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A 77-year-old man who underwent radiotherapy for hepatocellular carcinoma 6 months prior consulted for esophageal obstruction. Esophagogastroduodenoscopy revealed an esophageal ulcer caused by radiotherapy for hepatocellular carcinoma. He was treated with dietary counseling and vonoprazan. After 9 months, the ulcer improved but a moderate stenosis remained. Several factors such as high fraction size, history of chemotherapy, and stress associated with food intake might involve in the development of a radiation-associated ulcer. Opportunities to choose radiotherapy for hepatocellular carcinoma may increase, so we hypothesize that esophageal ulcers might be a complication that should be noted associated with this therapy.

Background: Endoscopic ultrasonography (EUS) is one of the helpful tools to diagnose depth of early gastric cancer (EGC). In this study, we examined efficiencies of EUS for EGC such as overall accuracy, risk factors of over/under-staging, and accuracies of each invasive distance. Methods: A total of 403 EGC lesions that could be investigated by EUS during pre-operation and histological diagnosis after endoscopic submucosal dissection (ESD) or surgery were enrolled in this study. For the 403 cases, we analyzed the accuracies of depth by conventional endoscopy (CE) and EUS retrospectively. We evaluated the clinical survey items of CE and EUS which will be described later to compare the differences between “accuracy group” and “over-staging group”, and between “accuracy group” and “under-staging group”, retrospectively. Additionally, 78 EGC lesions which were confined to the submucosa and for which it was possible to measure accurate invasive distance from the muscularis mucosae were examined for the relationship between preoperative diagnosis of depth by CE and EUS and invasive distance retrospectively. Results: The overall accuracies of both CE and EUS in predicting EGC invasion depth were 87.3%. For CE staging, histological classification was the factor which influenced over-staging. Gastric regions and tumor area were the factors which influenced under-staging of CE. For EUS staging, tumor area was the factor which influenced over-staging, and gastric regions were the factors which influenced under-staging. Both CE and EUS were not sufficient for predicting the lesions confined to < 500 µm from the muscularis mucosae because the accuracies of both in predicting depth were less than 50%. However, EUS has a higher accuracy than CE for the lesions confined to 500 - 2,000 µm. Conclusions: The overall accuracies of both CE and EUS in predicting EGC invasion depth were equal, but the contributing factors for over/under-staging were different. Both CE and EUS are not sufficient at present to predict the lesions confined to < 500 µm from the muscularis mucosae. However, the accuracy of EUS in predicting them may increase if high-performance EUS systems are developed in the future. J Clin Med Res. 2021;13(4):222-229 doi: https://doi.org/10.14740/jocmr4465

Background: Esophagogastroduodenoscopy (EGD) with iodine stain is a useful and diffused method for diagnosing esophageal cancer. We can perform the procedure easily with endoscopic system which does not comprise image-enhanced endoscopy. Several studies advocated that iodine-unstained streaks are a characteristic finding of gastroesophageal reflux disease (GERD). However, there are only a few reports about the subject. In this study, we investigated the usefulness of iodine chromoendoscopy for GERD consultation. Methods: The study was conducted with 154 GERD cases in which EGD with iodine stain to the esophagus was performed. For the 154 cases, we analyzed the existence of reflux esophagitis finding and iodine-unstained streaks. In 47 GERD cases (proton pump inhibitor (PPI): 45 cases, histamine H2-receptor antagonist (H2-RA): two cases) where medication was started after EGD, we examined predictive factors of the symptom improvement such as sex, age, weight, reflux esophagitis finding, and iodine-unstained streak. Results: An iodine-unstained streak was observed in 50/154 cases (32.5%). For 50 cases with iodine-unstained streak, there were only 24/50 cases (48.0%) that had both reflux esophagitis findings (? Los Angeles classification: grade M) and an iodine-unstained streak. For 47 cases in which medication was started, 34 cases showed improvement in their symptoms, and 13 cases did not show improvement. An iodine-unstained streak was observed more often in “Improved” group rather than in “Not improved” group (P < 0.01). When we supposed an iodine-unstained streak to be the predictive factor of the medication effect for GERD, sensitivity was 61.8% and specificity was 84.6%. Conclusions: No erosion was often found in the GERD cases without reflux esophagitis, and iodine-unstained streak was observed more often in “Improved” group rather than in “Not improved” group. We think that iodine-unstained streak can be useful for diagnosing of GERD and predictive factor of the medication effect. J Clin Med Res. 2020;12(11):699-704 doi: https://doi.org/10.14740/jocmr4331

Background We have reported that hypertension on admission in elderly patients with acute cerebral infarction is an independent predictor for the development of acute pneumonia. However, the relationship between blood pressure on admission owing to cerebral hemorrhage and the development of pneumonia has not been fully investigated. In this study, we evaluated the relationship between blood pressure levels on admission and the development of pneumonia in elderly patients with cerebral hemorrhage who were in the acute phase. Methods Subjects consisted of 117 elderly patients with cerebral hemorrhage who were in the acute phase and were emergently admitted to the Department of Geriatric Medicine, Kanazawa Medical University between 2005 and 2015 (59 males and 58 females, the mean age ± standard deviation (SD) of 80 ± 8 years, and the range of 65 - 98 years). Blood pressure levels on admission were classified into the following four groups: normal blood pressure/mild hypertension group (systolic blood pressure of < 160 mm Hg and diastolic blood pressure of < 100 mm Hg), moderate hypertension group (systolic hypertension of 160 - 179 mm Hg or diastolic blood pressure of 100 - 109 mm Hg), severe hypertension group (systolic hypertension of 180 - 199 mm Hg or diastolic blood pressure of 110 - 119 mmHg), and serious hypertension group (systolic blood pressure of ≥ 200 mm Hg or diastolic blood pressure of ≥ 120 mm Hg). Between the two groups (group of patients with acute pneumonia and group of those with absence of pneumonia), age, sex, body mass index (BMI), history of stroke, history of heart disease, chronic kidney disease, diabetes, dyslipidemia, prehypertension, blood pressure on admission, Japan Coma Scale (JCS) on admission, white blood cell count, C-reactive protein (CRP), albumin, bleeding sites, bleeding amount, and the presence or absence of centerline shift on brain computed tomography (CT) images were retrospectively evaluated. Furthermore, factors related to cerebral hemorrhage in the development of acute pneumonia in patients with cerebral hemorrhage were verified. Results Of the 117 patients, 30 (25.6%) had acute pneumonia. Age, sex, bleeding amount, midline shift, blood pressure classification on admission, JCS, white blood cell count, CRP, albumin, diabetes were adopted as confounding factors in the development of acute pneumonia. Results of multiple logistic regression analysis showed significant differences between these two groups in the following four items: CRP, white blood cell count, JCS, and blood pressure classification on admission. After adjustment of these confounding factors, the incidence of acute pneumonia in the blood pressure groups other than serious hypertension group was set as 1, and the odds ratio of pneumonia onset in serious hypertension group was revealed to be 5.54, with the 95% confidence interval of 1.49 - 20.6. Conclusions We found that serious hypertension on admission is a risk factor for the development of acute pneumonia in elderly patients with cerebral hemorrhage who are in the acute phase.

Background: We have reported that hypertension on admission in elderly patients with acute cerebral infarction is an independent predictor for the development of acute pneumonia. However, the relationship between blood pressure on admission owing to cerebral hemorrhage and the development of pneumonia has not been fully investigated. In this study, we evaluated the relationship between blood pressure levels on admission and the development of pneumonia in elderly patients with cerebral hemorrhage who were in the acute phase. Methods: Subjects consisted of 117 elderly patients with cerebral hemorrhage who were in the acute phase and were emergently admitted to the Department of Geriatric Medicine, Kanazawa Medical University between 2005 and 2015 (59 males and 58 females, the mean age ± standard deviation (SD) of 80 ± 8 years, and the range of 65 - 98 years). Blood pressure levels on admission were classified into the following four groups: normal blood pressure/mild hypertension group (systolic blood pressure of < 160 mm Hg and diastolic blood pressure of < 100 mm Hg), moderate hypertension group (systolic hypertension of 160 - 179 mm Hg or diastolic blood pressure of 100 - 109 mm Hg), severe hypertension group (systolic hypertension of 180 - 199 mm Hg or diastolic blood pressure of 110 - 119 mmHg), and serious hypertension group (systolic blood pressure of ? 200 mm Hg or diastolic blood pressure of ? 120 mm Hg). Between the two groups (group of patients with acute pneumonia and group of those with absence of pneumonia), age, sex, body mass index (BMI), history of stroke, history of heart disease, chronic kidney disease, diabetes, dyslipidemia, prehypertension, blood pressure on admission, Japan Coma Scale (JCS) on admission, white blood cell count, C-reactive protein (CRP), albumin, bleeding sites, bleeding amount, and the presence or absence of centerline shift on brain computed tomography (CT) images were retrospectively evaluated. Furthermore, factors related to cerebral hemorrhage in the development of acute pneumonia in patients with cerebral hemorrhage were verified. Results: Of the 117 patients, 30 (25.6%) had acute pneumonia. Age, sex, bleeding amount, midline shift, blood pressure classification on admission, JCS, white blood cell count, CRP, albumin, diabetes were adopted as confounding factors in the development of acute pneumonia. Results of multiple logistic regression analysis showed significant differences between these two groups in the following four items: CRP, white blood cell count, JCS, and blood pressure classification on admission. After adjustment of these confounding factors, the incidence of acute pneumonia in the blood pressure groups other than serious hypertension group was set as 1, and the odds ratio of pneumonia onset in serious hypertension group was revealed to be 5.54, with the 95% confidence interval of 1.49 - 20.6. Conclusions: We found that serious hypertension on admission is a risk factor for the development of acute pneumonia in elderly patients with cerebral hemorrhage who are in the acute phase. J Clin Med Res. 2020;12(11):693-698 doi: https://doi.org/10.14740/jocmr4330

Pneumonia is one of the most frequent complications in elderly patients with acute ischemic stroke. Although severe hypertension is often observed in the early phase of acute stroke, there are few studies of acute hypertension as a factor influencing the incidence of stroke-associated pneumonia (SAP) in elderly subjects with acute ischemic stroke. To assess the association of acute phase blood-pressure elevation with the incidence of SAP, we compared 10 elderly patients with acute ischemic stroke complicated with severe hypertension (⩾200/120 mm Hg) with 43 patients with moderate hypertension (160–199/100–119 mm Hg), as well as with 65 control normotensive or mildly hypertensive (

Objective: Cerebral hemorrhage is frequent condition in the elderly, and acute complications such as pneumonia increases the risk of mortality rate. However, there are few studies about the association with blood pressure on admission. We studied the association between the incidence of pneumonia and blood pressure on admission.

Goal of this study was to evaluate effects of Mao-to on development of myocarditis induced by encephalomyocarditis (EMC) virus in mice. Mice were randomly divided into five groups. Group N included uninfected controls (n= 18), while group A, B and C underwent intraperitoneal injection of EMC virus. Group A was administered oral saline from day 0 to day 4. Group B was administered oral Mao-to (500 mg−1kg−1day−1) from day 0 to day 4. Group C was administered Mao-to from day 2 to day 6. Group D was administered Mao-to from day 5 to day 10. Treated mice were followed for survival rates during 2 weeks after infection. Body weight (BW) and organ weights including heart (HW), lungs, thymus and spleen were examined on days 4, 6 and 14. Survival rate of group C (36.4%) was significantly improved compared with group A, B or D (0% of each,P< 0.05). HW and HW/BW ratio in group C was significantly (P< 0.05) lower than those in group A, B or D. Viral titers of hearts were significantly different among groups A, B and C. Cardiac expression in tumor necrosis factor-α (TNF-α) was significantly reduced in group C in comparison with group A, B or D on day 6 by immunohistochemical study. Administration of Mao-to starting on day 2 improves mortality resulting from viral myocarditis in mice with reduced expression of cardiac TNF-α. These findings suggest that timing of Mao-to is crucial for preventing cardiac damage in mice with viral myocarditis.

To clarify the mechanism of the effects of angiotensin II receptor type 1 antagonist, candesartan, upon cardiac adiponectin in the combination of myocarditis with obesity, we examined obese KKAy mice with acute viral myocarditis treated by candesartan and investigated cardiac adiponectin regulation.Mice were divided into candesartan early treatment group (Can-early) receiving orally candesartan at daily dose of 10 mg/kg 7 days starting before viral inoculation and then 7 days; candesartan late treatment group (Can-late) or vehicle (Vehicle) receiving candesartan starting simultaneously with viral inoculation and then 7 days. Encephalomyocarditis virus was used to induce the acute viral myocarditis. Differences in myocardial damages, serum adiponectin and myocardial expression of adiponectin, tumor necrosis factor-alpha (TNF-alpha), CCAAT/enhancer binding proteinalpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPAR-gamma) and nuclear factor-kappaB (NF-kappaB) mRNA among three groups were determined on days 0, 4 and 7 after viral inoculation.Mice in Can-early and Can-late groups showed reduced myocardial necrosis and cellular infiltration as compared with those in the Vehicle. On day 4 the circulating adiponectin levels were significantly higher in Can-early than those in Vehicle. Mice in Vehicle had significantly reduced in myocardial adiponectin mRNA after viral myocarditis. Cardiac adiponectin mRNA was significantly higher in Can-early and in Can-late than in Vehicle on days 4 and 7. Cardiac C/EBPalpha in Can-early and Can-early groups was significantly increased on day 4. Myocardial NF-kappaB and TNF-alpha mRNA in Can-early and Can-late groups were significantly reduced on day 7.Candesartan treatment improved myocardial injury in obese mice with acute viral myocarditis and induced expression of cardiac adiponectin with the induction of C/EBPalpha as well as the reduction of cardiac NF-kappaB and TNF-alpha.

We investigated role of beta-endorphin (END), which is released by immobilization stress, on intimal fibromuscular proliferation in a rat model of arterial remodeling after intimal injury. The endothelium of the abdominal aorta of Wistar-Kyoto rats was denuded, and the rats were subjected to immobilization stress (6 h/d), which raised the serum concentration of END, and intraperitoneal administration of either END (20 ng/kg/d) or naltrexone (NAL: 4 mg/kg/d). The proliferative activity (PA) of medial smooth muscle cells (SMCs) and the intima/media area ratio (R) were determined at 3 and 14 d after denudation, respectively. PA and R were significantly reduced by immobilization (PA: 64.8%, R: 34.6%), and NAL treatment completely reversed the decreases in PA and R. On the other hand, END reduced both PA and R (PA: 21.7% and R: 24.9%), and NAL also reversed the decreases in PA and R. END (20 pg/mL) inhibited both the proliferation (79% at 96 h) and migration (26%) of SMCs cultured with 5% fetal bovine serum in vitro, and NAL (100 microg/mL) reversed the inhibition of both activities. Our results suggest that immobilization stress stimulates the release of endogenous END, which then prevents both proliferation and migration of medial SMCs after intimal injury.

Endothelial function in elderly hypertensive patients with arteriosclerosis obliterans has not been evaluated. We examined whether antihypertensive drugs improve vasodilatory response to reactive hyperemia of the limbs in elderly hypertensive patients (83 +/- 8 [SD] years) without (n=46, 0.9 < or = ankle-brachial pressure index < or = 1.4) and with (n=24) arteriosclerosis obliterans (ankle-brachial pressure index < 0.2). Patients were randomized for treatment with monotherapy of either temocapril (14 with and 26 without arteriosclerosis obliterans) or amlodipine (10 with and 20 without arteriosclerosis obliterans) for 6 months. Blood flows of the forearms and legs were measured by strain-gauge plethysmography. The vasodilatory response to the release of compression of the forearms and thighs at 200 mmHg or 20 mmHg more than systolic blood pressure for 5 min and to sublingual administration of nitroglycerin (0.3 mg) was assessed. The maximum reactive hyperemic flow in 35 legs with arteriosclerosis obliterans was significantly (p < 0.001) decreased compared to the value in legs in the control hypertensive subjects. Moreover, maximum reactive hyperemic flow in the forearms of patients with arteriosclerosis obliterans was significantly (p = 0.002) decreased compared to that in the control subjects. Blood pressure was similarly decreased by treatment with temocapril or amlodipine. Response to nitroglycerin (0.3 mg) was not changed by either drug. Treatment with temocapril significantly improved maximum reactive hyperemic flow of not only the legs and forearms in control hypertensives but also the legs and forearms in patients with arteriosclerosis obliterans, and attenuated the worsening of activity of daily living in these patients, although treatment with amlodipine did not. These results suggest that the angiotensin-converting enzyme inhibitor temocapril has a beneficial effect on endothelial function in elderly patients with arteriosclerosis obliterans.

Introduction: Nucleostemin (NS) and nucleophosmin (NPM) are the nucleolar proteins which not only regulate the proliferation of stem cells, but also protect myocardial cells from oxidative stress. Hypothesis: We hypothesize that NS and NPM regulate the proliferation of the arterial smooth muscle cell (SMC) and contribute to their survival in the process of arteriosclerosis. This study investigated for the first time the expression pattern of them and consider their roles in arteriosclerosis. Methods and Results: Immunohistochemical examination revealed the expression of NS and NPM in the nuclei of SMCs and endothelial cells (ECs) both in the media and the intima of the human autopsy coronary arteries and the aorta of the apo E-deficient mice. Immunoreactivity was especially strong in the SMCs and ECs constructing the fibrous cap covering the plaques. The immunoreactivity of telomere reverse transcriptase (TERT) was at once observed in these NS- and NPM-positive nuclei, indicating of the strong proliferating activities. In the fibro-muscular proliferating intima after denudation of the endothelium of rat abdominal aorta confirmed the same localization of NS and NPM with TERT. In order to investigate the roles of NS in the SMC, mRNA of NS was knocked down with siRNA in cultured human arterial SMC. The 47S ribosomal RNA reduced to 35%, without reducing 18S ribosomal RNA (real-time PCR), indicating the promoting effect of NS on the pre-ribosomal RNA processing necessary for total protein synthesis. Knocking down of NS mRNA also reduced the expression of TERT to 65% and on the contrary up-regulated p21 mRNA to 150%, indicating anti-senescence activity of NS. Subculture of human SMCs ultimately to the replicative senescence gradually reduced the number of NS positive nucleoli from four to only one per cell, maybe reflecting the reduced activity of NS in the senescence process. Conclusion: These results indicate that NS and NPM promote the proliferation of arterial SMCs and ECs in the arteriosclerotic lesions, collaborating with TERT.

This study was conducted to assess the effects of antiatherosclerotic treatment with eicosapentaenoic acid (EPA) on the hemodynamics and physical properties of the common carotid artery in elderly patients with atherosclerosis. EPA, found in high levels in fish oil, is an omega-3 polyunsaturated fatty acid that has a variety of pharmacologic effects, including antiplatelet, arterial elasticity-maintaining, and hypolipidemic. EPA has proved to be useful in treating arteriosclerosis obliterans. A total of 18 patients (mean age, 76.2 ± 5.7 years) with atherosclerosis underwent complete Doppler ultrasonic examination of the common carotid artery before and after 16 weeks of treatment with EPA (900 mg or 1800 mg daily). The presence of atherosclerosis was determined by clinical findings, especially according to physical properties of the common carotid artery derived by ultrasound examination. The minimal diameter of the common carotid artery at minimal blood pressure decreased significantly from 7.64 ± 0.93 mm to 7.21 ± 0.97 mm ( P 5 dyne/cm 2 to 8.95 ± 2.78 × 10 5 dyne/cm 2 and from 6.44 ± 2.79 to 5.41 ± 1.79, respectively; P

The care of the aged population living at home is an urgent issue in the developed countries. It is important to investigate the factors in relation to the level of activities of daily life (ADL). It is also important to investigate the death situation in order to protect this population from accidental death. This study was undertaken to investigate whether the pathological change of the brain was one of the decisive factors of ADL and accidental death. Detailed information of ADL was obtained from the family and neighbors of 40 cases that were autopsied medicolegally at the medical examiner office of Osaka prefecture. The information regarding death situation was obtained from the coroner's documents. In each autopsied brain, senile plaques, neurofibrillary tangle (NFT), arteriosclerosis and ischemic changes of the brain were examined. Correlation between the neuropathological change, ADL and the death situation was statistically investigated. The severity and expansion of NFT, which was categorized as Braak's stage, showed significant correlation with ADL. Senile plaques and vascular change showed no significant correlation. Cases that had developed to Braak's isocortical stage showed a tendency to die in the bathroom or toilet. The NFT pathology of the limbic system has been shown to correlate with ADL. The damage of the limbic system might have an influence on the cognitive and behavior function of the brain and may lead to the reduced ADL. In addition, the NFT pathology may be a factor for the autonomic dysfunction and circulatory disorder. Therefore, the NFT pathology is considered to play a role in death during defecation and bathing.

Venous thrombosis is a relatively usual but serious complication of permanent transve nous pacing. However, the pathogenesis has not been defined. To clarify underlying abnormalities in the coagulation-fibrinolysis system in patients with permanent trans venous pacemakers, we measured serum levels of fibrinopeptide A (FPA), thrombin-antithrombin III complexes (TATs), plasmin-α2 plasmin inhibitor complexes (PICs), D-dimer (D-D), β-thromboglobulin (β-TG), and platelet factor 4 (PF4) in 53 patients with permanent transvenous pacemakers and 10 control subjects. The patients were divided into two groups, as follows, according to the presence of mural thrombus documented along the pacing lead(s) by digital subtraction angiography and trans esophageal echocardiography: Group Th (-), patients without venous route thrombus; and Group Th (+), patients with venous route thrombus. FPA and TAT levels increased significantly even in Group Th (-), and further increased in Group Th (+) compared with control subjects (FPA: 7.5 ±4.9, 15.3 ±8.8 vs 3.0 ±1.4 ng/mL, respectively, P

A reduction of elevated blood pressure (BP) is an important treatment goal in elderly hypertensive patients. However, excessive reduction of systolic BP (SBP) and/or diastolic BP (DBP) might be harmful in such patients. We investigated whether this was the case with regard to risk of incident disability or death in community-dwelling elderly subjects. We analyzed 570 patients receiving antihypertensive treatment aged 65-94 years. The endpoint was the composite outcome of incident disability, defined as first certification of a support/care need or death. Relationships among each of the four classes of SBP or DBP and the risk of incident disability or death were estimated using the Cox proportional hazards model. Over four years, 77 (13.5%) incident disabilities or deaths occurred. After adjustment for age, sex and variables selected according to their univariate analysis P-value0.20, the risk of events was significantly higher in subjects with baseline SBP120 mm Hg (hazard ratio (HR)=2.81, P=0.023) and ⩾160 mm Hg (HR=4.32, P0.001), compared with subjects with baseline SBP of 140-159 mm Hg, who showed the lowest incidence of events. This J-curve relationship was observed in very elderly patients (⩾75 years) but not in younger patients. Patients with SBP120 mm Hg tended to have a higher risk of incident disability caused by cerebral events, and those with SBP⩾160 mm Hg had a higher risk of incident disability caused by falls/bone fractures. These observations indicate that excessive BP reduction could cause discontinuance of disability-free survival in community-dwelling elderly patients.

To clarify the possible association of frailty with hypertension prevalence, treatment and blood pressure (BP) control in the elderly, we conducted a screening survey of 1091 elderly community-dwelling subjects aged ≥65 years, using data from public health check-ups and frailty was determined by a 25-item questionnaire, the Basic Checklist for Frailty (BCF). The significance of differences in the association of BCF categories or BCF items with each hypertension status was analyzed using multiple logistic regression analysis after adjusting for age, sex and possible confounding underlying chronic conditions. A total of 63% of subjects were hypertensive (BP≥140/90 mm Hg), and of those, 85% were receiving antihypertensive treatment, and 56.0% of those receiving treatment had controlled BP (

Recent studies have confirmed that PPARalpha agonists have not brought the anticipated benefits to patients with type 2 diabetes and potentially fatal heart disease. We hypothesized that such agonists may have a cardio-suppressive effect in treating such disorders, therefore, we inoculated diabetic KKAy mice with encephalomyocarditis virus (EMCv) to induce a diabetic model with severe myocardial damage. WY14643, a potent PPARalpha agonist, was administered intraperitoneally either simultaneously (WY14643-late group) or 3 days before viral inoculation (WY14643-early group). WY14643-treated mice, especially those in the WY14643-early group, had higher mortality than those in the vehicle-treated group (vehicle) in the first 5 days after EMCv inoculation. However, the survival rate in the vehicle group decreased rapidly after day 4 and was the lowest of all 3 groups by day 9. The WY14643-treated mice showed reduced body weight and blood glucose, improved myocardial pathological changes, lower cardiac TNF-alpha expression, and significantly higher adiponectin expression, whereas the LW/LC ratio was lower and cardiac UCP3 mRNA expression higher in the WY14643 treatment groups than in the vehicle group on day 4. WY14643 therefore has cardioprotective and cardio-suppressive effects when used to treat EMCv-induced myocarditis in diabetic mice. The cardioprotective effect may be due to its anti-inflammatory properties and its ability to increase cardiac adiponectin expression, whereas the reduced cardiac efficiency may be due to its enhancement of cardiac UCP3 mRNA expression.

To test the hypothesis that 5'-nucleotidase activity during ischemia is attenuated by oxygen-derived free radicals, we measured ischemia-induced reactive hyperemic flow, adenosine release, and 5'-nucleotidase activity in dogs (n = 62). A 1-minute occlusion of the coronary artery caused reactive hyperemic flow (307 +/- 5 versus 92 +/- 1 ml.100 g-1.min-1 at baseline) with increased release of adenosine (14.4 +/- 1.4 versus 0.4 +/- 0.1 nmol.100 g-1.min-1 at baseline). Superoxide dismutase augmented (p less than 0.001) both peak coronary blood flow (333 +/- 6 ml.100 g-1.min-1) and repayment (436 +/- 12 versus 320 +/- 7 ml/100 g in the untreated group). Adenosine release during reperfusion was augmented (22.7 +/- 1.9 nmol.100 g-1.min-1, p less than 0.001), and 8-phenyltheophylline completely abolished the enhanced reactive hyperemia. Enzymatic assay of 5'-nucleotidase activity revealed that the administration of superoxide dismutase increases ecto-5'-nucleotidase activity in ischemic myocardium. When an inhibitor of ecto-5'-nucleotidase, alpha, beta-methyleneadenosine 5'-diphosphate, was administered, the effects of superoxide dismutase were completely abolished. Thus, we conclude that 1) the augmentation of reactive hyperemic flow caused by superoxide dismutase is attributed to the enhanced release of adenosine and 2) the enhanced release of adenosine over the untreated controls is attributed to the protection of ecto-5'-nucleotidase activity during ischemia.

Sympathetic activations may deteriorate myocardial failure due to progression of myocardial cell injury. In the present study, to test whether microtubules, calcium ion (Ca2+) sensitive cytoskeletons, are disrupted by norepinephrine (NE) and whether beta-adrenoceptor antagonist could attenuate the disruption of microtubules, structures of microtubules are studied in rat hearts with continuous subcutaneous infusions of norepinephrine. In the sham operated rats the microtubules stained by immunohistochemical technique showed normal network structures. A low dose of NE infusion (2 micrograms/kg/h) for 6 h resulted in a minimal change in microtubule structures. However, infusion for 24 h of NE (2 micrograms/kg/h) and a large dose of NE infusion (20 micrograms/kg/h) for 6h caused disruptions of microtubules in small patchy lesions (8 +/- 3%, 12 +/- 4% of area, respectively). A large dose of NE infusion for 24 h increased systolic blood pressure from 116 +/- 6 to 152 +/- 4 mmHg and increased plasma NE concentration from 430 +/- 40 to 17100 +/- 3700 pg/ml and further disrupted the network of microtubules in 40 +/- 6% of the total area. Propranolol (500 micrograms/kg/h) markedly attenuated NE-induced disruptions of microtubules. Disruptions of microtubules may be one of the underlying mechanism of deterioration of myocardial failure in chronic heart failure in which sympathetic activity is markedly activated.

Sirtuin 1 (SIRT1), a member of the silent information regulator 2 in mammals, has recently been found to be involved in age-related diseases, such as cancer, metabolic diseases, cardiovascular disease, neurodegenerative diseases, osteoporosis and chronic obstructive pulmonary disease (COPD), mainly through deacetylation of substrates such as p53, forkhead box class O, peroxisome proliferator activated receptor gamma co-activator 1alpha, and nuclear factor-kappaB. It is widely reported that SIRT1 can promote not only carcinogenesis but also metastasis and insulin resistance, andhave beneficial effects in metabolic diseases, mediate high-density lipoprotein synthesis and regulate endothelial nitric oxide to protect against cardiovascular disease, have a cardioprotective role in heart failure, protect against neurodegenerative pathological changes, promote osteoblast differentiation, and also play a pivotal role as an anti-inflammatory mediator in COPD. However, there are controversial results suggesting that SIRT1 has an effect in protecting against DNA damage and accumulation of mutations, and preventing tumorigenesis. In addition, a high level of SIRT1 can induce cardiomyopathy and even heart failure. This article reviews recent developments relating to these issues.

BACKGROUND Oxygen-derived free radicals are thought to injure the ischemic heart during coronary microvascular embolization. METHODS AND RESULTS To test this idea, microspheres (15 microns in diameter) were repetitively administered into the left anterior descending coronary artery to cause microvascular embolization in dogs. Myocardial contractile and metabolic dysfunctions were significantly attenuated after treatments with recombinant human superoxide dismutase, an acyl derivative of ascorbic acid (CV3611, 2-O-octadecylascorbic acid), and xanthine oxidase inhibitor (allopurinol). The free radical scavengers and inhibitor enhanced the coronary hyperemic flow response during embolization, and the total number of microspheres causing maximal embolization was increased by these drugs. When 8-phenyltheophylline was additionally administered with superoxide dismutase, these beneficial effects were abolished, indicating that coronary effects of these drugs may be due to increased release of adenosine during coronary microvascular embolization. CONCLUSIONS We conclude that oxygen radicals worsen the ischemic injury in coronary microembolization.

We investigated serial changes in myocardial norepinephrine content and myocardial adrenergic receptors during the development of cardiomyopathy in Syrian hamsters (Bio 14.6) and their age-matched healthy controls. We also examined phosphatidylinositide hydrolysis after alpha 1-adrenergic stimulation and the effects of alpha 1-blockade. We found that in the prehypertrophic stage, myocardial norepinephrine content and densities of alpha 1- and beta-adrenergic receptors were significantly higher in the cardiomyopathic hamsters than in the controls. However, in the early heart failure stage, beta-receptor density was 28% lower than that of the age-matched controls, although alpha 1-receptor density remained 55% higher. Norepinephrine-stimulated phosphatidylinositide hydrolysis in the cardiomyopathic hamster in the hypertrophic stage was twice that in the controls, indicating that the increase in alpha 1-adrenergic receptors is coupled with the intracellular signal transduction. Furthermore, selective alpha 1-adrenoceptor blockade by bunazosin in the cardiomyopathic hamsters from 70 to 170 days of age reduced myocardial hypertrophy and focal myocardial necrosis. Thus we conclude that increased alpha 1-adrenergic activity plays an important role in progression of cardiac hypertrophy is cardiomyopathic Syrian hamsters.

Structural disruption of the cytoskeleton may be involved in irreversible ischemic injury. In the present study, ischemic changes in microtubules during various periods of myocardial ischemia were studied with an immunohistochemical technique in open-chest dogs. In intact myocardium, microtubules were stained as a filamentous network throughout cytoplasm and a circular network around the nucleus, which disappeared with colchicine treatment. In brief ischemia of less than 15 minutes, microtubule patterns were unaltered. After 20 minutes, however, characteristic microtubule stains were partly lost in patchy lesions. As an increase in ischemic period, lesions of loss of microtubule stains were increased in number and size. After 120 minutes of reperfusion following 60 minutes of ischemia, the lesions with intact actin filaments but with disrupted microtubules were replaced by the severely injured cells in which the regular myofibrillar registrations were distinctly disrupted. After 24 hours of reperfusion following 40 minutes of occlusion of the left circumflex artery, the percent area of disrupted microtubules at 40 minutes of ischemia was replaced by that of irreversibly injured lesions in the posterior papillary muscle. These results indicate that disruption of microtubules during ischemia heralds irreversible ischemic injury. However, in in vitro study, the myocardium incubated in hypoxic solution for 60-120 minutes demonstrated earlier disruption of the microtubules than the vinculin. Electron microscopic study also showed minimal irreversible changes in the lesions with disrupted microtubules. Thus, taken together, we conclude that microtubules that support the structural integration of myofibrils and other organelles are disrupted in severe myocardial ischemia before the irreversible injury, promoting the irreversible change after reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

It is reported that Na+ influx contributes to stretch-induced cardiac hypertrophy. Na+ influx may also be involved in cardiac hypertrophy induced by catecholamine. In the present study, to test whether Na+/H+ exchange plays an important role in norepinephrine-induced cardiac hypertrophy, the effect of Na+/H+ exchange inhibitor, amiloride on protein synthesis was studied in cultured neonatal rat cardiomyocytes in serum free medium. [3H]Phenylalanine uptake was determined 24 and 48 hours after administration of norepinephrine with and without amiloride. In the control, norepinephrine increased [3H]phenylalanine uptake in a dose dependent manner (10(-5)-10(-7) M). Prazosin (10(-7) M) and amiloride (10(-5)-10(-4) M) significantly attenuated the norepinephrine mediated protein synthesis. These results indicate that alpha 1-adrenergic stimulation enhances the protein synthesis through activation of Na+/H+ exchange. Therefore, Na+ influx and/or PH increase may play a key role in cardiac hypertrophy.

Brain-derived neurotrophic factor (BDNF) is associated with the main symptoms of chronic fatigue syndrome (CFS) and neuron apoptosis. Nevertheless, no study has been performed directly to explore the relationship between CFS, BDNF and neuron apoptosis. We induced a CFS model by six injections of killed Brucella abortus antigen in BALB/c mice and treated them with Hochu-ekki-to (TJ-41). Daily running activity, body weight (BW), ratio of cerebral weight to BW (CW/BW) and expression levels of BDNF and Bcl-2 mRNA in the hippocampus were determined. The daily activity and CW/BW decreased significantly in the CFS model. BDNF and Bcl-2 mRNA expression levels in the hippocampus were suppressed in the CFS model and TJ-41 treated mice, while no significant difference was found between them. We improved a murine model to investigate the relationship between CFS and brain dysfunction. In this model, reduced daily activity might have been associated with decreased hippocampal BDNF mRNA expression, hippocampal apoptosis and brain atrophy. TJ-41 increased the daily running activity of the model, which was independent of brain recovery.

We examined the effects of the angiotensin II receptor type 1 blocker candesartan on myocarditis injury in a murine model of acute myocarditis. We hypothesized that candesartan improves cardiac damage by inducing cardiac expression of adiponectin.We examined changes in heart failure caused by myocarditis in mice by candesartan based on induction of cardiac adiponectin expression. We intraperitoneally injected encephalomyocarditis virus in C3H mice, then orally administered candesartan (10 mg/kg/day) or vehicle (control). The 7 day survival rate was 18% in the control group, but 60% in the candesartan group. The heart weight/body weight ratio in the candesartan group was significantly lower than in the control group. Circulating adiponectin concentrations on day 7 were significantly higher in the candesartan group compared with the control group (7.91 +/- 0.61 vs. 6.04 +/- 2.26 microg/ml, P0.05). Comparative expression of cardiac adiponectin mRNA in the candesartan group was significantly higher than in the control group on day 7 (55.4 +/- 41.3 vs. 5.3 +/- 7.7, P0.05). Immunohistochemical staining and in situ hybridization showed that cardiac expression of adiponectin protein and mRNA was present in the candesartan group on day 7.Oral administration of candesartan improves survival and decreases myocardial damage in mice with viral myocarditis and induces expression of cardiac adiponectin. The induction of adiponectin might provide cardioprotective effects against acute heart failure due to viral myocarditis.

A 98-year-old woman was admitted to our hospital complaining of anorexia, epigastralgia, and vomiting. An elastic hard tumor was palpable in her epigastric region. CT and US examination revealed a huge cystic lesion adjacent to the left lobe of the liver and the stomach. Her serum levels of CEA (13.6 ng/ml), CA19-9 (95 U/ml) and CA125 (99 U/ml) were high. She suffered from aspiration pneumonia on the 10th day of admission, which progressed to acute respiratory distress syndrome. On the 20th day of admission, the epigastric tumor suddenly disappeared. She passed away on the 31st day due to respiratory failure. Autopsy revealed that she had a ruptured pancreatic anaplastic mucinous cystadenocarcinoma. To the best of our knowledge, this is the oldest reported case of ruptured pancreatic cystadenocarcinoma in the world.

Obesity is an important risk factor for heart disease. Whether weight loss affects the severity of heart failure induced by viral myocarditis is a matter of debate. We hypothesized that weight loss could improve cardiac dysfunction by inducing cardiac expression of a cardioprotective cytokine, adiponectin. We examined the relationship between weight loss by food restriction and heart failure due to viral myocarditis in obese KKAy mice. We intraperitoneally injected encephalomyocarditis virus (500 plaque-forming units/mouse) into KKAy mice fed ad libitum as a control (CF) or 60% restriction of that eaten by ad libitum (RF). The 14-day survival rate was 0% in FF, whereas it was 23% in RF (P

A mouse model of encephalomyocarditis (EMC) virus-induced myocarditis was used to investigate the expression of adiponectin in damaged cardiomyocytes. We intraperitoneally injected EMC virus into leptin-deficient ob/ob (OB) mice and wild-type (WT) mice. OB mice were divided into two subgroups consisting of mice with no intervention and mice receiving leptin replacement starting simultaneously with viral inoculation. We determined differences in heart weight, cardiac histological score, numbers of infiltrating and apoptotic cells in the myocardium, expression levels of adiponectin and TNF-alpha mRNA in the heart, adiponectin immunoreactivity in myocytes, adiponectin and TNF-alpha concentrations in the heart, and immunoreactivity of adiponectin receptors in myocytes between OB mice and WT mice. There was significantly decreased adiponectin mRNA expression, immunoreactivity, and protein level in the heart, and reduced immunoreactivity of adiponectin receptor 1 in myocytes from OB mice on days 4 and 8 after viral inoculation as compared with those in WT mice, together with increased cardiac weight, severe inflammatory myocardial damage, and increased levels of cardiac TNF-alpha mRNA and protein. Replacement of leptin in OB mice inhibited the development of severe myocarditis through augmentation of adiponectin mRNA, immunoreactivity, and protein level, increased adiponectin receptor 1 immunoreactivity in myocytes, and suppressed levels of TNF-alpha mRNA and protein. These results suggest that impaired expression of cardiac adiponectin may contribute to the progression of viral myocarditis through enhanced expression of TNF-alpha under a leptin-deficient condition.

Many clinical trials have been conducted to prevent cardiovascular complications and reduce mortality in hypertensive patients. Undoubted, but limited effects of beta-blocker and diuretic antihypertensive drugs had been established. Although angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist lowered the incidence of events and mortality less than classical antihypertensive drugs, recent studies revealed that prompt and enough lowering the blood pressure is more important than choosing the types of drugs.

Background We have reported that use of angiotensin I–converting enzyme (ACE) inhibitor, which is a class of antihypertensive agent that induces cough, is an independent factor in reducing risk of pneumonia among elderly inpatients. Insertion/deletion ( I/D ) polymorphism of the ACE gene ( ACE ) has been associated with the risk of pneumonia in elderly individuals. However, the ability of ACE inhibitors to reduce pneumonia-related morbidity in individuals with the ACE polymorphism is unclear. Therefore we determined the association of ACE inhibitor use and ACE genotypes with reduction of pneumonia risk in the Japanese elderly population. Methods We conducted a hospital-based, retrospective, case-control study to evaluate the effect of an ACE inhibitor and ACE polymorphism on incidence of pneumonia. Case subjects were pneumonia patients ( N = 105) ≥65 years of age, during an 8-month period of a nonwinter season. Control subjects ( n = 420) were elderly patients who were frequency matched to the case subjects by age (within ± 2 years) and gender. Data were collected on medication with the ACE inhibitor temocapril and on known risk factors for pneumonia. The significances of differences for the risk factors were analyzed using univariate and multivariate comparisons of the case and control subjects. Results After adjustment for potential confounders by multiple logistic regression analysis, the odds ratio (OR) estimates for pneumonia were 0.458 (95% confidential interval [CI]: 0.230 to 0.909, P = .026) for ACE inhibitor use. Conditional logistic regression analysis according to ACE genotypes revealed significant reduction of pneumonia risk by use of temocapril compared with that in nonhypertensive individuals (ie, the reference group) in those with ACE ID + II (OR: 0. 416, 95% CI: 0.177 to 0.976, P = .044), but not in those with ACE DD (OR: 0.706, 95% CI: 0.198 to 2.518, P = .592). Conclusion These results suggest that use of an ACE inhibitor is beneficial for reducing risk of pneumonia, particularly in individuals with the ACE genotypes ID + II.

A 90-year old man was admitted to a hospital because of consciousness loss with hyponatremia. Although his symptom promptly improved with Na supply, his chest X-ray film showed pulmonary infiltration and direct microscopy of sputum smear was positive for acid-fast bacilli, then he was referred our hospital and was admitted. We made a clinical diagnosis of pulmonary tuberculosis with SIADH based on detailed examinations. But he should neither respiratory symptoms nor fever. He was medicated with the standard antituberculosis drugs with fluid restriction, and his tuberculosis and hyponatremia were improved gradually. We should be more careful about pulmonary tuberculosis irrespective of its severity as a cause of SIADH.