Behçet's disease-induced massive small intestinal bleeding successfully treated with adalimumab.

We herein report a case of Behçet's disease in a 27-year-old female who suffered from generalized skin rashes for one week. After hospitalization, massive bloody stools accompanying hypovolemic shock occurred. Emergency abdominal computed tomography-angiography failed to detect the bleeding source. Esophagogastroduodenoscopy also demonstrated no definite bleeding points. Ileocolonoscopy showed multiple large and deep ulcers with some blood coating and mild oozing in the terminal ileum. We initially performed epinephrine injection and hemoclips for her intestinal bleeding. However, massive bloody stools still continued. Thus, we prescribed a loading dose of 160 mg adalimumab followed by weekly 80 mg adalimumab subcutaneous injections to the patient. Following this treatment, her gastrointestinal bleeding gradually subsided and completely stopped within a few days. After three-week therapy with adalimumab, capsule endoscopy showed several healing ulcers without bleeding in the distal to the terminal ileum. She continues to be treated with adalimumab, azathioprine, and mesalazine without recurrent bleeding.

Clinical outcomes of patients undergoing a cardiac implantable electronic device implantation following a recent non-device-related infection.

BACKGROUND: Clinical outcomes of patients undergoing a cardiac implantable electronic device (CIED) implantation following a recent non-device related infection are unknown. AIM: To evaluate the clinical outcomes of patients with recent infection before CIED implantation. METHODS: Consecutive patients (N = 1237) were classified as patients with recent infection (N = 72) and without recent infection (N = 1165). A recent infection was established by reviewing medical records, including symptoms and clinical manifestations, diagnosis of systemic inflammatory response syndrome, and quick Sequential Organ Failure Assessment (qSOFA) score. Multiple stepwise logistic regression analysis was used to identify independent predictors of in-hospital all-cause mortality. FINDINGS: During nearly three years of follow-up, 17 patients had CIED infection (1.4%), and the incidence of CIED infection did not significantly differ between patients with and without recent infection according to symptoms and clinical manifestations (2.8% vs 1.3%, respectively; not significant). However, patients with recent infection had a significantly higher in-hospital mortality rate compared to those without recent infection (22.2% vs 0.9%, respectively; P < 0.05). In multivariate analysis, predictors of in-hospital mortality were recent infection before CIED implantation (odds ratio: 20.3; 95% confidence interval: 8.4-49.3; P < 0.001) and end-stage renal disease (4.3; 1.4-12.8; P = 0.009). CONCLUSION: A CIED implantation is feasible in patients with recent infection if the patient is afebrile and has received an adequate duration of antibiotic therapy. Participants in shared decision-making before implant should be advised that recent infection increases in-hospital mortality risk, especially in patients with a qSOFA score of ≥2.

Bundled skin antiseptic preparation for complex cardiac implantable electronic device infection: a propensity-score matching cohort study.

BACKGROUND: Cardiac implantable electronic device (CIED) infection, a major complication of a CIED implant procedure, can prolong hospitalization and cause mortality. AIM: To evaluate the efficacy of a bundled skin antiseptic preparation for preventing infection after implantation of a complex CIED. METHODS: This study analysed 1163 consecutive patients who had received a bundled skin antiseptic preparation before CIED implantation from July 2012 to December 2017. According to the complexity of the CIED implant procedure, the patients were divided into a complex CIED group (N = 370) and a non-complex CIED group (N = 793). A complex procedure was defined as a pacemaker replacement, implantation of implantable cardioverter defibrillator and cardiac resynchronization therapy, device upgrade, or lead revision. FINDINGS: During a mean follow-up of 2.9 ± 1.7 years, CIED infection developed in 15 patients (1.3%), and the incidence of minor and major infection was 1.1% and 0.2%, respectively. The incidence of CIED infection did not significantly differ between the complex CIED group and the non-complex CIED group (1.1% vs 1.4%, respectively; non-significant). Multivariate analysis indicated that procedural complexity was not an independent predictor of CIED infection. After 2:1 propensity score matching, the matched non-complex CIED group and the matched complex CIED group still showed no significant difference in the incidence of CIED infection. CONCLUSION: Bundled skin antiseptic preparation is an effective and widely applicable strategy for decreasing infection risk after a complex CIED implantation.

Circadian peak dopaminergic activity response at the biological clock pacemaker (suprachiasmatic nucleus) area mediates the metabolic responsiveness to a high-fat diet.

Among vertebrate species of the major vertebrate classes in the wild, a seasonal rhythm of whole body fuel metabolism, oscillating from a lean to obese condition, is a common biological phenomenon. This annual cycle is driven in part by annual changes in the circadian dopaminergic signalling at the suprachiasmatic nuclei (SCN), with diminution of circadian peak dopaminergic activity at the SCN facilitating development of the seasonal obese insulin-resistant condition. The present study investigated whether such an ancient circadian dopamine-SCN activity system for expression of the seasonal obese, insulin-resistant phenotype may be operative in animals made obese amd insulin resistant by high-fat feeding and, if so, whether reinstatement of the circadian dopaminergic peak at the SCN would be sufficient to reverse the adverse metabolic impact of the high-fat diet without any alteration of caloric intake. First, we identified the supramammillary nucleus as a novel site providing the majority of dopaminergic neuronal input to the SCN. We further identified dopamine D2 receptors within the peri-SCN region as being functional in mediating SCN responsiveness to local dopamine. In lean, insulin-sensitive rats, the peak in the circadian rhythm of dopamine release at the peri-SCN coincided with the daily peak in SCN electrophysiological responsiveness to local dopamine administration. However, in rats made obese and insulin resistant by high-fat diet (HFD) feeding, these coincident circadian peak activities were both markedly attenuated or abolished. Reinstatement of the circadian peak in dopamine level at the peri-SCN by its appropriate circadian-timed daily microinjection to this area (but not outside this circadian time-interval) abrogated the obese, insulin-resistant condition without altering the consumption of the HFD. These findings suggest that the circadian peak of dopaminergic activity at the peri-SCN/SCN is a key modulator of metabolism and the responsiveness to adverse metabolic consequences of HFD consumption.

A modified compression model of spinal cord injury in rats: functional assessment and the expression of nitric oxide synthases.

STUDY DESIGN: Experimental study. OBJECTIVES: To investigate a modified compression model of spinal cord injury (SCI) in adult rats by using a room-air- inflated Fogarty balloon catheter. SETTING: Kaohsiung, Taiwan. METHODS: The rats were divided into injury, sham-operated and control groups. A 2-French Fogarty catheter was passed from the lumbar spine (L3-L4) epidurally, with a mini-laminectomy under the microscope, to the level of thoracic spine (T6-T7). The actual site of the catheter tip was confirmed with X-ray. The balloon of Fogarty catheter then was inflated with room air, 0.2 ml, for 10 min. Mini-laminectomy was performed without inserting the catheter in the sham-operated group. Quantitative neurological outcomes were evaluated with the Basso, Beattie and Bresnahan (BBB) locomotor rating scale daily. The gene expression of nitric oxide synthases (NOSs) of the spinal cord was investigated at the end of the functional assessment. RESULTS: The mean BBB locomotor scores were 10±1.85 and 10±1.85, respectively, on days 1 and 3 in the injury group, and 21 and 20.29±0.69, respectively, in the sham-operated group. There was a significantly increased gene expression of inducible NOS in the SCI group compared with the sham-operated group and control group. Endothelial NOS gene expression was not significantly different among the groups. CONCLUSION: The functional and molecular assessments show that this modified balloon-compression technique is a reproducible, simple and inexpensive model of SCI in rats.

RNA is favourable for analysing EGFR mutations in malignant pleural effusion of lung cancer.

Malignant pleural effusion (MPE) is a useful specimen allowing for the evaluation of EGFR status in nonsmall cell lung cancer (NSCLC). However, direct sequencing of genomic DNA from MPE samples was found not to be sensitive for EGFR mutation detection. To test whether EGFR analysis from RNA is less prone to interference from nontumour cells that have no or lower EGFR expression, we compared three methods (sequencing from cell-derived RNA versus sequencing and mass-spectrometric analysis from genomic DNA), in parallel, for EGFR mutation detection from MPE samples in 150 lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors (TKIs). Among these MPE samples, EGFR mutations were much more frequently identified by sequencing using RNA than by sequencing and mass-spectrometric analysis from genomic DNA (for all mutations, 67.3 versus 44.7 and 46.7%; for L858R or exon 19 deletions, 61.3 versus 41.3 and 46.7%, respectively). The better mutation detection yield of sequencing from RNA was coupled with the superior prediction of clinical efficacy of first-line TKIs. In patients with acquired resistance, EGFR sequencing from RNA provided satisfactory detection of T790M (54.2%). These results demonstrated that EGFR sequencing using RNA as template greatly improves sensitivity for EGFR mutation detection from samples of MPE, highlighting RNA as the favourable source for analysing EGFR mutations from heterogeneous MPE specimens in NSCLC.

Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction.

Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer's disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.

Catechin stimulates osteogenesis by enhancing PP2A activity in human mesenchymal stem cells.

SUMMARY: Using human mesenchymal stem cells, we identified catechin from a panel of herbal ingredients and Chinese traditional compounds with the strongest osteogenic effects. Catechin increased alkaline phosphatase activity, calcium deposition, and mRNA expression of Runx2 and osteocalcin. We further clarified the signaling pathway that catechin mediated to stimulate osteogenesis. INTRODUCTION: Human mesenchymal stem cells (hMSCs), useful as a species specific cell culture system for studying cell lineage differentiation, were examined as a tool to identify novel herbal ingredients and Chinese traditional compounds for enhancing osteogenesis. METHODS: Immortalized and primary hMSCs were induced in osteogenic induction medium in the presence of a variety of herbal ingredients and Chinese traditional compounds and osteogenic differentiation was evaluated by histochemical assays and quantitative RT-PCR. RESULTS: Using immortalized hMSCs, we first identified catechin, 18ß-glycyrrhetinic acid, baishao, and danggui with osteogenic properties, which enhanced calcium deposition at the dose without significant cytotoxic effects. Primary hMSCs were then applied for confirming the osteogenic effects of catechin, which increased alkaline phosphatase activity, calcium deposition, and mRNA expression of Runx2 and osteocalcin. We further found the extracellular signal-regulated kinase (ERK) pathway was downregulated upon stimulation with catechin. Catechin increased the level and activity of protein phosphatases 2A (PP2A) that dephosphorylates ERK kinase (MEK) and ERK. Further, PP2A inhibitor, okadaic acid, abolished the effect of catechin-mediated inactivation of ERK and stimulation of osteogenesis. The blocking effect of okadaic acid on osteogenesis was further reversed by PD98059, a specific inhibitor of MEK. Co-immunoprecipitation revealed the association of PP2A to both MEK and ERK. CONCLUSIONS: These studies propose catechin enhanced osteogenesis by increasing the PP2A level that inhibits the MEK and ERK signaling in hMSCs. These results prove the concept of using hMSCs as a convenient tool for rapid and consistent screening of the osteogenic herbal ingredients and traditional Chinese compounds.

Left atrial enlargement induced by pure mitral regurgitation: time frame in a new swine model.

BACKGROUND: Atrial enlargement occurs in patients with significant mitral regurgitation. However, the time frame of the development of atrial enlargement induced by mitral regurgitation remains unknown. METHODS: Fourteen Lanyu miniature pigs (age = 6.6 ± 0.9 months) were studied. Mitral regurgitation was created by placing a predefined hole on the middle scallop of the posterior mitral leaflet under cardiopulmonary bypass. The parasternal long-axis atrial dimension was measured by transthoracic echocardiographic examinations. RESULTS: All animals exhibited grade 3 mitral regurgitation immediately after surgery. Seven pigs expired within 2 weeks after the operation [technical complications (n = 1), acute cardiac tamponade (n = 1), and acute and subacute heart failure (n = 5)]. Seven pigs remained alive at a mean follow-up of 7.7 ± 2.1 months. The left atrial diameter indices of the 7 pigs increased significantly at 1 month (33.1 ± 8.6 mm, p = 0.018) and 3 months (41.3 ± 12.6 mm, p = 0.018) after surgery compared with baseline values (22.8 ± 5.2 mm), and the left atrial diameter index increased significantly at 3 months compared to 1 month (p = 0.018). CONCLUSIONS: Left atrial enlargement develops rapidly and progresses after the creation of significant pure mitral regurgitation.

Acute effects of ephedra on autonomic nervous modulation in healthy young adults.

The aim of this study was to assess the acute effects of ephedra on autonomic nervous modulation by means of heart rate variability (HRV) analysis, using a randomized, double-blind, placebo-controlled, crossover design. On three separate days, 20 healthy subjects took capsules containing either 1 or 2 g of ephedra dry extract or a placebo, and the sequential percentage changes in HRV measures were compared. After the subjects took ephedra, the normalized low-frequency component (LF) and the ratio of LF to high-frequency component (HF) increased significantly in a dose-dependent manner, whereas the normalized HF (HF%) decreased significantly. We conclude that ingestion of ephedra tilts the sympathovagal balance dose-dependently toward increased sympathetic activity and impairs parasympathetic activity.

Localized cyclotron mode driven by fast alpha particles under a nonuniform magnetic field.

Resonance requires precise synchronization. Surprisingly, relativistic cyclotron instability can survive under a magnetic field with its nonuniformity larger than the requirement of synchronism. Localized eigenmode observed in a hybrid simulation is found to be consistent with that predicted by an analytical theory including both profile and eigenvalue. Half of the spatial area of the wave profile is located where the frequency mismatch is negative as against to the positive requirement generally believed. The consequence on the alpha dynamics is also demonstrated.

Comparison of fluoroquinolones: cytotoxicity on human corneal epithelial cells.

PURPOSE: To compare the cytotoxicity of different fluoroquinolones (FQs) towards human corneal epithelial cells (HCECs). METHODS: HCECs were incubated with FQs (norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin), both as commercial ophthalmic formulations and as unpreserved solutions. Cells incubated in different formulations of gentamicin, cefazolin, and benzalkonium chloride (BAC) were also compared. A cell viability assay, using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, was used to evaluate the drug effects on cell viability after five incubation times (30 min, 1 h, 4 h, 8 h, and 24 h). Transepithelial electrical resistance (TEER) was measured with a voltohmmeter to help understand changes in paracellular permeability at five time points (4 h, 8 h, 12 h, 24 h, and 48 h). Cell morphology was observed with an inverted fluorescence microscope, with multiple stage position and in time-lapse mode. RESULTS: The preserving solutions and BAC at concentrations above 0.005% significantly decreased cell viability, when assayed by MTS. Increased paracellular permeability and decreased membrane integrity were also observed by TEER measurements and inverted fluorescence microscopy. Ofloxacin and levofloxacin were both free of preservatives and showed the least cytotoxicity towards HCECs in commercial FQ eye drops. CONCLUSIONS: The cytotoxicity observed with FQ eye drops seems to be caused mainly by the preservative, which induced a significant decrease in membrane integrity and increased paracellular permeability. We found the new generation of FQs (moxifloxacin and gatifloxacin) no less cytotoxic towards HCECs than the old generation ones.

Adding moxifloxacin is associated with a shorter time to culture conversion in pulmonary tuberculosis.

OBJECTIVE: To investigate whether adding moxifloxacin (MXF) to the standard anti-tuberculosis regimen can shorten the time to sputum culture conversion in pulmonary tuberculosis (PTB). METHODS: Adults with culture-positive PTB were divided into two treatment groups by their choice: standard regimen alone (HERZ group) and standard regimen plus daily 400 mg MXF in the first 2 months (MXF group). Sputum samples were collected thrice weekly in the first 8 weeks. The propensity score was calculated to estimate the conditional probability of entering the MXF group. Factors influencing time to culture conversion were investigated using Cox proportional hazards regression analysis stratified by propensity score. RESULTS: Sixty-two patients were enrolled in the MXF group and 88 in the HERZ group; respectively 51 and 72 completed the study. The regimen was modified before culture conversion in respectively 6 (12%) and 12 (16%; P = 0.47) patients, due to adverse effects. The time to culture conversion was shorter in the MXF group (HR 2.1, 95%CI 1.4-3.2). The culture conversion rate after 6 weeks of treatment was respectively 82% and 61% (P = 0.011, <0.05/4, calculated using the modified Bonferroni method). CONCLUSIONS: Adding MXF to the standard anti-tuberculosis regimen in the first 2 months was associated with a shorter time to culture conversion, a higher 6-week culture conversion rate and reduced transmission of tuberculosis.

Three-dimensional optical coherence tomography of Barrett's esophagus and buried glands beneath neosquamous epithelium following radiofrequency ablation.

We report three-dimensional (3D) endoscopic microscopy findings in Barrett's esophagus, using an endoscopic optical coherence tomography (OCT) system in one patient before and in one patient after radiofrequency ablation (RFA). Findings were compared with those in a normal patient without Barrett's esophagus. In the normal patient,findings were of regular flat squamous mucosa with small subepithelial vessels and glands. In the Barrett's esophagus patient, findings were of large, densely packed glands with distortion of mucosal architecture. In the post-RFA case, findings were of a small number of isolated glands buried beneath 300-500 microm of neosquamous epithelium and lamina propria. Neosquamous epithelium is a marker of successful ablative therapy, while buried glands may have potential for dysplastic progression and are difficult to detect using conventional methods. These results indicate a potential role of 3D-OCT endoscopic microscopy for follow-up, including subsurface assessment, of ablative treatments for Barrett's esophagus.