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Atrial fibrillation (AF) is associated with an increased risk of heart failure (HF), stroke, and death. Although fibrillation cycle length (FCL) is used as a surrogate for atrial refractoriness, its impact on outcomes remains unclear. This study aimed to identify predictors of cardiovascular events, including FCL, in patients with long-standing persistent AF. The study included 190 consecutive patients with long-standing persistent AF (mean age 74 years, 74% male). Patients with valvular AF or hemodialysis-dependent end-stage renal disease and those on anti-arrhythmic drugs were excluded. The primary composite outcome was occurrence of cardiovascular events (myocardial infarction, HF), cerebrovascular events (stroke, transient ischemic attack), and all-cause death. FCL was calculated by fast Fourier transformation analysis of fibrillation waves in the surface electrocardiogram. Over a median follow-up of 2.6 years, the primary outcome occurred in 31 patients (cardiovascular events, n = 18; cerebrovascular events, n = 8; all-cause death, n = 5). In multivariate analysis, longer FCL and history of HF were independent predictors of these outcomes. In a Cox proportional hazards model adjusted for age, sex, and history of HF, patients with an FCL > 160 ms (cut-off determined by receiver-operating characteristic curve analysis) were at increased risk of the outcome (hazard ratio 12.9; 95% confidence interval 4.99–44.10; p

Background The carriage prevalence of pneumococcus among community-dwelling older adults is not fully understood, especially in superaged societies. Our purpose was to elucidate the carriage prevalence of pneumococcus in the upper respiratory tract among Japanese community-dwelling adults aged ≥65 years. Methods We conducted a cross-sectional study of generally healthy community-dwelling adults aged ≥65 years in Nagasaki city, Japan. Demographic and clinical data and nasopharyngeal, oropharyngeal and saliva samples were collected from February 21st, 2018, to December 17th, 2018. The specimens were tested by culture and molecular methods. Results Among a total of 504 enrolled participants, none were positive for pneumococcus by culture, and 22 were positive by PCR. The overall carriage prevalence was 4.4% (95% CI: 2.8–6.5%). The prevalence was highest in saliva samples, followed by oropharyngeal and nasopharyngeal samples. No demographic characteristics were associated with carriage prevalence, including age (4.7% among participants aged 65–74 years and 4.1% among those 75 years and older). Among the pneumococcal-positive participants, 18.2% were PCV13-covered serotypes. Conclusions Our data suggest a low carriage prevalence of S. pneumoniae among community-dwelling older people in Japan.

Background Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. Methods Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction Results This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. Conclusions The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.

Acute heart failure from aortic stenosis secondary to chronic aortic dissection is very rare. We describe a case of acute heart failure secondary to aortic arch stenosis resulting from subacute type A aortic dissection. Resection of large thickened immobile intimal flap with total aortic arch replacement was successful, and cardiac function improved.

Background The relationship between atrial high-rate episode (AHRE) burden (i.e., the frequency of atrial tachyarrhythmia) and heart failure (HF) risk is unclear. We hypothesized that new-onset and higher burden of AHRE are associated with HF. Methods and Results: We included 104 consecutive patients with cardiac implantable electronic devices (CIEDs) capable of continuous atrial rhythm monitoring. Patients with AF history were excluded. To stratify patients, AHREs were evaluated only during the initial 1 year after CIED implantation. The primary endpoint was all-cause death or new-onset or worsening HF that required unplanned hospitalization or readjustment of HF drug therapy. At 1 year after CIED implantation, 34/104 patients (33%) exhibited AHREs. No difference in basal clinical characteristics except for left ventricular ejection fraction between patients with and without new-onset AHREs was found. AHRE groups had more HF events than the non-AHRE group. All patients were divided into 3 groups based on AHRE burden: none, low, and high. Worsening HF was observed in 12 patients (12%). Cox hazard analysis revealed that AHRE and higher AHRE burden were independent predictive factors for worsening HF. The high group showed a higher risk for HF than the non-AHRE groups, but no significant difference was found between the low- and non-AHRE groups. Conclusions New-onset higher AHRE burden was associated with subsequent risk for HF in patients with CIEDs.

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

Gastric hypomotility (GH) is a possible complication of catheter ablation (CA) for atrial fibrillation (AF). However, it is unclear which factors are associated with GH. We sought to elucidate the relationship between the CA procedure and GH.The study population consisted of 254 patients who underwent CA for AF from November 2017 to October 2018. Finally, 119 patients were enrolled and divided into two groups: with or without GH (GH or non-GH groups). To evaluate the association with GH, the clinical backgrounds and procedure characteristics of the radiofrequency CA (RFCA) were compared between the two groups.The median age was 69 years old with 34% of female. GH were observed in 27.7% of patients who underwent RFCA, which was significantly higher than that in the cohort of patients who underwent esophago-gastro-duodenoscopy during the same time period (1.9%: 151 in 8063 patients, p 0.0001). According to the detailed RFCA procedure, additional posterior wall isolation with pulmonary vein isolation (PVI) had a higher prevalence of GH than that with only PVI (54.8% vs. 18.2%; odds ratio 5.46, 95%CI 2.24-13.32, p = 0.0002). After an adjustment using a multivariate logistic analysis, a posterior wall isolation with the PVI was identified as the only independent predictor for GH (odds ratio 5.01, 95%CI 1.94-13.43, p = 0.0009).Additional posterior wall isolation with PVI was associated with gastric hypomotility.

Objective FDG-PET has been shown useful in the staging of malignant lymphoma (ML) and in evaluating treatment outcomes. Serum concentration of soluble interleukin-2 receptor (sIL-2R) has also been shown prognostic in patients with MLs. This study analyzed the clinical possibility of baseline FDG-PET parameters, such as maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and serum sIL-2R and lactate dehydrogenase (LDH) concentrations, as prognostic variables in patients with oral and neck non-Hodgkin’s lymphoma (NHL). Methods Baseline FDG-PET parameters and serum protein concentrations were correlated with 2-year prognosis in 12 patients with oral and neck NHL. The optimal cutoff values for FDG SUVmax, serum sIL-2R and LDH were determined by receiver operating characteristics analyses. Results At 2-year follow up, seven patients remained alive (good prognosis), and five had died (poor prognosis). The median FDG SUVmax was significantly higher in the poor than in the good prognosis groups (P = 0.04), but serum sIL-2R concentrations did not differ significantly between the two groups (P = 0.09). Baseline MTV and TLG were significantly higher in patients with poor than with good prognosis (P = 0.02 each). Serum LDH levels was significantly higher in patients with poor than with good prognosis (P = 0.01). Univariate logistic regression analysis showed significant correlations between FDG SUVmax and patient prognosis (P = 0.04, odds ratio, 23.4). Conclusion Comprehensive evaluation of baseline FDG SUVmax may have possibility for predicting the prognosis of patients with oral and neck NHLs.

Dipeptidyl peptidase 4 (DPP-4) inhibitors have recently been reported to exhibit additional cardioprotective effects; however, their effect in atrial remodeling, such as in atrial fibrillation (AF), remains unclear. In this study, the effect of linagliptin on atrial electrical and structural remodeling was evaluated in a canine AF model. Sixteen beagle dogs with 3-week atrial rapid stimulation were divided into the linagliptin group (9 mg/kg/day, n = 8) and pacing control group (n = 8). Three additional dogs without rapid pacing were assigned into non-pacing group, which was used as sham in this study. In the dogs with rapid pacing, the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated and blood was sampled every week. After the entire protocol, atrial tissue was sampled for histological examinations using HE, Azan, and dihydroethidium (DHE) staining to evaluate any tissue damage or oxidative stress. The pacing control group exhibited a gradual AERP shortening and CV decrease along the time course as previously reported. In the linagliptin group, the AERP shortening was not affected, but the CV decrease was suppressed in comparison to the control group (p

It is known that the efficacy of catheter ablation for atrial fibrillation (AF) is high, but cardiac tamponade may occur in 1–2% cases. Even in such cases, fatal condition can be avoided by appropriate drainage, but reversal of anticoagulation therapy might also be necessary. Here, we report a case of use of idarucizumab for cardiac tamponade during AF ablation. Although the drainage with pericardial centesis should be selected, we could not perform because echo free space was too thin at least at the precordial or apical side of the ventricle. Fortunately, dabigatran reversal by idarucizumab suppressed cardiac tamponade progress and the patient recovered without undergoing any invasive procedures. The pericardial drainage must be the principal therapy for cardiac tamponade, but reversal of anticoagulant might be helpful for patients’ recovery. It might be thought that dabigatran, the only direct oral anticoagulant with a specific reversal agent, should be the safest choice in case of risk for bleeding complications such as AF ablation.

Background: Cardiac troponin T (cTnT) has been reported to be associated with cardiac mortality. In the present study, we evaluated the role of routine assessment of cTnT as a predictor of future cardiac death in patients with left ventricular (LV) dysfunction. Methods: Patients who were eligible for prophylactic implantable cardioverter defibrillator (ICD) were included from cardiac catheterization database. Inclusion criteria were patients with LV ejection fraction of ≤ 35% and with New York Heart Association (NYHA) ≥class II. Exclusion criteria were patients with acute coronary syndrome, ICD for secondary prevention, NYHA class IV, and lack of data. The final study patients were divided into the following three groups in accordance with two quartile points of serum cTnT levels: low cTnT, intermediate cTnT, and high cTnT groups. The primary endpoint of this study was cardiac death. Results: A total of 70 patients were included (mean age, 62±13 years; male individuals, 56; ischemic, 36; and non-ischemic, 34). During the observation period of 2.2 years, cardiac death was observed in 17 patients (fatal arrhythmic event, 9; heart failure, 7; myocardial infarction, 1). In the Kaplan–Meier analysis, the high cTnT group showed the highest risk among all the groups (p

Background Catheter ablation of premature ventricular complexes (PVCs) has been used as a curative therapy in many cases. Intracardiac ultrasound with a magnetic sensor probe has recently become available for catheter ablation. In this study, we assessed a new mapping method, contraction mapping, for determining the optimal ablation sites using intracardiac ultrasound and M-mode. This study sought to assess the accuracy of the new mapping method using intracardiac echocardiography. Methods Eighteen patients (10 males and eight females; mean age, 63±12 years) with 104 mapping points diagnosed as idiopathic PVCs were included in this study. At the mapping points, the time interval from the onset of the QRS to the onset of the contraction (QRS-c-time) and the local activation time were measured using M-mode with an intracardiac echo probe and using the conventional method. The correlation between the QRS-c-time and local activation time were studied. Results The QRS-c-time was significantly correlated with the local activation time (activation time=−66.8+0.882 * QRS-c-time, R 2=0.728, p Conclusions Contraction mapping could help determine the local activation time without the delivery of a catheter to the mapping points.

A seventy year-old male was referred to our hospital to undergo radiofrequency catheter ablation (RFCA) for drug-refractory paroxysmal atrial fibrillation (AF). Pre-operative three-dimensional computed tomography revealed a unique left atrial (LA) roof vein. Electrophysiological findings showed expansion of the myocardial sleeve and local firing in the LA roof vein. We performed isolation of this arrhythmogenic abnormal vein concomitant with general pulmonary vein isolation in this case, and AF did not recur after the procedure.

Background Distinction of paroxysmal atrial fibrillation (PAF) from non-PAF is important in clinical practice, but this is often difficult at the time of first documented AF. Given that fibrillation cycle length (FCL) is longer in PAF than in non-PAF, the aim of this study was to compare various clinical parameters including FCL to establish a scoring system to distinguish PAF and non-PAF.Methods and Results:The subjects consisted of 382 consecutive patients with AF on digital ECG at the present institute between 2008 and 2011. They were divided into PAF and non-PAF groups according to the following clinical course. Propensity score matching yielded 88 matched patient pairs with similar mean age and gender between the 2 groups. FCL was evaluated using customized fibrillation wave analyzer with fast Fourier transform analysis. On multivariate analysis, higher HR, longer FCL, and smaller LAD were independent predictors of PAF. For the scoring, cut-offs for each parameter were determined according to highest sensitivity and specificity on the ROC curves, and 1 point assigned for each parameter. Using this scoring system, 2 points detected PAF with 64% sensitivity and 84% specificity. Conclusions We propose a scoring system including FCL to distinguish PAF from non-PAF. Further studies are needed to validate the results.

Optimal antithrombotic strategy for atrial fibrillation (AF) patients with a history of percutaneous coronary intervention (PCI) has been under debate. The actual prescription trend of antithrombotic therapy for these patients remains unclear, especially in chronic phase.Patients with AF having at least a 1-year history of PCI were retrospectively evaluated in 2010, 2012, 2014, and 2016. A total of 266 patients were finally enrolled in this study. The proportion of patients prescribed with oral anticoagulants (OACs) gradually increased over the study period (56%, 67%, 73%, and 74% in 2010, 2012, 2014, and 2016, respectively). According to the type of OACs, the proportion of direct oral anticoagulant (DOAC), launched in 2011, increased compared with warfarin (DOAC versus warfarin = 3% versus 64% in 2012, 24% versus 49% in 2014, and 32% versus 42% in 2016). Single antiplatelet therapy (SAPT) with OAC was the most popular prescription every year, and its proportion increased over the study period (41%, 44%, 55%, and 59%, respectively). The proportion of OAC monotherapy gradually increased (2%, 3%, 8%, and 9%, respectively), whereas that of triple therapy, i.e., dual antiplatelet therapy with OAC, gradually decreased (14%, 22%, 8%, and 5% in 2010, 2012, 2014, and 2016, respectively).Antithrombotic therapy trends for AF patients with a history of PCI were changing every year. The prescription rate of triple therapy gradually decreased, in contrast, that of OAC monotherapy gradually increased from 2010 to 2016. However, the evidence for OAC monotherapy in these patients remains insufficient.

The effect of DPP-4 inhibitor on the electrical and structural remodeling in myocardial injury has not been evaluated. We hypothesized that linagliptin, DPP-4 inhibitor, suppresses myocardial remodeling in the isoproterenol (ISP)-induced myocardial injury model.Sprague-Dawley rats were assigned to 3 groups: 1) sham group, 2) ISP group (subcutaneous ISP injection of 70 mg/kg), and 3) ISP + linagliptin (ISP + Lin) (5 mg/kg/day, p.o.) group. Serum was sampled on day 1 (acute phase) and day 7 (sub-acute phase) to evaluate derivatives of reactive oxidative metabolites (d-ROMs). The electrophysiological study was performed in sub-acute phase for the evaluation of the ventricular effective refractory period (VERP) and monophasic action potential duration (MAPD). The VERP and MAPD were markedly prolonged in the ISP group in comparison with the sham (MAPD20: 14 ± 6 versus 11 ± 3 ms, MAPD90: 57 ± 8 versus 44 ± 7 ms, VERP: 74 ± 22 versus 38 ± 10 ms, P < 0.05). In contrast in the ISP + Lin group, such prolongations were suppressed, and the parameters were shorter than the ISP group (MAPD20: 9 ± 2 ms, MAPD90: 35 ± 6 ms, VERP: 52 ± 13 ms, P < 0.05). ISP treatment induced myocardial injury. The injured area was reduced in the ISP + Lin group in comparison with the ISP group (P < 0.05). Serum d-ROMs level in acute phase was higher in ISP group than the other 2 groups (sham: 214 ± 55 versus ISP: 404 ± 45 versus ISP + Lin: 337 ± 20 U.CARR, P < 0.05).Linagliptin suppressed structural and electrical changes, possibly through the antioxidative effect, in this myocardial injury model.

Ventricular capture management is an automatic pacing threshold adjustment algorithm that automatically measures pacing threshold through detection of the evoked response after a pacing stimulus. Although it is principally designed to save device battery under the maintenance of the patient׳s safety, we experienced a rare case with serious pacing failure due to a weakness of this algorithm. This pacing failure might be explained by a large variation in the ventricular pacing threshold depending on the atrioventricular interval and daily variation of pacing threshold and concomitant steroid use in this patient. Keywords: Automatic pacing threshold adjustment algorithm, Pacing failure

We have shown that a dipeptidyl peptidase 4 (DPP-4) inhibitor suppresses atrial remodeling in a canine atrial fibrillation (AF) model. Glucagon-like peptide-1 (GLP-1) is increased by DPP-4 inhibitors. However, it is not clear whether GLP-1 is involved in the suppression of atrial remodeling. In this study, we evaluated the effect of liraglutide (a GLP-1 analog) on atrial electrophysiological changes using the same canine AF model. We established a canine AF model using continuous 3-week rapid atrial stimulation in seven beagle dogs divided into two groups: a liraglutide group with four dogs (3-week atrial pacing with liraglutide (150 µg/kg/day) administration) and a pacing control group with three dogs (3-week pacing without any medicine). We evaluated the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility every week during the protocol using implanted epicardial wires against the surfaces of both atria. In the pacing control group, the AERP was gradually shortened and the CV was decreased along the time course. In the liraglutide group, the AERP was similarly shortened as in the pacing control group (94 ± 4% versus 85 ± 2%, respectively; p = 0.5926), but the CV became significantly higher than that in the pacing control group after 2 and 3 weeks (95 ± 4 versus 83 ± 5%, respectively; p = 0.0339). The AF inducibility was gradually increased in the pacing control group, but it was suppressed in the liraglutide group (5 ± 9% versus 73 ± 5%; p = 0.0262). Liraglutide suppressed electrophysiological changes such as AF inducibility and CV decrease in our canine AF model.

Neuromuscular electrical stimulation (NMES) is one of the few exercise modes that have been confirmed to be effective for advanced heart failure patients. Previous clinical trials that verified the effects of NMES excluded patients with implantable cardioverter defibrillators (ICDs). We investigated whether NMES to leg muscles could be applied in heart failure patients implanted with ICDs. As a result, we found that NMES could be conducted without any instances of electromagnetic interference. NMES to leg muscles could be applied safely to ICD patients if the aforementioned common stimulation methods were used with sufficient monitoring during NMES.

Patients with recently diagnosed atrial fibrillation (AF) tend to exhibit a longer fibrillation cycle length (FCL) than those having a longer clinical history. However, the electrophysiological properties of new-onset AF may vary because of the clinical background of patients. In this study, we evaluated clinical factors to identify the determinants of FCL in new-onset AF. Electrocardiograms (ECGs) recorded from 2008 through 2011 were analyzed using our digital ECG-profiling system. In the 1,578 AF episodes recorded, 466 new-onset AF episodes were identified using clinical referral history and previous ECGs. After evaluating FCL in these new-onset AF episodes, using a customized fibrillation wave analyzer with fast Fourier transform analysis, we divided the patients into a longer-FCL group and a shorter-FCL group using the median FCL (158 ms). Propensity score matching yielded 135 matched pairs of patients with comparable mean ages between the two groups. Four factors (brain natriuretic peptide levels, and use of angiotensin receptor blockers, calcium channel blockers or statins) exhibited a significant difference between the two groups. Multivariate analysis revealed that statin use was the only significant independent predictor of longer FCL (Odds ratio, 3.86; 95% CI, 1.659.63; P = 0.003). Among various clinical parameters, statin use was related to longer FCL at the time of new-onset AF in patients with AF.

Aliskiren, a direct renin inhibitor is expected to achieve sufficient suppression of renin-angiotensin system. We evaluated the effect of aliskiren on the electrical and structural remodeling in a canine atrial fibrillation (AF) model. Twenty-eight dogs were divided into three groups: (1) pacing control group (n = 12), with continuous atrial rapid pacing for 3 or 6 weeks, (2) pacing + aliskiren group (n = 12), with oral aliskiren (30 mg/kg/day), and (3) sham group (n = 4), no pacing nor drug administration. Electrophysiological properties and AF inducibility were evaluated every week. After the protocol, the left atrial tissue was sampled for the further histological and mRNA analysis. The electrical remodeling, AF inducibility, the left atrial enlargement and interstitial fibrosis were observed in pacing control group and were more prominent in the 6-week protocol (vs. 3 week, p

Background Dabigatran etexilate (DE), an effective direct oral anticoagulant for patients with atrial fibrillation (AF), should be carefully used in patients with renal insufficiency. Data on the safety of DE in Japanese “real world” patients with mildly impaired renal function are limited. We hypothesized that low-dose DE (110 mg, twice daily) could be safely used in Japanese AF patients with mildly impaired renal function compared to those with preserved renal function. Methods and results One hundred ninety-six consecutive AF patients taking low-dose DE were retrospectively enrolled in this study, and were divided into two groups: preserved creatinine clearance (CCr ≥50 ml/min; n = 127) and reduced CCr (30–49 ml/min; n = 69). Baseline characteristics including CHADS2, CHA2DS2-VASc, and HAS-BLED scores were evaluated. Activated partial thromboplastin time (aPTT) was measured as a surrogate marker of the anticoagulant activity of DE, which was evaluated at 661 time points in total and the data were divided into five time windows after the last DE intake. The incidence of bleeding complications was compared between the two groups of reduced and preserved CCr. Reduced CCr group showed higher age (76.9 ± 6.3 years vs. 67.6 ± 6.7 years), higher CHADS2 (2.6 ± 1.4 vs. 1.8 ± 1.2), higher CHA2DS2-VASc (4.3 ± 1.6 vs. 3.2 ± 1.6), and higher HAS-BLED (2.3 ± 1.0 vs. 2.0 ± 1.0) scores in comparison with preserved CCr group (p Conclusion Low-dose DE was safe in AF patients with mildly reduced CCr.

BackgroundAlthough powerful defibrillation devices are available in clinical practice, risk stratification is important in asymptomatic Brugada syndrome. In this study, vector-projected 187-channel electrocardiogram (VP-ECG) was used to calculate the ST-elevation score in Brugada-type ECG and test its usefulness in risk stratification.Methods and resultsVP-ECG was recorded in 108 patients with Brugada-type ECG having ventricular fibrillation (VF) episodes (±; n=13/95). The ST morphologies were evaluated in 80/187 precordial leads. The coved- and saddleback types (4–6 vs. 1–3 points) of ST-elevation scores in 332 recordings were 58±57 points, which were calculated using virtual ECG leads. Compared with types 1–3 ECG patterns, the scores were significantly different among the groups (107±65, 62±45, and 14±22, respectively; p

Controlling blood pressure is essential for prevention of events after acute aortic dissection (AAD). However, in some instances a cardiac event occurs despite controlled blood pressure, and its prediction is difficult. We continuously monitored C-reactive protein (CRP) in patients receiving medical treatment for AAD and retrospectively examined the utility of CRP measurement for prediction of in-hospital events. Five hundred and eight patients were diagnosed as having AAD between 1993 and 2009, 240 of whom underwent antihypertensive medical therapy. These subjects were 156 males and 84 females, average age 67.4 years, with 68 cases of Stanford type A and 172 cases of Stanford type B. C-reactive protein was measured in all patients daily until a peak; subsequently, CRP was measured 2-3 times per week following the peak until discharge. In the event-free group CRP demonstrated a peak on the 4th day after the onset (average 13.7 mg/dl), then gradually decreased to an average of 4.6 mg/dl 4 weeks later, displaying a "gradual decay" pattern. Despite controlled systolic arterial pressure of approximately 120 mmHg, 7 of 68 Stanford A cases (10.3 %) and 8 of 172 Stanford B cases (4.7 %) developed cardiovascular events. The group characterized by events exhibited a CRP pattern distinct from that of the event-free group, i.e., prolonged elevation and/or re-elevation. We demonstrated that the CRP pattern could provide information regarding prediction of cardiovascular events. Prolonged elevation or re-elevation of CRP may indicate the necessity of (1) application of computed tomography or magnetic resonance imaging, (2) more rigorous blood pressure management, or (3) early surgical intervention.

In this study we tried to confirm the effect of an astaxanthin-rich Haematococcus pluvialis extract on cognitive function in 96 subjects by a randomised double-blind placebo-controlled study. Healthy middle-aged and elderly subjects who complained of age-related forgetfulness were recruited. Ninety-six subjects were selected from the initial screen, and ingested a capsule containing astaxanthin-rich Haematococcus pluvialis extract, or a placebo capsule for 12 weeks. Somatometry, haematology, urine screens, and CogHealth and Groton Maze Learning Test were performed before and after every 4 weeks of administration. Changes in cognitive performance and the safety of astaxanthin-rich Haematococcus pluvialis extract administration were evaluated. CogHealth battery scores improved in the high-dosage group (12 mg astaxanthin/day) after 12 weeks. Groton Maze Learning Test scores improved earlier in the low-dosage (6 mg astaxanthin/day) and high-dosage groups than in the placebo group. The sample size, however, was small to show a significant difference in cognitive function between the astaxanthin-rich Haematococcus pluvialis extract and placebo groups. No adverse effect on the subjects was observed throughout this study. In conclusion, the results suggested that astaxanthin-rich Haematococcus pluvialis extract improves cognitive function in the healthy aged individuals.

Objective We have previously reported that the histologic mode of invasion of oral squamous cell carcinoma (OSCC) is a significant risk factor for pain. Here we sought to determine whether pain is a risk factor for poor prognosis in patients with OSCC. Study design We evaluated the relationships between overall survival rates and clinicopathologic variables, including gender, age, T- and N-stages, pathologic findings, and pain in 109 consecutive patients with untreated OSCC. Results Of these 109 patients, 40 (37%) reported spontaneous pain. Univariate analysis showed that the overall survival rates of patients with spontaneous pain was significantly lower than those of patients without pain (P = .002). Multivariate analysis revealed that spontaneous pain and N-stage were significant independent predictors of overall survival rates. Conclusions This is the first report showing that spontaneous pain before treatment may be associated with poor prognosis in patients with OSCC.

Four hundred and seventy-six patients with acute myocardial infarction (AMI) were interviewed to evaluate the clinical features of angina before AMI. Two hundred and sixty-six of the 476 patients had angina before AMI, of which 137 had new onset of angina within 2 months before AMI, and 129 had chronic angina of more than 2 months before AMI. Forty of the 129 chronic angina patients noted worsening of symptoms within 2 months before AMI. Of the 177 patients with new onset angina or worsening angina such as unstable angina, the incidence of new onset angina was higher than that of worsening angina. Twenty-eight (70%) of the 40 patients with worsening of symptoms had started with effort angina, 16 of whom turned to resting angina from effort angina at the onset of unstable angina in spite of the fact that 12 had worsening of effort angina. Of the 137 patients with new onset angina, 65 (40%) started with resting angina and 72 (53%) with exertional angina. In the former group, 43 (66%) developed AMI within 1 week after the onset of angina, which was greater than 19 (26%) in the latter group. These results may suggest that the appearance of the resting angina would herald AMI in both groups of unstable angina. The onset of resting angina in the group of new onset angina could be the warning of AMI development within a shorter interval than those of exertional angina.

Phospholipid hydroperoxides (PLOOH) accumulate abnormally in the erythrocytes of dementia patients, and dietary xanthophylls (polar carotenoids such as astaxanthin) are hypothesised to prevent the accumulation. In the present study, we conducted a randomised, double-blind, placebo-controlled human trial to assess the efficacy of 12-week astaxanthin supplementation (6 or 12 mg/d) on both astaxanthin and PLOOH levels in the erythrocytes of thirty middle-aged and senior subjects. After 12 weeks of treatment, erythrocyte astaxanthin concentrations were higher in both the 6 and 12 mg astaxanthin groups than in the placebo group. In contrast, erythrocyte PLOOH concentrations were lower in the astaxanthin groups than in the placebo group. In the plasma, somewhat lower PLOOH levels were found after astaxanthin treatment. These results suggest that astaxanthin supplementation results in improved erythrocyte antioxidant status and decreased PLOOH levels, which may contribute to the prevention of dementia.

OBJECTIVES: To determine whether serum dehydroepiandrosterone sulfate (DHEAS) levels could predict longevity in residents. DESIGN: Prospective community-based cohort study. SETTING: Community. PARTICIPANTS: Nine hundred forty subjects (396 men, 544 women; aged 21 to 88) underwent a health examination in 1978. Serum DHEAS levels were measured according to radioimmunoassay at baseline in all subjects, and subjects were followed periodically until 2005. RESULTS: Baseline DHEAS levels were higher in men than in women and decreased with age in both sexes. In a Cox proportional hazards model, age, DHEAS (inversely), blood pressure, and fasting plasma glucose were significantly associated with shorter longevity in men but not in women. Of these variables, high DHEAS levels in men were the strongest predictor of longevity (\u03b2=\u22122.032, hazard ratio=0.131, 95% confidence interval=0.029\u20130.584 in the Cox proportional hazards model after adjustment for age). The Kaplan-Meier survival curve, stratified according to tertiles of DHEAS levels, in men after adjustments for age, systolic blood pressure, and fasting plasma glucose showed significantly (log-rank stat =10.6; P

Mitf is a transcription factor of the basic/helix-loop-helix/leucine-zipper family which is indispensable for development of melanocytes and the retinal pigment epithelium. Our previous work using Xenopus laevis as a model system suggested that Mitf regulates melanosome dispersal in vivo though whether this was via melanosome transport or melanophore dendricity was not obvious. To better understand the role of Mitf, we have now characterized neural tube cultures from wild-type Mitf-injected or a dominant-negative Mitf-injected embryos and compared them with controls. In vitro, lower levels of Mitf activity induced less dendritic melanophores with aggregated melanosomes, whereas melanophores overexpressing Mitf had an extensive dendritic morphology with dispersed melanosomes. Moreover, immunorfluoresence assays reveal that expression of a dominant-negative Mitf leads to decreased Rab27a expression. These results suggest that Mitf is involved in the regulation of melanosome transport and the level of dendricity in melanophores.

Telmisartan, a new angiotensin II type 1 receptor blocker (ARB), was recently reported to stimulate PPARgamma, and stronger effects of Telmisartan on insulin sensitivity has been expected than the class effect of ARB. In the present study, we examined the effects of Telmisartan on insulin sensitivity and adipokine levels in hypertensive and type 2 diabetic patients. Outpatients with both hypertension and type 2 diabetes mellitus (n=36; male 23, female 13), received 20-40mg Telmisartan orally once daily for 6 months. Physical examinations and blood or urine tests were performed before and 3 or 6 months after starting Telmisartan treatment. Results were statistically compared using Wilcoxon analysis. Telmisartan treatment for 3 or 6 months reduced systolic and diastolic blood pressure and urinary albumin excretion. Fasting plasma glucose, HbA1c, total and HDL-cholesterol, triglyceride, body weight, BMI and waist length were not changed. Fasting IRI and HOMA-IR were significantly decreased after Telmisartan treatment, suggesting the improved insulin sensitivity. Total and high molecular adiponectin were not changed. Interestingly, serum leptin was significantly increased by 3 months Telmisartan treatment, suggesting a possible involvement of leptin in improved insulin sensitivity. In conclusion, Telmisartan improved insulin resistance with increased serum leptin level in hypertensive and type 2 diabetic patients.

In Japan, metabolic syndrome used to be rare, and the level of coffee consumption was low. However, the Japanese life style has been changing rapidly, and these changes have been associated with a steady increase in the frequency of metabolic syndrome and with greater consumption of coffee. We examined the relationship between metabolic syndrome and the consumption of coffee or green tea. A total of 1902 Japanese aged over 40 years (785 men and 1117 women) received population-based health check-up in 1999. We measured components of metabolic syndrome (blood pressure, waist circumference, fasting plasma glucose, and lipid profiles). Eating and drinking patterns were evaluated by a food frequency questionnaire. Multivariate analyses were performed to clarify the association between coffee or green tea consumption and the components of metabolic syndrome. All components of metabolic syndrome except for HDL-cholesterol were significantly (p < 0.01) and inversely related to coffee but not green tea consumption by multivariate analysis after adjusting for confounding factors. The larger was the number of components of metabolic syndrome, the lower was the level of coffee consumption (p < 0.0001). In addition, there was a high frequency of metabolic syndrome in small coffee drinkers. Thus, coffee but not green tea consumption was inversely associated with metabolic syndrome.

Asymmetric dimethylarginine (ADMA) is a circulating endogenous nitric oxide (NO) synthase inhibitor. It has been reported that plasma levels of ADMA are related to intima-media thickness (IMT) in small numbers. We investigated this issue in a large number of subjects without overt cerebro-cardiovascular diseases. A total of 712 subjects (305 men and 407 women; age, 62.6+/-11.2 years) received a health examination in 1999 in a farming community. We measured blood pressure (BP), blood chemistries, and fasting plasma total ADMA levels. IMT of the common carotid artery was determined with the use of duplex ultrasonography as an index of atherosclerosis. Uni- and multi-variate analyses for determinants of IMT were performed. For the total population, the mean ADMA level was 0.50 micromol/l. By the use of multiple stepwise regression analysis, IMT was significantly associated with ADMA (p

Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients. Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m2 and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m2 and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy. Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11–52 %) and 5.9 months (95 % CI, 3.6–9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts. Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m2 of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted. UMIN Clinical Trial Registry; UMIN000004240 .

Objective Sequential postoperative salivary interleukin-6 (IL-6) concentrations were examined in patients with oral squamous cell carcinoma (OSCC) who had early or late locoregional recurrences or those who did not. Study Design Twenty-seven consecutive patients with OSCC were originally included in the study. All patients underwent radical surgery. Four saliva samples were collected before (periods I and II) and after (periods III and IV) surgery, and IL-6 concentrations were measured. Results Although postoperative (period III: at the time of discharge) salivary IL-6 level was significantly higher in patients with early locoregional recurrence ( P = .02) than in those without, no such relationships were observed for preoperative IL-6 concentrations (periods I and II). Postoperative (period IV: 24 months after surgery) IL-6 level was significantly higher in patients with late locoregional recurrence ( P = .03) than in those without, but no such relationships were observed for IL-6 concentrations in periods I, II, and III. Conclusions Sequential postoperative salivary IL-6 concentration may be a useful marker for diagnosis of early and late locoregional recurrence in OSCC.

BACKGROUND Humoral rejection after ABO-incompatible liver transplantation often causes graft loss and a life-threatening situation. We used rituximab, which can eliminate B cells highly selectively, as an additional therapy for ABO-incompatible living-related liver transplantation. CASES Patient 1 was a 1-year-old girl with biliary atresia. Her blood type was O, and the donor's was A. She underwent two plasma exchanges before liver transplantation and had triple immunosuppressants (mycophenolate mofetil, tacrolimus, and methylprednisolone). She was diagnosed with humoral rejection by needle biopsy on postoperative day 6. Rituximab was used for 3 days at 375, 187, and 187 mg/m(2) and successfully reduced the antibody titer, transaminase, and CD19(+) cells count in peripheral blood lymphocytes. The patient has not had any severe rejection, infection, or serious complications 2 years posttransplantation. Patient 2 was a 42-year-old woman with primary biliary cirrhosis. The blood type was O, and the donor's was B. She received three plasma exchanges, triple immunosuppressants, splenectomy, intraarterial anticoagulant therapy, and rituximab (375 mg/m(2) immediately after transplantation). The titer and CD19(+) cells count remained persistently low throughout the recovery course. She did not develop humoral rejection 1 year after transplantation. CONCLUSIONS Rituximab efficiently reduces anti-ABO antibody titer by selectively eliminating B cells and is safe and effective against humoral rejection after ABO-incompatible liver transplantation.

A spike, a resultant regenerate made after amputation of a Xenopus froglet limb, has no muscle tissue. This muscle-less phenotype was analyzed by molecular approaches, and the results of analysis revealed that the spike expresses no myosin heavy chain or Pax7, suggesting that neither mature muscle tissue nor satellite cells exist in the spike. The regenerating blastema in the froglet limb lacked some myogenesis-related marker genes, myoD and myf5, but allowed implanted muscle precursor cells to survive and differentiate into myofiber. Implantation of hepatocyte growth factor (HGF) -releasing cell aggregates rescued this muscle-less phenotype and induced muscle regeneration in Xenopus froglet limb regenerates. These results suggest that failure of regeneration of muscle is due to a disturbance of the early steps of myogenesis under a molecular cascade mediated by HGF/c-met. Improvement of muscle regeneration in the Xenopus adult limb that we report here for the first time will give us important insights into epimorphic tissue regeneration in amphibians and other vertebrates.

Epidemiological studies have shown an inverse relationship between intake of N-3 fatty acids and incidence of stroke. And, there is a high incidence of stroke in patients with carotid atherosclerosis. We investigated the relationship between intake of N-3 fatty acids and carotid atherosclerosis in the cross-sectional study. A total of 1920 Japanese, aged over 40 years, received a population-based health examination in 1999. They underwent B-mode carotid ultrasonography to evaluate the carotid intimal-medial thickness (IMT). Eating patterns were evaluated by a 105 items food frequency questionnaire. A complete data set was available for 1902 subjects (785 men and 1117 women). The mean eicosapentaenoic acid (EPA) intake in men was 0.32+/-0.23 g/day and in women was 0.31+/-0.20 g/day. The mean docosahexaenoic acid (DHA) intake in men was 0.52+/-0.34 g/day and in women was 0.49+/-0.29 g/day. With multiple linear regression analysis, after adjustments for age, sex, and total energy intake, intakes of EPA (P < 0.05), DHA (P < 0.05), and docosapentaenoic acid (P < 0.05) were significantly and inversely related to IMT. These data indicate that dietary N-3 fatty acid, especially very long chain N-3 fatty acids, may protect against carotid atherosclerosis.

The association between plasminogen activator inhibitor-1 (PAI-1) and insulin resistance is established in western countries. The major component of this association is obesity. Accordingly, we examined this association in Japan where the prevalence of obesity is low. Data for fasting PAI-1 levels of 404 subjects were obtained from a general population in a farming area. We measured body mass index (BMI), systolic and diastolic blood pressure, high-density lipoprotein (HDL)-cholesterol, triglycerides, fasting plasma glucose (FPG), insulin, creatinine, and uric acid. The use of alcohol was ascertained by a questionnaire. The formula for the homeostasis model assessment (HOMA) score was used as an index of insulin resistance. Uni- and multivariate analyses were applied for the determinants of plasma PAI-1. Age and sex did not affect plasma PAI-1. The average BMI was 23.0 +/- 3.2 kg/m(2). Thus, most of the subjects were not obese. Because, even in this population, BMI (P.001) was the strongest determinant for PAI-1 after univariate analysis, we performed multiple linear regression analyses after adjustment for BMI. The significance of triglycerides, FPG, insulin, and the HOMA score still remained. PAI-1 levels were linearly related to the HOMA score. From the subanalysis of the non-obese subjects (BMI25; n = 298), waist-hip ratio, triglycerides, FPG, and HOMA scores were significant determinants of PAI-1. This is the first demonstration that increased PAI-1 levels were significantly related to insulin resistance in a Japanese general population. PAI-1 levels are associated with insulin resistance, irrespective of obesity.

Background and Purpose— We examined whether hyperhomocysteinemia is an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) in a large, randomly selected community in Japan where the dietary habit is different and the incidence of coronary artery disease is lower compared with those of western countries. Methods— In 1111 cases (452 men, 659 women) aged 63±10 years old (range, 40 to 94 years) recruited from a population-based survey performed in 1999, we measured fasting plasma total homocysteine levels and performed bilateral carotid B-mode ultrasound. The participants underwent measurements of other blood chemistries (total cholesterol, HDL cholesterol, glycosylated hemoglobin A 1c , and creatinine). Results— For the total population, the mean total homocysteine level was 10.9 μmol/L. Total homocysteine levels were higher in men than in women and increased with aging. With multiple linear regression analysis after adjustments for age and sex, the most powerful determinant of total homocysteine levels was serum creatinine ( P P P Conclusions— Plasma total homocysteine levels in Japan are similar to those reported in western countries. Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness in Japan as well.

It is unknown whether 12-lead ECG can predict new-onset AF. In the present study, we identified patients with new onset AF from our digitally stored ECG database, and the P wave morphologies were analyzed in their preceding sinus rhythm recordings as the precursor state for AF. The P wave was analyzed in the most recent ECG recording of sinus rhythm preceding new onset AF within 12 months. The duration and amplitude of P waves were analyzed in 12 leads and compared between the 2 groups with the other clinical parameters. The study population consisted of 68 patients with new-onset AF and 68 age and sex-matched controls. Multivariate analysis revealed that the P wave amplitude in leads II and V1 (0.157 ± 0.056 versus 0.115 ± 0.057 mV, P = 0.032, and 0.146 ± 0.089 versus 0.095 ± 0.036 mV, P = 0.002) and P wave dispersion (56.9 ± 14.8 versus 33.5 ± 12.9 ms, P = 0.001) were significant independent factors for the prediction of new-onset AF. By using these factors, new-onset AF could be predicted with a sensitivity of 69.1% and specificity of 88.2%. P wave analysis is useful for predicting new onset AF.

Object A modified World Federation of Neurosurgical Societies scale (m-WFNS scale) for aneurysmal subarachnoid hemorrhage (SAH) recently has been proposed, in which patients with Glasgow Coma Scale (GCS) scores of 14 are assigned to grade II and those with GCS scores of 13 are assigned to grade III regardless of the presence of neurologic deficits. The study objective was to evaluate outcome predictability of the m-WFNS scale in a large cohort. Methods This was a multicenter prospective observational study conducted in Japan. A total of 1656 patients with SAH were registered during the 2.5-year study period, and the outcome predictability, using the Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) scores at discharge and at 90 days after onset, was evaluated by comparing the m-WFNS with the original WFNS scale. We focused on whether significant differences in these scores were present between the neighboring grades. Results In the m-WFNS scale, significant difference between any neighboring grades was observed both in the mean GOS and mRS scores at 90 days except between grades III/IV. However, differences were not significant between grades II/III and between grades III/IV in the original WFNS scale. Conclusions SAH-induced brain injury may be substantially severer in patients with GCS 13 than those with GCS 14, which may explain why grade III patients faired significantly worse than grade II patients by the modified WFNS scale. Although further validation is necessary, the m-WFNS scale has a potential of providing neurosurgeons with simpler and more reliable prognostication of patients with SAH.

Objective The purpose of this study was to investigate whether this semiquantitative measurement of the motor end-plate acetylcholine receptors (AChRs) can be used to confirm the diagnosis of myasthenia gravis (MG), and in particular ocular MG. Methods Motor point biopsies were performed from the biceps brachii muscles. Measurement of AChRs was made in peroxidase-labeled cc-bungarotoxin stained muscle specimens. Patients Twenty patients with ocular MG, 37 with generalized MG, 5 with Lambert-Eaton myasthenic syndrome, 3 with botulism, 8 with amyotrophic lateral sclerosis, and 8 controls were included in this study. Results AChRs were decreased in all patients with generalized MG and in 80% of ocular MG including patients without detectable circulating anti-AChR antibodies, as compared with the control subjects. Conclusion This method is useful to confirm the diagnosis of MG, in particular ocular MG without detectable anti-AChR antibodies.(Internal Medicine 40: 376-381, 2001)

Serum parathyroid hormone (PTH) and calcitonin (CT) levels in fractured racehorses were measured by radioimmunoassay. Racehorses with fracture of large bone such as the radius, third metacarpus, third carpus, digital bone or tibia, showed normal PTH level and elevated CT level in the serum. Serum PTH level was slightly higher in racehorses with sesamoid bone fracture compared to that of healthy racehorses, but not statistically significant. Moreover, serum CT level of racehorses with sesamoid bone fracture was significantly higher than that of healthy racehorses. Racehorses with sesamoid bone fracture and large bone fracture might be in different conditions of calcium regulation.

We retrospectively studied 167 patients with oral squamous cell carcinoma (SCC) who were treated at our department from 1984 through 1994 to evaluate the effect of preoperative radiotherapy on outcome. Analyses were performed with Cox's proportional hazards model. Forty-five patients received preoperative radiotherapy with a mean dose of 39.0 Gy (R+S group), and the remaining 122 patients underwent surgical excision without radiotherapy (S group). These groups differed significantly with respect to the distribution of age, T and N categories, histological grade according to the World Health Organization (WHO) criteria, and mode of invasion as proposed by Yamamoto and Kohama. There was a significant negative correlation between the 5-year cumulative survival rate and N category, WHO grade, and mode of invasion. We also investigated the relationship of outcome to N category, WHO grade, mode of invasion, and treatment (between the R+S and the S groups) by Cox's proportional hazards model. Hazard ratios (weight of prognostic factors) were 3.31 (p