Sustained Myocarditis following Messenger RNA Vaccination against Coronavirus Disease 2019: Relation to Neutralizing Antibody and Amelioration by Low-Dose Booster Vaccination.

We recently reported that sub-acute myocarditis occurred following the initial two doses of messenger RNA-based vaccination against coronavirus disease 2019 (0.3 mL Comirnaty®) in elderly Japanese patients with cardiac dysfunction. The present retrospective study of 76 patients revealed that myocarditis following the initial doses persisted for 12 months, was associated with low levels of neutralizing antibodies, and was ameliorated by reducing the third vaccine dose. Low neutralizing antibody levels (<220 U/mL) after the initial doses were an independent predictor of persistent clinical events, defined as death or marked changes in brain natriuretic peptide levels. When the third dose was reduced (0.1 mL), changes in brain natriuretic peptide levels were significantly smaller (p = 0.02, n = 25), no deaths occurred due to heart failure, and neutralizing antibody levels increased 41-fold (p < 0.001) compared with the initial doses. Reduced booster doses could facilitate the worldwide distribution of messenger RNA vaccines.

A rotating cerium anode X-ray system allows visualization of intramural coronary vessels after cardiac stem cell therapy for myocardial infarction.

Conventional angiography is insufficient for evaluating the therapeutic effect of cardiac regeneration therapy. A microangiographic X-ray system using a cerium anode was developed. Cerium has a characteristic X-ray with a peak at 34.6 keV, which allows visualization of tiny amounts of iodine. The performance of the cerium anode X-ray system was evaluated in two excised normal canine hearts and in excised ischemic canine hearts treated with c-kit-positive cardiac stem cells (5 canines) or without cells (5 control canines). In the normal canines, branches penetrating from the left anterior descending artery into the myocardium were visualized, down to third-order branches. In just the treated hearts treated with stem cells, small vessels characterized by irregular vessel walls were observed. The cerium anode X-ray system allowed visualization of microvessels in excised ischemic canine hearts, and may evaluate the effect of cardiac stem cell therapy.

Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts.

PURPOSE: Although nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) scavenge free radicals, their short half-life and considerable side effects such as systemic hypotension and bradycardia have limited their clinical application. Since a radical-containing nanoparticle (RNP) delivers nitroxyl radicals with a prolonged half-life specific to ischemic hearts, we investigated whether RNPs reduce infarct size without the occurrence of substantial side effects and whether nitric oxide (NO) contributes to the cardioprotective effects of RNPs. METHODS: The left anterior descending coronary arteries of dogs were occluded for 90 min, followed by reperfusion for 6 h. Either RNPs, micelles (not containing TEMPO) (control), or 4-hydroxy-TEMPO (TEMPOL) was injected into a systemic vein for 5 min before reperfusion. We evaluated the infarct size, myocardial apoptosis, plasma NO levels in coronary venous blood, and the RNP spectra using an electron paramagnetic resonance assay. RESULTS: RNPs reduced infarct size compared with the control group and TEMPOL group (19.5 ± 3.3 vs. 42.2 ± 3.7 vs. 30.2 ± 3.4%). RNPs also reduced myocardial apoptosis compared with the control and TEMPOL group. Coronary venous NO levels increased in the RNP group. CONCLUSIONS: In conclusion, the administration of 2,2,6,6-tetramethylpiperidine-1-oxyl as a RNP exerted cardioprotective effects against ischemia and reperfusion injury in canine hearts without exerting unfavorable hemodynamic effects. RNPs may represent a promising new therapy for patients with acute myocardial infarction.

Common and specific risk factors for ischemic stroke in elderly: Differences based on type of ischemic stroke and aging.

BACKGROUND: The risk factors among the types of ischemic stroke (atherothrombotic cerebral infarction: ATI, cardio-embolic infarction: CEI, lacunar infarction: LI) in aged stroke patients have rarely been compared to each other. METHODS: We compared the clinical parameters of 300 elderly patients with ischemic stroke, age 65-98years, to 100 age-matched control patients. RESULTS: Comparison by parametric test and logistic regression analysis between all 300 and 100 control patients showed higher systolic and diastolic blood pressures (p<0.001, p=0.03), lower estimated glomerular filtration rate (eGFR) (p=0.01), larger cardiothoracic ratio (CTR) (p<0.001), smoking (p<0.01) and possibly poor adherence to anti-hypertensive agents in the ischemic stroke patients (p<0.001). Comparisons among three types (n=100 for each) showed the highest atheromatous risk factors for ATI to be hemoglobin A1c (p=0.01) and low-density lipoprotein (p<0.001) and for CEI to be largest cardiac load, indicated by largest left atrial dimension (p<0.001), and CTR (p<0.001). Triglyceride level was found to be a borderline risk factor for LI (p=0.054). Comparison between those aged <74 versus ≥75years (n=150 for each) showed a lower eGFR (p=0.02) and larger right atrial dimension (p<0.001) in patients ≥75. CONCLUSION: The risk factors were quite different among the subtypes and aging.

Evaluation of Intracranial Microvessel Visualization in Mouse and Dog Models by Using a New Rotating Cerium Anode X-ray System.

OBJECTIVE: Lacunar stroke may be caused by infarction of small perforating branches of the middle cerebral artery. We developed a microangiographic X-ray system using a cerium anode to evaluate the perforating branches. METHODS: Iodine has K-edges at 33.2 kilo electron volts. Cerium yields a characteristic X-ray of 34.6 kilo electron volts, therefore, the cerium anode X-ray system could detect tiny amounts of contrast material. First, an X-ray chart was used to evaluate the resolution. Second, the brains of mice were dissected and irradiated. Third, the brains of dogs were excluded and irradiated. Fourth, iodine was perfused into the carotid artery of living dogs during brain imaging. RESULTS: In the first experiment, the cerium anode X-ray system elicited 4.86 clear line pairs. In mice, the perforating branches of the middle cerebral artery could be visualized. The perforating branches were clearly observed in dog brains ex situ even through an acrylic plate, but not in conventional X-ray images. Iodine moving inside the perforating branches was visualized in dog brains in situ using the cerium anode X-ray system. CONCLUSION: The cerium anode X-ray system allowed us to visualize the perforating branches of the middle cerebral artery in living dogs.

The vital prognosis of elderly adults living in a group home in their mid-eighties.

The purpose of the present study is to evaluate the vital prognoses of elderly people in their mid-eighties living in a group home (GH) compared to age- and sex-matched outpatient clinic (OPC) in an observational study conducted over 6 years. We investigated the association between mortality and general, cardiac, and nutritional parameters, including eicosapentaenoic acid (EPA) in 54 GH residents (83 ± 8 years old) and 57 OPC attendees (83 ± 5 years old). Kaplan-Meier curves and Cox proportional hazard ratio analyses were used to assess the association between EPA drug administration and mortality in the GH residents and OPC attendees, respectively. The 54 GH residents had higher mortality and poorer nutritional states, as indicated by lower EPA/arachidonic acid values (median 0.20 vs 0.55, p < 0.001), and BMI under the condition without EPA drug administration (1800 mg daily) than did the OPC group. The significant factors that differed between survivors and deceased in the GH residents and OPC attendees were nutritional and cardiac factors. Cox proportional hazard ratio analysis confirmed that a possible determinant of the prognosis was a lower incidence of EPA drug administration and lower hemoglobin in GH. Kaplan-Meier curves and Cox proportional hazard ratio analyses revealed that EPA drug administration significantly reduced the relative mortality by 82 % in the GH residents (p < 0.001) but not in the OPC attendees. The vital prognosis in individuals from GHs was potentially improved by EPA drug administration, which was not the case in the OPC group; however, further prospective studies are needed.

Nutrition-dependent eicosapentaenoic acid deficiency in care house residents.

OBJECTIVE: We have identified that vital prognosis of adults in a group home (GH) in their mid-80s is associated with lower eicosapentaenoic acid (EPA) levels. We investigated the cause of EPA deficiency in residents in a GH and the effect of EPA treatment on cardiac function and nutritional function in 130 older adults. METHODS: We compared blood chemistry data among three age- and sex-matched groups-outpatient clinic (OPC) attendees (n = 54, 87 ± 5 y old), GH residents (n = 40, 85 ± 8 y old), and older adults in a geriatric welfare home for the elderly (GWHE) (n = 36, 87 ± 6 y old)-using non-parametric test. Furthermore, we investigated the sequential changes in blood chemistry and cardiac function at 4 to 12 mo after the initiation of EPA administration (1800 mg/d). RESULTS: Non-parametric test revealed that the EPA/arachidonic acid ratio as well as EPA levels were lower in the GH and GWHE residents than in the OPC attendees (OPC: 0.56 ± 0.3, GH: 0.23 ± 0.12, GWHE: 0.31 ± 0.1). Fish consumption was lower in the GH and GWHE group than in the OPC group. Repeated measured analyses using analysis of variance revealed that EPA administration increased serum EPA levels (54.0 ± 29.0 to 210.5 ± 50.6 µg/mL, P < 0.001); decreased arachidonic acid, docosahexaenoic acid, triacylglycerol, and LDL cholesterol levels at 4.5 ± 3.4 mo after administration; and reduced the severity of supraventricular arrhythmias on ambulatory electrocardiogram at 12.5 ± 4.5 mo (P < 0.05). CONCLUSION: EPA deficiency in GH residents could be related to the nutritional characteristics of older adults in care facilities. EPA treatment induced changes in various lipids and reduced the severity of supraventricular arrhythmias.

Severity of white matter hyperintensities in older adults aged in their mid 80s and its relationship with hemodynamic and cardiac parameters.

AIM: In the present study, we analyzed the severity of white matter hyperintensities detected on magnetic resonance imaging of the brain in older Japanese adults who were aged in their mid 80s, and examined its relationships with the clinical parameters. METHODS: To identify factors related to the severity of white matter hyperintensities in 33 older adult attendees of our outpatient clinic and 17 older adults living in a group home, we carried out logistic regression analyses and/or correlation analyses. RESULTS: Cognitive function and activities of daily living were significantly correlated with the severity of white matter hyperintensities. Multivariate analysis identified activities of daily living, but not cognitive function, as being independently associated with the severity of white matter hyperintensities. Several hemodynamic and cardiac parameters, including diastolic blood pressure, hemoglobin, serum level of N-terminal pro-brain natriuretic peptide, cardiothoracic ratio on the chest X-ray, severity of supraventricular arrhythmias on a Holter electrocardiogram and serum levels of docosahexaenoic acid, were significantly correlated with the severity of white matter hyperintensities. In contrast, the serum cholesterol, glycosylated hemoglobin value and systolic blood pressure were not correlated with the severity of white matter hyperintensities. CONCLUSIONS: The severity of white matter hyperintensities detected on magnetic resonance imaging of the brain in older Japanese patients aged in their mid 80s was significantly correlated with activities of daily living, hemodynamic and cardiac parameters, and the serum level of docosahexaenoic acid.

Altered blood flow in cerebral perforating arteries of rat models of diabetes: A synchrotron radiation microangiographic study toward clinical evaluation of white matter hyperintensities.

AIM: As altered blood flow in the cerebral perforating arteries (PA) might be related to development of cerebral white matter hyperintensities, we examined whether the hemodynamic relationship of the PA and middle cerebral artery (MCA) is altered in rat models of diabetes, compared with normal rats and a rat model of sinoatrial denervation (blood pressure fluctuation model). METHODS: We used microangiography with monochromatic synchrotron radiation to measure the diameters of the PA and MCA at 4.5 µm resolution in five groups of rats: (i) Long-Evans Tokushima Otsuka (LETO); (ii) Otsuka Long-Evans Tokushima Fatty (a model of type 2 diabetes with obesity); (iii) LETO with sinoaortic denervation (LETO + SAD); (iv) F344; and (v) F344 + streptozotocin (a model of type 1 diabetes). RESULTS: Compared with LETO, Otsuka Long-Evans Tokushima Fatty rats showed a significant reduction in the diameter of both PA and MCA, though the PA/MCA diameter ratio was unchanged. In contrast, compared with LETO, LETO + SAD rats showed an increased MCA diameter, and the PA/MCA diameter ratio was decreased. Compared with F344 rats, the MCA diameter was increased in F344 + streptozotocin rats, and the PA/MCA diameter ratio was decreased. Scatter diagrams showed that the diameters of the PA and MCA were essentially independent of each other in the two types of diabetic models. CONCLUSION: PA were consistently visualized at high resolution by means of microangiography using synchrotron radiation. The present results show that rat diabetic models exhibit changes in PA diameter and PA/MCA diameter ratio, which might be related to the development of diabetes-associated cerebral white matter hyperintensities.

Development of Fingertip Synchrotron Radiation Microangiography toward Clinical Prediction of Diabetic Microangiopathy.

OBJECTIVES: The spatial resolution of conventional angiographic systems is not enough to predict diabetic microangiopathy in arterioles (20-200 µm). METHODS: To determine whether fingertip synchrotron (SR) radiation microangiography has enough spatial resolution to quantitate arteriolar diameter changes, and whether an arteriolar paradoxical vasoconstriction is a characteristic observation for diabetic microangiopathy, diameter reduction as arteriolar branching and difference of the diameter changes induced by acetylcholine between control (n = 5) and diabetic rats (n = 5) were analyzed. RESULTS: Fingertip SR microangiography visualized the arterioles with a diameter range of 30-300 µm and demonstrated vascular diameter reduction as branching with a fixed ratio (r = 0.93, P < 0.004 and r = 0.73, P < 0.001). A vasodilatory reaction was induced by acetylcholine in the control (142.4 ± 61.9 to 190.9 ± 73.5, P < 0.05, n = 25), in contrast, paradoxical vasoconstriction in diabetic rats (201.6 ± 83.0 to 16 0.4 ± 67.9, P < 0.05, n = 37). Histological angiopathy was noted only in the diabetic rats. CONCLUSION: In conclusion, the fingertip SR microangiography is useful to predict diabetic micrangiopahty.

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury.

Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 ± 2.5% to 17.1 ± 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3ß, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways.

Japan as the front-runner of super-aged societies: Perspectives from medicine and medical care in Japan.

BACKGROUND: The demographic structure of a country changes dramatically with increasing trends toward general population aging and declining birth rates. In Japan, the percentage of the elderly population (aged ≥65 years) reached 25% in 2013; it is expected to exceed 30% in 2025 and reach 39.9% in 2060. The national total population has been decreasing steadily since its peak reached in 2008, and it is expected to fall to the order of 80 million in 2060. Of the total population, those aged ≥75 years accounted for 12.3% as of 2013, and this is expected to reach 26.9% in 2060. As the demographic structure changes, the disease structure changes, and therefore the medical care demand changes. To accommodate the medical care demand changes, it is necessary to secure a system for providing medical care. Japan has thus far attained remarkable achievements in medical care, seeking a better prognosis for survival; however, its medical care demand is anticipated to change both qualitatively and quantitatively. As diseases in the elderly, particularly in the old-old population, are often intractable, conventional medical care must be upgraded to one suitable for an aged society. What is required to this end is a shift from "cure-seeking medical care" focusing on disease treatment on an organ-specific basis to "cure and support-seeking medical care" with treatments reprioritized to maximize the quality of life (QOL) for the patient, or a change from "hospital-centered medical care" to "community-oriented medical care" in correlation with nursing care and welfare. CURRENT SITUATION AND PROBLEMS: (1) Necessity for a paradigm shift to "cure-and-support seeking medical care" In addition to the process of aging with functional deterioration of multiple organs, the elderly often suffer from systemically disordering diseases, such as lifestyle-related diseases, as well as geriatric syndrome and daily activity dysfunction; therefore, integrated and comprehensive medical care is required. In addition, with regard to diseases in the elderly, not only their acute stage, but also their chronic and intermediate stages must be emphasized in their treatment. Aiming to achieve a complete cure of disease by exploring the cause and implementing radical treatment, the conventional medical care model is difficult to apply to the medical care of the elderly; medical care suitable for the elderly is required. (2) Spread of home-based care and the necessity for human resources development Many elderly people want to continue to live in their house and their community where they have been living for a long time, even with disease. There are increasing needs for QOL-emphasizing home-based care for patients in the intermediate stage after completion of acute stage treatment, or for end-of-life care. Hence, there is a demand for a shift to "community-oriented medical care" for providing comprehensive care supported with medical and nursing resources available in the community. As the percentage of the elderly population (aged ≥65 years) and the availability of medical care resources vary considerably among different regions, it is important that specialists in the fields of public health, medical care, nursing care, and welfare work on establishing a collaborative system suitable for the local characteristics of each region by making the best use of their own specialties. (3) Necessity for establishing a department of gerontology or geriatric medicine at each medical school In line with the increasing number of elderly people, it is necessary to upgrade the systems for educating and nurturing physicians engaged in healthcare and nursing care for the elderly. It is also necessary to develop the organic cooperation with other medical and nursing care professionals, such as registered nurses and care workers. At present, just approximately 30% of medical schools in Japan have a department specializing in medical care for the elderly and relevant medical education; there is an urgent need to improve the situation, as the majority of universities do not provide any such education. (4) Necessity for establishing a medical center for promoting medical care provider collaboration, multidisciplinary training and a means to increase public awareness In the medical care for the elderly, comprehensive care must be provided from the viewpoints of both healthcare and nursing care; to improve the quality of such care services, multidisciplinary collaboration and team-based medicine are indispensable. Therefore, physicians, nurses, therapists, pharmacists, dieticians, care managers, and other health care professionals who have thorough knowledge about medical care for the elderly are of utmost necessity. In reality, however, the collaboration of these health care professionals is unsatisfactory, and the degree of understanding of team-based medicine by each medical professional is low. Therefore, as in the case of the establishment of cancer centers within individual regions to promote medical care for cancer, there is a demand to nurture professionals engaged in medical care for the elderly, and to establish a core facility for the promotion of multidisciplinary collaboration and team-based medicine for each region. (5) Do the people understand the paradigm shift? Currently, not only healthcare professionals, but also many citizens seek "cure-seeking medical care" aiming at a restoration of organ function; however, surveys of the elderly often show that they want to restore independent daily activity, rather than to achieve a "cure." In contrast, in the actual medical care setting, contradictory situations prevail in which the public awareness of the shift to "cure-and-support seeking medical care" is unsatisfactory, including the fact that the majority of recipients of tertiary emergency care are elderly patients. CONTENTS OF THE PROPOSAL: The Science Council of Japan has the task to propose future visions for the Japanese aging society not only from the viewpoint of the health of each individual, but also from a broader perspective, taking into account the relationship between humans and society. Various issues related to general population aging are posing serious problems, which require prompt resolution. Although we made a number of proposals at the 21st Subcommittee for Aging, the situation has not changed satisfactorily. Accordingly, the present proposals on specific solutions were designed. (1) In a super-aged society, a paradigm shift to "cure-and-support seeking medical care" should be implemented A super-aged society will consist of an unprecedented demographic structure in which the percentage of only those people aged ≥75 years will increase in the entire population. Therefore, there is an urgent need to prepare for increasing populations of persons in need of long-term care and those who are likely to become in need of long-term care. Given the consideration that "patients are not merely sick persons, but rather living persons," a paradigm shift from conventional "cure-seeking medical care" to "cure and support-seeking medical care" must be implemented. (2) Facilitate a paradigm shift to community-oriented medical care, and promote the activity of female physicians in the medical care for the elderly A paradigm shift should be promptly facilitated by reorganizing hospital functions and establishing a community comprehensive care system for home-based care to promote the participation of the elderly by themselves in care-supporting society. To further promote the collaboration of medical care and welfare, not only persons in charge of actual regional settings, but also university schools of medicine and regional core medical institutions experienced in medical care for the elderly should take the initiative to promote home-based care and facilitate a paradigm shift to community-oriented medical care. In addition, programs should also be developed to re-educate female physicians who became housewives in order to nurture them to become facilitators of geriatric medicine. (3) Physicians who are required at local medical facilities must be nurtured through the establishment of a department of gerontology or geriatric medicine at each medical school To facilitate efficient medical care services, medical education and research, and human resources development in support of expected paradigm shifts, it is considered that a department of gerontology or geriatric medicine should be established at each medical school. Furthermore, it is necessary to allocate dedicated teachers of medical care for the elderly to all medical schools, as well as to upgrade practice-participatory drills and to collaborate with a broad range of entities, including local medical institutions, and welfare and nursing care facilities. Efforts must be made to nurture locally wanted physicians through specific efforts concerning team-based medicine. (4) Promote the establishment of centers for geriatrics and gerontology (provisional name) for medical care collaboration, multidisciplinary training, and a means to increase public awareness To promote the uniform accessibility of expertise on efficient medical care that is best suited for a super-aged society, it is necessary to build a post-graduation educational system under the initiatives of the Japan Geriatrics Society and the National Center for Geriatrics and Gerontology across the nation in cooperation with regional medical schools and the Japan Medical Association. Furthermore, at least one hospital serving as a center for geriatrics and gerontology should be established in each regional block (Hokkaido, Tohoku, Koshinetsu, Hokuriku/Tokai, Kinki, Chushikoku and Kyushu/Okinawa) by making the best use of existing hospitals. Byestablishing these centers, uniform accessibility for the quality of medical care for the elderly in each region is expected. (ABSTRACT TRUNCATED).

Low plasma eicosapentaenoic acid concentration as a possible risk factor for intracerebral hemorrhage.

N-3 fatty acids, including eicosapentaenoic acid (EPA), prevent ischemic stroke. The preventive effect has been attributed to an antithrombic effect induced by elevated EPA and reduced arachidonic acid (AA) levels. However, the relationship between intracranial hemorrhage and N-3 fatty acids has not yet been elucidated. In this cross-sectional study, we compared common clinical and lifestyle parameters between 70 patients with intracranial hemorrhages and 66 control subjects. The parameters included blood chemistry data, smoking, alcohol intake, fish consumption, and the incidences of underlying diseases. The comparisons were performed using the Mann-Whitney U test followed by multiple logistic regression analysis. Nonparametric tests revealed that the 70 patients with intracerebral hemorrhages exhibited significantly higher diastolic blood pressures and alcohol intakes and lower body mass indices, high-density lipoprotein (HDL) cholesterol levels, EPA concentrations, EPA/AA ratios, and vegetable consumption compared with the 66 control subjects. A multiple logistic regression analysis revealed that higher diastolic blood pressure and alcohol intake and lower body mass index, HDL cholesterol, EPA/AA ratio, and vegetable consumption were relative risk factors for intracerebral hemorrhage. High HDL cholesterol was a common risk factor in both of the sex-segregated subgroups and the <65-year-old subgroup. However, neither EPA nor the EPA/AA ratio was a risk factor in these subgroups. Eicosapentaenoic acid was relative risk factor only in the ≥65-year-old subgroup. Rather than higher EPA levels, lower EPA concentrations and EPA/AA ratios were found to be risk factors for intracerebral hemorrhage in addition to previously known risk factors such as blood pressure, alcohol consumption, and lifestyle.

Adipose-derived stem cell sheet transplantation therapy in a porcine model of chronic heart failure.

Adipose-derived stem cells (ASCs) are a promising resource for cell transplantation therapy for damaged heart tissue. Cell death in the graft early after transplantation represents the main cause of unsatisfactory therapeutic efficacy, but tissue-engineered cell sheets grown in temperature-responsive cell culture dishes may enable improved engraftment of transplanted cells. We investigated the therapeutic potential of this method in chronic myocardial ischemia in swine. We created a porcine model of chronic heart failure by implanting an ameroid constrictor around the main trunk of the left anterior descending artery, just distal to the circumflex branch. Simultaneously, ASCs were obtained from a piece of subcutaneous adipose tissue and expanded to form ASC sheets using temperature-responsive dishes. Four weeks after ameroid constrictor placement, triple-layered ASC sheets were transplanted onto the area of the ischemic myocardium (sheet group, n = 7). Controls (n = 7) received no sheet. Just before and 4 weeks after transplantation, left ventriculography (LVG) and coronary angiography (CAG) were performed. LVG revealed a significant improvement in the left ventricular ejection fraction of the sheet group compared with controls (47.6 ± 2.9% vs 41.4 ± 2.8%, P < 0.05). Furthermore, development of collateral vessels was only detected in the sheet group with right CAG. Histologic analysis demonstrated that engrafted ASC sheets grew to form a thickened layer that included newly formed vessels. ASC sheet transplantation therapy is an intriguing therapeutic method for ischemic heart failure.

Visualization of microvessels by angiography using inverse-Compton scattering X-rays in animal models.

The fundamental performance of microangiography has been evaluated using the S-band linac-based inverse-Compton scattering X-ray (iCSX) method to determine how many photons would be required to apply iCSX to human microangiography. ICSX is characterized by its quasi-monochromatic nature and small focus size which are fundamental requirements for microangiography. However, the current iCSX source does not have sufficient flux for microangiography in clinical settings. It was determined whether S-band compact linac-based iCSX can visualize small vessels of excised animal organs, and the amount of X-ray photons required for real time microangiography in clinical settings was estimated. The iCSX coupled with a high-gain avalanche rushing amorphous photoconductor camera could visualize a resolution chart with only a single iCSX pulse of ∼3 ps duration; the resolution was estimated to be ∼500 µm. The iCSX coupled with an X-ray cooled charge-coupled device image sensor camera visualized seventh-order vascular branches (80 µm in diameter) of a rabbit ear by accumulating the images for 5 and 30 min, corresponding to irradiation of 3000 and 18000 iCSX pulses, respectively. The S-band linac-based iCSX visualized microvessels by accumulating the images. An iCSX source with a photon number of 3.6 × 10(3)-5.4 × 10(4) times greater than that used in this study may enable visualizing microvessels of human fingertips even in clinical settings.

Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: role of NO.

Carperitide is effective for heart failure (HF) owing to its diuretic and vasodilatory effects. This recombinant peptide may also have direct cardioprotective effects because carperitide reduces the severity of heart failure and limits infarct size. Because coronary vasodilation is an important cardioprotective treatment modality, we investigated whether carperitide increased coronary blood flow (CBF) and improved myocardial metabolic and contractile dysfunction during ischemia in canine hearts. We also tested whether carperitide is directly responsible for limiting the infarct size. We infused carperitide at 0.025-0.2 µg kg(-1) min(-1) into the canine coronary artery. A minimum dose of 0.1 µg kg(-1) min(-1) was required to obtain maximal vasodilation. To test the effects of carperitide on ischemic hearts, we reduced perfusion pressure in the left anterior descending coronary artery such that CBF decreased to one-third of the baseline value. At 10 min after carperitide was infused at a dose of 0.1 µg kg(-1) min(-1), we observed increases in CBF, fractional shortening (FS) and pH levels in coronary venous blood without concomitant increases in cardiac nitric oxide (NO) levels; these changes were attenuated using either the atrial natriuretic peptide receptor antagonist HS-142-1 or the NO synthase inhibitor L(ω)-nitroarginine methyl ester (L-NAME). Cyclic guanosine monophosphate (GMP) levels in the coronary artery were elevated in response to carperitide that also limited the infarct size after 90 min of ischemia and subsequent reperfusion. Again, these effects were blunted by L-NAME. Carperitide increases CBF, reduces myocardial contractile and metabolic dysfunction and limits infarct size. In addition, NO is necessary for carperitide-induced vasodilation and cardioprotection in ischemic hearts.

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis.

BACKGROUND/AIMS: Little is known about the anti-colitis effect of tryptophan or its metabolites. Here, the protective effect and its mechanism of tryptophan administration on dextran sulfate sodium -induced colitis in mice was studied. MATERIALS AND METHODS: Twenty C57black6 female mice were equally divided into the control group, and treatment group. The control group received a standard CE-2 diet, while the tryptophan group received a CE-2 diet containing 0.5% l-tryptophan. After one week on this diet, all mice were orally administered a solution of 3.5% dextran sulfate sodium for 12 days to induce colitis. Changes in body weight and bloody stool frequency were monitored during dextran sulfate sodium administration. At 12 days post initial dextran sulfate sodium administration, all mice were sacrificed and the histology of their colonic tissue was examined. The nitrotyrosine levels in colonic tissues in both groups, and nitrate and nitrite levels in the urine of the control group, the tryptophan group and the group of mice without dextran sulfate sodium administration was measured. RESULTS: The tryptophan group showed significantly attenuated body weight loss, bloody stool frequency and ameliorated histological changes of colitis. While tryptophan treatment significantly reduced nitrotyrosine level in the colonic tissues, there was no significant reduction in urine nitrate and nitrite levels compared with the (dextran sulfate sodium-induced) control group. CONCLUSION: Tryptophan treatment ameliorated dextran sulfate sodium-induced colitis in this study. One of the anti-colitis mechanisms of tryptophan treatment is attributable to an anti-nitration effect, and may not be via the suppression of nitric oxide generation.

Comparison of eicosapentaenoic acid concentrations in plasma between patients with ischemic stroke and control subjects.

OBJECTIVE: ω-3 fatty acids, including eicosapentaenoic acid (EPA), prevent ischemic stroke. However, the clinical importance of EPA for ischemic stroke and its subtype has not been fully elucidated. METHODS: In a cross-sectional study, we determined whether ω-3 fatty acids were predictive factors for ischemic stroke. We compared common clinical parameters among 65 patients with ischemic stroke and 65 control subjects. The parameters included blood chemistry data; concentrations of EPA, docosahexaenoic acid, and arachidonic acid (AA); EPA/AA ratio; smoking; alcohol intake; fish consumption more than four times per week; and the incidence of underlying diseases. The comparisons were performed using the Mann-Whitney U test, and multiple logistic regression analysis was applied to the significant factors in the non-parametric test. We also applied the same approach to the ischemic stroke subtypes, cardioembolism and large-artery atherosclerosis. RESULTS: In the multiple logistic regression analysis after the Mann-Whitney U test, a lower EPA concentration was one of the significant risk factors for ischemic stroke, as were a lower body mass index, lower high-density lipoprotein cholesterol, and smoking (sensitivity 0.846, specificity 0.831, positive predictive value 0.833). In the analysis of subtypes, a lower EPA/AA ratio and a lower body mass index were the significant risk factors for cardioembolism (sensitivity 0.800, specificity 0.733, positive predictive value 0.750). However, large-artery atherosclerosis was not related to the EPA concentration or the EPA/AA ratio. CONCLUSIONS: In this study, the plasma EPA concentration and the EPA/AA ratio were potential predictive risk factors for ischemic stroke, especially for cardioembolism. Further prospective studies are necessary.

H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs.

PURPOSE: Inhalation of hydrogen (H(2)) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H(2) gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mK(ATP)) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H(2) gas in canine hearts. METHODS: The left anterior descending coronary artery of beagle dogs was occluded for 90 min followed by reperfusion for 6 h. Either 1.3% H(2) or control gas was inhaled from 10 min prior to start of reperfusion until 1 h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mK(ATP) blocker), or atractyloside (Atr; a mPTP opener). RESULTS: Systemic hemodynamic parameters did not differ among the groups. Nevertheless, H(2) gas inhalation reduced infarct size normalized by risk area (20.6±2.8% vs. control gas 44.0±2.0%; p<0.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H(2) gas (42.0±2.2% with 5-HD and 45.1±2.7% with Atr; both p<0.001 vs. H(2) group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H(2) was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway. CONCLUSIONS: Inhalation of H(2) gas reduces infarct size in canine hearts via opening of mitochondrial K(ATP) channels followed by inhibition of mPTP. H(2) gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.