Heparin cofactor II is an independent protective factor against peripheral arterial disease in elderly subjects with cardiovascular risk factors.

AIM: Heparin cofactor II (HCII) specifically inactivates thrombin action at the injured vascular wall. We have reported that HCII is a protective factor against coronary in-stent restenosis and carotid atherosclerosis; however, it is unclear whether there is any correlation between plasma HCII levels and the development of peripheral arterial disease (PAD). METHODS: Plasma HCII activity and the ankle brachial pressure index (ABI) were determined in 494 elderly subjects with cardiovascular risk factors. PAD was diagnosed by ABI below 0.9, and 62 subjects were diagnosed with PAD. The relationship between factors that affect cardiovascular events and the prevalence of PAD was statistically evaluated. RESULTS: Mean HCII activity in PAD subjects was significantly lower than in non-PAD subjects (87.5+/-19.7% v.s. 94.6+/-17.8%, p=0.009). Multivariate logistic regression analysis showed that age (odds ratio [OR]: 1.062, p=0.0016), current smoking (OR 3.028, p=0.002) and diabetes mellitus (OR 2.656, p=0.008) were independent and progressive determinants of PAD. In contrast, HCII was an independent inhibitory factor of PAD (OR: 0.982, p=0.048). CONCLUSIONS: Plasma HCII activity is inversely related to the prevalence of PAD. HCII may function as the sole protective factor against PAD in elderly people with cardiovascular risk factors.


アンジオテンシンII受容体拮抗薬バルサルタンのNO bioavailability改善効果に関する臨床的検討

バルサルタンの降圧作用，動脈硬化抑制作用および糖代謝改善作用に一酸化窒素(NO)のバイオアベイラビリティの改善効果が関与しているか検討した．高血圧治療目的で通院加療中の42例を対象とした．バルサルタン投与にて，BMIやリポプロテイン(a)を含む脂質プロファイルに有意な変化は認めなかったが，収縮期血圧，脈圧，baPWVおよびHbA1cは有意に低下した．投与3ヵ月後には投与前と比較して，NOのバイオアベイラビリティのマーカーである血清硝酸/亜硝酸イオン(NOx)は約1.5倍に増加した．血清NOxの増加が，他の測定因子にどのように影響を与えているか，単変量および多変量解析を用いて解析し，血清NOxの増加量は収縮期血圧の低下と脈圧の減少との間においてそれぞれ有意な相関がみられた．また，HbA1cはバルサルタン投与3ヵ月後に有意に低下していたが，その変化はNOxの増加量と有意な相関がみられた．


Platypnea-orthodeoxia syndrome associated with patent foramen ovale and aortic ectasia.

A 59-year-old man was admitted for dyspnea on exertion and edema. The patient did not have any pulmonary diseases that could cause dyspnea. Transesophageal echocardiography on the tilting bed with contrast infusion revealed a right-to-left shunt through the patent foramen ovale. Therefore, he was diagosed as platypnea-orthodeoxia syndrome due to the patent foramen ovale. Surgical closure was done and all of his symptoms had improved.


A case of neurogenic myocardial stunning presenting transient left ventricular mid-portion ballooning simulating atypical takotsubo cardiomyopathy.

A 57-year-old female patient, who was initially suspected to have subarachnoid hemorrhage, was admitted to our hospital. She experienced severe dyspnea and chest pain owing to pneumonia on the fourth admission day. Electrocardiography showed ST-segment elevation in leads V(2) through V(5), and echocardiography revealed hypokinetic left ventricular wall motion. No stenosis was found in the coronary arteries by urgent coronary angiography. However, left ventriculography revealed that the basal and apical areas were hyperkinetic and the mid portion was akinetic. After a month, left ventricular wall motion was improved and coronary artery spasm provocation tests were negative. Although the clinical course of this patient was similar to that of neurogenic myocardial stunning, the shape of her left ventricle was not typical.


高コレステロール血症患者に対するピタバスタチンの有効性 総合的脂質プロファイルに関する検討

高コレステロール血症患者を対象にピタバスタチンを投与し，総合的脂質プロファイルへの影響について検討した．高コレステロール血症と診断され，ピタバスタチンを投与した87例を対象とした．ピタバスタチン投与によりTC，LDL-Cは有意に低下した．HDL-Cは有意な上昇，TGは有意な低下を認めた．ピタバスタチンを新規に投与した症例で，TC，LDL-Cは有意かつ良好な低下作用を認めた．また，HDL-Cは有意な上昇，TGは有意な低下作用を示した．Non HDL-Cは有意に低下し，LDL-C/HDL-C比は有意に減少した．動脈硬化指数は，いずれも有意に改善した．投与前後でLp(a)を測定した76例で，有意な変化は認めなかった．投与前後におけるALT，ASTの平均変化量に，有意な変化は認めなかった．CKも有意な変化は認めなかった．治療上，問題となる副作用は認めなかった．


Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice

Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII(-/-) mice were embryonically lethal. In HCII(+/-) mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII(+/-) mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII(+/-) mice. The intimal hyperplasia in HCII(+/-) mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.


Intra-vascular ultrasound findings of diffuse coronary atherosclerotic change in systemic lupus erythematosus with secondary antiphospholipid syndrome

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune inflammatory diseases associated with juvenile atherosclerosis and thrombosis, respectively. A 44-year-old woman who had SLE with secondary APS had been treated with corticosteroid therapy, however, her inflammatory marker had never been within a normal range in her clinical course, and finally acute myocardial infarction was developed. Intra-vascular ultrasound also revealed diffuse coronary atherosclerosis progression for her age, which might result from SLE and APS, including vascular inflammation.


Parkin enhances mitochondrial biogenesis in proliferating cells.

We describe a novel function of parkin, a RING protein, which is elaborately involved in mitochondrial biogenesis. Parkin was located within the mitochondrial organelle of proliferating cells. Anti-proliferative treatments released parkin from mitochondria to cytosol. Results of pharmacological treatments indicate that parkin was released from mitochondria when permeability transition pore was opened. The extra-mitochondrial localization was also observed in differentiated cells. In proliferating cells, transcription and replication of mitochondrial DNA was enhanced by parkin overexpression and attenuated by parkin suppression with siRNA. Parkin was associated with mitochondrial transcription factor A (TFAM) and enhanced TFAM-mediated mitochondrial transcription. These results indicate that parkin is involved in the regulation of mitochondrial transcription/replication other than the ubiquitin-mediated protein degradation system in proliferating cells.


Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis.

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.


Aspirin inhibits thrombin action on endothelial cells via up-regulation of aminopeptidase N/CD13 expression.

OBJECTIVE: We hypothesized that aspirin may exhibit its anti-atherosclerotic effects via mechanisms other than cyclooxygenase inhibition in platelets. METHODS AND RESULTS: Using enhanced subtraction hybridization analysis, we found in human umbilical vein endothelial cells (HUVECs) that aspirin up-regulates the expression of aminopeptidase N (APN/CD13) mRNA and its surface protein levels in a dose-dependent manner. Enzymatic activity of APN/CD13 on HUVECs was increased approximately 1.5-fold by 1 mmol L(-1) of aspirin, and treatment with bestatin, an inhibitor for APN/CD13 metalloprotease activity, attenuated the enhanced activities of APN/CD13. Since activated thrombin receptor is reported to be inactivated by APN/CD13 in vitro, protective actions of aspirin on HUVECs by thrombin stimulation were examined, resulting in the suppression of endothelin-1 and reactive oxygen species productions in HUVECs. These inhibitory actions of aspirin were partially abrogated by bestatin. CONCLUSIONS: Aspirin may exert its anti-atherothrombotic effects in part via the inhibition of thrombin action by up-regulating APN/CD13 on endothelial cells.


Vascular smooth muscle cell proliferation is dependent upon upregulation of mitochondrial transcription factor A (mtTFA) expression in injured rat carotid artery

Consistent with the physiological response to increased energy demand in proliferating cells, the number of mitochondria is upregulated in synthetic states of vascular smooth muscle cells (VSMC) in atherosclerotic lesion. We hypothesized that mitochondrial transcription factor A (mtTFA), a prerequisite factor for the transcription and replication of mtDNA, may be upregulated in VSMC of injured rat carotid artery, and that inhibition of its expression can attenuate the intimal thickening. Changes of intimal thickening and mtTFA expression by a treatment with antisense oligodeoxynucleotides (ODN) for mtTFA were investigated in balloon-injured rat carotid artery model. The expression of mtTFA was upregulated as early as 3 h up to 7 days after balloon injury. Delivery of ansisense ODN for mtTFA from adventitia side to injured arterial wall caused a significant decrease in intima-to-media (I/M) ratio. Furthermore, the increase in immunoreactivity and mRNA expression of mtTFA in injured artery as well as the number of mitochondria in intimal VSMC was abrogated by antisense ODN treatment. These data demonstrate that expression of mtTFA is upregulated in intimal VSMC of injured rat carotid artery, and that suppression of mtTFA expression by antisense ODN can attenuate intimal thickening after balloon injury.


アミオダロン肺合併症との鑑別を要したマイコプラズマ肺炎合併拡張型心筋症の1例

アミオダロン肺合併症との鑑別を要したマイコプラズマ肺炎合併拡張型心筋症の1例

52歳男.47歳時に拡張型心筋症と診断され,持続性心室頻拍でアミオダロン150mg/日を開始した.その後,心室頻拍が頻回となり,心臓電気生理学的検査で心室細動が誘発されたため除細動器植込み術を受け,アミオダロンは増量して継続していた.今回,乾性咳が出現し,胸部X線で左右下肺野にスリガラス状陰影を指摘された.検査所見では高度の炎症所見を認めたが,KL-6は正常範囲で,C型肝炎ウイルスとヒトT細胞性白血病ウイルスI型のキャリアであった.胸部CTでは両側下肺野を中心として壁の肥厚を伴う気管支拡張や小葉中心性の粒状・樹枝状の陰影が多発しており,周囲の肺野に淡い濃度上昇を認めた.アミオダロンの副作用か感染症かは判断できなかったが,アミオダロンは中止し,アンピシリンナトリウム・スルバクタムナトリウム合剤を開始すると共にサイトメガロウイルス高力価免疫グロブリン投与を行った.入院10日目にマイコプラズマ抗体異常高値が判明し,マイコプラズマ肺炎と診断しミノサイクリン100mg/日を開始した.その結果,炎症所見,画像所見は徐々に軽快し,アミオダロンも再開して退院となった


The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor γ1 (PPARγ1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPARγ1 Transcriptional Activation --- Involvement in Flow-Induced PPARγ Activation in Endothelial Cells

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. Since both flow and PPARgamma have atheroprotective effects and extracellular signal-regulated kinase 5 (ERK5) kinase activity is significantly increased by flow, we investigated whether ERK5 kinase regulates PPARgamma activity. We found that activation of ERK5 induced PPARgamma1 activation in endothelial cells (ECs). However, we could not detect PPARgamma phosphorylation by incubation with activated ERK5 in vitro, in contrast to ERK1/2 and JNK, suggesting a role for ERK5 as a scaffold. Endogenous PPARgamma1 was coimmunoprecipitated with endogenous ERK5 in ECs. By mammalian two-hybrid analysis, we found that PPARgamma1 associated with ERK5a at the hinge-helix 1 region of PPARgamma1. Expressing a hinge-helix 1 region PPARgamma1 fragment disrupted the ERK5a-PPARgamma1 interaction, suggesting a critical role for hinge-helix 1 region of PPARgamma in the ERK5-PPARgamma interaction. Flow increased ERK5 and PPARgamma1 activation, and the hinge-helix 1 region of the PPARgamma1 fragment and dominant negative MEK5beta significantly reduced flow-induced PPARgamma activation. The dominant negative MEK5beta also prevented flow-mediated inhibition of tumor necrosis factor alpha-mediated NF-kappaB activation and adhesion molecule expression, including vascular cellular adhesion molecule 1 and E-selectin, indicating a physiological role for ERK5 and PPARgamma activation in flow-mediated antiinflammatory effects. We also found that ERK5 kinase activation was required, likely by inducing a conformational change in the NH(2)-terminal region of ERK5 that prevented association of ERK5 and PPARgamma1. Furthermore, association of ERK5a and PPARgamma1 disrupted the interaction of SMRT and PPARgamma1, thereby inducing PPARgamma activation. These data suggest that ERK5 mediates flow- and ligand-induced PPARgamma activation via the interaction of ERK5 with the hinge-helix 1 region of PPARgamma.


Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice

Vitamin D metabolites influence the expression of various genes involved in calcium homeostasis, cell differentiation, and regulation of the immune system. Expression of these genes is mediated by the activation of the nuclear vitamin D receptor (VDR). Previous studies have shown that a hormonally active form of vitamin D, 1alpha,25-dihydroxyvitamin D3, exerts anticoagulant effects in cultured monocytic cells. To clarify whether activation of VDR plays any antithrombotic actions in vivo, hemostatic/thrombogenic systems were examined in normocalcemic VDR knock-out (KO) mice on a high calcium diet and compared with wild type and hypocalcemic VDRKO mice that were fed a regular diet. Platelet aggregation was enhanced significantly in normocalcemic VDRKO mice compared with wild type and hypocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretions were reduced in hypocalcemic VDRKO mice, but not in normocalcemic VDRKO mice. Northern blot and RT-PCR analyses revealed that the gene expression of antithrombin in the liver as well as that of thrombomodulin in the aorta, liver and kidney was down-regulated in hypo- and normocalcemic VDRKO mice. Whereas tissue factor mRNA expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that activation of nuclear VDR elicits antithrombotic effects in vivo, and suggest that the VDR system may play a physiological role in the maintenance of antithrombotic homeostasis.


Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals.

Thrombin plays a crucial role in atherothrombotic changes. Because heparin cofactor II (HCII) inhibits thrombin actions after binding to dermatan sulfate at injured arterial walls, HCII may negatively regulate thrombin actions in vascular walls. We hypothesized that plasma HCII activity is a preventive factor against atherosclerotic changes, especially in elderly individuals who already have atherosclerotic vascular injuries. Maximum plaque thickness (MPT) in the carotid artery was measured by ultrasonography in 306 Japanese elderly individuals (154 men and 152 women; age, 40 to 91 years; 68.9+/-11.1 years, mean+/-SD). The relevance of cardiovascular risk factors including plasma HCII activity to the severity of MPT was statistically evaluated. Plasma HCII activity decreased with age. Simple linear regression analysis after adjustments for age and sex showed that lipoprotein(a), glycosylated hemoglobin A1c, and presence of diabetes mellitus significantly contributed to an increase in MPT values (r=0.119, P<0.05; r=0.196, P<0.001; and r=0.227, P<0.0001, respectively). In contrast, high-density lipoprotein (HDL) cholesterol and HCII activity were negatively correlated with MPT values (r=-0.117, P<0.05, and r=-0.202, P<0.0005, respectively). Multiple regression analysis revealed that plasma HCII activity and HDL cholesterol independently contributed to the suppression of MPT values and that the antiatherogenic contribution of HCII activity was stronger than that of HDL cholesterol (P<0.001 and P<0.05, respectively). These results suggest that HCII can be a novel and independent antiatherogenic factor. Moreover, HCII is a stronger predictive factor than HDL cholesterol against carotid atherosclerosis in elderly individuals.


日本動脈硬化学会による診療ガイドラインからみた高コレステロール血症治療の動向とその問題点 --- 四国高脂血症スタディ(続報)


High plasma heparin cofactor II activity is associated with reduced incidence of in-stent restenosis after percutaneous coronary intervention

Thrombin plays an important role in the development of atherosclerosis and restenosis after percutaneous coronary intervention. Because heparin cofactor II (HCII) inhibits thrombin action in the presence of dermatan sulfate, which is abundantly present in arterial wall, HCII may affect vascular remodeling by modulating thrombin action. We hypothesized that patients with high plasma HCII activity may show a reduced incidence of in-stent restenosis (ISR). Sequential coronary arteries (n=166) with NIR stent (Boston Scientific Corp) implantation in 134 patients were evaluated before, immediately after, and at 6 months after percutaneous coronary intervention. Patients were divided into the following groups: high HCII (> or =110%, 45 lesions in 36 patients), normal HCII (> or =80% and <110%, 81 lesions in 66 patients), and low HCII (<80%, 40 lesions in 32 patients). Percent diameter stenosis at follow-up in the high-HCII group (18.7%) was significantly lower (P=0.046) than that in the normal-HCII group (30.3%) or the low-HCII group (29.0%). The ISR rate in the high-HCII group (6.7%) was significantly lower than that in the low-HCII group (30.0%) (P=0.0039). Furthermore, multivariate analysis demonstrated that high plasma HCII activity is an independent factor in reducing the incidence of angiographic restenosis (odds ratio, 0.953/1% increase of HCII; 95% CI, 0.911 to 0.998). The results demonstrate that HCII may have a hitherto unrecognized effect in inhibiting ISR. The effect of HCII may be mediated by inactivating thrombin in injured arteries, thereby inhibiting vascular smooth muscle cell migration and proliferation.


Deletion of Vitamin D Receptor Gene in Mice Results in Abnormal Skeletal Muscle Development with Deregulated Expression of Myoregulatory Transcription Factors


ビタミンD-ビタミンD受容体システムは生体における血液凝固調節因子である

ビタミンD-ビタミンD受容体システムは生体における血液凝固調節因子である

第25回日本血栓止血学会学術集会

第25回日本血栓止血学会学術集会


Motor neuron involvement in a patient with long-term corticosteroid administration

An asthmatic patient with corticosteroid treatment for 45 years presented with slowly progressive limb muscle atrophy. His muscle symptoms were involved in four limbs and tongue, and deep tendon reflexes were exaggerated. Biopsied muscle pathology indicated the presence of neurogenic muscular atrophy in combination with corticosteroid myopathy. Furthermore, 8-hydroxy-deoxyguanosine (8-OH-dG) was prominently increased in mitochondrial and nuclear DNA. An aerobic exercise test demonstrated remarkable serum lactate elevation, which was attenuated by the administration of coenzyme Q10. These findings are consistent with the assumption that long-term corticosteroid administration potentially induces not only myopathy but also motor neuron involvement as in mitochondrial diseases.


Inhibition of Tumor Necrosis Factor- Induced SHP-2 Phosphatase Activity by Shear Stress

Atherosclerosis preferentially occurs in areas of turbulent flow, whereas laminar flow is atheroprotective. Inflammatory cytokines have been shown to stimulate adhesion molecule expression in endothelial cells that may promote atherosclerosis, in part, by stimulating c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-kappaB transcriptional activity. Because Src kinase family and Src homology region 2-domain phosphatase-2 (SHP-2) may regulate JNK activation, we studied the effect of shear stress on endothelial inflammation and JNK. Human umbilical vein endothelial cells preexposed to flow showed decreased tumor necrosis factor (TNF)-alpha-induced c-Jun and NF-kappaB transcriptional activation. TNF-alpha-mediated JNK, c-Jun, and NF-kappaB activation required Src and SHP-2 activity. Shear stress significantly inhibited SHP-2 phosphatase activity without affecting TNF-alpha-induced Src family kinase activation. Because MEKK3 and Gab1 are critical for TNF-alpha-induced c-Jun and NF-kappaB activation, we determined the role of SHP-2 phosphatase activity in MEKK3 signaling. A catalytically inactive form of SHP-2 increased MEKK3/Gab1 interaction and inhibited MEKK3 (but not MEKK1)-mediated c-Jun and NF-kappaB activation. These results suggest that SHP-2 is a key mediator for the inhibitory effects of shear stress on TNF-alpha signaling in part via regulating MEKK3/Gab1 interaction, MEKK3 signaling, and subsequent adhesion molecule expression.

Arteriosclerosis, Thrombosis, and Vascular Biology


Overexpressions of myoglobin and antioxidant enzymes in ragged-red fibers of skeletal muscle from patients with mitochondrial encephalomyopathy

To determine the relationship between myoglobin (Mb) and the defense system against reactive oxygen species in various myopathies, we performed immunohistochemical analyses of Mb and various antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), copper zinc SOD (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Biopsied muscle specimens were obtained from patients with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Duchenne muscular dystrophy (DMD), and polymyositis (PM). In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs. These pronounced stainings corresponded to ragged-red lesions. The staining intensities of these antioxidant enzymes were significantly correlated with that of Mb (P < 0.001). Atrophic RRFs in specimens from patients with CPEO/KSS showed intense stainings of these antioxidant enzymes but not intense staining of Mb. In specimens from patients with DMD/PM, the antioxidant enzymes but not Mb were overexpressed in degenerative fibers. These results suggest that oxidative stress is associated with Mb expression specifically in mitochondrial diseases. The antioxidant enzymes seem to be upregulated to protect against muscle damage in nonatrophic RRFs. However, the Mb-mediated oxidative damage may become more extensive and result in further mitochondrial dysfunction and progressive atrophy of RRF with impaired upregulation of Mb.


Aggressive antiplatelet therapy before coronary stent implantation in acute coronary syndrome with essential thrombocythemia--a case report

A 52-year-old man was admitted to the hospital because of unstable angina pectoris. Coronary angiography revealed severe stenosis at a proximal site of the left anterior descending artery. Essential thrombocythemia (ET) was diagnosed on the basis of findings of marked thrombocytosis (106 x 10(4)/microL) and an increased number of immature megakaryocytes in the bone marrow. Because hyperaggregability of platelets was demonstrated by an ex vivo platelet aggregation assay and by elevated plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4), antiplatelet therapy with aspirin and ticlopidine and cytoreduction therapy with hydroxyurea were started. This combination treatment resulted in a decrease in the platelet count to less than 60 x 10(4)/microL and decreases in plasma levels of both beta-TG and PF4 to almost normal values. Percutaneous coronary angioplasty and stenting were then performed successfully without thrombotic complications. These findings suggest that combination therapy with antiplatelet and cytoreduction agents before catheter intervention is useful for the prevention of thrombotic complications in patients with acute coronary syndrome associated with essential thrombocythemia.


Regulation of Epidermal Growth Factor-induced Connexin 43 Gap Junction Communication by Big Mitogen-activated Protein Kinase 1/ERK5 but Not ERK1/2 Kinase Activation

The gap junction protein, Cx43, plays a pivotal role in coupling cells electrically and metabolically, and the putative phosphorylation sites that modulate its function are reflected as changes in gap junction communication. Growth factor stimulation has been correlated with a decrease in gap junction communication and a parallel activation of ERK1/2; the inhibition of epidermal growth factor (EGF)-induced Cx43 gap junction uncoupling was observed by using the MEK1/2 inhibitor, PD98059. Because 1) BMK1/ERK5, another MAPK family member also activated by growth factors, possesses a phosphorylation motif similar to ERK1/2, and 2) it has been reported that PD98059 can inhibit not only MEK1/2-ERK1/2 but also MEK5-BMK1 activation, we investigated whether BMK1 can regulate EGF-induced Cx43 gap junction uncoupling and phosphorylation, comparing this to the role of ERK1/2 on Cx43 function and phosphorylation induced by EGF. Selective activation or inactivation of ERK1/2 by using a constitutively active form or a dominant negative form of MEK1 did not regulate Cx43 gap junction coupling. In contrast, we found that BMK1, selectively activated by constitutively active MEK5alpha, induced gap junction uncoupling, and the inhibition of BMK1 activation by transfection of dominant negative BMK1 prevented EGF-induced gap junction uncoupling. Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo, but not on S279/S282, which are reported as the consensus phosphorylation sites for MAPK. Furthermore, by co-immunoprecipitation, we found that BMK1 directly associates with Cx43 in vivo. These data indicate that BMK1 is more important than ERK1/2 in EGF-mediated Cx43 gap junction uncoupling by association and Cx43 Ser- 255 phosphorylation.


Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction

Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43+/-8.9% (mean+/-SEM) from the values obtained before GC therapy (130+/-14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5+/-3.3% of control values by 10(-7) mol/L dexamethasone (DEX) treatment (P<0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (P<0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess.


Effect of Aspirin Treatment on Serum Concentrations of Lipoprotein(a) in Patients with Atherosclerotic Diseases

Increased serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. We previously reported that aspirin reduced Lp(a) production by cultured hepatocytes via the reduction of apolipoprotein(a) [apo(a)] gene transcription. We evaluated both the effect of aspirin treatment (81 mg/day) on serum Lp(a) concentrations and the correlation between the degree of reduction in serum Lp(a) and the type of apo(a) isoform in 70 patients with coronary artery disease or cerebral infarction. Aspirin lowered serum Lp(a) concentrations to approximately 80% of the baseline values in patients with high Lp(a) concentrations (>300 mg/L). The percentage of decrease in serum Lp(a) was larger in patients with high Lp(a) than in patients with low Lp(a) (<300 mg/L), irrespective of apo(a) isoform size. The decreases in serum Lp(a) in high Lp(a) patients with both the high-molecular-weight and the low-molecular-weight isoforms were positively correlated with the baseline Lp(a) concentrations. Because the secretory efficiencies of apo(a) in the same isoform are likely to be similar, the difference in serum Lp(a) concentrations in patients having the same apo(a) isoform depends on the transcriptional activity of the apo(a) gene. These findings suggest that aspirin decreases serum Lp(a) concentrations via a decrease in apo(a) gene transcription more effectively in patients with high transcriptional activity of this gene.


Mitochondrial damage in patients with long-term corticosteroid therapy: development of oculoskeletal symptoms similar to mitochondrial disease

Two patients with long-term corticosteroid administration sporadically developed limb muscle wasting followed by ophthalmoplegia, and the skeletal muscle pathology revealed ragged-red fibers (RRFs) with abnormal mitochondria, in addition to the findings of corticosteroid myopathy. The oculoskeletal symptoms of the present cases resemble those of chronic progressive external ophthalmoplegia, a type of mitochondrial disease. The ocular muscles have more RRFs than limb muscles, and large multiple deletions of mitochondrial DNA was detected in ocular and limb muscles of the two patients by PCR but not by Southern blotting. Immunohistochemistry demonstrated that 8-hydroxy-deoxyguanosine (8-OH-dG) and 4-hydroxy-2-nonenal were intensely stained in skeletal muscles of these patients particularly in RRFs. High-performance liquid chromatography with electrochemical detection analysis revealed an increase in 8-OH-dG from mitochondrial DNA. These findings may suggest that long-term corticosteroid administration potentially induces oxidative stress-mediated mitochondrial damage, resulting in the development of the oculoskeletal symptoms in some patients.


Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle

Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.


Apoptosis-related changes in skeletal muscle of patients with mitochondreal disease.

Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.


Homozygous deletion mutation of the parkin gene in patients with atypical parkinsonism

Autosomal recessive juvenile parkinsonism (AR-JP) is characterised by homogenous clinical features and selective degeneration of nigral neurons. Recent progress in molecular genetic analyses of AR-JP has led to the identification of a novel ubiquitin-like protein, parkin, whose precise function still remains to be elucidated. Two unrelated Japanese families had levodopa unresponsive parkinsonism complicated with cerebellar and pyramidal tract dysfunction. Genetic analysis of the parkin gene and mRNA in both families disclosed identical mutations with large deletions extending from exons 3 to 4. These results suggest that the parkin protein possesses an important function not only in the substantia nigra but also in extranigral neurons of the CNS and that the phenotype of multiple system dysfunction can also be a complication in patients with AR-JP due to variations in sites of or changes in functions by parkin mutation.

Journal of Neurology, Neurosurgery, and Psychiatry


Successful combination therapy--flunarizine,pentoxifylline, and cholestyramine--for spur cell anemia

Spur cell anemia, a hemolytic anemia observed in patients with alcoholic cirrhosis, is characterized by unusual erythrocyte morphology and an increased ratio of free cholesterol to phospholipid in the erythrocyte membrane. The prognosis of spur cell anemia is usually extremely poor, however, we describe here a patient with spur cell anemia who was successfully treated with combination therapy consisting of flunarizine, pentoxifylline, and cholestyramine. Initial therapy with flunarizine alone for 6 weeks did not significantly decrease the number of spur cells on peripheral blood smears. So pentoxifylline was added to the regimen. The patient recovered from the anemia, showed remarkable improvement with regard to the hyperbilirubinemia, and the changes were accompanied by a significant decrease in the number of spur cells in peripheral blood smears. To correct the hypercholesterolemia, cholestyramine was added to the regimen, which resulted in a reduction in the serum level of free cholesterol and an increase in the molar ratio of free cholesterol to phospholipid in erythrocyte membrane. However, 6 months later a skin eruption developed that was considered an adverse reaction to the drugs, so the flunarizine and pentoxifylline were discontinued. With cholestyramine therapy alone, the remission of spur cell anemia was maintained for more than 11 months. These observations suggest that non-invasive combination therapy with flunarizine, pentoxifylline, and cholestyramine is effective and valuable in the treatment of patients with spur cell anemia.


Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima

We found a 66-year-old Japanese patient with type I congenital heparin cofactor (HC) II deficiency manifesting multiple atherosclerotic lesions. To investigate the molecular pathogenesis of our patient, we performed sequencing analysis and expressed recombinant human wild-type and mutant HC II molecules in COS-1 and CHO-K1 cells. Sequencing analysis following amplification of each of all 5 exons and its flanking region showed a single C to T transition at nucleotide position 12,854 in exon 5, which changed a Pro443 codon (CCG) to Leu codon (CTG). Because this mutation generates a new Bhv I site, the Bbv I digestion pattern of the PCR-amplified exon 5 fragments from each family member was analyzed. In all cases, the patterns were consistent with the activities and antigen levels of plasma HC I1 in those members. Transient transfection, metabolic labeling and pulse-chase experiments followed by immunoprecipitation analysis showed that the recombinant mutant HC II molecules were secreted from COS-1 cells in reduced amounts compared with the wild-type, and that an enhanced intracellular association of the mutant molecules with a chaperone, GRP78/BiP, was observed in CHO-K1 cells. Northern blot analysis indicated that the mutant HC I1 mRNA was transcribed at a similar level as that of wild-type. Immunohistochemical staining of the transfected cells revealed that COS-1 cells expressing the mutant HC II molecules were stained mainly in the perinuclear area. We conclude that the impaired secretion of the mutant HC II molecules, due to intracellular degradation, is the molecular pathogenesis of type I congenital HC II deficiency caused by a Pro443 to Leu mutation at reactive P2 site.


冠動脈疾患の予防ならびに治療の観点からみた高コレステロール血症治療の現状とその問題点 --- 四国高脂血症スタディ


Sarcoglycan Gene Mutations,Clinical Features and Pathology of Autopsied Heart in Patients with Malignant Limb-Girdle Muscular Dystorphy(Miyoshi)

悪性肢帯型筋ジストロフィー(三好)患者におけるサリコグリカンの遺伝子異常ならびに臨床像と剖検心所見

Japanese Journal of National Medical Services


Functional association between nicotinic acetylcholine receptor and sarcomeric proteins via actin and desmin filaments


Aspirin Reduces Apolipoprotein(a) (Apo(a)) Production in Human Hepatocytes by Suppression of Apo(a) Gene Transcription

High serum lipoprotein(a) (Lp(a)) is a risk factor for vascular disorders. Our preliminary observations suggest that, in some patients with coronary heart disease with high serum Lp(a) levels, administration of aspirin reduced Lp(a) levels. Therefore, we aimed to analyze the effects of aspirin on the production of apo(a), the expression of apolipoprotein(a) (apo(a)) mRNA and the transcriptional activity of apo(a) gene promoter. Aspirin (5 mM) reduced the apo(a) levels in culture medium of human hepatocytes and suppressed apo(a) mRNA expression to 73% and 85% of the controls, respectively. Aspirin also reduced the transcriptional activity of apo(a) gene transfected into HepG2 hepatoma cells in a dose-dependent manner, with a maximal effect at 5 mM (44.3 +/- 1.5% of the control). Sodium salicylate (5 mM) also reduced apo(a) gene transcription, whereas indomethacin (10 microM) had no effect. Deletion analysis of apo(a) gene promoter showed that promoter region extending from -30 to +138 is critical for the effect of aspirin. Furthermore, enhanced production, mRNA expression, and gene transcription of apo(a) by interleukin-6 were also inhibited by aspirin. These results demonstrate that aspirin reduces apo(a) production from hepatocytes via reduction of the transcriptional activity of apo(a) gene with suppression of apo(a) mRNA expression. The suppression of apo(a) production by aspirin may at least in part play a role in the anti-atherogenic effect of aspirin in vascular disorders.


Effect of Aspirin Treatment on Serum Levels of Lipoprotein(a) --- Analysis From the Apolipoprotein(a)Isoforms

高リポ蛋白(a)血症に及ぼすaspirinの影響 --- アポリポ蛋白(a)アイソフォームとの関連


Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families

We report on the clinical, pathological, and genetic features of 7 patients with limb-girdle muscular dystrophy type 2A (LGMD2A) from three Japanese families. The mean age of onset was 9.7+/-3.1 years (mean+/-SD), and loss of ambulance occurred at 38.5+/-2.1 years. Muscle atrophy was predominant in the pelvic and shoulder girdles, and proximal limb muscles. Muscle pathology revealed dystrophic changes. In two families, an identical G to C mutation at position 1080 the in calpain 3 gene was identified, and a frameshift mutation (1796insA) was found in the third family. The former mutation results in a W360R substitution in the proteolytic site of calpain 3, and the latter in a deletion of the Ca2+-binding domain.


Psoriatic arthritis associated with dilated cardiomyopathy and Takayasu's arteritis

A 40-year-old Japanese man with psoriatic arthritis (PA) involving the spine, sacroiliac and peripheral joints presented with dyspnoea and ankle oedema. Blood pressure was 180/110 and 114/80 mmHg in the right and left upper arms, respectively. Examinations showed left ventricular dilatation and diffuse hypokinesis of the left ventricle, with no involvement of the coronary arteries. Aortography detected total occlusion of the left subclavian artery and stenosis of the origin at the right renal artery. Dilated cardiomyopathy and Takayasu's arteritis associated with PA was diagnosed. A few cases of PA have been reported in association with cardiovascular diseases, but the association of these three diseases has not been documented in the literature to date. Dermatologists need to be aware of cardiovascular manifestations in patients with PA, because cardiovascular diseases are not rare in other seronegative spondyloarthropathies.


Plasma levels of brain natriuretic peptide as an index for evaluation of cardiac function in female gene carriers of Duchenne muscular dystrophy


Cardiac dysfunction in patients with chronic progressive external ophthalmoplegia


多腺性自己免疫症候群3型に強皮症を合併したHTLV-1キャリアの1例

多腺性自己免疫症候群3型に強皮症を合併したHTLV-1キャリアの1例


Duchenne型筋ジストロフィー女性保因者における不顕性の心障害

Duchenne型筋ジストロフィー女性保因者における不顕性の心障害


Different secretion profiles of atrial and brain natriuretic peptides after acute volume loading in patients with ischemic heart disease

In order to clarify the different secretion profiles of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in response to acute hemodynamic change by volume expansion, we measured plasma ANP and BNP levels after intravenous isotonic saline infusion for 3 min at a rate of 3 ml/kg body weight/min in 15 patients with ischemic heart disease. Plasma ANP and BNP levels before the volume loading were 30.7 +/- 16.7 and 19.4 +/- 24.6 pg/ml, respectively. Five and 10 minutes after infusion, plasma ANP levels rose significantly to 43.5 +/- 20.7 and to 46.0 +/- 22.5 pg/ml, respectively (p < 0.01), and plasma BNP levels rose significantly to 27.3 +/- 30.8 and 24.8 +/- 23.2 pg/ ml, respectively (p < 0.01). The BNP/ANP ratio was not affected by volume loading. The maximum increments of plasma ANP level correlated significantly with those of the mean pulmonary capillary wedge pressure (mPCWP, r = 0.78, p < 0.01) or left ventricular end-diastolic pressure (LVEDP, r = 0.86, p < 0.01). However, there were no significant correlations between the maximum increments of plasma BNP levels and those of mPCWP or LVEDP. Plasma ANP level can be a useful parameter for atrial pressure even if the hemodynamic state change rapidly. However, in an early phase of ventricular overload BNP secretion is not increased sufficiently despite the raised LVEDP, and plasma BNP level may not always reflect ventricular hemodynamics.


The efficacy of inhaled nitic oxide in a patient with acute massive pulmonary thromboembolism.

Journal of the Japanese Society of Intensive Care Medicine


Cardiac Dysfunction with Becker Muscular Dystrophy


High frequencies of human T-lymphotropic virus type I (HTLV-I) infection and presence of HTLV-II proviral DNA in blood donors with anti-thyroid antibodies

To investigate the relationship between human T-lymphotropic virus (HTLV) types I and II and the pathogenesis of autoimmune thyroid diseases, we examined serum anti-thyroid antibodies in 1019 blood donors with or without serum anti-HTLV-I antibody as well as proviral DNA for HTLV-II in leukocyte DNA by the polymerase chain reaction in 395 blood donors with or without anti-thyroid antibodies. The frequency of donors with anti-HTLV-I antibody who also showed anti-thyroid antibodies (7.9%) tended to be higher than that (6.3%) among donors who did not have the anti-HTLV-I antibody. The frequency of anti-thyroid antibodies in 125 young male donors aged 16-39 years with anti-HTLV-I antibody (4.8%) was significantly higher (P < 0.05) than that (0.6%) in 164 control donors without the antibody. In blood donors with anti-thyroid antibody, 25.0% of those with anti-HTLV-I antibody and 14.3% of those without the antibody had HTLV-II proviral DNA. In contrast, in donors without anti-thyroid antibody HTLV-II proviral DNA was detected in 2.3% of those with anti-HTLV-I antibody and in 0.6% of those without the antibody. Thus the detection rates in donors with anti-thyroid antibody were significantly higher (P < 0.001) than those in donors without the antibody, regardless of HTLV-I infection. These results suggest that HTLV-I infection and the presence of HTLV-II proviral DNA may be independently related to the pathogenesis of autoimmune thyroid diseases.


自己免疫性甲状腺疾患の発病とHTL-2との関係について --- 自己免疫性甲状腺疾患には白血球DNA中にHTLV-2関連プロウイルスDNAを有する患者が高頻度に存在する


Oxidative damage to skeletal muscle DNA from patients with mitochondrial encephalomyopathies


Evidence of HTLV-I in thyroid tissue in an HTLV-I carrier with Hashimoto's thyroiditis


悪性肢帯型筋ジストロフィーにみられたadhalin遺伝子の異常とadhalin欠損筋ジストロフィーにおける臨床像の特徴


Localization and amount of myoglobin and myoglobin mRNA in ragged-red fiber of patients with mitochondrial encephalomyopathy.


Localization and amount of myoglobin and myoglobin mRNA in ragged-red fiber of patients with mitochondrial encephalomyopathy


Duchenne型筋ジストロフィーにおける心機能の血漿脳性ナトリウム利尿ペプチド濃度による評価


Parkin enhances mitochondrial biogenesis in proliferating cells


一酸化窒素吸入療法が有効であった急性広汎型血栓塞栓症の1例

一酸化窒素吸入療法が有効であった急性広汎型血栓塞栓症の1例


播種性血管内血液凝固症候群を合併した孤立性腸骨動脈瘤の1例

播種性血管内血液凝固症候群を合併した孤立性腸骨動脈瘤の1例


Adhalin Gene Mutations in Patients with Autosomal Recessive Childhood Onset Muscular Dystrophy with Adhalin Deficiency

Homozygous adhalin gene mutations were found in three patients from two consanguineous families with autosomal recessive childhood onset muscular dystrophy. Muscle biopsies from patients in each family showed complete absence of adhalin. Sequencing of adhalin cDNA prepared from skeletal muscle by reverse transcription PCR demonstrated a cytosine to thymidine substitution at nt 229 in the patient in family 1 and an adenine to guanine substitution at nt 410 and a 15-base insertion between nt 408 and 409 in the two patients in family 2. Sequencing of genomic DNA prepared from peripheral blood leukocytes by PCR confirmed these mutations. The parents in each family were found to be heterozygous for the respective mutations. These adhalin gene mutations are presumed to be responsible for the absence of adhalin in the skeletal muscle. Adhalin deficiency likely causes disruption of the muscle cell membrane, resulting in dystrophic changes in the skeletal muscle similar to dystrophin deficiency in Duchenne muscular dystrophy.


Two Elderly Patiencs with Multiple Cerebral Infarctions Who Had Antiphospholipid Antibodies

抗リン脂質抗体が陽性であった高齢者多発性脳梗塞の2例


HTLV-1 感染に関連した自己免疫性甲状腺疾患の存在

HTLV-1 感染に関連した自己免疫性甲状腺疾患の存在


Mitochondrial encephalomyopathy with autosomal dominant inheritance --- a clinical and genetic entity of mitochondrial diseases


Presence of human T-lymphotropic virus type II-related genes in DNA of peripheral leukocytes from patients with autoimmune thyroid diseases


無症状の母親に筋ミトコンドリア異常が認められたKearns-Sayre症候群の1例


低分子ヘパリンによる抗凝固治療法を併用し救命し得た急性抗汎型肺血栓塞栓症の1例

低分子ヘパリンによる抗凝固治療法を併用し救命し得た急性抗汎型肺血栓塞栓症の1例


慢性甲状腺炎の経過中にインスリン依存性糖尿病を発生した多腺性自己免疫症候群3型の1例


冠動脈疾患を合併した高脂血症に対するSimvastatinの有用性

冠動脈疾患を合併した高脂血症に対するSimvastatinの有用性


心房浸潤による心房細動を初発症状とした悪性リンパ腫の1剖検例

心房浸潤による心房細動を初発症状とした悪性リンパ腫の1剖検例


Clinical Feature and Mechanism of Cardiac Failure in Patients with Becker Muscular Dystrophy

Becker型筋ジストロフィーにおける心不全の病態とその発生機序


Enhanced Secretion and Impaired Natriuretic Natriuretic Action of Atrial Natriuretic Peptide in Response to Hypertonic saline Infusion in Patients with Essential Hypertension


抗リン脂質抗体陽性の高齢者大動脈炎症候群の1例

抗リン脂質抗体陽性の高齢者大動脈炎症候群の1例


バセドウ病を発症したHTLV-Iキャリアの2家系3症例

バセドウ病を発症したHTLV-Iキャリアの2家系3症例


中枢性尿崩症を合併したリンパ球性下垂体炎の1例

中枢性尿崩症を合併したリンパ球性下垂体炎の1例


腹部真性大動脈瘤に汎播種性血管内凝固を合併した2症例と凝固線溶系の活性化

腹部真性大動脈瘤に汎播種性血管内凝固を合併した2症例と凝固線溶系の活性化


常染色体優性の遺伝型を示すミトコンドリアミオパチー --- 自験例と貢献例における臨床的特徴とミトコンドリアDNA異常


橋本病患者の白血球DNAに見出されたHTLV-2プロウイルスDNA

橋本病患者の白血球DNAに見出されたHTLV-2プロウイルスDNA

Journal of Clinical and Experimental Medicine


rhG-CSFが著効を示した塩酸チクロピジンによる再生不良貧血の1例

rhG-CSFが著効を示した塩酸チクロピジンによる再生不良貧血の1例


播種性血管内凝固症候群(DIC)と腎不全を合併した高齢者腹部大動脈瘤の1手術治験例


Direct secretion from left atrium and pulmonary extraction of human atrial natriuretic peptide


Scar Formation in the Cardiac Conduction System of a Patient


Alterations in Atrial Filling Fraction in Patients with Mitral Stenosis After Percutaneous Transvenous Mitral Commissurotomv


Determination of Calcitonin Gene-Related Peptid(CGRP) in Plasma and Cerebrospinal spinal Fluid in patients with Various Diseases


Balloon diameter of the Inoue balloon catheter during percutaneous transvenous mitral commissurotomy: clinical and experimental study

Catheterization and cardiovascular diagnosis


Effects of percutaneous transvenous mitral commissurotomy on levels of plasma atrial natriuretic peptide during exercise


Improvement in mitral flow dynamics during exercise after percutaneous transvenous mitral commissurotomy. Noninvasive evaluation using continuous wave Doppler technique


月経時喀血を呈した肺子宮内膜症の1例

月経時喀血を呈した肺子宮内膜症の1例


胃病変を主とした成人T細胞性リンパ腫の1症例

胃病変を主とした成人T細胞性リンパ腫の1症例


An annual report 2015 on campus wide Faculty Development programs at The University of Tokushima

2015年度徳島大学FD推進プログラムの実施報告

Journal of University Education Research


An annual report 2014 on campus wide Faculty Development programs at The University of Tokushima

2014年度徳島大学FD推進プログラムの実施報告


Long-term endothelial dysfunction after coronary artery stenting with drug-eluting stent associated with local inflammatory response.


Local hypercoagulability and endothelial dysfunction after sirolimus-eluting stent implantation: implication for late stent thrombosis.


Long-term local inflammatory response after coronary artery stenting with drug-eluting stent.


Assessment of Left Atrial Ejection Force in Patients with Hypertensive Heart Disease.

Journal of the American Society of Echocardiography


Importance of Left Atrial Function in Cardiac Response to Increment of Preload in Patients with Old Myocardial Infarction: Assessment by Automated Left Atrial Volume Tracking Method.


Beat-To-Beat Variation of Mitral Annular Velocities in Atrial Fibrillation.


The Mitral L-Wave Predicts the Cardiac Response to Preload Increment in Atrial Fibrillation.


Usefulness of Tei Index in Atrial Fibrillation: Assessment by Dual Doppler Echocardiography.


Multicenter Trial for the Validation of Automated Function Imaging in Patients with Local Left Ventricular Asynergy (VANILLA Study).


Role of Left Atrial Function for Pseudonormalization of Transmitral Flow Velocity Pattern in Patients with Hypertrophic Cardiomyopathy.


末梢単核球細胞を用いた抹消動脈閉塞症に対する新たな血管新生治療の試み

末梢単核球細胞を用いた抹消動脈閉塞症に対する新たな血管新生治療の試み


Effects of Transthoracic Echocardiographic Simulator Training on Performance and Satisfaction in Medical Students.