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A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Approximately 40% of Japanese patients with essential hypertension, including low-renin hypertension, are inadequately managed. Low-renin hypertension generally responds poorly to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, but may respond more optimally to diuretics, calcium channel blockers, and aldosterone blockers. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluated the efficacy and safety of the selective aldosterone blocker eplerenone in 193 Japanese patients with essential hypertension. Although not a study inclusion criterion, baseline active plasma renin levels were consistently low (5.7-10.1 mU/L); most patients met the criteria for low-renin hypertension (< or =42.5 mU/L; normal range, 7-76 mU/L). Patients received placebo or eplerenone 50, 100, or 200 mg once daily for 8 weeks. Systolic blood pressure decreased significantly (-6.8 to -10.6 mm Hg vs. -2.1 mm Hg; p< or =0.0022 vs. placebo). Eplerenone offers significant blood pressure reduction with good tolerability in Japanese patients with hypertension, including those with low-renin hypertension.

A 60-year-old Japanese man with obstructive hypertrophic cardiomyopathy was found to have a mutation in the cardiac myosin binding protein C gene: a single base deletion of a thymidine residue at nucleotide 11645 (codon 593) in exon 18. He was diagnosed at the age of 43 and has been followed for 17 years. During this follow-up period, echocardiograms and mechanocardiograms revealed progressive hypertrophy until the age of 54, then gradual dilation of the left ventricle associated with a decrease in the obstruction. Paroxysmal atrial fibrillation occurred at the age of 52 and progressed to chronic atrial fibrillation at the age of 53. He had congestive heart failure at the age of 58.

High urinary albumin excretion rate (AER) has been associated with the presence of atherosclerotic vascular damages and is an independent risk factor for all causes of death and cardiovascular morbidity and mortality in essential hypertensive patients. Serum cystatin C (s-CC) is a recently identified nonglycosylated 13-kD basic protein that has been suggested to be a useful marker of glomerular filtration rate. In the present study, we investigated the relationship between s-CC level and end-organ damages in the kidney, heart, and vessels of patients with essential hypertension. Sixty patients with essential hypertension participated in the present study. Patients with renal failure were excluded. Serum-CC level was measured by a particle-enhanced turbidimetric assay. Left ventricular mass index (LVMI) and intima media thickness (IMT) in the common carotid arteries were evaluated by ultrasound images. Twenty-four-hour blood pressure was measured by a cuff-oscillometric method. Serum-CC level was negatively correlated with creatinine clearance (r=-0.617, p<0.0001). It was also correlated with mean 24-h systolic blood pressure (24h-SBP) (r=0.308, p= 0.0167), LVMI (r=0.528, p<0.0001), and IMT (r=0.539, p<0.0001). Both AER and s-CC level were independently associated with mean 24h-SBP. AER but not s-CC level was associated with HDL-cholesterol. The present study was the first to demonstrate that s-CC level is a useful and convenient parameter of renal function, and may also prove to be an early marker of the severity of end-organ damage in patients with essential hypertension.

A patient with non-Q wave myocardial infarction had severe luminal narrowing in the first major septal perforator branch, which arose anomalously from the first diagonal branch. In this case, an exercise ECG showed a transient leftward QRS axis shift.

A 71-year-old woman with fever and dry cough was admitted to our hospital. Chest computed tomography, bronchoalveolar lavage and transbronchial lung biopsy were performed, and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed. The patient was treated with corticosteroid, and marked improvement was noted. However, when the dosage was tapered, the BOOP recurred. We increased the dosage of corticosteroid and also put the patient on a daily regimen of cyclosporin. The cyclosporin was administered orally, and was effective, so that we could gradually decrease the dosage of corticosteroid. We concluded that cyclosporin may be useful in the treatment of refractory BOOP.

T-helper (Th)1 cells have a pivotal role in the pathogenesis of hypersensitivity pneumonitis. Continued low-level exposure to the antigens may induce chronic hypersensitivity pneumonitis with lung fibrosis. Although such exposure may activate Th1 cells in the lung, it is not known whether activation of Th1 cells per se can lead to pulmonary fibrosis. To determine this, the lung pathology induced by Th1 clones was investigated. Mice (BALB/c) were injected intraperitoneally with Th1 clones 1-4 times. Each injection was performed 4 days apart and was followed by repeated exposure to aerosolised ovalbumin (OVA) once a day for 5 days. The number of macrophages and lymphocytes in bronchoalveolar lavage fluids (BALF) increased as the number of Th1 transfers increased. The number of neutrophils also increased but peaked in the second transfer and then decreased following further transfers. Increased cell infiltration, thickness of alveolar walls and number of type II cells in the lung occurred. However, histological findings showed no evidence of fibrosis and hydroxyproline levels did not increase. Findings of histology and BALF were ameliorated 2 weeks after the discontinuation of OVA exposure, indicating the reversibility of the Th1-induced pathology. In conclusion, adoptive transfer of T-helper 1 cells results in reversible alveolitis but does not lead to pulmonary fibrosis.

An 18-year-old male patient with biventricular hypertrophic obstructive cardiomyopathy (HOCM) had successful reduction of the pressure gradients by cibenzoline. At 11 months after birth, he was first diagnosed with cardiac murmurs and by the age of 5 years, he was diagnosed with subpulmonic infundibular stenosis with a pressure gradient of 10 mmHg by cardiac catheterization. At the age of 14, re-catherterization revealed hypertrophic cardiomyopathy with isolated obstruction of the right ventricular outflow tract, with a pressure gradient of 70 mmHg, but no obstruction in the left ventricle. He began daily treatment with 30 mg propranolol. At the age of 18, he was admitted for cardiac evaluation. An echocardiogram revealed left mid-ventricular and subpulmonic obstructions associated with pressure gradients of 88 mmHg and 65 mmHg, respectively. A single oral dose of 200 mg of cibenzoline decreased the pressure gradients in the left and right ventricles (38 mmHg and 36 mmHg, respectively). He was then given 300 mg daily of cibenzoline, and both pressure gradients remained low without any complications 8 months later at the time of discharge.

Background: Insulin resistance (IR) is implicated in the pathogenesis of atherosclerosis. One mechanism is thought to be the impaired vasodilation, which can lead to a reduction in peripheral blood flow. Hypertensive patients with IR have greater intima-media thickness (IMT) in the common carotid artery (CCA) than those without IR. However, the relationship between IR and hemodynamic alterations of the CCA has not been clarified., Methods: Seventy patients with essential hypertension (EHT) and 11 normotensive controls (NT) participated in this study. The IMT, number of plaques, and internal dimensions of the CCA were evaluated by ultrasound imaging. Mean diastolic (Vd) and systolic (Vs) velocity were determined by the Doppler flow method, and other parameters such as Vd/Vs and the cross-sectional distensibility coefficient (CSDC) were further calculated. When the homeostasis model assessment (HOMA) index exceeded 2.0, the subject was considered to have IR., Results: The IMT was positively correlated with the HOMA index in all subjects. The Vd/Vs and CSDC were significantly decreased in EHT patients with IR compared to NT and EHT patients without IR. The Vd/Vs and CSDC were negatively correlated with the HOMA index. A stepwise regression analysis revealed that age, HDL-cholesterol, and the HOMA index were independently associated with IMT in patients with EHT. Age, the HOMA index, and mean blood pressure (MBP) were independently associated with CSDC, and the first two factors were independently associated with Vd/Vs., Conclusions: Decreased distensibility of the arterial wall and ensuing low diastolic perfusion are possible mechanisms of atherosclerotic changes in the CCA in EHT patients with IR.

CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-gamma gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-delta plays a pivotal role in transactivation of PPAR-gamma gene. It has been well known that the interaction between C/EBPs and PPAR-gamma plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-gamma and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-delta expression induced by inflammation positively regulated transcription and protein expression of PPAR-gamma in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-gamma ligands troglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited IL-1beta-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-gamma ligands inhibited IL-1beta-induced transactivation of IL-6 gene via suppression of not only nuclear factor-kappaB but also C/EBP-DNA binding. Moreover, PPAR-gamma ligands suppressed protein expression and transcription of C/EBP-delta through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-delta is negatively autoregulated via transactivation of PPAR-gamma. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.

We examined the effects of aging and hypertensive left ventricular hypertrophy on the plasma level of brain natriuretic peptide (BNP), and assessed BNP as a risk marker for incident hypertensive cardiovascular events. One hundred and eighty-five hypertensive patients were echocardiographically divided into a hypertensive group with normal left ventricular mass (n=96; age range, 37-86 years; left ventricular mass, 97+/-14 g/m2) and a hypertensive group with left ventricular hypertrophy (n=89; 37-90 years; 140+/-20 g/m2). Forty-four normotensive subjects served as the normotensive group (32-84 years; 91+/-15 g/m2). We examined the association of age with BNP in the three groups and also evaluated BNP as a risk marker for incident cardiovascular events by following up all patients for 40 months. All three groups demonstrated a significant positive relationship between age and BNP. The slope of the relation between age and BNP was steepest in the hypertensive group with left ventricular hypertrophy (p<0.0001 vs. the other two groups). Multiple regression analysis revealed that age, pulse pressure and left ventricular mass index were significantly associated with the increase in BNP. Multivariate Cox proportional hazards regression analysis, which was used to assess the potential association of age, pulse pressure, left ventricular mass index and BNP with the cardiovascular events during follow-up, revealed the highest correlation between BNP and incident cardiovascular events (risk ratio=1.011; p=0.0011). BNP, which is synergistically increased with aging and left ventricular hypertrophy, may be an important risk marker for hypertensive cardiovascular events.

Background: In vitro studies suggest that angiotensin II type 1 and type 2 (AT1 and AT2) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT1a in vascular remodeling., Methods and Results: Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), AT2-null (AT2KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT2KO mice, but they were both suppressed in AT1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT1aKO mice but decreased in AT2KO mice. Reverse transcriptase-polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT2KO mice. On the other hand, the expression of bcl-2 and bcl-x(L) mRNA was enhanced in AT2KO mice but attenuated in AT1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results., Conclusions: Our results suggest that AT2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT1a in the process of neointimal formation after vascular injury.

Objective: Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers improve prognosis inpatients with chronic heart failure. Some patients, however, show little response to combined treatment with an ACE inhibitor and a beta-blocker. In addition, the ACE inhibitor cannot completely suppress angiotensin II production. Our objective was to examine whether replacing the ACE inhibitor with an angiotensin II antagonist can improve the condition of patients with chronic heart failure., Methods: In 11 patients with chronic heart failure treated with an ACE inhibitor and a beta-blocker, who have had severe left ventricular dysfunction or high plasma level of natriuretic peptides, left ventricular dimension, and fractional shortening, plasma atrial and brain natriuretic peptide (ANP and BNP) levels were determined before and 3 months after the change of treatment., Results: After substituting the ACE inhibitor with an angiotensin II antagonist, patients showed New York Heart Association functional class improvement, and significant decrease in left ventricular dimension and BNP., Conclusion: In patients with severe chronic heart failure treated with an ACE inhibitor and a beta-blocker, replacing the ACE inhibitor with an angiotensin II antagonist may be effective. However, this has to be confirmed by an adequately powered randomized controlled study.

Study Objectives: We sought to assess the incidence of transient U-wave inversion during vasospasm of the left anterior descending coronary artery (LAD) with ST-segment depression as opposed to that with ST-segment elevation., Design: Retrospective study., Setting: Cardiology division of acute-care hospitals., Patients: We studied 49 patients with vasospastic angina whose vasospasm was induced in the LAD, not in the left circumflex coronary artery, by intracoronary injection of acetylcholine., Measurements and Results: The ECG traces obtained during acetylcholine-induced vasospasm of the LAD were examined. Based on the direction of ST-segment shift, the patients were categorized into two groups: the ST-segment elevation group (n = 27) and the depression group (n = 22). There were no differences in age, gender, or cardiovascular risk factors between the two groups. The distribution of the spastic site in the LAD was also similar. A total reduction in luminal diameter during a provoked attack was more often observed in the ST-segment elevation group than in the ST-segment depression group (37% vs 9%, p = 0.02). Collateral circulation to the LAD was found in only one patient in each group. There were no differences between the two groups in heart rate, systolic BP, and double product of heart rate and systolic BP during the attack. The incidence of acetylcholine-induced anginal attack with U-wave inversion in the ST-segment depression group was nearly as high as that in the ST-segment elevation group (77% vs 78%, p > 0.99)., Conclusions: The development of transient U-wave inversion during vasospasm of the LAD induced by intracoronary injection of acetylcholine does not depend on the magnitude of myocardial ischemia as judged by the direction of ST-segment shift.

Insulin-like growth factor-1 (IGF-1) is important in the hypertrophic response of the myocardium, so the present study was designed to elucidate whether the circulating levels of IGF-1 and its binding proteins (IGFBPs) are related to the disease condition of patients with hypertrophic cardiomyopathy (HCM), in particular the occurrence of congestive heart failure (CHF). The study group comprised 124 patients with HCM and 15 healthy control subjects. The HCM patients were subdivided into 3 groups: 39 with hypertrophic obstructive cardiomyopathy (HOCM), 67 with hypertrophic non-obstructive cardiomyopathy (HNCM), and 18 with HCM and a history of CHF (HF-HCM, n=18). Serum levels of IGF-1 and IGFBPs (IGFBP-1 and -3) were compared between groups. IGF-1 levels were significantly higher in patients with HOCM and HNCM, and lower in patients with HF-HCM than in control subjects (p<0.0001, p<0.005, and p<0.05, respectively). IGFBP-1 levels were significantly higher in patients with HF-HCM than in the other 3 groups (p<0.0001 for all). The findings suggest that circulating levels of IGF-1 and IGFBP-1 are related to the extent of myocardial injury in patients with HCM.

Background: The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis., Objective: To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients., Patients and Main Outcome Measures: Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay., Results: Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r =0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030)., Conclusions: These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension.

Eosinophilic pleural effusion occurs in many diseases. The mechanisms of eosinophil accumulation are not well understood. We showed previously that eotaxin was readily detectable in most pleural effusions, and its concentration significantly correlated with eosinophil number. To test the hypothesis that pleural eotaxin is produced by resident mesothelial cells, we examined its production by normal pleural mesothelial cells (NPMC). Eotaxin was induced by tumor necrosis factor (TNF)-alpha or interleukin (IL)-4 and was drastically increased by their combination. In contrast, interferon (IFN)-gamma inhibited eotaxin production. Regulated on activation, normal T cells expressed and secreted (RANTES) was also induced by TNF-alpha and was drastically increased by the addition of IFN-gamma. These effects were observed at both protein and mRNA levels. Stabilization of RANTES mRNA was observed with IFN-gamma but not IL-4; neither cytokine stabilized eotaxin mRNA. Eosinophil chemoattractant activity in culture supernatants of NPMC stimulated with TNF-alpha plus IL-4 was diminished by an anti-eotaxin antibody; that induced by TNF-alpha plus IFN-gamma was attenuated by an anti-RANTES antibody. Thus, NPMC can produce eotaxin, and different cytokines act on NPMC to induce different chemokines by different mechanisms. IFN-gamma, a Th1 cytokine, acts at least at the posttranscriptional level to induce RANTES production, but it inhibits eotaxin production. In contrast, IL-4, a Th2 cytokine, acts at the transcriptional level to induce eotaxin.

The exact mechanisms responsible for the progression of heart failure remain unclear. We investigated the in vivo relationship between the incidence of apoptotic cell death and left ventricular function serially from the beginning of hypertension to decompensated heart failure in Dahl salt-sensitive rats. Dahl salt-resistant and Dahl salt-sensitive rats were fed on a high-salt diet from 6 weeks of age. Systolic blood pressure was recorded by the tail-cuff method every week. Cardiac function in vivo was evaluated by echocardiography and cardiac catheterization. Cardiomyocyte apoptosis was detected by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) method. The gene expression of Bax, Bcl-2 and Bcl-xL was analysed by Northern blotting. The TUNEL method revealed that the incidence of cardiomyocyte apoptosis was significantly increased in the hearts of 18-week-old Dahl salt-sensitive rats (apoptotic index 1.3 +/- 0.1%). Northern blot analysis revealed that the Bcl-xL mRNA level increased gradually during the progression towards heart failure. In conclusion, these data suggest that cardiomyocyte apoptosis is a terminal event, and plays a role as an aggravating factor in the vicious cycle of heart failure.

Serum response factor and the (CC(A/T)(6)GG) (CArG) box interact to promote the transcription of c-fos and muscle genes; this tissue-specific activity may require co-regulators for serum response factor. The alpha(1) integrin promoter contains two cis-elements besides the CArG box: a TAAT sequence, a consensus binding site for homeoproteins, and a GATA-binding box. As a candidate TAAT-binding factor, we cloned an NK family homeobox gene, Nkx-3.2, which is expressed mainly in smooth muscle tissues and skeletal structures. Nkx-3.2, serum response factor, and GATA-6 were co-expressed only in the medial smooth muscle layer of arteries. These three transcription factors formed a complex with their corresponding cis-elements and cooperatively transactivated smooth muscle genes, including alpha(1) integrin, SM22alpha, and caldesmon. Cardiac muscle-specific members of the NK and GATA families exist, and the triad of Nkx-2.5, serum response factor, and GATA-4 also transactivated the cardiac atrial natriuretic factor gene, which contains a CArG-like box, a GATA-binding box, and an NK-binding element. Our findings demonstrate that smooth and cardiac muscle have a shared transcriptional machinery and that the GATA and NK families confer muscle specificity on the serum response factor/CArG interaction.

Oxidative stress plays a critical role in normal functioning of cardiac and vascular cells as well as in the pathogenesis of cardiovascular disease. Growth arrest and DNA damage-inducible gene 153 (GADD153), which is upregulated by oxidative stress, regulates the cell cycle and apoptosis. Previously an AP-1 was reported to contribute significantly to GADD153 gene transcriptional activation by oxidative stress. Recently, we have reported that GADD153 gene promoter activity is negatively regulated by nuclear factor 1 (NF1), in vascular smooth muscle cells (VSMCs). The aim of this study was to elucidate the roles of AP-1 and NF1 in GADD153 gene induction by oxidative stress in VSMCs. H(2)O(2) induced GADD153 mRNA and reduced NF1 mRNA expression. In the electromobility shift assay, H(2)O(2) induced AP-1-binding activity and reduced NF1-binding activity. Overexpression of NF1 significantly suppressed the induction of the GADD153 gene after treatment with H(2)O(2). These results revealed that induction of the GADD153 gene by oxidative stress is regulated mainly by two nuclear factors, NF1 and AP-1., (©2002 Elsevier Science (USA).)

A 58-year-old man was admitted to our hospital because of cough, polydipsia and polyuria. Chest CT films showed mediastinal lymphadenopathy, nodules in the lung fields, and pleural effusion. Histopathologic examination of transbronchial biopsy specimens showed oat cell carcinoma. MRI films revealed tumorous swelling of the pituitary stalk. Central diabetes insipidus caused by pituitary metastasis of small cell lung cancer was diagnosed. After treatment with whole-brain irradiation and chemotherapy, the size of the swollen pituitary stalk was reduced and his urine volume decreased. He died of respiratory insufficiency 15 months after the initial diagnosis. No recurrence of pituitary metastasis was apparent. This was a rare case of central diabetes insipidus caused by pituitary metastasis of small cell lung cancer successfully treated with radiotherapy and chemotherapy.

KL-6, surfactant protein (SP)-A, SP-D, and monocyte chemoattractant protein-1 (MCP-1) are reported to be sensitive markers for interstitial lung diseases (ILD). However, each marker has been studied independently. The aim of this study was a comparative analysis of the diagnostic values of these markers. Subjects consisted of 33 patients with ILD (21 cases of idiopathic pulmonary fibrosis and 12 associated with collagen vascular diseases) and 82 control subjects (12 cases of bacterial pneumonia and 70 healthy volunteers). Receiver operating characteristic curves revealed that KL-6 was superior to the other markers. The cut-off levels for these markers that resulted in the highest diagnostic accuracy were determined to be 465 U/ml for KL-6, 48.2 ng/ml for SP-A, 116 ng/ml for SP-D, and 1080 pg/ml for MCP-1. The sensitivity, specificity, and diagnostic accuracy were 93.9%, 96.3%, and 95.7% for KL-6; 81.8%, 86.6%, and 85.2% for SP-A; 69.7%, 95.1%, and 87.8% for SP-D; and 51.5%, 92.7%, and 80.9% for MCP-1; respectively. The serum levels of SP-A and SP-D, but not of KL-6, were significantly higher in patients with bacterial pneumonia than in healthy volunteers. These results suggest that of the markers studied, KL-6 is the best serum marker for ILD.

Recent studies have demonstrated that elevated levels of cholesterol in the form of remnant-like particles (RLP-C) induce deterioration of endothelial function during the fasting state, but it is not known whether postprandial RLP-C elevation has the same effect. The objective of this study was to assess the effect of postprandial RLP-C elevation on endothelial function in 24 fasting normolipidemic subjects. Flow-mediated dilatation (FMD) during reactive hyperemia in the brachial artery was investigated. Serum lipids and lipoproteins during fasting and 4h after regular fat-loading were measured. Subjects were divided into 2 groups: the high responders (postprandial RLP-C level >7.5mg/dl, n=8) and the normal responders (postprandial RLP-C level < or =7.5mg/dl, n=16). Significant increases in the level of both triglycerides and RLP-C were observed in the high responders. Basal FMD in the high responders (4.3+/-3.0%) was significantly lower than that in the normal responders (8.3+/-2.4%) (p<0.01), but FMD after the fat-loading in both groups did not change significantly. The change in RLP-C levels during the fat-loading test correlated significantly with basal FMD (r=-0.588, p<0.01). Multiple regression analysis showed a significant correlation between basal FMD and the change in RLP-C levels (r=-0.488, p<0.02). The results of this study suggest that postprandial RLP-C elevation could be associated with atherosclerotic progression even in normolipidemic subjects.

At the age of 53, a 65-year-old man had been diagnosed with extra-adrenal pheochromocytoma in the retroperitoneum and underwent total tumorectomy. Afterward, he had his serum catecholamine periodically measured in an outpatient clinic. In February 1999, 12 years after surgery, he complained of lower left abdominal pain. Computed tomography and magnetic resonance imaging revealed an osteolytic lesion in thoracic vertebrae 11Th (Th 11). Although his basal serum and urine catecholamines were at normal levels, glucagon injection increased blood pressure and plasma catecholamine levels. 131I-metaiodobenzylguanidine (MIBG) scintigraphy was specifically taken up to Th 11. By bone biopsy, the osteolytic lesion in Th 11 was finally diagnosed with metastasis of pheochromocytoma. For post-operative pheochromocytoma, long-term follow-up involving biochemical tests, including serum catecholamines, and MIBG is needed.

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/ deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3-7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.

A questionnaire survey was administered to Japanese clinical specialists in hypertension in order to gauge their opinions on the 1999 revised version of the Guidelines for Hypertension in the Elderly prepared by the Comprehensive Research Project on Aging and Health of the Ministry of Health and Welfare. Out of 162 council members of the Japanese Society of Hypertension, 122 (75%) replied. The majority (93%) of respondents approved of the guidelines in general, and 72% of them approved of the age-related setting of a therapeutic goal for blood pressure. Sixty-five percent of respondents selected long-acting Ca antagonists, ACE inhibitors and low-dose diuretics as first-line agents for hypertension without complications in the elderly. The results of the questionnaire survey should be reflected in the next version of the guidelines.

Ischemic preconditioning (IP) and pretreatment with lipopolysaccharide (LPS) reduce myocardial infarct size, but the precise mechanisms remain unknown. Rats were divided into 3 groups: the Control (C) group was subjected to 30 min ischemia followed by 3 h reperfusion; the IP and LPS groups had the same ischemia-reperfusion (I-R) insult with either preconditioning stimuli or pretreatment with LPS, respectively. Infarct size was smaller in the IP (23.4+/-2.3% of risk zone size) and LPS groups (28.5+/-2.0% of risk zone size) than in the C group (52.3+/-3.4% of risk zone size). Nuclear factor kappa-B (NF-kappaB) binding activity increased at 30 min reperfusion and declined thereafter, then rose again at 3 h reperfusion in the C group. The values in the IP (362% of control) and LPS (324% of control) groups were higher before I-R, and then decreased from 30 min (46% and 64% of control, respectively) until 3 h reperfusion (22% and 36% of control, respectively). Nuclear staining of NF-kappaB after reperfusion was less in the IP and LPS groups than in the C group. Expressions of cytokine mRNAs (interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha) were detected 30 min after the onset of reperfusion and their levels remained high after 3 h of reperfusion. These expressions of cytokine mRNAs after I-R were substantially suppressed by IP and LPS, although IP and LPS alone induced modest expressions of these cytokine mRNAs. These data suggest that IP and LPS contribute to infarct size reduction via the downregulation of NF-kappaB and the attenuation of cytokine gene expression.

Background: In naive rodents, repeated exposure to aerosolized antigen induces suppression of the Th2 response to the antigen. We hypothesized that more prolonged exposure of established asthma model to antigen aerosols may downregulate asthmatic phenotype., Methods: After establishing an ovalbumin (OVA)-induced asthma model, mice were further exposed to OVA (prolonged exposure group) or phosphate-buffered saline (positive controls) 3 days per week for 6 weeks. During week 7, the mice of both groups were finally challenged with OVA., Results: Prolonged OVA exposure resulted in marked suppression of serum OVA-specific immunoglobulin E (IgE) antibody levels, eosinophilia of the airway, and airway hyperresponsiveness (AHR). However, airway remodeling characterized by goblet cell hyperplasia and airway fibrosis was observed to the same degree in both groups. These effects were accompanied by diminished production of Th2 cytokines such as interleukin-4 (IL-4), IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF) and cultured supernatant of splenocytes. Furthermore, prolonged exposure markedly increased IL-12 levels in BALF., Conclusions: Prolonged antigen exposure has inhibitory effects on eosinophilic inflammation, AHR and IgE response to antigen, but not on airway remodeling, presumably via inhibition of Th2 cytokines and increased IL-12 production in the lungs., (Copyright 2001 S. Karger AG, Basel)

Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, the PDGF receptor. The PDGF alpha-receptor (PDGFalphaR) plays an important role in the growth and proliferation of vascular smooth muscle cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFalphaR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGFalphaR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and we have also suggested that C/EBP-delta is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFalphaR gene in VSMCs. To explore the definitive roles of C/EBP-delta protein on PDGFalphaR gene transcription in VSMCs, we developed C/EBP-delta transgenic rats by using a chimeric fusion gene of the mouse smooth muscle alpha-actin promoter and an entire coding region of rat C/EBP-delta cDNA. This report describes the first successful targeted overexpression of C/EBP-delta capable of inducing PDGFalphaR gene transcription and modifying cell proliferative activity to PDGFs. Targeted overexpression of C/EBP-delta evokes high levels of PDGFalphaR gene expression, susceptibility to VSMC growth, and proliferation of VSMCs to PDGFs. The results obtained reveal evidence of a new role and new functional significance of C/EBP-delta on VSMC growth via the PDGFalphaR during the process of vascular remodeling and atherosclerosis.

A 65-year-old man with sarcoidosis, accompanied by muscle nodules, noticed a painless and enlarged nodule in his forearm. MRI of the nodule showed that a star-shaped area of lower signal intensity was surrounded by an area of higher signal intensity. Histological examination showed granulomas composed of multinuclear giant cells and epithelioid cells. Sarcoidosis was diagnosed. Eight months later, he was admitted to our hospital because of enlargement of the nodular region with pain and stiffness. Marked uptake of 67Ga was observed in the right arm and leg. MRI revealed sarcoid nodules in these regions. An enlargement of the higher signal intensity area was observed in the right forearm nodule. We started administration of prednisolone. Forty days later, his symptoms had disappeared and the size of higher signal intensity area of the nodule had reduced dramatically. 67Ga scintigram and MRI were useful for diagnosis and monitoring during therapy in this patient.

A 65-year-old Japanese woman was admitted to hospital because of exertional dyspnea. Transthoracic echocardiography showed diffuse hypokinesis of the left-sided ventricular wall, but was not clear enough to provide useful information because of the rotation of the cardiac apex and the presence of lung tissue. Systemic ventriculography showed that the left-sided ventricle with heavy trabeculations was morphologically similar to a normal right ventricle. Magnetic resonance imaging (MRI) clearly revealed corrected transposition of the great arteries. Because this patient had no severe associated cardiac anomalies, systemic ventricular dysfunction is thought to be the major cause of exertional dyspnea. MRI is a useful non-invasive method for the rapid evaluation of cardiac morphology.

Congestive heart failure is a common and serious complication in patients undergoing chronic dialysis. However, there have been no studies on preferential medical therapies to improve left ventricular function in haemodialysis patients. Beta-blocker treatment is known to improve left ventricular function in patients with dilated cardiomyopathy; moreover, plasma levels of noradrenaline and natriuretic peptides are sensitive markers of left ventricular dysfunction. The present study investigated whether beta-blocker treatment could improve left ventricular function in haemodialysis patients with a dilated left ventricle. Our study group comprised 14 haemodialysis patients with a dilated left ventricle, who had undergone maintenance haemodialysis for a mean of 11 years. The following haemodynamic parameters were evaluated before and after 4 months of treatment with the beta-blocker metoprolol: left ventricular dimension at end-systole and end-diastole, and fractional shortening. Plasma levels of noradrenaline, atrial natriuretic peptide and brain natriuretic peptide were also determined. Dry body weight and haemoglobin concentration showed no significant change after compared with before treatment with metoprolol. Heart rate decreased significantly, from 79+/-9 beats/min to 69+/-9 beats/min, but systolic blood pressure remained unchanged. The left ventricular dimension both at end-systole and at end-diastole was decreased, and fractional shortening increased significantly. Plasma levels of noradrenaline did not change significantly, but those of atrial natriuretic peptide and brain natriuretic peptide decreased markedly [from 100+/-89 pg/ml to 46+/-29 pg/ml (P=0.0051) and from 549+/-516 pg/ml to 140+/-128 pg/ml (P=0.0035) respectively]. In conclusion, beta-blocker therapy with metoprolol can markedly attenuate left ventricular remodelling and decrease the plasma levels of natriuretic peptides in haemodialysis patients with a dilated left ventricle.

We report a patient with a severe inclusion body myositis (IBM). His illness was unusual in terms of a rapid progression, high creatine kinase levels, and complication with interstitial pneumonia. He responded well to immunosuppressive agents such as corticosteroids, cyclosporin A, cyclophosphamide, and immunoglobulin. The present patient indicates the wide range of the disease, and that immunosuppressive agents may be useful for treatment of IBM.

The objective of this study was to elucidate the relationship between left ventricular geometry and left ventricular (LV) function in patients with untreated essential hypertension. We evaluated LV systolic and diastolic functions by M-mode echocardiography in 24 normotensive control subjects (NC) and 129 patients with essential hypertension. Patients were divided into four groups according to the relative wall thickness and LV mass index: a normal left ventricle (n=57), a concentric remodeling (n=7), a concentric hypertrophy (n=31), and an eccentric hypertrophy (n=34) group. LV systolic function as measured by midwall fractional shortening (FS) was significantly decreased in both the concentric remodeling and concentric hypertrophy groups; no differences were observed for endocardial FS. LV diastolic function as measured by isovolumic relaxation time (IRT) was also decreased in both the concentric remodeling and concentric hypertrophy groups. In multivariate analysis, relative wall thickness (p<0.0001), end-systolic wall stress (p<0.0001), and systolic blood pressure (p=0.002) were independently associated (r2=0.72) with midwall FS in a model including age, LV mass index, body mass index, diastolic blood pressure and IRT. In addition, relative wall thickness (p=0.0008) and age (p<0.0001) were independently associated (r2=0.31) with IRT in a model including LV mass index, end-systolic wall stress, body mass index, systolic and diastolic blood pressures and midwall FS. We conclude that LV geometry as evaluated by relative wall thickness may provide a further independent stratification of LV systolic and diastolic functions in essential hypertension.

A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.

The effect of cibenzoline on left ventricular diastolic function was investigated in patients with hypertrophic cardiomyopathy (HCM). Before and 2 h after an oral administration of 200 mg of cibenzoline, echocardiographic, apexcardiographic and gated radionuclide angiographic studies were performed in 12 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 7 with hypertrophic nonobstructive cardiomyopathy (HNCM). After administration of cibenzoline, the left ventricular pressure gradient decreased from 96+/-33 mmHg to 29+/-22 mmHg (<0.0001). Fractional shortening decreased from 53.3+/-7.5 to 45.4+/-6.2% (p=0.0008) in patients with HOCM and from 49.9+/-8.7 to 40.9+/-7.5% (p=0.0039) in patients with HNCM. On the other hand, E-wave velocity increased and A-wave velocity decreased in both groups. The time between the second heart sound and O point was shortened from 253+/-53 to 176+/-21 ms (p<0.0001) in patients with HOCM and from 245+/-54 to 185+/-44 ms (p=0.0050) in patients with HNCM. The time to peak filling rate was shortened from 248+/-79 to 190+/-40 ms (p=0.0072) in patients with HOCM and from 218+/-33 to 163+/-26 ms (p=0.0052) in patients with HNCM. These results indicate that in patients with HCM, cibenzoline suppresses left ventricular systolic function, but can markedly improve left ventricular diastolic dysfunction through its direct action.

Tropomyosin (TM) is a regulatory protein of actomyosin system. Muscle type-specific expression of TM isoforms is generated from different genes and by alternative splicing. beta-TM isoforms in chicken skeletal and smooth muscles are encoded by a single gene and transcribed from the same promoter. We previously reported a smooth muscle cell (SMC) phenotype-dependent change in beta-TM expression (Kashiwada, K., Nishida, W., Hayashi, K., Ozawa, K., Yamanaka, Y., Saga, H., Yamashita, T., Tohyama, M., Shimada, S., Sato, K., and Sobue, K. (1997) J. Biol. Chem. 272, 15396-15404), and identified beta-TM as an SMC-differentiation marker. Here, we characterized the transcriptional machinery of the beta-TM gene in SMCs. Promoter and gel mobility shift analyses revealed an obligatory role for serum response factor and its interaction with the CArG box sequence in the SMC-specific transcription of the beta-TM gene in differentiated SMCs. We further isolated a novel homologue of the Barx homeoprotein family, Barx1b, from chicken gizzard. Barx1b was exclusively localized to SMCs of the upper digestive organs and their attached arteries and to craniofacial structures. Serum response factor and Barx1b bound each other directly, coordinately transactivated the beta-TM gene in differentiated SMCs and heterologous cells, and formed a ternary complex with a CArG probe. Taken together, these results suggest that SRF and Barx1b are coordinately involved in the SMC-specific transcription of the beta-TM gene in the upper digestive organs and their attached arteries.

Hemodialysis patients frequently show associated hypertension, which can lead to a number of cardiovascular complications. The aim of this study was to assess the effects of hypertension on the structure and function of the carotid artery and left ventricle (LV) in hemodialysis patients. In addition, we investigated the contribution of hemodialysis and other risk factors. Fifty-two hemodialysis patients, 71 hypertensive patients (HT group) and 30 normotensive subjects (NT group) were included in this study. Hemodialysis patients were divided into two groups: 35 patients with hypertension (HDHT group), and 17 patients without hypertension (HDNT group). We measured intima-media thickness (IMT), plaque score, end-diastolic diameter, and stiffness index beta of the carotid artery by ultrasonography, and LV mass index (LVMi), endocardial fractional shortening (FS), and midwall FS (MWS) by echocardiography. A multiple stepwise regression analysis including hemodialysis, hypertension, diabetes mellitus, and other risk factors was also performed. IMT was significantly higher in the HT and HDHT groups than in the NT group. Plaque score and diameter of the carotid artery were higher in the HDHT group than in the other three groups. The stiffness index beta was higher in the HDHT group than in the non-hemodialysis groups. In multivariate analysis, IMT was independently correlated with age and hypertension. Plaque score and stiffness index beta were independently associated with age, hypertension, and hemodialysis. LVMi was higher in HT and hemodialysis-patients groups than in the NT group. Hypertension and hemodialysis were strong and independent predictors of LVMi. FS showed no significant differences among the four groups, but MWS was significantly lower among the hemodialysis patients than in the NT group. MWS was independently correlated with hemodialysis and diabetes. In conclusion, hemodialysis per se advanced both atherosclerosis and arteriosclerosis of the carotid artery. Moreover, it increased LVMi and caused cardiac dysfunction. Associated hypertension might thus accelerate the progression of atherosclerosis and arteriosclerosis of the carotid artery and the increase of LVMi.

In this review first I described the procedures of diagnosis in patients with essential hypertension. Blood pressure level, risk factor for cardiovascular disease and organ damage due to hypertension are essential in evaluating a patient with hypertension at outpatient clinic. Those criteria are based on Hypertension Treatment Guidelines 2000 published by Japanese Society of Hypertension last year. Next I described the outline of treatment of hypertensive patients according to the above guidelines. The guidelines is our interpretation of the world literature and of current opinions together with our largely documented experience based on the management of many hypertensive patients in Japan. The first-line antihypertensive drugs are long-acting Ca antagonists, ACE inhibitors, angiotensin II receptor antagonists, diuretics, beta-blockers and alpha-blockers.

Angiotensin II (Ang II) and apoptosis contribute significantly to myocardial ischemia-reperfusion (I-R) injury. Evidence indicates that Ang II may activate apoptosis in myocytes. The present study was undertaken to investigate the effects of angiotensin receptor blockers (ARBs), candesartan, on the apoptosis of cardiac myocytes in rats after I-R. Rats were divided into a control group, a candesartan group I (0.015 mg/kg), and a candesartan group II (0.03 mg/kg). Candesartan was intravenously administered 30 min before ischemia. All rats were subjected to 30 min of coronary occlusion followed by 3 h of reperfusion. The data showed that left ventricular (LV) systolic pressure and LV +dp/dt was decreased after administration of candesartan, but increased after reperfusion in the candesartan group II, compared with those in the candesartan group I and control group. LV -dp/dt was decreased after candesartan administration in candesartan group II. The number of apoptotic cells in the candesartan groups (497+/-204 and 543+/-254, respectively) was higher than that in the control group (287+/-166; p<0.05). There was no significant difference in infarct size among the three groups. However, plasma CPK was lower in the candesartan groups than in the control group. Northern blot analysis showed that p53 mRNA was upregulated in the candesartan groups, in association with increased expression of bax mRNA. Immunohistochemical analysis showed that p53 and bax immunoreactivity were increased in both of the candesartan groups. In conclusion, candesartan increased apoptosis in the rat hearts after acute I-R, and this increase was possibly mediated by upregulation of p53 and bax gene expressions. In addition, candesartan was shown to improve LV function, in association with reduction of CPK release.

A 27-year-old woman with atrial septal defect (ASD) and a sensation of squeezing in the anterior chest by effort was admitted to our hospital. In addition to the ASD, the coronary angiogram showed an abnormal anomalous position of the right coronary artery. Exercise thallium (Tl)-201 cardiac scintigram with an electrocardiogram clearly detected myocardial ischemia in the inferior area. In the operative findings, the orifice of the right coronary artery was positioned high above the commissure between the right and left sinuses of Valsalva, and it ran between the aorta and pulmonary trunk. Considering myocardial ischemia possibly caused by the anomalous origin of the right coronary artery, a coronary artery bypass graft (CABG) was simultaneously performed to the right coronary artery with direct closure of ASD. The myocardial ischemic finding in the inferior area disappeared after the operation, and she was also relieved from the chest pain. In view of these findings, we suggest that an active combination treatment such as CABG and ASD closure is highly successful in a patient with a threatening coronary anomaly and congenital heart disease.

CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-alpha, and platelet-derived growth factor-alpha receptor (PDGFalphaR). Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs). In the present study, we clarified a functional relationship between C/EBPs and PPARgamma in the regulation of IL-1beta-induced PDGFalphaR expression in VSMCs. PPARgamma activators, troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), inhibited IL-1beta-induced PDGFalphaR expression and suppressed PDGF-induced proliferation activity of VSMCs. Electromobility shift and supershift assays for a C/EBP motif in the PDGFalphaR promoter region revealed that PPARgamma activators suppressed IL-1beta-induced DNA binding activity of C/EBPdelta and beta. PPARgamma activators also suppressed IL-1beta-induced C/EBPdelta expression. In contrast, overexpression of C/EBPdelta reversed the suppressive effect of PPARgamma activators on PDGFalphaR expression almost completely. From these results, we conclude that the inhibitory effect of PPARgamma activators on PDGFalphaR expression is mainly mediated by C/EBPdelta suppression. Regulation of C/EBPdelta by PPARgamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.

GADD153 (growth arrest- and DNA damage-inducible gene 153) is expressed at very low levels in growing cells, but is markedly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to genotoxic agents and other growth-arresting situations. Forced expression of GADD153 induces cell cycle arrest in many types of cells. It is also reported that GADD153 is directly associated with apoptosis. Recently we have reported that platelet-derived growth factor (PDGF)-BB induces apoptosis in cultured vascular smooth muscle cells (VSMC), but only when 100% confluency is reached. These results suggested that cell-cell contact inhibition (cell growth arrest) may be a critical factor for induction of VSMC apoptosis by PDGF-BB. In the present study, we explored the role of GADD153, one of a number of growth-arrest-related gene products, in the molecular mechanisms of VSMC apoptosis in vitro and in vivo. GADD153 was markedly induced at both the mRNA and protein levels, in parallel with the induction of VSMC apoptosis, after treatment with PDGF-BB. Moreover, overexpression of GADD153 in VSMC significantly reduced cell viability and induced apoptosis. In the carotid artery balloon injury model in rats, GADD153 protein was expressed in apoptotic VSMC which were positively stained by in situ DNA labelling. These results demonstrate an important role for GADD153 in the molecular mechanisms of VSMC apoptosis.

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.

A 65-year-old Japanese woman with dilated cardiomyopathy, hypothyroidism and refractory sustained ventricular tachycardia experienced a near-death hypoglycemic syncope. The attack seemed to be induced by a high level of serum insulin, probably due to cibenzoline and by concomitant use of an angiotensin converting enzyme inhibitor (ACEI). Additionally, decreased food intake because of a severe toothache may have contributed to the deterioration of her condition. This case warns cardiologists that a combined cibenzoline and ACEI therapy can provoke serious adverse effects such as hypoglycemic syncope in the elderly. Therefore, the possibility of a hypoglycemic attack associated with these drugs should be explained to patients who are in poor condition.