Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

BACKGROUND AND OBJECTIVES: BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs. METHODS: Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. RESULTS: Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. CONCLUSION: BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

Heart Rate Fragmentation, Ambulatory Blood Pressure, and Coronary Artery Calcification: A Population-Based Study.

Background: Little is known regarding whether ultra-rapid patterns of heart rate variability (eg, heart rate fragmentation [HRF]) are associated with coronary artery calcification (CAC) in a general population. Objectives: This study aimed to assess the association between HRF and CAC, and whether these associations are independent of systolic blood pressure (SBP) levels. Methods: From SESSA (the Shiga Epidemiological Study of Subclinical Atherosclerosis), we used data from 24-hour ambulatory blood pressure monitoring to identify awake and asleep SBP levels, and data from concurrent 24-hour Holter monitoring to quantify HRF using the awake and asleep percentage of inflection points (PIP). CAC on computed tomography scanning was quantified using an Agatston score. We used multivariable binomial logistic regression to assess the associations of PIP and ambulatory SBP with the presence of CAC, as defined by Agatston score >0. Results: Of the 508 participants in this study (mean age: 66.5 ± 7.3 years), 325 (64%) had CAC and 183 (36%) did not. In fully adjusted models of prevalent CAC that also included office SBP, the ORs with 95% CIs for awake PIP, awake SBP, asleep PIP, and asleep SBP were 1.23 (95% CI: 0.99-1.54), 1.40 (95% CI: 1.11-1.77), 1.31 (95% CI: 1.05-1.62), and 1.28 (95% CI: 1.02-1.60), respectively. There was no evidence of interaction between PIP and ambulatory SBP in association with CAC. Results were similar when other HRF indices instead of PIP were used. Conclusions: Higher HRF and SBP levels during sleep are each associated with the presence of CAC in a general male population.

Relationship Between Hemoglobin Concentration and Cardiovascular Disease Mortality in a 25-Year Follow-up Study of a Japanese General Population　- NIPPON DATA90.

BACKGROUND: Deviations of hemoglobin from normal levels may be a factor in cardiovascular disease (CVD) risk; however, conclusive evidence is lacking. In addition, preclinical conditions may influence hemoglobin concentrations, but studies focusing on reverse causation are limited. Thus, we examined the relationship between hemoglobin concentrations and CVD mortality risk, considering reverse causation.Methods and Results: In a prospective cohort representative of the general Japanese population (1990-2015), we studied 7,217 individuals (mean age 52.3 years; 4,219 women) without clinical CVD at baseline. Participants were categorized into sex-specific hemoglobin quintiles (Q1-Q5) and data were analyzed using the Cox proportional hazards model adjusted for possible confounders. During a 25-year follow-up, 272 men and 334 women died from CVD. Adjusted hazard ratios for CVD mortality across sex-specific quintiles, using Q3 as the reference, were significantly higher for Q1 (1.40; 95% confidence interval [CI] 1.08-1.82) and Q5 (1.49; 95% CI 1.14-1.96), and remained significant after excluding deaths within the first 5 years of follow-up to consider reverse causation (1.35 [95% CI 1.02-1.79] and 1.45 [95% CI 1.09-1.94], respectively). A similar U-shaped association was seen between transferrin saturation levels and CVD mortality, but after excluding deaths within the first 5 years the association was significant only for Q1. CONCLUSIONS: Low and high hemoglobin concentrations were associated with an increased risk of CVD mortality.

High blood pressure and colorectal cancer mortality in a 29-year follow-up of the Japanese general population: NIPPON DATA80.

Onco-hypertension has been proposed, although associations of high blood pressure (BP) with cancer risk remain inconsistent. We examined associations of high BP with risk of mortality from stomach, lung, colorectal, liver, and pancreatic cancers independent of possible confounders in an analysis that excluded deaths within the first 5 years of follow-up to consider the reverse causality. In a prospective cohort representative of the general Japanese population (1980-2009), we studied 8088 participants (mean age, 48.2 years; 56.0% women) without clinical cardiovascular disease or antihypertensive medication at baseline. Fine-Gray competing risks regression was used to estimate hazard ratios for 10 mmHg higher BP adjusted for confounders including smoking, alcohol-drinking, obesity, and diabetes mellitus. During 29-year follow-up, 159 (2.0%), 159 (2.0%), 89 (1.1%), 86 (1.1%), and 68 (0.8%) participants died from stomach, lung, colorectal, liver, and pancreatic cancers, respectively. We observed a positive association of high BP with risk of colorectal cancer mortality but not with mortality risks from any other cancers. The association with colorectal cancer mortality for systolic and diastolic BP was evident in those aged 30-49 years (hazard ratios 1.43 [95% confidence interval, 1.22-1.67] and 1.86 [1.32-2.62], respectively) but not in those aged 50-59 years and ≥60 years (P for age interaction <0.01 for systolic and diastolic BP). The associations with colorectal cancer mortality were similar in the analyses stratified by smoking, alcohol-drinking, obesity, and diabetic status. In conclusion, high BP among young to middle-aged adults was independently associated with risk of colorectal cancer mortality later in life.

Association of Pro-Inflammatory Diet with Long-Term Risk of All-Cause and Cardiovascular Disease Mortality: NIPPON DATA80.

AIM: A pro-inflammatory diet may increase the risk of cardiovascular disease (CVD) and all-cause mortality. However, this remains inconclusive as there is yet no study using a dietary record method that has been conducted in a large general population. Furthermore, an underestimation of the pro-inflammatory diet may exist due to the unmeasured effect of salt intake. Thus, in this study, we aimed to examine how pro-inflammatory diet is associated with the long-term risk of all-cause and CVD mortality in a representative Japanese population. METHODS: A national nutrition survey was conducted throughout Japan in 1980. After considering the exclusion criteria, 9284 individuals (56% women aged 30-92 years) were included in this study. In total, 20 dietary parameters derived from 3-day weighed dietary records were used to calculate the dietary inflammatory index (DII). The causes of death were monitored until 2009. The Cox proportional hazards model was used to determine multivariable-adjusted hazard ratios (HRs). Stratified analysis according to salt intake level was also performed. RESULTS: Compared with the lowest quartile of DII, multivariable-adjusted HRs (95% confidence intervals) in the highest quartile were 1.28 (1.15, 1.41), 1.35 (1.14, 1.60), 1.48 (1.15, 1.92), 1.62 (1.11, 2.38), and 1.34 (1.03, 1.75) for all-cause mortality, CVD mortality, atherosclerotic CVD mortality, coronary heart disease mortality, and stroke mortality, respectively. Stratified analysis revealed stronger associations among individuals with higher salt intake. CONCLUSIONS: As per our findings, a pro-inflammatory diet was determined to be positively associated with the long-term risk of all-cause and CVD mortality in a representative Japanese population. Thus, considering both salt intake and pro-inflammatory diet is deemed crucial for a comprehensive assessment of CVD risk.

Epidemiology of Acute Aortic Dissection in a General Population of 1.4 Million People in Japan　- Shiga Stroke and Heart Attack Registry.

BACKGROUND: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease, with a reported incidence rate ranging from 2.5 to 7.2 per 100,000 person-years in several population-based registries in Western countries, but epidemiological data are lacking in Japan.Methods and Results: The Shiga Stroke and Heart Attack Registry is an ongoing multicenter population-based registry of cerebro-cardiovascular diseases. We enrolled patients who developed AAD, defined by any imaging examination method from 2014 to 2015 in Shiga Prefecture. Death certificates were used to identify cases that were not registered at acute care hospitals. The incidence rates of AAD were calculated by age categories and adjusted using standard populations for comparison. We evaluated differences in patient characteristics between Stanford type A-AAD and type B-AAD subtypes. A total of 402 incident cases with AAD were analyzed. The age-adjusted incidence rates using the 2015 Japanese population and the 2013 European Standard Population were 15.8 and 12.2 per 100,000 person-years, respectively. Compared with cases of type B-AAD, those with type A-AAD were older (75.0 vs. 69.9 years, P=0.001) and more likely to be women (62.3% vs. 28.6%, P<0.001). CONCLUSIONS: Population-based incidence rates of AAD in Japan appear to be higher than in previous reports from Western countries. Incident cases with type A-AAD were older and female predominance.

Association between Dietary Patterns and Serum Low Density Lipoprotein Cholesterol in Japanese Women and Men: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.

AIMS: The association between dietary patterns and serum low density lipoprotein (LDL) cholesterol would be changing in recent dietary habits in Japan. We investigated the relationship between dietary patterns and serum LDL cholesterol in a large general population. METHODS: From the baseline survey of Japan Multi-Institutional Collaborative Cohort Study between 2005 and 2013, 27,237 participants (13,994 were women) aged 35-69 years were cross-sectionally analyzed. Using a semi-quantitative food frequency questionnaire, five major sex-specific dietary patterns were identified using factor analysis. We assessed serum LDL cholesterol by quintiles of dietary pattern factor score. RESULTS: We identified dietary patterns; "vegetable rich pattern" , "meat and fried food rich pattern" and "high bread and low rice pattern" in women and men; "fish and shellfish rich pattern" and "high confectioneries and low alcohol pattern" in men; "healthy Japanese diet pattern" and "high alcohol and low rice pattern" in women. Serum LDL cholesterol in men was associated with "high bread and low rice pattern" score (Q5 was 4.2 mg/dL higher than Q1, p for trend ＜0.001) and "high confectioneries and low alcohol pattern" scores (Q5 was 9.5 mg/dL higher than Q1, p for trend ＜0.001). In women, serum LDL cholesterol was associated with "high bread and low rice pattern" score (Q5 was 7.1 mg/dL higher than Q1, p for trend ＜0.001). CONCLUSION: Some recent dietary patterns in Japan were associated with serum LDL cholesterol. Serum LDL cholesterol was associated with high bread and low rice pattern in both sex, and high confectioneries and low alcohol pattern in men.

Incidence and In-Hospital Mortality of Acute Myocardial Infarction: A Report from a Population-Based Registry in Japan.

AIM: To investigate the incidence and in-hospital mortality of acute myocardial infarction (AMI) by conforming to the Universal Definition of Myocardial Infarction (UDMI) in a population-based registry. METHODS: The Shiga Stroke and Heart Attack Registry is a multicenter, population-based registry in the Shiga Prefecture, designed to evaluate the incidence and prognosis of acute cerebro-cardiovascular diseases. We registered patients with AMI as defined by the UDMI, who developed AMI from January 2014 to December 2015 in the Shiga Prefecture. The incidence rate of AMI was calculated and standardized for age by a direct method using the 2015 Japanese population. We also evaluated the in-hospital mortality among hospitalized patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). RESULTS: A total of 1,587 patients were diagnosed with AMI, and the age-adjusted incidence rate was 61.9 per 100,000 person-years. The proportions of patients with STEMI, NSTEMI, and type 3 myocardial infarction were 57%, 30%, and 12%, respectively. The incidence rates of AMI increased with age regardless of sex, which was the highest in those 85 years and older, with 389.7 per 100,000 person-years in men and 221.8 per 100,000 person-years in women. Age-adjusted in-hospital mortality among hospitalized patients with STEMI and NSTEMI was 12.3% and 5.8%, respectively. CONCLUSIONS: This population-based registry clarified the age-adjusted incidence rate of AMI under the application of the UDMI, highlighting that in-hospital mortality is still high among patients with STEMI in Japan.

[A case of non-fluent/agrammatic variant of primary progressive aphasia with logoclonia].

We report a case of non-fluent/agrammatic variant of primary progressive aphasia in a 79-year-old right-handed man who was admitted with a 5-year history of non-fluent speech and apraxia of speech. He also presented with agrammatism and logoclonia (the meaningless repetition of the middle or final syllable of a word). Furthermore, brain MRI revealed atrophy of the bilateral frontal and temporal lobes, while N-isopropyl-p-123I-iodoamphetamine single-photon emission computed tomography (SPECT) revealed relative hypoperfusion in the right basal ganglia. In addition, dopamine transporter SPECT revealed a decrease in specific binding ratio values, indicating neural dopamine dysfunction, which led to his diagnosis of progressive non-fluent aphasia with logoclonia. Logoclonia is a severe linguistic dysfunction usually observed in the advanced stages of Alzheimer's disease. However, based on the clinical course and cerebrospinal fluid evaluation results, our patient did not show any features of Alzheimer's disease. Thus, logoclonia might be associated with lesions involving the basal ganglia, right hemisphere, and left frontotemporal lobe.

Effect of diabetes and prediabetes on the development of disability and mortality among middle-aged Japanese adults: A 22-year follow up of NIPPON DATA90.

AIMS/INTRODUCTION: To examine the association between diabetes and prediabetes at baseline, and disability, mortality over a 22-year period among middle-aged Japanese adults. MATERIALS AND METHODS: Participants consisted of 1,788 adults aged 45-64 years at baseline from the cohort study National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 1990 (NIPPON DATA90). Disability, defined as having a decline in activities of daily living (ADL), was assessed by a modified Katz questionnaire at four time points. Disability and death without disability for 22-year follow up were used as outcomes to test the association with a diagnosis of diabetes or prediabetes at baseline, using multinomial logistic regression. Adjusted odds ratios (ORs) were obtained from four models that contained appropriate adjustment factors, such as age, sex, smoking status, drinking status, body mass index and cardiovascular risk factors (hypertension, hypercholesterolemia, triglycerides, low serum high-density lipoprotein), at baseline. RESULTS: In the present study, 334 participants (18.7%) reported at least one disability, and 350 (19.6%) were reported dead without observation of disability during follow up. Adjusting sex and other risk factors, participants with diabetes and prediabetes had a higher risk for disability (OR 1.43, 95% confidence interval [CI] 1.07-1.91 and OR 1.66, 95% CI 1.10-2.50, respectively) and for mortality (OR 1.56, 95% CI 1.16-2.08 and OR 1.77, 95% CI 1.18-2.65, respectively) than individuals with normal glucose tolerance. CONCLUSIONS: In middle-aged Japanese adults, individuals with diabetes and prediabetes were more likely to be associated with disability and mortality. Our findings suggest that prediabetes and diabetes in middle-aged adults should be paid more attention, and requires more intervention to prevent disability and mortality in later life.

Association of ambulatory blood pressure with aortic valve and coronary artery calcification.

OBJECTIVE: We aimed to investigate the effect of ambulatory blood pressure (BP) on aortic valve calcification (AVC) and coronary artery calcification (CAC), which are subclinical atherosclerotic diseases. METHODS: In this population-based, cross-sectional study, we assessed office BP, mean ambulatory BP (24-h, awake, and asleep), and variability of ambulatory BP, as determined by the coefficient of variation (awake and asleep). AVC and CAC were quantified using an Agatston score (>0) based on computed tomography scanning. We calculated relative risks (RRs) and 95% confidence intervals (CIs) with a 1-standard deviation increment in each BP index for the presence of AVC and CAC using a multivariate-adjusted Poisson regression with robust error variance. RESULTS: Of 483 participants (mean age: 66.8 years), 154 (31.9%) and 310 (64.2%) had AVC and CAC, respectively. The presence of AVC was associated with office systolic BP (SBP; RR, 1.15; 95% CI, 1.03-1.28), awake diastolic BP (DBP) variability (RR, 1.12; 95% CI, 1.01-1.25), and asleep SBP variability (RR, 1.14; 95% CI, 1.03-1.27). The presence of CAC was associated with office SBP (RR, 1.08; 95% CI, 1.01-1.15), mean 24-h SBP (RR, 1.10; 95% CI, 1.04-1.16), mean awake SBP (RR, 1.11; 95% CI, 1.04-1.17), mean asleep SBP (RR, 1.07; 95% CI, 1.01-1.13), and asleep SBP variability (RR, 1.07; 95% CI, 1.01-1.13). CONCLUSION: These findings highlight the association of ambulatory BP indices with both AVC and CAC, but with different effects on their presences.

[Investigating the relationship between higher life functions, overall mortality, and incidence of care needs in long-term follow-up study of the local population: The Kamogawa Cohort Study].

Objectives　In addition to physical independence such as ADLs, higher-level functional capacity ("instrumental self-maintenance," "intellectual activity," and "social role") are necessary to lead the final stage of life as independently and for as long as possible. Accordingly, in a long-term follow-up study of the local population, we examined the association of health status (total mortality and incidence of care needs) with instrumental independence, intellectual activity, and social role.Methods　We used participant data from the Kamogawa cohort study, which included surveyed use of health service, health status, disease prevalence, and use of long-term care insurance service for Kamogawa citizens in Chiba prefecture from 2003 to 2013. We compared the differences in lifestyle and higher-level functional capacity, by status of death and using the Long-term Care Insurance service. Higher-level functional capacity was assessed with the Tokyo Metropolitan Institute of Gerontology-Index of Competence (TMIG-IC); answer to each question, each domain score, and total score were examined.Results　During the follow-up period to the end of March 2013, 810 deaths and 917 care needs were observed among the 6,503 people who consented to be followed up. The adjusted HR of higher-level functional capacity for all-cause mortality was "instrumental self-maintenance," score 4 or 5 to less than 3: 2.03 (95%CI: 1.59-2.60), "intellectual activity," score 4 to less than 3: 1.39 (95%CI: 1.09-1.77), and "social role," score 4 to less than 3: 1.28 (95%CI: 1.03-1.59). In subgroup analyses by sex, "instrumental self-maintenance" was associated with both men and women, but "intellectual activity" and "social roles" were associated with women only. The adjusted HRs for the incidence of care needs were 1.93 (95%CI: 1.55-2.40) for "instrumental self-maintenance" and 1.30 (95%CI: 1.07-1.58) for "social role." In subgroup analyses by sex, "instrumental self-maintenance" was associated with both genders, but "social role" was observed only for women.Conclusion　Higher-level functional capacity ("instrumental self-maintenance," "intellectual activity," and "social role") was significantly associated with total mortality and incidence of care needs.

[Secular trends of breast cancer detection rate in Japan: Age, period, birth cohort, and region effects from 2004 to 2015].

Objective　The purpose of this study was to investigate the influence of age, period, birth cohort, and regional differences in the detection of breast cancer using screening data.Method　Data from the Japan Cancer Society's breast cancer screening program, collected from 21 prefectural branches between 2004 to 2015, were used to generate age-specific estimates of cancer detection for women aged between 40 to 79 years. We used Bayesian age-period-cohort (APC) analyses based on the cohort table to describe the simultaneous effects of age, period, and cohort on breast cancer detection rates to understand the population dynamics underlying the detection patterns. We also incorporated region as a random effect to examine regional characteristics.Results　The age effect showed bimodality in the late 40s and late 50s. The period effect decreased from 2004 to 2007 and remained constant thereafter. The cohort effect showed that the detection rate for women born between 1943 and 1958 was high. Furthermore, we found regional differences in the breast cancer detection rate: Miyazaki, Fukui, Tochigi, and Hokkaido prefectures showed higher detection rates, while Kagoshima and Chiba prefecture had lower rates.Conclusion　Age effect has the strongest influence on the secular trend of breast cancer detection, and there is a regional difference in the detection rate. The present study that used screening data presented similar results to those of previous studies. The National Cancer Registry, based on the Cancer Registry Act of 2016, reports accurate national data. Similar to the National Cancer Registry data, analysis using screening data has immediacy and could be used for disease prevention.

Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study.

INTRODUCTION: Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with high affinity and reverses its anticoagulant effect. This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab in healthy Chinese subjects at steady state of dabigatran and explored the effect of idarucizumab on PK and PD of dabigatran. METHODS: Twelve subjects received dabigatran etexilate treatment alone (220 mg twice daily, b.i.d., oral). After a washout period, the 12 subjects again received dabigatran etexilate (220 mg b.i.d., oral) and idarucizumab (2.5 + 2.5 g, intravenous) 2 h after the last administration of dabigatran etexilate. RESULTS: The geometric mean (gMean) values of area under the plasma concentration-time curve (AUC0-∞) and maximum concentration (Cmax) were 44,200 nmol h/L and 30,900 nmol/L, respectively. An amount of 35.3 µmol of idarucizumab, corresponding to 33.8% of the total dose, was excreted by urine over 72 h. The area under the effect (AUECabove,2-12) in the presence and absence of idarucizumab was close to zero for all coagulation parameters, diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT), which indicated the reversal of dabigatran anticoagulation by idarucizumab. There were no serious adverse events reported in this study. No subject tested positive for anti-idarucizumab antibodies. CONCLUSION: Idarucizumab was well tolerated and no subject tested positive for anti-idarucizumab antibodies in this study. PK and PD of idarucizumab in healthy Chinese subjects at a steady state of dabigatran were comparable with those in Japanese and Caucasian subjects. CLINICAL REGISTRATION: ClinicalTrials.gov Identifier No. NCT03086356.

Pharmacokinetics and Safety of Dabigatran Etexilate after Single and Multiple Oral Doses in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Dabigatran etexilate is a non-vitamin K antagonist oral anticoagulant (NOAC) that is used to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation (NVAF) and one or more risk factors. Pharmacokinetic data on this anticoagulant in Chinese subjects are limited. This study aimed to provide further information on the pharmacokinetic profile of dabigatran in healthy Chinese subjects, together with its safety profile. METHODS: This was an open-label, single-centre, phase I study. Subjects were randomized into 110 and 150 mg dabigatran etexilate treatment groups. Each subject received 7 days of treatment: a single dose on day 1, no dose on days 2-3, and then multiple doses on days 4-10. Blood samples were collected to analyze the pharmacokinetic profile of dabigatran. All adverse events (AEs) were recorded. Routine clinical laboratory tests, a physical examination, vital signs, and 12-lead electrocardiogram (ECG) measurements were performed. RESULTS: A total of 28 subjects (14 males and 14 females) were randomized in this trial. The plasma concentration of total dabigatran reached its maximum measured concentration at a median time of 3-4 h from the dose of interest (either the initial single dose on day 1 or the final dose on day 10) under fed conditions, and declined with an elimination half-life of 10.7-10.9 h following the dose of interest. There was a modest difference in pharmacokinetic profile between male and female subjects. None of the subjects experienced a serious adverse event (SAE) or an AE of moderate or severe intensity. The investigator reported that 17 of the 28 subjects had mild treatment-emergent AEs that resolved without any concomitant treatment or intervention. No clinically significant changes in vital signs or ECG parameters were observed. CONCLUSIONS: This study revealed the pharmacokinetic characteristics and good safety profile of dabigatran in healthy Chinese subjects.

Role of Proton Motive Force in Photoinduction of Cytoplasmic Streaming in Vallisneria Mesophyll Cells.

In mesophyll cells of the aquatic monocot Vallisneria, red light induces rotational cytoplasmic streaming, which is regulated by the cytoplasmic concentration of Ca2+. Our previous investigations revealed that red light induces Ca2+ efflux across the plasma membrane (PM), and that both the red light-induced cytoplasmic streaming and the Ca2+ efflux are sensitive to vanadate, an inhibitor of P-type ATPases. In this study, pharmacological experiments suggested the involvement of PM H+-ATPase, one of the P-type ATPases, in the photoinduction of cytoplasmic streaming. We hypothesized that red light would activate PM H+-ATPase to generate a large H+ motive force (PMF) in a photosynthesis-dependent manner. We demonstrated that indeed, photosynthesis increased the PMF and induced phosphorylation of the penultimate residue, threonine, of PM H+-ATPase, which is a major activation mechanism of H+-ATPase. The results suggested that a large PMF generated by PM H+-ATPase energizes the Ca2+ efflux across the PM. As expected, we detected a putative Ca2+/H+ exchange activity in PM vesicles isolated from Vallisneria leaves.

Bioequivalence of a Newly Developed Dabigatran Etexilate Tablet Versus the Commercial Capsule and Impact of Rabeprazole-Induced Elevated Gastric pH on Exposure in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Dabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran. METHODS: BE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged ≥ 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC0-tz) and maximum plasma concentration (Cmax) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC0-tz and Cmax of total dabigatran. RESULTS: In total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC0-tz (101.4-116.0%) and Cmax (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC0-tz (667 to 192 ng h/mL) and Cmax (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study. CONCLUSION: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166.

tRNA Wobble Modification Affects Leaf Cell Development in Arabidopsis thaliana.

The tRNA modification at the wobble position of Lys, Glu and Gln (wobbleU* modification) is responsible for the fine-tuning of protein translation efficiency and translation rate. This modification influences organism function in accordance with growth and environmental changes. However, the effects of wobbleU* modification at the cellular, tissue, or individual level have not yet been elucidated. In this study, we show that sulfur modification of wobbleU* of the tRNAs affects leaf development in Arabidopsis thaliana. The sulfur modification was impaired in the two wobbleU*-modification mutants: the URM1-like protein-defective mutant and the Elongator complex-defective mutants. Analyses of the mutant phenotypes revealed that the deficiency in the wobbleU* modification increased the airspaces in the leaves and the leaf size without affecting the number and the area of palisade mesophyll cells. On the other hand, both mutants exhibited increased number of leaf epidermal pavement cells but with reduced cell size. The deficiency in the wobbleU* modification also delayed the initiation of the endoreduplication processes of mesophyll cells. The phenotype of ASYMMETRIC LEAVES2-defective mutant was enhanced in the Elongator-defective mutants, while it was unchanged in the URM1-like protein-defective mutant. Collectively, the findings of this study suggest that the tRNA wobbleU* modification plays an important role in leaf morphogenesis by balancing the development between epidermal and mesophyll tissues.

Absolute risk score for stroke, myocardial infarction, and all cardiovascular disease: Japan Arteriosclerosis Longitudinal Study.

To develop a risk chart or score that is based on recent data and applicable to the Japanese people, we need a large cohort study representative of the Japanese people without a need for long-term follow-up. The purpose of the present study was to develop a risk scoring system to estimate the 5- and 10-year absolute and cumulative incidence risk of stroke and acute myocardial infarction (AMI), composite outcome of stroke and AMI, and death from all cardiovascular disease (CVD). The cumulative incidence risk ratios were calculated using a multiple Poisson regression model and data from the Japan Arteriosclerosis Longitudinal Study, which included 67,969 men and women aged 40-89 years. An absolute risk scoring system for 5- and 10-year risk was developed. For blood pressure categories, the risk ratios for all outcomes increased from normal blood pressure (systolic blood pressure (SBP) 120-129 mmHg and diastolic blood pressure (DBP) 80-89 mmHg) to grade III hypertension (SBP ≥ 180 and/or DBP ≥ 110) based on the 2014 Guidelines for the Management of Hypertension compared to the reference optimal blood pressure (SBP < 120 and DBP < 80). Grade II (SBP 160-179 and/or DBP 100-109) and III hypertension treated with medication showed a lower risk compared to counterparts without medication. Other risk factors showed reasonable figures. The total of scores for each risk factor indicated the estimated absolute risk for stroke and AMI, the composite outcome of stroke and AMI, and all CVD. This scoring system may contribute to patient education and to the development of strategies for reducing CVD in the population.