Matched comparison of catheter ablation versus conservative management for atrial fibrillation.

It is still controversial whether catheter ablation for atrial fibrillation (AF) could improve clinical outcomes in general AF population. Among 4398 patients with diagnosis of AF in the outpatient department of Kyoto University Hospital between January 2005 and March 2015, we identified 537 pairs of patients who received first-time catheter ablation (ablation group) or conservative management (conservative group), matched for age, gender, AF duration, AF type, AF symptoms, and previous heart failure (HF). The primary outcome measure was a composite of cardiovascular death, HF hospitalization, ischemic stroke, or major bleeding. Most baseline characteristics were well balanced between the 2 groups, except for the higher prevalence of low body weight, history of malignancy, and severe chronic kidney disease in the conservative group. Median follow-up duration was 5.3 years. The cumulative 5-year incidence of the primary outcome measure was significantly lower in the ablation group than in the conservative group (5.2% versus 15.6%, log-rank P < 0.001). Even after adjusting for the imbalances in the baseline characteristics, the lower risk of the ablation group relative to the conservative group for the primary outcome measure remained highly significant (HR 0.32, 95% CI 0.21-0.47, P < 0.001). Ablation compared with conservative management was also associated with significantly lower risks for the individual components of the primary outcome. In this matched analysis in AF patients, ablation as compared with conservative management was associated with better long-term clinical outcomes, although we could not deny the possibility of selection bias and unmeasured confounding.

Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial.

AIMS: Most of recurrent atrial tachyarrhythmias after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are due to reconnection of PVs. The aim of the present study was to evaluate whether elimination of adenosine triphosphate (ATP)-induced dormant PV conduction by additional energy applications during the first ablation procedure could reduce the incidence of recurrent atrial tachyarrhythmias. METHODS AND RESULTS: We randomly assigned 2113 patients with paroxysmal, persistent, or long-lasting AF to either ATP-guided PVI (1112 patients) or conventional PVI (1001 patients). The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at 1 year with the blanking period of 90 days post ablation. Among patients assigned to ATP-guided PVI, 0.4 mg/kg body weight of ATP provoked dormant PV conduction in 307 patients (27.6%). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4%). At 1 year, 68.7% of patients in the ATP-guided PVI group and 67.1% of patients in the conventional PVI group were free from the primary endpoint, with no significant difference (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.74-1.09; P = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the 1-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; P = 0.16). CONCLUSION: In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.

The Relationship between H. pylori Infection and Osteoporosis in Japan.

Background and Objective. H. pylori infection causes a chronic inflammation in the gastric mucosa. However, this local inflammation may result in extra-digestive conditions. Our aim is to investigate the relationship between H. pylori infection and osteoporosis in Japan. Methods. This cross-sectional study was conducted among outpatients at the Juntendo University Hospital between 2008 and 2014. Participants for patient profile, H. pylori infection status, comorbidity, internal medical therapies, lumbar dual-energy X-ray absorptiometry (DXA), and bone turnover marker were collected and upper gastrointestinal endoscopy for reflux esophagitis, hiatal hernia, peptic ulcer disease (PUD), and endoscopic gastric mucosal atrophy (EGA) was performed. The diagnosis of osteoporosis was performed in accordance with the Japanese criteria. We investigated risk factors of osteoporosis. Results. Of the eligible 200 study subjects, 41 cases were of osteoporosis. Bivariate analysis showed that age, being female, BMI, alcohol, smoking, H. pylori, bone-specific ALP, PUD, and EGA were related to osteoporosis. Multivariate analysis showed that age (OR 1.13; 95%CI 1.07-1.20), being female (OR 4.77; 95%CI 1.78-12.77), BMI (OR 0.79; 95%CI 0.68-0.92), H. pylori (OR 5.33; 95%CI 1.73-16.42), and PUD (OR 4.98; 95%CI 1.51-16.45) were related to osteoporosis. Conclusions. H. pylori infection may be a risk factor of osteoporosis in Japan.

Clinical feature of asymptomatic reflux esophagitis in patients who underwent upper gastrointestinal endoscopy.

BACKGROUND AND AIM: Prevalence of gastroesophageal reflux disease (GERD) varies in regions, but few reports on clinical features and quality of life (QOL) of asymptomatic GERD exist in Japan. METHODS: Endoscopy was performed in our department between April 2008 and September 2010. Among 6409 cases answering Frequency of Scale for the Symptoms of GERD (FSSG) and SF8 QOL (PCS: physical component summary; MCS: mental component summary), proton pump inhibitor or histamine 2 receptor antagonist users were excluded, and 388 cases diagnosed as reflux esophagitis (RE) (Los Angeles Classification grade A, B, C, D) were analyzed. Asymptomatic cases with FSSG total score = 0 were defined as asymptomatic RE (AsymRE) and FSSG total score ≥ 1 as symptomatic RE (SymRE). Each clinical feature was analyzed. RESULTS: The frequency of AsymRE was 11.6% of RE (AsymRE, n = 45; SymRE, n = 343). Patient characteristics in AsymRE, SymRE were male/female = 35/10; 239/104 (not significant), mean age (year) = 63.5 ± 14.3; 58.3 ± 12.7 (P < 0.01), body mass index = 23.9 ± 4.3; 23.5 ± 3.7 (ns), respectively. Regarding the grade of RE, grade A 80.0%, B 17.8%, C 2.2% and D 0% in AsymRE, and grade A 72.6%, B 24.8%, C 2.0% and D 0.6% in SymRE (ns). PCS in SF8 was AsymRE; SymRE = 51.8 ± 9.8; 49.0 ± 7.7 (P < 0.01) and MCS in SF8 was AsymRE; SymRE = 51.4 ± 9.4; 48.2 ± 7.6 (P < 0.01), respectively. CONCLUSION: The prevalence of asymptomatic RE was high, particularly in elderly subjects. Unlike symptomatic RE, QOL was not impaired at all with asymptomatic RE. No differences were seen between groups in clinical features such as endoscopic severity of RE, indicating that asymptomatic RE is a condition that should not be overlooked clinically.

NaCl induced high cationic hydroxyethylated cholesterol-based nanoparticle-mediated synthetic small interfering RNA transfer into prostate carcinoma PC-3 cells.

The RNA interference (RNAi) effect is an alternative technology to antisense DNA as an experimental method of down-regulating a specific target protein. Optimal gene therapy for tumors must deliver synthetic small interfering RNA (siRNA) to tumor cells with high efficiency and minimal toxicity. Previously, we reported that cationic nanoparticles composed of cholesteryl-3beta-carboxyamidoethylene-N-hydroxyethylamine and Tween 80 (NP-OH) could deliver plasmid DNA with high transfection efficiency. In this study, to apply NP-OH for siRNA transfection, we optimized the charge ratio (+/-) of NP-OH/siRNA and nanoplex-forming solution, and evaluated the transfection efficiency into PC-3 cells. Positively charged nanoplex prepared in the presence of sodium chloride exhibited efficient siRNA transfer. The distribution of siRNA after transfection was strongly detected both in the cytoplasm and nucleus. Furthermore, we demonstrated that NP-OH nanoplex of bcl-2 siRNA significantly inhibited tumor growth compared with control siRNA, and the efficacy was comparable to commercial products. The results of the experiments showed that NP-OH nanoparticles have potential as a viable vector candidate for synthetic siRNA delivery.

Presence of vertebral fractures is highly associated with hiatal hernia and reflux esophagitis in Japanese elderly people.

OBJECTIVE: Recent studies have shown the correlation between vertebral fractures (VFs) and gastrointestinal disorders in postmenopausal women. The aim of this study was to assess the association between VFs and hiatal hernia (HH) and/or reflux esophagitis (RE) in our patient population of both men and women. METHODS: We analyzed retrospective data of 280 patients aged 60 years or older (140 men and 140 women, mean +/- SD 73.5 years +/-7.05) who had undergone upper gastrointestinal endoscopy and chest X-rays in our hospital from August 2005 to February 2006. We analyzed the correlation between the presence of VFs and the presence of HH and/or RE. RESULTS: The incidence of RE in this study was 13.9% (39/280) and that of HH was 30.0% (84/280). Among these patients, 12.1% (41/280) had VFs. The incidence of RE in patients with VFs was 24.4% (10/41) and without VFs was 12.1% (29/239), with the difference being significant between those with and without VFs (p<0.05). The incidence of HH in patients with VFs was 43.9% (18/41) and in those without VFs was 27.6% (66/239), p<0.05. We subdivided subjects into four groups: HH only group, RE only group, HH/RE group and neither condition present group. We compared the incidence of VFs among these groups. VFs were observed in 16.4% (11/67) of the HH only group, 13.6% (3/22) of the RE only group, 41.2% (7/17) of the HH/RE group and 11.5% (20/174) in the neither condition present group. There was a significant difference in the incidence of VFs between the HH/RE group and neither condition present group (p<0.05). CONCLUSION: The presence of VFs was significantly associated with the presence of either RE or HH. This association became more significant when HH and RE were present together in elderly Japanese people.

Folate-linked lipid-based nanoparticles for synthetic siRNA delivery in KB tumor xenografts.

RNA interference (RNAi) is a sequence-specific gene-silencing mechanism triggered by synthetic small interfering RNA (siRNA), and is utilized in a wide range of fields including cancer gene therapy by down-regulating a specific target protein. In this study, for tumor-targeted siRNA delivery, we developed a folate-linked nanoparticle (NP-F), and evaluated the potential of NP-F-mediated tumor gene therapy in human nasopharyngeal KB cells, which overexpressed folate receptor (FR). NP-F was composed of cholesteryl-3beta-carboxyamidoethylene-N-hydroxyethylamine (OH-Chol), Tween 80 and folate-poly(ethylene glycol)-distearoylphosphatidylethanolamine conjugate (f-PEG(2000)-DSPE), and NP-P was substituted f-PEG(2000)-DSPE in NP-F PEG(2000)-DSPE for a non-targeting nanoparticle. The NP-F and siRNA complex (nanoplex) formed at a charge ratio (+/-) of 2/1 in the presence of 5mM NaCl was injectable size and increased transfection efficiency in the cells. NP-F showed a significantly higher intracellular amount of siRNA and stronger localization of siRNA in the cytoplasm than NP-P. When Her-2 siRNA was transfected into cells by NP-F and NP-P, NP-F significantly inhibited tumor growth, and selectively suppressed Her-2 protein expression more than NP-P. In in vivo gene therapy, a NP-F nanoplex of Her-2 siRNA by intratumoral injection significantly inhibited tumor growth of KB xenografts compared with control siRNA, but a NP-P nanoplex did not. These results of the experiments have provided optimal conditions to form folate-linked nanoparticle complexes with siRNA for folate-targeted gene therapy.

Evaluation of EORTC QLQ-C30 questionnaire in patients undergoing in-hospital chemotherapy for gastrointestinal cancer in Japan.

BACKGROUND AND AIM: There have been few studies in Japan of the utility of quality of life (QOL) questionnaires as an evaluation of chemotherapy for gastrointestinal (GI) cancer. The present study investigated whether QOL can be an indicator of the clinical benefit of chemotherapy, by analyzing the changes in the QOL scores of patients who underwent in-hospital chemotherapy for GI cancer. METHODS: From August 2004 to August 2006, 75 patients with GI cancer who were scheduled to undergo in-hospital chemotherapy were studied. The QOL score was measured with a questionnaire, the European Organization for Research Treatment of Cancer (EORTC) QLQ-C30 (version 3.0, Japanese version), before chemotherapy, and at 2 weeks and 1 month after the initiation of chemotherapy. Patients were divided into three groups according to the clinical response to chemotherapy (partial response [PR], no change [NC], and progressive disease [PD]). RESULTS: In total, 65 patients were included in the analysis. Global QOL and physical functioning scores worsened significantly at 2 weeks. Pain and constipation scores improved significantly at 1 month. Nausea and vomiting, appetite loss, and diarrhea scores worsened significantly at 2 weeks. The global QOL score improved significantly after chemotherapy in the PR group. The pain score improved significantly in the PR and NC groups after chemotherapy. QOL scores improved in the NC group to almost the same level as in the PR group, whereas QOL worsened in the PD group. CONCLUSIONS: Measurement of QOL score is a meaningful marker of the benefit of chemotherapy, other than tumor reduction. The NC group could be considered to have responded with improved QOL.

Gastrointestinal stromal tumor of the stomach with a giant abscess penetrating the gastric lumen.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. In large GISTs, cystic degeneration, necrosis and focal hemorrhage that occur inside the tumor can result in gastrointestinal bleeding. We describe a case of a 74-year old male with GIST of the stomach accompanied with a giant abscess that penetrated the gastric lumen. The patient experienced undiagnosed fever for two months prior to hospitalization. Gastrointestinal endoscopy, X-ray series and computed tomography of the patient's abdomen revealed a gastric submucosal tumor in the fornix, with a fistula to the gastric lumen that was inundated with a great deal of pus. The mass was diagnosed as a GIST from biopsy specimens. The patient was treated by endoscopic drainage of the abscess and intravenous administration of antibiotics. Eventually, a partial gastrectomy was performed. He was also administered Imanitib mesylate as adjuvant therapy. He was followed up for 2 years and no metastasis or recurrence was recognized at the follow-up examinations. This is the first report of a patient with clearly diagnosed GIST with endoscopic evidence of an abscess penetrating into the gastric lumen.

Combination of non-viral connexin 43 gene therapy and docetaxel inhibits the growth of human prostate cancer in mice.

Docetaxel (DTX) is used for the treatment of advanced hormone refractory prostate cancer. Connexin 43 (Cx43) is a tumor suppressor gene, and transfection of the Cx43 gene increases sensitivity to several chemotherapeutic agents. The objective of this study was to evaluate the effectiveness of combination therapy of Cx43-expressing plasmid DNA (pCMV-Cx43) and DTX both in vitro and in vivo using a non-viral vector in human prostate cancer PC-3 cells. Transfection of pCMV-Cx43 into the cells neither inhibited tumor growth nor increased gap junctional intercellular communication; however, combination therapy of pCMV-Cx43 and DTX significantly inhibited cell growth. Forced expression of Cx43 in the cells induced apoptotic cells by down-regulation of Bcl-2 expression and significantly more up-regulation of caspase-3 activity than either treatment alone. The combination of repeated intratumoral injection of pCMV-Cx43 (10 microg/tumor) with non-viral vector and a single intravenous injection of DTX (15 mg/kg) was compared with a repeated injection of Cx43 alone and a single injection of DTX alone on PC-3 tumor xenografts. Significant antitumoral effects were observed in mice receiving combined treatment, compared with DTX alone. The data presented here provide a rational strategy for treating patients with advanced hormone refractory prostate cancer.

Low-dose flunitrazepam for conscious sedation for EGD: a randomized double-blind placebo-controlled study.

BACKGROUND: EGD with conscious sedation is a safe procedure, but complications such as hypoxia can occur. The efficacy and safety of low-dose flunitrazepam (0.25 mg) was compared with a standard dose of flunitrazepam (0.5 mg) for moderate sedation during EGD. METHODS: In a randomized, double-blind, placebo-controlled trial, 75 outpatients (40 men, 35 women, mean age 45 [11] years) undergoing screening EGD were randomly assigned to one of 3 treatment arms: 0.25 mg of flunitrazepam (F0.25 group), 0.5 mg of flunitrazepam (F0.5 group), or placebo (normal saline solution), each administered intravenously. Patient tolerance was scored by using self-assessment questionnaires with visual analogue scales. Cardiopulmonary complications were assessed by monitoring blood pressure, heart rate, oxygen saturation, and the electrocardiogram during the procedure. RESULTS: The patient tolerance scores in the F0.25 and F0.5 groups, respectively 2.1 (2.1) and 2.3 (2.5), were significantly lower than that for the placebo group (6.5 [3.0]); there was no significant difference between F0.25 and F0.5. Cardiopulmonary complications in the F0.25 group were significantly lower than in the F0.5 group. Oxygen desaturation (oxygen saturation < 90%) was noted in two of 25 patients in the F0.5 group. Post-procedure drowsiness was observed in two of 24 (8.3%) patients in the F0.25 group and 3 of 21 (14.3%) in the F0.5 group (p = 0.2438). CONCLUSIONS: Patient tolerance of EGD with low-dose flunitrazepam (0.25 mg intravenously) was similar to that with a standard dose (0.5 mg intravenously) and significantly better than in the placebo group. Oxygen desaturation was observed only in the group that received the standard dose, suggesting that sedation with low-dose flunitrazepam is efficacious and safe for EGD.

[Changes in 1H-MRS in glioma patients before and after irradiation: the significance of quantitative analysis of choline-containing compounds].

The evaluation of the response to radiation therapy in brain tumor patients is a major and an important issue. Although CT and MRI can measure changes in tumor size, it is difficult to use these imaging methods to evaluate the viability or the proliferation activity of a tumor. In this study, we investigated the metabolite changes in glioma patients using 1H-MRS from before to after radiation therapy, to see whether or not early metabolic changes occur during therapy. Seven patients with histologically proven glioma (1 astrocytoma, 1 anaplastic astrocytoma, 2 oligoastrocytoma, 1 oligodendroglioma, 2 glioblastoma) were examined by means of 1H-MRS using a point-resolved spectroscopy (PRESS) sequence with a repetition time of 2,000 ms and echo times of 68 ms, 136 ms and 272 ms. The 1H-MRS was evaluated by both the spectrum pattern and the quantification of the metabolites. As to radiation therapy, each patient received a total dose of 64.8 Gy (1.8 Gy/fraction) with a 10-MeV linear accelerator. The results revealed that the concentration of choline-containing compounds (Cho) was 4.55 +/- 1.08 mmol/kg wet weight before radiation therapy and was reduced to 2.69 +/- 0.56 mmol/kg wet weight (p < 0.01) after radiation therapy. Moreover, both the N-acetylaspartate (NAA) peak and creatine/phosphocreatine (t-Cr) peak were lower after radiation therapy than before. The peaks of both the lipids (Lip) and lactate (Lac) were higher after radiation therapy than before. In conclusion, Cho concentration is thought to be a useful marker for the evaluation of early post-radiation response. The effect of radiation therapy can be evaluated according to the value of Cho. Further long-term MRS study is needed to prove whether or not the decrease of the Cho value in the present study will change before recurrence at later stages.

Quantification of cerebral metabolites in glioma patients with proton MR spectroscopy using T2 relaxation time correction.

This study was aimed to investigate the significance of absolute concentration of metabolites in glioma patients using proton MR spectroscopy (MRS) with T2 relaxation time correction using three different echo times. The absolute concentrations of metabolites in 7 normal subjects and in 23 gliomas (10 low-grade, 13 high-grade) were obtained by proton MRS using a tissue water signal as an internal standard. The signal intensities of metabolites and tissue water were corrected by T2 relaxation time. In low-grade glioma, the T2 relaxation time of NAA was shorter, and T2 relaxation time of water was prolonged as compared to normal subjects (p < 0.001). In high-grade glioma, the T2 relaxation time of NAA (p < 0.001) and T2 relaxation time of Cr (p < 0.01) were shorter, and T2 relaxation time of water (p < 0.001) was prolonged as compared to normal subjects. Moreover, high-grade gliomas revealed a shorter T2 relaxation time of Cr than low-grade gliomas (p < 0.05). In glioma, NAA and Cr concentration were decreased, and Cho were increased as compared to normal subjects. Moreover, high-grade glioma revealed a significant lower Cr (p < 0.001) and Cho (p < 0.01) concentration compared to low-grade gliomas. Low Cr concentration is the most reliable indicator of malignancy in glioma. Cho concentration did not correlate with malignancy in gliomas.

[Proton MRS in a case of intracerebellar epidermoid].

We report a case of epidermoid, in which proton MR spectroscopy(MRS) provided additional information to MRI. The tumor revealed high signal intensity on T2-weighted images(WI) and low signal intensity on T1 WI. No enhancement was observed. Proton MRS was acquired with the Proton Regional Imaging of Metabolites(PRIME) method(TR/TE/measurements = 2,000 ms/136,272 ms/128 times). Proton MRS revealed lactate(Lac) peak at 1.33 ppm as negative peak at TE 136 ms and positive peak at TE 272 ms. N-acetylaspartate(NAA), creatine/phosphocreatine(Cr) and choline-containing compounds(Cho) were not visible. Lac peak without other peaks such as NAA, Cr, Cho is a unique finding of proton MRS for epidermoid and this could be useful in the differential diagnosis.