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Internet-based information and communication technology is altering our lives. Although medicine is traditionally conservative, it can benefit in many ways from adopting new technology and styles of care. Hypertension is a prime condition for the practical application of digital health management because it is prevalent and undercontrolled, and its primary index, home blood pressure, can be effectively telemonitored. Compared to other conditions that require laboratory measures or the use of drugs with frequent side effects, hypertension can be managed without actual office visits with sufficiently low risk. In this review of hypertension in Japan, we discuss the current and somewhat fragmented state of internet technology and the components and processes necessary for smooth, integrated, and multidisciplinary care in the future. Although further clinical trials are required to show the safety and efficacy of information and communication technology-based care for hypertension, the deployment of telemonitoring and telemedicine in daily practice should be expedited to solve the hypertension paradox. Challenges remain relating to cost, data integration, the redesigning of team-based care, and the improvement of user experience, but information and communication technology-based hypertension management is sure to become pivotal in improving public health.

The saline infusion test (SIT) is widely used to confirm PA, but some patients may not tolerate the standard loading volume of 2 L saline over 4 h. The shortened SIT, loading only 1 L saline over 2 h, is suggested to be useful and would be more acceptable if the diagnostic utility of the shortened SIT is comparable to that of the standard SIT. We compared the diagnostic values of the plasma aldosterone concentration after 2 h of 1 L saline loading (2 h PAC) and that after 4 h of 2 L saline loading (4 h PAC) for the prediction of unilateral aldosterone hypersecretion and postoperative outcome. This retrospective, single-center study involved 555 PA-suspected patients who underwent SIT, 153 patients with adrenal vein sampling (AVS) results, and 37 patients with a 1-year postoperative evaluation. To detect the Japanese cutoff of 4 h PAC > 60 pg/mL, a 2-h PAC Youden Index at 66 pg/mL showed 91% sensitivity and 75% specificity. For unilateral aldosterone hypersecretion, the sensitivity and specificity of 2 h PAC were not inferior to those of 4 h PAC by Markov chain Monte Carlo (MCMC) methods. The sensitivity and specificity of 2 h PAC for postoperative reduction of anti-hypertensive drugs were also not inferior to those of 4 h PAC. Although using the 2 h PAC > 66 pg/mL cutoff may increase false positives for PA diagnosis, the shortened SIT, possibly using a cutoff value higher than 66 pg/mL, may be as useful as the standard SIT for selecting PA patients for AVS and to predict postoperative outcomes with reduced burden on patients.

Urinary measurement of fractionated metanephrines is one of the best available biochemical tests for the diagnosis of pheochromocytoma and paraganglioma; however, false-positive results remain an issue. In addition, despite their convenience, there is no evidence to suggest that spot urine samples should replace the standard 24-h urine collection method. The objective of this study is to elucidate clinical variables that may influence the levels of spot urine fractionated metanephrines and to examine their instability. The study is a retrospective review of prospectively collected data from 949 patients whose spot urine fractionated metanephrines were measured under suspicion of pheochromocytoma or paraganglioma at our institution from January 2011 to June 2017. The effects of clinical factors such as age, sex, renal function, and medications on the level of spot urine fractionated metanephrines were evaluated. Urinary fractionated metanephrines were significantly higher in female subjects. They correlated with age but not with estimated glomerular filtration rate (eGFR). A multivariate regression model for urinary fractionated metanephrine levels revealed that age, female sex, eGFR, and the presence of α1-blocker medication were significantly positively correlated with urinary metanephrine (M) levels. Age, female sex, eGFR, and presence of α1-blockers and antidepressant and antipsychotic medications positively correlated with urinary normetanephrine (NM). In addition, age, female sex, eGFR, and presence of α1-blockers and antidepressant and antipsychotic medications were positively correlated with urinary M + NM. In conclusion, sex, age, eGFR, and treatment with α1-blockers, antidepressants, and antipsychotics may affect the levels of urinary fractionated metanephrines. When assessing urinary fractionated metanephrines in patients with suspected PPGLs, we must consider these factors.

Summary Primary aldosteronism (PA) is more common than expected. Aberrant adrenal expression of luteinizing hormone (LH) receptor in patients with PA has been reported; however, its physiological role on the development of PA is still unknown. Herein, we report two unique cases of PA in patients with untreated Klinefelter’s syndrome, characterized as increased serum LH, suggesting a possible contribution of the syndrome to PA development. Case 1 was a 39-year-old man with obesity and hypertension since his 20s. His plasma aldosterone concentration (PAC) and renin activity (PRA) were 220 pg/mL and 0.4 ng/mL/h, respectively. He was diagnosed as having bilateral PA by confirmatory tests and adrenal venous sampling (AVS). Klinefelter’s syndrome was suspected as he showed gynecomastia and small testes, and it was confirmed on the basis of a low serum total testosterone level (57.3 ng/dL), high serum LH level (50.9 mIU/mL), and chromosome analysis. Case 2 was a 28-year-old man who had untreated Klinefelter’s syndrome diagnosed in his childhood and a 2-year history of hypertension and hypokalemia. PAC and PRA were 247 pg/mL and 0.3 ng/mL/h, respectively. He was diagnosed as having a 10 mm-sized aldosterone-producing adenoma (APA) by AVS. In the APA, immunohistochemical analysis showed co-expression of LH receptor and CYP11B2. Our cases of untreated Klinefelter’s syndrome complicated with PA suggest that increased serum LH levels and adipose tissues, caused by primary hypogonadism, could contribute to PA development. The possible complication of PA in hypertensive patients with Klinefelter’s syndrome should be carefully considered. Learning points: The pathogenesis of primary aldosteronism is still unclear. Expression of luteinizing hormone receptor has been reported in aldosterone-producing adenoma. Serum luteinizing hormone, which is increased in patients with Klinefelter’s syndrome, might contribute to the development of primary aldosteronism.

To retrospectively evaluate the variations of deep femoral artery (DFA) bifurcation on computed tomography (CT) and technical success in femoral venous access.CT images of 353 patients who underwent adrenal venous sampling were evaluated. Height with relation to the inferior border of the femoral head and direction of DFA bifurcations were classified as follows: type L, low bifurcation; type H1, high lateral bifurcation; type H2, high posterior to posterolateral bifurcation; type H3, high posteromedial bifurcation; and type H4, high medial bifurcation crossing in front of the femoral vein. Technical success and complications during femoral venous access were also evaluated.The frequencies of types L, H1, H2, H3, and H4 were 82.7%, 9.1%, 6.9%, 0.4%, and 0.9%, respectively. In 92.2% of type H1 and 69.4% of type H2, the superior femoral artery displaced medially by the high DFA partially overlapped the femoral vein. Upon the inclusions of H3 and H4, in 14.4% of cases, the high DFAs could obstruct the access route to the femoral vein. Using Doppler ultrasound guidance, no significant differences were observed in the rates of success for puncture in the first attempt (84.5% vs. 75.4%, p = 0.122) and accidental arterial puncture (1.0% vs. 0%, p = 1.00) between low and high DFA bifurcations, respectively.High DFA bifurcation is observed in 17.3% of patients and could obstruct the access route to the femoral vein. This can be evaluated using Doppler ultrasound guidance to avoid accidental arterial puncture during femoral venous access.

Background: Primary aldosteronism (PA) is more common than expected. Aberrant adrenal expression of LH receptor in patients with PA has been reported, however, its physiological role on the development of PA is still unknown. Herein, we report two unique cases of PA in patients with untreated Klinefelter’s syndrome, characterized as increased serum LH, suggesting a possible contribution of the syndrome to PA development. Clinical Cases: Case 1 was a 39-year-old man with obesity and hypertension since his 20s. His plasma aldosterone concentration (PAC) and renin activity (PRA) were 220 pg/mL and 0.4 ng/mL/h, respectively. He was diagnosed as having bilateral PA by confirmatory tests and adrenal venous sampling (AVS). Klinefelter’s syndrome was suspected as he showed gynecomastia and small testes, and it was confirmed on the basis of a low serum total testosterone level (57.3 ng/dL), high serum LH level (50.9 mIU/mL), and chromosome analysis. Case 2 was a 28-year-old man who had untreated Klinefelter’s syndrome diagnosed in his childhood and a two-year history of hypertension and hypokalemia. PAC and PRA were 247 pg/mL and 0.3 ng/mL/h, respectively. He was diagnosed as having a 10 mm-sized aldosterone-producing adenoma (APA) by AVS. In the APA, immunohistochemical analysis showed co-expression of LH receptor and CYP11B2. Conclusion: Our cases of untreated Klinefelter’s syndrome complicated with PA suggest that increased serum LH levels and adipose tissues, caused by primary hypogonadism, could contribute to PA development. The possible complication of PA in hypertensive patients with Klinefelter’s syndrome should be carefully considered.

To assess the safety and feasibility of unilateral double femoral venous access including double sheath insertion via a single-hole method (two-in-one method) for adrenal venous sampling (AVS). Two 5-Fr sheaths were percutaneously inserted into a single femoral vein for AVS in 324 patients. Two needles were inserted sequentially in tandem under ultrasound guidance; furthermore, two sheaths were individually inserted (two-in-two method) if both punctures were successfully achieved. In the presence of a single puncture, two sheaths were inserted through two guidewires and a temporarily inserted sheath (two-in-one method). This protocol was repeated until two sheaths were successfully inserted. Thus, two sheaths were inserted with the two-in-one method in 56 patients (17.3%) and two-in-two method in 268 patients (82.7%). No significant differences in the technical success rates of AVS were observed (p = 0.067–0.647). Minor groin hematoma was observed more frequently in the two-in-one than in the two-in-two method (8.9% vs. 2.6%, p = 0.039). No major groin hematoma, deep venous thrombosis, or pulmonary embolization was observed. The mean number of needle puncture was 2.5 ± 1.3 and duration of inserting two sheaths 5.1 ± 3.9 min. Unilateral double femoral venous access including the two-in-one method is safe and feasible for AVS.

Elevated soluble (pro)renin receptor (s(P)RR) concentration in maternal blood is associated with gestational hypertension and preeclampsia. Placenta has abundant expression of (P)RR, and the binding of (P)RR with pyruvate dehydrogenase E1 beta subunit (PDHB) is reported to maintain oxidative metabolism. Thus, we hypothesized that placental hypoxia may increase (P)RR, and the increased (P)RR may preserve PDHB expression. Expression and functional analyses were performed using human placental trophoblast cells, mainly JAR cells. (P)RR co-immunoprecipitated and showed co-immunofluorescence with PDHB mainly in the mitochondria. Hypoxia treatment significantly increased intracellular s(P)RR protein expression, but secreted s(P)RR in the culture medium was decreased by hypoxia. Hypoxia treatment did not alter PDHB expression or activity in the basal condition, but when (P)RR was knocked down by siRNA, PDHB protein and activity were reduced by hypoxia. Acetyl-CoA, the product of PDH activity, was significantly reduced by hypoxia treatment with (P)RR siRNA. S(P)RR is generated from full-length PRR when cleaved by specific proteases. Protease inhibitor experiments suggested furin and site 1 protease as the enzymes generating s(P)RR in JAR cells, and only when treated by site 1 protease inhibitor, PF429242, PDHB protein showed a significant trend to decrease with hypoxia. In JAR cells, hypoxia increased intracellular s(P)RR, and (P)RR preserved the expression and function of PDHB during hypoxia. (P)RR may help maintain oxidative metabolism and efficient energy production during placental ischemia in hypertensive disorders of pregnancy.

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Context Growth hormone deficiency (GHD) leads to obesity and may induce tissue hypoxia. As (pro)renin receptor [(P)RR] is reported to contribute to the aerobic metabolism by stabilizing pyruvate dehydrogenase (PDH), it may play a substantial role in GHD. Objective We aimed to investigate serum soluble (P)RR [s(P)RR] concentration, the origin of s(P)RR, and significance of (P)RR in GHD. Design, Setting, and Participants Serum s(P)RR concentration was examined in 72 patients with pituitary diseases, including 32 patients with severe GHD (SGHD) and after GH replacement in 16 SGHD patients. Leptin-deficient ob/ob obese mice were treated with pegvisomant, a GH receptor antagonist, to explore the source of elevated serum s(P)RR in GHD. Adipocytes were cultured with 5% O2 to examine the effects of hypoxia. Results Serum s(P)RR concentration was higher in patients with SGHD than in those without SGHD. Obesity was the important determinant of s(P)RR concentration. Serum s(P)RR concentration significantly decreased after GH replacement in SGHD patients. (P)RR mRNA expression was increased specifically in the adipose tissue (AT) of pegvisomant-treated obese mice compared with that of control obese mice. Hypoxia in cultured adipocytes increased (P)RR expression without affecting the PDH E1 β subunit (PDHB) expression; however, with (P)RR knockdown by small interfering RNA, hypoxia significantly decreased the expression of PDHB. Conclusion GHD patients showed increased serum s(P)RR concentration, possibly caused by obesity and hypoxia. (P)RR expression in AT of GHD patients may be elevated to help maintain aerobic metabolism under hypoxia. Thus, the elevated serum s(P)RR level may reflect hypoxia in ATs., Serum (pro)renin receptor [(P)RR] concentrations were elevated in GHD patients and mice, which may reflect adipocyte hypoxia-induced (P)RR interacting with PHDB to maintain aerobic metabolism.

Background The burden of time is often the primary reason why patients discontinue their treatment. Telemedicine may help patients adhere to treatment by offering convenience. Objective This study examined the efficacy and safety of telemedicine for the management of hypertension in Japan. Methods Patients with uncomplicated hypertension were recruited through web advertising between November 2015 and February 2017. They were then screened, stratified by office systolic blood pressure (SBP), and randomized into two groups: usual care (UC) and telemedicine. The telemedicine group used a 3G network–attached home blood pressure (BP) monitoring device, consulted hypertension specialists from an academic hospital through web-based video visits, and received prescription medication by mail for 1 year. The UC group used the same BP monitoring device but was managed using self-recorded BP readings, which included their diary entries and office BP taken in a community practice setting. Results Initial screening was completed by 99 patients, 54% of whom had untreated hypertension. Baseline BP was similar between the groups, but the weekly average SBP at the end of the 1-year study period was significantly lower in the telemedicine group (125, SD 9 mmHg vs 131, SD 12 mmHg, respectively; P=.02). SBP in the telemedicine group was 3.4 mmHg lower in the morning and 5.8 mmHg lower in the evening. The rate of SBP control (135 mmHg) was better in the telemedicine group (85.3% vs 70.0%; P=.01), and significant adverse events were not observed. Conclusions We present evidence suggesting that antihypertensive therapy via home BP telemonitoring and web-based video visits achieve better BP control than conventional care and is a safe treatment alternative that warrants further investigation. Trial Registration UMIN-CTR UMIN000025372; https://tinyurl.com/47ejkn4b

Although self-measurement of home blood pressure (HBP) is common in Japan and HBP telemonitoring via the Internet is possible, whether telemonitoring improves HBP control better than conventional practice remains unclear. Furthermore, hypertension care with online communication using telemonitored HBP is feasible, whereas the efficacy and safety of such telemedicine have not been established. We aim to compare traditional care, care with office visits using HBP telemonitoring, and antihypertensive telemedicine based on HBP telemonitoring.In total, 444 patients with uncontrolled hypertension will be recruited and randomly assigned to three groups: (1) control: usual care with office visits and HBP self-report, (2) telemonitoring: weekly assessment of transmitted HBP by physicians and treatment adjustment upon office visits, or (3) telemedicine: online communication instead of office visits to adjust medication using telemonitored HBP. Primary outcome is the time to control of HBP, and secondary outcomes include achieved HBP levels, adherence, treatment intensity, adverse events, patient satisfaction and cost-effectiveness.Hypertension care with telemonitoring and telemedicine are expected to require shorter time to achieve HBP control compared to usual care. Combining HBP telemonitoring with telemedicine may lower the hurdles for starting and persisting to hypertension treatment and eventually reduce cardiovascular events.

The clinical picture of IgG4-related disease (IgG4-RD) is diverse because various organs can be affected. We describe the case of a 56-year-old man with acute renal failure and tuberoinfundibular hypophysitis due to IgG4-RD. Steroid therapy lowered the serum IgG4 level and ameliorated renal dysfunction, bilateral hydronephrosis and retroperitoneal fibrosis. However, polyuria from post-obstructive diuresis and unmasked central diabetes insipidus ensued. The patient's polyuria continued despite the administration of a therapeutic dose of glucocorticoid; the patient's pituitary swelling and anterior pituitary dysfunction were partially ameliorated. The pituitary swelling recurred seven months later. In patients with IgG4-RD, the manifestation of polyuria after steroid therapy should prompt suspicion of post-obstructive diuresis and the unmasking of central diabetes insipidus.

The importance of cosyntropin stimulation during adrenal vein sampling (AVS) is not fully established, partly due to insufficient AVS data relating the presence and absence of cosyntropin stimulation with postoperative outcome. Therefore, we investigated differences in AVS indices before and after cosyntropin stimulation, and determined whether unstimulated or stimulated AVS indices better correlated with treatment outcome. A retrospective study was conducted in two parts: one with 185 patients who underwent AVS and the other with 81 patients who underwent unilateral adrenalectomy for unilateral aldosterone oversecretion. The selectivity index (SI), lateralized ratio (LR), and contralateral ratio (CR) before and after cosyntropin stimulations were determined, along with blood pressure outcome 1 year after surgery. Primary aldosteronism was diagnosed according to the Japanese Endocrine Society 2009 guidelines. The percentage of AVS patients with successful catheterization, defined as unstimulated SI > 2 before and stimulated SI > 5, increased after cosyntropin stimulation from 52% to 93% and from 74% to 98% for the right and left adrenal veins, respectively. LR decreased after cosyntropin stimulation (P

Aldosterone/renin ratio (ARR) >200 [(pg/mL)/(ng/mL/hr)] is a widely accepted threshold to screen for primary aldosteronism (PA) (1). Because using ARR as a sole index leads to excessive inclusion of cases with low renin essential hypertension, it may be desirable to combine ARR with a minimum plasma aldosterone concentration (PAC) value to increase diagnostic accuracy, but currently there is no consensus on the minimum PAC value. Therefore, we carried out a single-center, retrospective study to investigate optimal PAC cutoff to be used with ARR >200. The subjects were 385 individuals (240 female and 145 male) with ARR >200 who underwent PA screening tests between 2010 and 2015. They were diagnosed according to the Japan Endocrine Society guideline (2) with either PA or essential hypertension (EH). The optimal cutoff value for baseline PAC that best distinguished between PA and EH was calculated. Of the 385 subjects, 297 were diagnosed with PA and 88 with EH. Of 194 PA patients who underwent adrenal venous sampling, 141 exhibited aldosterone hypersecretion from both adrenal glands, and 53 were diagnosed with aldosterone-producing adenoma (APA) on the basis of adrenalectomy. There was no difference between the PA (n = 194) and EH (n = 88) groups in terms of age, body mass index, or glucose and lipid profiles. Receiver operating characteristic curve analysis found that the optimal baseline PAC for distinguishing between PA and EH was 171 pg/mL, which provided a sensitivity of 0.75 and a specificity of 0.65 (area under the curve 0.718 and 95% confidence interval 0.656-0.780). Baseline PAC was ≥171 pg/mL for all 53 subjects with APA (minimum 171 pg/mL, maximum 943 pg/mL, and median 341 pg/mL), and if the cutoff value for baseline PAC is set at 171 pg/mL, it is unlikely that significant cases of APA will be overlooked in PA screening using ARR >200. Combining PAC ≥171 pg/mL with ARR >200 increases diagnostic accuracy for PA without compromising APA detection. Reference: (1)Hiramatsu et al., Arch Intern Med. 1981 Nov;141(12):1589-93. (2) Nishikawa et al., Endocr J. 2011;58(9):711-21.

Context Cyclic Cushing syndrome is a rare variant of Cushing syndrome that demonstrates periodic cortisol excess. It has been thought that inhibition of a glucocorticoid positive-feedback loop is associated with remission of hypercortisolism in ACTH-dependent cyclic Cushing syndrome. However, the underlying mechanism that triggers the development of the hypercortisolism is still unknown. We observed a case of ACTH-dependent cyclic Cushing syndrome that was developed by exogenous glucocorticoids, possibly through a glucocorticoid positive-feedback loop. Case Description A 75-year-old woman had experienced cyclic ACTH and cortisol elevations six times in the previous 4 years. Her diagnosis was cyclic Cushing syndrome. During the hypercortisolemic phase, neither low-dose nor high-dose dexamethasone suppressed her plasma ACTH and cortisol levels. Daily metyrapone therapy decreased her plasma cortisol and ACTH levels during every hypercortisolemic phase. After the sixth remission of a hypercortisolemic phase, she took 25 mg of hydrocortisone for 4 weeks and developed ACTH-dependent hypercortisolemia. Treatment with 1 mg of dexamethasone gradually increased both plasma ACTH and cortisol levels over 2 weeks, resulting in the eighth hypercortisolemic phase. Treatment using a combination of dexamethasone and metyrapone did not increase plasma ACTH or cortisol level and successfully prevented development of ACTH-dependent hypercortisolism. Conclusion We present an interesting case of cyclic Cushing syndrome in which ACTH-dependent hypercortisolemic phases relapsed during exogenous glucocorticoid treatment. A glucocorticoid positive-feedback loop and endogenous glucocorticoid synthesis may play key roles in the periodicity of hypercortisolism in cyclic Cushing syndrome.

Background Clostridium ramosum is a generally non-pathogenic enteric anaerobe, and Fournier’s gangrene is a rare necrotizing soft tissue infection with male predisposition affecting the perineum and the genital area. We report, to our knowledge, the first case of Fournier’s gangrene caused by C. ramosum in a female patient with multiple underlying conditions. Case presentation A 44-year-old woman with a 6-year history of insulin-dependent diabetes mellitus after total pancreatectomy and an 11-year history of central diabetes insipidus developed a pain in the genital area after a month of urinary catheter use. The lower abdominal pain worsened gradually over 2 weeks, and the pain, general fatigue, and loss of appetite prompted the patient’s hospital admission. As she had severe edema in her pelvic and bilateral femoral areas, ceftriaxone was started empirically after collecting two sets of blood cultures. On hospital day 2, CT examination revealed the presence of necrotizing faciitis in the genital and pelvic areas, and the antibiotics were changed to a combination of meropenem, vancomycin, and clindamycin. Gram-positive cocci and gram-positive rods were isolated from blood cultures, which were finally identified as Streptococcus constellatus and C. ramosum using superoxide dismutase and 16S rDNA sequencing. An emergent surgery was performed on hospital day 2 to remove the affected tissue. Despite undergoing debridement and receiving combined antimicrobial chemotherapies, the patient’s clinical improvement remained limited. The patient’s condition continued to deteriorate, and she eventually died on hospital day 8. In the present case, the underlying diabetes mellitus, urinary incontinence due to central diabetes insipidus, undernutrition, and edema served as the predisposing conditions. Conclusions C. ramosum is a potentially opportunistic pathogen among immunosuppressed persons and a rare cause of necrotizing fasciitis.

Autophagy is an intracellular catabolic process contributing to the regulation of nutrient homeostasis and cellular remodeling. Studies revealed that the nuclear translocation of transcription factor EB (TFEB) plays a key role in lysosomal biogenesis and autophagic pathways. The (pro)renin receptor [(P)RR] is a multifunctional protein playing a pivotal role in regulation of the tissue renin–angiotensin system and is known as an essential constituent of vacuolar H+‐ATPase, considered to be necessary for the autophagy–lysosome pathway. On the basis of these findings, we postulated that (P)RR may also contribute to the regulation of starvation‐induced autophagy. In this study, starvation increased the expression of (P)RR and autophagy‐related genes, especially, in the skeletal muscles of mice. In C2C12 mouse myoblast cells, starvation increased (P)RR expression and TFEB translocation, leading to the expression of autophagy‐related genes. Knockdown of (P)RR enhanced both the TFEB translocation to the nucleus and the expression of autophagy‐related genes during starvation. These results suggest that (P)RR plays a buffering role in starvation‐induced autophagy by affecting the nuclear translocation of TFEB. Thus, (P)RR, which increases during starvation, is one of the important factors that control autophagy in the skeletal muscles. (P)RR may act as a buffer to reduce excessive TFEB‐dependent autophagy flux.

To assess the effectiveness of image fusion guidance (IF) with pre-procedural computed tomography (CT) with intraprocedural fluoroscopy for adrenal venous sampling (AVS). AVS before and after ACTH stimulation including bilateral segmental sampling of effluent tributaries was performed in 62 patients with IF. A 3D volume rendering image, including adrenal glands and veins extracted from previously obtained contrast-enhanced CT images, was manually registered to the real-time X-ray fluoroscopy. The technical success rates, procedure time, radiation exposure, and volume of contrast medium used were compared with 49 patients who underwent AVS without IF. No significant differences in the technical success rates with and without IF were observed (98.4 vs. 91.8% for the right adrenal veins, p = 0.168, and 98.4 vs. 100% for the left adrenal veins, p = 1.000). The procedure time with IF was significantly shorter than that without IF (95.6 ± 18.8 vs. 108.4 ± 20.0 min, p = 0.001). The total dose-area product with IF was significantly lower than that without IF (43.1 ± 30.7 vs. 72.2 ± 45.3 Gy cm2, p

The Na/K ratio is considered to be a useful index, the monitoring of which allows an effective Na reduction and K increase, because practical methods (self-monitoring devices and reliable individual estimates from spot urine) are available for assessing these levels in individuals. An intervention trial for lowering the Na/K ratio has demonstrated that a reduction of the Na/K ratio mainly involved Na reduction, with only a small change in K. The present study aimed to clarify the relationship between dietary Na intake and the urinary Na/K molar ratio, using standardized low- and high-salt diets, with an equal dietary K intake, to determine the corresponding Na/K ratio. Fourteen healthy young adult volunteers ingested low-salt (3 g salt per day) and high-salt (20 g salt per day) meals for seven days each. Using a portable urinary Na/K meter, participants measured their spot urine at each voiding, and 24-h urine was collected on the last day of each diet period. On the last day of the unrestricted, low-salt, and high-salt diet periods, the group averages of the 24-h urine Na/K ratio were 4.2, 1.0, and 6.9, while the group averages of the daily mean spot urine Na/K ratio were 4.2, 1.1, and 6.6, respectively. The urinary Na/K ratio tracked changes in dietary salt intake, and reached a plateau approximately three days after each change in diet. Frequent monitoring of the spot urine Na/K ratio may help individuals adhere to an appropriate dietary Na intake.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the β-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–48) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [3H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion–transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (Km) = 84.3 μmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC50 = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine. Clinical Pharmacology & Therapeutics (2014); 95 4, 432–438. doi:10.1038/clpt.2013.241

Author Manuscript (Submitted version), OBJECTIVES: Malnutrition is a major risk factor of pressure ulcers (PU). However, the best method of nutritional assessment to prevent PU is still unclear. This study was designed to determine the usefulness of Mini Nutritional Assessment (MNA) and plasma amino acid analysis to predict the formation of PU among inpatients. DESIGN: This was a prospective, observational cohort study with a mean observation period of 62.2±86.4 days. SETTING: Intermediate and acute care wards of a hospital in rural Japan. PARTICIPANTS: The 422 patients analyzed had an average age of 85.0±7.6 years. MEASUREMENTS: MNA, Subjective Global Assessment (SGA), Braden Scale (PU prognostic score), pressure ulcer formation, and biochemical analysis including plasma amino acid concentrations. RESULTS: PU developed in 7.1% of the patients. A MNA score of less than 8 was more sensitive than a rating of moderate or severe malnourishment on the SGA combined with a Braden Scale score of

To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective β-adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-∞ ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-∞ of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics.

We previously reported a case of pulmonary hypertension, where the symptoms were improved by oral L-arginine (arginine) administration. Arginine may increase nitric oxide (NO) production in the pulmonary artery. Exhaled NO may reflect pulmonary artery NO production. It has been demonstrated that exhaled NO concentration is higher in patients with allergic diseases, but whether oral arginine administration alters exhaled NO is unknown. Therefore, in this study, we investigated whether oral arginine administration increases exhaled NO among healthy volun- teers with and without a history of allergy. Eleven subjects were given a single oral dose (200 mg/kg) of arginine, and their plasma arginine concentrations and exhaled NO were measured up to 150 minutes. Baseline values of exhaled NO concentration were significantly higher in those with a history of allergy (56.4±20.3 ppb, n=5, P

The effect of unilateral adrenalectomy on blood pressure (BP) outcome in primary aldosteronism (PA) is diverse. Therefore, we sought to investigate the preoperative factors contributing to postoperative BP outcome. Data for 96 PA patients who underwent unilateral adrenalectomy at our institution from January 2000 to February 2015 were retrospectively collected. Based on postoperative BP after a 12-month follow-up period, the patients were categorized into two groups: cured (C) (

In primary aldosteronism (PA), insulin response to glucose is not fully understood. Insulin action was elucidated using indices in 32 PA and 21 essential hypertension (EH) patients. These patients were evaluated using homeostasis model assessment (HOMA) indices, quantitative insulin sensitivity check index (QUICKI), and insulinogenic index (IGI), which were expressed for insulin sensitivity/secretion and the early phase of insulin secretion. Insulin sensitivity and early phase of insulin secretion were decreased in PA, and there was a negative correlation between serum potassium concentration and insulin sensitivity indices. These findings suggest that glucose intolerance in PA may be caused by hypokalemia-induced insulin resistance and hypokalemia-independent impairment of early-phase insulin secretion.

The aim of this study was to establish a causal relationship between excess body weight and the onset of diabetes in a retrospective cohort study.This 10-year observational cohort study investigated 969 men and 585 women (23 to 80 years of age), who underwent voluntary complete medical check-ups and an annual 75-g oral glucose tolerance test (75 g-OGTT). Participants with fasting plasma glucose ≥126 mg/dL, 2-h glucose level in a 75 g-OGTT ≥200 mg/dL and/or received medical treatment for type 2 diabetes during the previous year were considered as new-onset diabetics. We assessed the independent contribution of increased BMI to the risk of developing type 2 diabetes with Cox proportional hazard model.During the follow-up period, we diagnosed 86 men and 49 women with new-onset type 2 diabetes. In the Cox proportional hazards model, the risk of diabetes mellitus increased with increasing BMI, even after adjusting for age, sex, blood pressure, metabolic profiles, and insulin resistance. In the final model, setting BMI less than 25 as a reference group, the Hazard ratios for diabetes mellitus was 3.12 for those with a BMI of 25-27.4 and it was increased to 3.80 for participants with a BMI of 27.5 or higher.Overweight/obesity (high BMI) is an independent and dose-dependent risk factor for type 2 diabetes in overweight Japanese patients. Our results confirmed the usefulness of BMI as a classic parameter, and the importance of lifestyle modification and better management among people with overweight/obesity for prevention of type 2 diabetes mellitus.

Angiotensin II (Ang II) and Ang III stimulate aldosterone secretion by adrenal glomerulosa, but the angiotensin receptor subtypes involved and the effects of Ang IV and Ang (1–7) are not clear. In vitro, different angiotensins were added to rat adrenal glomerulosa, and aldosterone concentration in the medium was measured. Ang II-induced aldosterone release was blocked (30.3 ± 7.1%) by an Ang II type 2 receptor (AT2R) antagonist, PD123319. Candesartan, an Ang II type 1 receptor (AT1R) antagonist, also blocked Ang II-induced aldosterone release (42.9 ± 4.8%). Coadministration of candesartan and PD123319 almost abolished the Ang II-induced aldosterone release. A selective AT2R agonist, CGP42112, was used to confirm the effects of AT2R. CGP42112 increased aldosterone secretion, which was almost completely inhibited by PD123319. In addition to Ang II, Ang III also induced aldosterone release, which was not blocked by candesartan. However, PD123319 blocked 22.4 ± 10.5% of the Ang III-induced aldosterone secretion. Ang IV and Ang (1–7) did not induce adrenal aldosterone secretion. In vivo, both Ang II and Ang III infusion increased plasma aldosterone concentration, but only Ang II elevated blood pressure. Ang IV and Ang (1–7) infusion did not affect blood pressure or aldosterone concentration. In conclusion, this report showed for the first time that AT2R partially mediates Ang III-induced aldosterone release, but not AT1R. Also, over 60% of Ang III-induced aldosterone release may be independent of both AT1R and AT2R. Ang III and AT2R signaling may have a role in the pathophysiology of aldosterone breakthrough.

Recent studies demonstrated a possible role of aldosterone in mediating cell senescence. Thus, the aim of this study was to investigate whether aldosterone induces cell senescence in the kidney and whether aldosterone-induced renal senescence affects the development of renal injury. Aldosterone infusion (0.75 μg/h) into rats for 5 weeks caused hypertension and increased urinary excretion rates of proteins and N-acetyl-β-D-glucosaminidase. Aldosterone induced senescence-like changes in the kidney, exhibited by increased expression of the senescence-associated β-galactosidase, overexpression of p53 and cyclin-dependent kinase inhibitor (p21), and decreased expression of SIRT1. These changes were abolished by eplerenone (100 mg/kg/d), a mineralocorticoid receptor (MR) antagonist, but unaffected by hydralazine (80 mg/liter in drinking water). Furthermore, aldosterone induced similar changes in senescence-associated β-galactosidase, p21, and SIRT1 expression in cultured human proximal tubular cells, which were normalized by an antioxidant, N-acetyl L-cysteine, or gene silencing of MR. Aldosterone significantly delayed wound healing and reduced the number of proliferating human proximal tubular cells, while gene silencing of p21 diminished the effects, suggesting impaired recovery from tubular damage. These findings indicate that aldosterone induces renal senescence in proximal tubular cells via the MR and p21-dependent pathway, which may be involved in aldosterone-induced renal injury.

Objectives Elevated soluble (pro)renin receptor [s(P) RR] concentration in maternal blood is associated with gestational hypertension and preeclampsia. Placental ischemia is a presumed trigger of gestational hypertension, and because placenta has abundant expression of (P) RR, the binding of which with pyruvate dehydrogenase E1 beta subunit (PDHB) is recently reported to maintain oxidative metabolism, we hypothesized that placental (P) RR may be induced by hypoxia and have a role in the pathogenesis or maintenance of hypertensive disorders of pregnancy. Methods Expression and functional analyses were performed using human trophoblast cells, JAR and JEG3. Results Endogenous expression of (P) RR and PDHB were confirmed in two trophoblast cell lines, and (P) RR showed co-immunoprecipitation and co-immunofluorescence with PDHB mainly in mitochondria. Subjecting the cells to hypoxia in a chamber system increased s(P) RR protein expression by 4.3 ± 0.4-fold (1% O2 for 8 h, N = 6, P Conclusion Induction of s(P) RR in trophoblasts may serve to maintain oxidative metabolism and efficient energy production during hypoxia. While increased serum s(P) RR concentration in maternal blood may reflect placental ischemia, whether elevated s(P) RR leads to deleterious effects on the mother such as by activating systemic renin angiotensin system remains to be determined.

It has been reported that mechanical strain activates extracellular signal-regulated protein kinases (ERK) without the involvement of angiotensin II (Ang II) in cardiomyocytes. We examined the effects of mechanical strain on ERK phosphorylation levels in the absence of Ang II using rat mesangial cells. The ratio of phosphorylated ERK (p-ERK) to total ERK expression was increased by cyclic mechanical strain in a time- and elongation strength-dependent manner. With olmesartan [Ang II type 1 receptor (AT1R) antagonist] pretreatment, p-ERK plateau levels decreased in a dose-dependent manner (EC50= 1.3 × 10−8M, maximal inhibition 50.6 ± 11.0% at 10−5M); a similar effect was observed with RNA interference against Ang II type 1A receptor (AT1AR) and Tempol, a superoxide dismutase mimetic. In addition to the inhibition of p-ERK levels, olmesartan blocked the increase in cell surface and phosphorylated p47phoxinduced by mechanical strain and also lowered the mRNA expression levels of NADPH oxidase subunits. These results demonstrate that mechanical strain stimulates AT1R to phosphorylate ERK in mesangial cells in the absence of Ang II. This mechanotransduction mechanism is involved in the oxidative stress caused by NADPH oxidase and is blocked by olmesartan. The inverse agonistic activity of this AT1R blocker may be useful for the prevention of mesangial proliferation and renal damage caused by mechanical strain/oxidative stress regardless of circulating or tissue Ang II levels.

Here we reviewed our recent work on the chronic effects of nicotine on the Na+ -Ca2+ exchanger (NCX) gene and protein expressions in various organs of rats treated with nicotine in the drinking water for 4-12 weeks. Microarray analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) did not detect significant changes in NCX mRNA expression in cerebral cortex, hippocampus, heart and skeletal muscle. However, NCX1 protein was up-regulated by nicotine in cerebral cortex and hippocampus, but was down-regulated in the heart. NCX2 protein was up-regulated by nicotine in hippocampus. We suggest that although mRNA change was insignificant, NCX protein expression was altered by chronic nicotine administration in brain and heart in rats. We also reviewed our work on modulators of NCX gene expression and function in cardiac myocytes.

Background: (Pro)renin receptor[(P)RR] is a single trans-membrane receptor that binds to both renin and its precursor prorenin to activate tissue renin-angiotensin system (RAS). (P)RR is cleaved by furin to generate soluble (pro)renin receptor [s(P)RR], which is secreted into the extracellular space. Blood s(P)RR level is a candidate biomarker reflecting the status of the tissue RAS, and we have reported that serum s(P)RR levels are associated with renal function. Endocrine or metabolic factors contribute to progression of endorgan damages in hypertensive patients. Therefore, in the present study, we investigated the relationships between serum s(P)RR levels and endocrine or metabolic factors in patients with essential hypertension. Methods: We measured serum s(P)RR levels and assessed the relationships between serum s(P)RR levels and background factors including endocrine or metabolic factors such as age, body mass index (BMI), abdominal circumference, hemoglobin, uric acid, HbA1c, LDL-cholesterol (C), HDL-C, triglyceride (TG), high-sensitivity (hs) CRP, plasma renin activity, aldosterone concentration, noradrenaline, adrenaline, thyroid stimulating hormone, free T3, and free T4 in essential hypertensive patients. Results: A total of 302 patients (138 males) were enrolled. The mean value for age was 57±12 y.o., BMI was 24.9±5.1 Kg/m2, blood pressure was 140±16/85±12 mmHg, hemoglobin was 14.0±1.3 g/dl, estimated glomerular filtration rate (eGFR) was 75.2±20.6 ml/min/1.73 m2, HbA1c was 5.7±0.7%, and serum s(P)RR level was 21.0±5.8 ng/ml. Serum s(P)RR levels were significantly positively correlated with age (r=0.209, p Conclusion: In patients with essential hypertension, serum s(P)RR levels were shown to be associated with endocrine or metabolic factors in addition to renal function, suggesting serum s(P)RR level as a useful biomarker that reflects the status of endocrine or metabolic disorders.