The Keio Journal of Medicine
Online ISSN : 1880-1293
Print ISSN : 0022-9717
ISSN-L : 0022-9717
Volume 45, Issue 3
Displaying 1-17 of 17 articles from this issue
  • Minoru Kanazawa
    1996 Volume 45 Issue 3 Pages 131-139
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Acute lung injury (ALI) was defined recently as a syndrome of inflammation and increased permeability of the lungs that is associated with clinical, radiologic, and physiologic abnormalities that can not be explained by left atrial hypertension. ALI has the same clinical spectrum, although in a milder form, as acute respiratory distress syndrome (ARDS). The risk factors, incidence, and prognosis of ALI are described based on the medical literature and data collected at Keio University Hospital. We estimate that 20, 000 to 40, 000 cases of ALI, half of which also have ARDS, occur annually in Japan. Despite the new diagnostic criteria, the clinical entity of ALI remains to be clarified both physiologically and biochemically because of the lack of direct diagnostic methods. I briefly review the central mediator(s) and their role in the inflammatory cascade of ALI. Experimental studies and pharmacological interventions from our laboratory are also described.
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  • David Hicks
    1996 Volume 45 Issue 3 Pages 140-154
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    There is increasing evidence that soluble polypeptide growth factors such as those belonging to the fibroblast growth factor (FGF) family play important roles in many aspects of photoreceptor cell biology, including differentiation, continued survival and pathology. At least two members of this family, acidic FGF and basic FGF, are synthesized by, bind to and have profound effects upon these highly specialized retinal first-order neurons. The present review presents an overview of the evidence accumulated to date and will try to suggest future directions for research.
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  • Jonathan D Kaunitz, Shin Tanaka
    1996 Volume 45 Issue 3 Pages 155-160
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The gastric mucosa is constantly exposed to conditions that would normally be damaging to living cells. A complex defensive system has evolved that involves multiple mechanisms arranged in a laminar fashion, that as a whole constitute the gastric mucosal barrier to acid. As antisecretory therapy becomes perfected, more attention has been focused on these defensive components of the gastric mucosal barrier in disease. Recently, our laboratory has developed a means of measuring intracellular pH (pHi), mucosal blood flow, acid secretion, surface cell acidification rate, and acid secretion simultaneously in vivo. This system has enabled our laboratory to explore how the different components of the gastric mucosal barrier interact so as to protect the pHi of the surface cells under a variety of conditions. Analysis of these studies has revealed a significant inverse correlation between the initial fall in pH; of surface cells during luminal acid exposure and the thickness of the mucus gel, suggestive of a role of adherent gastric mucus in retarding the permeation of luminal protons into the epithelial cells. Another correlation has been between recovery of pH; and the presence of a hyperemic response to luminal acid, which suggests that the hyperemic response is an important defense mechanism in the intact mucosa. Our data is consistent with the hypothesis that gastric mucosal defense mechanisms, like gastric acid secretion, are dynamically regulated according to need. Disturbance of the regulation of these mechanisms, for example by cirrhosis, might be one of the major factors underlying clinical ulcer disease.
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  • Hidetsugu Saito, Kanji Tsuchimoto, Shingo Miyaguchi, Shinichiro Tada, ...
    1996 Volume 45 Issue 3 Pages 161-167
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The efficacy of two different high-dose treatment of IFN-α2b was evaluated in this study. Serum hepatitis C virus (HCV) RNA levels were semi-quantified by simplified reverse transcription-polymerase chain reaction. Seventy-one patients with chronic hepatitis C received 10 million units of IFN-α2b daily for 2 weeks or trice a week for 24 weeks. Alanine aminotransferase (ALT) levels overall normalized in 78.1% and 51.6% of the cases at the end of the therapy and 6 months after that, respectively. HCV RNA disappeared in 71.9% and 35.7% of the patients at the end of the therapy and 6 months after that, respectively. There was no significant difference between the 2 different regimes. The efficacy of the treatment was fair in cases in which the pretreatment level of the viral amount was low. The results of this study indicate that daily administration of IFN in the first 2 weeks during 6-month course does not increase the efficacy of the therapy in such a high-dose treatment regime.
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  • James E Carter
    1996 Volume 45 Issue 3 Pages 168-171
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Bladder neck suspension is now possible under laparoscopic control. The advantages of laparoscopy now apply to laparoscopic colposuspension. The technique described in this paper simplifies the laparoscopic Burch procedure by utilizing the harmonic scalpel for dissection of space of Retzius in a sharp and blunt fashion, providing for a bloodless dissection of the space, suturing of the perivaginal tissue avoiding penetration of the vaginal mucosa, placing the Stamey needle through a small skin incision, allowing for a variation in the shape of the pelvic bone so that the dissection of Cooper's ligament is performed in a very atraumatic fashion, extracorporeal knotting of the suture for ease of fixation of the perivaginal fascia to the Cooper's ligament and stapling of the peritoneal surface for reclosure of the space. With the adoption of this technique, the procedure of laparoscopic bladder suspension can be performed in most cases in approximately 1 hour of surgical time. The results are very encouraging, and the procedure as described in fact does not differ from the classical Burch procedure in any significant detail. Therefore, the long-term results are expected to be similar to those obtained by the standard Burch approach. No failures have thus far occurred in 50 patients over two years follow up. One patient did require urinary drainage through the suprapubic catheter for a period of one week prior to ability to void spontaneously.
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  • Yasuo Fukuuchi, Minoru Tomita
    1996 Volume 45 Issue 3 Pages 175-176
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
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  • Mária A Deli, Ferenc Joó
    1996 Volume 45 Issue 3 Pages 183-199
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The endothelium is a single-cell layer fining the blood vessels and represents an interface between blood and tissue. It acts as a selective permeability barrier, regulates coagulation and contributes to the behaviour of cells both in the circulation and in the vessel wall. Because of its location, one of the most important function of the endothelium is the regulation of the movement from the vascular to the extravascular space of water and solutes containing nutrients. Recent advances in our knowledge of the blood-brain barrier (BBB) have in part been made by studying the properties and function of cerebral endothelial cells (CECs) in vitro. After an era working with a fraction, enriched in cerebral microvessels by centrifugation, the next generation of in vitro BBB model systems was introduced, when the conditions for routinely culturing the endothelial cells were established. This review summarizes the results from this rapidly growing field. In addition to providing a better insight into the chemical composition of CECs, much has been learned from these studies about the characteristics of transport processes and cell-to-cell interactions during the last years. Astrocytes and neuronal elements contribute to the induction of BBB properties of CECs during ontogenesis and in tissue culture conditions. With the application of new technologies, the approach offers new means to investigation, applicable not only to biochemistry and physiology but also to the drug research, and may improve the transport of substances through the BBB. CECs grown on microporous cell culture inserts and co-cultured with astrocytes or treated by astrocyte-conditioned media proved to be excellent models for studying the direct effects of mediators and second messengers on the transendothelial permeability. The in vitro approach has been and should remain an excellent model of the BBB to help unravel the complex molecular interactions underlying and regulating the permeability of cerebral endothelium.
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  • Zoltán Nagy, Mónika Vastag, Judit Skopál, Krasimi ...
    1996 Volume 45 Issue 3 Pages 200-206
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Cerebral ischemia is caused by reduced blood supply at the microcirculatory level. In the microvessels, the main elements of the reperfusion injury following brain ischemia are the transformation of endothelial cell-surface from anticoagulant to procoagulant property, leukocyte adhesion, sludge or clot formation. There is a paucity of information on how hemostatic factors, cytokines, lipoprotein(a) (Lp(a)) and endothelin-1 (ET-1), being responsible for ischemic/reperfusion injury, interact with human brain microvessel endothelium (HBEC). There are no data furthermore about the expression of complement proteins of HBEC influenced by cytokines or fibrinolytic factors. Previously we established optimal conditions for culturing HBEC. Cell contraction induced by thrombin, plasmin, miniplasmin was recorded. The reassembly of F-actin was observed after thrombin treatment. ICAM-1 upregulation was measured following TNF-α, IL-1-α and thrombin incubation. Plasmin and miniplasmin downregulated the ICAM-1 in our cell culture system. Lp(a) modulated the thromboresistant cell-surface by reduction of t-PA and u-PA, but PAM remained unchanged. Lp(a) modulated the ET-1 production by early increasing and late decreasing, in a bimodal manner. The increased secretion of ET-1 by cytokines (TNF-α, IL-1-α) was reduced in the presence of Lp(a). Gradual increase of complement proteins (factor H, factor B, C4) was induced by cytokines. Plasmin and miniplasmin augmented a rapid increase of C4. Some factors of complex relationship between regulators and modulators of endothelial adhesion molecules have been demonstrated in a human cell culture system prepared from brain microvessel endothelium. A unified concept of sequential events of ischemia/reperfusion in the brain has not yet developed.
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  • Sei-itsu Murota, Hiroshi Fujita, Yoshiyuki Wakabayashi, Ikuo Morita
    1996 Volume 45 Issue 3 Pages 207-212
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Addition of PMA (phorbol myristate acetate)-stimulated neutrophils to an endothelial cell monolayer caused a significant increase in the intracellular peroxide level of the endothelial cells after 15 minutes and endothelial cell injury after 5 hours. Both the early and the late events were abolished in the presence of specific antibodies against CD (cluster of differentiation) 11a, CD11b, CD18 and ICAM (intercellular adhesion molecule) 1, but not CD11c. These antibodies affected neither the production of active oxygen species by the neutrophils nor the rate of adhesion of neutrophils to endothelial cells. Pretreatment of endothelial cells with allopurinol caused significant inhibition of both the early and the late events, suggesting that the binding of adhesion molecules may trigger the activation of XO (xanthine oxidase) of endothelial cells, and have the cells produce more hydrogen peroxide and ferrous ions, followed by producing more hydrogen peroxide. The hydrogen peroxide produced by endothelial cells themselves and by neutrophils may be converted to hydroxyl radicals by ferrous ions, which may cause lethal cell damage. Examination of XO activity in endothelial cells showed that the enzyme activity increased double within 15 minutes after the addition of PMA activated neutrophils. Monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD (xanthine dehydrogenase) to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors also inhibited the increased conversion of XD to XO. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells, which results in endothelial cell injury.
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  • Minoru Tomita, Yasuo Fukuuchi, Norio Tanahashi, Masahiro Kobari, Hidet ...
    1996 Volume 45 Issue 3 Pages 213-224
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The detailed assembly used by us for video-enhanced contrast-differential interference contrast (VEC-DIC) microscopy (video microscopy) is first described. Employing such video microscopy, we then examined the morphological changes occurring during locomotion and activation processes of polymorphonuclear leukocytes (PMNL) and microglia at an almost electron microscopic magnification. Upon contacting the substratum, PMNL transformed into a polarized ameboid shape and crawled extending pseudopodia, as has been well documented previously. The PMNL sometimes displayed a peculiar locomotion as if they were stepping on “tiny legs”, or sliding on a treadmill of cell membrane. Cultured microglia were observed to exist in 4 forms; ramified, reactive, villous, and ameboid. Microglia in the reactive form pivoted, circled and crawled on the astroglial cell layer using their transparent lamellipodia with no morphological changes in their cell body. Unlike PMNL, reactive microglia exhibited no agitated movements of their intracellular organelles, including granules and cytosol, during locomotion. Lamellipodia on the undersurface of the cell body touching the cell layer adhesively, appeared to serve as the locomotive apparatus. When activated, both floating PMNL and microglia of villous form assumed an ameboid shape within a few seconds. Microglia occasionally swam in the medium waving their lamellipodia towards a target object (e.g. zymosan A particles), remodelling to an amorphous ameboid form and covering up the target. We attempt to discuss such swift morphological changes from the standpoint of thermodynamic potential of Gibbs free energy which is stored within the cells.
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  • Yasundo Yamasaki, Yasuto Itoyama, Kyuya Kogure
    1996 Volume 45 Issue 3 Pages 225-229
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The contribution of cytokines in an inflammatory cascade on cerebral reperfusion injury are characterized as typical phases; leukocytes invsion, microglial activation, and remodeling. Within 1-2 days, IL-1 (interleukin-1) and TNF (tumour necrosis factor) induce the expression of adhesion molecules that cause leukocytes adhere to endothelial cells. IL-8 (CINC; cytokine-induced neutrophil chemoattractant) is a well-known chemokine that promotes invasion of these leukocytes into brain parenchyma. The activation of proteases and free radical formation by invading neutrophils induces lipid peroxidation and subsequently neuronal damage. From 2 to 7 days, microglia is activated mainly in the “reactive zone” at the boundary of the infarct, and secrete IL-1 and TNF. These cytokines induce astroglial proliferation and production of trophic factors by astroglia to limit the neuronal damage. However, excess astrogliosis exert a negative effect on neuroregeneration. From 7 to 30 days, phagocytic macrophages are observed in the core of infarction sites. The macrophages release a number of cytophylactic agents including proteases and superoxide anions to degrade the damaged areas. TGF-β and basic FGF (fibroblast growth factor) from glial cells and macrophages induce angiogenesis to discard the debris for subsequent remodeling. These complicated cascade after cerebral reperfusion injury are indeed controlled by cytokines: IL-1 and TNF are considered to be primary mediators that work in concert with IL-8 and growth factors to initiate and regulate the local inflammation in the brain.
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  • A Lorris Betz, Gerald P Schielke, Guo-Yuan Yang
    1996 Volume 45 Issue 3 Pages 230-238
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    During the past several years, it has become increasingly apparent that interleukin-1 (IL-1), particularly IL-1β plays an important role in brain injury during ischemia. Studies from various laboratories have shown that IL-1β mRNA and IL-1β protein are synthesized early in ischemia and that the injection of IL-1β into ischemic brain enhances edema formation. The most direct evidence that IL-1β contributes to ischemic injury, however, is the demonstration that infarct volume in focal ischemia is reduced following intraventricular injection of an endogenous interleukin-1 receptor antagonist (IL-1ra), or after IL-lra is overexpressed in brain using an adenoviral vector to transfer IL-Ira cDNA to brain cells. Ischemic injury is also reduced in mice that fail to produce IL-1β because of an abnormal interleukin-1β converting enzyme gene (ICE knockout mice). At the present time, it is unclear how IL-1β causes brain injury, but several possible mechanisms include 1) stimulation of an inflammatory response through the activation of glia or the induction of other cytokines and/or endothelial adhesion molecules and 2) release of free radicals through stimulation of arachidonic acid metabolism and/or nitric oxide synthase activity.
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  • Gennadij Raivich, Horst Bluethmann, Georg W Kreutzberg
    1996 Volume 45 Issue 3 Pages 239-247
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Injury of the central nervous system leads to a highly reproducible activation of neurons, astrocytes and microglia, which plays an important role in the posttraumatic repair of the damaged neural tissue. Recent work on proinflammatory cytokines has begun to shed light on the molecular mechanisms that direct and control this repair process. Here we summarize data on the regulation of these cytokines, which led to the identification of the macrophage colony-stimulating factor and interleukin-6 as key factors in microglial and astrocyte activation.
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  • Deborah A Dawson, Christl A Ruetzler, Timothy M Carlos, Patrick M Koch ...
    1996 Volume 45 Issue 3 Pages 248-253
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    In order to determine the effect of depleting circulating polymorphonuclear neutrophils (PMN's) on brain microcirculation and lesion size in an acute stroke model, Spontaneously Hypertensive Rats (SHR) were injected intraperitoneally with either 2 ml RP-3 antineutrophil antibody followed in 4 hours by MCAO (n=5), 2 ml saline followed in 4 hours by middle cerebral artery occlusion (MCAO) (n=6), or 2 ml saline followed in 4 hours by sham operation (n=3). After 4 hours of ischemia or a 4 hour interval (sham-operated animals), microvascular perfusion was assessed by means of an intravascular fluorescent tracer technique: FITC-dextran and Evans blue were injected intravenously 10 seconds and 5 seconds, respectively, before decapitation. Lesion volume was calculated by interpolation from histologic sections cut from 8 predefined stereotactic levels. MCAO with the normal complement of neutrophils led to significant impairment of perfusion in nutrient vessels and a maximal ischemic lesion volume. Depletion of circulating leukocytes by RP-3 significantly attenuated the microvessel perfusion impairment and reduced the volume of ischemic brain injury.
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  • Perttu J Lindsberg
    1996 Volume 45 Issue 3 Pages 254-262
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Leukocytes and their actions have been implicated in the pathogenesis of microcirculatory and cytotoxic perturbations in experimental stroke models. Experiments in several models of stroke patho-physiology have demonstrated the important role of endothelial intercellular adhesion molecule (ICAM-1) in targeting the leukocyte response to the ischemic brain region and transmigration of polymorphonuclears into the parenchyma. In this article, investigations suggesting beneficial effects of anti-adhesion therapies blocking the endothelial ICAM-1 or its counter-receptor CD11/CD18 on leukocytes are reviewed. This evidence should be viewed also in the context of human stroke, which has also recently been shown to overexpress ICAM-1 molecules on the infarcted endothelium. Well-tolerated monoclonal antibodies (mAb) blocking ICAM-1 might eventually be shown to possess therapeutic value acutely in clinical stroke victims, perhaps in combination with thrombolytic therapy.
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  • Shinichi Kohsaka, Makoto Hamanoue, Kazuyuki Nakajima
    1996 Volume 45 Issue 3 Pages 263-269
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    We have demonstrated that microglia produce certain secretory proteases which have been found to be important determinants of microglial properties, in surrounding cells and regenerative processes. In recent years, it has become clear that secretory proteases, particularly PGn-PA (plasminogen-plasminogen activator) system, work not only on catalysis of proteins in the extracellular space but also on cell growth, cell function, differentiation, proliferation and remodeling. These diverse effects may be derived from the unique structures of these enzymes, including their accesary domains. In particular, kringle domains have been shown to be important for interactions with other proteins. The results of these studies indicate that microglial secretory proteases participate to a great extent in physiological processes involving the regulation of neuronal growth, neuronal function and regenerative stages in the CNS.
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  • Yoshiyuki Matsuo, Yasundo Yamasaki, Kyuya Kogure
    1996 Volume 45 Issue 3 Pages 270-274
    Published: 1996
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Cytokines which promote emigration of leukocytes from the vascular lumen into the injured brain tissue are produced at the site of incipient cerebral infarction. The blood-borne invaders then accelerate the decomposition of brain cells by their toxic by-products, phagocytic action, and by the immune reaction. Recently accumulated data in our laboratories and other research facilities show that depleting the amount of circulating leukocytes or administering anti-inflammatory chemicals such as cytokine blocking agents, anti-adhesion molecule antibodies, and immunosuppressants effectively minimize the size of ischemia induced cerebral infarction. Based on the fact that leukocyte invasion of the affected brain tissue occurs 6 to 24 hours after onset of ischemia, administration of an anti-inflammatory therapy may widen the therapeutic window against stroke.
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