Validation of claims data to identify death among aged persons utilizing enrollment data from health insurance unions.

The identification of death is critical for epidemiological research. Despite recent developments in health insurance claims databases, the quality of death information in claims is not guaranteed because health insurance claims are collected primarily for reimbursement. We aimed to examine the usefulness and limitations of death information in claims data and to examine methods for improving the quality of death information for aged persons.We used health insurance claims data and enrollment data (as the gold standard) from September 2012 through August 2015 for nondependent persons aged 65-74 years enrolled in Japanese workplace health insurance. Overall, 3,710,538 insured persons were registered in the database during the study period. We analyzed 45,441 eligible persons. Inpatient and outpatient deaths were identified from the discharge/disease status in the claims, with sensitivities of 94.3% and 47.4%, specificities of 98.5% and 99.9%, and PPVs of 96.3% and 95.7%, respectively, using enrollment data as the gold standard. For outpatients, death defined as a combination of disease status and charge data for terminal care still indicated low sensitivity (54.7%).The validity of death information in inpatient claims was high, suggesting its potential usefulness for identifying death. However, given the low sensitivity for outpatient deaths, the use of death information obtained solely from records in outpatient claims is not recommended.

Visceral fat accumulation is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

BACKGROUND: The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. The elevated visceral fat accumulation (VFA) has been reported to be closely related to the development of atherosclerosis. This preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with VFA and insulin resistance in type 2 diabetic patients not receiving insulin treatment. MATERIAL AND METHODS: Based on brain magnetic resonance imaging (MRI), 95 type 2 diabetic patients were divided into two groups: WML-positive group (aged 59 +/- 7 years, mean +/- SD n = 37) and WML-negative group (aged 58 +/- 5, years, n = 58). The level of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, homeostasis model assessment (HOMA) index, and haemoglobin A1c. The fat distribution was evaluated by measuring the visceral fat accumulation by abdominal computerized tomography at the umbilical level. RESULTS: The body mass index was higher in the WML-positive group than in the WML-negative group (P < 0.005). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < 0.05 and P < 0.01, respectively). FPG (P < 0.01), insulin concentrations (P < 0.0001), HOMA index (P < 0.0001) and VFA (<0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high VFA and insulin resistance (P < 0.001, P < 0.0001, respectively). CONCLUSIONS: The results of this preliminary study indicate that the presence of WML was associated with the high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus. Further larger cohort studies are warranted to confirm these findings.

Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus.

BACKGROUND: Insulin resistance significantly correlated with a non-dipper type of essential hypertension. Thiazolidinediones (TZD), oral hypoglycaemic agents that act as insulin sensitizers, have been demonstrated in multiple in vivo and in vitro studies to possess antihypertensive properties. This study examined the efficacy of TZD therapy with pioglitazone at transforming the circadian rhythms of blood pressure from a non-dipper to a dipper type. MATERIALS: We examined 31 patients with type 2 diabetes mellitus during both a baseline period and a period of treatment with pioglitazone. Patients received 15 mg day(-1) pioglitazone for four weeks and 30 mg day(-1) for 12 weeks. Twenty-four hour ambulatory blood pressure monitoring (ABPM) and laboratory data (blood tests for cardiovascular risk factors) were obtained at the beginning and end of the study. RESULTS: In non-dippers (n = 16), but not dippers (n = 15), we observed a significant interaction between pioglitazone therapy and nocturnal falls in systolic and diastolic blood pressure. This examination indicated that the magnitude of the nocturnal blood pressure fall was affected by pioglitazone therapy. In non-dippers, but not dippers, a significant correlation was observed between the percent decrease in nocturnal BP and the homeostasis model assessment (HOMA) index (r = 0.774, P = 0.0007). CONCLUSIONS: The present study demonstrated that pioglitazone can restore the nocturnal BP declines in parallel to reductions in the HOMA index, suggesting that insulin resistance may play an important role in the genesis of circadian BP rhythms. TZD-based treatment may thus have the additional therapeutic advantage of reducing the risk of cardiovascular complications by transforming the circadian rhythm of BP.

Preceding stimulus frequency-dependent potentiation of the postrest shortening of the action potential duration in rabbits.

Action potential duration (APD) in rabbit ventricular myocardium shortens after a rest period (postrest shortening). However, the effects of preceding stimulus frequency on the postrest shortening have not been elucidated. We recorded transmembrane action potentials (TAPs) and monophasic action potentials (MAPs) from the rabbit ventricle. In in vitro experiments. repetitive regular stimuli (S1) at cycle lengths ranging between 500 to 3000 ms were followed by a single extrastimulus (S2) at a coupling interval of 5000 ms. A decrease in S1S1 interval resulted in a progressive shortening of the duration of TAP (TAPD) elicited by S2 (S2-TAPD), which was potentiated by increasing extracellular calcium concentration ([Ca2+]o) or application of ouabain and was inhibited by lowering [Ca2+]o or verapamil. Application of ryanodine was most effective in lengthening S2-TAPD following a short S1S1 interval. 4-aminopyridine and E4031 caused marked lengthening of S2-TAPD when S1S1 was long. However, the lengthening effect was attenuated and disappeared with a shorter S1S1 interval. In in vivo experiments, regular ventricular pacing (S1) at cycle lengths ranging between 250 to 1000 ms was followed by a single extrastimulus (S2) with a coupling interval (S1S2) of 1500 ms. A decrease in the S1S1 interval also resulted in progressive shortening of the duration of MAP elicited by S2. Our results indicate that the postrest shortening is potentiated by an increase in the preceding stimulus frequency in the rabbit ventricle, in which the function of sarcoplasmic reticulum may play a significant role.

Suppression of cesium-induced ventricular tachyarrhythmias by atrial natriuretic peptide in rabbits.

BACKGROUND: Intravenous injection of cesium chloride (Cs) causes ventricular tachyarrhythmias in rabbits. We investigated whether these tachyarrhythmias were caused by increased pressure load and whether they could be suppressed by atrial natriuretic peptide (ANP). METHODS AND RESULTS: Cs was injected in a bolus dose (1.5 mmol/kg), which was repeated 20 minutes later. Rabbits were then divided into 3 groups: control, ANP-treated, and hydralazine-treated groups. ANP or hydralazine was administered between the first and second Cs injections. The experiments were performed during intrinsic sinus rhythm (protocol A) or during ventricular pacing (protocol B). In protocol A, the second injection of Cs in the control group induced early afterdepolarizations and ventricular tachycardia, which were preceded by a marked increase in left ventricular end-diastolic pressure (LVEDP). Both ANP and hydralazine significantly suppressed Cs-induced increase in LVEDP. The arrhythmia score after the second injection of Cs was significantly lower in the ANP-treated and hydralazine-treated group compared with the control group (P < .005 and P < .05, respectively). In protocol B, the duration of left ventricular monophasic action potential and early afterdepolarization amplitude before and/or after the injections of Cs did not differ significantly between control and ANP-treated groups. CONCLUSIONS: Our results suggest that increased pressure load may play a role in the arrhythmogenic effect of Cs. The protective effect of ANP against Cs-induced ventricular tachycardia may be explained in part by a reduction in pressure overload. However, this effect might also be explained by the diverse action of ANP on the cardiovascular system.

Radiofrequency catheter ablation from the left sinus of Valsalva in a patient with idiopathic ventricular tachycardia.

We report the case of a 54-year-old woman with idiopathic VT originating in the left ventricular outflow tract. She initially presented with palpitations and light-headedness. The morphology of the PVCs exhibited an inferior axis and tall R waves were noted in all the precordial leads. Spontaneous PVCs were transiently terminated by an intravenous injection of adenosine triphosphate. Radiofrequency catheter ablation from the left sinus of Valsalva successfully abolished the PVCs and the VT.

Effect of constant and intermittent vagal stimulation on the heart rate and heart rate variability in rabbits.

To examine whether the high-frequency (HF) component of heart rate variability (HRV) reflects fluctuation or tonic level of vagal outflow, we investigated the effects of vagal efferent nerve stimulation (VS) on the heart rate and HRV in anesthetized open-chest rabbit under artificial respiration at a rate of 52 breaths/min (0.86 Hz). A power spectral analysis was performed at baseline and during VS (stimuli at 2 ms, 1-10 V and 5-25 Hz). VS was applied using two different patterns. The first was constant VS; continuous stimulation at graded frequency or voltage to simulate changes in the level of vagal "tone." The second pattern was intermittent VS; stimulation at 0.5 Hz of on-off cycle to simulate fluctuations in vagal efferent activity. The power spectrum at baseline showed a single narrow component at 0.86 Hz, identical to respiration rate. Both the constant and intermittent VS prolonged RR interval. The amplitude of the component at 0.86 Hz remained unaffected by either the constant or intermittent VS, whereas the latter evoked a distinct narrow component at 0.5 Hz, reflecting the on-off cycle of intermittent VS. Our results suggest that the HF component of the power spectrum of HRV measures the magnitude of fluctuations of vagal input associated with respiratory modulation.

High plasma cardiac natriuretic peptides associated with enhanced cyclic guanosine monophosphate production in preascitic cirrhosis.

BACKGROUND/AIMS: The initial abnormalities of renal sodium handling in cirrhosis remain unclear. The aim of this study was to characterize sodium metabolism in preascitic cirrhosis. METHODS: Ten patients with preascitic cirrhosis and ten controls were studied. All subjects ate a diet providing 120 mmol sodium during an equilibration period lasting 5 days and the study day. On the study day, after remaining in bed, plasma levels of atrial natriuretic peptide, brain natriuretic peptide, renin activity, aldosterone, noradrenaline, and cyclic guanosine monophosphate were measured at 7 am. Thereafter, they were instructed to maintain an upright posture until dinner and the measurements were repeated at 9 am and 6 pm. After having dinner, all subjects were asked to remain in bed and the measurements were repeated at 11 pm. To measure renal sodium and cyclic guanosine monophosphate excretion, 24-h urine collections were performed, starting from 7 pm on the day before the experimental day. RESULTS: Plasma levels of atrial natriuretic peptide, brain natriuretic peptide and cyclic guanosine monophosphate in patients with preascitic cirrhosis were significantly elevated compared with those in controls at every sampling time (p=0.03 or less, p= 0.04 or less, and p=0.01 or less). In contrast, plasma renin activities at every sampling time were significantly lower in patients than in controls (p= 0.04 or less). Plasma aldosterone and noradrenaline levels were not significantly different at every sampling time in the two groups. No significant differences in daily renal sodium excretion were found. However, urinary cyclic guanosine monophosphate excretion was significantly higher in patients than in controls (p<0.01). CONCLUSIONS: The initial abnormalities of sodium metabolism in cirrhosis might be characterized by blunted renal responsiveness to natriuretic peptides. The results of the study also provide indirect evidence that the impairment is mainly located at postreceptor levels of signal transduction pathway to the peptides, if the activation of antinatriuretic factors other than renin-angiotensin or sympathoadrenergic systems does not play a role.

Influence of autonomic tone on the filtered QRS duration from signal averaged electrocardiograms in healthy volunteers.

We recently reported that signal averaged electrocardiograms (SAECG) measurements possess a circadian rhythm and are closely related to heart rate or heart rate variability in healthy volunteers. This study determines the influence of autonomic tone on the filtered QRS (f-QRS) duration from SAECG by using pharmacologic autonomic blockade and exercise in healthy volunteers. Eleven healthy male volunteers were studied. Three protocols were designed to study the effects of exercise (Ex) under control conditions, beta adrenergic blockade or double blockade. SAECGs and heart rate variability (LF and HF: low and high frequency power, LF/HF ratio) were determined from Holter recordings. Ex significantly decreased the f-QRS duration and HF and significantly increased heart rate and LF/HF. Ex during beta adrenergic blockade significantly increased heart rate and decreased f-QRS duration and HF, but did not change LF/HF. Ex during double blockade did not affect the f-QRS duration, HF, or LF/HF. The changes in f-QRS duration induced during Ex, autonomic blockade, or both were inversely correlated with changes in heart rate and LF/HF and positively correlated with changes in HF. These data suggest that f-QRS duration in healthy subjects is shortened by Ex with increased sympathetic tone or decreased parasympathetic tone or the combination.

Evaluation of autonomic influences on QT dispersion using the head-up tilt test in healthy subjects.

Our objective was to examine the autonomic influence on QT interval dispersion using the head-up tilt test in healthy subjects. RR and QT intervals, heart rate variability, and plasma norepinephrine concentration were measured in the supine position and tilting to 70 degrees for 20 minutes using a footboard support in 15 healthy male volunteers (mean age +/- SD: 28.0 +/- 4.5 years). The rate-corrected QT interval (QTc) was calculated using Bazett's formula, and QT and QTc dispersions were defined as the maximum minus minimum values for the QT and QTc, respectively, from the 12-lead ECG. Spectral analysis of the heart rate variability generated values for the low- and high-frequency powers (LF and HF) and their ratio (LF/HF). Compared with values obtained in the supine position, tilting significantly increased QT (P < 0.05) and QTc dispersion (P < 0.01), the LF/HF ratio (P < 0.0001), and plasma norepinephrine concentration (P < 0.0001), and significantly decreased HF (P < 0.0001). QTc dispersion was positively correlated with the LF/HF ratio and plasma norepinephrine concentration, and negatively correlated with HF. These results suggest that head-up tilt testing increases QT dispersion by increasing sympathetic tone and/or decreasing vagal tone in healthy subjects.

Upright posture blunts postprandial splanchnic hyperemia in patients with cirrhosis and portal hypertension.

The aim of this study was to compare postprandial hemodynamic changes observed during assumption of the recumbent posture and upright posture in patients with cirrhosis and portal hypertension. Eleven patients with cirrhosis and portal hypertension were studied. Echo-Doppler examinations were performed to measure flow volume in the portal vein (PV), superior mesenteric artery (SMA), and splenic artery (SA) in the fasting condition. Collateral blood flow was indirectly calculated by determining the difference between the sum of SMA, SA, and PV blood flows. After these measurements were done, each patient received a standardized liquid meal and was then randomly assigned to either maintain supine or upright posture, in a crossover design, on 2 different days (recumbent day and upright day). On each study day, the above-mentioned measurements were repeated 30 min and 60 min after the meal. PV blood flow increased significantly after the meal on the recumbent day (P < 0.01) but not on the upright day (P = 0.78). Although there were significant postprandial increases in SMA blood flow on both study days (P < 0.01, P < 0.01), the effect was less pronounced on the upright day than on the recumbent day (P < 0.01). Postprandial SA blood flow showed no change on the recumbent day (P = 0.64), but decreased significantly on the upright day (P < 0.01). The calculated postprandial collateral blood flow increased significantly on the recumbent day (P < 0.05), but showed no change on the upright day (P = 0.53). These results suggest that the upright posture blunts postprandial splanchnic hyperemia in patients with cirrhosis and portal hypertension.

Erythropoietic protoporphyria with fatal liver failure.

A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction. On admission, levels of protoporphyrin and coproporphyrin within erythrocytes were markedly increased. Autofluorescent erythrocytes were also detected, leading to a diagnosis of erythropoietic protoporphyria. A liver biopsy specimen revealed cirrhosis with dark brown granules filling hepatocytes, bile canaliculi, and bile ductules. Transfusion of washed erythrocytes, hemodialysis, and administration of cholestyramine and beta-carotene transiently improved levels of porphyrins and liver function. The patient died of rupture of esophageal varices followed by multiple organ failure. However, the treatments were believed to have extended survival.

Effect of transcatheter arterial chemoembolization on kidney hemodynamics and function in patients with cirrhosis and hepatocellular carcinoma.

BACKGROUND/AIMS: Transcatheter arterial chemoembolization (TACE) may have deleterious effect on the kidney in patients with cirrhosis and hepatocellular carcinoma. The aim of the study was to test this hypothesis. METHODS: Twenty-four patients with cirrhosis and hepatocellular carcinomas were included. They consisted of 16 patients undergoing a single TACE and eight patients undergoing diagnostic angiography. Doppler ultrasonography was used to measure hepatic artery pulsatility index (HA-PI) and renal artery pulsatility index (RA-PI) before and 1 day and 10 days after the procedure. Similarly, kidney function was assessed by measuring creatinine clearance. In addition, plasma renin activity, noradrenaline, and endothelin-1 were also measured. RESULTS: In patients receiving diagnostic angiography, no significant changes in HA-PI were observed after the procedure. In contrast, HA-PI increased significantly 1 day after the procedure (19%, p<0.01) in patients undergoing TACE, although it returned to baseline value 10 days after the procedure. In patients undergoing diagnostic angiography, no significant changes in RA-PI were observed after the procedure. Similarly, no detectable changes in RA-PI were noted in patients undergoing TACE. A transient small reduction in creatinine clearance was noted after the procedure in patients undergoing diagnostic angiography (-12%, p<0.05) and in those undergoing TACE (-11%, p<0.05). However, the effect was similar in the two groups (two-way ANOVA, p=0.72). No significant changes in plasma renin activity, noradrenaline, and endothelin-1 were observed after either diagnostic angiography or TACE. CONCLUSIONS: These results suggest that TACE per se has no deleterious effect on the kidney hemodynamics and function in patients with cirrhosis and hepatocellular carcinoma.

Noninvasive assessment of the cardiac baroreflex: response to downward tilting and comparison with the phenylephrine method.

OBJECTIVES: We studied the relation between changes in systolic blood pressure and RR interval during downward tilting in comparison with assessment of baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and with measures of heart rate variability (HRV). BACKGROUND: The method most extensively used for assessing BRS involves bolus injections of phenylephrine. Several noninvasive methods proposed to assess BRS have not been widely applied in the clinical setting. METHODS: Sixteen healthy male volunteers were studied (mean age +/- SD 27.5+/-4.6 years). Arterial blood pressure using tonometry and electrocardiogram was simultaneously recorded. After 20 min of 70 degrees upright tilting, the table was returned to supine position at a speed of 3.2 degrees/s. Subsequently, BRS was assessed using an intravenous bolus injection of phenylephrine (2 to 3 microg/kg). Heart rate variability under resting conditions also was analyzed. RESULTS: In all subjects, a beat to beat systolic blood pressure increase associated with corresponding RR interval lengthening was observed during downward tilting as well as during phenylephrine administration. During both testing procedures, these two variables showed linear correlation, and the slope of regression line during downward tilting (DT-BRS) correlated significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also correlated significantly with the high frequency component of resting HRV (r = 0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS). CONCLUSIONS: We conclude that in a small homogeneous group DT-BRS provided an assessment of reflex cardiac vagal function comparable to that obtained by the phenylephrine method.

Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.

OBJECTIVE: In this study, we examined the mutational spectrum of K-ras in cases of gallbladder and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct (AJPBD). METHODS: We examined 35 gallbladders with AJPBD (20 with hyperplasia, 15 with carcinoma) and 38 gallbladders without AJPBD (four normal gallbladders, four with hyperplasia, six with adenoma, 24 with carcinoma). Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and direct sequencing were performed to detect mutations in codon 12 or 13 of K-ras. RESULTS: In the cases with AJPBD, the prevalences of K-ras mutation were 15% (3/20) in hyperplasia, 60% (6/10) in stage I carcinoma, and 100% (5/5) in stage II-IV carcinoma. In the cases without AJPBD, the prevalences of K-ras mutation were 0% (0/4) in normal gallbladder, 0% (0/4) in hyperplasia, 17% (1/6) in adenoma, 7% (1/16) in stage I carcinoma, and 38% (3/8) in stage II-IV carcinoma. Prevalences of K-ras mutation in hyperplasia and carcinoma with AJPBD were greater than those without AJPBD (p < 0.05). The point mutation of GGT to GAT in codon 12 was frequently observed in the cases with AJPBD. CONCLUSION: These results suggest that the specific K-ras mutation in codon 12 (GGT to GAT) may contribute to the early stage of carcinogenesis in the gallbladder with AJPBD.

Cholecystokinin regulates the invasiveness of human pancreatic cancer cell lines via protein kinase C pathway.

We have previously reported that cholecystokinin (CCK) plays an important role in the invasiveness and the production of matrix metalloproteinase-9 (MMP-9) in two human pancreatic cancer cell lines. In this study we investigated the pathway of the invasiveness associated with MMP-9 of those lines regulated by CCK. Two human pancreatic cancer cell lines were treated with CCK-8 alone, CCK-8 and staurosporine, or CCK-8 and indomethacine. The invasiveness and the production of MMP-9 were decreased with staurosporine but not indomethacine. These results suggest that CCK may regulate the invasiveness and the production of MMP-9 via protein kinase C in human pancreatic cancer cell lines.

Vagal modulation of ventricular tachyarrhythmias induced by left ansae subclaviae stimulation in rabbits.

Previous evidence has shown that vagal nerve activity modulates ventricular arrhythmias in patients and in animal models. However, the effects of direct vagus nerve stimulation on ventricular tachyarrhythmias brought by direct sympathetic nerve stimulation have not been elucidated. In the present study, the effects of electrical stimulation of the left cervical vagus nerve on ventricular tachycardia (VT) which was induced by electrical stimulation of the left ansae subclaviae (LAS) in rabbits were assessed. Monophasic action potentials (MAPs) of the left ventricular endocardium were recorded simultaneously with surface ECG. In 27 rabbits tested, the stimulation of LAS induced VT in 19 rabbits. Polymorphic VT (PVT) was induced in 14 rabbits (PVT group), whereas monomorphic VT (MVT) was induced in 5 rabbits (MVT group). Vagus nerve stimulation during the sympathetically-induced PVT led to a restoration of sinus rhythm in 10 of 14 rabbits, while that during the sympathetically-induced MVT did not restore sinus rhythm in any of the 5 rabbits. Vagus nerve stimulation during the stimulation of LAS, which was of subthreshold intensity for the induction in VT, did not result in an induction of PVT in any of the 14 rabbits in the PVT group, while it induced slow MVT in 3 of 5 rabbits in the MVT group. These results indicate that vagus nerve stimulation preferentially exerts protective antiarrhythmic effects against PVT induced by sympathetic neural stimulation in this model, while it occasionally induces slow MVT under conditions in which sympathetic nerve activity in potentially elevated.