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To explore the differences among grades of recanalization on outcomes of endovascular treatment for acute anterior large vessel occlusion with small infarct core beyond the 6-hour time window. Patients beyond the 6-hour time window with Alberta Stroke Program Early Computed Tomography Score >7 were retrospectively enrolled from the endovascular treatment for acute anterior circulation ischemic stroke (ACTUAL) registry. They were divided into 3 groups according to the degree of recanalization: modified treatment in cerebral infarction (mTICI) 0–2a, 2b, and 3. We compared the differences of outcomes among groups on modified Rankin Scale score at 90 days, symptomatic intracerebral hemorrhage within 72 hours, and mortality. A total of 101 patients were enrolled. Median time from onset to groin puncture was 415 minutes (interquartile range: 387–497 minutes). Favorable functional outcomes were significantly better in patients with successful recanalization than in patients with failed recanalization (mTICI 0–2a, 22.7% [5/22]; mTICI 2b, 48.0% [12/25]; and mTICI 3, 61.1% [33/54]; trend P = 0.01). Complete recanalization (mTICI 3) (odds ratio, 5.34; 95% confidence interval, 1.71–16.66; P = 0.004) was associated with good functional outcome. Mortality was different among groups at 90 days (mTICI 0–2a, 36.4% [8/22]; mTICI 2b, 0, [0/25]; P = 0.001; mTICI 0–2a, 36.4% [8/22]; mTICI 3, 9.3% [5/54]; P = 0.008; and mTICI 2b, 0, [0/25]; mTICI 3, 9.3% [5/54]; P = 0.173). There were no significant differences of symptomatic intracranial hemorrhage among groups (mTICI 0–2a, 22.7% [5/22]; mTICI 2b, 12.0% [3/25]; and mTICI 3, 9.3% [5/54]; P = 0.28). For acute anterior circulation stroke patients, who were beyond the 6-hour time window, yet with small ischemic core, complete recanalization following endovascular treatment may play the most important role on clinical outcome. [ABSTRACT FROM AUTHOR]

Oxidative stress plays an important role in the progression of cardiac diseases, including ischemia/reperfusion injury, myocardial infarction, and heart failure. Growing evidence indicates that cabbage has various pharmacological properties against a wide range of diseases, such as cardiovascular diseases, hepatic diseases, and cancer. However, little is known about its effects on oxidative stress in cardiomyocytes or the underlying mechanisms. Therefore, the present study examined the effects of cabbage extract on oxidative stress in H9c2 cardiomyoblasts. Cell viability, reactive oxygen species (ROS) production, apoptosis, mitochondrial functions, and expression levels of mitogen-activated protein kinase (MAPK) proteins were analyzed to elucidate the antioxidant effects of this extract. Cabbage extract protected against H2O2-induced cell death and did not elicit any cytotoxic effects. In addition, cabbage extract suppressed ROS production and increased expression of antioxidant proteins (SOD-1, catalase, and GPx). Cabbage extract also inhibited apoptotic responses and activation of MAPK proteins (ERK1/2, JNK, and p-38) in oxidative stress-exposed H9c2 cells. Notably, cabbage extract preserved mitochondrial functions upon oxidative stress. These findings reveal that cabbage extract protects against oxidative stress and suggest that it can be used as an alternative therapeutic strategy to prevent the oxidative stress in the heart. [ABSTRACT FROM AUTHOR]

Chronic constipation is a functional gastrointestinal disease that is detrimental to the quality of patient life. Cassia obtusifolia L. (CO) and Foeniculum vulgare M. (FV) are commonly used as medicinal foods in many countries. We aimed to examine the laxative effect and their underlying mechanism of CO and FV mixture on loperamide (lop)-induced constipated rats. To determine the laxative effects of these compounds, Sprague-Dawley rats were divided into six groups: the control, lop-induced constipated (2mg/kg), and three doses (100, 300, and 500mg/kg) of CO and FV mixture-, and Bisacodyl (bis, 3.3mg/kg)-treated groups. The mixture of CO and FV and bis were orally administered once a day for 4 weeks. For induction of constipation, the lop were treated with a dose of 2 mg/kg twice a day on the 3rd week after treatments of CO and FV extracts and bis. The results were revealed that the CO and FV mixture has the laxative effects more than those in CO and FV-alone treatments on constipated rats by determining the stool parameters, including stool number and weight. Indeed, stool parameters, such as, stool number, weight, and water contents and colonic peristalsis from the intestinal transit length and ratio were dramatically improved by CO and FV mixture treatment. Histological study also revealed that CO and FV mixture enhanced the thicknesses of mucosa and muscular layers of the colon in constipated rats. For their underlying mechanism, the mRNAs and proteins expression of muscarinic acetylcholine receptors (mAchR) M2 and M3 and their downstream signaling were preserved by CO and FV mixture treatment in constipated rats. Therefore, this study suggests that treatment with CO and FV mixture has beneficial effects against constipation. We further suggest that CO and FV mixture may be utilized as an alternative therapeutic strategy for constipation. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery.Methods: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded.Results: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS ≥70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process.Conclusions: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities. [ABSTRACT FROM AUTHOR]

Central serous chorioretinopathy (CSCR) is a challenging disease characterized by subretinal serous fluid accumulation. The complex pathogenesis is still not fully understood, but is thought to be multifactorial and involves exogenous and endogenous factors affecting the choroid and retinal pigment epithelium. The involvement of corticosteroids is undisputed, while the contribution of mineralocorticoid pathways is under investigation. This review addresses the proposed pathogenesis models and the evidence for systemic treatment of CSCR with mineralocorticoid antagonists. [ABSTRACT FROM AUTHOR]

Objective To evaluate how different methods for storage and preservation of urine samples affected the outcome of analysis of risk factors for stone formation. Methods Spot urine samples were collected from 21 healthy volunteers. Each fresh urine sample was divided into ten 10-mL aliquots: 2 without preservative, 2 with thymol, 2 with toluene, 2 with hydrochloric acid (HCl), and 2 with sodium azide. One sample of each pair was stored at 4°C and the other at room temperature. The concentrations of calcium, magnesium, sodium, phosphate, urate, oxalate, citrate, and pH in each urine sample were analyzed immediately after collection (0 hour) and after 24 and 48 hours. Results There were no significant differences in calcium, oxalate, magnesium, phosphate, sodium, urate or pH (without acidification) between samples with different preservation methods ( P >.05). Urinary citrate, however, was significantly lower in the urine collected with HCl than when other preservatives were used, both at room temperature and at 4°C. Urine pH was significantly higher after 48 hours than after 24 hours, whether the samples were stored at room temperature or at 4°C. Conclusion Antibacterial preservatives (eg, thymol or toluene) can be recommended as preservatives for 24-hour urine collections. Ideally, the samples should be stored at 4°C. When HCl is used as a preservative, it seems essential to neutralize the samples before analysis. This is particularly obvious with the chromatographic method used for analysis of citrate that was used in this study. [ABSTRACT FROM AUTHOR]

Background: In this prospective cohort study, we evaluated features of "adult‐onset megacolon with focal hypoganglionosis." Methods: We assessed the radiologic, endoscopic, and histopathologic phenotyping and treatment outcomes of 29 patients between 2017 and 2020. Data from community controls, consisting of 19,948 adults undergoing health screenings, were analyzed to identify risk factors. Experts reviewed clinical features and pathological specimens according to the London Classification for gastrointestinal neuromuscular pathology. Key results: The median age of the patients with adult‐onset megacolon with focal hypoganglionosis at symptom onset was 59 years (range, 32.0–74.9 years), with mean symptom onset only 1 year before diagnosis. All patients had focal stenotic regions with proximal bowel dilatation (mean diameter, 78.8 mm; 95% confidence interval [CI], 72–86). The comparison with community controls showed no obvious risk factors. Ten patients underwent surgery, and all exhibited significant hypoganglionosis: 5.4 myenteric ganglion cells/cm (interquartile range [IQR], 3.7–16.4) in the stenotic regions compared to 278 cells/cm (IQR, 190–338) in the proximal and 95 cells/cm (IQR, 45–213) in the distal colon. Hypoganglionosis was associated with CD3+ T cells along the myenteric plexus. Colectomy was associated with significant symptom improvement compared to medical treatment [change in the Global Bowel Satisfaction score, −5.4 points (surgery) vs. ‐0.3 points (medical treatment); p < 0.001]. Conclusions and inferences: Adult‐onset megacolon with focal hypoganglionosis has distinct features characterized by hypoganglionosis due to inflammation. Bowel resection appears to benefit these patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationships between the Controlling Nutritional Status (CONUT) score and ascites fluid lactate dehydrogenase (LDH) level, and prognosis in patients with malignant peritoneal mesothelioma (MPeM). Methods: A total of 125 patients with MPeM were selected for the study using a pathological screening method. Once the diagnosis is established, before the treatment their clinical characteristics and nutritional evaluations were recorded including CONUT score and ascites LDH level. The associations between CONUT, ascites LDH, and other clinicopathological features including body mass index, asbestos exposure, pathological type, and treatment method were analyzed. Prognostic parameters predicting overall survival (OS) were analyzed by Cox regression. Results: High CONUT score, high ascites LDH level were positively associated with poor prognosis in patients with MPeM according to univariate analyses (P < 0.001, P < 0.001, respectively), and CONUT score and ascites LDH were independent predictors of a poor prognosis according to multivariate analysis. When the CONUT score is greater than 3 and the ascites LHD is greater than 474 IU/l, it indicates a poor prognosis. Conclusions: CONUT score and ascites LDH are important factors influencing the prognosis of MPeM patients and should thus be considered in clinical applications. [ABSTRACT FROM AUTHOR]

Backgrounds: To preliminary evaluate the application of novel SaCoVLM video laryngeal mask -guided intubation for anesthetized children. Methods: One hundred twenty-four children with microtia (ages 5-15 years,) who required general intubation anaesthesia, were enrolled in the study. After induction of general anesthesia,guided tracheal intubation under direct vision of the SaCoVLM was performed. Our primary outcome was first-pass success rate of guided tracheal tube placement. Secondary outcome included glottic visualization grades, the first-attempt success rate of LMA placement, the time for LMA placement and time to endotracheal intubation as well as the time for LMA removal after successful intubation, the fiberoptic grade of laryngeal view, the baseline and postinduction hemodynamic parameters were also recorded,and the incidence 24 h complications after operation. Results: The first-pass success rate of guided tracheal tube placement was 91.1% (95%CI = 1.04–1.14), the status of glottic visualization was classified: grade 1 in 27cases, grade 2 in 36 cases, grade 3 in 41 cases and grade 4 in 20 cases. The first success rate of LMA placement was 92.7% (95%CI = 1.03–1.13), the time for LMA insertion was 15.7 (±9.1) s, intubation time was 30.9 (±17.6) s and withdrawl time was 24.9 (±9.3) s. The incidence of postoperative sore throat at 2 h was 29%, and 16.1% at 24 h, without dysphagia and hypoxia. Conclusion: The SaCoVLM video laryngeal mask-guided intubation is feasible in children, with a high success rate, could be a new promising device to guide intubation in airway management. Trial registration: This study was approved by the University's Institutional Review Board and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (ChiCTR2200061481, http://www.chictr.org.cn. Principal investigator: Juan Zhi; Date of registration: 26/06/2022. [ABSTRACT FROM AUTHOR]

The current study aims to identify the pathogenic sites in a core pedigree of Usher syndrome (USH). A core pedigree of USH was analyzed by whole exome sequencing (WES). Mutations were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing. Two pathogenic variations (c.849+2T>C and c.5994G>A) in MYO7A were successfully identified and individually separated from parents. One variant (c.849+2T>C) was nonsense mutation, causing the protein terminated in advance, and the other one (c.5994G>A) located near the boundary of exon could cause aberrant splicing. This study provides a meaningful exploration for identification of clinical core genetic pedigrees. [ABSTRACT FROM AUTHOR]

The availability of a large quantity of MSCs (mesenchymal stem cells) would greatly advance liver-directed cell therapies. However, MSCs have a limited lifespan in vitro. Therefore we tested whether hUCMSCs (human umbilical cord MSCs) could be immortalized by transduction with a lentiviral vector carrying the hTERT (human telomerase reverse transcriptase) catalytic subunit gene, and investigated their differentiation potential. Transfected hUCMSCs overexpressed the hTERT gene and up-regulated their telomerase activity. The transfected hUCMSCs maintained their typical morphology and MSC-specific markers, and vigorously proliferated, undergoing more than 100 PDs (population doublings) to date. Following incubation with hepatogenic agents, the transfected hUCMSCs differentiated into hepatocyte-like cells, and expressed hepatic markers, such as albumin, AFP (α-fetoprotein) and CK-18 (cytokeratin-18). Transfected hUCMSCs showed no transformation into tumours in nude mice. In conclusion, telomerization of hUCMSCs by hTERT overexpression extends their replicative lifespan without influencing their hepatogenic differentiation potential. This offers opportunities for obtaining sufficient quantities of cells for liver-directed therapies. [ABSTRACT FROM AUTHOR]

Background: Previous randomised trials have shown an overwhelming benefit of mechanical thrombectomy for treating patients with stroke caused by large vessel occlusion of the anterior circulation. Whether endovascular treatment is beneficial for vertebrobasilar artery occlusion remains unknown. In this study, we aimed to investigate the safety and efficacy of endovascular treatment of acute strokes due to vertebrobasilar artery occlusion.Methods: We did a multicentre, randomised, open-label trial, with blinded outcome assessment of thrombectomy in patients presenting within 8 h of vertebrobasilar occlusion at 28 centres in China. Patients were randomly assigned (1:1) to endovascular therapy plus standard medical therapy (intervention group) or standard medical therapy alone (control group). The randomisation sequence was computer-generated and stratified by participating centres. Allocation concealment was implemented by use of sealed envelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 or lower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treat basis. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial haemorrhage, device-related complications, and other severe adverse events. The BEST trial is registered with ClinicalTrials.gov, NCT02441556.Findings: Between April 27, 2015, and Sept 27, 2017, we assessed 288 patients for eligibility. The trial was terminated early after 131 patients had been randomly assigned (66 patients to the intervention group and 65 to the control group) because of high crossover rate and poor recruitment. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0-3 at 90 days according to treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of 65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81-3·74). Secondary prespecified analyses of the primary outcome, done to assess the effect of crossovers, showed higher rates of mRS 0-3 at 90 days in patients who actually received the intervention compared with those who received standard medical therapy alone in both per-protocol (28 [44%] of 63 patients with intervention vs 13 [25%] of 51 with standard therapy; adjusted OR 2·90, 95% CI 1·20-7·03) and as-treated (36 [47%] of 77 patients with intervention vs 13 [24%] of 54 with standard therapy; 3·02, 1·31-7·00) populations. The 90-day mortality was similar between groups (22 [33%] of 66 patients in the intervention vs 25 [38%] of 65 in the control group; p=0·54) despite a numerically higher prevalence of symptomatic intracranial haemorrhage in the intervention group.Interpretation: There was no evidence of a difference in favourable outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone. Results might have been confounded by loss of equipoise over the course of the trial, resulting in poor adherence to the assigned study treatment and a reduced sample size due to the early termination of the study.Funding: Jiangsu Provincial Special Program of Medical Science. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD), a liver function disorder caused by excessive alcohol intake, is a serious threat to global public health and social development. Toxic metabolites and reactive oxygen species produced during the metabolism of alcohol can alter the epigenetic state including DNA methylation, histone modifications, and expression of microRNAs. Epigenetic alterations can conversely involve various signaling pathways, which could contribute to the initiation and progression of ALD. To elucidate the relationship between epigenetic alterations and alcohol damage not only reinforces our understanding on pathogenesis of ALD, but also provides novel targets for clinical diagnosis, treatment, and drug research of ALD. In this review, we have summarized the research progress of epigenetic alterations and related mechanisms caused by alcohol in the pathogenesis of ALD. Considering the invertibility of epigenetic alterations, treatment of ALD through epigenetic modification with common less harmful compounds is also related. [ABSTRACT FROM AUTHOR]

The bleomycins (BLMs) belong to a subfamily of glycopeptide antibiotics and are clinically applied in combination chemotherapy regimens to treat various malignancies. But the therapeutic applications of BLMs are restricted by the accompanied dose-dependent lung toxicity and potential incidence of lung fibrosis. Many efforts have been devoted to develop novel BLM analogues, for seeking of drug leads with improved antitumor activity and/or reduced lung toxicity. The progresses in the biosynthetic studies of BLMs have greatly expedited the process to achieve such goals. This review highlights the discovery and development of microbial BLM analogues in the past two decades, especially those derived from engineered biosynthesis. Moreover, the summarized structure-activity relationship, which is specifically focusing on the sugar moiety, shall shed new insights into the prospective development of BLM analogues. [ABSTRACT FROM AUTHOR]

This study aims to investigate the role of transcutaneous neuromodulation (TN) on the regulation of gastrointestinal hormones and bile acids in patients with functional constipation (FC). Twenty FC patients were treated with TN for four weeks. The effects of TN on symptoms were evaluated by questionnaires. Plasma levels of serotonin (5-HT), motilin, somatostatin, and vasoactive intestinal peptide (VIP) were measured by ELISA and 12 individual bile acids assayed by liquid chromatography tandem mass spectrometry. Results were as follows. (1) TN treatment increased the frequency of spontaneous bowel movement, improved the Bristol Stool Score, and reduced Patient Assessment of Constipation Symptom score and Patient Assessment of Constipation Quality of Life score. (2) FC patients showed decreased plasma levels of 5-HT, motilin, and VIP and an increased plasma level of somatostatin (P<0.05). Four-week TN treatment increased plasma levels of 5-HT and motilin and decreased the plasma level of somatostatin in the FC patients (P<0.05). (3) Taurocholic deoxycholate, taurocholic acid, and taurocholic lithocholic acid were increased in the FC patients (P<0.005) but reduced by TN treatment (P<0.05). This study has suggested that the therapy may improve the symptoms of FC by alleviating the disorders of gastrointestinal hormones and bile acids. [ABSTRACT FROM AUTHOR]

Previous reports, including our experimental results, showed that macrophages migrate to prostate cancer (PCa) cells. We tested whether the migrated macrophages affect the susceptibility of castration-resistant PCa (CRPC) cells to cytotoxic actions of natural killer (NK) cells. We found treatment of tumor cells with the conditioned media (CM) of the PMA/IL-4 treated THP-1 cells (M2 type macrophages) (THP-1 CM) decreased the susceptibility of tumor cells to NK cell cytotoxicity, as a result of increased programmed death receptor ligand 1 (PD-L1) and decreased NK group 2D (NKG2D) ligands in CRPC cells. Meanwhile, the decreased susceptibility of tumor cells was also detected when NK cells were treated with THP-1 CM and used in NK cell cytotoxicity tests. Therefore, we observed higher resistance of CRPC cells when both tumor and NK cells were treated with THP-1 CM than when tumor cells or NK cells were individually treated. We further discovered that the PMA/IL-4 treated THP-1 cells secrete a high level of IL-6, so blocking the IL-6 action significantly decreased the PD-L1 level while recovering the NKG2D ligands, thus increasing the susceptibility of CRPC cells to NK cell action. Moreover, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling in triggering the THP-1 CM effect. Consequently, we found the susceptibility of CRPC cells to NK cells was increased when either JAK or Stat 3 inhibitor was added when tumor cells were treated with THP-1 CM, and that the best effect was observed when the JAK inhibitor and PD-L1 Ab were added together. [ABSTRACT FROM AUTHOR]

Background. Although immunomodulators are increasingly used in Crohn’s disease (CD), a significant number of gastroenterologists still use 5-aminosalicylate (5-ASA) in combination with azathioprine (AZA) or 6-mercaptopurine (6-MP); there is limited evidence regarding the benefit of concomitant 5-ASA with AZA/6-MP compared with AZA/6-MP monotherapy for the treatment of CD. Study Design. A total of 106 patients who received AZA/6-MP for more than 3 months between January 1991 and May 2014 were identified retrospectively. Each patient was matched with 3 randomly selected controls who were treated with concomitant therapy during the same period. Results. The cumulative probabilities of steroid use at 5 and 10 years were 24.9% and 75.8% in the 5-ASA + AZA/6-MP group and 31.2% and 87.8% in the AZA/6-MP group, respectively (P=0.187). The cumulative probabilities of anti-TNF use, resectional surgery, and disease-related hospitalization were comparable between the groups. The younger age and the use of lower doses of immunomodulators were associated with higher requirement of rescue therapy. Conclusions. This study did not demonstrate that the concomitant use of 5-ASA with AZA/6-MP showed the proof or effect in terms of steroid requirements, anti-TNF use, resectional surgery, or disease-related hospitalization compared with that of AZA/6-MP alone. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a serious threat for the aging society. In this study, we examined the preventive effect of the total prenylflavonoids (TPFB) prepared from the dried fruits of Psoralea corylifolia L., using an age-related AD mouse model SAMP8. We found that long-term dietary TPFB at 50 mg/kg·day significantly improved cognitive performance of the SAMP8 mice in Morris water maze tests, similar to 150 mg/kg·day of resveratrol, a popular neuro-protective compound. Furthermore, TPFB treatment showed significant improvements in various AD markers in SAMP8 brains, which were restored to near control levels of the normal mice, SAMR1. TPFB significantly reduced the level of amyloid β-peptide 42 (Aβ42), inhibited hyperphosphorylation of the microtubule-associated protein Tau, induced phosphorylation of Ser9 of the glycogen synthase kinase 3β (GSK-3β), and decreased the expression of the proinflammatory cytokines TNFα, IL-6, and IL-1β. Finally, TPFB also markedly reduced the level of serum derivatives of reactive oxygen metabolites (d-ROMs), a biomarker of oxidative stress in vivo. These results showed that dietary TPFB could effectively prevent age-related cognitive deficits and AD-like neurobiochemical changes, and may have a potential role in the prevention of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Globus pharyngeus is common and has a low cure rate. Its etiology is complex and reported to be associated with laryngopharyngeal reflux (LPR). However, some patients with globus do not exhibit any reflux symptoms or respond to proton pump inhibitors (PPIs) treatments. The purpose of this study was to clarify the related risk factors of these patients with a final objective of improving the curative effect.Methods: Forty two patients afflicted with globus pharyngeus (G group) and 38 patients without globus pharyngeus (NG group) were included in this study. According to the laryngopharyngeal Reflux Symptom Index and the response to PPIs treatments, the patients were further divided into reflux groups (G-R, NG-R) and non-reflux groups (G-NR, NG-NR). High Resolution Manometry (HRM) was performed to assess esophageal motility. Questionnaires, including categories such as life exposure factors, were conducted.Results: a) The average resting and residual pressures of the upper esophageal sphincter (UES) in the G-NR group was higher than in the NG-NR and NG-R groups (P < 0.05). b) The average resting and residual pressures of the lower esophageal sphincter showed no differences between the G-NR group and the NG-NR group (P > 0.05). c) The esophageal distal contractile integral score of the G-NR group was not different from the NG-NR group (P > 0.05). d) Compared to the NG-NR group, the G-NR group showed higher incidence of stress, smoking, drinking, high salt and anxiety (P < 0.05).Conclusions: Globus pharyngeus without LPR may occur due to high UES pressure. Stress, smoking, alcoholic drinking, high salt and anxiety may be its risk factors. [ABSTRACT FROM AUTHOR]

Background: Incidence of and risk factors for intestinal free perforation (FP) in patients with Crohn's disease (CD) are not established.Aim: To establish rate of and risk factors for FP in a large cohort of CD patients.Methods: Medical records of CD patients who visited Asan Medical Center from June 1989 to December 2012 were reviewed. After matching the FP patients to controls (1:4) by gender, year, and age at CD diagnosis, and disease location, their clinical characteristics were compared using conditional logistic regression analysis.Results: Among 2043 patients who were included in our study cohort, 44 patients (2.15%) developed FP over a median follow-up period of 79.8 months (interquartile range 37.3-124.6), with an incidence of 3.18 per 1000 person-years [95% confidence interval (CI) 2.37-4.28]. All 44 patients underwent emergency surgery, and eight patients underwent reoperation within 12 months (8/44, 18.2%). Multivariable-adjusted analysis revealed that anti-TNF therapy [odds ratio (OR), 3.73; 95% CI 1.19-11.69; p = 0.024] was associated with an increased risk of FP.Conclusions: The incidence of FP in a large cohort of Korean CD patients was 2.15%, which was similar to that in Western reports. Anti-TNF therapy could be risk factors for FP. [ABSTRACT FROM AUTHOR]

Noise exposure has been well characterized as an environmental stressor, and is known to have auditory and non-auditory effects. Phosphodiesterase 5 (PDE5) inhibitors affect memory and hippocampus plasticity through various signaling cascades which are regulated by cGMP. In this study, we investigated the effects of sildenafil on memory deficiency, neuroprotection and oxidative stress in mice caused by chronic noise exposure. Mice were exposed to noise for 4 h every day up to 14 days at 110 dB SPL of noise level. Sildenafil (15 mg/kg) was orally administered 30 min before noise exposure for 14 days. Behavioral assessments were performed using novel object recognition (NOR) test and radial arm maze (RAM) test. Higher levels of memory dysfunction and oxidative stress were observed in noise alone-induced mice compared to control group. Interestingly, sildenafil administration increased memory performance, decreased oxidative stress, and increased neuroprotection in the hippocampus region of noise alone-induced mice likely through affecting memory related pathways such as cGMP/PKG/CREB and p25/CDK5, and induction of free radical scavengers such as SOD1, SOD2, SOD3, Prdx5, and catalase in the brain of stressed mice. [ABSTRACT FROM AUTHOR]

Background: Effective treatments to alleviate depression in Alzheimer's disease (AD) have been scarce.Objective: To investigate the efficacy and tolerability of escitalopram in the treatment of depression in AD.Methods: In this 12-week randomized, double-blind, placebo-controlled trial with open-label, 12-week extension, AD subjects over 50 years of age, with depression defined by Olin's provisional diagnostic criteria, were enrolled. The Cornell Scale for Depression in Dementia (CSDD), and other measures of depression and cognition were repeated.Results: 91 subjects were screened, and 84 were randomized into either the study group or placebo group (n = 42 for both groups). Twenty-four subjects (29%) were unable to finish the study, yielding a per protocol population of 60 subjects (study group: n = 27; placebo group: n = 33). At week 12, differences in measures of depression and cognition between the two groups were not statistically significant. However, exploratory analysis suggested that further research on a subset of subjects with 'definite major depression' (baseline CSDD score ≥18) is needed. The number of treatment-related adverse-events (AE) did not differ between groups (p = 0.83) and no serious treatment-related AE were observed.Conclusion: The use of escitalopram was well tolerated in depressive dementia patients. Future studies focusing on subjects with more severe levels of depression, and with more statistical power, will be needed. [ABSTRACT FROM AUTHOR]

Background: The recurrence rate after standard cold forceps polypectomy (CFP) of diminutive polyps of ≤5 mm has not been fully determined. The aim of this study was to analyze the long-term follow-up results and recurrence rate after CFP of diminutive polyps.Methods: We retrospectively reviewed the medical records of 884 (738 men; age 53 years) asymptomatic subjects who underwent surveillance colonoscopy after CFP of 1-2 diminutive adenomatous polyps. Cumulative recurrence at the CFP site and risk factors for recurrence were analyzed.Results: Overall recurrence over 59.7 months was 17 % after CFP of 1111 diminutive polyps. The rate of definite recurrence was 4 %, and probable recurrence was 13 %. Recurrence as advanced adenoma was 0.5 % (5/1111). The cumulative probabilities of recurrence at 3, 5, and 7 years after CFP were 10.0, 16.0, and 21.1 %, respectively. Multivariate analysis revealed that polyp 4-5 mm in size and right colonic polyp were risk factors for recurrence (hazard ratio [HR] 1.37; 95 % confidence interval [CI] 1.01-1.86 and HR 1.49; 95 % CI 1.08-2.04, respectively). The recurrence rate for 10 endoscopists who performed at least 50 CFPs ranged from 11.0 to 25.2 %; the probability of recurrence in those in the top half in terms of recurrence rate was 1.6-fold higher than that of those in the bottom half (95 % CI 1.17-2.19).Conclusions: Although recurrence may develop after standard CFP of diminutive polyps, recurrence as advanced adenoma is rare. Large polyp size, right colon polyp, and endoscopist are risk factors for recurrence after standard CFP. [ABSTRACT FROM AUTHOR]

Background and Objective: Combination therapy is recommended for the effective management of hypertension according to most treatment guidelines, including those of the US Joint National Committee. Therefore, pharmacokinetic drug interactions are an important issue in combination therapy for hypertension. In this study, the pharmacokinetic properties of telmisartan and chlorthalidone were evaluated to investigate their pharmacokinetic interactions in healthy subjects. Methods: Two separate, randomized, multiple-dose, two-period, one-sequence studies were conducted. In study A, 43 participants received 80 mg of telmisartan orally for 7 days, and were then administered oral chlorthalidone 25 mg for 14 days (days 8-21), coadministered with 80 mg of telmisartan from day 15. In study B, 14 participants received oral chlorthalidone (25 mg) for 13 days, followed by coadministration with 80 mg of telmisartan orally for 7 days. Results: The geometric mean ratios (GMRs) (90 % confidence intervals [CIs]) of the maximum plasma concentration ( C ) and area under the concentration-time curve for the dosing interval at steady state (AUC) of telmisartan (with and without chlorthalidone) were 1.018 (0.861-1.203) and 1.099 (1.015-1.190), respectively. For chlorthalidone (with/without telmisartan), the GMRs (90 % CIs) for C and AUC were 0.996 (0.922-1.075) and 0.992 (0.925-1.064), respectively. The GMRs and 90 % CIs for telmisartan and chlorthalidone were all within the 0.80-1.25 range. Conclusion: Thus, in this study, there was no significant pharmacokinetic interaction between telmisartan and chlorthalidone. ClinicalTrial.gov identifier: NCT01806363. [ABSTRACT FROM AUTHOR]

Background and Aims: To date, no large-scale studies have evaluated long-term outcomes of infliximab (IFX) treatment in Korean patients with Crohn's disease (CD).Methods: We analyzed long-term clinical responses to IFX in 582 Korean CD patients who received scheduled IFX treatments at Asan Medical Center. Clinical responses were defined as maintaining IFX without major abdominal surgery (MAS) or dose intensification.Results: Between February 2002 and July 2015, a total of 11,990 IFX infusions were administered to 582 Korean patients with CD over a median period of 36 months. At the end of follow-up, 316 (54.3 %) were still receiving IFX without MAS (71 patients, 12.2 %) or dose intensification (86 patients, 14.8 %). IFX was stopped in 109 (18.7 %) patients because of a loss of response (48 patients, 8.2 %), adverse events (30 patients, 5.2 %), or patient preferences or problems with reimbursement (31 patients, 5.3 %). The cumulative survival for maintenance of IFX without MAS or dose intensification was 89.0, 75.9, 68.3, and 50.8 % at 1, 2, 3, and 5 years, respectively. Multivariate regression analysis identified older age at the initiation of IFX (≥40 years, P = 0.006) and a longer disease duration (≥3 years, P = 0.020) as independent positive predictors of a poorer response to IFX.Conclusions: The long-term efficacy of IFX in a large, real-life cohort of Korean patients with CD appears to be similar to that in previously published Western studies. Our findings support the early use of IFX to obtain better clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Hexokinase-2 (HK2) and Beta2-adrenergic receptor (Beta2AR) are overexpressed in hepatocellular carcinoma (HCC) tissues and associated with poor prognosis. However, the synergistic effect of HK2 and Beta2AR in HCC prognosis is not elucidated. The present study aims to investigate the association between HK2 and Beta2AR expressions in HCC tissues, and to evaluate the synergistic effect of HK2 and Beta2AR in HCC prognosis.Methods: Immunohistochemistry of HK2 and Beta2AR was performed on 155 paraffin embedded HCC samples retrieved from the archives of pathology department. Corresponding clinical data and prognostic data were collected through searching medical record systems, death registration systems and interviews with patient families. Spearman correlation test was performed to evaluate the association between HK2 and Beta2AR expression. Kaplan-Meier survival curves and Cox regressions were employed to evaluate HK2 and Beta2AR expression in HCC prognosis, respectively and synergistically.Results: 109 of 155 HCC patients reached the death point, the survival time of HCC patients was 46.23 ± 31.01 months after curative surgical resections of HCC. Kaplan-Meier survival analysis showed that large tumor size (more than 5 cm) (hazard ratio (HR) = 8.42, 95 % confidence interval (CI) = 3.81-18.59, P < 0.0001), advanced TNM stage (III and IV stages) (HR = 2.09, 95%CI = 1.21-3.62, P < 0.001) and AFP more than 20 μg/L (HR = 1.49, 95%CI = 1.02-2.18, P = 0.0302) were predictors for poor prognosis. HK2 and Beta2AR positive expression was detected in 66 (42.58) and 122 (78.71 %) HCC samples respectively. In univariate analysis, HK2(+) (HR = 2.70, 95%CI = 1.76-4.15, P < 0.0001) and Beta2AR(+) (HR = 4.61, 96%CI = 3.14-6.76, P < 0.0001) were associated with poor prognosis. In multivariate analysis, HK2(+) (P < 0.0001) and Beta2AR(+) (P < 0.0001) were also associated with poor prognosis. HK2(+)/Beta2AR(+) in HCC samples had poorer prognosis compared with HK2(-)/Beta2AR(-) in both univariate analysis (HR = 4.69, 95%CI = 2.91-7.57, P < 0.0001) and multivariate analysis (P < 0.0001). HK2(+)/Beta2AR(+) in HCC samples had poorer prognosis compared with HK2(-)/Beta2AR(+) in both univariate analysis (HR = 1.76, 95%CI = 1.17-2.64, P = 0.003) and multivariate analysis (P = 0.004).Conclusion: HK2 and Beta2AR play important roles in HCC progression. HK2 and Beta2AR expression in HCC is correlated positively. Beta2AR may increase HCC invasion and metastasis in collaboration with HK2. HK2 and Beta2AR can predict HCC prognosis both independently and synergistically. [ABSTRACT FROM AUTHOR]

Aims Neuroimaging studies have demonstrated both structural and functional abnormalities in widespread brain regions in patients with subcortical vascular mild cognitive impairment (sv MCI). However, whether and how these changes alter functional brain network organization remains largely unknown. Methods We recruited 21 patients with sv MCI and 26 healthy control ( HC) subjects who underwent resting-state functional magnetic resonance imaging scans. Graph theory-based network analyses were used to investigate alterations in the topological organization of functional brain networks. Results Compared with the HC individuals, the patients with sv MCI showed disrupted global network topology with significantly increased path length and modularity. Modular structure was also impaired in the sv MCI patients with a notable rearrangement of the executive control module, where the parietal regions were split out and grouped as a separate module. The sv MCI patients also revealed deficits in the intra- and/or intermodule connectivity of several brain regions. Specifically, the within-module degree was decreased in the middle cingulate gyrus while it was increased in the left anterior insula, medial prefrontal cortex and cuneus. Additionally, increased intermodule connectivity was observed in the inferior and superior parietal gyrus, which was associated with worse cognitive performance in the sv MCI patients. Conclusion Together, our results indicate that sv MCI patients exhibit dysregulation of the topological organization of functional brain networks, which has important implications for understanding the pathophysiological mechanism of sv MCI. [ABSTRACT FROM AUTHOR]

Background: The usefulness of the 2013 ACC/AHA guidelines for the management of blood cholesterol in the Asian population remains controversial. In this study, we investigated whether eligibility for statin therapy determined by the 2013 ACC/AHA guidelines is better aligned with the presence of subclinical coronary atherosclerosis detected by CCTA (coronary computed tomography angiography) compared to the previously recommended 2004 NCEP ATP III guidelines. Methods: We collected the data from 5,837 asymptomatic subjects who underwent CCTA using MDCT during routine health examinations. Based on risk factor assessment and lipid data, we determined guideline-based eligibility for statin therapy according to the 2013 ACC/AHA and 2004 NCEP ATP III guidelines. We defined the presence and severity of subclinical coronary atherosclerosis detected in CCTA according to the presence of significant coronary artery stenosis (defined as >50% stenosis), plaques, and the degree of coronary calcification. Results: As compared to the 2004 ATP III guidelines, a significantly higher proportion of subjects with significant coronary stenosis (61.8% vs. 33.8%), plaques (52.3% vs. 24.7%), and higher CACS (CACS >100, 63.6% vs. 26.5%) was assigned to statin therapy using the 2013 ACC/AHA guidelines (P < .001 for all variables). The area under the curves of the pooled cohort equation of the new guidelines in detecting significant stenosis, plaques, and higher CACS were significantly higher than those of the Framingham risk calculator. Conclusions: Compared to the previous ATP III guidelines, the 2013 ACC/AHA guidelines were more sensitive in identifying subjects with subclinical coronary atherosclerosis detected by CCTA in an Asian population. [ABSTRACT FROM AUTHOR]

Multidrug resistance proteins (MRP2, ABCC2) may play a role in drug resistance in epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). We sought to investigate the effects of ABCC2 polymorphisms on plasma carbamazepine (CBZ) concentrations and pharmacoresistance in Chinese patients with epilepsy. ABCC2 rs717620, rs2273697, rs3740066 polymorphisms were genotyped by polymerase chain reaction amplification followed by restriction fragment length polymorphism analysis or direct automated DNA sequencing in 80 patients treated with CBZ monotherapy. There were no differences in CBZ maintenance doses or adjusted plasma CBZ concentrations among the ABCC2 rs717620, rs2273697 and rs3740066 genotypic groups. No associations between all the studied genotypes and haplotypes involving the three SNPs of ABCC2 and CBZ resistance were observed in this patient cohort. These results suggest that ABCC2 polymorphisms may not contribute to interindividual variabilities in CBZ daily maintenance doses, plasma concentrations, and treatment efficacy. [ABSTRACT FROM AUTHOR]

Objectives:Digital rectal examination (DRE) is a simple clinical method to diagnose anorectal disorders. High-resolution antorectal manometry (HRAM) based on a spatiotemporal plot is expected to promote improved diagnostic accuracy. However, there are no reports comparing the effectiveness of DRE and HRAM. The aim of our study was therefore to evaluate the diagnostic value of DRE compared with HRAM.Methods:A total of 309 consecutive patients with chronic constipation (n=268) or fecal incontinence (n=41) who underwent a standardized DRE, HRAM, and balloon expulsion test were enrolled in this study. The diagnostic yield of DRE compared with HRAM was determined, and agreement between DRE and HRAM data was evaluated.Results:Of the constipated patients, 207 (77.2%) were diagnosed with dyssynergia using HRAM. The sensitivity, specificity, and positive predictive value of DRE in the diagnosis of dyssynergia were 93.2%, 58.7%, and 91.0%, respectively, and moderate agreement was seen between the two modalities (κ-coefficient =0.542, P<0.001). In patients with fecal incontinence, there was moderate agreement in terms of anal squeeze pressure between the two modalities (κ-coefficient =0.418, P=0.006); however, there was poor agreement for anal resting tone (κ-coefficient =0.079, P=0.368).Conclusions:DRE shows high sensitivity and positive predictive value in detecting dyssynergia compared with HRAM, and could therefore be used as a bedside screening test for the diagnosis of this disorder. Further studies are warranted to evaluate the correlation between DRE and HRAM in assessing anal sphincter pressure. [ABSTRACT FROM AUTHOR]

In this study, two independent and complementary liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were respectively developed and validated for the determination of edaravone or taurine in rat urine, feces and bile after intravenous administration, using 3-methyl-l- p -tolyl-5-pyrazolone and sulfanilic acid as the internal standards (IS). Edaravone was separated on an Agilent Eclipse Plus C 18 column (100 × 2.1 mm, 3.5 μm) using methanol and water (containing 5 mM ammonium formate and 0.02% formic acid) as mobile phase, while taurine was performed on a Waters Atlantis HILIC Silica column (150 × 2.1 mm, 3 μm) using acetonitrile and water (containing 5 mM ammonium formate and 0.2% formic acid) as mobile phase. The mass analysis was performed in a Triple Quadrupole mass spectrometer via multiple reaction monitoring (MRM) with negative ionization mode. The optimized mass transition ion pairs ( m/z ) for quantification were 173.1→92.2 and 187.2→106.0 for edaravone and its IS, 124.1→80.0 and 172.0→80.0 for taurine and its IS, respectively. The validated methods have been successfully applied to the excretion and metabolism interaction study of edaravone and taurine in rats after independent intravenous administration and co-administration with a single dose. The results demonstrated that there were no significant alternations on the metabolism and cumulative excretion rate of edaravone and taurine, implying that the proposed combination therapy was pharmacologically viable. [ABSTRACT FROM AUTHOR]

We conducted a meta-analysis to compare the outcomes of a self-expanding metallic stent (SEMS) vs. surgery for the palliative treatment of colorectal obstruction caused by advanced colorectal malignancy. The databases of MEDLINE, EMBASE, Cochrane controlled trials registry and the Chinese Wanfang were retrieved (updated to 31 August 2011) to identify eligible studies. We calculated the odds ratio or weighted mean difference and its corresponding 95 % confidence interval. In total, nine primary studies were included in this analysis. The success rate of SEMS placement was 93.9 %, with short-term and long-term complication rates of 26.2 and 16.1 %, respectively. Combined analyses revealed that the SEMS group had a similar risk of short-term complications as the surgical group ( P = 0.22). Moreover, SEMS was not associated with a higher mortality risk than surgical intervention ( P = 0.22) and it required a significantly shorter hospitalization time ( P < 0.01); however, SEMS patients had a higher risk of long-term complications ( P = 0.03). Because of great heterogeneities between patients and chemoradiotherapy, we did not analyze the survival times of the two groups. These results support the feasibility of SEMS as a palliative treatment for malignant colorectal obstruction caused by incurable malignancy, as it requires shorter hospitalization and is followed by quick recovery. However, the risk of long-term complications such as perforation and stent migration should be borne in mind. [ABSTRACT FROM AUTHOR]

Background and Aim Chronic constipation is frequently seen in women who have undergone hysterectomy or delivery. However, reports regarding anorectal physiologic features in those patients are rare. Patients with constipation associated with either radical hysterectomy or vaginal delivery were analyzed in order to clarify the anorectal physiologic features and the effectiveness of biofeedback therapy. Methods Of the constipated patients, a hysterectomy group ( n = 40), delivery group ( n = 41), and a control group ( n = 89), who had no history of either surgery or delivery before developing functional constipation were included. Their anorectal physiological tests and the effectiveness of biofeedback therapy were investigated. Results The volume of desire to defecate was greater in the hysterectomy group than in the control group (86.5 ± 55.0 mL vs 62.9 ± 33.7 mL; P = 0.03), and more than 240 mL of maximal volume of toleration was more frequently noted in the hysterectomy group (32.5%) than in the delivery group (14.6%) and control group (13.5%) ( P = 0.02).The failure of balloon expulsion was more frequently noted in the delivery group (44.0%) than in the hysterectomy group (15.0%) and control group (25.0%) ( P = 0.01). The defecation satisfaction score was significantly increased after biofeedback therapy in the hysterectomy group (2.0 ± 2.7 vs 7.8 ± 1.5, P < 0.001), the delivery group (1.6 ± 2.1 vs 6.7 ± 2.0, P < 0.001), and the control group (2.5 ± 2.7 vs 6.9 ± 2.1, P < 0.001). Conclusions Rectal hyposensitivity could have been the characteristic mechanism in the hysterectomy group, whereas dyssynergic defecation could have been the cause in the delivery group. Biofeedback therapy was effective for both groups. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that suppress gene expression via degradation or translational inhibition of their target genes. Many miRNAs are associated with cardiac hypertrophy and heart failure. In this study, we pursued to identify miRNAs that negatively regulate cardiac hypertrophy by utilizing a surgical model for regression of cardiac hypertrophy. Microarray analysis revealed that 15 miRNAs out of the 696 miRNAs tested were specifically up-regulated during the regression period. Among these regression-specific miRNAs, nine microRNAs, which have not been previously reported, were further tested for their effects on phenylephrine (PE)-treated neonatal cardiomyocytes. Consequently, five miRNAs (miR-101b, 142-3p, 181d, 24-2∗, and 450a) completely abrogated PE-induced hypertrophy as determined by measurements of cell size and fetal gene expression. Conversely, antagomers of these miRNAs exacerbated the PE-induced hypertrophy. Collectively, these findings suggest that the five miRNAs newly identified by using our cardiac hypertrophy-regression surgical model negatively regulate cardiac hypertrophy and could be used as potential therapeutic targets for the treatment of heart diseases. [Copyright &y& Elsevier]

Abstract: Lipopolysaccharide (LPS) is a known trigger in the pathogenesis of sepsis, lipid A being the toxic component. One of several adjuvant therapeutic approaches for severe sepsis is currently focusing on the neutralization of LPS. In order to obtain the components from traditional Chinese herbs that can neutralize the endotoxin, aqueous extractions of twelve herbs were tested using affinity biosensor technology. From twelve herbs, Scutellaria baicalensis Georgi (Huang Qin) found to possess high lipid A-binding abilities, and was selected in subsequent experiments. After subjected to macroporous adsorptive resins and HPLC, we obtained 2′,5,6′,7-tetrahydroxyflavanonol (THF) from S. baicalensis Georgi under the direction of neutralization of LPS and reducing proinflammatory cytokines. In vitro, THF directly bound to LPS and neutralized its activity. THF not only down-regulated TNF-α mRNA expression but also decreased TNF-α and IL-6 release from RAW264.7 cells induced by LPS in a dose-dependent manner. THF-mediated inhibition on proinflammatory cytokine release is probably associated with downregulation of LPS-induced TLR4 mRNA augmentation. In vivo, THF could significantly protect mice against a lethal challenge with heat-killed E. coli 35218 (E. coli 35218) in a dose-dependent manner, and decreased the plasma LPS level in endotoxemia mice. These findings provide compelling evidence that THF may be an important potential drug for sepsis treatment. Considering the inhibitory effects of THF on LPS-induced cytokine release are unlikely due to its nonspecific cellular toxicity, THF should be considered as a safe putative candidate for development as a drug for sepsis treatment. [Copyright &y& Elsevier]