The G7 presidency and universal health coverage, Japan's contribution.

PROBLEM: If universal health coverage (UHC) is to be achieved globally, it needs sustained promotion and political awareness and support. APPROACH: During its presidency of the Group of Seven (G7) industrialized nations in 2016, Japan aimed to raise the issue of UHC to the top of the global health agenda. LOCAL SETTING: Japan has promoted a health agenda at all of the G7 summits since 2000 that it has hosted. Human security has been the core foundation of Japan's foreign diplomacy for several decades and, consequently, there was no apparent opposition within Japan to the inclusion of UHC on the agenda of the summit in 2016. Other G7 governments appeared keen to promote such coverage. RELEVANT CHANGES: Since the 2016 summit, UHC has remained a central agenda item for the United Nations and World Health Organization, even though the leaders of both these global organizations have changed. In 2017, Japan hosted the UHC Forum in Tokyo. The participants, who were the heads of United Nations agencies, politicians and other decision-makers from all over the world, showed their continued commitment towards UHC. LESSONS LEARNT: In the raising of awareness of an item on the global health agenda, high-level champions are critical. Although they may be very diverse, all relevant stakeholders need to be connected and allowed to discuss policies with each other. Having too many allies can, however, lead to policy fragmentation, especially when there is commitment from the highest echelons within each country.

Response to Ebola virus disease outbreak in West Africa by the Ministry of Health, Labour and Welfare of Japan in 2014-2015.

Ebola Virus Disease (EVD) is categorized in the Category 1 Infectious Disease under the Act on Infectious Disease Control. Since the Act came into effect in 1999, no confirmed case of viral hemorrhagic fevers (VHF) has been reported, though some clinical samples have been tested for VHF in the National Institute of Infectious Diseases of Japan. Ministry of Health, Labour and Welfare has monitored the situation of the EVD outbreak in West Africa since the first report from Guinea in March 2014 and reinforced quarantine and public health preparedness in August. The whole-of-government response was activated at the end of October, establishing the Ministerial meeting on the Response to the EVD presided by the Prime Minister. The responses have raised the level of preparedness for such a rare import disease like VHF; however elicited many lessons. Even if the current VHF outbreak is over, the risk of the global infectious diseases outbreak will be unchanged. The maintenance and improvement of preparedness and response for infectious diseases emergency such as the Category 1 Infectious Disease outbreak by the improvement of manuals and continuous exercises are crucial for a future domestic response. In addition, human resource development is essential for contributing to global response efforts.

High catalytic performance of Al-Pd-(Ru, Fe) icosahedral approximants for acetylene semi-hydrogenation.

Three cubic crystalline icosahedral approximants (C phase: Al72.0Pd16.4Fe11.6, P40 phase: Al72.0Pd16.4Ru11.6, P20 phase: Al70.0Pd22.3Ru7.7) exhibit high ethylene selectivity of over 90% for hydrogenating acetylene at 150 °C. Moreover, the powdered P20 also demonstrates a high catalytic performance under an industry-like ethylene feed containing 0.5% acetylene as an impurity. Overall, icosahedral approximants in the Al-Pd-(Ru, Fe) systems are promising as a novel class of alloy catalysts.

A case of primary aldosteronism associated with renal artery stenosis and preclinical Cushing's syndrome.

We identified a left adrenal tumor, left renal atrophy, and left renal artery stenosis (RAS) in a 52-year-old man by MRI/magnetic resonance angiography (MRA) during evaluation of hypertension. Laboratory tests revealed hypokalemia, a high plasma aldosterone concentration (PAC), low plasma renin activity (PRA), and normal plasma cortisol. An excessive response of aldosterone and cortisol to adorenocorticotrophic hormone (ACTH) was found upon selective sampling of the left adrenal vein. Selective renal venous sampling showed a left/right renal venous PRA ratio of 1.7. A dexamethasone (8 mg) suppression test showed insufficient suppression of cortisol. We diagnosed this patient as having aldosterone-producing adrenal adenoma (APA) associated with renovascular hypertension (RVH) and preclinical Cushing's syndrome. As an initial treatment, percutaneous transluminal renal angioplasty was performed. Postoperatively, the patient's blood pressure decreased. One month later, the tumor was removed by complete laparoscopic left adrenalectomy. Postoperatively, blood pressure decreased further and both PAC and PRA were normalized. However, antihypertensive therapy could not be completely stopped. The renal dysfuntion that occurred prior to treatment seemed to prevent complete normalization of blood pressure.

Mapping stakeholders and policies in response to deliberate biological events.

BACKGROUND: Recent infectious disease outbreaks have brought increased attention to the need to strengthen global capacity to prevent, detect, and respond to natural biological threats. However, deliberate biological events also represent a significant global threat, but have received relatively little attention. While the Biological Weapons Convention provides a foundation for the response to deliberate biological events, the political mechanisms to respond to and recover from such an event are poorly defined. METHODS: We performed an analysis of the epidemiological timeline, the international policies triggered as a notional deliberate biological event unfolds, and the corresponding stakeholders and mandates assigned by each policy. FINDINGS: The results of this analysis identify a significant gap in both policy and stakeholder mandates: there is no single policy nor stakeholder mandate for leading and coordinating response activities associated with a deliberate biological event. These results were visualized using an open source web-based tool published at https://dbe.talusanalytics.com. INTERPRETATION: While there are organizations and stakeholders responsible for leading security or public health response, these roles are non-overlapping and are led by organizations not with limited interaction outside such events. The lack of mandates highlights a gap in the mechanisms available to coordinate response and a gap in guidance for managing the response. The results of the analysis corroborate anecdotal evidence from stakeholder meetings and highlight a critical need and gap in deliberate biological response policy.

[Measurement and evaluation of home blood pressure monitoring with particular emphasis on evaluating anti-hypertensive effects using a home blood pressure distribution diagram].

Tight blood pressure control over a long period is important to prevent end-organ damage to the brain, heart, and kidneys, and to avoid the complications of hypertension. Control requires an accurate evaluation of treatment through an appropriate monitoring of home blood pressure. In this study, we evaluated a method of home blood pressure monitoring, in which we propose a home blood pressure distribution diagram to evaluate the effectiveness of anti-hypertensive therapy. 1 ) In home blood pressure measurements, the first reading was high, while the second and third readings were essentially similar and thus stable. 2 ) Home blood pressure showed great daily variations, thus necessitating the use of the mean blood pressure over a fixed period, and not the individual blood pressure readings. The mean (morning, mid-day, and evening) over a one-week period was unstable, while the readings were stable over a three-week period. 3 ) The diagrams showing the distribution of home blood pressure measurements obtained in the morning and at night over a long period allowed the degree of early morning hypertension and the effectiveness of long-term blood pressure control to be assessed, and thus were useful for selecting anti-hypertensive agents. 4 ) In elderly patients, a mid-day systolic pressure of 100 mmHg or less (particularly 90 mmHg or less) resulted in the onset of symptoms of excessive hypotensive effects, such as lightheadedness and fainting, which affected ADL and QOL. 5 ) Because of great daily variations, it is difficult to achieve the blood pressure target of 130/80 mmHg or less in patients with hypertension associated with diabetes mellitus or renal insufficiency. 6 ) The home blood pressure distribution diagram facilitated an understanding of the status of anti-hypertensive therapy by patients, and was useful for motivating patients to continue treatment.

The combination therapy of hypertension to prevent cardiovascular events (COPE) trial: rationale and design.

A number of major clinical trials have demonstrated the clinical benefits of lowering blood pressure and have indicated that a majority of patients with hypertension will require more than one drug to achieve optimal blood pressure control. However, there is little data showing which antihypertensive combination best protects patients from cardiovascular events and which best achieves the target blood pressure with the fewest adverse events. The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial is the first large-scale investigator-initiated multicenter study with a prospective, randomized, open, blinded endpoint evaluation (PROBE) design to directly compare cardiovascular mortality and morbidity, incidence of adverse drug reaction, and degree of blood pressure reduction in Japanese hypertensive patients for a combination of angiotensin receptor blockers, beta-blockers or thiazide diuretics in addition to a calcium antagonist, benidipine hydrochloride, with a response-dependent dose titration scheme. The COPE trial is being conducted with the cooperation of more than 100 centers and clinics in Japan and involves 3,000 patients, who will be followed for 3 years. Eligible patients are being enrolled from May 2003 until May 2006. Results from the COPE trial should provide new evidence for selecting optimal combination therapies for hypertensive patients.

Renoprotective effect of angiotensin-converting enzyme inhibitor combined with alpha1-adrenergic antagonist in spontaneously hypertensive rats with renal ablation.

To assess the renal benefits of combined angiotensin-converting enzyme inhibition and alpha(1)-adrenergic antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone and in combination with doxazosin (DOX) in spontaneously hypertensive rats (SHR)/Izumo rats with renal ablation. Five-Sixths-nephrectomized rats were assigned to receive TMP (10 mg/kg/day) (TMP group), TMP plus DOX (2 mg/kg/day) (TMP+DOX group), or vehicle (control group) orally for 12 weeks. Both systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) in the control group progressively increased during the experimental period and were significantly higher than in sham-operated rats. Treatment with either TMP or TMP plus DOX had similar antihypertensive effects in this rat model. Twelve weeks after initiation of treatment, the SBP values in the control, TMP, and TMP+DOX groups were 265+/-8, 157+/-4, and 163+/-3 mmHg, respectively, in comparison with 233+/-4 mmHg in sham-operated rats (p<0.0001 control vs. sham, p<0.001 TMP vs. control, p<0.001 TMP+DOX vs. control). UalbV, serum creatinine (Scr), blood urea nitrogen (BUN), and heart weight/body weight (HW/BW) ratio were significantly lower in the TMP and TMP+DOX groups than in the control group (UalbV: p<0.05; Scr: p<0.01; [BUN, HW/BW ratio]: p<0.0001; and [UalbV, Scr, BUN, HW/BW ratio]: p<0.0001 vs. control, respectively). The index of glomerular sclerosis (IGS) and relative interstitial volume (RIV) were significantly lower in the TMP+DOX group than in the control group (IGS: p<0.05; RIV: p<0.01). Especially, UalbV, IGS, and RIV were significantly better in the TMP+DOX group than in the TMP group ([IGS, RIV]: p<0.05; UalbV: p<0.01). These results suggest that simultaneous administration of TMP and DOX provides greater renoprotective effects than administration of TMP alone.

Combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and a calcium antagonist: beyond the renoprotective effects of ACE inhibitor monotherapy in a spontaneous hypertensive rat with renal ablation.

To assess the renal benefits of combined angiotensin-converting enzyme inhibition and calcium antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone or in combination with azelnidipine (AZN) in a spontaneously hypertensive rat (SHR) remnant kidney model of chronic renal failure. Male 5/6-nephrectomized SHR/Izumo rats were randomly assigned to receive vehicle (control group), TMP (TMP group; 10 mg x kg(-1) x day(-1)), AZN (AZN group; 3 mg x kg(-1) x day(-1)), or both (TMP+AZN group) orally for 12 weeks. Systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) were measured every 2 weeks. At the end of the experiment, serum creatinine (Scr), heart weight (HW), and blood urea nitrogen (BUN) levels were measured and the remnant kidneys were examined to determine the index of glomerular sclerosis (IGS). SBP and UalbV in the control group increased progressively throughout the experimental period. TMP, AZN, and TMP+AZN blocked the development of hypertension. TMP+AZN did not enhance the antihypertensive effects of either TMP or AZN used singly. TMP, AZN, and TMP+AZN all significantly decreased the UalbV, Scr, BUN, and HW/body weight (BW) ratio. The level of UalbV and the HW/BW ratio in the TMP+AZN group were significantly lower than those in the TMP and AZN groups, and the level of Scr in the TMP+AZN group was significantly lower than that in the TMP group. TMP, AZN, and TMP+AZN all significantly protected against an increase in the IGS. The IGS in the TMP+AZN group was significantly lower than that in the TMP and AZN groups. These results indicate that both TMP and AZN have antihypertensive and renoprotective effects in this model. They also suggest that simultaneous administration of TMP and AZN provides greater renoprotective effects than TMP alone.

Increase in pulse pressure relates to diabetes mellitus and low HDL cholesterol, but not to hyperlipidemia in hypertensive patients aged 50 years or older.

Higher pulse pressure is associated with higher cardiovascular risk. We investigated the relationship between pulse pressure and known metabolic risk factors in hypertensive patients who had not experienced stroke or myocardial infarction. In a multicenter cross-sectional survey made in 1995, we registered 939 hypertensive patients aged > or = 50 years. Of these, 734 had never experienced stroke or myocardial infarction. We divided these 734 patients into two groups based on the value of their pulse pressures: 396 patients with a pulse pressure > or = 60 mmHg, and 338 patients with a pulse pressure<60 mmHg. The average pulse pressure value was 72 +/- 12 mmHg in the former group, and 49 +/- 8 mmHg in the latter group. The former group exhibited advanced age, a higher women-to-men ratio, lower high-density lipoprotein (HDL) cholesterol, and higher systolic and lower diastolic blood pressure. Diabetes mellitus (DM) and left ventricular hypertrophy were more frequently noticed in the former group than in the latter group. The prevalence of hyperlipidemia, however, was similar in the two groups. The association of pulse pressure with DM and low HDL cholesterol was statistically significant by multiple logistic analysis adjusted for age, sex, and other known cardiovascular risk factors. In conclusion, pulse pressure increases with advancing age. DM made a substantially larger contribution to the increase in pulse pressure than hyperlipidemia.

Antiproteinuric effect of candesartan cilexetil in patients with chronic glomerulonephritis.

A prospective, randomised, double-blind, parallel-group, dose-response trial was conducted to investigate the antiproteinuric effect of candesartan cilexetil, the angiotensin II type 1 receptor blocker, in patients with chronic glomerulonephritis. Patients (n=280) were treated for 12 weeks with candesartan cilexetil 2, 4, or 8 mg given orally once-daily (o.d.). The improvement in urinary protein excretion observed at the end of the treatment period was 15.9% in the 2 mg group, 25.6% in the 4 mg group, and 34.6% in the 8 mg group, respectively, showing a clear dose-response (2 mg <4 mg <8 mg; p=0.003). The mean reduction in urinary protein excretion was 11.3% in the 2 mg group, 26.3% in the 4 mg group, and 26.0% in the 8 mg group, showing a dose-response pattern, in that the effect of 4 mg and 8 mg was greater than that of 2 mg (2 mg <4 mg asymptotically equal to 8 mg; p=0.010). As the observed reduction in urinary protein excretion failed to correlate with changes in mean blood pressure, it could not be attributed to the antihypertensive effect of the study drug alone. This suggests that candesartan cilexetil, 4 8 mg o.d., has antiproteinuric effects in patients with chronic glomerulonephritis.

Effects of the long-acting calcium channel blocker barnidipine hydrochloride on 24-h ambulatory blood pressure.

The effect of the long acting calcium channel blocker, barnidipine hydrochloride (barnidipine) on 24-h ambulatory blood pressure (ABP) was evaluated in J-MUBA (Japanese Multicentre Study on Barnidipine with Ambulatory Blood Pressure Monitoring). Following an observation period of two weeks, antihypertensive treatment with barnidipine was continued for at least six months. At the end of each period, ABP were measured. The patients were divided into high- and low-range groups based on ABP measurement. Throughout the 24 h, barnidipine exerted an excellent antihypertensive effect in the high-range group, but not in the low-range group. Barnidipine had comparable effects in the daytime and nighttime in inverted dippers and non-dippers, but it was more effective on daytime ABP than on nighttime ABP in dippers and in extreme dippers. Morning blood pressure before and after waking was evaluated before and after barnidipine administration in 233 patients. Barnidipine inhibited increases in blood pressure before and after waking, especially in surge-type patients whose blood pressure increased rapidly after waking. A positive correlation among 24-h ABP, daytime and night time ABP, morning blood pressure, and clinic blood pressure during the observation period and the antihypertensive effect of barnidipine was observed, with barnidipine exhibiting stronger antihypertensive effects in patients with persistently high blood pressure. It was concluded that the antihypertensive effects of barnidipine are maintained for 24 h but it has no excessive hypotensive effects on lower blood pressure and is thus a safe antihypertensive agent.

Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial.

OBJECTIVES: Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events. METHODS: We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90 mmHg) with calcium channel blocker (CCB) benidipine 4 mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), ß-blocker, or thiazide diuretic in addition to benidipine. RESULTS: Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-ß-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-ß-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P  = 0.3505) and 1.54 in the benidipine-ß-blocker (P = 0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P = 0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P = 0.0240) compared with benidipine and ß-blocker. All trial treatments were safe and well tolerated. CONCLUSION: CCB combined with ARB, ß-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.