct to filtering surgery in rabbits to determine its effect in vivo on the outcome of filtering surgery. Fifteen rabbits underwent a posterior-lip sclerectomy in both eyes. In experimental eyes 1.4 ml preoperative aqueous humor and in fellow eyes 1.4 ml balanced salt solution were injected intracamerally. Gross and histopathological differences of bleb were observed. In this animal experiment, although there was no statistical significance or late postoperative effect, the rabbit eyes refilled with preoperative aqueous humor intracamerally just after filtering surgery, had a larger bleb and less fibroconnective tissue on the bleb than the control eyes in the early postoperative period.