Abstract Background Rivaroxaban, a direct oral anticoagulant (DOAC), has become available for stroke prevention in patients with non-valular atrial fibrillation (NVAF). However, little is known about ...its effectiveness and safety when prescribed by general practitioners in real-life settings. Methods GENERAL is a multicenter, prospective, non-interventional observational study of patients receiving rivaroxaban for NVAF in daily clinical practice prescribed specifically by general practitioners. The target number of participating medical institutions is 500–700 clinics with fewer than 20 beds and the target number of participants is 5000. The baseline clinical data, including antidementia medication and frailty, and follow-up data including concomitant treatment and outcomes until September 2018 (maximum three years) will be collected. The primary efficacy endpoints will be stroke and/or systemic embolism and the secondary endpoints will be major bleeding meeting the ISTH guidelines, non-major and clinically relevant bleeding, onset of symptomatic stroke (ischemic/hemorrhagic), systemic embolism, deep vein thrombosis/pulmonary thromboembolism, myocardial infarction and/or cardiovascular death, and systemic embolism. Based on the provided information, the event assessment committee will investigate the endpoint-related events. The annual incidence and predictive factors for primary/secondary endpoint will be investigated based on underlying disease, age, renal function, and CHADS2 , CHA2 DS2 -VASC, and HAS-BLED scores using Cox regression. We will also compare the incidence of the primary/secondary endpoint between the present study, EXPAND study, and FUSHIMI AF registry study. Results The results of this study are currently under investigation. Conclusion This study will provide important information regarding the effectiveness and safety of rivaroxaban treatment in Japanese patients with NVAF among general practitioners.
DNA methylation is involved in many diseases such as cancer and autoimmunity. We generated recombinant single-chain Fv (scFv) antibodies against 5-methyl-2′-deoxycytidine (m5dCyd) using phage display ...technology and a hyperimmunized mouse, and the scFv of most interest were contructed as fusion proteins with green fluorescent protein obtained from Aequorea coerulescens GFP (AcGFP). Using RNA isolated from mouse spleens, we constructed a scFv library consisting of λ light chains. The scFv library was selected against m5Cyd-BSA and enriched through four rounds of panning. The scFv library was concentrated about 390-fold and an individual clone was reacted with m5Cyd-BSA. Two scFvs with high reactivity for m5Cyd-BSA termed 1–2 and 1–12 were produced. Furthermore, methylated DNA-binding activities of the scFvs were confirmed using an indirect immunofluorescence assay. Additionally, N- and C-terminal scFv 1–2 fusion with AcGFP were constructed, and we observed the N-terminal AcGFP exhibited much higher fluorescence intensity than the C-terminal fusions. The AcGFP-scFv 1–2 modified N-terminus of scFv with AcGFP had high fluorescence intensity, but the scFv 1-2-AcGFP modified C-terminus of scFv with AcGFP had low fluorescence intensity. The cross-reactivity of AcGFP-scFv 1–2 was similar to scFv 1–2, and thus, AcGFP-scFv 1–2 could be used in a direct immunofluorescence assay. The scFv fusion proteins may be useful for the detection and quantification of cellular methylated DNA in various specimens.
OBJECTIVE
To study the recovery of testosterone levels and erectile function in men who received radiotherapy plus long‐term adjuvant androgen deprivation (LTAD) with luteinizing hormone‐releasing ...hormone (LHRH) agonists.
PATIENTS AND METHODS
From April 2000 to July 2001, men who had completed prostate radiotherapy with ≥ 2 years of LTAD, and had their last LHRH agonist injection at least 6 months before, were invited to participate. At study entry, the men completed the International Index of Erectile Function (IIEF), and their serum total testosterone (TT), prostate‐specific antigen, LH, follicle‐stimulating hormone, haemoglobin, and body mass were measured. This assessment was repeated at 1 year.
RESULTS
In all, 20 men were recruited, with a mean (range) age of 70 (55–81) years. Defining a normal TT level as ≥ 8.0 nmol/L, the median time to a normal level was 2.3 years (95% confidence interval (CI), 1.9–4.2). The median duration of castrate TT levels was 8 months (95% CI, 6.2–14.9). LH recovered before TT, suggesting that the rate‐limiting step in the recovery of TT may be at the testicular level. The median time to recovery of normal LH levels was 3.8 months, compared to 8.0 months to reach supracastrate TT levels, and 2.3 years to reach normal TT levels. Age and the LH/TT ratio were associated with the time to recovery of both supracastrate and normal levels of TT. The IIEF was completed by 17 men; there were no significant changes in the scores in any domain of the IIEF during the study.
CONCLUSIONS
Most men recover supracastrate testosterone levels after LTAD and external beam radiotherapy, but recovery of ‘normal’ testosterone levels is slow. Few men recover potency and sexual desire. The patients age and LH/TT ratio may be predictive of the time to recovery of both supracastrate and normal testosterone levels.
Background There are currently no dedicated plastic stents for EUS-guided hepaticogastrostomy (EUS-HGS). Objective We prospectively evaluated the feasibility and the technical and functional success ...rates of our newly designed plastic stent for EUS-HGS. Design Prospective preliminary feasibility study. Setting A tertiary-care referral center. Patients Twenty-three consecutive patients were treated. The reasons for requiring EUS-HGS were periampullary tumor invasion (n = 9), altered anatomy (n = 7), failed duodenal intubation (n = 3), and previous ERCP failure (n = 4). Interventions An 8F single-pigtail plastic stent with 4 flanges was placed for EUS-HGS. Main Outcome Measurements Technical success, clinical success, and adverse events according to the American Society for Gastrointestinal Endoscopy lexicon. Results All stents were successfully deployed without procedural adverse events (100% technical success rate). Bleeding from the punctured gastric wall occurred in 1 patient 3 days postoperatively. We exchanged the plastic stent for a fully covered self-expandable metal stent. A mild adverse event of self-limited abdominal pain occurred in 3 patients. Treatment success was achieved in all patients. The occlusion rate was 13.7% (3/22) during the median follow-up period (5.0 months, range 0.5-12.5 months). The median duration of stent patency was 4.0 months (range 0.5-9.0 months). There was no stent migration or dislocation during the follow-up period. Limitations Small number of patients and lack of a control group. Conclusions This newly designed single-pigtail plastic stent dedicated for EUS-HGS was technically feasible and can possibly be used for highly selected patients with advanced malignancy or benign stricture. (Trial Registration: http://www.umin.ac.jp/english/ : UMIN000012993.)
Sandhoff disease is a lysosomal storage disease caused by simultaneous deficiencies of β‐hexosaminidase A (HexA; αβ) and B (HexB; ββ), due to a primary defect of the β‐subunit gene (HEXB) associated ...with excessive accumulation of GM2 ganglioside (GM2) and oligosaccharides with N‐acetylhexosamine residues at their non‐reducing termini, and with neurosomatic manifestations. To elucidate the neuroinflammatory mechanisms involved in its pathogenesis, we analyzed the expression of chemokines in Sandhoff disease model mice (SD mice) produced by disruption of the murine Hex β‐subunit gene allele (Hexb–/–). We demonstrated that chemokine macrophage inflammatory protein‐1 α (MIP‐1α) was induced in brain regions, including the cerebral cortex, brain stem and cerebellum, of SD mice from an early stage of the pathogenesis but not in other systemic organs. On the other hand, little changes in other chemokine mRNAs, including those of RANTES (regulated upon activation, normal T expressed and secreted), MCP‐1 (monocyte chemotactic protein‐1), SLC (secondary lymphoid‐tissue chemokine), fractalkine and SDF‐1 (stromal derived factor‐1), were detected. Significant up‐regulation of MIP‐1α mRNA and protein in the above‐mentioned brain regions was observed in parallel with the accumulation of natural substrates of HexA and HexB. Immunohistochemical analysis revealed that MIP‐1α‐immunoreactivity (IR) in the above‐mentioned brain regions of SD mice was co‐localized in Iba1‐IR‐positive microglial cells and partly in glial fibrillary acidic protein (GFAP)‐IR‐positive astrocytes, in which marked accumulation of N‐acetylglucosaminyl (GlcNAc)‐oligosaccharides was observed from the presymptomatic stage of the disease. In contrast, little MIP‐1α‐IR was observed in neurons in which GM2 accumulated predominantly. These results suggest that specific induction of MIP‐1α might coincide with the accumulation of GlcNAc‐oligosaccharides due to a HexB deficiency in resident microglia and astrocytes in the brains of SD mice causing their activation and acceleration of the progressive neurodegeneration in SD mice.
Summary Background The clinical relevance of the diagnostic criteria for prediabetes to prediction of progression to diabetes has been little studied. We aimed to compare the prevalence of ...prediabetes when assessed by the new glycated haemoglobin A1c (HbA1c ) 5·7–6·4% criterion or by impaired fasting glucose, and assessed differences in progression rate to diabetes between these two criteria for prediabetes in a Japanese population. Methods Our longitudinal cohort study included 4670 men and 1571 women aged 24–82 years without diabetes at baseline (diabetes was defined as fasting plasma glucose ≥7·0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA1c ≥6·5%) who attended Toranomon Hospital (Tokyo, Japan) for a routine health check between 1997 and 2003. Participants with a baseline diagnosis of prediabetes according to impaired fasting glucose (fasting plasma glucose 5·6–6·9 mmol/L) or HbA1c 5·7–6·4%, or both, were divided into four groups on the basis of baseline diagnosis of prediabetes. Rate of progression to diabetes was assessed annually. Findings Mean follow-up was 4·7 (SD 0·7) years. 412 (7%) of 6241 participants were diagnosed with prediabetes on the basis of the HbA1c 5·7–6·4% criterion. Screening by HbA1c alone missed 1270 (61%) of the 2092 prediabetic individuals diagnosed by a combination of impaired fasting glucose and HbA1c 5·7–6·4%. Overall cumulative probability of progression to diabetes did not differ significantly between participants with prediabetes discordantly diagnosed by either HbA1c or impaired fasting glucose alone (incidence was 7% for HbA1c alone n=412 individuals and 30 incident cases and 9% for impaired fasting glucose alone n=1270, 108 cases; log-rank test, p=0·3317). Multivariate-adjusted hazard ratios for incident diabetes were 6·16 (95% CI 4·33–8·77) for those diagnosed with prediabetes by impaired fasting glucose alone and 6·00 (3·76–9·56) for diagnosis by HbA1c alone, and were substantially increased to 31·9 (22·6–45·0) for diagnosis by both impaired fasting glucose and HbA1c compared with normoglycaemic individuals. Interpretation Diagnosis of prediabetes by both the new HbA1c criterion and impaired fasting glucose identified individuals with an increased risk of progression to diabetes. Although the new HbA1c criterion identified fewer individuals at high risk than did impaired fasting glucose, the predictive value for progression to diabetes assessed by HbA1c 5·7–6·4% was similar to that assessed by impaired fasting glucose alone. The two tests used together could efficiently target people who are most likely to develop diabetes and allow for early intervention. Funding Japan Society for the Promotion of Science; Ministry of Health Labor and Welfare, Japan.
Background The prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms is still an important problem. Objective To investigate the efficacy and safety of a shielding ...method that uses polyglycolic acid (PGA) sheets and fibrin glue to prevent post-ESD bleeding in high-risk patients. Design A nonrandomized trial with historical control subjects. Setting A single academic hospital in Japan. Patients From July 2013 to February 2014, 45 ESD-induced ulcers in 41 patients with a high risk of bleeding were enrolled in a study group. Forty-one consecutive ESD-induced ulcers in 37 control subjects with a high risk of bleeding were treated in 2013 before the first enrollment. Interventions We placed PGA sheets on the mucosal defect and fixed with fibrin glue in the study group. Main Outcome Measurements The post-ESD bleeding rate. Results The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups ( P = .041). Limitations A nonrandomized trial with historical control subjects; a single-center analysis; small sample size. Conclusions The endoscopic tissue shielding method with PGA sheets and fibrin glue appears to be promising for the prevention of post-ESD bleeding. (Clinical trial registration number: UMIN000011058 .)
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