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• DS-5670a, an mRNA vaccine, targets the RBD of the SARS-CoV-2 spike protein. • Immunologically-naïve adults received 2 injections of DS-5670a, 4 weeks apart. • Safety, immunogenicity and pharmacokinetics were evaluated in two dose groups. • DS-5670a was well tolerated and most TEAEs were mild or moderate. • 60 µg of mRNA provided greater humoral immunity and will be investigated further. DS-5670a is a vaccine candidate for coronavirus disease 2019 (COVID-19) harnessing a novel modality composed of messenger ribonucleic acid (mRNA) encoding the receptor-binding domain (RBD) from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encapsulated in lipid nanoparticles. Here, we report the safety, immunogenicity, and pharmacokinetic profile of DS-5670a from a phase 2 clinical trial in healthy adults who were immunologically naïve to SARS-CoV-2. The study consisted of an open-label, uncontrolled, dose-escalation part and a double-blind, randomized, uncontrolled, 2-arm, parallel-group part. A total of 80 Japanese participants were assigned to receive intramuscular DS-5670a, containing either 30 or 60 µg of mRNA, as two injections administered 4 weeks apart. Safety was assessed by characterization of treatment-emergent adverse events (TEAEs). Immunogenicity was assessed by neutralization titers against SARS-CoV-2, anti-RBD immunoglobulin (Ig)G levels, and SARS-CoV-2 spike-specific T cell responses. Plasma pharmacokinetic parameters of DS-5670a were also evaluated. Most solicited TEAEs were mild or moderate with both the 30 and 60 µg mRNA doses. Four participants (10 %) in the 60 µg mRNA group developed severe redness at the injection site, but all cases resolved without treatment. There were no serious TEAEs and no TEAEs leading to discontinuation. Humoral immune responses in both dose groups were greater than those observed in human convalescent serum; the 60 µg mRNA dose produced better responses. Neutralization titers were found to be correlated with anti-RBD IgG levels (specifically IgG1). DS-5670a elicited antigen-specific T helper 1-polarized cellular immune responses. The novel mRNA-based vaccine candidate DS-5670a provided favorable immune responses against SARS-CoV-2 with a clinically acceptable safety profile. Confirmatory trials are currently ongoing to evaluate the safety and immunogenicity of DS-5670a as the primary vaccine and to assess the immunogenicity when administered as a heterologous or homologous booster. Trial registry: https://jrct.niph.go.jp/latest-detail/jRCT2071210086. [ABSTRACT FROM AUTHOR]

Background: Cardiac allograft vasculopathy (CAV), a disorder characterized by rapid development and progression of obliterative vasculopathy in the transplanted heart, continues to be a major cause of graft failure in long-surviving human transplants. The mechanisms and histopathologic processes of CAV remain unknown. Previous animal studies have shown that inhibition of matrix metalloproteinase (MMP) prevents migration and proliferation of smooth muscle cells in CAV. In this study, we hypothesized that MMPs may be expressed in and may play an important role in CAV.Methods: An F344-to-WKAH rat heterotopic heart transplantation model was used. Tacrolimus was administered intramuscularly 14 days after transplantation to prevent acute rejection and to allow the development of CAV. We divided the animals into 2 groups according to post-operative treatment: an ONO group received an MMP inhibitor (ONO-4817) daily by oral gavage for 14 days after transplantation (n = 6), and a control (n = 6) group received no treatment. Grafts were harvested 60 days after treatment.Results: Immunohistochemical staining revealed that MMP-2 and tissue inhibitors of metalloproteinase-2 (TIMP-2) were expressed more strongly in the neointima and media of the control CAV animals than in the ONO-CAV animals. The animals given ONO-4817 exhibited a significant decrease in the percentage of affected vessels, in the percentage of intimal proliferation, in the intima-to-media ratio, and in the expression of MMP-2 and TIMP-2.Conclusion: These results suggest that MMP-2 and TIMP-2 play an important role in the development of CAV and that the use of an MMP inhibitor (ONO-4817) may prevent neointimal proliferation in patients with CAV. [Copyright &y& Elsevier]

Purpose: To clarify the intraocular pressure (IOP)-lowering effect of a selective prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI) during a 24-hour period. Patients and Methods: Subjects aged ≥ 20 years and with diagnosed, untreated primary open-angle glaucoma or ocular hypertension were enrolled. IOP measurements were performed every 4 hours over a 24-hour period using a Goldmann applanation tonometer (GAT) and Icare PRO tonometer (PRO). The baseline 24-hour IOP was measured in untreated subjects. After the baseline measurements, participants were given OMDI 1 drop once daily at night for 4 weeks. At week 4, the IOP measurement was repeated under the same conditions. Diurnal (9 am, 1 pm, 5 pm) and nocturnal (9 pm, 1 am, 5 am) IOP measurements were compared between baseline and treatment with OMDI. Safety measures included adverse events, slit-lamp biomicroscopy, visual acuity, heart rate and blood pressure. Results: Of 27 participants enrolled, 25 patients (20 males and 5 females, average age 52.2 ± 8.5 years) completed the study. In the sitting position, the baseline diurnal and nocturnal mean IOPs (GAT) were 19.1 ± 2.1 mmHg and 18.2 ± 2.6 mmHg, respectively, the diurnal and nocturnal mean IOP reduction from baseline were – 2.8 ± 2.6 mmHg (p < 0.0001) and – 3.3 ± 2.9 mmHg (p < 0.0001), respectively, mean 24-hour IOP (GAT) was significantly lower with the OMDI treatment (− 3.1 ± 2.5 mmHg, p < 0.0001). In the supine position, the baseline nocturnal mean IOP (PRO) was 17.99 ± 2.22 mmHg, and the nocturnal mean IOP reduction from baseline was − 1.78 ± 2.37 mmHg (p = 0.0009) after 4 weeks of the treatment. Nine adverse events were observed in 8 patients including mild conjunctival hyperemia (n = 8) and mild iritis (n=1). There were no significant effects on systemic safety. Conclusion: Once daily OMDI treatment was able to produce stable 24-hour IOP reduction. [ABSTRACT FROM AUTHOR]

Direct vasodilator effects of nitroglycerin, nifedipine, cilnidipine and diltiazem on human skeletonized internal mammary artery graft harvested with ultrasonic scalpel were assessed in the presence of 0.1 or 0.2 µM of noradrenaline. Ring preparations were made of distal end section of the bypass grafts, and those dilated by acetylcholine were used for assessment. Each drug dilated the artery in a concentration-related manner (0.01-10 µM, n = 6 for each drug) with a potency of nitroglycerin > nifedipine = cilnidipine > diltiazem. These results indicate that nitroglycerin can be useful for treating internal mammary artery spasm, that clinical utility of diltiazem may not depend on its vasodilator effect on the bypass graft, and that cilnidipine as well as nifedipine will have anti-spastic action which is in the middle between those of nitroglycerine and diltiazem. [ABSTRACT FROM AUTHOR]

Brachial systolic pressure (BSP) is often monitored during exercise by the stress test; however, central systolic pressure (CSP) is thought to be a more direct measure of cardiovascular events. Although some studies reported that exercise and aging may play roles in changes of both BSP and CSP, the relationship between BSP and CSP with age following the exercise stress test remains unclear. The aim of this study was to evaluate the effect of age on the relationship between BSP and CSP measured after exercise. Ninety-six subjects underwent the diagnostic treadmill exercise stress test, and we retrospectively divided them into the following 3 groups by age: the younger age group (43 ± 4 years), middle age group (58 ± 4 years), and older age group (70 ± 4 years). Subjects exercised according to the Bruce protocol, to achieve 85 % of their age-predicted maximum heart rate or until the appearance of exercise-associated symptoms. BSP, CSP, and pulse rate (PR) were measured using a HEM-9000AI (Omron Healthcare, Japan) at rest and after exercise. BSP, CSP, and PR at rest were not significantly different among the 3 groups ( p = 0.92, 0.21, and 0.99, respectively). BSP and PR immediately after exercise were not significantly different among the groups ( p = 0.70 and 0.38, respectively). However, CSP immediately after exercise was 144 ± 18 mmHg (younger age), 149 ± 17 mmHg (middle age), and 158 ± 19 mmHg (older age). CSP in the older age group was significantly higher than that in the younger age group ( p < 0.01). Despite similar BSPs in all age groups after exercise, CSP was higher in the older age group. Therefore, older subjects have a higher CSP after exercise, which is not readily assessed by conventional measurements of BSP. [ABSTRACT FROM AUTHOR]

Background and aims. Arterial hypertension doubles the risk of coronary heart disease, heart and kidney failure, and peripheral arterial disease. Less variation in diurnal ambulatory blood pressure monitoring (ABPM) patterns may affect mortality outcome. Therefore, as hypertension occurs in over 95% of older subjects, the prognostic value of dipping status in older hypertensive patients will be assessed. Method. The retrospective study group consisted of 170 hypertensive patients, aged 75-84 years, enrolled in the years 2005 to 2007. Baseline measures included 24-h ABPM. Diurnal index and dipping status was calculated and stratified the group into dippers (40 patients, 23.5%), non-dippers (65 patients, 38.2%) and reverse-dippers (65 patients, 38.2%). Results. During a 5-year observation, after baseline we have observed 69 deaths (40.9%) from the whole group of 170 patients with 23 (35.4%) being non-dippers and 36 (55.4%) reverse-dippers. There were significant differences between the groups divided according to diurnal dipping status in survival time, number of recorded deaths and night mean blood pressure. We have identified and confirmed risk factors for the all-cause mortality: age, mean systolic and diastolic blood pressure, diurnal index and dipping status (dipping, non-dipping or reverse-dipping). Conclusion. Reverse-dippers and non-dippers revealed worse prognosis compared with dippers. [ABSTRACT FROM AUTHOR]

Abstract: Objective: This trial evaluated the effects of casein hydrolysate containing milk-derived peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), on central blood pressure and arterial stiffness. Methods: A randomized, double-blind, placebo-controlled trial was conducted in 70 Japanese subjects aged 50–69 years with untreated stage-I hypertension. They were randomly assigned to two groups, which received either placebo tablets or active tablets containing 3.4mg of VPP and IPP. At the beginning and end of the 8-week intervention, hemodynamic parameters, including central blood pressure and brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, were measured. Results: A significant difference in changes in central systolic blood pressure between the groups was observed (active: −11.0±11.0 vs placebo: −4.5±9.6mmHg, P <0.01). In the active group, reductions in baPWV (−73.9±130.0 vs −8.4±137.1cm/s, P <0.05), brachial SBP (−10.5±11.5 vs −3.9±9.6mmHg, P <0.05), and radial mean blood pressure (−7.3±8.9 vs −2.0±7.4mmHg, P <0.01) were significantly greater as compared with the placebo group. Conclusion: Casein hydrolysate containing VPP and IPP improves central SBP and baPWV in hypertensive subjects, which suggests VPP and IPP might have beneficial effects on arterial properties. [Copyright &y& Elsevier]

Abstract: The coagulase-negative Staphylococcus lugdunensis, a bacterium similar to Staphylococcus aureus, produces tannase that degrades tannin. We developed a polymerase chain reaction-based method to rapidly and simply identify this species by detecting the tanA gene for S. lugdunensis tannase. [Copyright &y& Elsevier]

AbstractPharmaceutical angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce arterial stiffness; the possible effect of food-derived putative ACE inhibitory peptides on this degenerative process, however, has not been reported. In the present study, casein hydrolysate containing the lactotripeptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), which has been found to have an antihypertensive effect in a number of clinical studies, was investigated for its ability to improve hemodynamic parameters, including central systolic blood pressure (cSBP), in hypertensive subjects. Twelve hypertensive subjects who were not on prescribed medication were monitored for various hemodynamic parameters, including brachial blood pressure (peripheral blood pressure), cSBP, and augmentation index (AI), at the start and then after 3, 6, and 9 weeks of a daily treatment comprising four tablets containing VPP and IPP. Compared with basal levels, treatment with casein hydrolysate for 6 and/or 9 weeks showed a significant reduction in peripheral systolic and diastolic blood pressure, AI, and cSBP, but not in heart rate or pulse pressure. cSBP showed a reduction sooner and greater (−21.8 mm Hg) than did brachial systolic blood pressure (−16.4 mm Hg) during the 9-week treatment. Although small and not placebo-controlled, this study suggests that continuous intake of VPP and IPP might have the potential to improve arterial stiffness as well as cSBP and peripheral brachial blood pressure. [ABSTRACT FROM AUTHOR]

The effect of cibenzoline, a class-Ia antiarrhythmic drug, on coronary flow velocity reserve (CFVR) was examined in patients with hypertrophic cardiomyopathy using transthoracic Doppler echocardiography. Coronary flow velocity reserve was assessed in 11 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 12 patients with hypertrophic nonobstructive cardiomyopathy (HNCM), before and after the intravenous administration of cibenzoline (1 mg/kg). Coronary hyperemia was induced by an intravenous infusion of adenosine triphosphate and CFVR was calculated as the ratio of hyperemic to basal mean coronary diastolic flow velocity. At baseline, CFVR was significantly correlated with left ventricular outflow tract pressure gradient (LVPG) in patients with HOCM ( r = 0.67, P < 0.03). In patients with HOCM, administration of cibenzoline significantly improved impaired CFVR (2.0 ± 0.8 to 3.0 ± 1.0, P < 0.001), and reduced LVPG (55 ± 30 to 23 ± 18 mmHg, P < 0.001), while CFVR remained unchanged in patients with HNCM (2.6 ± 0.9 to 2.9 ± 0.8, P not significant). Cibenzoline not only reduces LVPG but also improves CFVR in patients with HOCM. In addition left ventricular outflow obstruction plays an important role in impaired coronary circulation in patients with HOCM. [ABSTRACT FROM AUTHOR]

Evaluates the treatment efficacy of apple polyphenol (Ap) on cedar pollinosis patient in Japan. Guidelines for allergic rhinitis diagnosis and treatment; Symptoms of cedar pollinosis; Mechanisms for the action of Ap, a red perilla extract and rubus suavissimus extract; Details on the major components of Ap.

Recently, a measurement device that can simultaneously measure the ankle-brachial pressure index (ABI) and brachial-ankle pulse wave velocity (PWV) has become available. The present study compares the applicability of ABI and PWV as markers for predicting the prevalence of coronary artery disease (CAD) in subjects with a high risk of atherosclerotic cardiovascular disease. The ABI and brachial-ankle PWV were measured in 472 consecutive subjects who subsequently underwent coronary angiography for diagnosis or exclusion of CAD. The prevalence of CAD in the lowest ABI quartile was higher than those in the other 3 ABI quartiles, whereas the prevalence in the lowest brachial-ankle PWV quartile was lower than those in the other 3 brachial-ankle PWV quartiles. A multivariate logistic regression analysis demonstrated that the lowest ABI quartile was a significant independent variable for the prevalence of CAD and that the lowest brachial-ankle PWV quartile was a significant independent variable for the absence of CAD in a population. Thus, a low ABI is an independent marker for an additive risk of CAD, whereas a low brachial-ankle PWV may be used as an independent marker for excluding the risk of CAD among subjects with a high risk of atherosclerotic cardiovascular disease. [Copyright &y& Elsevier]

Hemodynamics is often the focus of dementia research, but methodological difficulties have precluded such research. To clarify the role of hemodynamic factors in the pathogenesis of dementing illness, the newly developed, second-derivative finger photoplethysmography (SD-PTG), which can provide hemodynamic indices, was studied in 173 patients with dementia. The subject group consisted of 41 patients with Binswanger's disease (BD group), 31 patients with Alzheimer's disease with severe periventricular lucency (PVL; AD + PVL group), and 101 patients with Alzheimer's disease without PVL. The SD-PTG findings as well as the clinical findings of each group were compared with those of 114 controls without dementia. The heights of the a-, b-, c-, d-, and e-waves on SD-PTG waveforms were measured, and b/a and d/a ratios were used as indices of distensibility of the aorta and peripheral vascular impedance in the systemic circulation, respectively. The b/a ratio was significantly higher in the BD and AD + PVL groups than in the AD − PVL group ( P < 0.01). The d/a ratio was significantly lower in the BD group than in the AD + PVL, AD − PVL, and control groups ( P < 0.01). The d/a ratio in the BD group correlated significantly with mini-mental state examination (MMSE) score ( r = 0.47, P = 0.0023). The results indicate that decreased distensibility of the aortic wall is associated with the white matter lesions in both types of dementia, while the low d/a ratio and the correlation between the d/a ratio and the MMSE score in the BD group indicate that increased peripheral impedance was associated with more extensive involvement of the white matter and cognitive decline in Binswanger's disease. [ABSTRACT FROM AUTHOR]

In 167 patients with suspected coronary artery disease, 74 of whom had myocardial infarction (MI), measurement of myocardial fractional flow reserve (FFR) in previous infarction territories, using a cut-off point of 0.75, showed a sensitivity of 79% and a specificity of 79% for myocardial ischemia as demonstrated by thallium-201 myocardial imaging. This sensitivity and specificity were similar to a sensitivity of 79% and a specificity of 72% observed in territories not related to MI. In addition, a receiver-operating characteristic curve analysis revealed that the best predictability of FFR for myocardial ischemia was between 0.74 and 0.76, regardless of the presence or absence of MI. [Copyright &y& Elsevier]

We determined whether aortic prosthesis size influences survival and hemodynamic function. Eighty-nine patients who underwent small aortic valve replacement were followed. The small internal orifice area index (IOAI) group was defined as having an internal orifice area/body surface area ratio of ≤1.3 cm2 /m2 (n = 34). The control group was defined as having an IOAI >1.3 cm2 /m2 (n = 55). The actuarial survival rate at 10 years was 74.5% in the small IOAI group and 75% in the control group (NS). Freedom from valve-related impairment at 10 years was 87% in the small IOAI group and 85% in the control group (NS). Postoperative pressure gradients were higher in the small IOAI group (p < 0.05). Left ventricular mass index decreased in both groups (albeit nonsignificantly in the small group, but significantly decreased in the control group). The long-term results of aortic valve replacement for patients with small aortic annulus were satisfactory. However, the postoperative pressure gradient through the prosthesis and left ventricular hypertrophy remained at a high level in the small IOAI group. [ABSTRACT FROM AUTHOR]

The article presents an abstract on a paper titled "The Impact of Mid-Wall Striate of LGE at Interventricular Septum to the Beta-Broker (Carvedilol) Titrating to the Target Dose and the Improvement of Cardiac Function With DCM," presented at the 2011 Society for Cardiovascular Magnetic Resonance (CMR)/Euro CMR Joint Scientific Sessions held in France.