桑原 政成

BACKGROUND: High serum uric acid (SUA) is associated with the dyslipidemia, but whether hyperuricemia predicts an increase in serum low-density lipoprotein (LDL) cholesterol is unknown. This study is to evaluate whether an elevated SUA predicts the development of high LDL cholesterol as well as hypertriglyceridemia. METHODS: This is a retrospective 5-year cohort study of 6476 healthy Japanese adults (age, 45.7 ± 10.1 years; 2.243 men) who underwent health examinations at 2004 and were reevaluated in 2009 at St. Luke's International Hospital, Tokyo, Japan. Subjects were included if at their baseline examination they did not have hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, or if they were on medication for hyperuricemia and/or gout. The analysis was adjusted for age, body mass index (BMI), smoking and drinking habits, baseline estimated glomerular filtration rate (eGFR), baseline SUA and SUA change over the 5 years. RESULTS: High baseline SUA was an independent risk for developing high LDL cholesterol both in men (OR: 1.159 per 1 mg/dL increase, 95% CI:1.009-1.331) and women (OR: 1.215, 95% CI:1.061-1.390). Other risk factors included a higher baseline LDL cholesterol, higher BMI, and higher baseline eGFR (the latter two in women only). Increased SUA over 5 years were also independent risks for developing high LDL cholesterol and hypertriglyceridemia, but not for low high-density lipoprotein (HDL) cholesterol. CONCLUSIONS: This is the first study to report that an elevated SUA increases the risk for developing high LDL cholesterol, as well as hypertriglyceridemia. This may shed light into the role of SUA in cardiovascular disease.

BACKGROUND: Serum uric acid (SUA) and oxidized LDL (oxLDL) may be associated with arterial aging. The aim of our study was to evaluate the relationship between SUA, oxLDL and arterial stiffness in subjects with normal renal function and in patients with mild or moderate renal impairment. METHODS: From the database of the 2012 Brisighella Heart Study, we compared age-matched adult, non-smoker subjects without cardiovascular disease and with normal renal function (n = 205), subjects with stage II chronic kidney disease (CKD) (n = 118) and subjects with stage III CKD (n = 94). All subjects underwent a determination of the LDL oxidative susceptibility, oxLDL levels, SUA and Pulse Wave Velocity (PWV). RESULTS: By univariate analysis, PWV correlated with a large number of clinical, haemodynamic and metabolic parameters, including estimated glomerular filtration rate (eGFR) in subjects with normal renal function and in those with stage II or III CKD. Stepwise multiple regression analyses showed that in the presence of normal renal function or stage II CKD, the main predictors of PWV were age, systolic blood pressure (SBP), ox-LDL, apolipoprotein B and SUA (p < 0.05), while in the presence of stage III CKD only age, SBP and apolipoprotein B remained significant (p < 0.05). CONCLUSION: Both ox-LDL and SUA independently predicts PWV only in subjects with normal or mildly reduced renal function, but not in the subjects with more compromised eGFR. This study confirms the complex relationship of SUA with cardiovascular and metabolic disease in the patient with established renal disease.

Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup [HFCS]) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.

BACKGROUND: Fontan-associated liver disease (FALD) is an important late complication involving liver dysfunction, such as liver cirrhosis (LC) and hepatocellular carcinoma (HCC), in patients undergoing the Fontan procedure. However, the prevalence, clinical manifestation, and methods of diagnosis of FALD are still not well established.Methods and Results:This study comprised 2 nationwide surveys in Japan. First, the prevalence of LC and/or HCC in patients undergoing the Fontan procedure was determined. Second, clinical manifestations in patients with LC and/or HCC were analyzed, along with data from blood tests, echocardiography, and right heart catheterization. In the 1st survey, of the 2,700 patients who underwent the Fontan procedure, 31 were diagnosed with LC and/or HCC (1.15%), and 5 died due to liver diseases (mortality: 0.19%). In the 2nd survey, data were collected from 17 patients (12 with LC, 2 with HCC, and 3 with LC+HCC. Of these 17 patients, 5 died (mortality: 29.4%). The mean age at diagnosis of LC and HCC was 23 and 31 years, respectively. Computed tomography followed by ultrasound was most frequently used for diagnosis. Blood tests revealed low platelet counts, increased hemoglobin, aspartate aminotransferase, γ-guanosine triphosphate, and total bilirubin levels, and an elevated international normalized ratio of prothrombin time. CONCLUSIONS: LC and/or HCC in patients undergoing the Fontan procedure were not rare late complications and were associated with high mortality rates.

BACKGROUND: Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion. CONCLUSIONS: Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

<p>Background: Irbesartan has been reported to inhibit renal uric acid reabsorption and thereby decrease serum uric acid (Sur) levels. However, its effect on uric acid metabolism in hypertensive patients has not been reported. Methods and Results: We conducted a retrospective observational study that included 40 hypertensive patients to clarify the effects of irbesartan (mean dose 87.5 mg) on blood pressure (BP) and uric acid metabolism [Sur, urinary uric acid (Uur), serum creatinine (Scr), urinary creatinine (Ucr), uric acid clearance (Cur), creatinine clearance (Ccr), urinary uric acid to urinary creatinine ratio (Uur/Ucr), and uric acid clearance to creatinine clearance ratio (Cur/Ccr) ] at baseline and after 3 months of treatment. We allocated patients into two groups, patients with Uur/Ucr <0.5 (low Uur/Ucr group) or those with Uur/Ucr ≥0.5 (normal/high Uur/Ucr group), into other two groups, patients with Cur/Ccr <5.5% (low Cur/Ccr group) or those with Cur/Ccr ≥5.5% (normal/ high Cur/Ccr group). The hypoexcretion group contained low Uur/Ucr group and low Cur/Ccr group, and the normal/ hyperexcretion group contained normal/high Uur/Ucr group and normal/ high Cur/Ccr group. Further, we allocated patients into another two groups, patients with Sur ≥7 mg/dl (hyperuricemic group) or those with Sur <7 mg/dl (normouricemic group). Irbesartan significantly decreased systolic BP without affecting heart rate, and decreased Sur without altering Uur/Ucr or Cur/Ccr. In the hypoexcretion group, irbesartan decreased Sur while increasing Uur/Ucr and Cur/Ccr. In contrast, in the normal/hyperexcretion and hyperuricemic groups, irbesartan decreased Sur without changing Uur/Ucr or Cur/Ccr. In a normouricemic group, patients showed no changes in Sur after treatment with irbesartan. Conclusions: Irbesartan improved the secretion of uric acid, and reduced Sur in the hypoexcretion group, but did not influence uric acid excretion in the normal/hyperexcretion group. In hyperuricemic patients, irbesartan did not affect uric acid excretion but may have influenced uric acid production.</p>

The patients with anorexia nervosa (AN) are known to be associated with high mortality, but the actual causes of death are still undefined. We tested the hypothesis that AN patients had cardiac disorders, including left ventricular (LV) dysfunction and LV atrophy. This study is a cross-sectional study at St. Luke's International Hospital, Tokyo. We analyzed 13 female inpatients with AN. We assessed cardiac function and heart volume in AN by echocardiography, LV ejection fraction (LVEF), LV mass, and LV mass index (LVMI). We assessed the correlations between body mass index (BMI) and heart volume (LV mass and LVMI). The mean age and BMI were 34.8 ± 11.2 years and 15.5 ± 3.1 kg/m2, respectively. There was no patient with mitral valve prolapse, but 3 patients had trivial to small amount of pericardial effusion. The mean LVEF was 67.7 ± 6.5%, and 12 out of 13 patients had normal LVEF. Their LV mass (89.0 ± 27.3 g) and LVMI (66.3 ± 16.4 g/m2) were small. BMI positively correlated with LVMI (r = 0.58, p = 0.040), as well as LV mass (r = 0.74, p = 0.004). Lower BMI reflects lower LVMI, as well as smaller LV mass. These issues suggest that heart volume is initially decreased in severe AN conditions. Low LVMI could be a good marker of severity of AN.

Prehypertension frequently progresses to hypertension, a condition associated with high morbidity and mortality from cardiovascular diseases and stroke. However, the risk factors for developing hypertension from prehypertension remain poorly understood. We conducted a retrospective cohort study using the data from 3584 prehypertensive Japanese adults (52.1±11.0 years, 2081 men) found to be prehypertensive in 2004 and reexamined in 2009. We calculated the cumulative incidences of hypertension over 5 years, examined risk factors, and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, body mass index, smoking and drinking habits, baseline systolic and diastolic blood pressure, pulse rate, diabetes mellitus, dyslipidemia, chronic kidney disease, and serum uric acid levels. The additional analysis evaluated whether serum uric acid (hyperuricemia) constituted an independent risk factor for developing hypertension. The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%. There were no significant differences between women and men (24.4% versus 26.0%; P=0.28). The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2858; 30.7% versus 24.0%; P<0.001). After multivariable adjustments, the risk factors for developing hypertension from prehypertension were age (OR, 1.023; P<0.001), female sex (OR, 1.595; P<0.001), higher body mass index (OR, 1.051; P<0.001), higher baseline systolic (OR, 1.072; P<0.001) and diastolic blood pressure (OR, 1.085; P<0.001), and higher serum uric acid (OR, 1.149; P<0.001). Increased serum uric acid is a strong risk marker for developing hypertension from prehypertension. Further studies are needed to determine whether treatment of hyperuricemia in prehypertensive subjects could impede the onset of hypertension.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). One of the most important pathophysiological mechanisms for CVD in patients with CKD is the widespread and possibly accelerated formation of atherosclerotic plaques due to hyperlipidemia, uremic toxins, inflammation, oxidative stress, and endothelial dysfunction. Recent studies showed that the level of oxidized low-density lipoprotein cholesterol increases, and that high--density lipoprotein cholesterol dysfunction occurs as kidney function declines and inflammation becomes more prevalent. In this review, we aimed to discuss the effect of kidney dysfunction, oxidative stress, and inflammation on lipid -profile.

【背景】口腔内環境が全身の健康状態へ影響を及ぼすことが注目されている。心血管疾患の発症が歯磨きの頻度と負の関連を示すとの報告があるが、生活習慣を考慮した上で、歯磨きと心血管疾患のリスクとの関係性を検討された報告は少ない。【目的】歯磨き習慣と心血管疾患のリスク因子:高血圧、糖尿病、脂質異常症、高尿酸血症、心房細動との関連を検討する。【方法】横断研究と後向きコホート研究。1)横断研究:2004年1月から2010年6月の間に、聖路加国際病院予防医療センターを健康診断のため受診した90,143人(男性49.1%、46.3±12.0歳)の内、30歳以上85歳未満の85,866人のデータを解析対象とした。歯磨き習慣を3群(毎食後歯を磨く、1日1回は磨く、1日1回も磨かない)に分け、3群間で高血圧、糖尿病、脂質異常症、高尿酸血症、心房細動の有病率について検討を行った。多変量解析では、年齢、性別、Body Mass Index、飲酒習慣、喫煙の有無、運動習慣(歩行時間)、睡眠時間、慢性腎臓病の有無を共変数としてロジスティック回帰分析を行った。2)コホート研究:2004年に上記医療機関を受診した31,233人の内、2009年にも再受診し両期間でデータ利用可能な13,201人を抽出し、30歳以上85歳未満の13,070人を解析対象とした。高血圧、糖尿病、脂質異常症、高尿酸血症、心房細動の5年間の累積罹患を歯磨き頻度の3群で比較した。さらに、毎食後歯を磨く群と、毎食後は歯を磨かない群の2群に分け、糖尿病、脂質異常症の新規発症頻度を、性別ごとに、年齢、肥満、糖尿病、脂質異常症、高血圧、高尿酸血症を共変数としたロジスティック回帰分析を行った。【結果】1)横断研究:歯磨き頻度が少ない程、高血圧(毎食後歯を磨く:13.3%、1日1回は磨く:17.9%、磨かない:31.0%)糖尿病(3.1%、5.3%、17.4%)、脂質異常症(29.0%、42.1%、60.3%)、高尿酸血症(8.6%、17.5%、27.2%)、慢性腎臓病(3.8%、3.1%、8.3%)、心房細動の有病率が高かった(p<0.001)。多変量解析の結果、毎食後菌を磨く群と比較したオッズ比は、1日1回は磨く群、及び1日1回も磨かない群において、糖尿病は1.17倍(p=0.001)、2.03倍(p=0.002)、脂質異常症は1.18倍(p<0.001)、1.50倍(p=0.023)であった。2)コホート研究:2004年から2009年の糖尿病、脂質異常症、高血圧症、高尿酸血症、心房細動の累積罹患(率)はそれぞれ318人(2.5%)、1.454人(18.3%)、1,108人(10.6%)、489人(4.4%)、53%(10.4%)であった。多変量解析の結果、毎食後に歯磨きをしない群で、毎食後に歯磨きをする群と比較し、男性の糖尿病が1.43倍(p=0.028)、女性の脂質異常症が1.18倍(p=0.045)のオッズ比が認められた。【結論】歯磨きの頻度が少ない程、心血管疾患を増加させる原因として、男性で糖尿病、女性で脂質異常症の関与が大きいことが示された。循環器病の予防に、歯磨き習慣が1つの指標として有効である可能性が示唆された。(著者抄録)

OBJECTIVE: Whether obesity without metabolic syndrome (i.e., "metabolically healthy" obesity) confers similar or less metabolic risk remains controversial. METHODS: A retrospective 5-year cohort study of 9,721 Japanese subjects (48.5 ± 10.5 years, 4,160 men) was conducted in 2004 and reevaluated 5 years later. Subjects were excluded if they were hypertensive or diabetic or were receiving medications for dyslipidemia and/or gout or hyperuricemia in 2004. Study subjects were categorized according to baseline BMI  ≥ 25 kg/m2 (overweight/obesity) and < 25 kg/m2 (lean/normal weight) and also whether they had metabolic syndrome. The cumulative incidence of hypertension and diabetes over 5 years between groups was assessed. A second analysis evaluated whether baseline hyperuricemia provided additional risk. RESULTS: Subjects with overweight/obesity but without metabolic syndrome carried increased cumulative incidence of hypertension (14.6% vs. 7.2%, P < 0.001) and diabetes (2.6% vs. 1.1%, P = 0.004) over 5 years compared to lean/normal subjects without metabolic syndrome. Overweight/obesity conferred an increased risk for diabetes even in individuals with normal fasting blood glucose. Hyperuricemia became an independent risk factor for developing hypertension over 5 years in lean/normal subjects without metabolic syndrome. A 1 mg/dL increase in serum uric acid carried increased risk for hypertension (19%) and diabetes (27%). CONCLUSIONS: Metabolically healthy obesity and hyperuricemia confer increased risk for hypertension and diabetes.

Metabolic syndrome and diabetes are main health problems of modern life in the twenty-first century. Alarming ratios of global prevalence lead to conduct more and more researches about etiological factors and pathogenesis. Disease mechanism is elementary for advancing more efficient and practicable treatment methods. Concurrent increase in both fructose consumption with Western diet and metabolic syndrome has revealed fructose hypothesis that suggests fructose as one of etiological factor of metabolic syndrome (insulin resistance, central obesity, hypertension, etc.). Recent studies have increasingly lightened the unknowns about role of fructose on pathogenesis. This review discusses fructose hypothesis by exploring current studies and their results in wide perspective. Potential mechanisms covering low-grade inflammation or de novo lipogenesis, etc., in the development of insulin resistance and obesity are explained. Clinical trials have revealed connection of fructose-induced hyperuricemia with insulin resistance and chronic inflammatory state leading to hepatosteatosis or obesity. Further, novel hypothesizes suggesting role of fructose-induced modifications in epigenetics, gut microbiota and oxidative stress on disease pathogenesis are reviewed based on recent clinical trials. More innovative theories including fructose-induced malignancy; decreased satiety feeling, and unfavorable bone health are argued covering fructose-induced neurotransmitter changes in central nervous system, more aggressive malignancy phenotype and impaired calcium absorption.

BACKGROUND: We previously reported the association between toothbrushing practices and diabetes mellitus (DM) and dyslipidemia (DL) in a cross-sectional study. This study was conducted to clarify whether low frequency of toothbrushing practices is an independent risk factor for DM and DL using a follow-up design. METHODS: This study was a 5-year retrospective cohort study at St. Luke's International Hospital, Tokyo, Japan. We analyzed study subjects between 30 and 85 years old in 2004, who underwent annual medical examination both in 2004 and 2009. We compared the cumulative incidences of developing DM, DL, hypertension (HT), and hyperuricemia (HUA) between 2004 and 2009 among 3 groups: toothbrushing practices 'after every meal,' 'at least once a day,' and 'less than once a day'. Furthermore, we analyzed odds ratios (ORs) of risk for developing DM and DL by sex after making adjustments for age, obesity, DM, DL, HT, and HUA between two groups: 'after every meal' and 'not after every meal.' RESULTS: The number of study subjects was 13,070. Of 13,070 study subjects, 575 had DM, 5118 had DL, 2599 had HT, and 1908 had HUA in 2004. We excluded the subjects with each disease in 2004. The cumulative incidences (rates) of DM, DL, HT, and HUA between 2004 and 2009 were 318 (2.5%), 1454 (18.3%), 1108 (10.6%), and 489 (4.4%), respectively. Toothbrushing practices 'not after every meal' was a significant risk factor for developing DM in male [OR: 1.43; 95% confidence interval (CI), 1.040-1.970] and developing DL in female (OR: 1.18; 95% CI, 1.004-1.383) compared with toothbrushing practices 'after every meal.' CONCLUSION: Toothbrushing practices 'after every meal' prevented developing DM in males and DL in females significantly. Toothbrushing practices may be beneficial to reduce developing risk factors for cardiovascular disease.

わが国では高齢化が急速に進んでおり、心房細動の患者数も増加している。心房細動の危険因子としては、加齢のほかに、男性・高血圧・糖尿病・慢性閉塞性肺疾患などが知られているが、近年の多くの研究で高尿酸血症も心房細動に関与することが報告されている。心房細動の予防については、残念ながら確立したものはなく、今後の大きな研究課題である。本稿では、心房細動の危険因子としての尿酸に注目し、これまでの臨床疫学研究、尿酸の炎症を含めた基礎研究を紹介しつつ、今後の展望について述べる。(著者抄録)

BACKGROUNDS: The relationship between serum uric acid (SUA) and atrial fibrillation (AF) remains unclear because many parameters and diseases influence AF. This study was conducted to clarify the role of hyperuricemia as an independent competing risk factor for AF in an apparently healthy general population. METHODS: We retrospectively analyzed the medical records of 90,143 Japanese subjects who underwent annual regular health check-up in St. Luke's International Hospital, Tokyo, between January 2004 and June 2010. Of those subjects, 291 (0.32%) were identified as having AF by 12 leads electrocardiography. First, we analyzed 90,117 subjects to clarify the independent competing risk factors for AF and obtained odds ratios (ORs) by logistic regression analysis. Second, we excluded 40,825 subjects with hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, and current medication for hyperuricemia and/or gout, and we analyzed 49,292 subjects. RESULTS: First, AF groups were significantly higher SUA level (OR: 1.35; 95% confidence interval (CI), 1.22-1.50) than non-AF group. OR of hyperuricemia (>7.0mg/dL of SUA) for AF was 2.75 (95% CI, 2.10-3.60). Second, after multiple adjustments, higher SUA level (OR: 1.53; 95% CI, 1.21-1.92) was a significantly independent competing risk factor for AF, as well as older age, male sex, higher body mass index, lower FEV1/FVC, and higher hemoglobin. OR of hyperuricemia for AF was 3.19 (95% CI, 1.81-5.62). CONCLUSIONS: Hyperuricemia is an independent competing risk factor for AF. Further prospective intervention studies are needed to prove whether lowering SUA level might be important for preventing AF or not.

AIM: We previously proposed the concept of caregiver daily impression (CDI) as a practical tool for emergency triage. We herein assessed how CDI varies by sex, education and career length by determining CDI scores as quantitative outcome measures. METHODS: We carried out a cross-sectional study using a self-reported questionnaire among caregivers in 20 long-term care facilities in Hyogo, Japan. A total of 10 CDI variables measured participants' previous experience of emergency transfers using a scale from 0-10. The resulting total was defined as the CDI score. We hypothetically considered that higher scores indicated greater caregiver focus. The CDI scores were compared by sex, education and career length using analysis of covariance. RESULTS: A total of 601 personal caregivers were evaluated (mean age 36.7 years; 36% men). The mean career length was 6.9 years, with the following groupings: 1-4 years (38%), 5-9 years (37%) and >10 years (24%). After adjustment for sex and education, the CDI scores for the variable, "poor eye contact," significantly differed between caregivers with ≥10 and <5 years of experience (scores of 5.0 ± 3.1 and 4.0 ± 2.7, respectively). The CDI scores for variables related to eyes tended to increase with experience, whereas other CDI scores decreased. Male caregivers focused on residents' eyes significantly more than did female caregivers. CONCLUSIONS: We found that the CDI variable, "poor eye contact," is influenced by career length. Caregivers with more experience attach more importance to their impression of residents' eyes than do those with less experience. Sex-related differences in CDI might also exist. Geriatr Gerontol Int 2016; 17: 410-415.

Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway.

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. NEW & NOTEWORTHY: This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated.

BACKGROUND: Epidemics of chronic kidney disease (CKD) not due to diabetes mellitus (DM) or hypertension have been observed among individuals working in hot environments in several areas of the world. Experimental models have documented that recurrent heat stress and water restriction can lead to CKD, and the mechanism may be mediated by hyperosmolarity that activates pathways (vasopressin, aldose reductase-fructokinase) that induce renal injury. Here we tested the hypothesis that elevated serum sodium, which reflects serum osmolality, may be an independent risk factor for the development of CKD. METHODS: This study was a large-scale, single-center, retrospective 5-year cohort study at Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, between 2004 and 2009. We analyzed 13,201 subjects who underwent annual medical examination of which 12,041 subjects (age 35 to 85) without DM and/or CKD were enrolled. This analysis evaluated age, sex, body mass index, abdominal circumference, hypertension, dyslipidemia, hyperuricemia, fasting glucose, BUN, serum sodium, potassium, chloride and calculated serum osmolarity. RESULTS: Elevated serum sodium was an independent risk factor for development of CKD (OR: 1.03, 95% CI, 1.00-1.07) after adjusted regression analysis with an 18 percent increased risk for every 5 mmol/L change in serum sodium. Calculated serum osmolarity was also an independent risk factor for CKD (OR: 1.04; 95% CI, 1.03-1.05) as was BUN (OR: 1.08; 95% CI, 1.06-1.10) (independent of serum creatinine). CONCLUSIONS: Elevated serum sodium and calculated serum osmolarity are independent risk factors for developing CKD. This finding supports the role of limiting salt intake and preventing dehydration to reduce risk of CKD.

BACKGROUND: While elevated serum uric acid level (SUA) is a recognized risk factor for chronic kidney disease, it remains unclear whether change in SUA is independently associated with change in estimated glomerular filtration rate (eGFR) over time. Accordingly, we examined the longitudinal associations between change in SUA and change in eGFR over 5 years in a general Japanese population. METHODS: This was a large, single-center, retrospective 5-year cohort study at St. Luke's International Hospital, Tokyo, Japan, between 2004 and 2009. We included 13,070 subjects (30-85 years) in our analyses whose data were available between 2004 and 2009. Of those, we excluded 492 subjects with eGFR <60 mL/min/1.73 m2 at baseline. In addition to examining the entire cohort (n = 12,578), we stratified our analyses by baseline eGFR groups: 60-90, 90-120, and ≥120 mL/min/1.73 m2. Linear and logistic regressions models were applied to examine the relationships between baseline and change in SUA, change in eGFR, and rapid eGFR decline (defined as the highest quartile of change in eGFR), adjusted for age, gender, body mass index, abdominal circumference, hypertension, dyslipidemia, and diabetes mellitus. RESULTS: After multivariable adjustments including baseline eGFR, 1 mg/dL increase in baseline SUA was associated with greater odds of developing rapid eGFR decline (OR 1.27, 95% CI 1.17-1.38), and 1 mg/dL increase in SUA over 5 years was associated with 3.77-fold greater odds of rapid eGFR decline (OR 3.77, 95% CI 3.35-4.26). CONCLUSIONS: Elevated baseline SUA and increasing SUA over time were independent risk factors for rapid eGFR decline over 5 years.

BACKGROUNDS: Hypouricemia was reported as a risk factor for exercise-induced acute renal injury (EIAKI) and urinary stones. However, the prevalence of kidney diseases among hypouricemic subjects has not been evaluated. This study was conducted to clarify the prevalence of hypouricemia and the association of hypouricemia with kidney diseases by using a large-scale Japanese population data. METHODS: This study is a retrospective cross-sectional study at the Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, and Sanin Rousai Hospital, Yonago, Japan. We analyzed the medical records of 90,143 Japanese subjects at the center in St. Luke's International Hospital, Tokyo, and 4,837 subjects in Sanin Rousai Hospital, Yonago, who underwent annual regular health check-up between January 2004 and June 2010. We defined hypouricemia as serum uric acid level of ≤2.0 mg/dL. We checked the medical history of all the study subjects and compared the rates of complications including urinary stones and kidney diseases among those with or without hypouricemia. RESULTS: The prevalence of hypouricemia was 0.19% in St. Luke's International Hospital, Tokyo, and 0.58% in Sanin Rousai Hospital, Yonago. The prevalence of hypouricemia in women was larger than that in men both in Tokyo (0.31% vs 0.068%, p<0.001) and in Yonago (1.237% vs 0.318%, p<0.001). Among 172 hypouricemic subjects (30 men), the rates of previous urinary stones and kidney diseases (including nephritis/nephrosis) were 1.2% (3.3% men, 0.7% women) and 2.3% (10% men, 0.7% women), respectively. Hypouricemic men had a 9-fold higher rate of previously having kidney diseases compared to non-hypouricemic men (p<0.001). However, the rates of other diseases including urinary stones were not significantly different between the two groups. CONCLUSIONS: Hypouricemia was associated with a history of kidney disease especially in men.

Proepicardium (PE) cells generate cardiac fibroblasts, smooth muscle cells (SMCs) and endothelial cells that form coronary arteries. T-box18 (Tbx18) is a well-known marker of PE cells and epicardium. We examined whether Tbx18-positive cells differentiated from murine embryonic stem (ES) cells serve as PE progenitors to give rise to vascular SMCs and fibroblasts. To collect Tbx18-positive cells, we established Tbx18-EGFP knock-in mouse ES cells using the CRISPR/Cas9 system. We harvested the Tbx18-EGFP-positive cells on day 8, 10 and 14 after the initiation of differentiation; Tbx18 mRNA was enriched on day 8 to 14 and Snai2 mRNA was enriched on day 8 and 10, indicating successful collection of Tbx18-positive cells. Tbx18-EGFP-positive cells expressed the PE marker WT1 on day 8 and 10. They also expressed the SMC marker Acta2 and fibroblast markers Thy1 and Fsp1 on day 8 to 14, but did not express the endothelial cell marker PECAM or the cardiac cell marker CD166 or Myh7. In conclusion, Tbx18-positive cells represent a part of PE cells in the initial phase of differentiation and subsequently include SMCs as well as fibroblasts. These results indicate that Tbx18-positive cells serve as a PE progenitor to supply a variety of cells that contribute to the formation of coronary arteries.

Background: Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. Purpose: In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. Patients and methods: 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. Results: In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Conclusion: Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

The importance of atrial fibrillation (AF) as a cause of mortality and morbidity has prompted research on its pathogenesis and treatment. Recognition of AF risk factors is essential to prevent it and reduce the risk of death. Hyperuricemia has been widely accepted to be associated with the incidence of paroxysmal or persistent AF, as well as to the risk of AF in post cardiovascular surgery patients. The possible explanations for this association have been based on their relation with either oxidative stress or inflammation. To investigate the link between hyperuricemia and AF, it is necessary to refer to hyperuricemia-induced atrial remodeling. So far, both ionic channel and structural remodeling caused by hyperuricemia might be plausible explanations for the occurrence of AF. Inhibition of xanthine oxidase and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, or the use of antioxidants, along with serum uric acid (SUA) level reduction to prevent inflammation, might be useful. Uric acid transporters (UATs) play a key role in the regulation of intracellular uric acid concentration. Intracellular rather than serum uric acid level is considered more important for the pathogenesis of AF. Identification of UATs expressed in cells is thus important, and targeting UATs might become a potential strategy to reduce the risk of hyperuricemia-induced atrial fibrillation.

背景:高血圧患者の約20%に高尿酸血症が合併しており、高血圧患者の高尿酸血症は心血管イベントの危険因子となる可能性がある。自由行動下血圧(ABPM)は高血圧の診断・治療に使用され、高い予後予測能力が示されている。またNon-Dipper型(ND)はDipper型(D)に比して心血管イベントが多い。これまで血清尿酸値と血圧日内変動タイプについての関連を示す研究は少なかった。方法:外来通院中のABPMを行った高血圧患者(52例)の血清尿酸値、腎機能、尿中尿酸排泄を検討した。併存疾患・併用薬での除外は行わなかったが、血清尿酸値への影響が強い尿酸低下薬服用者を除外して同様の検討を行った。結果:ND(19例)はD(33例)に比べ血清尿酸値は有意に高かった(6.3±1.1mg/dL vs.5.4±1.0mg/dL、p=0.018)。腎機能と尿中尿酸排泄は両群間で有意差がなかった。またNDの高尿酸血症(UA>7.0mg/dL)患者の割合はDより有意に多い(42.1% vs.6.1%、p<0.001)。単変量解析では尿酸に対し有意な説明変数は体重、夜間収縮期血圧、収縮期血圧低下度、拡張期血圧低下度、血清クレアチニン及びCua/Ccrであった。多変量解析では収縮期血圧下降度、血清クレアチニンとCua/Ccrであった。尿酸低下薬非服用群での検討でも同様の結果であった。結論:高血圧患者の血清尿酸値はNDのマーカーとなる可能性がある。(著者抄録)

＜ポイント＞12誘導心電図でT波増高,P波消失(減高)を見たら,高カリウム血症を疑う.水様性下痢が主訴の高カリウム血症もありうる.高齢者では,既往がなくても急激な腎機能障害・高カリウム血症を認めることがある.高カリウム血症では,突然徐脈を呈することがあり,モニター装着と緊急対応できる体制を整えておく.(著者抄録)

In recent years, there has been an increase in the prevalence of hyperuricemia, and the latter has attracted attention as an adult lifestyle-associated disease, together with hypertension, diabetes, and dyslipidemia. Although hyperuricemia is known to be an independent risk factor for hypertension, whether it is an independent risk factor for cardiovascular disease remains controversial. Recently, some small-scale interventional studies on antihyperuricemic medications showed that the latter improved angina symptoms and prevented cardiovascular disease. Here, we will mainly explain the cause of hyperuricemia and the associations between hyperuricemia, hypertension, and cardiovascular disease based on the latest published evidence.

Background: Although urate impaired the endothelial function, its underlying mechanism remains unknown. We hypothesized that urate impaired nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) via activation of uric acid transporters (UATs). Purpose and method: In the present study, we studied effects of urate on NO production and eNOS protein expression in HUVEC cells in the presence and absence of urate lowering agents using molecular biological and biochemical assays. Results: HUVECs expressed the 4 kinds of UATs, URATv1, ABCG2, MRP4 and MCT9. Exposure to urate at 7mg/dl for 24h significantly reduced production of NO. Pretreatment with benzbromarone, losartan or irbesartan normalized NO production. The same exposure resulted in dephosphorylation of endothelial NO synthase (eNOS) in HUVECs. Again pretreatment with benzbromarone, losartan or irbesartan abolished this effect. Conclusion: Urate reduced NO production by impaired phosphorylation of eNOS in HUVEC via activation of UATs, which could be normalized by urate lowering agents.

OBJECTIVES: To clarify the association between toothbrushing and risk factors for cardiovascular disease--namely, hypertension (HT), diabetes mellitus (DM), dyslipidaemia (DL), hyperuricaemia (HUA) and chronic kidney disease (CKD). DESIGN: A large-scale, single-centre, cross-sectional study. SETTING: St Luke's International Hospital, Center for Preventive Medicine, Tokyo, Japan, between January 2004 and June 2010. PARTICIPANTS: This study examined the toothbrushing practices of 85,866 individuals according to the 3-category frequency criterion: 'after every meal', 'at least once a day' and 'less than once a day'. The ORs by frequency were calculated for the prevalences of HT, DM, DL, HUA and CKD according to binominal logistic regression analyses adjusted for age, gender, body mass index and lifestyle habits--smoking, drinking, walk time and sleep time. RESULTS: The prevalences of the risk factors were as follows: HT ('after every meal': 13.3%, 'at least once a day': 17.9% and 'less than once a day': 31.0%), DM (3.1%, 5.3% and 17.4%, respectively), DL (29.0%, 42.1% and 60.3%, respectively), HUA (8.6%, 17.5% and 27.2%, respectively) and CKD (3.8%, 3.1% and 8.3%, respectively). The prevalences were significantly higher in the 'less than once a day' group than in the 'after every meal' group for DM (OR=2.03; 95% CI 1.29 to 3.21) and DL (OR=1.50; 95% CI 1.06 to 2.14), but not for HT, HUA and CKD. CONCLUSIONS: Even taking into account lifestyle habits, a lower frequency of toothbrushing was associated with high prevalences of DM and DL. Toothbrushing practices may be beneficial for oral health improvement and also for prevention of certain systemic diseases.

Olprinone is an inotropic agent that inhibits phosphodiesterase (PDE) III and causes vasodilation. Olprinone has been shown to be less proarrhythmic and possibly affect expression of functional Kv1.5 channels that confer the ultra-rapid delayed-rectifier K+ channel current (IKur) responsible for action potential repolarization. To reveal involvement of Kv1.5 channels in the less arrhythmic effect of olprinone, we examined effects of the agent on the stability of Kv1.5 channel proteins expressed in COS7 cells. Olprinone at 30-1000 nM increased the protein level of Kv1.5 channels in a concentration-dependent manner. Chase experiments showed that olprinone delayed degradation of Kv1.5 channels. Olprinone increased the immunofluorescent signal of Kv1.5 channels in the endoplasmic reticulum (ER) and Golgi apparatus as well as on the cell surface. Kv1.5-mediated membrane currents, measured as 4-aminopyridine-sensitive currents, were increased by olprinone without changes in their activation kinetics. A protein transporter inhibitor, colchicine, abolished the olprinone-induced increase of Kv.1.5-mediated currents. The action of olprinone was inhibited by 4-aminopyridine, and was not mimicked by the application of 8-Bromo-cAMP. Taken together, we conclude that olprinone stabilizes Kv1.5 proteins at the ER through an action as a chemical chaperone, and thereby increases the density of Kv1.5 channels on the cell membrane. The enhancement of Kv1.5 currents could underlie less arrhythmogenicity of olprinone.

近年、尿酸と不整脈、特に心房細動との関係が明らかとなってきた。2010年にギリシャのLetsas KPらによって尿酸と心房細動の関係がはじめて報告されてから、現在までに尿酸と心房細動に関する論文は数十本にも及ぶ。これらの論文のほとんどが疫学研究によるものだが、コホート研究で、他のリスクを十分に考慮に入れたうえでも、尿酸が心房細動の独立した発症因子となることを明らかにした報告もある。尿酸と心房細動とが関係することは明らかとなってきたが、尿酸がどのように心房細動発症に関与するのかについては、まだ明らかにされていない。本稿ではこれまでの研究報告をまとめるとともに、その機序について考察する。(著者抄録)