島田 順一 Jun-ishi Shimada

The innovations with themedical applications of white LEDs and the breakthorough for new business

Junichi Shimada1and Yoishi Kawakami2

1Department Cardiovascular and Thoracic Surgery,Kyoto Prefectural University of Medicine Graduate School of Medical Science
2Kyoto University Graduate School of Engineering

 Abstract: The distance between the LED and the surface of the target organ is about 4-5 cm, and we think this will become the “ultimate super-localized LED lighting”. In an experiment with swine, we placed a LED module at the tip of the retractor. When compared to endoscopic lighting, this method illuminated the entire thoracic cavity more brightly. Since the light is emitted from the cylinder-shaped camera component, the light is unidirectional, and the shadows from the surgical instruments are moved to the side of the incision. Retractor LED lights provided enough light in the thoracic cavity. we believe that “medical white LEDs” can contribute in clinical settings as a light source for performing safe operations with bright surgical fields in the near future. Also, we use our LEDs for new real business. In the summer of 2004, LED lighting was world first used in the 1200 year-old Gion Festival for the first time in history as “a lighting device that does not destroy cultural assets by light heat”. And the next is “Lighting at the “Diva status at diva gate” and the “Thousand Armed Avalokiteshwara in innermost sanctuary in the main hall” at Kiyomizudera in Kyoto”. It was a great success, and we were invited back in the spring of 2005 and for future applications. We think this is the first real application of LEDs as an outdoor lighting device. The number of people who visit Kiyomizudera is 4000,000 annually, and LEDs were adopted to illuminate the diva gate.

 KeyWords:LED lighting goggle,White LED module,Medical lighting,Cultural property,KIYOMIZU-DERA

 
木村 修,ほか Osamu Kimura et al.

Result of laparoscopic anorectal pell-through in infants with high type of anorectal malformation

Osamu Kimura,Toshihisa Iwabuchi,Shigehisa Fumino,Shinichi Shimadera,Yasunari Sasaki,
Eiichi Deguchi and Naomi Iwai

Department of Pediatric Surgery,Kyoto Prefectural University of Medicine Graduate School of
Medical Sciece

 Abstract:
Results of laparoscopic anorectal pull-through in 3 infants with high type of anorectal malformation were evaluated. In a manometric study, the maximum anal resting pressure in the 3 cases was 48, 42 and 47 cm H2O, respectively. The anorectal reflex was observed in 1 of the 3 cases. Barium enema studies showed good anterior angulation of the rectum in all 3 cases. All of the infants were totally continent. However, 2 of the 3 had mild constipation that could be easily controlled by enema once every 2 or 3 days. One infant with positive anorectal reflex had voluntary bowel movement without laxatives or enema. All of the 3 infants had no difficulty in daily activities as typical of healthy infants. In conclusion, the middle term results of laparoscopic anorectal pull-through for high type of anorectal malformation were quite satisfactory. To establish the efficacy of this procedure, long term results of more cases should be further evaluated.

 Key Words:Anorectal malformation,Laparoscopic operation,Anorectal function.

 
辻 肇 Hajime Tsuji
Regulation of thrombus formation by endothelial cell

Hajime Tsuji

Divishion of Blood transfusion Cell therapy,Hospital of Kyoto PRefectural University of Medicine

 

 Abstract:The vascular endothelial cell (EC), once considered to provide a passive vessel wall lining, plays an important role in the maintenance of homeostasis. EC regulates the selective transport, influences vascular tone, and modulates the antithrombotic and/or thrombotic properties of vessel wall. The resting EC exerts an antithrombotic properties to prevent thrombus formation in the blood vessel and keep intact blood fluidity. For this purpose, the EC synthesizes and presents on its surface various antithrombotic molecules. EC expresses anticoagulantly active proteoglycan and thrombomodulin , which binds plasma thrombin and alters its procoagulant activity to antithrombotic one. The fibrinolytic mediators, tissue plasminogen activator and urokinase-type plasminogen activator, are synthesized by EC and activate the fibrinolytic processes. Platelet reactivity is also controlled by prostacyclin and nitric oxide synthesized by EC.
   On the other hand, EC has the potential to exert procoagulant influences in response to various environmental stimuli. These two antithrombotic and procoagulant functions of EC are well controlled, however, injury-induced EC dysfunction brings the unbalance of these functions, and comes to be the causes of thrombotic diseases and also is considered to the first events in the development of atherosclerosis.

 Key words:Endothelial cell,Thrombus,Blood coagulation,FibrinolysisPlatele,,aggregation
 
田中 秀央,ほか Hideo Tanaka et al.
Spatiotemporally non-uniform dynamics of intracellular Ca2+in the heart

Hideo Tanaka and Tetsuro Takamatsu

Department of Pathology and Cell Regulation,Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract
:Intracellular Ca2+ ([Ca2+]i) plays a key role in the excitation and contractile functions of the heart. In the intact heart the cardiomyocytes exhibit spatially uniform Ca2+ transients on systole and indiscernible rise of [Ca2+]i during diastole, whereas under pathological conditions the myocytes evoke non-uniform [Ca2+]i dynamics in the cardiac cycle. Under Ca2+ overload in the sarcoplasmic reticulum (SR), spontaneous, wave-like Ca2+ release arises from the SR during diastole (diastolic Ca2+ wave), which can generate triggered arrhythmias. On the other hand, under ischemic injury or metabolic inhibition the diastolic Ca2+ waves barely arise; instead, the myocytes exhibit beat-to-beat alternans of the Ca2+ transient amplitude (Ca2+ alternans) with concomitant appearance of Ca2+ waves in systole (systolic Ca2+ waves) due to depressed Ca2+ release of the SR. The myocytes in the non-ischemic failing heart also evoke non-uniform [Ca2+]i dynamics: the Ca2+ transient is slowed in upstroke phase and prolonged with the accompaniment of non-uniform elementary Ca2+ release events identified as dyssynchronous or delayed Ca2+ sparks.  These diverse abnormalities in [Ca2+]i dynamics, explained mainly by impaired Ca2+ handling in the SR Ca2+-release channels (the ryanodine receptors), provide deeper insight into the pathologic basis of cardiac dysfunction in various heart diseases.

 Key Words:Cardiomyocyte Ca2+transient,Ca2+spark,Ca2+alternans,sarcoplasmic reticulum.


心筋細胞内カルシウム動態の時空的不均一性

田中秀央,高松哲郎

京都府立医科大学大学院医学研究科細胞分子機能病理学

和文抄録

 カルシウムイオン(以下Ca2+)は心臓の興奮収縮の要をなす細胞内シグナルである.近年の共焦点
顕微鏡技術の進歩により, 心筋のCa2+動態は高い時空的分解能で解析され,筋小胞体(SR)のカル
シウム放出チャネル等の微細な領域(μmレベル)のCa2+動態(Ca2+スパーク等)を捉えることが可能
となった.正常の心筋細胞では,興奮に伴って空間的に均一な一過性の Ca2+の上昇(Ca2+トランジェ
ント)が生じるのに対し、病的心筋では,SRのCa2+放出様式の異常により,時空的に不均一な 細胞内
Ca2+動態を示す.SR内がCa2+過負荷に陥ると,心筋は電気的拡張期に自発性のCa2+の波状伝播
(拡張期Ca2+波) を示し,撃発性自動能が生じ易くなる.虚血や代謝障害時には,SRからのCa2+
放出が障害され,Ca2+の不均一な細胞内 伝播(収縮期Ca2+波)が生じ,これに伴ってCa2+トランジェ
ントの振幅が交代性の増減(Ca2+交代現象)を示す.不全心筋で はCa2+トランジェントに非同期性の
Ca2+スパークを伴い,細胞内Ca2+動態が不均一になる.このような心筋の不均一なCa2+動態は,
興奮・伝導異常や収縮・拡張異常の病態を考える上で重要な情報である.
 
濱口 真英,ほか Masahide Hamaguchi et al.
Serum anti-ribosomal P antibody reflected the activity of neuropsychiatric syndromes in systemic lupus erythematosus

Masahide Hamaguchi1,Yutaka Kawahito1,Atsushi Omoto1,Mizuho Kimura1,Makoto Wada1
Hidetaka Ishino1,Makie Yoshida1,Aihiro Yamamoto1,Yasunori Tsubouchi1,Masataka Kohno1
Wataru Fukuda2,Hajime Sano3,Shunsei Hirohata4 and Toshikazu Yoshikawa1

1Department of Inflammation and Immunology,Kyoto Prefectural University of Medicine Graduate School of Medical Science

2Department of Diabetes,Endocrinology and Rheumatology,Kyoto First Red-Cross Hospital
3Arthritis and Rheumatism Branch Department of Internal Medicine,Hyogo College of Medicine
4Department of Internal Medicine,Teikyo University School of Medicine

 Abstract
:Although detection of autoantibody in the serum or cerebrospinal fluid, magnetic resonance imaging, and electroencephalography have been used as diagnostic examinations for the neuropsychiatric syndromes of systemic lupus erythematosus, no examination has been established as providing a routine laboratory diagnosis of the syndromes. Serum anti-ribosomal P antibody is reported to be associated with the neuropsychiatric syndromes of systemic lupus erythematosus. We experienced two cases with neuropsychiatric syndromes, in whom methylprednisolone pulse therapy was effective in controlling the neuropsychiatric manifestations, and the level of serum anti-ribosomal P antibody reflected the activity of the neuropsychiatric manifestations. These cases indicated that the level of serum anti-P antibody might reflect the activity of the neuropsychiatric manifestations and the efficacy of therapy when serum anti-P antibody is positive before treatment.

 Key Words:Anti-ribosomal P antibody,Neuropsychiatric syndromes,Systemic lupus erythematosus,Methylpredisolone pulse therapy.


血清抗 リボソームP抗体が全身性エリテマトーデスの精神神経症状の活動性を反映した2例

濱口真英1,川人 豊1,尾本篤志1,木村瑞穂1,和田 誠1,石野秀岳1,吉田牧恵1,山本相浩1
坪内康則1,河野正孝1,福田 亙2,佐野 統3,廣畑俊成a4,吉川敏一1


1京都府立医科大学大学院医学研究科生体機能制御学
2京都第一赤十字病院糖尿病・内分泌・リウマチ科
3兵庫医科大学膠原病科
4帝京大学内科

和文抄録

 中枢神経系ループスの診断方法としてMRI,脳波検査,髄液検査及び血液検査による特異的抗体の
測定があるが確立され されているた診断方法はない.血清抗リボソームP抗体は中枢神経系ループス
との関連が報告.われわれはステロイドパルス 療法が精神症状の改善に有効であり,血清抗リボソー
ムP抗体の抗体価が精神症状の活動性を反映した2例を経験した. これらの症例より治療前に血清抗リ
ボソームP抗体の抗体価が上昇している中枢神経系ループス症例では,血清抗リボソー ムP抗体の抗
体価が精神症状の活動性を反映する可能性が示唆された.
谷脇 雅史 Masafumi Taniwaki.
New agents and role of allogeneic stem cell transplantion in the current treatment of hematological malignancies and future of medical oncology

Masafumi Taniwaki

Department of Molecular Hematology and Oncology,Kyoto Prefectural University of Medicine
Graduate School Medical Science

  Abstract
: Many new agents with diverse mechanisms of action are currently entering clinical trial of hematological malignancies as well as solid tumors. The development of these agents, coupled with new insights into the molecular pathogenesis of the disease, provides hope for significant progress in the treatment of leukemia, lymphoma, multiple myeloma, and solid tumors. On the other hand, allogeneic stem cell transplantation is a life-saving procedure for hematopoietic malignancies, bone marrow failure syndromes, and hereditary immunodeficiency disorders. However, wide application of this procedure is limited in terms of availability of suitable HLA-matched adult donors. This review summarizes recent progress of both molecular-targeting therapies and hematopoietic stem cell transplantation.

 Key Words:Molecular-targeting therapies,Allogeneic stem cell transplantation,Oncology.
 
荒金 英樹,ほか Hideki Aragane et al.

Management of malignant ascites with peritoneovenous shunt

Hideki Aragane,Masanori Shimomura,Tomoko Katano,Hitoshi Yasui,Keitaro Kan
and MasahiroShimizu

Department of Surgery,Aiseikai Yamashina Hospital

  Abstract
: The effective palliation of malignant ascites remains a difficulty management problem. We performed peritoneovenous shunts (PVS) in 5 patients with malignant ascites uncontrolled by diuretics. The primary cancer types of these patients were two gastric cancers, two colon cancers and one ovarian cancer. Four patients suffered from metastatic liver tumor or peritonitis carcinomatosa. The number of platelet cells decreased below 100,000/mm3 in all patients, but no patients fulfilled with the disseminated intravascular coagulation (DIC) diagnostic criteria. Although we could not recognize any improvement in the level of serum albumin and body weight, no severe complications occurred, ascites was controlled in all cases, and the quality of life (QOL) of the patients was improved by PVS.
   PVS allowed many patients to be treated successfully in selected cases.

 Key Words:Peritoneovenous shunt (PVS),Malignant tumor,Peritonitis carcinomatosa,Palliative care.

 
小森 秀樹 Hideki Komori.
Suppression of diabetic macular edema follwing panaretinal photocoagulation by pre-intravitreal injection of triamcinolone acetonide

Hideki Komori

Department of Ophthalmology,Kyoto Prefectural Uiversity of Medicine Graduate School of Medical Science

  Abstract
: Abstract:Macular edema following panretinal photocoagulation (PRP) is one of the major clinical issues in diabetic retinopathy. The purpose of this prospective study is to examine if intravitreal injection of triamcinolone acetate (TA) prior to PRP suppresses macular edema. Subjects in this study included 19 cases (38 eyes) requiring PRP treatment. The patients received a TA injection prior to PRP for one eye (TA group) and PRP alone (control group) for the lateral eye. The TA group received an intravitreal injection of 4mg TA one week prior to PRP. The effect of TA on macular edema was evaluated by visual acuity, and measurement of both foveal thickness (FT) and macular volume (MV) by optical coherence tomography (OCT). After 12 weeks, FT was changed from 386±42.0μm(mean±SEM) to 304±29.1μm (p=0.04) and MV was changed from 9.94±0.64mm3 to 8.90±0.46mm3 (p=0.007). Both factors were significantly reduced in the TA group, yet FT was not significantly changed in the control group. Moreover, MV significantly increased from 9.36±0.56mm3 to 10.65±0.65mm3 in the control group (p<0.0001). After 12 weeks, both FT and MV were significantly higher in the control group compared to the TA group (p=0.04 and p=0.03). Of the control group, 32% exhibited a 2-step reduction in visual acuity. However, no reduction of visual acuity was exhibited in any cases within the TA group. Thus, we concluded that intravitreal injection of TA one week prior to PRP is effective on the suppression of macular edema.

 Key Words:Triamcinolone acetonide,panretinal photocoagulation,Diabetic macular edema,Opatical Ciherence Tomography.
 
廣瀬 宗孝 Munetaka Hirose
Role of anesthesiologists in palliative care

Munetaka Hirose

Department of Anesthesiology,Kyoto Prefectural University of Medicine Graduate School of Medical Science

  Abstract
:Although non-invasive pharmacological therapeutics resulted in satisfactory pain control in over 80% of cancer patients, 10% of patients still suffer severe pain despite aggressive pharmacological therapy. With experience of both acute pain control during and after surgery and chronic pain control in the pain clinic, anesthesiologists are expected to provide their pain management for severe cancer pain. Roles of anesthesiologists in palliative care are, 1) to optimize cancer pain management in their hospital, following the World Health Organization analgesic ladder, 2) to control severe cancer pain, and 3) to investigate new therapies for cancer pain.

 Key WordsCancer pain,Interventional pain therapy,Neuropathic pain,Noxious pain
 
濱元 泰子 Yasuko Hamamoto et al.
The role of consultation-liaison psychiatrist in palliative care-team

Yasuko Hamamoto1,2,Masanori Kunizawa1,2,and Masatoshi Kawase3

1Department of Psychiatry,Kyoto Prefectual University of Medicine Graduate School of Medicine
2Pain Treatment and Palliative Care Unit,University Hospital,Kyoto Prefectural University of Medicine
3Department of Psychology,Kyoto Notre Dame University

 Abstract:
In consultation-liaison psychiatry,psychiatrist will keep close attention to patient,s family and medical staffs,mental health as well as treat patient. They even need to resolve issues exists in patient and patient,s family or patient and medical staff. In psycho-oncology(as a part of the field of oncology), psycho-oncologist will manage patient,s problems psycho-biologically, psychologically, and sociologically. As a palliative care-team, psychiatrists are required to have expertise and experience in consultation-liaison psychiatry, and psycho-oncology. Between November, 2005 and January 2006, in consultation-liaison outpatient at Kyoto Prefectural University Hospital average of 84 patients were treated per month, and average of 2.2 new patients were treated per day. The cancer patients were over half of the entire number. Adjustment disorder, depression, delirium cases were recognized about 80% of them. The consultation-lesion psychiatrist plays important role within the palliative care-team providing smooth and excellent care for the patient and family.

 Key Words:Consultatio-liaisonpsychiatry,Psycho-oncology,Palliative care-team.
 
坪倉 卓司 ほか Takuji Tsubokura et al.
The role of radiologists in the palliative care team

Takuji Tsubokura1,2 and Tsunehiko Nishimura1

1Department of Radiology,Kyoto Prefectural University of Medicine Graduate School of Medical Science
2Pain Control and Palliative Care Unit,Univerity Hospital,Kyoto Prefectural University of Medicine

 Abstract: There are three specialized fields in the radiology; diagnostic radiology, IVR (interventional radiology) and radiation oncology. These all can be helpful to The Palliative Care Team. Diagnostic radiology include X-ray photography, fluoroscopy, CT(computed tomography), MRI(magnetic resonance imaging), RI(radio isotope), and so on. Radiologists use them properly to investigate the cause of the symptom. They are very useful tools in palliative medicine because physical burdens with examinations are generally few. IVR is the general term for various new procedure, for example, Stenting, TAE(transcatheter arterial embolization), TAI(transcatheter arterial infusion), PEIT(percutaneous ethanol injection therapy), RFA(radiofrequency ablation), PVP(percutaneous vertebroplasty), etc. These belong to minimally invasive treatment, and can became help for symptom management in palliative care. Palliative radiation therapy can be used to control various symptoms associated with many localized tumors. It's particularly useful in alleviating pain associated with metastatic bone tumors, pain relief can be achieved in 70-80% of patients. Generally, if careful treatment planning is done, side effects are minimal and are limited to the area receiving radiation. Therefore, radiation therapy is one of the most useful treatment in palliative medicine.

 Key Words:Palliative care,Diagnostic radiology,IVR,Palliative radiation therapy.
 
神林 祐子 ほか  Yuko Kanbayashi et al.
The roles of pharmacist in the pain treatment and palliative care unit

Yuko Kanbayashi1,2,Yoko Konishi1,2 and Hisaji Nishii1,2

1Department of Hospital Pharmacy,Univerity Hospital,Kyoto Prefectural University of Medicine
2Painm Treatment and Palliative Care Unit,University Hospital,Kyoto Prefectural University of Medicine

 Abstract:
Major roles of pharmacist in the ward are pharmaceutical consultation, monitoring the therapeutic and adverse effects of the drugs, checking the drug-interactions and instructing patient drug compliance. Enlightenment of medical staff is also included to ensure appropriate handling of drugs. Through these activities pharmacists in our institution have been contributing to ensuring fair handling of drugs and improving the QOL (quality of life) of patients even before the launch of the pain treatment and palliative care unit. Roles of pharmacists as members of the pain treatment and palliative care unit are as follows; patient compliance instruction, collection and offer of drug information, risk management, staff education for drug proper use, an offer of specific pharmaceutical and pharmacotherapeutic monitoring, etc. We believe that higher quality care can be provided by the pain treatment and palliative care unit including such various experts as a pain clinician, psychiatrist, radiologist, pharmacist and nurse. A pharmacist shows their specialty from a pharmaceutical point of view, in order to improve proper use of medicine and the QOL of the patient.

 Key Words:
Pharmacist,Pain treatment and palliative care unit,Pharmaceutical,Pharmacotherapeutic,QOL
 
冨田 英津子,ほか Etsuko Tomita et al.
Impact of nusing on palliative care team

Etsuko Tomita1,2,3,Sawako Fujimoto1,2,and Kanako Sekikawa1,2

1Nursing University Hospital,Kyoto Prefectural University of Medicine
2Pain Treatment of Palliative Care Unit,University Hospital,Kyoto Prefectural University of Medicine
3Outpatient Cancer Chemotherapy Center,University Hospital,Kyoto Prefectural University of Medicine

 Abstract:
Team approach in medical care is one of the keys in practice of palliative care. A palliative care team practices care in form such as a combination team. A role of a nurse among this team is very important and there is a role as a coordinator and a person of practice of palliative care. Our palliative care team started at on January 4, 2005. We coordinate requests regards palliative care from other doctors and nurse, and also work as a person of adjustment at team conference for palliative care. We also educate “palliative care” to other nurses and do their mental care. Our future role includes to inform continuously the significant role of palliative care team, and to improve our quality of palliative care.

  Key Words:Palliative care team, Palliative care cordinator, Plliative care practitioner
 
山岸 正明 Masaaki Yamagishi
 Development of pediatric cardiovascular surgery

Masaaki Yamagishi

Department of Pediatric Cardiovascular Surgery,Children's Research Hospital,Kyoto Prefectural University of Medicine

 Abstract
:Recently, remarkable surgical results of pediatric cardiovascular surgery are obtained. We have developed various innovative surgical techniques to explore the possibilities of performing a better quality of life of children. An outline of recent surgical strategy for univentricular hearts and newly developed original surgical techniques are described.
   Staged operation for univentricular heart: Final goal of surgical repair for univentricular hearts is Fontan operation. Fontan circulation is characterized by one-pump circulating system with non-pulsatile pulmonary circulation. Recent strategy is 3-staged operation. After first stage palliative operation, second stage bidirectional cavopulmonary connection (anastomosis between superior vena cava and pulmonary artery) is interposed before the final stage total cavopulmonary connection (connection between the inferior vena cava and pulmonary artery). Surgical results were markedly improved by the staged strategy.
   Hybrid pulmonary reconstruction during Ross operation: Right ventricular outflow tract is reconstructed using autologous aortic wall with non-coronary cusp and expanded polytetrafluoroethylene (ePTFE) patch with fan-shaped bicuspid ePTFE valves.
   Hybrid mitral valve: Mitral valve is replaced by autologous pulmonary valve reinforced with ePTFE cylinder.
   One-staged unifocalization of the major aortopulmonary collateral arteries (MAPCA) and palliative right ventricular outflow reconstruction: Under the cardiopulmonary bypass, MAPCA is completely uniforcalized through the median sternotomy. A small conduit between the right ventricle and the pulmonary artery provides antegrade pulmonary blood flow.
   Transference of posterior left atrial wall for cardiac type total anomalous pulmonary venous return: Posterior left atrial wall is translocated toward the atrial septum. Wide pulmonary venous opening is provided by this technique.
   Half-turned truncal switch operation for transposition of the great arteries with pulmonary stenosis: Truncal block including both aortic and pulmonary valves is resected and anastmosed after half-turn maneuver. Wide and straight left ventricular outflow channel and non-stretched pulmonary artery are provided by this technique.

 Key Words:Fontan operation,Palliative right ventricular outflow reconstruction,
         Transference of the posterior left atrial wall,Half-turned truncal switch operation.
 
荒木 美治 Biji Araki
Factors affecting the surgical prognosis of orbital bone fracture

Biji Araki

Department of Opthalmology,Kyoto Prefectural University of Medicine Graduate School of Medical Science


  Abstract:Orbital bone fracture is one of the most common injuries leading to impaired eye movement. To improve the surgical prognosis of this disease, we investigated various clinical factors that might affect the results of the surgical treatment. 39 patients with orbital bone fracture were enrolled in this study. Clinical findings, including the fracture type (open or closed), patient's age, severity of impaired eye movement, recovery rate by surgery and preoperative period, were statistically analyzed retrospectively. The closed-type fracture was found with statistical significance only in patients under 20 years of age (p<0.001). The severity of impaired eye movement was significantly worse in patients with the closed-type fracture than those with the open-type (p<0.05), although the improvement rate by surgery was almost the same in both. The length of the pre-operative period tended to be inversely correlated (r=−0.31) with the improvement rate achieved through surgery. Patients who received surgery within 14 days after the injury exhibited better recovery in eye movement. Age of patients, type of fracture, and length of the preoperative period are major factors that decide treatment strategy.

 Key Words: Trauma, Orbital fractures,Hess chart.
山田 浩之,ほか Hiroyuki Yamada et al.

The role of bone marrow-renin-angiotensin system in atherosclerosis

Hiroyuki Yamada,Yoshinori Tsubakimoto and Hiroaki Matsubara

Department of Molecular Cardiology and Vascular Regenerative Medicine,
Kyoto Prefectural University of Medicine Graduate School of Medical Science


 Abstract:Renin-angiotensin system(RAS)plays an important role in the inflammatory process of
atherosclerosis, however, the main focus has been on the vessel wall, in particular, endothelial cells and
vascular smooth muscle cells and their interactions with the blood flow. Recently, hematopoietic bone
marrow(BM)-derived cells have been reported to be involved in the development of atherosclerosis.
To clarify the role of BM AngUtype 1(AT1)receptor in atherogenesis, total BM cells from wild type or
AT1a-KO mice were transplanted into apoE-KO mice. Atherosclerotic lesion area was markedly reduced
by 60% in BM-AT1a receptor deficient mice compared with apoE-KO control mice. The accumulation of
monocyte/macrophage and T lymphocyte was also reduced by 55% and 87%, respectively in BM-AT1a
receptor deficient mice. Furthermore, the number of macrophage colony-forming unit was markedly
reduced by 82% in BM-AT1a receptor deficient mice, suggesting that BM-AT1a receptor are crucially
involved in the differentiation and/or self-renewal activity of macrophage progenitors. The study of the
BM-RAS is imperative especially in further understanding the mechanism of plaque rupture and could be
useful for the newly development of the therapeutic strategy targeting on the BM-derived progenitor
cells and/or circulating inflammatory cells.

 Key Words:Atheroscleorosis,,AngiotensinII,,Bone marrow.
高橋 知三郎 Tomosaburo Takahashi

Cardiac regeneration with stem cell transplantation

Tomosaburo Takahashi

Department of Molecular Cardiology and Vascular Regenerative Medicine,
Kyoto Prefectural University of Medicine Graduate School of Medical Science


Abstract:Current modalities of treatment for congestive heart failure include pharmacological therapy, temporary assist devices and for a selected few, cardiac transplantation. Despite significant therapeutic advances, a subset of patients is still refractory to or not eligible for these methods of treatment, resulting in poor prognosis. The recent advance in stem cell biology has triggered attempts to directly regenerate or repair heart tissue including vasculature and cardiac muscle by stem cell transplantation as novel therapeutic options, and we have shown for the first time that thetransplantation of angiogenic bone marrow-derived stem cells is indeed a potent therapeutic option for ischemic diseases. Cell-based cardiac regeneration, however, is still in the midst of a intense research, where various cell types including myoblasts, bone marrow stromal cells, tissue-derived somatic stem cells and ES cells are competing as cellular sources. Several clinical and experimental studies revealed that cell-based cardiac regenerative therapy is a potential cure for damaged hearts, although there are many gaps in our knowledge, which need to be resolved to achieve these future perspectives. Here, the current status and the recent progress in the field will be reviewed, and our results with adult stem cells derived from hearts and skeletal muscles and ES cells are briefly introduced.

 Key Words: Regeneration,Stem cells,Cardiac Muscle,Heart Failure.

白山 武司 Takeshi Shirayama

Progress in Anti-arrhythmic Therapy

Takeshi Shirayama

Department of Molecular Cardiology and Vascular Regenerative Medicine,
Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract: Abstract:Anatomical approach against clinical arrhythmias has been widely accepted instead of conventional electro-pharmacological treatment. The indication of the treatment with catheter ablation is rapidly expanding and this method is established as a powerful tool to abolish various types of arrhythmias. Recent research is focused on the final frontier, i.e. fibrillation. Pulmonary vein isolation by catheter ablation is effective against atrial fibrillation in many patients. Pharmacological rate-control is, however, the most cost-effective treatment because atrial fibrillation is less life-threatening. Ablation to triggering extra-systole may reduce the incidence of ventricular fibrillation. Patients at high risk of sudden cardiac death can be treated with implantable cardioverter defibrillator(ICD), or cardiac resynchronization therapy. Genetic analysis revealed many types of inherited arrhythmias (long QT, some Brugada syndrome). Individually-tailored treatment is emerging on the horizon.

 Key Words:Catheter ablatio,Implantable carsioverter defibrillator, Cardiac resyncronization therpy,
          Long QT,brugada.

沢田 尚久 Takahisa Sawada

The state of common incidences and therapeutic progrnosis of patients with acute
myocardial infarction in Kyoto prefectuture

Takahisa Sawada

Department of Molecular Cardiology and Vascular Regenerative Medicine,
Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract: Abstract:Acute myocardial infarction (AMI) is a critical disease that has high mortality rate in acute phase, and should be immediately treated using reperfusion therapy and intensive care. AMI Kyoto Multi Center Risk Study started in the year 2000, and has been assessed in-hospital AMI prognosis as a joint project with cardiology hospitals in Kyoto.
   Among the 1824 AMI patients from 2000 to 2004, male were 71.3%, averaged age, 68.6 years, and the ratio of older/super advanced age, over 70%. Overall in-hospital mortality was 13.3%, and female and advanced age had higher mortality. Onset-arrival time and door-to-needle/balloon time were correlated with in-hospital mortality. Patients with non-ST elevation or non-Q wave in the first ECG required longer time for therapeutic decision. The preliminary study using Utstein protocol for cardio-pulmonary arrest on arrival in 2004 showed 53.7% of cardiac origin, 16.7% of return of spontaneous circulation, and only 2.5% of successful rehabilitation.
   Kyoto has six demographic divisions of medical services, and medical resources are unevenly distributed in Kyoto-Otokuni urban district. For further improvement of AMI prognosis, administrative government branches, fire departments, the medical association and emergency hospitals should mutually investigate solutions that are suitable for the actual situation in Kyoto.

 Key Words:Acute myocardial infarction,Reperfusion therapy,,Sudden cardiac death.

辰巳 哲也 Tetsuya Tatsumi

Therapeutic angiogenesis for acute myocardial infraction by autologous peripheral
blood-derived mounuclear cells implantation


Tetsuya Tatsumi

Department of Molecular Cardiology and Vascular Regenerative Medicine,
Kyoto Prefectural University of Medicine Graduate School of Medical Science


 Abstract:
Postnatal neovascularization was initially thought to result exclusively from the migration and proliferation of pre-existing, fully differentiated endothelial cells(a process referred to as angiogenesis). Several lines of evidence, however, demonstrated that circulating endothelial progenitor cells(EPCs)home to sites of neovascularization and differentiate into endothelial cells in situ in a manner consistent with a process termed vasculogenesis. Moreover, recent studies demonstrated that transplantation of bone marrow-derived or expanded peripheral blood-derived EPCs enhances neovascularization and improves cardiac function after acute myocardial infarction (AMI). EPCs were reportedly elevated in patients with AMI. We previously published that transplantation of peripheral blood mononuclear cells(PBMNCs)enhances angiogenesis in hindlimb ischemia. Our present study was therefore designed to examine whether transplantation of non-expanded PBMNCs improves cardiac function after AMI. After successful percutaneous coronary intervention (PCI) for ST-elevation AMI with occlusion of proximal LAD coronary artery within 24 hours, patients were assigned to either control(PCI alone)group or PBMNCs group that received intracoronary infusion of PBMNCs within 5 days after PCI. We obtained PBMNCs(7−8×109 cells)from patients by use of COBE spectra apheresis and concentrated to 10 ml, 3.3 ml of which was infused via over-the-wire catheter under 3 min low pressure balloon inflation(3 times). Primary endpoint was global left-ventricular ejection fraction(LVEF)change from baseline to 6 month's follow up. The number of circulating EPCs in PBMNCs assessed by CD34+/acLDL uptake/Lectin binding was significantly increased in patients with AMI. Our on-going data show that mean LVEF has increased by 7.4% in the control group and 13.4% in the PBMNCs group. So far our cell transfer has not increased any adverse clinical events. Intracoronary infusion of non-expanded PBMNCs promotes improvement of left ventricular systolic function. This less invasive and more feasible approach to collect EPCs may provide a novel therapeutic option to improve cardiac function.

 Key Words:
Endothelia progenitor cell,Angiogenesis, Acute myocardial infarction,
         Cardiacregeneration,Peripheral blood-derived mononuclear cells implantation.

西 真弓,ほか  Mayumi Nishi et al.

Corticosteroid receptor dynamics:implications from live cell imaging

Mayumi Nishi and Mitsuhiro Kawata

Department of Anatomy and Neurobiology,
Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract:Adrenal corticosteroids (cortisol in man/corticosterone in rodents) readily enter the brain and exert markedly diverse effects, such as stress response of the target neural cells. These effects are regulated via two receptor systems, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), both of which are ligand-inducible transcription factors. It has been generally accepted that GR and MR are predominantly resided in the cytoplasm in the absence of corticosterone (CORT), and they are quickly translocated into the nucleus upon CORT binding. Then these receptors form dimers to bind hormone responsive elements and regulate the expression of target genes. Thus their subcellular trafficking is an important component of their biological functions. However the precise mechanisms of these processes are still not completely clarified. In order to address these issues, we have tried to see more dynamic subcellular trafficking processes in living cells by employing a green fluorescent protein. In this review, we would like to show our recent living cell studies of corticosteroid receptor dynamics focusing on the following three points:  1 )the effects of ligand, corticosteroid; 2 )carrier molecules involved in active nuclear trasnsport, importins;  3 )possible interactions of MR and GR in the nucleus, and discuss various factors affecting the dynamics of these receptors.

Key Words :Glucocorticoid receptor,Mineralocorticoid receptor,Hippocampus,
         GFP,Real-time imaging.


コルチコステロイド受容体のダイナミクス: 生細胞イメージングによる解析

西  真弓,河田 光博

京都府立医科大学大学院医学研究科生体構造科学


 抄録: 副腎皮質から分泌されるステロイドはコルチコステロイド(ヒトではコーチゾール/齧歯類ではコルチコステロン)と
呼ばれ,脂溶性であるため細胞膜を容易に通過し,細胞内の特異的レセプターであるglucocorticoid receptor(GR)とmineralocorticoid receptor(MR)と結合し,転写因子として働き,標的遺伝子の発現を通して代謝や免疫反応,さらにはストレス応答の制御に関るなど生体のホメオスタシス維持に重要な役割を果たしている.MRはコルチコステロイドに対する親和性がGRより約10倍高いことが知られているが,これらレセプターはこのようなコルチコステロイドに対する親和性の差を反映して,日内変動やストレス負荷などに伴う血中コルチコステロイドの変化に応答し,その下流遺伝子の転写を制御することによって多彩な機能を発揮するものと考えられる.その細胞内局在について,これまでに生化学的な方法,免疫組織化学的方法などで調べられてきたが,その詳細は未だ完全には解明されていない.近年,green fluorescent protein(GFP)やその色変異体との融合蛋白を用いることによって,生細胞内でのレセプターの動きをリアルタイムに可視化して解析することが可能となり,これまでの固定した細胞内では見られなかった新しい知見が得られるようになってきた.本稿では,生細胞内におけるコルチコステロイドレセプターの動態のリアルタイムイメージングによる解析について概説する.
沖田 美香  Mika Okita

Serum 8-hydroxydeoxyguanosine levels in chronic hepatitis C patients treated with
interferon and ribavirin


Mika Okita

Deparmtne of Molecular Gastroenterology and Hepatology,
Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract:To evaluate the effects of combined therapy withα-interferon(IFN)and ribavirin(RBV)on oxidative status in chronic hepatitis C(CHC)patients, serum 8-hydroxydeoxyguanosine(8-OHdG)levels were measured in 55patients with CHC before and during the IFN and RBV administration. Serum 8-OHdG levels were determined using an enzyme-linked immunosorbent assay(ELISA)kit(New 8-OHdG check). In the 20 CHC patients who have no treatment with hepatoprotective drugs, serum 8-OHdG levels increased in the early(A1/F1)stages of CHC. Moreover, 8-OHdG levels were higher in patients with more pronounced steatosis and iron deposits in the liver. In the 55 CHC patients, serum 8-OHdG levels before and during IFN and RBV administration were not related to efficacy of IFN and RBV. However, in endpoint or sustained viral responders, levels of serum 8-OHdG/white blood counts tended to increase during IFN and RBV administration. Oxidative stress may be an important factor underlying the response to IFN and RBV combination therapy.

Key Words:
8-Hydroxydeoxyguanosine(8-OHdG),Chronic Hepatitis C,α-Interferon,
        Ribavirin,Oxidative stress.


C型慢性肝炎における血清8-hydroxyguanosine値と
インターフェロン・リバビリン併用療法の影響

沖田  美香
京都府立医科大学大学院医学研究科消化器病態制御学


 
[目的・方法]C型慢性肝炎(CHC)患者の血清において,DNA酸化障害のmarkerである8-hydroxy-2´ deoxyguanosine(8-OHdG)を最近開発されたNew 8-OHdG check ELISAキットを用いて測定した.対象はαインターフェロン・リバビリン(IFN/RIB)併用療法を受けたCHC患者55名で,治療前に肝生検を施行した.強力ネオミノファーゲンCやウルソによる治療を併用していた投薬群とこれらの投薬を受けていない無投薬群に分けて検討した.
  [成績]
無投薬群において,血清8-OHdG値は肝組織所見のA1,F1で最も高く,また肝脂肪化と肝組織の鉄沈着の程度が増すにつれて高値を示した.IFN/RIB治療前の血清8-OHdG値と抗ウィルス効果との間に関連はなかった.しかし血清8-OHdG値を末梢白血球数で割った値は,IFN/RIB 治療中にウイルス学的有効例において無効例に比べて高値であった.血清8-OHdG値は末梢リンパ球中8-OHdG濃度と相関した.
  [結語]
CHCに対するIFN/RIB治療の効果には酸化ストレスが関連した.血清8-OHdG値はリンパ球の酸化ストレス状態を反映する可能性が考えられた.

石原 靖紀 Yasunori Ishihara

The effect of granulocyte colony stimulating factor on hematopoietic stem cells in skeletal muscle

Yasunori Ishihara

  Abstract:CD45 and stem cell antigen 1(Sca1), hematopoietic cell surface markers, are expressed in some parts of cells in skeletal muscle, and murine CD45+Sca1+cells resident in muscle participate in their regeneration. We examined the effect of granulocyte colony stimulating factor(G-CSF)on skeletal muscle during muscle injury. Mononuclear cells were obtained from muscle of 8-week-old mice that had received cardiotoxin(CTX)injury and daily G-CSF injections for 5 days. FACS analysis revealed that CD45+Sca1highcells existed in skeletal muscle but not in peripheral blood or bone marrow, and that they had myeloid characteristics. G-CSF increased the CD45+Sca1high population in the regenerating muscles. Muscle-derived hematopoietic stem cells are likely to generate skeletal muscle through myeloid lineage cells. Our findings demonstrate that G-CSF has effects on the skeletal muscle tissues, which raises the possibility of using G-CSF for muscle-derived cell therapy for muscular diseases.

Key Words :G-CSF, CD45Sca1high ,Muscle-derived hematopoietic stem cell,muscle injury,
         Muscle regeneration.

高橋 知三郎,ほか Tomosaburo Takahashi et al.

Regenerative medicine; from peripheral vascular disease to cardiac regeneration

Tomosaburo Takahashi and Hiroaki Matsubara

Department of Molecular Cardiology and Vascular Regenerative Medicine,
Kyoto Prefectural University of Medicine Graduate School of Medical Science

Abstract

   While the current treatments against ischemic heart disease and chronic heart failure have made significant progress to improve prognosis and quality of life of these patients, there is a subset of the patients, who are refractory to these conventional therapies and have poor prognosis. Stem cell therapy for cardiac disease is a rapidly evolving field, and therapeutic angiogenesis with bone marrow-derived angiogenic stem cells is being shown to be effective against ischemia in clinical settings, while the larger, well-controlled clinical trials are still needed to expand our knowledge to improve its efficacy. Cardiac regeneration with stem cells is foreseen as a potential cure against severe heart failure; although additional experiments are warranted to elucidate the fundamental knowledge to guide the application of stem cell therapy in hear failure.
Key Words:stem cells, Therapeutic angiogenesis, Cardiac regeneration.



再生医療 末梢血管病から心筋再生へ

高橋知三郎,松原 弘明


京都府立医科大学大学院医学研究科循環器病態制御学


抄  録
  虚血性心疾患,慢性心不全に対して,薬物療法に加え,血行再建術や補助人工心臓,脳死心臓移植などの治療法は予後の改善と生活の質の向上に寄与してきたが,心臓移植ドナー数の絶対的な不足もあり,治療効果 が不充分で予後不良な患者が存在する.最近,心筋細胞を含む従来増殖しないと考えられていた臓器においても増殖する細胞が観察され,さらに多くの臓器において幹細胞が存在し,その幹細胞は多分化能を持つこと, などが示され,これらの幹細胞を用いた再生医療が注目されている.循環器領域においても虚血性疾患,慢性心不全症例に対する新しい治療法として細胞移植・再生療法が注目され,虚血の解除を目指した細胞移植に よる血管新生療法の有用性は確立されつつあり,心筋細胞を再生あるいは補充することによる心不全治療も期待されている.今後の研究の発展により,最適な細胞種や移植経路,さらにその分子機序が明らかになることにより,この治療法が,心疾患患者の予後と生活の質の改善に寄与することを切望する.
キーワード:再生医療,虚血性心疾患,慢性心不全,血管新生,心筋再生

新里 直美,ほか  Nomi Niisato et al.

Regulatory mechanism of renal Na+ reabsorption for undersanding salt-sensitive hypertension

Nomi Niisato1, Wataru Aoi1 and Yoshinori Marunaka1

1Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine
Graduate School of Medical Science

2Sports Medical Research Center, Office Froe Research Intiative and Development,
Doshisha University


Abstract

  Renal Na+ reabsorption has a crucial role in body Na+ homeostasis and control of blood pressure. In salt-sensitive hypertension, the feedback system for plasma volume homeostasis by aldosterone is thought to be disturbed. In this review, we discuss the mechanism of salt-sensitive hypertension caused by abnormal regulation of renal Na+ reabsorption and the action of aldosterone on epithelial Na+ channel.
 Key Words: Na+reabsorption, ENaC, SGK1,Aldsterone.



食塩感受性高血圧と腎ナトリウム再吸収制御機構

新里直美1,青井 渉1,2,丸中良典1

1京都府立医科大学大学院医学研究科生理機能制御学
2現:同志社大学研究開発推進機構スポーツ医科学研究センター

抄  録

  正常人では,高食塩食を摂取して一時的に体液量が増大しても,アルドステロン(ALD)の分泌を抑制して Na+を効率的に排泄し,体液量増大による高血圧症を引き起こさないよう恒常性を維持する仕組みが備わ っている.この恒常性維持には,腎臓の皮質集合管での上皮型ナトリウムチャネル(epithelial Na+channel; ENaC)を介するNa+再吸収が重要な役割を担っていることが知られている.しかし,食塩感受性高血圧患 者では,このようなALDを介したフィードバック機構が破綻し,血圧が上昇するのではないかと考えられる. 本総説では,食塩感受性高血圧の発症要因として考えられるNa+ 再吸収の異常制御とALDによるNa+
再吸収制御機構に関する最近の知見について概説する.
キーワード:上皮型ナトリウムチャネル,SGK1,アルドステロン

小川 貢,ほか Mitsugu Ogawa et al.

Innovations of the surgical treatment for ischemic cardiomyopathy:
Advantages of assessing myocardial viability by delayed-enhanced magnetic resonance imaging
before surgical ventricular restoration in ischemic cardiomyopathy
                       

Mitsugu Ogawa, Kiyoshi Doi and Hitoshi Yaku

Department of Cardiovascular and Thoracic Surgery,Kyoto Prefectural University of Medicine
Graduate School of Medical Science

Abstract
   Assessment of myocardial viability is important when deciding whether and on which areas of the left ventricle (LV) surgical ventricular restoration (SVR) should be performed in patients with ischemic cardiomyopathy. Eight consecutive patients with poor cardiac function (ejection fraction <30%) due to ischemic cardiomyopathy underwent surgical treatment based on preoperative MRI. Our surgical strategy consists of (1) complete revascularization (2) SVR for patients with extensive non-viable segments (hyperenhancement >75%) (3) mitral valve plasty (MVP) on patients with a more than moderate degree of mitral regurgitation. Four of the patients (Group A) had isolated oronary bypass surgery while the other 4 (Group B) had SVR+MVP concomitant with coronary bypass surgery. LV end-diastolic volume index was reduced from 109±34ml/m2 to 95±14ml/m2 in Group A and from 161±33ml/m2
to123±31ml/m2 in Group B. LV end-systolic volume index was reduced from 87±29ml/m2 to 69±17ml/m2 in Group A and from 132±34ml/m2 to 97±30ml/m2 in Group B. Ejection fraction increased from 20±6% to 28±9% in Group A and from 19±7% to 21±4% in Group B. Wall thickening was slightly improved in all segments in both groups. Delayed-enhanced MRI was very effective in helping to select which patients and which areas of the left ventricle should be indicated for SVR, which helped to obtain excellent early clinical outcomes.
Key Words:Myocardial viability,Ischemic cardiomyopathy, Surgical ventricular restoration,
        Delayed-enhanced magnetic resonance imaging


虚血性心筋症に対する外科治療の最前線
−遅延造影MRIによる局所心筋バイアビリティー評価に基づいた左室形成術の適応と術式選択−
                         
小川 貢,土井 潔,夜久 均

京都府立医科大学大学院医学研究科心臓血管・呼吸器機能制御外科学

抄  録

  [目的] 遅延造影MRI(DE-MRI)による心筋バイアビリティー評価が虚血性心筋症に対する左室形成術の適応決定および術式選択に有用であるかを定量的に検討する.
  [対象と方法] 対象は術前後に心臓MRIが施行可能であった虚血性心筋症の中でEF<30%であった最近の 8例(男性8例,60±7.7歳).治療方針は( 1 )完全血行再建( 2 )壁内進展度が75%以上を血行再建によって も改善不可能な壊死心筋と判断し,その部位が連続的に存在する症例には左室形成術を追加( 3 )僧帽弁逆 流(MR)の程度が中等度以上存在する症例には僧帽弁形成術(MVP)を追加.それらに基づき施行した術式に よって,CABG単独4例(A群,全例MRはmild以下),CABGに左室形成術+MVPを追加した4例(B群)の2群に 分けられた.MRI評価に基づき造影範囲,術前後の心機能を検討.術後MRIは術後15±7日に施行.
  [結果] 手術死亡,病院死亡なし.EDVIはA群で109±34ml/m2から95±14ml/m2,B群で161±33ml/m2から123±31ml/m2に減少.ESVIはA群で87±29ml/m2から69±17ml/m2,B群で132±34 ml/m2から97±30ml/m2 に減少.EFはA群で20±6%から28±9%,B群で19±7%から21±4%に改善.壁厚変化率は両群とも全ての セグメントで増加.B群ではMRは全例で消失.
  [結語] DE-MRIに基づき決定した治療方針を実践した2群の手術成績は良好であった.DE-MRIは壊死心筋 の定量化を可能とし,虚血性心筋症における左室形成術の適応並びに切除範囲の決定に有用な情報を提供す ることが示唆された.
キーワード: 遅延造影MRI,心筋バイアビリティー,虚血性心筋症,左室形成術.

横山 尚彦 Takahiko Yokoyama 

The emerging role of altered intracellular Ca2+ dynamics in cardiac arrhythmogenesis

Takahiko Yokoyama

Department of Anatomy and Development Biology,Kyoto Prefectural Universty of Medicine
Graduate School of Medical Science

Abstract

   Though the left and the right sides of vertebrate body are externally symmetrical, almost all internal structures show marked left-right asymmetry such as left sided stomach and heart, and more lung lobes in the right side than that in the left side. Randomization of this organ asymmetry often results in severe heart malformation. The mechanism to place the heart to the left has been enigma for a long time. Recent advancement revealed that cilia have an important role on the heart laterality as well as the left-right asymmetry of other organs in the body. Cilia on the primitive node show rotational movement that produces a leftward current. This current is now shown to be important to determine the left-right asymmetry of the body. This short review summarized recent advancement for the role of cilia in the left-right determination.
Key Words:Left-right asymmentry,Cilia,Heart


心臓と繊毛

横山尚彦

京都府立医科大学大学院医学研究科生体機能形態科学

抄  録

  私たちの身体は,外見は左右対称であるが,心臓などほぼすべての内部臓器は左右非対称的な配置となっ ている.この内部臓器の配置が逆転するなどの異常をきたすと,しばしば心奇形を合併する.心臓がなぜ左に 位置するのかという機構については長い間謎であった.近年の研究により,身体の臓器の左右決定に繊毛が 大きな役割を果たしていることが示されるようになった.原始結節に存在する繊毛は,気管などの繊毛と異なり, 一次繊毛と呼ばれ,細胞に一本のみ生えている.この原始結節の繊毛は回転運動をし,その回転運動により 細胞外液の右から左への流れを形成する.この流れによって臓器の左右が決定される.本小論では,最近の 左右決定に関する繊毛機能に関して述べる.
キーワード:左右非対称,繊毛,心臓

白石 公 Isao Shiraishi

Recent advances in molecular embryology of the heart

Isao Shiraishi

Department of Cardiology and Nephrology,Kyoto Prefectural University of Medicine
Graduate School of Medical Scienc

Abstract

   Congenital heart disease is the leading cause of deaths in birth defects of newborns. The etiology of congenital heart disease is multi-factorial, but genetic disorder plays central roles. Recent advance in molecular biology, including genetic manipulation in mice, has uncovered the molecular basis of cardiac embryology and pathogenesis of congenital heart disease. The formation of multi-chambered heart requires a cascade secretion of growth factors and activation of transcription factors under temporal and spatial control. Congenital heart disease may occur when the strictly regulated cascade of growth factors or transcription factors is perturbed. Here, we review the recent advances in molecular embryology of the heart. The investigation of cardiac embryology is important not only to understand the etiology of congenital heart disease but also to promote regeneration of injured heart tissue in adults.

Key Words:Congenital heart disease, Embryology, Morphogenesis,Mouse engineering.


分子心臓発生学研究の最前線

白石 公

京都府立医科大学大学院医学研究科発達循環病態学

抄  録

  先天性心疾患は生産児の先天性疾患の死亡原因のなかで最も多く,遺伝的要因,環境要因,母胎感染, 薬物の服用など様々な原因によって起こりうる.最近の発生工学の発達により,心臓形態形成を制御する転写 因子や成長因子のカスケードがかなり明らかになってきた.本論文では分子心臓発生学研究における最近の 知見を紹介する.心臓形態形成を理解することは,先天性心疾患の病因を知るにとどまらず,障害された心筋 組織の再生医療にもつながる大変重要な研究分野である.
キーワード:先天性心疾患,発生学,形態形成,マウス遺伝子工学

田中 秀央,ほか  Hideo Tanaka et al.

The emerging role of altered intracellular Ca2+ dynamics in cardiac arrhytmogenesis

Hideo Tanaka adn Tetsuro Takamatsu

Department of Pathology and Cell Regenelation,Kyoto Prefectural University of Medicine
Graduate School of Medical Science

Abstract

   Despite much effort on antiarrhythmic therapy in preventing sudden cardiac death, its mortality and morbidity have remained unchanged. A recent approach for the treatment of fatal arrhythmias, focusing on the upstream arrhythmogenic elements, has provided us deeper insight into understanding arrhythmias. Of various elements aberrations of calcium cycling play important roles in arrhythmogenesis. Mutations of cardiac ryanodine receptors (RyR2) or calsequestrin (CASQ2) are responsible for the pathogenesis of triggered tachyarrhythmias in catecholaminergic polymorphic ventricular tachycardia (CPVT). Diastolic calcium leak from the sarcoplasmic reticulum that originates from unstable RyR2 functions in the failing heart also contributes to generation of triggered arrhythmias. Ischemic hearts exhibit spatiotemporally
inhomogeneous calcium dynamics due to the depressed function of RyR2, leading to electrical dispersion and reentrant tachyarrhythmias. Thus, arrhythmias are unstable electromechanical events that may be determined by various substrates especially calcium dynamics. We propose that cardiac arrhythmias should be understood not merely from the voltage-centric point of view but from more integrated perspectives.
Key Words:Arrhythmia,Arrythmogenic substrate,Calcium,Triggered activity, Ryanodine receptors


不整脈の発生基質を求めて−心筋カルシウムシグナリング異常と不整脈−

田中秀央,高松哲郎

京都府立医科大学大学院医学研究科細胞分子機能病理学

抄  録

  心臓の電気現象を捉える心電図が登場して約百年後の現在,不整脈は単なる心臓の電気的興奮・伝導の 異常ではなく,様々な不整脈基質の集積によって形成される心臓の病態の表現型であると理解されるように なった.不整脈基質のなかでも心臓の興奮・収縮の要となる細胞内カルシウムイオンシグナルの調節異常は, 不整脈の直接の原因となる重要な発生基質である.遺伝性の致死性不整脈疾患であるカテコラミン感受性 多形心室頻拍(CPVT)は,カルシウム放出チャネルのリアノジン受容体(RyR2)や筋小胞体内のカルシウム 貯蔵に関わるcalsequestrin2(CASQ2)の変異によって生じる撃発活動に起因する.また後天性の不全心に おいても,RyR2の機能異常やNa+-Ca2+交換機構などのカルシウム調節蛋白の発現の変化による撃発性
不整脈の易発生性が指摘されている.虚血心ではRyR2のカルシウム放出障害により細胞内カルシウム動態 の不均一化が生じ,リエントリー性不整脈の素地となる興奮伝導異常が形成される.このようにカルシウム ハンドリングに関わる分子の異常は,不整脈の発生を考える上で重要であり,新たな治療戦略にもつながる ものと考える.
キーワード:不整脈,不整脈基質,カルシウム,撃発活動,リアノジン受容体
山岸 久一  Yamagishi Hisakazu

Current status and future prospect of immune-cell for refractory solid cancer

Hisakazu Yamagishi

President,Kyoto Prefectural University of Medicine

Abstract
   Immune-cell therapy for solid cancer is always challenging. Adoptive cell therapy with cultured killer T lymphocytes and interleukin-2 has been actively tried since the middle of the 1980's. However, the main stream has become dendritic cell-based, tumor-specific active immunotherapy since the latter half of the 1990's. Despite much effort, immune-cell therapy has not yet achieved an adequate anti-tumor effect comparable with that of chemotherapy. In addition, there is a lot of problem with immune-cell therapy which needs in vitro cell processing under the observance of good manufacturing practice(GMP). It is labor- and resource-consuming, and cannot avoid the risk of microbial contamination. In view of these problems, we started research on a new immunotherapy technique with direct hemoperfusion in 2003. We have succeeded in developing a direct hemoperfusion column for cancer immunotherapy which consists of extra-fine synthetic fibers removing immunosuppressive cytokines from the peripheral blood of advanced cancer patients. In addition, we are developing another column consisting of fibers immobilized with lipoteichoic acid that can activate immune cells widely. Direct hemoperfusion with these columns can be a novel strategy of cancer immunotherapy and is expected to achieve synergistic effects with already-established immune-cell therapies or chemotherapy.
   In this article, current status and future prospect of immune-cell therapy for refractory solid cancer are discussed.
Key Words: Cell therapy, Cancer immunotherapy, Dendritic cell, Direct hemoperfusion, Solid Cancer

難治性固形腫瘍に対する細胞免疫療法
 〜過去・現在・未来〜

山岸 久一

京都府立医科大学学長

抄  録

  難治性固形腫瘍に対する細胞免疫療法の変遷と問題点を概説し,今後の新しい治療戦略の一つとして, 我々が現在取り組んでいる,完全閉鎖系体外循環による細胞免疫療法の開発研究について解説した.   固形癌に対する細胞免疫療法は,樹状細胞のin vitro誘導方法の確立と数々の腫瘍拒絶抗原の分子レベル での解明を契機に,培養T細胞を用いた受動免疫療法から樹状細胞を用いた能動免疫療法へと1990年代後半 に大きく変化した.しかし,よくデザインされた臨床試験でその有効性が客観的に評価された報告は未だにわず かである.今後は造血幹細胞移植や化学療法を併用した集学的細胞療法の開発研究が盛んになるであろうが, 抗腫瘍効果が不十分であれば,トランスレーショナル・リサーチの枠を抜け出して真の癌医療として定着していく のは困難であろう.
  in vitroでの細胞処理が必要な細胞免疫療法は,治療に至るまでの労力,経費ともに莫大で尚且つ細胞培養 過程における微生物汚染の危険性を避けて通れない.換言すれば,経済性,普遍性,安全性の面での問題を 常に内包している.京都府立医科大学消化器外科では東レ(株)との共同研究で,ポリスチレン系極細繊維を 充填された二種類の癌治療用体外循環カラムの開発研究を行っている.ひとつは進行癌患者の血液中に著しく 増加する免疫抑制性サイトカインを効率的に吸着除去することを目的とし,他方は免疫賦活剤を固定化すること により血中の免疫担当細胞を直接活性化することを目的としている.安全に,簡便に,繰り返し施行可能な完全 閉鎖系体外循環による細胞免疫療法の新しい治療体系の構築を目指している.
キーワード:細胞療法,癌免疫療法,樹状細胞,対外循環治療,固形癌

片岡 慶正  Keisyo Kataoka

Specialized nutrition support corresponding to pathophysiological changes
in acute and chronic pancreatitis

Keisho Kataoka

Department of Molecular Gastroentarology and Hepatology,
Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract:
Pancreatic diseases cause a functional disturbance of exocrine and endocrine pancreas, and it follows that digestion, absorption and systemic metabolism as an original physiological function of the pancreas break down. Pancreas has a most important role in the digestion process of nutrients. In pancreatic juice, there are various kinds of pancreatic digestive enzymes that are essential for nutritive digestion as well as bicarbonate that provided an optimized pH for intraluminal action of digestive pancreatic enzymes. Quality and quantity of pancreatic juice is depending on the numbers of functioning acinar and ductal cells of the pancreas. While there are enteral feeding and intravenous nutrition for the method of nutrition support, the former is more physiological and should be performed as a first choice if the functional bowel is present. However, enteral feeding has at least stimulatory effect on pancreatic enzyme secretion, and so a decision of its timing and route is important in acute pancreatitis. On the other hand, intravenous hyperalimentation
independent on the bowel is useful for the treatment of acute pancreatitis because exocrine pancreatic secretion is suppressed by the procedure. However, intravenous hyperalimentation for a long term might cause bacterial translocation due to mucosal atrophy and decreasing immunity of the intestine. In severe acute pancreatitis or advanced chronic pancreatitis with extensively destroyed exocrine and endocrine pancreas, nutritional management based on an appropriate nutrition assessment of the individual should be performed for maldigestion, malabsorption, and pancreatic diabetes. Specialized nutrition support including immunonutrition is required as a foresighted therapy for pancreatic diseases.

Key Words:Specialized nutrition support,Excrine and endocrine pancreatic function,Acute and chronic
         pancreatitis, Pathophysiological evaluation, Immunonutrition.


急性および慢性膵炎における生体侵襲の病態解析と栄養療法

片  岡  慶  正

京都府立医科大学大学院医学研究科消化器病態制御学

抄録

  膵疾患に起因する膵実質細胞障害は膵の内外分泌機能障害を引き起こし,病態に応じて程度の差こそあ れ,膵本来の生理的機能としての消化・吸収・代謝の調節機構が破綻する.膵は栄養素の消化吸収過程で, 消化の主役を演ずる.膵液には栄養素の消化に必要な消化酵素と十二指腸内での至適pHを保持するのに必 要な重炭酸塩が含まれる.膵液の質と量はその分泌に関与する膵機能細胞数に依存する.生体に対する栄 養補給法には,経腸栄養と経静脈栄養があり,生理的な経腸栄養は機能的腸管が存在すれば第一選択とな る.しかし,膵外分泌機構からみると,経腸栄養それ自体には膵外分泌刺激効果があることから膵炎の場合に は投与ルートの工夫が必要となる.一方,完全静脈栄養は腸管を介さない栄養補給であり,膵外分泌はむしろ 抑制されることから膵の病態を改善するのに役立つ.しかし,長期に及ぶと腸管粘膜萎縮や腸管免疫低下から bacterial translocationを誘発する.急性膵炎は数日間の絶食と輸液で軽快する軽症例から致死率の高い重症例まで様々であり,重症急性膵炎は本来良性疾患でありながら,致命的な敗血症,DICおよびMOFを来す.この ような高度侵襲時のhypercatabolismに応じた輸液と栄養補給をいかにすべきか,迅速かつ適切な判断が求め られる.一方では膵機能が進行性かつ非可逆的に荒廃した慢性膵炎では消化吸収障害と代謝障害としての 糖尿病が顕性化してくる.“いわゆる膵炎発作”状態では膵の安静庇護を目的に絶食が基本となり,またアル コールや脂肪食は膵外分泌刺激作用のために膵炎発作の誘因となる.一方では,膵疾患患者の栄養管理の うえで,食事中脂肪の長期にわたる過度の制限はn-3系脂肪酸欠乏を生じるだけでなく,immunonutritionの観点からも好ましくない.三大栄養素をはじめとする食事成分の膵内外分泌刺激機構,静脈栄養や経腸栄養 の膵および腸管に及ぼす影響などの理解と,急性および慢性膵炎の病態に応じた栄養評価のもとにきめ細か な栄養管理が膵疾患治療に求められる.

笠井 高士,ほか  Takashi Kasai et al.

A case of amyotrophic lateral sclerosis that partially responded toimmunomodulating therapy

Takashi Kasai1, Kenji Yoshikawa1,Kyoko Itoh2, Shinji Fusiki2 and Masanori Nakagawa1

1Department of Molecular Neurology and Gerontology,Kyoto Prefectural University of Medicine Graduate School of Medical Science
2Department of Pathology and Applied Neurobiology,Kyoto PRefectural University of Medicine Graduate School of Medical Science


Abstract: A 64-year-old female complained of progressive weakness localized in the left upper limb. Muscularatrophy was observed in the left upper arm without sensory involvement. Intravenous immunoglobulin was administered, which tentatively improved the weakness.  Although she underwent plasmapheresis and immunosuppressive treatment one year later, the amyotrophy with hyperreflexia emerged in other extremities, which were refractory to these therapies. She died three years after the obset.  Autopsy revealed the pathology of amyotrophic lateral sclerosis(ALS)with lymphocyte infiltration in the anterior horn. Inflammatory processes in ALS and the contribution of immunomodulating therapies are discussed.
Key Words:Amyotrophoc lateral sclerosis, Intravenous immunoglobulin therapy.


一過性に免疫療法に反応した筋萎縮性側索硬化症の一例

笠井 高士1,吉川 健治1,伊東 恭子2
伏木 信次2,中川 正法1

1京都府立医科大学大学院医学研究科神経病態制御学
2京都府立医科大学大学院医学研究科分子病態病理学

抄録
症例は64歳の女性で主訴は左上肢脱力である.初診時に感覚障害はなかった.免疫グロブリン療法で, 一時的に筋力は改善した.しかし,その後,他の四肢に脱力が進行し,さらに腱反射の亢進が出現した.血漿 交換療法および免疫抑制療法を行ったが,一時的な効果であった.発症3年後に呼吸不全で死亡した.病理解 剖の結果,筋萎縮性側索硬化症と確定診断した.脊髄前角細胞には炎症細胞浸潤がみられた.筋萎縮性側索 硬化症における免疫機序の関与と免疫介入療法の寄与について考察する.

中西 正芳,ほか  Masayoshi Nakanishi et al.

Clinical Study gallbladder carcinoma diagnosed after laparoscopic cholecystectomy

Masayoshi Nakanishi,Akinori Noguchi,Hiroki Takeshita Tadao Ito,Naoki Tani,Yasushi Suganuma
Masahide Yamaguchi,Shinji Okano and Tetsuro Yamane

Department of Surgery,Matsushita Memorial Hospital

Abstract
   Between August 1992 and May 2006, 851 patients underwent laparoscopic cholecystectomy(LC)in our department. Of these patients, 7(0.8%)were postoperatively diagnosed as having histopathologically proven gallbladder cancer. The subjects were 3 men and 4 women, and their mean age was 70.0 years old. Before surgery, 2 patients were diagnosed as having cholelithiasis, 3 cholecystitis, and 2 gallbladder polyp. Intraoperative frozen section examination was not performed, and all patients were diagnosed with gallbladder cancer by postoperative pathological examination. Histopathological examination revealed m cancer in 2 patients, and ss cancer in the remaining 5 patients. Of the 5 patients with ss cancer, 4 underwent additional resection. The patient diagnosed as Binf3 with poorly differentiated gallbladder cancer did not undergo additional resection. To date, 20 to 113 months after surgery, the patient diagnosed as Binf3 has died of the primary disease, 1 has died of another cancer, and the remaining 5 are alive and free from recurrence. When performing LC, it is necessary to always consider the possible complications of gallbladder cancer, and to give additional treatment according to the results of postoperative pathological examination if gallbladder cancer is confirmed.
Key Words:
Laparoscopic cholecystectomy, Gallbladder cancer ,Operation.



腹腔鏡下胆嚢摘出術後に診断された胆嚢癌症例の検討

中西 正芳,野口 明則,竹下 宏樹,伊藤 忠雄,谷 直樹,菅沼 泰 山口 正秀,岡野 晋治,山根 哲郎


松下記念病院外科

抄  録  
1992年8月から2006年5月までに当科で施行されたLC症例は術中に開腹移行した症例41例を含めて851例
であり,その内で術後に病理組織学的検査により胆嚢癌と診断された症例は7例(0.8%)であった.平均年齢 は70.0歳(66歳〜76歳),性別は男性3例,女性4例,術前診断は胆石症2例,胆嚢炎3例,胆嚢ポリープ2例で あった.術中迅速病理検査は施行しておらず,いずれの症例も術後の病理検査で胆嚢癌と診断された.病理 組織検査ではm癌が2例で,その他の5例はいずれもss癌であった.ss癌5例の内,4例に対して追加切除を施 行した.手術は肝床切除,肝門部リンパ節郭清を施行,1例のみ胆管切除,胆道再建も行った.きわめて浸 潤傾向が強く,binf3と診断された1例には追加切除を施行しなかった.LC術後1年8ヶ月から9年5ヶ月経過した 現在,原病死した症例が追加切除を施行しなかった1例,他癌死した症例が1例であり,その他の5例は無再
発生存中である.腹腔鏡下胆嚢摘出術を施行する際は胆嚢癌合併の可能性を常に念頭におき,術後の病理検査で胆嚢癌が確認された際はその結果に応じて追加治療を検討する必要がある
キーワード:腹腔鏡下胆嚢摘出術、胆嚢癌、手術.

横田 昇平  Shohei Yokota

Mutation of FLT3 tyrosine kinase and molecularly targeted therapy

Shohei Yokoto

Department of Molecular Hematology and Oncology, Kyoto Prefectural University of Medicine
Graduate School of Medical Science


Abstract
   The activation of receptor tyrosine kinases(RTKs)initiates the multiple intracellular signaling pathways that lead to cell proliferation and activation. Overexpression and activating mutations of these genes are involved in the pathophysiology of several kinds of cancer cells. Class III RTKs including FMS-like receptor tyrosine kinase 3 (FLT3), cKIT, FMS and PDGFR are expressed on hematopoietic cells.
   We found a unique mutation of FLT3 in which some part of the juxtamembrane domain-coding sequence shows internal tandem duplication(FLT3/ITD). FLT3/ITD together with point mutations surrounding the D835 within a FLT3 tyrosine kinase domain (FLT3/KDMs)are the most frequent genetic alterations so far reported in acute myeloid leukemia and activate the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Several large-scale clinical studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis.
   These findings lead to a survey for the agents which inhibit FLT3 kinase activity. Although ongoing clinical studies showed no remarkable effect as a single agent, new agents or combination with the conventional drugs might overcome the adverse effects of FLT3 mutation.

Key Words:FLT、Tyrosine kinase,Leukemogenesis,Molecular Targeted therapy.



造血器腫瘍における新たな分子標的としてのFLT3変異

横  田  昇  平


京都府立医科大学大学院医学研究科血液病態制御学

抄  録
  受容体型チロシンキナーゼ(RTK)は,細胞の増殖と分化のシグナル伝達経路の開始点として 重要である.また, これらの遺伝子の過剰発現や突然変異は,多くのがん細胞の発生に関与して いる.なかでも,FLT3,KIT,FMS, PDGF-Rなど第3群のRTKは造血 細胞に発現していることが 知られ,白血病発症との関連が注目されてきた.
  1996年私たちは世界で初めて,FLT3遺伝子のjuxtamembrane領域に直列型の重複(internal tandem duplication,FLT3/ITD)というユニークな変異を発見した.この変異は急性骨髄性白血病 (AML)の約1/4にみられ, その後発見されたFLT3チロシンキナーゼ領域(FLT3/KDM)D835残基 やその周辺コドンにおける塩基置換,欠失, 挿入などの点突然変異を含めると,全AML患者の 1/3が FLT3遺伝子変異を持つことがわかった.さらに大規模な 治療研究を通じて,FLT3/ITDは
患者の初診時白血病細胞数および予後に強く相関しているのが確認された.
  これらの知見から,FLT3キナーゼ活性を阻害する分子標的薬の探索が始まり,一部の薬剤は 第1〜3相臨床試験 まで開発が進んでいる.いまのところ,単剤で十分な臨床効果を持つものは 見いだされていないが,従来の抗癌剤 との併用による効果や新た な薬剤の開発が期待されて いる.

キーワード:FLT3,チロシンキナーゼ,分子標的治療.

繻エ 康通,ほか  Yaumichi Kuwahara et al.

The possibility of gefitinib, epidermal growth factor receptorinhibitor, for pediatric solid tumors

Yasumichi Kuwahara and Tohru Sugimoto


Department of Pediatrics,Kyoto Prefectural University of Medicine
Graduate School of Medical Science

Abstract
 
  The prognoses of pediatric solid tumors(PST)have improved according to progression of therapies. However, current treatments have had only limited success. Then innovative therapies, such as molecular target therapy, are needed. Epidermal growth factor receptor(EGFR)was found to be expressed on some PST. Gefitinib is an oral EGFR-tyrosine kinase inhibitor and has been demonstrated to be effective in inhibiting the proliferation of cancer cells in vivo as well as
in clinical trials. The effective molecular predictors for gefitinib are reported that mutation or gene amplification of EGFR and AKT phosphorylation, however this predictors are controversial.
   Among PST, malignant rhabdoid tumor(MRT)is a rare and highly aggressive neoplasm in young children. EGFR was found to be expressed on MRT cell lines and tumor tissues. This encouraged us to examine the antitumor effects of gefitinib on MRT cells in vitro and in vivo. Gefitinib inhibited EGFR-phosphorylation and in vitro cell growth, and a high concentration of gefitinib(20μM) induced apoptosis in vitro. Furthermore, gefitinib had a cytostatic effect on established MRT xenografts. Our results demonstrate that gefitinib has antitumor effects in MRT cells in vitro andin vivo, and has promise as a novel and therapeutic strategy for MRT.
   Recently, the result of Phase I study of gefitinib in children with refractory solid tumor demonstrated that gefitinib is well tolerated. The possibility that gefitinib has the efficacy for PST was demonstrated, however, further clinical studies are needed for the establishment of treatments with gefitinib for PST.

Key Words:
Pediatric solid tumor,EGFR,Gefitinib,MRT.

EGFR阻害剤(gefitinib/イレッサ®)の小児固形腫瘍における臨床応用への可能性

繻エ 康通,杉本  徹

京都府立医科大学大学院大学医学研究科小児発達医学


抄  録

  小児固形腫瘍の予後は治療の進歩により改善してきた.しかし,難治性の腫瘍に関しては 分子標的療法など新規の 治療の開発が望まれている.上皮性増殖因子受容体(EGFR)は小児 固形腫瘍においても確認されている.また,EGFR チロシンキナーゼ阻害剤のゲフィチニブは腫瘍 細胞の増殖を抑制し,非小細胞性肺がんの臨床試験でも有効性が 確認されている.有効性の
予測因子の結論は出ていないが,EGFRの遺伝子変異,遺伝子の増幅また下流のシグナルの
AKTのリン酸化などが報告・議論されている.
  我々は,小児固形腫瘍のなかでも特に難治性である悪性横紋筋肉腫様腫瘍(MRT)における EGFRの発現とゲフィチニブ の効果をin vitroin vivoで検討し,MRTにおいてもin vitroin vivo ともに抗腫瘍効果があることを明らかにした. ゲフィチニブはMRTの治療に有効な新規治療薬 である可能性を示した.
  最近,治療抵抗性の小児固形腫瘍の患児に対するゲフィチニブの第T相試験の結果が報告 され,その耐用性が示された. ゲフィチニブは小児固形腫瘍の治療において大きな可能性を 持つ薬剤であると考えられる.そのためには,腫瘍別に 分子標的を明確にし,基礎研究の成果 を臨床へと繋ぐ,トランスレーショナルリサーチの基盤整備が必要である.

キーワード:小児固形腫瘍,EGFR,ゲフィチニブ,悪性横紋筋肉腫様腫瘍

木村 晋也,ほか  Shinya Kimrua et al.

Molecular targeting therapy for chronic myeloid leukemia
─A novel dual Bcr-Abl/Lyn kinase inhibitor, INNO-406─


Shinya Kimura,Eishi Ashihara and Taira Maekawa


Department of Transfusion Medicine and Cell Therapy,Kyoto University Hospital


Abstract

   Though the Abl tyrosine kinase inhibitor imatinib mesylate(GlivecTM)has improved the treatment of Bcr-Abl-positive(Bcr-Abl)leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib-resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Bcr-Abl/Lyn inhibitor, INNO-406(formerly NS-187), which is 25-55 times more potent than imatinib in vitro and at least 10 times more potent in vivo against not only wild type Bcr-Abl but also Bcr-Abl harboring point mutations in Abl kinase domain except T315I. INNO-406 also inhibits Lyn without affecting the phosphorylation of other Src family proteins such as Src, Blk or Yes. Moreover, INNO-406 suppresses the growth of Bcr-Abl leukemic cells in the central nervous system. These suggest that INNO-406 may be a potentially valuable novel agent to combat imatinib-resistant Bcr-Abl leukemia. A multi-center phase I
clinical study on INNO-406 has started in the U.S.A. and Germany in July 2006. The efficacy
and safety of INNO-406 in the treatment of Bcr-Abl leukemias is expected to be verified
by early-phase clinical trials.

Key Words:INNO-406,NS-187,Chronic myeloid leukemia,Bcr-Abl,Lyn.


慢性骨髄性白血病に対する分子標的治療
 ─新規Bcr-Abl/Lyn同時阻害剤INNO-406の開発─

木村 晋也,芦原 英司,前川  平


京都大学医学部付属病院輸血細胞治療部

抄  録
  メシル酸イマチニブ(グリベック®; IM)は, 臨床応用開始後 わずか数年で 慢性骨髄性白血病(CML)の第一選択薬となった.しかし,耐性出現などの問題点 も明らかとなってきた.われわれ は, IMを凌駕する新規チロシンキナーゼ阻害剤の開発に取り組み, INNO-406(NS-187)という Bcr-Abl/Lyn同時阻害剤を見出した.IM耐性の原因として,Bcr-Ablの 活性化,Ablキナーゼドメ インのATP結合領域の変異,多剤耐性遺伝子の 出現,Lynの活性化などが 報告されている.
 またIMは中枢神経白血病には効果を示さない.INNO-406は,IMより in vitroで 25〜55倍,in vivoでも少なくとも10倍以上活性が高く,ほとんどのATP結合領域の変異に有効であり, さらに 他の キナーゼへの特異性は保ちつつAblとLynを同時に阻害するなど,効果を示す.これら 臨床試験 の結果をふまえ, 200ほとんどのIM耐性原因の克服を可能とする.またINNO-406は 中枢神経性 白血病にも6年7月より,欧米でINNO-406 の臨床試験がIM耐性CML患者を対象に開始 されている.
キーワード:INNO-406,NS-187,慢性骨髄性白血病,Bcr-Abl,Lyn.

阪倉 長平,ほか  Chohei Sakakura et al.

Significance of Imatinib mesylate for the treatment of GIST

Chohei Sakakura1,Akeo Hagiwara1 and Hisakazu Yamagishi2

1Department of Surgery and Physiology of Digestive System,Kyoto Prefectural University of Medicine
Graduate School of Medical Science

2Department of Surgery and Oncology of Digestive System, Kyoto Prefectural University of Medicine
Graduate School of Medical Science

Abstract

   Constitutive activation of KIT receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate(IM), a selective tyrosine kinase inhibitor, has been shown in clinical studies to work against such tumors. But there is little information on whether combination of IM and surgical treatment can prolong survival in case with unresectable multiple liver metastases. We report a case of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor imatinib mesylate(IM)and surgical treatment. Therefore, we discuss some important implications.
   This 37-year-old Japanese man underwent a pancreaticoduodenectomy for GIST of the duodenum in January 2003.
The postoperative course was good at first, but 3 months after the initial operation, MRI showed multiple liver metastases. The patient was treated with 400mg of IM once daily with only weak liver dysfunction a side effect. The initial response to treatment of CR continued for 20 months.
   Currently, Imatinib is the first-line therapy for non-resectable GISTs, but a single agent therapy often leads to tumor resistance. As the mechanisms of recurrence and resistance to imatinib in GIST remain unclear, they should be intensively performed in the sight of both clinical and molecular biological viewpoints. Further examination in more cases of recurrent GIST is also necessary to estimate the effectiveness of treatment with IM.

Key Words:c-kit,GIST,Imatinib mesylate.


消化管間質腫瘍(GIST)治療における イマチニブ(グリベック)の意義:
                 分子標的としてのc-kit

            阪倉 長平1,萩原 明於1,山岸 久一2**

1京都府立医科大学大学院医学研究科消化器機能制御外科学
2京都府立医科大学大学院医学研究科消化器腫瘍制御外科学

                       **(現:京都府立医科大学学長)

抄  録
  【緒言】 消化管のKIT陽性の紡錘形腫瘍細胞からなる間葉系腫瘍をgastrointestinal stromal tumor (GIST)と呼ぶ. GISTは切除によって根治を望める腫瘍であるが,切除不能な進行例もしくは術後 再発例に おいては従来の化学療法, 放射線療法,動脈 塞栓療法が効奏せず,予後は極めて不良で あった.近年, 分子標的治療薬であるイマチニブがGIST 治療に用いられるようになり, その治療方針 が劇的に変化しつつある. この領域においては毎年新たなエビデンスが 示され,分子標的療法の
世界に新たな方向性 をもたらしている. 本稿では,このようなGIST発生の分子生物学的メカニズム, 分子標的治療薬としてのイマチニブの作用機序, これに 対する耐性獲得機構などに関する最近の 知見に ついて述べる.さらに我々は十二指腸原発GIST術後 多発性肝転移例に対して イマチニブ投与 が著効を示した一例を 経験したので報告する.
  【結語】イマチニブはGISTの切除不能多発肝転移に対する治療選択の一つとして有用であると考え られた. 今後 イマチニブ感受性に関連するc-kit変異の解析など基礎的研究と臨床データの集積が 必要になると 考えられた.

キーワード:イマチニブ,GIST,c-kit,分子標的療法

野村 憲一,ほか  Kenichi Nomura et al.

Strategies for malignant lymphomas using anti-CD20 chimeric monoclonal antibody

Kenichi Nomura,Yoshiko Fujimoto and Daisuke Shimizu

Department of Molecular Hematology and Oncology,Kyoto Prefectural University of Medicine
Graduate School of Medical Science

Abstract
   The recent development of therapies for non Hodgkin's lymphoma has improved prognosis extremely. Above all, anti-CD20 chimeric monoclonal antibody (rituximab) has performed significant role.
The randomized study has proved already that rituximab-CHOP for diffuse large B-cell lymphoma may be standard therapy substituted for CHOP. Even for advanced indolent lymphoma, including follicular lymphoma, rituximab has clinical utility. Other randomized studies investigated the efficacy of combined other chemotherapy with rituximab and maintenance therapy of rituximab for lymphoma. These previous studies reported the elongation of overall survival. The effectivity of in vivo pruged auto-PBSCT for relapsed and/or advanced follicular lymphoma and mantle cell lymphoma may be suggested by some studies. Therapeutic yttrium-90-ibritumomab tiuxetan (zevalin) has been established to have more clinical utility than rituximab. Molecular targeting therapy is expected to be more useful agent for malignancies.

Key Words:Rituximab,Malignant lymphoma,Molecular targeting ther

抗CD20抗体を用いた悪性リンパ腫の治療戦略

野村 憲一,藤本 佳子,清水 大介

京都府立医科大学大学院医学研究科血液病態制御学

抄  録
  近年のB細胞性リンパ腫に対する治療法の進歩により,不良であった予後は劇的に改善されて きている.なかでもキメラ型の抗CD20モノクローナル抗体(リツキシマブ)の果たした役割は大きい. びまん性大細胞型B細胞性リンパ腫(diffuse large B-cell lymphoma; DLBCL)に対し,リツキシマブ 併用の「R-CHOP療法」が,CHOP療法に替わる新たな標準的治療法となりうることが,すでに 無作為試験で示されている.リツキシマブは,濾胞性リンパ腫をはじめとする低悪性度リンパ腫の 限局期,あるいは進行期に対しても効果があり,化学療法との併用,さらには維持療法としての 有効性までもが無作為比較試験で検証され,明らかな生存の延長をもたらしている.また, 再発進行期の濾胞性リンパ腫やマントル細胞性リンパ腫に対するin vivo purged auto-PBSCTの 有用性も示唆されている.CD20抗体に放射性同位元素を抱合した放射免疫療法薬剤もすでに作成され,リツキシマブよりも優れた奏効率を示している.このように,分子標的療法は悪性腫瘍
の治療成績向上に極めて役立っており,今後の発展が楽しみである.

キーワード:リツキシマブ,悪性リンパ腫,分子標的薬剤

長崎 生光  Ikumitsu Nagasaki

Topology of DNA

Ikumitsu Nagasaki

Department of Statistics,Kyoto Prefectural University of Medicine
Graduate School of Medical Science

Abstract
   Topology is one of major fields in modern mathematics. Recently the idea of topology is applied to the study of DNA. In this review, we will introduce the idea of topology; especially, that of knot theory, and then we will overview the tangle model of site-specific recombination of DNA, advocated by D.W. summers.

Key Words: Topology,Theory,Tangle Model,DNA,Site-Specific,Recombination


DNAのトポロジー

長崎 生光


京都府立医科大学大学院医学研究科統計学


抄  録
  トポロジーは現代数学における主要分野のひとつであり,近年トポロジーのアイディアがDNA
研究に応用されている.本総説ではトポロジーのアイディア,特に結び目理論の考え方について
紹介し,D. W. Summersにより提唱されたDNAの部位特異的組換えのタングルモデルについて
概説する.

キーワード:トポロジー,結び目理論

園山 輝久,ほか  Teruhisa Sonoyama et al.

Surgical treatment for hepatocellular carcinoma

Teruhisa Sonoyama and Toshiya Ochiai

Department of Surgery and Oncology of Digestive System,
Kyoto Prefectural University of Medicine Graduate School of Medical Science


Abstract
   The risk factor of disease-free survival and survival in 252 hepatocellular carcinoma (HCC) patients who underwent hepatic resection was analyzed. As a result, the risk factors were ICG20% or more, gross classification (infiltrative type), invasion to vessels (portal vein, hepatic vein and bile duct) and less resection from subsegment of tumor existence (Hr≦H).
Disease-free survival rate of tumor diameter 30mm or less was more significant than that of tumor diameter 31mm or more. Therefore, tumor diameter 30mm or less, ICG20% or less, gross classification (not infiltrative type), no invasion to vessels and single tumor are good indication f or hepatic resection.
   Resection of the subsegment in which HCC exists and another adjacent subsegment (Hr>H) was a good prognosis. To perform hepatic resection to the group of tumor diameter 30mm or less, ICG20% or less, gross classification (not infiltrative type), no invasion to vessels and single tumor leads to the prognosis improvement.
   It is necessary to consider other treatment methods for an advanced HCC besides hepatic resection, in addition, the liver transplantation as one option of surgical treatment.

Key Words:Hepatocellular carcinoma,Hepatic risection,Survival,Disease-free survial,
         Risk factor


肝細胞癌に対する外科治療

園山 輝久, 落合登志哉
 
京都府立医科大学大学院医学研究科消化器腫瘍制御外科学

抄  録
  肝細胞癌に対する外科治療について自験例の解析を基に述べた.肝切除例252例について 無再発生存率,生存率を求め,それに関わる因子を解析した.その結果,規定因子のICG20% 以上,肉眼型(浸潤型),脈管侵襲あり,切除範囲と腫瘍存在範囲(Hr≦H)が危険因子となった.
無再発生存率を比較すると,明らかに腫瘍径30mm以下の症例が良好であり,腫瘍径30mm以下, ICG20%以下,肉眼型(浸潤型でない),脈管侵襲がないこと,単発であることがよい手術適応で あることがわかった.手術術式では切除範囲と腫瘍存在範囲(Hr>H)が予後良好であった.
従って,腫瘍径30mm以下,ICG20%以下,肉眼型(浸潤型でない),脈管侵襲がないこと,単発で ある症例にHr>Hの手術をすることが予後向上につながると思われた.高度進行肝細胞癌に対して は肝切除を中心に,集学的治療が必要である.さらに,外科治療のオプションとして肝移植も考慮 すべきである.

キーワード:肝細胞癌,肝切除,生存率,無再発生存率,危険因子

橋本 保,ほか  Tamotsu Hashimoto-Gotoh et al.

Presenilins: clarification of contradictory observationsusing molecular and
developmental animal models

Tamotsu Hashimoto-Gotoh, Atsushi Tsujimura and Yoshihisa Watanabe

Department of Biochemistry and Molecular Genetics,
Research Institute for Neurological Disease and Geriatrics,Kyoto Prefectural University of Medicine

 Abstract: Presenilins (PS1 and PS2) were discovered first as human genes through linkage analyses of pedigrees with familial Alzheimer's disease. The PS proteins may form the catalytic core of a high molecular weight aspartyl protease complex that cleaves β-amyloid precursor protein (APP) within the transmembrane (TM) domain, yielding neurotoxic and apoptotic products such as Aβ peptide and APP C-terminal intracellular domain (AICD) fragments. Accumulating evidence indicates that PS proteins also cleave a number of type I TM proteins involved in various multicellular functions such as cell differentiation and cell-cell interaction/adhesion. Notch1 is one such protein, from which Nβ peptide and Notch intracellular domain (NICD) fragments are similarly generated. Thus, AICD and NICD fragments should conflict with each other by transducing contradictory signals to the nucleus. PS proteins undergo autocatalytic processing to form a heterodimeric complex from the full-length(FL)molecule. There appear to be two main hypotheses for the functional differences between the FL and heterodimeric form of PS proteins; 1)FL-PS is inactive and premature, and is activated by autolytic processing to form an active form of PS proteins as a heterodimeric complex (Wolfe's model),
and 2)FL-PS and heterodimeric PS are responsible for cell apoptosis and differentiation, respectively, both of which are inhibited by stabilized C-terminal fragments (the Unifying Model). Recent reports suggest that PS-mediated proteolytic activities on APP and Notch are differentially regulated, and FL-PS is responsible for the apoptotic activation of cells. These observations seem to favor the Unifying Model rather than Wolfe's model, unless additional factors are presumed. We provide an overview of controversial observations obtained in human PS proteins and try to reconcile these data with genetic and developmental studies of ps genes in Caenorhabditis elegans and Xenopus laevis.

Key Words:Alzheimaer's disease, Apoptosis,Differention,Develop,Development,APP,
        Notch,Multicellular transition

<和文抄録>
プレセニリン:ツメガエル分子発生学に基づく活性制御モデル

橋本  保,辻村  敦,渡邊 義久

京都府立医科大学附属脳・血管系老化研究センター神経化学・分子遺伝学部門


  プレセニリン(PS)はアスパラギン酸プロテアーゼの仲間で,脊椎動物ではPS1, PS2の二種類が 存在する.両者とも家族性アルツハイマー病(AD)の原因遺伝子の変異体として,家系解析により発見 された.ADの解剖学的な病理所見である脳内老人斑の主要成分として蓄積するAβペプチドは, β‐アミロイド前駆体タンパク質(APP)の限定分解によって生成するが,PSタンパク質は,その分解反応に 関わるγ‐セクレターゼと仮称されていたプロテアーゼの触媒中心サブユニットであった.細胞内でのPS
タンパク質は全長分子か,あるいは自己限定分解を受けたヘテロ二量体として存在する.両者の機能的 な違いについては,全長分子は不活性な前駆体であり,ヘテロ二量体が活性型プロテアーゼであるという 説(Wolfe's model)と,我々が提唱した統一モデル(The Unifying Model)がある.後者は,全長分子とへテロ 二量体はそれぞれ,アポトーシスと細胞分化の機能に対応すると考える.APPの限定分解反応によって生 じるのは,Aβだけでなく,隣接する細胞内領域(AICD)断片も同時に切り出されるが,後者は核に細胞死 (apoptosis)シグナルを伝達する.一方,PSタンパク質は,細胞分化,細胞接着などの多細胞機能に関わる 多くのI型膜貫通受容体タンパク質を同様に切断し,それらのC-末端からも種々のICD断片が生じることが, 次々と,明らかになった.そのなかでは,Notch1受容体がよく知られており,Notch1はPSによる限定分解を 受けてNβ,NICD断片を生じる.しかし,NICDは細胞分化シグナルを核に伝達するので,AICDの細胞死シ グナルとは両立しない.従って,APPとNotch切断に関わるPSタンパク質の活性は,異なる制御を受けてい ることが示唆されている.さらに,PS全長分子はアポトーシスを誘導することが示されており,これらの 観察結果はWolfeのモデルよりも,むしろ統一モデルを支持するように思われる.この総説は,これまでに 報告されたPSタンパク質の生化学的,薬理学的研究における争点を概説し,センチュウ,ツメガエルを用 いた分子遺伝学的,分子発生学的研究結果との整合性を検討する.

田代 啓  Kei Tashiro

Significance and outcomes of the Signal Sequence Trap
method as a genomic strategy

Kei Tashiro

Department of Genomic Medical Sciences, Kyoto Prefectural
University of Medicine Graduate School of Medecal Science

Abstract
   To establish a general cDNA cloning method for secretary pathway proteins including
cytokines, adhesion molecules, their receptors, transporters and so-called surface markers,
we have developed an expression cloning strategy for selecting cDNA fragments bearing
N-terminal signal sequences. This general expression cloning method was named as the
Signal Sequence Trap and used in all over the world. As a representative example, Stromal
cell-Derived Factor-1 (SDF-1) was cloned by this strategy and named as SDF-1. SDF-1
(CXCL12) is now studied very actively as a chemotactic factor for stem cells and
anti-HIV-1 infection activity.
Key words: Signal Sequence Trap, Secretion, SDF-1, Expression Cloning.



ゲノム研究としてのシグナルシークエンストラップ法の意義とその成果

田  代     啓
   
京都府立医科大学大学院医学研究科ゲノム医科学

抄  録

  シグナルシークエンストラップ法とは,発現クローニング法の一種である.N末端領域に
シグナルシークエンスをもつ分泌タンパク質cDNAを選択的に単離するため著者らによって
開発され,世界中で広く用いられている.分泌タンパク質,細胞膜上T型タンパク質,及び
小胞体等管腔オルガネラの膜タンパク質と内腔タンパク質は「分泌経路タンパク質」と総称
され,シグナル配列に依存して粗面小胞体で生合成される.本方法はこの現象を捕えたた
アッセイであるが,分泌シグナルシークエンスを持たなくても,何らかのメカニズムで分泌経
路に入るタンパク質も多数単離されため,「分泌経路タンパク質トラップ法」の呼称が最適で
ある.
  本方法で骨髄由来ストロマ細胞から単離したSDF-1(ストロマ細胞由来因子1)は,CXC
ケモカインの一員であり,CXCL12とも呼ばれる.SDF-1の重要な機能は,幹細胞に対する
遊走活性と,HIVウイルス感染阻止活性である.2006年秋,PubMed検索ではSDF-1で942
論文,CXCL12で1,510論文がヒットし,Google検索ではSDF-1で約50万件,CXCL12では約
17万件がヒットする一大研究分野となった.

キーワード:シグナルシークエンストラップ,分泌,SDF-1,発現クローニング.

藤井 秀樹,ほか  Hideki Fujii et al.

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma:
analysis of prognostic factors in patients receiving low-dose cisplatin and 5-fluorouracil


Hideki Fujii1, Natsuko Tatsumi1, Takaharu Yoh1, Atsuhiro Morita1
Hiroto Kaneko1, Tohru Ohkawara1, Masahito Minami3, Kazushige Ueda2
Yoshihiko Sawa1, Takeshi Okanoue3and Yasuo Ohkawara1


1Department of Internal Medicine, Aiseikai Yamashina Hospital
2Department of Gastroenterology and Hepatology, Kameoka Municipal Hospital
3Department of Molecular Gastroenterology and Hepatology,
 Kyoto Prefectural University of Medicine Graduate School of Medical Science

 Abstract: Background: Advanced hepatocellular carcinoma (HCC) with multiple intrahepatic
metastases or marked portal vein tumor thrombosis (PVTT) has a poor prognosis. The aim of this
study was to evaluate prognostic factors treated with hepatic arterial infusion chemotherapy
(HAIC).
   Methods: 32 patients with advanced HCC were treated with HAIC. A single course of
chemotherapy included a daily low-dose cisplatin (CDDP) (10mg) followed by 5-fluorouracil(5-FU)
(250mg) from day 1 to 5. Patients were scheduled to receive four serial courses. These four courses
were defined as one cycle, and the cycle was repeated at 4-weeks intervals for as long as it
  was tolerable. Tumor regression was assessed after the first cycle, and prognostic factors were
evaluated by univariate and multivariate analyses of the patient and disease characteristics.
   Results: The response rate was 59.4%. Univariate analysis indicated four variables -liver
damage, tumor staging, grade of portal invasion, and therapeutic effect after HAIC. Multivariate
analysis indicated liver damage and therapeutic effect after HAIC to be independent prognostic
factors influencing survival.
   Conclusions: Patients with advanced HCC who have a hepatic reserve capacity are suitable
candidates for HAIC. Tumor responses after one cycle of HAIC may be useful in deciding whether to
continue the treatment

Key words:Hepatic arterial infusion chemotherapy, Prognostic factors,
        Low-dose cisplatin (CDDP)+5-fluorouracil (5-FU).


 〈和文抄録〉
進行肝癌への肝動注療法:low-dose cisplatin+5-fluorouracil療法の予後因子


藤井 秀樹1,辰巳菜津子1,楊  孝治1,盛田 篤広1
兼子 裕人1,大川原 徹1,南  祐仁3,上田 和茂2
澤  美彦1,岡上  武3,大川原康夫1


1愛生会山科病院内科
2亀岡市立病院消化器肝臓内科
3京都府立医科大学大学院医学研究科消化器病態制御学

 背景:肝内多発病変や門脈浸潤を伴った進行肝癌の予後は極めて悪い.今研究では肝動注療法を
受けた患者の予後因子の解析を行なった.
  方法:32名の進行肝癌患者が肝動注療法を受けた.1コースは1日目から5日目までlow-dose CDDP
(10mg/body)と5-FU) (250mg/body)治療とした.患者は4コース受けることを予定とした.その4コースを
1サイクルとし,4週間休薬後可能な限り継続した.1サイクル後効果を判定し,患者背景からの予後因子
を単変量と多変量解析行なった.
  結果:奏功率は59.4%であった.単変量解析では肝障害度,腫瘍の進行度,門脈浸潤の程度,動注療
法後の治療効果の4因子が生存率に優位に寄与した.多変量解析では肝障害度と動注療法後の治療効
果が独立した因子であった.
  結語:進行肝癌に対し動注療法はよい適応である.1サイクル後の効果判定が治療を続けるか判断に
有用と思われた.

キーワード:肝動注療法,予後因子,低用量シスプラチン+5‐フルオロウラシル.

 

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