Hsp70 promotes maturation of uromodulin mutants that cause familial juvenile hyperuricemic nephropathy and suppresses cellular damage.

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD. Here we studied effects of genetic expression and pharmacological induction of Hsp70 on the UMOD mutants C112Y and C217G. METHODS: We expressed wild type (WT), C112Y and C217G in HEK293 cells and studied their maturation and cellular damage using western blot and flow cytometry. RESULTS: Expression of C112Y or C217G increased pro-apoptotic proteins, decreased anti-apoptotic proteins, and induced cellular apoptosis as examined by annexin V staining and flow cytometry. Overexpression of Hsp70 or administration of an Hsp70 inducer geranylgeranylacetone (GGA) promoted maturation of the mutant proteins, increased their secreted forms, normalized the levels of pro- and anti-apoptotic proteins and suppressed apoptosis. CONCLUSION: These findings indicated that Hsp70 enhanced maturation of C112Y and C217G and reduced cellular apoptosis, suggesting that Hsp70 induction might be of a therapeutic value for treatment of FJHN.

ß-Adrenergic Blocker, Carvedilol, Abolishes Ameliorating Actions of Adipose-Derived Stem Cell Sheets on Cardiac Dysfunction and Remodeling After Myocardial Infarction.

BACKGROUND: Treatment of myocardial infarction (MI) includes inhibition of the sympathetic nervous system (SNS). Cell-based therapy using adipose-derived stem cells (ASCs) has emerged as a novel therapeutic approach to treat heart failure in MI. The purpose of this study was to determine whether a combination of ASC transplantation and SNS inhibition synergistically improves cardiac functions after MI.Methods and Results:ASCs were isolated from fat tissues of Lewis rats. In in vitro studies using cultured ASC cells, mRNA levels of angiogenic factors under normoxia or hypoxia, and the effects of norepinephrine and a ß-blocker, carvedilol, on the mRNA levels were determined. Hypoxia increased vascular endothelial growth factor (VEGF) mRNA in ASCs. Norepinephrine further increased VEGF mRNA; this effect was unaffected by carvedilol. VEGF promoted VEGF receptor phosphorylation and tube formation of human umbilical vein endothelial cells, which were inhibited by carvedilol. In in vivo studies using a rat MI model, transplanted ASC sheets improved contractile functions of MI hearts; they also facilitated neovascularization and suppressed fibrosis after MI. These beneficial effects of ASC sheets were abolished by carvedilol. The effects of ASC sheets and carvedilol on MI heart functions were confirmed by Langendorff perfusion experiments using isolated hearts. CONCLUSIONS: ASC sheets prevented cardiac dysfunctions and remodeling after MI in a rat model via VEGF secretion. Inhibition of VEGF effects by carvedilol abolished their beneficial effects.

Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia.

BACKGROUND: Uric acid (UA) serves as an antioxidant in vascular endothelial cells. UA transporter 1 (URAT1) encoded by SLC22A12 is expressed in the kidney and vessels and its loss of function causes hypouricemia. The purpose of this study was to examine whether there is any endothelial dysfunction in patients with hypouricemia. METHODS AND RESULTS: Twenty-six patients with hypouricemia (<2.5 mg/dl) and 13 healthy control subjects were enrolled. Endothelial function was evaluated using flow-mediated dilation (FMD). mRNA of UA transporters expressed in cultured human umbilical endothelial cells (HUVEC) was detected on RT-PCR. There was a positive correlation between FMD and serum UA in the hypouricemia group. URAT1 loss-of-function mutations were found in the genome of 21 of 26 patients with hypouricemia, and not in the other 5. In the hypouricemia groups, serum UA in homozygous and compound heterozygous patients was significantly lower than in other groups, suggesting that severity of URAT1 dysfunction may influence the severity of hypouricemia. Thirteen of 16 hypouricemia subjects with homozygous and compound heterozygote mutations had SUA <0.8 mg/dl and their FMD was lower than in other groups. HUVEC do not express mRNA of URAT1, suggesting the null role of URAT1 in endothelial function. CONCLUSIONS: Depletion of UA due to SLC22A12/URAT1 loss-of-function mutations causes endothelial dysfunction in hypouricemia patients.

Effects of azelnidipine on uric acid metabolism in patients with essential hypertension.

PURPOSE: To examine effects of a long-acting calcium channel blocker (CCB) azelnidipine on uric acid metabolism in hypertensive patients. METHODS: Azelnidipine was administered to 72 patients at a daily dose of 8 mg or 16 mg. In 22 cases out of the 72 patients, a different CCB was switched to azelnidipine. Blood pressure was measured and biochemical parameters of blood and urine were evaluated before and 2-3 months after the administration. RESULTS: Azelnidipine significantly decreased both systolic and diastolic blood pressure and the heart rate. It decreased both serum urate levels and the urinary uric acid to creatinine ratio (Uur/Ucr), but did not affect the uric acid clearance to creatinine clearance ratio (Cur/Ccr). Azelnidipine decreased both Uur/Ucr and Cur/Ccr in patients with Uur/Ucr ≥ 0.5 or ≥ 0.34, although it did not change these clearance parameters in patients with Uur/Ucr <0.5 or <0.34. Azelnidipine decreased the serum urate levels and Uur/Ucr in hyperuricemic patients with uric acid levels ≥ 7.0 mg/dL in males and ≥ 6.0 mg/dL in females. It did not change these parameters in normouricemic patients with serum urate levels <7.0 mg/dL in males and <6.0 mg/dL in females. Azelnidipine decreased Uur/Ucr and Cur/Ccr in hyperuricemic patients with normal or over excretion of uric acid, although it did not change these clearance parameters in hyperuricemic patients with uric acid hypoexcretion. CONCLUSIONS: Azelnidipine decreased the serum urate acid levels and Uur/Ucr, and this response was most prominent in hyperuricemic patients or patients with normal and over excretion of uric acid.

A comparative study on the effectiveness of losartan/hydrochlorothiazide and telmisartan/hydrochlorothiazide in patients with hypertension.

PURPOSE: Long-term effects of a low-dose hydrochlorothiazide (HCTZ) with losartan (LOS) on uric acid (UA) metabolism as well as glucose metabolism have been studied in hypertensive patients in comparison with those of a low-dose HCTZ with telmisartan (TEL). METHOD: Fifty-nine hypertensive patients were allocated to a combination therapy with either losartan (50 mg/day)/HCTZ (12.5 mg/day) (LOS + HCTZ group: n = 37) or telmisartan (40 mg/day)/HCTZ (12.5 mg/day) (TEL + HCTZ group: n = 22), respectively. Before and 1 year after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. RESULTS: Both systolic and diastolic blood pressures significantly decreased in two groups, without any statistical differences among them. LOS + HCTZ caused no changes in the serum UA level or the ratio of UA clearance to creatinine clearance (CUA/Ccr), whereas TEL + HCTZ significantly increased the serum UA level and reduced CUA/Ccr. LOS + HCTZ did not influence CUA/Ccr in patients with their serum UA below 5.4 mg/dl, while LOS + HCTZ significantly increased CUA/Ccr in patients with their serum UA above 5.5 mg/dl. TEL + HCTZ significantly reduced CUA/Ccr in patients with their serum UA below and above 5.4 mg/dl to increase serum UA level significantly. Neither combination therapies caused any changes in fasting plasma glucose, HbA1c and HOMA-R. In patients with their serum UA level above 5.4 mg/dl, TEL + HCTZ increased HOMA-R, whereas LOS + HCTZ did not. CONCLUSIONS: LOS + HCTZ did not influence UA metabolism as well as glucose metabolism, likely because of inhibitory action of losartan on URAT1, although TEL + HCTZ were accompanied with impairment of the UA metabolism and glucose metabolism.

Association between multimorbidity and utilization of medical and long-term care among older adults in a rural mountainous area in Japan.

Objective: With the accelerated population aging, multimorbidity has become an important healthcare issue. However, few studies have examined multimorbidity and its impact on the use of medical and long-term care services in Japan. Therefore, this study aimed to examine the association between multimorbidity and the use of medical and long-term care services among older adults living in the depopulated mountainous areas of Japan. Patients and Methods: A cross-sectional study was conducted using insurance claims data from late-stage medical insurance and long-term care insurance (April 2017 to March 2018) for older adults ≥75 years residing in a mountainous area in the Tottori prefecture. In addition to the descriptive analysis, multiple generalized linear regressions with family gamma and log-link functions were used to examine the association between the number of morbidities and total annual medical and long-term care expenditures. Results: A total of 970 participants ≥75 years were included in the analysis. Participants who had two or more morbidities constituted 86.5% of the total sample. Furthermore, participants with mental disorders were found to have more comorbidities. The number of comorbidities is associated with higher medical and long-term care expenditures. Conclusion: Multimorbidity was dominant among late-stage older adults living in depopulated mountainous areas of Japan, and the number of morbidities was associated with higher economic costs of medical and long-term care services. Mitigating the impact of multimorbidity among older adults in depopulated regions of Japan is an urgent challenge. Future research should investigate the degree and effectiveness of social protections for vulnerable older adults living in remote areas.

A Case of Weight Gain and Edema With Difficulty in Moving Legs Due to Intravascular Large B-cell Lymphoma Diagnosed by Skin Biopsy.

We report a case of intravascular large B-cell lymphoma (IVL) with spinal cord involvement. A 76-year-old woman was referred to our department due to generalized edema and weight gain. She also had difficulty moving her legs. She had no superficial lymphadenopathy upon examination. Her laboratory tests showed a markedly elevated blood lactate dehydrogenase (LDH) level. Although heart failure or interstitial lung disease was initially suspected, she was diagnosed with IVL by skin biopsy. An MRI revealed spinal cord involvement. Post-hospitalization, she began rituximab-combined chemotherapy. In this case, we considered that the spinal cord involvement of the lymphoma caused the neurogenic bladder and leg weakness. IVL often infiltrates the central nervous system and presents with neurological symptoms, including neurogenic bladder. Therefore, imaging studies should be planned to search for the involvement of the central nervous system in lymphoma if accompanied by neurological symptoms. In addition, in patients with a markedly elevated LDH or soluble interleukin-2 receptor level without lymphadenopathy, IVL should be suspected, and consultation with hematologists should be considered.

Late-Onset Intracranial Hemorrhage Presenting as Refractory Hyponatremia: A Case Report.

Here, we report a case of refractory hyponatremia and delayed intracranial hemorrhage following a head injury. A 70-year-old male patient was admitted with complaints of left chest pain and light-headedness after a fall. Hyponatremia recurred despite the correction with intravenous saline. Head computed tomography revealed a chronic subdural hematoma. The subsequent introduction of tolvaptan improved hyponatremia and disorientation. Delayed intracranial hemorrhage is a differential cause of refractory hyponatremia after head contusion. This case is clinically relevant because (i) the diagnostic delay of late-onset intracranial hemorrhage is common but fatal, and (ii) refractory hyponatremia can be a hint of late-onset intracranial hemorrhage.

Effects of Using a Video-Sharing Application on Multidisciplinary Staff During Pre-discharge Home Assessment Visits for Elderly Hospitalized Patients.

Background: Pre-discharge home assessment visits for elderly hospitalized patients are conducted by the hospital staff to ensure a smooth transition to home care and are effective in preventing falls and reducing the rehospitalization rates. However, the effect of an application that enables the viewing of videos of the patient's home activities during the pre-discharge visit on the multidisciplinary professionals who provide services to the patient has not yet been fully clarified. Methods: Multidisciplinary professionals at 23 facilities located in western Tottori Prefecture who used a video-sharing application (Patto-Mie Net) were invited to be interview participants. Those who agreed were interviewed about the usefulness of the application in their work and its effect on multidisciplinary collaboration. A verbatim transcript was made, and thematic analysis was conducted using the qualitative analysis software NVivo. Results: Twenty-eight people participated in the interviews, including nurses, care managers, rehabilitation specialists, care workers, and other social care professions. Fourteen themes and five categories were generated from the analysis: comprehensive information visualization and transferability, identification of changes over time and prognostic prediction, promoting multidisciplinary collaboration, patient and family reality, and disadvantages and concerns. Conclusion: The use of an application that allows video-sharing of a patient's home movement status during a pre-discharge visit has revealed a variety of benefits for multiple professionals in hospitals and other facilities. In particular, the results were characterized by the psychological closeness between multiple professionals, promotion of interprofessional communication, and sharing of reality, including the psychosocial background of the patient and family.

Comparison of Recommendations Made by Committee Members with and without Financial Conflict of Interest on Japanese Guideline of Treatment of Hyperuricemia and Gout, Third Edition.

Clinical practice guidelines (CPGs) consist of clinical questions (CQs) and corresponding recommendations. Considering the estimation of body of evidence, patients' opinions, and medical economics, recommendations can vary depending on the votes of the committee members of CPGs. Taking this into consideration, concerns have already been raised on how financial conflict of interest (COI) potentially influences recommendations. In this study, we developed the third edition of guideline for the management of hyperuricemia and gout. This CPG was composed of seven CQs and recommendations. The direction and strength of the recommendations were determined by votes. There are three CQs. Individual questions asked whether uric acid-lowering-agents (ULAs) could be applied to hyperuricemic patients with chronic kidney disease (CKD) (CQ A), hypertension (CQ B), or heart failure (CQ C) to prevent organ damage. We examined whether the absence (18 members) or presence (8 members) of COIs of committee members could influence the votes. In total, 26 committee members with and without COI have equally determined the direction and strength of recommendations. In CQ A, members without financial COIs and those with financial COI selected conditional recommendation for the use of ULAs in patients with CKD (without COI, 17/18; with COI, 7/8). In CQ B, members without financial COIs and those with financial COI selected conditional recommendation against the use of ULAs in hypertensive patients (without COI, 14/18; with COI, 5/8). In CQ C, members without financial COIs and those with financial COIs have selected conditional recommendation against the use of ULAs in patients suffering from heart failure (without COI, 15/18; with COI, 4/8). We found that members with financial COIs have determined their recommendations in the same direction and strength as those without financial COIs.

Characterization of Urate Metabolism and Complications of Patients with Renal Hypouricemia.

Objective Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dL, and the Uur/Ucr and Cur/Ccr were 0.56±0.14% and 45.7±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.

The Effectiveness of the Multiple-Attending-Physicians System Compared With the Single Attending-Physician System in Inpatient Setting: A Mixed-Method Study.

OBJECTIVES: Medical facilities have been required to effectively utilize insufficient human resources in many countries. Therefore, we qualitatively and quantitively compared physicians' working burden, and assessed advantages and disadvantages of the single- and the multiple-attending physicians systems in inpatient care. METHODS: In this cross-sectional study, we extracted electronic health record of patients from a hospital in Japan from April 2017 to October 2018 to compare anonymous statistical data between the single-attending and multiple-attending-physicians system. Then, we conducted a questionnaire survey for all physicians of single and multiple-attending systems, asking about their physical and psychiatric workload, and their reasons and comments on their working styles. RESULTS: The average length of hospital stay was significantly shorter in the multiple-attending system than in the single-attending system, while patients' age, gender, and diagnoses were similar. From the questionnaire survey, no significant difference was found in all categories although physical burden in multiple-attending system tended to be lower than that in single-attending system. Advantages of multiple-attending system extracted from qualitative analysis are (1) improvement of physicians' quality of life (QOL), (2) lifelong-learning effect, and (3) improving the quality of medical care, while disadvantages were (1) risk of miscommunications, (2) conflicting treatment policies among physicians, and (3) patients' concern. CONCLUSIONS: The multiple-attending physician system in the inpatient setting can reduce the average length of stay for patients and also reduce the physical burden on physicians without compromising their clinical performance.

Effects of cilnidipine on serum uric acid level and urinary nitrogen monoxide excretion in patients with hypertension.

The effects of cilnidipine on the serum uric acid level and urinary NO excretion in hypertensive patients were investigated. Blood and urine samples of 16 hypertensive outpatients were collected before and 2 months after cilnidipine therapy (10 mg). The serum uric acid level decreased significantly after cilnidipine treatment, while the uric acid-creatinine clearance ratio was unaffected. The cilnidipine medication produced a significant increase in urinary NO excretion, although amlodipine did not change it significantly. Therefore, cilnidipine has a profound antihypertensive effect and may reduce the serum uric acid level and increase NO production in the kidney.

Anorexia in a hemodialysis patient due to pneumatosis intestinalis: A case report.

We report a case of pneumatosis intestinalis (PI) in a hemodialysis patient who presented with anorexia and nausea. Anorexia with postprandial nausea can be caused by gastrointestinal diseases, with one of the rare causes being PI. PI may occur in hemodialysis patients, but it is rarely reported. We experienced a case of benign PI in a hemodialysis patient, for whom the conservative treatment with antibiotics improved the patient's clinical symptoms. In patients with PI, it is important to rule out potentially life-threatening complications, such as the presence of hepatic intraportal gas on CT scan.

Lactobacillus gasseri PA-3 reduces serum uric acid levels in patients with marginal hyperuricemia.

Several studies have reported that Lactobacillus gasseri PA-3 reduces the level of serum uric acid (SUA) in patients with hyperuricemia. However, it remains unknown how PA-3 affects uric acid metabolism. In the present study, we examined effects of PA-3-containing yoghurt on uric acid metabolism in patients with marginal hyperuricemia. Sixteen patients with SUA > 357 µmol/L (marginal hyperuricemia) were enrolled. PA-3-containing yoghurt was administered for 8 weeks. Uric acid metabolism was evaluated just before and 8 weeks after the administration and at 4 weeks after the administration ended (post-administration). SUA levels after the administration were significantly lower than that before the administration and remained low at post-administration. Urinary uric acid concentration (Uur) after the administration were significantly lower than that before the administration. However, post-administration Uur levels were comparable to those before the administration. Therefore, PA-3-containing yoghurt significantly reduced the levels of SUA and Uur in patients with marginal hyperuricemia.

Xanthinuria Type 1 with a Novel Mutation in Xanthine Dehydrogenase and a Normal Endothelial Function.

Whether or not extremely low levels of serum uric acid (SUA) in xanthinuria are associated with impairment of the endothelial function and exercise-induced acute kidney injury (EIAKI) is unclear. A 59-year-old woman without EIAKI or urolithiasis had undetectable levels of UA in serum and urine and elevated levels of hypoxanthine and xanthine in urine. A genetic analysis revealed homozygous mutations in the XDH gene [c.1585 C>T (p. Gln529*)]. Flow-mediated dilation was within the normal range. This is the first report of a case with extremely low levels of SUA, xanthinuria with novel mutations of xanthine dehydrogenase (XDH) and a normal endothelial function.

[Calcium antagonists: current and future applications based on new evidence. The mechanisms on lowering serum uric acid level by calcium channel blockers].

In hypertensive subjects, their serum uric acid levels tend to be higher because of decreasing urinary secretion or overproduction of uric acid. Among calcium channel blockers (CCBs) , long acting nifedipine and cilnidipine reveal serum uric acid lowering action. They decrease the production of uric acid precursor in skeletal muscles under anaerobic condition induced by hypertension or insulin resistance. Hyperuricemia is considered to be a risk factor of not only gout but also renal and cardiovascular diseases, thus, it is important to use CCBs without adverse effect on uric acid metabolisms.

Pretreatment with cilnidipine attenuates hypoxia/reoxygenation injury in HL-1 cardiomyocytes through enhanced NO production and action potential shortening.

Myocardial ischemia/reperfusion injury worsens in the absence of nitric oxide synthase (NOS). Cilnidipine, a Ca2+ channel blocker, has been reported to activate endothelial NOS (eNOS) and increases nitric oxide (NO) in vascular endothelial cells. We examined whether pretreatment with cilnidipine could attenuate cardiac cell deaths including apoptosis caused by hypoxia/reoxygenation (H/R) injury. HL-1 mouse atrial myocytes as well as H9c2 rat ventricular cells were exposed to H/R, and cell viability was evaluated by an autoanalyzer and flow cytometry; eNOS expression, NO production, and electrophysiological properties were also evaluated by western blotting, colorimetry, and patch clamping, respectively, in the absence and presence of cilnidipine. Cilnidipine enhanced phosphorylation of eNOS and NO production in a concentration-dependent manner, which was abolished by siRNAs against eNOS or an Hsp90 inhibitor, geldanamycin. Pretreatment with cilnidipine attenuated cell deaths including apoptosis during H/R; this effect was reproduced by an NO donor and a xanthine oxidase inhibitor. The NOS inhibitor L-NAME abolished the protective action of cilnidipine. Pretreatment with cilnidipine also attenuated H9c2 cell death during H/R. Additional cilnidipine treatment during H/R did not significantly enhance its protective action. There was no significant difference in the protective effect of cilnidipine under normal and high Ca2+ conditions. Action potential duration (APD) of HL-1 cells was shortened by cilnidipine, with this shortening augmented after H/R. L-NAME attenuated the APD shortening caused by cilnidipine. These findings indicate that cilnidipine enhances NO production, shortens APD in part by L-type Ca2+ channel block, and thereby prevents HL-1 cell deaths during H/R.

Influence of a community-based approach to improve risk factors of lifestyle diseases by Japanese public health nurses: A case-control study.

BACKGROUND AND OBJECTIVES: It is important to examine the roles of specific health check-up and specific health guidance in individuals at high risk of common lifestyle diseases, but evaluation based on a stratified analysis of people undergoing a health check-up has not been adequately performed. In this study, we examined the effects of providing specific health guidance to individuals considered at high risk for a lifestyle disease after specific health check-ups. METHOD: Subjects who underwent a specific health check-up in 2012 were assigned to either a group that received health guidance from public health nurses over three years (n = 393) or a control group (n = 109). Clinical findings of both groups were analysed to evaluate the correlation between their changes and health guidance. RESULTS: A significant decrease was observed in blood pressure, and lipid and glucose levels only in the health guidance group. Multiple regression analysis revealed that health guidance was the explanatory variable of serum lipid improvement. DISCUSSION: Continued support by Japanese public health nurses through health guidance closely related to the subject's lifestyle over three years may lead to a comprehensive reduction in the risk of lifestyle diseases.