Bladder training for treating overactive bladder in adults.

BACKGROUND: Overactive bladder (OAB) is a common chronic and bothersome condition. Bladder training is widely prescribed as a first-line treatment for OAB, but the efficacy has been systematically evaluated for urinary incontinence rather than OAB alone. OBJECTIVES: To evaluate the benefits and harms of bladder training for treating adults with OAB compared to no treatment, anticholinergics, ß3-adrenoceptor agonists, or pelvic floor muscle training (PFMT) alone or in combination. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 6 November 2022. SELECTION CRITERIA: We included randomized controlled trials involving adults aged 18 years or older with non-neurogenic OAB. We excluded studies of participants whose symptoms were caused by factors outside the urinary tract (e.g. neurologic disorders, cognitive impairment, gynecologic diseases). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported cure or improvement, 2. symptom- and condition-related quality of life (QoL), and 3. ADVERSE EVENTS: Secondary outcomes included 4. participant-reported satisfaction, 5. number of incontinence episodes, 6. number of urgency episodes, and 7. number of micturition episodes. For the purpose of this review, we considered two time points: immediately after the treatment (early phase) and at least two months after the treatment (late phase). We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 15 trials with 2007 participants; participants in these trials were predominantly women (89.3%). We assessed the risk of bias of results for primary and secondary outcomes, which across all studies was similar and predominantly of high risk of bias, and none were at low risk of bias. The certainty of evidence was low to very low, with some moderate, across measured outcomes. Bladder training versus no treatment: three studies involving 92 participants compared bladder training to no treatment. The evidence is very uncertain about the effects of bladder training on cure or improvement at the early phase (risk ratio (RR) 17.00, 95% confidence interval (CI) 1.13 to 256.56; 1 study, 18 participants; very low-certainty evidence). Bladder training may reduce the number of incontinence episodes (mean difference (MD) -1.86, 95% CI -3.47 to -0.25; 1 study, 14 participants; low-certainty evidence). No studies measured symptom- and condition-related QoL, number of adverse events, participant-reported satisfaction, number of urgency episodes, or number of micturition episodes in the early phase. Bladder training versus anticholinergics: seven studies (602 participants) investigated the effects of bladder training versus anticholinergic therapy. Bladder training may be more effective than anticholinergics on cure or improvement at the early phase (RR 1.37, 95% CI 1.10 to 1.70; 4 studies, 258 participants; low-certainty evidence). The evidence is very uncertain about the effects of bladder training on symptom- and condition-related QoL (standardized mean difference (SMD) -0.06, 95% CI -0.89 to 0.77; 2 studies, 117 participants; very low-certainty evidence). Although the evidence is very uncertain, there were fewer adverse events in the bladder training group than in the anticholinergics group (RR 0.03, 95% CI 0.01 to 0.17; 3 studies, 187 participants; very low-certainty evidence). The evidence is very uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.36, 95% CI -0.27 to 1.00; 2 studies, 117 participants; very low-certainty evidence), the number of urgency episodes per 24 hours (MD 0.70, 95% CI -0.62 to 2.02; 2 studies, 92 participants; very low-certainty evidence), and the number of micturition episodes per 24 hours (MD -0.35, 95% CI -1.90 to 1.20; 3 studies, 175 participants; very low-certainty evidence). No studies measured participant-reported satisfaction in the early phase. Bladder training versus PFMT: three studies involving 203 participants compared bladder training to PFMT. The evidence is very uncertain about the different effects between bladder training and PFMT on symptom- and condition-related QoL at the early phase (SMD 0.10, 95% CI -0.19 to 0.40; 2 studies, 178 participants; very low-certainty evidence). There were no adverse events in either group at the early phase (1 study, 97 participants; moderate-certainty evidence). The evidence is uncertain about the effects of the number of incontinence episodes per 24 hours (MD 0.02, 95% CI -0.35 to 0.39, 1 study, 81 participants; low-certainty evidence) and very uncertain about the number of micturition episodes per 24 hours (MD 0.10, 95% CI -1.44 to 1.64; 1 study, 81 participants; very low-certainty evidence). No studies measured cure or improvement, participant-reported satisfaction, or number of urgency episodes in the early phase. Although we were interested in studies examining bladder training versus ß3-adrenoceptor agonists, in combination with ß3-adrenoceptor agonists versus ß3-adrenoceptor agonists alone, and in combination with PFMT versus PFMT alone, we did not identify any eligible studies for these comparisons. AUTHORS' CONCLUSIONS: This review focused on the effect of bladder training to treat OAB. However, most of the evidence was low or very-low certainty. Based on the low- or very low-certainty evidence, bladder training may cure or improve OAB compared to no treatment. Bladder training may be more effective to cure or improve OAB than anticholinergics, and there may be fewer adverse events. There may be no difference in efficacy or safety between bladder training and PFMT. More well-designed trials are needed to reach a firm conclusion.

Effect of Minocycline Pleurodesis in Infants With Refractory Chylothorax After Palliative Surgery for Complex Congenital Heart Disease.

Chylothorax is a critical complication after surgery for congenital heart disease, which markedly compromises the postoperative course with increased mortality. As the cardiovascular load additively causes stagnation of the thoracic duct, chylothorax after palliative cardiac surgery can be highly refractory to the therapies. Here we report a case of two patients with refractory chylothorax attributed to hemodynamic load which was successfully treated with minocycline pleurodesis. In combination with congenital heart disease, extremely low birth weight coupled with prematurity in case 1 and venous obstruction with excessive volume load due to additional aortopulmonary shunt in case 2 additively increased resistance to the therapies, including fasting with total parenteral nutrition (TPN), XIII factor supplementation, octreotide infusion, as well as the use of steroids. As pleural effusion was sustained at more than 50 ml/kg/day, the condition of both patients deteriorated severely; pleurodesis using minocycline was urgently introduced. Pleural effusion declined at every session and both cases were in remission in a few sessions without unfavorable acute reaction. No symptoms suspecting chronic adverse effects were observed during follow-up, including respiratory dysfunction, pulmonary hypertension, tooth staining, or abnormal bone mineralization. Although the application of minocycline for children should be minimized, minocycline pleurodesis can be an option for patients with refractory and life-threatening chylothorax.

A novel challenge of nondestructive analysis on OGATA Koan's sealed medicine by muonic X-ray analysis.

OGATA Koan (1810-63) was a physician and the director of Tekijuku, and he contributed to Western medicine in the late Edo period. Osaka University preserves two of his medicine chests. One of the chests, which was used in his last years (the second chest) contained 22 glass bottles and 6 wooden cylinders. These bottles and cylinders contained formulated medicines; however, about half cannot be opened because of the long-term storage. It is necessary to comprehend the physical property of both the containers and their contents for investigation of this adequate preservation method; however, destructive analysis is not allowed. To analyze the medicines sealed in the glass bottles, we focused on muonic X-ray analysis, which has high transmittance. First, we certified the analytical methods using a historical medicinal specimen preserved in Osaka University. Thereafter, we applied the method on the bottles stored in the second chest. X-ray fluorescence identified the glass of those bottles to be lead potash glass. Among these bottles, we chose the bottle with the label "," which contains white powdered medication, for muonic X-ray analysis. We identified the contents of the medication in the glass to be Hg2Cl2. Through this study, we first applied muonic X-ray analysis on the medical inheritances and succeeded to detect the elements contained both in the container and in the contents of the sealed bottle. This would be a new method for nondestructive analysis of such cultural properties.

Characteristics of the nonpulmonary vein foci induced after second-generation cryoballoon ablation for paroxysmal atrial fibrillation.

INTRODUCTION: Pulmonary vein isolation (PVI) using cryoballoon is effective for patients with paroxysmal atrial fibrillation (PAF); however, few reports have evaluated the non-pulmonary vein (PV) foci after cryoballoon ablation. We aimed to evaluate the characteristics of non-PV foci and predictors of atrial fibrillation (AF) recurrence after cryoballoon ablation. METHODS AND RESULTS: This was a single-center retrospective study of 647 patients with PAF who underwent initial PVI using a second-generation cryoballoon. After PVI, all patients underwent high-dose isoproterenol infusion to assess the existence of non-PV foci. Non-PV foci were observed in 211 patients (32.6%), which were most frequently observed in the superior vena cava. Higher age (odds ratio [OR] = 1.02; 95% confidence interval [CI] = 1.00-1.04; P = .025), female sex (OR = 1.65; 95% CI = 1.13-2.41; P = .009), and lower body mass index (OR = 0.95; 95% CI = 0.89-1.00; P = .049) were significantly associated with non-PV foci. The existence of non-PV foci was an independent predictor of AF recurrence (Hazard's ratio = 1.70; 95% CI = 1.12-2.60; P = .014). When non-PV foci were mappable and successfully ablated, patients with non-PV foci showed similar outcomes with those without non-PV foci (1-year AF-free survival rates of 88.5% vs 91.5%; P = .338). Conversely, when we failed to detect and eliminate non-PV foci because they had multiple origins and were not consistently inducible (multichanging non-PV foci), the 1-year AF-free survival rate was 56.4% even after substrate modification. CONCLUSION: Non-PV foci were observed in one-third of patients with PAF after cryoballoon ablation and were associated with AF recurrence. Catheter ablation for non-PV foci was effective when they were mappable; however, multichanging non-PV foci were associated with worse prognosis.

Differences in the electrophysiological findings of repeat ablation between patients who first underwent cryoballoon ablation and radiofrequency catheter ablation for paroxysmal atrial fibrillation.

INTRODUCTION: Several studies have revealed that second-generation cryoballoon (CB)-based pulmonary vein (PV) isolation is noninferior to radiofrequency (RF)-based PV isolation for patients with drug-refractory paroxysmal atrial fibrillation (AF). However, electrophysiological differences in repeat ablation remain unclear. METHODS AND RESULTS: This study examined electrophysiological differences during the repeat ablation between patients who first underwent RF catheter ablation and CB ablation; PV durability and non-PV AF foci were assessed for these patients. We enrolled 919 and 491 patients who underwent CB ablation (CB group) and RF catheter ablation (RF group), respectively, for paroxysmal AF between January 2013 and June 2017 at our institution. PV isolation using RF ablation involved the left atrium (LA) antrum and part of the LA posterior wall. After 2 years of follow-up, 62 and 80 patients in the CB and RF groups, respectively, underwent repeat ablation. PV reconnections were more frequent in the RF group than in the CB group (left superior PV: 46.2% and 14.5%, P < .001; left inferior PV: 35.0% and 11.2%, P = .001; right superior PV: 40.0% and 22.6%, P = .031; right inferior PV: 36.2% and 19.4%, P = .039; PVs: 39.8% and 16.9%, P < .001). LA AF foci were more frequent in the CB group than in the RF group (27.4% and 7.5%; P = .002). Other non-PV foci were prevalent in both groups. CONCLUSION: Fewer LA-PV reconnections occurred with CB ablation. However, extensive PV isolation may eliminate many LA AF foci.

Effects of laughter therapy on quality of life in patients with cancer: An open-label, randomized controlled trial.

BACKGROUND: Few randomized controlled trials have assessed the effects of laughter therapy on health-related quality of life (QOL) in cancer patients. This study aimed to evaluate these effects as an exploratory endpoint in cancer patients as part of a randomized controlled trial conducted at a single institution in Japan. METHODS: The Initiative On Smile And CAncer (iOSACA) study was an open-label randomized controlled trial conducted in 2017 in which participants aged 40-64 years with cancer were randomly assigned to either an intervention group (laughter therapy) or control group (no laughter therapy). Each participant in the intervention group underwent a laughter therapy session once every two weeks for seven weeks (total of four sessions). Each session involved a laughter yoga routine followed by Rakugo or Manzai traditional Japanese verbal comedy performances. We assessed QOL as a secondary endpoint in this intention-to-treat population using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The questionnaire was completed at baseline (Week 0) and at Weeks 3 and 7. Mixed-effects models for repeated measures were developed to compare time-dependent changes in each QOL domain from baseline between the intervention and control groups. RESULTS: Four participants retracted consent and one participant was retrospectively excluded from analysis due to unmet inclusion criteria. The analysis was conducted using 56 participants, with 26 in the intervention group and 30 in the control group. Questionnaire completion rates were high (>90%), with similar QOL scores reported at baseline in both groups. The mixed-effects models showed that the intervention group had significantly better cognitive function and less pain than the control group for a short period. CONCLUSION: Laughter therapy may represent a beneficial, noninvasive complementary intervention in the clinical setting. Further studies are needed to verify the hypotheses generated from this exploratory study.

Preoperative management using inhalation therapy for pulmonary complications in lung cancer patients with chronic obstructive pulmonary disease.

OBJECTIVE: This study aimed to investigate whether perioperative inhalations of long-acting beta-agonists (LABAs) or long-acting muscarinic antagonists (LAMAs) might decrease the incidence of postoperative complications in lung cancer patients with chronic obstructive pulmonary disease (COPD). METHODS: We retrospectively analyzed 108 patients with COPD who underwent pulmonary resections for primary lung cancer at our hospital between January 2013 and January 2016 to determine the association between the incidence of postoperative complications (e.g., prolonged air leakage and pneumonia) and the use of LABAs or LAMAs. RESULTS: Thirty patients with COPD experienced postoperative complications (27.8%): Fourteen patients had prolonged air leakages (more than 7 days), ten patients developed pneumonia. The frequency of these postoperative pulmonary complications was significantly higher among the patients with COPD (24/108 cases, 22.2%), compared with the frequency among non-COPD patients (15/224 cases, 6.7%). Inhaled bronchodilators, such as LAMA or LABA, were prescribed for 34 of the 108 patients with COPD; the remaining 74 patients were not treated with bronchodilators. Pulmonary complications were significant lower among the LAMA or LABA users (3/34 cases, 8.8%) than among the untreated COPD patients (21/74 cases, 28.4%). CONCLUSION: For lung cancer patients with COPD, preoperative management using LABA or LAMA bronchodilators and smoking cessation can reduce the frequency of postoperative pulmonary complications after surgical lung resection. LAMA or LABA inhalation might be useful for not only perioperative care, but also for the long-term survival of COPD patients after surgery.

Left septal atrial tachycardia after open-heart surgery: relevance to surgical approach, anatomical and electrophysiological characteristics associated with catheter ablation, and procedural outcomes.

BACKGROUND: Septal atrial tachycardia (AT) can occur in patients without structural heart disease and in patients with previous catheter ablation of atrial fibrillation. We aimed to assess septal AT that occurs after open-heart surgery. METHODS AND RESULTS: This study comprised 20 consecutive patients undergoing catheter ablation of macroreentrant AT after open-heart surgery. Relevance to surgical approach, mechanisms, anatomic and electrophysiological characteristics, and outcomes were assessed. Septal AT was identified in 7 patients who had all undergone mitral valve surgery. All septal ATs were localized in the left atrial septum, whereas 10 of 13 nonseptal ATs originated from the right atrium. Patients with left septal AT had a thicker fossa ovalis (median, 4.0; 25th-75th percentile, 3.6-4.2 versus 2.3; 1.6-2.6 mm; P=0.006) and broader area of low voltage (<0.3 mV) in the septum than patients with nonseptal AT (82; 76-89 versus 31; 28%-36%; P=0.02). Repeated gradual prolongations of the tachycardia cycle length without change of the septal circuit were observed in all patients with septal AT (70; 63-100 versus 15; 10-40 ms; P=0.0008). Although ablation terminated all ATs, recurrence of targeted ATs was more frequent in patients with left septal AT during 30-month follow-up (71 versus 0%; P=0.001). CONCLUSIONS: Left septal AT after open-heart surgery was characterized by a thicker septum, more scar burden in the septum, and repeated prolongations of the tachycardia cycle length during ablation. Such an arrhythmogenic substrate may interfere with transmural lesion formation by ablation and may account for higher likelihood of recurrence of left septal AT.

Sudden cardiac arrest immediately after stent graft deployment during treatment of iliac aneurysm with iliocaval fistula.

An 84-year-old woman with heaviness of the right lower extremity had an iliocaval fistula related to a right internal iliac aneurysm. Immediately after deployment of an endovascular device, cardiac arrest occurred because of severely decreased sympathetic activity. After surgery, the patient recovered well and has been followed up with exclusion of the arteriovenous fistula and resolution of the type II endoleak. Endovascular treatment for large arteriovenous fistulas induces rapid closure of the fistula together with restoration of blood supply to the lower extremity. Markedly deactivated sympathetic nerve traffic could result in a critical hemodynamic status in association with endograft deployment.

New preclinical antimalarial drugs potently inhibit hepatitis C virus genotype 1b RNA replication.

BACKGROUND: Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed. METHODOLOGY/PRINCIPAL FINDINGS: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect. CONCLUSIONS/SIGNIFICANCE: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.

Comparison of effects of serum n-3 to n-6 polyunsaturated fatty acid ratios on coronary atherosclerosis in patients treated with pitavastatin or pravastatin undergoing percutaneous coronary intervention.

A low n-3 to n-6 polyunsaturated fatty acid (PUFA) ratio is associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined, particularly in patients treated with different types of statins. This study compared the effects of n-3 to n-6 PUFA ratios on coronary atherosclerosis in patients treated with pitavastatin and pravastatin. Coronary atherosclerosis in nonculprit lesions in the percutaneous coronary intervention vessel was evaluated using virtual histology intravascular ultrasound in 101 patients at the time of percutaneous coronary intervention and 8 months after statin therapy. Pitavastatin and pravastatin were used to treat 51 and 50 patients, respectively. Changes in the docosahexaenoic acid (DHA)/arachidonic acid (AA) and eicosapentaenoic acid+DHA/AA ratios were not correlated with the percentage change in plaque volume in the pitavastatin group, whereas the percentage change in plaque volume and the changes in the DHA/AA ratio (r = -0.404, p = 0.004) and eicosapentaenoic acid+DHA/AA ratio (r = -0.350, p = 0.01) in the pravastatin group showed significant negative correlations. Multivariate regression analysis showed that age (ß = 0.306, p = 0.02), the presence of diabetes mellitus (ß = 0.250, p = 0.048), and changes in the DHA/AA ratio (ß = -0.423, p = 0.001) were significant predictors of the percentage change in plaque volume in patients treated with pravastatin. In conclusion, decreases in n-3 to n-6 PUFA ratios are associated with progression in coronary atherosclerosis during pravastatin therapy but not during pitavastatin therapy.

Effects of statins on serum n-3 to n-6 polyunsaturated fatty acid ratios in patients with coronary artery disease.

BACKGROUND: A low n-3 to n-6 polyunsaturated fatty acids (PUFAs) ratio is reported to be associated with cardiovascular events. However, the effects of statins on this ratio have not been fully examined. METHODS: A total of 101 patients with coronary artery disease, who were not receiving lipid-lowering therapy were randomly assigned to receive either 4 mg/day of pitavastatin or 20 mg/day of pravastatin. Serum PUFA levels were measured at baseline and 8 months after treatment with statins. RESULTS: Pitavastatin was used to treat 51 patients and the remaining 50 patients were treated using pravastatin. A significant positive correlation was observed between the percent change in low-density lipoprotein cholesterol and that in dihomogamma-linolenic acid (r = .376, P = .007), arachidonic acid (AA; r = .316, P = .02), eicosapentaenoic acid (EPA; r = .408, P = .003), or docosahexaenoic acid (DHA; r = .270, P = .056) in the pitavastatin group. However, these correlations were not observed in the pravastatin group. The DHA/AA ratio decreased significantly in the pitavastatin group only (from 0.96 to 0.83, P = .0002) and the DHA/AA ratio was significantly lower in the pitavastatin group at 8 months (0.83 vs 0.96, P = .03). The EPA/AA ratio did not show significant changes in either group. CONCLUSIONS: Pitavastatin decreased the serum DHA/AA ratio, whereas pravastatin had no effect on this ratio. Neither pitavastatin nor pravastatin had an effect on the serum EPA/AA ratio in patients with coronary artery disease.

Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease.

A low ratio of n-3 to n-6 polyunsaturated fatty acids has been associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined. The purpose of the present study was to evaluate the correlations between the n-3 to n-6 polyunsaturated fatty acid ratio and coronary atherosclerosis. Coronary atherosclerosis in nonculprit lesions in the percutaneous coronary intervention vessel was evaluated using virtual histology intravascular ultrasound in 101 patients at the time of percutaneous coronary intervention and 8 months after statin therapy. Forty-six patients (46%) showed atheroma progression and the remaining 55 patients (54%) showed atheroma regression at 8-month follow-up. Significant negative correlations were observed between percentage change in plaque volume and change in the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (r = -0.190, p = 0.05), docosahexaenoic acid (DHA)/AA ratio (r = -0.231, p = 0.02), and EPA+DHA/AA ratio (r = -0.240, p = 0.02). Furthermore, percentage change in the fibrous component volume was negatively and significantly correlated with change in the EPA/AA ratio (r = -0.206, p = 0.04) and EPA+DHA/AA ratio (r = -0.217, p = 0.03). Multivariate regression analysis showed that change in the EPA+DHA/AA ratio was a significant predictor of percentage change in plaque volume and fibrous component volume (ß = -0.221, p = 0.02, and ß = -0.200, p = 0.04, respectively). In conclusion, decreases in serum n-3 to n-6 polyunsaturated fatty acid ratios are associated with progression in coronary atherosclerosis evaluated using virtual histology intravascular ultrasound in statin-treated patients with coronary artery disease.

Electrogram organization predicts left atrial reverse remodeling after the restoration of sinus rhythm by catheter ablation in patients with persistent atrial fibrillation.

BACKGROUND: Despite the informative nature of atrial fibrillation (AF) electrograms, electrophysiological aspects of predicting reversal of structural remodeling of the left atrium (LA) have not been evaluated. OBJECTIVES: To identify predictors of reverse remodeling after restoration of sinus rhythm by catheter ablation in patients with persistent AF. METHODS: This study included 90 patients with persistent AF and enlarged LA (left atrial volume indexed to body surface area [LAVi] ≥32 mL/m(2)). LAVi was measured by echocardiography before ablation and 12 months after sinus rhythm restoration. We divided 73 (81%) patients free from recurrences into 2 groups according to reduction in LAVi: responders, reduction ≥23% (n = 35); nonresponders, reduction <23% (n = 38). Serological testing and electrophysiological characteristics on electrocardiogram and magnetocardiogram were analyzed. RESULTS: LAVi decreased from 43 ± 12 to 27 ± 7 mL/m(2) in responders and from 37 ± 8 to 33 ± 8 mL/m(2) in nonresponders. Higher LAVi at baseline (P = .01), lower age (59 ± 7 years vs 63 ± 7 years; P <.05), higher brain natriuretic peptide level (median = 92, interquartile range [IQR] = 98 pg/mL vs median = 60, IQR = 64 pg/mL; P = 0.01), higher atrial natriuretic peptide level (median = 73, IQR = 74 pg/mL vs median = 54, IQR = 70 pg/mL; P = .02), and higher organization index of AF signals (0.51 ± 0.11 vs 0.42 ± 0.09; P = .0001) were observed in responders. There was a linear correlation between organization index and % reduction in LAVi (R = 0.63; P <.0001). Multiple linear regression analysis showed relations between reverse remodeling and age (ß = -0.28; P = .002), atrial natriuretic peptide level (ß = 0.21; P = .03), and organization index (ß = 0.53; P <.0001). CONCLUSIONS: Electrogram organization was a robust predictor of reverse remodeling of the enlarged LA after sinus rhythm restoration by catheter ablation in patients with persistent AF.

Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives.

Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.

Coexistence of left-sided atrioventricular accessory pathways with a common inferior pulmonary vein ostium.

BACKGROUND: As the technique for radiofrequency catheter ablation for atrial fibrillation (AF) has progressed, so has our knowledge of both normal and abnormal anatomy of the left atrium and pulmonary veins (PV). We treated several AF patients with accessory conduction pathways (ACP) who were also found to have a common ostium of inferior PVs (CIPV), a relatively rare PV anomaly. No relation between ACP and PV anomalies has ever been reported, and the aim of our study was to study this association. METHODS AND RESULTS: This study included 137 consecutive patients (104 men; mean age, 60±9 years) who underwent AF ablation for paroxysmal and persistent AF at our institution from March 2009 to August 2010. We analyzed coexisting supraventricular tachycardias and left atrium and PV morphology by multidetector row CT. Thirty-eight of 137 patients (27.7%) were found to have some PV anomaly, consisting of 13 with a common trunk of left PV, 19 with right additional PV, 3 with a common trunk of right PV, and 3 with CIPV. Thirty-one patients (22.6%) had supraventricular tachycardias. They were 26 cases of atrial flutter, 4 of Wolff-Parkinson-White syndrome, and 3 of atrioventricular nodal reentrant tachycardia. The prevalence of a coexisting ACP was significantly higher in patients with CIPV than in those without CIPV (3 of 3 [100%] versus 1 in 134 [0.7%]; P<0.0001). All ACPs with CIPV were located in the left side. The other supraventricular tachycardias were not associated with any PV anomalies. CONCLUSIONS: There is a possible association between CIPV and left-sided ACP in AF patients. This suggests that there is a likelihood of developmental association between them.

TRPM7 regulates gastrulation during vertebrate embryogenesis.

During gastrulation, cells in the dorsal marginal zone polarize, elongate, align and intercalate to establish the physical body axis of the developing embryo. Here we demonstrate that the bifunctional channel-kinase TRPM7 is specifically required for vertebrate gastrulation. TRPM7 is temporally expressed maternally and throughout development, and is spatially enriched in tissues undergoing convergent extension during gastrulation. Functional studies reveal that TRPM7's ion channel, but not its kinase domain, specifically affects cell polarity and convergent extension movements during gastrulation, independent of mesodermal specification. During gastrulation, the non-canonical Wnt pathway via Dishevelled (Dvl) orchestrates the activities of the GTPases Rho and Rac to control convergent extension movements. We find that TRPM7 functions synergistically with non-canonical Wnt signaling to regulate Rac activity. The phenotype caused by depletion of the Ca(2+)- and Mg(2+)-permeant TRPM7 is suppressed by expression of a dominant negative form of Rac, as well as by Mg(2+) supplementation or by expression of the Mg(2+) transporter SLC41A2. Together, these studies demonstrate an essential role for the ion channel TRPM7 and Mg(2+) in Rac-dependent polarized cell movements during vertebrate gastrulation.

The therapeutic importance of home blood pressure assessment and combination antihypertensive therapy for achieving target blood pressure control: Ibaraki hypertension assessment trial.

Tight blood pressure (BP) control is important for the prevention of cardiovascular disease in hypertensive patients. A cross-sectional study of 2339 patients from 101 clinics and hospitals in Ibaraki Prefecture was performed to evaluate BP control with the patients' current antihypertensive medication. Group A (n=892) included high-risk hypertensive patients with at least one of the following risk factors: diabetes mellitus, chronic kidney disease or a history of myocardial infarction. Group B (n=586) included patients <65 years old and Group C (n=859) included patients ≥65 years old. Both groups B and C included hypertensive patients without the above risk factors. A mean of 1.8±1.0 antihypertensive drugs per patient were prescribed. A total of 35.8% of all patients received monotherapy, 40% received a combination of three therapies and 20.3% received more than three kinds of drugs. The percentage of patients achieving the target BP at the office and at home was significantly higher in Group C than in the other groups (P<0.001). A combination of more than two antihypertensive drugs, including a high dose of either an angiotensin receptor blocker or a calcium channel blocker, was frequently prescribed to Group A to achieve the target office BP. Although the target BP should be lower in Group A (given their comorbidities), the absolute BP value and the number of medications were similar to the other groups. In conclusion, we demonstrated that physicians should treat hypertension more intensively with a combination of more than two antihypertensive drugs, using a high dose to achieve the target BP. In addition, it is important to teach hypertensive patients the clinical importance of monitoring their BP at home and the need to achieve home BP targets.

Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.

Mutations of genes encoding alpha4, beta2, or alpha2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.

Sall1, a causative gene for Townes-Brocks syndrome, enhances the canonical Wnt signaling by localizing to heterochromatin.

The Spalt (sal) gene family plays an important role in regulating developmental processes of many organisms. Mutations of human SALL1 cause the autosomal dominant disorder, Townes-Brocks syndrome (TBS), and result in ear, limb, anal, renal, and heart anomalies. Targeted deletion of mouse Sall1 results in kidney agenesis or severe dysgenesis. Molecular mechanisms of Sall1, however, have remained largely unknown. Here we report that Sall1 synergistically activates canonical Wnt signaling. The transcriptional activity of Sall1 is related to its nuclear localization to punctate nuclear foci (pericentromeric heterochromatin), but not to its localization or association with beta-catenin, the nuclear component of Wnt signaling. In contrast, the RNA interference of Sall1 reduces reporter activities of canonical Wnt signaling. The N-terminal truncated Sall1, produced by mutations often found in TBS, disturbs localization of native Sall1 to heterochromatin, and also down-regulates the synergistic transcriptional enhancement for Wnt signal by native Sall1. Thus, we propose a new mechanism for Wnt signaling activation, that is the heterochromatin localization of Sall1.