Sturge-Weber syndrome with cemento-ossifying fibroma in the maxilla and giant odontoma in the mandible: A case report.

Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome with vascular lesions of the cerebral meninges, port wine spots on the face, and glaucoma of the eyes; it is a congenital, non-genetic disease whose etiology and mechanisms are unknown. In this report, we describe a rare case of SWS with unilateral large odontogenic tumors in the maxilla and mandible. The histopathological diagnosis of the maxillary bone lesion on biopsy was juvenile psammomatoid ossifying fibroma, which is considered a type of ossifying fibroma of craniofacial bone origin. However, the final pathological diagnosis of the excision was cemento-ossifying fibroma derived from periodontal ligament cells, and we discuss the histopathology in detail. In addition, the mandibular lesion was one of the largest odontomas reported to date. Furthermore, in this case, we suggest the possibility that the maxillary and mandibular bone lesions are not separate lesions, but a series of lesions related to SWS.

Clinical utility of QRS duration normalized to left ventricular volume for predicting cardiac resynchronization therapy efficacy in patients with "mid-range" QRS duration.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT. OBJECTIVE: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd. METHODS: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography. RESULTS: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01). CONCLUSION: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd.

Utilization and Efficacy of Cardiac Resynchronization Therapy in Patients With Chronic Heart Failure　- A Report From the CHART-2 Study.

Background: Although cardiac resynchronization therapy (CRT) is effective for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction and wide QRS (≥120 ms), data on the use of or long-term outcomes after CRT implantation in Japan are limited. Methods and Results: We examined proper CRT utilization and outcomes in 3,447 consecutive symptomatic CHF patients registered in the CHART-2 Study. We identified 167 potentially eligible patients and divided them into 4 groups according to the presence (+) or absence (-) of an indication for and implantation of CRT: Group A (reference group), (+)indication/(+)CRT; Group B, (+)indication/(-)CRT; Group C, (-)indication/(+)CRT; and Group D, (-)indication/(-)CRT. Based on the Japanese Circulation Society guidelines, 91 patients met the eligibility for CRT implantation, with 43 (47%) of them undergoing CRT implantation. After adjusting for confounders, age was significantly associated with no CRT use (odds ratio per 5-year increase 1.46; 95% confidence interval 1.11-2.05; P=0.012). Among the 4 groups, the cumulative incidence of cardiovascular death and CHF admission were highest in Group B and lowest in Group D (P=0.029). Conclusions: In this study, only half the eligible CHF patients properly received CRT. Aging was a significant risk factor for no CRT use. Patients without CRT despite having an indication could be at higher risk of mortality and CHF admission.

Therapeutic effects of sertraline on improvement of Ovariectomy-induced decreased spontaneous activity in mice.

We have already reported that ovariectomized (OVX) rats reduced the spontaneous activity during the dark period due to the decease of serotonin release in the amygdala. In this study, we examined the potential of sertraline, a selective serotonin reuptake inhibitor, on the recovery of less spontaneous activity seen in mice with OVX-induced despair-like behaviors. Female 9-week old ICR mice were underwent either OVX or sham surgery. Sertraline (10 mg/kg/day, s.c.) or saline were started to administer to each group for 8 weeks (6 times/week) from the 8th week after OVX. Each spontaneous activity of mouse was evaluated during the dark period (19:00-07:00) using an infrared sensor. Moreover, mRNA expression levels of tryptophan hydroxylase (TPH) and X-box binding protein 1 (XBP1) were measured in the hippocampus and prefrontal cortex using by a real-time PCR method. We found out that the OVX-induced despair-like behaviors were improved by the continuous administration of sertraline. After treatment of OVX, our real-time PCR data showed that sertraline significantly suppressed the upregulation of XBP1 expression levels in both hippocampus and prefrontal cortex, although this suppression of the downregulation of TPH expression levels was seen in only hippocampus. These results suggest that sertraline improves the decrease in spontaneous activity induced by OVX assessed by the hippocampus suppressing decreased serotonin synthesis in the serotonergic neuron.

Estimation of inter-individual variability of protein requirement by indicator amino acid oxidation method.

The indicator amino acid oxidation (IAAO) method is a recently developed method to determine the protein requirement and is particularly useful for analyzing human subjects because of its minimal invasiveness. IAAO study is performed using two-phase regression analysis, with the break-point between these phases being the estimated average requirement. However, this method requires that the break-point lie within a certain range in advance, which is in practice difficult. Recently, the change-point regression model (CPRM) has been proposed to be more effective for two-phase regression analysis. There is also a need to re-evaluate the value corresponding to the recommended dietary allowance. Calculation of the recommended dietary allowance requires data on the average requirement and the inter-individual variability of this requirement. However, no inter-individual variability values have been reported in the IAAO method. The aim of this study was thus to estimate the inter-individual variation in protein requirement using CPRM. From seven IAAO studies, the inter-individual variability was estimated as a coefficient of variation of about 20%. The coefficient of variation of the protein requirement determined by IAAO study was wider than the ordinary coefficient of variation obtained from the nitrogen balance test.

Lactoferrin Suppresses Decreased Locomotor Activities by Improving Dopamine and Serotonin Release in the Amygdala of Ovariectomized Rats.

BACKGROUND: Decreases in female hormones not only affect bone metabolism and decrease bone mass, but also affect the central nervous system, causing brain disorders such as depression and dementia. Administration of estradiol by hormone replacement therapy can improve dementia, while reduced estradiol in ovariectomized (OVX) model rats can reduce both bone density and locomotor activity. The antidepressant fluvoxamine, which is widely used in clinical practice, can improve this effect on locomotor reduction. Similarly, lactoferrin (LF) can reportedly improve inhibitory locomotion due to stress. OBJECTIVE: In this study, we examined the effect of LF on neurite outgrowth in vitro and in vivo using PC12 cells and rats, respectively. METHODS: We performed an in vivo study in which 8-week-old female OVX rats were administered LF five days a week for 6 weeks from the day after surgery. After administration was completed, spontaneous locomotor activity in the dark period, immobility time in a forced swim test, and release amount of dopamine and serotonin in the brain were measured. RESULTS: LF was found to have a neurite outgrowth function in PC12 cells. Moreover, LF was found to improve OVX-induced decreases in locomotor activity and increases in immobility time in the forced swim test. Furthermore, the administration of LF elicited significant recovery of decreased dopamine and serotonin release in the brains of OVX group rats. CONCLUSION: These results strongly suggest that LF improved OVX-induced decreases in momentum during the dark period and, moreover, that release of dopamine and serotonin in the brain was involved in this effect.

Impacts of sinus rhythm maintenance with catheter ablation on exercise tolerance in patients with paroxysmal atrial fibrillation.

BACKGROUND: It has been recently reported that sinus rhythm (SR) maintenance with catheter ablation therapy improves exercise tolerance (ET) in patients with persistent atrial fibrillation (AF). However, it remains to be elucidated whether this is also the case for patients with paroxysmal AF (PAF). METHODS: We enrolled consecutive 54 patients with PAF (age; 63 ± 10 [SD] years old, male/female 46/8) and 26 patients with persistent AF (non-PAF) (age; 57 ± 12 [SD] years old, male/female 23/3) who underwent AF ablation without recurrence. ET and cardiac function were evaluated by cardio-pulmonary exercise test and ultrasound echocardiography before and 6 months after ablation. RESULTS: The parameters of cardiopulmonary exercise test were comparable between the 2 groups. When PAF group was divided into 2 groups according to the time since diagnosis, peak oxygen uptake (peak VO2) before ablation was significantly lower in patients with PAF duration of more than 1 year (n = 26), compared with those with less than 1 year (n = 28) (18.1 ± 3.7 vs 21.3 ± 5.8 ml/kg/min, P = 0.022). At 6 months after SR maintenance without AF burden, peak VO2 significantly improved in both PAF (19.8 ± 5.1 to 22.0 ± 4.8 ml/kg/min, P = 0.0001) and non-PAF (20.6 ± 3.9 to 23.4 ± 5.0 ml/kg/min, P < 0.01). Furthermore, the improvement rate of peak VO2 after successful ablation had a highly significant inverse relationship with peak VO2 at baseline in patients with PAF (r = - 0.48, P = 0.0003). CONCLUSIONS: These results indicate that SR maintenance with ablation improves ET in patients with PAF, especially in those with reduced ET.

Comprehensive Safety Assessment of l-Lysine Supplementation from Clinical Studies: A Systematic Review.

BACKGROUND: Despite the widespread use of l-lysine in dietary supplements, the safety information pertinent to excessive l-lysine ingestion is limited and, to the best of our knowledge, there is no published systematic review of safety. OBJECTIVE: The objective of this study was to assess the clinical safety of l-lysine supplementation of a regular diet. METHODS: We searched PubMed, Cochrane Library, Ichushi Web, and EBSCOhost using the relevant keywords, "l-lysine" and "clinical trial." To investigate all adverse events observed during intervention trials, we included all intervention studies with orally ingested l-lysine without restricting background factors, environment, study designs, and sample sizes. RESULTS: We identified 71 articles, which included 3357 study subjects. The l-lysine doses ranged from 16.8 to 17.5 g/d, and the dosing period ranged from 1 to 1095 d. The observed adverse events were mainly subjective gastrointestinal tract symptoms; however, the risk analysis for incidence of gastrointestinal symptoms was not statistically significant (risk ratio of 1.02). CONCLUSION: The provisional no-observed-adverse-effect level in healthy human subjects was based on gastrointestinal symptoms and identified at 6.0 g/d. The review protocol was registered at umin.ac.jp as UMIN000028914 before the beginning of the study.

Cardiac Resynchronization Therapy for Improving Non-Uniform Thickening of Left Ventricular Wall: Assessment by Quantitative Gated Myocardial Perfusion SPECT.

Cardiac resynchronization therapy (CRT) improves cardiac dyssynchrony in heart failure patients with a wide QRS electrocardiogram (ECG). Assessment of left ventricular (LV) dyssynchrony using echocardiography or other imaging modalities is important to predict CRT effectiveness. In this study, we retrospectively evaluated cardiac nuclear imaging of ECG-gated myocardial perfusion single-photon emission computed tomography (SPECT) with 99mTc-sestamibi for CRT candidate (n = 120) with severe heart failure and wide QRS (> 120 msec) in ECG. To analyze LV non-uniformity, we used the quantitative gated SPECT (QGS) software to calculate changes in regional LV wall thickness during a cardiac cycle (i.e., wall thickening scores). Cardiac events (heart failure, ventricular arrhythmias and cardiac death) after CRT during 38 ± 22 (SD) months were also evaluated. In 97 of 120 patients who underwent QGS before and 6 months after CRT, CRT homogenized non-uniform wall thickening between septal and lateral of the LV especially in CRT responders. This observation was indicated as increase in the lateral deflection (XWT) of wall thickening scores before CRT and its decrease after CRT. In 120 patients with QGS before CRT, the larger XWT before CRT (≥ 16.5) predicted better prognoses after CRT. This finding was similarly observed even in patients with narrower baseline QRS (≤ 140 msec; n = 41 of 120), who usually have less benefits from CRT. In conclusion, CRT improved non-uniformity of wall thickening between the LV septal and lateral regions evaluated using QGS, which is predictive of better prognosis in the chronic phase after CRT.

Two Cases of Atraumatic Chylous Ascites Characterized by Hypotriglyceridemia and Partially Managed with an Oral Fat-Free Elemental Diet.

Most cases of chylous ascites occur after surgery, but it also develops in nonoperative cases, although rarely. Such cases are often difficult to treat. In this study, we treated 2 cases of atraumatic chylous ascites, which were controlled by combining diuretic treatment with an oral fat-free elemental diet (Elental®, EA Pharma Co., Ltd., Tokyo, Japan). Elental can provide oral nutrition compatible with a lipid-restricted diet, which may be useful for control of chylous ascites. We report on these cases, including literature review-based considerations.

Prognosis and risk stratification in cardiac sarcoidosis patients with preserved left ventricular ejection fraction.

BACKGROUND: Although recent reports showed that left ventricular ejection fraction (LVEF) is a prognostic factor in patients with cardiac sarcoidosis (CS), advances in diagnostic imaging have enabled us to detect CS patients with preserved LVEF in the early stage of the disorder. In the present study, we examined the prognosis and risk stratification in CS patients with preserved LVEF. METHODS AND RESULTS: We retrospectively examined 91 consecutive CS patients at our hospital from October 1998 to December 2015 (age, 57±11 years; male/female, 25/66) for the relationship between LVEF and major adverse cardiac events (MACE), including ventricular tachycardia and fibrillation (VT/VF), heart failure (HF) admission, complete atrioventricular block, and all-cause death. CS patients with preserved LVEF (≥50%), as compared with those with reduced LVEF (<50%), showed significantly higher survival free from total MACE or VT/VF (log-rank p<0.001) and significantly smaller LV myocardial damaged area as evaluated by magnetic resonance imaging (MRI) (p<0.001). Although CS patients with preserved LVEF had a good prognosis in general, persistent right ventricular (RV) pacing and reduced EF were significant predictors for MACE after 1 year from introduction of steroid therapy (hazard ratio, 5.25; 95% confidence interval, 1.31-22.50, p=0.020, hazard ratio, 9.01; 95% confidence interval, 2.45-72.09; p=0.001). Patients with the 2 factors (LVEF reduction rate >13.9% per year and persistent RV pacing) had significantly higher risk for MACE, compared with those without them (log-rank p<0.001). CONCLUSION: The present study demonstrates that CS patients with preserved LVEF have better long-term prognosis than those with reduced LVEF in general. However, we should carefully follow them up, since chronological reduction in LVEF and persistent RV pacing could predict worse prognosis in those patients.

Different characteristics of postoperative atrial tachyarrhythmias between congenital and non-congenital heart disease.

PURPOSE: The chance of encountering tachyarrhythmias has been increasing in adult congenital heart disease (CHD) patients with previous open-heart surgery, along with the improvement of their longevity. However, the characteristics of these arrhythmias remain to be elucidated. METHODS: We examined the characteristics of atrial tachyarrhythmias (ATs) in 26 consecutive CHD patients (M/F 17/9) referred for catheter ablation and compared them with 16 non-CHD patients with cardiac surgery (M/F 11/5). RESULTS: The CHD group was younger and had a longer period from cardiac surgery until the occurrence of ATs compared with the non-CHD group (44.8 ± 19.5 vs. 67.6 ± 12.5 years old, and 23.3 ± 13.2 vs. 6.3 ± 4.9 years, respectively, both P < 0.05). Multiple ATs were equally induced in both groups, 12 in CHD (46.1%) and 5 in non-CHD (31.3%). Although the prevalence of macro-reentrant ATs (cavo-tricuspid isthmus-dependent atrial flutter (AFL) or intra-atrial reentrant tachycardia (IART)) was comparable, the mechanisms were different between the 2 groups (AFL and IART), 34% and 27% in CHD and 71% and 24% in non-CHD, respectively. Furthermore, focal AT (FAT) was noted in 9 patients (34.6%) in CHD but none in non-CHD (P < 0.05). Electroanatomical mapping showed that the surface area and low-voltage area (LVA) of the right atrium were significantly larger in CHD than in non-CHD (197.1 ± 56.4 vs. 132.4 ± 41.2 cm2, and 40.8 ± 33.3 vs. 13.6 ± 9.0 cm2, respectively, both P < 0.05). Ten out of 14 FATs (71.4%) were highly associated with LVA, especially near the crista terminalis. CONCLUSIONS: The development of ATs in CHD patients could be associated with large atrial remodeling, resulting in complicated ATs.

Characteristics of ventricular tachycardia and long-term treatment outcome in patients with dilated cardiomyopathy complicated by lamin A/C gene mutations.

BACKGROUND: Dilated cardiomyopathy caused by lamin A/C gene (LMNA) mutation is complicated with atrioventricular (AV) conduction disturbances, malignant ventricular arrhythmias, and progressive severe heart failure. Radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) has been reported to be challenging due to the high recurrence rate in patients with LMNA-related cardiomyopathy. However, electrophysiological and histopathological characteristics of VT substrate remain to be fully elucidated. METHODS AND RESULTS: We experienced 6 familial patients with LMNA-related cardiomyopathy in 3 pedigrees (6 males, 43.7±4.5 [SD] years). All patients had first VT attack at 50±6.6 [SD] years of age, and 4 underwent RFCA for incessant VT. Their electrocardiograms during VT showed similar QRS morphologies, characterized by an inferior axis, SR pattern in aVR, and QS pattern in aVL, suggesting the origin of the basal anterior ventricle. Indeed, the VTs had multiple exits around the basal anterior ventricular septum in all RFCA cases. Although we performed multiple RFCA procedures including epicardial ablation and surgical cryoablation, all cases experienced VT recurrences in 4.5±6.4 [SD] months after last procedure. All patients developed end-stage heart failure with frequent VT events, and died at 59.5±3.6 years of age (severe heart failure in 5 and lung disease in 1). In three autopsy cases with RFCA, fibrofatty degeneration was noted in the AV node. In addition, in the deep basal ventricular septum, inhomogenous fibrotic degenerated tissue was noted beyond the reach of RF lesions. CONCLUSIONS: These results demonstrate that patients with LMNA-related cardiomyopathy are characterized by VTs refractory to RFCA probably because of the deep intramural focus at the basal ventricular septum, resulting in poor prognosis with progressive severe heart failure despite all available optimized therapies. Thus, we should consider heart transplantation in their early 50s when several VT events begin to occur.

Risk factors and localization of silent cerebral infarction in patients with atrial fibrillation.

BACKGROUND: It is important to identify the risk factors and localization of silent cerebral infarction (SCI), especially in younger patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine the characteristics and risk factors for SCI in AF patients, with particular attention to localization of SCI. METHODS: The study enrolled 286 consecutive neurologically asymptomatic patients who underwent AF ablation from January 2014 to July 2017 (age 61.7 ± 10.2 [SD] years; 208 male and 78 female). All patients underwent magnetic resonance imaging (MRI) before ablation. RESULTS: SCIs were classified independently by 2 radiologists as follows: cardiogenic SCI in 19 (10.6%), lacunar SCI in 13 (8.9%), undetermined causes in 6 (1.6%), and no SCI in 248 (controls, 78.7%). Importantly, no patients with CHA2DS2-VASc score 0 had SCI on MRI. In univariable analysis, significant risk factors for lacunar SCI included age (P = .007), hypertension (P = .037), congestive heart failure (P = .040), left atrial (LA) diameter (P = .013), and cardio-ankle vascular index (P = .004). In multivariable analysis, significant risk factors for cardiogenic SCI were AF duration (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.00-1.02; P = .038), ankle-brachial pressure index (OR 0.002; 95% CI 0-0.68; P = .030), and LA abnormality (OR 8.99; 95% CI 2.78-31.00; P <.001), defined by the presence of spontaneous echo contrast and/or decreased LA appendage emptying velocity. CONCLUSION: The study results indicate that among AF patients, SCIs localized in the cerebral cortex and cerebellum are frequently noted, for which cardiogenic mechanisms may be mainly involved; CHA2DS2-VASc score could be useful for screening SCI; and LA abnormality is the specific marker for cardiogenic SCI, providing useful information for risk stratification of SCI.

[Drug properties of fosravuconazole L-lysine ethanolate (NAILIN® Capsules 100†mg), a new oral azole therapeutic for onychomycosis: an analysis based on non-clinical and clinical trial data].

Ravuconazole is a fourth generation azole exerting strong antifungal activity, with low drug-drug interaction and hepatic dysfunction risks. Fosravuconazole l-lysine ethanolate (fosravuconazole; NAILIN® Capsules 100 mg) was developed as a ravuconazole prodrug. Ravuconazole exerts strong antifungal activity against various pathogenic fungi including dermatophytes and Candida. Through prodrug formation, pharmacokinetic improvement was achieved, and bioavailability after oral administration reached 100%. The plasma ravuconazole concentration became 10-35 times higher than with current oral anti-onychomycosis drugs, and showed good skin and nail tissue transition plus tissue retention. This improvement obtained with fosravuconazole reflects its superior pharmacokinetic properties. We conducted a clinical trial with fosravuconazole orally administered once a day (100 mg ravuconazole) for 12 weeks in Japanese onychomycosis patients. The ravuconazole concentration in nail tissues exceeded the MIC90 against dermatophytes, even after treatment completion. Furthermore, the placebo-controlled, double-blind, comparative trial showed significantly superior effects (at 48 weeks after starting treatment, with a complete cure rate of 59.4%, a marked clinical improvement rate of 83.1%, and a mycological cure rate by direct microscopy of 82.0%). The major adverse reactions were laboratory abnormalities and gastrointestinal disorders with no severe symptoms, suggesting good tolerability. Fosravuconazole has fewer drug-drug interactions, is not affected by food, and is also expected to improve medication adherence since the administration period is only 12 weeks and there is no drug-free period as required with pulse therapy. Thus, fosravuconazole has many favorable pharmacological properties and can reasonably be expected to become a new oral treatment option for onychomycosis.

Development of a Shock-Wave Catheter Ablation System for Ventricular Tachyarrhythmias: Validation Study in Pigs In Vivo.

Background Although radiofrequency catheter ablation is the current state-of-the-art treatment for ventricular tachyarrhythmias, it has limited success for several reasons, including insufficient lesion depth, prolonged inflammation with subsequent recurrence, and thromboembolisms due to myoendocardial thermal injury. Because shock waves can be applied to deep lesions without heat, we have been developing a shock-wave catheter ablation ( SWCA ) system to overcome these fundamental limitations of radiofrequency catheter ablation. In this study, we evaluated the efficacy and safety of our SWCA system for clinical application to treat ventricular tachyarrhythmia. Methods and Results In 33 pigs, we examined SWCA in vivo for the following 4 protocols. First, in an epicardial substrate model (n=8), endocardial SWCA significantly decreased the sensing threshold (pre- versus postablation: 11.4±3.8 versus 6.8±3.6 mV ; P<0.05) and increased the pacing threshold (pre- versus postablation: 1.6±0.8 versus 2.0±1.1 V; P<0.05), whereas endocardial radiofrequency catheter ablation failed to do so. Second, in a myocardial infarction model (n=3), epicardial SWCA of the border zone of the infarcted lesion was as effective as ablation of the normal myocardium. Third, in a coronary artery application model (n=10), direct application of shock waves to the epicardial coronary arteries caused no adverse effects in either the acute or chronic phase. Fourth, with an epicardial approach (n=8), we found that 90 shots per site provided an ideal therapeutic condition to create deep lesions with less superficial damage. Conclusions These results indicate that our new SWCA system is effective and safe for treatment of ventricular tachyarrhythmias with deep arrhythmogenic substrates.

Safety assessment of L-lysine oral intake: a systematic review.

Currently, the use of amino acids in supplements and functional foods is increasing globally. However, there are no guidelines for the upper limit of ingestion for the safe use of these amino acids. Safety evaluation of chemical substances is generally performed through non-clinical and clinical studies. However, amino acids that have these safety data are limited. Therefore, we used a systematic review approach for evaluating the safety of amino acids. In the present study, we evaluated the safety of L-lysine added to an ordinary diet in humans. Using PubMed, Cochrane Library, Ichushi Web, and EBSCOhost as search databases, we comprehensively searched human studies on oral ingestion of L-lysine. Ultimately, 71 studies were selected for evaluation. Of these, 12 studies were of relatively high quality with Jadad scores ≥ 3. The dose range of L-lysine in the selected studies was 16.8-17,500 mg/day, and the range of dosing period was 1-1095 days. The observed adverse events were mainly subjective symptoms related to the gastrointestinal tract such as nausea, stomachache, and diarrhea. The provisional no-observed-adverse-effect level obtained based on these gastrointestinal symptoms was 6000 mg/person/day. Integrated analysis of the risk for developing gastrointestinal symptoms revealed that the risk ratio was 1.02 (95% CI, 0.96-1.07; p = 0.49); thus, no significant increase was observed. (UMIN000028914).

Prognostic Significance of PR Interval Prolongation in Adult Patients With Total Correction of Tetralogy of Fallot.

BACKGROUND: Several studies have demonstrated the importance of mechanoelectrical interaction in patients with surgically corrected tetralogy of Fallot. However, the significance of atrioventricular conduction disturbance, that is PR interval prolongation, on adverse cardiac events in those patients remains to be elucidated. METHODS: We examined electrocardiograms at baseline and their temporal change in a total of 176 patients with repaired tetralogy of Fallot (49% men; median age, 17.4 years). Then, we evaluated their correlation with right ventricular volume and function measured by cardiac magnetic resonance and the significance as a risk factor of adverse cardiac events: lethal ventricular arrhythmias, atrial arrhythmias, heart failure hospitalization, complete atrioventricular block (AVB), and all-cause death. RESULTS: First-degree AVB was noted in 25 patients (14%). During a median follow-up of 10.0 (5.0-14.2) years, there was a progressive prolongation of PR interval (2.00±3.99 ms/y). Importantly, there were significant correlations between PR interval prolongation and right ventricular enlargement or right ventricular dysfunction. In contrast, in patients who underwent pulmonary valve replacement (n=23), significant shortening of PR interval by pulmonary valve replacement was noted (204±32 versus 176±34 ms; P=0.007). Cox regression analysis showed that first-degree AVB was an independent risk factor for lethal ventricular arrhythmias (hazard ratio, 5.479; 95% CI, 1.181-25.42; P=0.030) and complete AVB (hazard ratio, 27.67; 95% CI, 4.152-184.3; P<0.001) and had a tendency for heart failure hospitalization (hazard ratio, 3.301; 95% CI, 0.864-11.80; P=0.069). In addition, PR interval prolongation >2 ms/y was also a significant risk factor for lethal ventricular arrhythmias, regardless of the presence or absence of first-degree AVB at enrollment (hazard ratio, 24.18; 95% CI, 2.080-281.1; P=0.011). CONCLUSIONS: These results indicate that progressive atrioventricular conduction disturbance is correlated with right ventricular enlargement and could be a useful predictor for increased risk of lethal ventricular arrhythmias in patients with repaired tetralogy of Fallot.

Efficacy of Endocardial Ablation of Drug-Resistant Ventricular Fibrillation in Brugada Syndrome: Long-Term Outcome.

Background Both endocardial trigger elimination and epicardial substrate modification are effective in treating ventricular fibrillation (VF) in Brugada syndrome. However, the primary approach and the characteristics of patients who respond to endocardial ablation remain unknown. Methods Among 123 symptomatic Brugada syndrome patients (VF, 63%; syncope, 37%), ablation was performed in 21 VF/electrical storm patients, the majority of whom were resistant to antiarrhythmic drugs. Results Careful endocardial mapping revealed that 81% of the patients had no specific findings, whereas 19% of the patients, who experienced the most frequent VF episodes with notching of the QRS in lead V1, had delayed low-voltage fractionated endocardial electrograms. Ablation of VF triggers followed by endocardial substrate modification was performed in the right ventricular outflow tract in 85% of the cases and in the right ventricle in 15%. VF triggers could not be completely eliminated in 1 patient and VF became noninducible in 14 (88%) patients among 16 patients who underwent VF induction with normalization of Brugada-type ECG in 3. During follow-up (56.14±36.95 months), VF recurrence was observed in 7 patients. Importantly, all patients who had nothing of QRS in lead V1 did not respond to endocardial ablation despite presence of VF-triggering ectopic beats during ablation. Conclusions With careful documentation of VF-triggering ectopic beats and detailed endocardial mapping, endocardial VF trigger elimination followed by endocardial substrate modification has an excellent long-term outcome, whereas presence of QRS notching in lead V1 was associated with high VF recurrence suggesting epicardial substrate ablation as effective initial approach.

Indications for Small-bowel Capsule Endoscopy in Patients with Chronic Abdominal Pain.

Objective The aim of the present study is to assess the difference in the detection rates of small-bowel lesions in chronic abdominal pain (CAP) patients with irritable bowel syndrome (IBS) and non-IBS. Patients Ninety-nine CAP patients who were scheduled to undergo capsule endoscopy (CE) to investigate their abdominal symptoms were included in this study. Among the subjects, 34 patients fulfilled the Rome III criteria for IBS (IBS group); the remaining 65 patients were categorized as the non-IBS group. CE was performed in both groups and the total enteroscopy achievement rate, small-bowel lesion detection rate, and the presence of small-bowel lesions were evaluated. We also evaluated the patients' blood test results and the rate at which abdominal symptoms improved following internal medication. Results Total enteroscopy was achieved in 62% (21/34) and 86% (56/65) of the IBS and non-IBS patients, respectively. The total enteroscopy achievement rate was significantly higher in non-IBS patients. The small-bowel lesion detection rates were 3% (1/34) and 19% (12/65), respectively, and the detection rate was significantly higher in the non-IBS patients. In the non-IBS patients, mean C-reactive protein (CRP) was significantly higher in the patients with small-bowel lesions. The abdominal symptoms of 12 (92%) of the CAP patients with small-bowel lesions were improved by internal medication. Conclusion CE may be considered for non-IBS CAP patients with high levels of CRP.