Harnessing the Natural Healing Power of Colostrum: Bovine Milk-Derived Extracellular Vesicles from Colostrum Facilitating the Transition from Inflammation to Tissue Regeneration for Accelerating Cutaneous Wound Healing.

As wound healing is an extremely complicated process, consisting of a cascade of interlocking biological events, successful wound healing requires a multifaceted approach to support appropriate and rapid transitions from the inflammatory to proliferative and remodeling phases. In this regard, here the potential use of bovine milk extracellular vesicles (EVs) to enhance wound healing is investigated. The results show that milk EVs promote fibroblast proliferation, migration, and endothelial tube formation. In particular, milk EVs derived from colostrum (Colos EVs) contain various anti-inflammatory factors facilitating the transition from inflammation to proliferation phase, as well as factors for tissue remodeling and angiogenesis. In an excisional wound mouse model, Colos EVs promote re-epithelialization, activate angiogenesis, and enhance extracellular matrix maturation. Interestingly, Colos EVs are further found to be quite resistant to freeze-drying procedures, maintaining their original characteristics and efficacy for wound repair after lyophilization. These findings on the superior stability and excellent activity of milk Colos EVs indicate that they hold great promise to be developed as anti-inflammatory therapeutics, especially for the treatment of cutaneous wounds.

Astrocytes Control Sensory Acuity via Tonic Inhibition in the Thalamus.

Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.

Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence.

Both sorafenib and mammalian target of rapamycin inhibitor (mTORi) have antitumor effects. This study aimed to evaluate their antitumor effects in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) recurrence. We performed a laboratory study using sorafenib and mTORi and subsequently validated their survival benefit in a clinical LT setting. In the laboratory study, the HepG2.2.15 liver tumor cell line and 5 patient-derived graft HCC cell lines were used for in vitro cytotoxic studies. After treatment with everolimus and sorafenib, cell viability and apoptosis assays revealed noticeable cytotoxic effects with individual agents and augmented effects by combination therapy. An in vivo mouse study also demonstrated similar cytotoxic outcomes. In the clinical study including 232 LT recipients with HCC recurrence, the 3-month medication drop-out rate was 35.6% for sorafenib administration and 23.5% for mTORi administration. Postrecurrence survival rates were not different according to sorafenib administration (P = 0.17) but were significantly improved following mTORi administration (P < 0.001). In mTORi subgroups with and without sorafenib, there was no difference in the overall postrecurrence patient survival period (P = 0.26), indicating an absence of synergistic or additional antitumor effect from sorafenib. The median progression-free and overall survival period was 6.4 and 11.8 months, respectively, after sorafenib administration. Time of tumor recurrence and use of mTORi were independent risk factors. In conclusion, our laboratory study demonstrated synergistic antitumor effects of sorafenib and mTORi, but this was not reproduced in our clinical LT study. Our clinical result of mTORi administration showed improved postrecurrence survival, thus administering mTORi in LT recipients with HCC recurrence appears worthwhile. However, the antitumor effect of sorafenib on posttransplant recurrence was not determined in this retrospective study, thus requiring further studies with early start of sorafenib administration. Liver Transplantation 24 932-945 2018. © 2018 AASLD.

Supraventricular tachyarrhythmias in patients with a persistent left superior vena cava.

Aims: A persistent left superior vena cava (PLSVC) is the most common thoracic venous anomaly. This venous anomaly can impact the evaluation and treatment of supraventricular tachyarrhythmia (SVA). The aim of this study was to assess the proportion and characteristics of PLSVC in adult SVA patients. Methods and results: From July 2002 to July 2012, clinical and procedural data from databases of 10 cardiac electrophysiology laboratories in the Yeungnam region of the Republic of Korea were reviewed. Of 6662 adult SVA patients who underwent an EP study or catheter ablation of SVA during the 10-year study period, 18 patients had PLSVC (mean age 47.6 ± 14.8 years, 10 men). The proportion of PLSVC in adult SVA patients was 0.27% (18/6662). SVA type and procedural outcomes of radiofrequency (RF) catheter ablation in these patients were investigated and the results were as follows: successful slow pathway modification in six of seven patients with atrioventricular nodal reentrant tachycardia (AVNRT), successful ablation of accessory pathway in three of four patients with atrioventricular reentrant tachycardia, and successful ablation of atrial tachycardia (cavotricuspid isthmus-dependent in two, septal macroreentry in one, focal from the PLSVC in one) in three of four patients. In one patient with junctional tachycardia, catheter ablation failed. In two patients with atrial fibrillation, catheter ablation was successful. Conclusion: Among adult SVA patients who underwent an EP study or RF catheter ablation during the 10-year study period, 0.27% had PLSVC. The most common type of SVA was AVNRT. The success rate of catheter ablation was 82% in SVA patients with PLSVC. There were no procedure-related complications.

Altered Biodistribution of 99mTc-DPD on Bone Scan After Intravenous Iron Supplement.

We report a case with altered biodistribution of 99mTc-dicarboxypropane diphosphonate (99mTc-DPD) on whole body bone scan after intravenous iron supplement therapy. A 47-year-old male patient who had recently been detected with a hepatic mass suggestive of hepatocellular carcinoma underwent bone scan as staging work-up before surgery. Bone scan images at 3 h after injection of 99mTc-DPD demonstrated unusually increased blood pool activities in the heart, liver, and spleen with usual skeletal uptakes. The patient had been treated for severe anemia from hemorrhoid with two intravenous administration of ferric hydroxide carboxymaltose complex at approximately 22 h and 2 h prior to the 99mTc-DPD injection, which we consider as the most probable cause of altered biodistribution of 99mTc-DPD.

Effect of substrate modification in catheter ablation of paroxysmal atrial fibrillation: pulmonary vein isolation alone or with complex fractionated electrogram ablation.

Catheter ablation of atrial fibrillation that targets complex fractionated electrogram sites has been widely applied in the management of persistent atrial fibrillation. The clinical outcomes of pulmonary vein isolation alone and pulmonary vein isolation plus the use of complex fractionated electrogram-guided ablation (CFEA) have not been fully compared in patients with paroxysmal atrial fibrillation.This prospective study included 70 patients with symptomatic paroxysmal atrial fibrillation that remained inducible after pulmonary vein isolation. For radio-frequency catheter ablation, patients were nonrandomly assigned to a control group (pulmonary vein isolation alone, Group 1, n=35) or a CFEA group (pulmonary vein isolation plus additional CFEA, Group 2, n=35). The times to first recurrence of atrial tachyarrhythmias were compared between the 2 groups.In Group 2, CFEA rendered atrial fibrillation noninducible in 16 patients (45.7%) and converted inducible atrial fibrillation into inducible atrial flutters in 12 patients (34.3%). Atrial fibrillation remained inducible in 7 patients (20%) after the combined ablation procedures. After a mean follow-up of 23 months, freedom from recurrence of atrial tachyarrhythmias was significantly higher in Group 2 than in Group 1 (P=0.037). In Group 1, all of the recurrent tachyarrhythmias were atrial fibrillation, whereas regular tachycardia was the major mechanism of recurrent arrhythmias in Group 2 (atrial tachycardia or atrial flutter in 5 of 6 patients and atrial fibrillation in 1 patient).We found that CFEA after pulmonary vein isolation significantly reduced recurrent atrial tachyarrhythmia and might modify the pattern of arrhythmia recurrence in patients with paroxysmal atrial fibrillation.

Circadian and seasonal variations of ventricular tachyarrhythmias in patients with early repolarization syndrome and Brugada syndrome: analysis of patients with implantable cardioverter defibrillator.

INTRODUCTION: The circadian and seasonal patterns of ventricular tachyarrhythmia (VTA) in patients with early repolarization syndrome (ERS) have not been determined. We compared the timing of VTAs in patients with ERS and Brugada syndrome (BS). METHODS AND RESULTS: We enrolled patients with ERS (n = 14) and BS (n = 53) who underwent implantable cardioverter defibrillator (ICD) implantation. The timing of VTAs, including cardiac arrest and appropriate shocks, was determined. During follow up of 6.4 ± 3.6 years in the ERS group and 5.0 ± 3.3 years in the BS group, 5 of 14 (36%) ERS and 10 of 53 (19%) BS patients experienced appropriate shocks (P = 0.37). Cardiac arrest showed a trend of nocturnal distribution peaking from midnight to early morning (P = 0.14 in ERS, P = 0.16 in BS). Circadian distribution of appropriate shocks showed a significant nocturnal peak in patients with ERS (P < 0.0001) but a trend toward a nocturnal peak in patients with BS (P = 0.08). There were no seasonal differences in cardiac arrest in patients with ERS and BS. However, patients with ERS showed a seasonal peak in appropriate shocks from spring to summer (P < 0.0001). There was no significant seasonal peak in patients with BS. The timing of VTAs (cardiac arrest plus appropriate shock) showed significant nocturnal distributions in patients with ERS and BS (P < 0.01, respectively). A significant clustering of VTAs was noted from spring to summer (P < 0.01) in patients with ERS, but not in patients with BS (P = 0.42). CONCLUSIONS: Incidence of VTAs showed marked circadian variations with night-time peaks in patients with ERS and BS.

Sorafenib for recurrent hepatocellular carcinoma after liver transplantation.

OBJECTIVE: Sorafenib is the only drug that has shown a survival benefit in patients with hepatocellular carcinoma in randomized Phase 3 trials. The efficacy and safety of sorafenib in the treatment of recurrent hepatocellular carcinoma after liver transplantation, however, has not been determined. METHODS: We retrospectively analyzed 13 patients who were treated with sorafenib for recurrent hepatocellular carcinoma after liver transplantation. RESULTS: The median time to recurrence from liver transplantation was 12.3 months (95% confidence interval: 8.5-16.1 months). Six of 10 evaluable patients showed stable disease, which was the best response and the median duration of stabilization was 3.9 months (95% confidence interval: 1.6-6.2 months). At a median follow-up duration of 3.7 months (range: 0.3-10.9 months) in surviving patients, the median time to progression and the median overall survival from commencement of sorafenib were 2.9 months (95% confidence interval: 0.0-6.8 months) and 5.4 months (95% confidence interval: 3.7-7.0 months), respectively. Grade 3 neutropenia was observed in one patient, which was the only high-grade hematologic toxicity observed. Grade 3 hand-foot skin reactions were observed in three patients. Adverse events could be managed with dose adjustment. CONCLUSIONS: These findings suggest that sorafenib may be a feasible treatment option regarding its efficacy and safety for recurrent hepatocellular carcinoma after liver transplantation.

Mechanism of regular atrial tachyarrhythmias during combined pulomonary vein isolation and complex fractionated electrogram ablation in patients with atrial fibrillation.

BACKGROUND: Atrial tachyarrhythmias (ATA) frequently develop during catheter ablation of atrial fibrillation (AF), but the mechanism of ATA during combined pulmonary vein isolation (PVI) and complex fractionated electrogram-guided ablation (CFEA) has not been reported. METHODS AND RESULTS: This study involved 105 patients with symptomatic, drug-refractory AF. After PVI, CFEA was performed in the left/right atrium if AF remained inducible in paroxysmal AF (PAF) or persisted in persistent AF (PeAF). For the 70 PAF patients, PVI alone rendered AF non-inducible in 29 patients (41.4%), and converted inducible AF into inducible atrial flutter (AFl) in 10 patients (14.3%). For the remaining 31 PAF patients, additional CFEA rendered AF non-inducible in 11 patients (15.7%), whereas only AFl was inducible in 11 patients (15.7%). For 35 PeAF patients, PVI and CFEA converted AF into sinus rhythm in 2 (5.7%) and into AFl in 21 (60.0%) patients, while AF persisted in 12 patients (34.3%). The mechanism of ATA was focal (20/114, 17.5%), roof-dependent (20/114, 17.5%), peri-mitral (33/114, 28.9%), cavotricuspid isthmus-dependent (34/114, 29.8%) AFl or unknown (7/114, 6.1%). Successful ablation was achieved in 93/114 (81.6%) tachycardias. CONCLUSIONS: The major mechanism of ATA during the combined approach of PVI and CFEA is macroreentry around large anatomic obstacles such as the pulmonary vein or the mitral or tricuspid annuli.

A new pyrrole alkaloid isolated from Arum palaestinum Boiss. and its biological activities.

The phytochemical analysis of the ethyl acetate fraction of Arum palaestinum Boiss. (Araceae) led to the isolation and identification of a new polyhydroxy alkaloid compound; (S)-3,4,5-trihydroxy-1 H-pyrrol-2(5H)-one (1), and other five known compounds; caffeic acid (2), isoorientin (3), luteolin (4) and vicenin 11 (5), as well as the rare compound 3,6,8-trimethoxy, 5,7,3',4'-tetrahydroxy flavone (6). The structural elucidations of all the compounds were based on spectroscopic data (1H- and 13C-NMR, DEPT, HSQC, HMBC and NOE difference techniques) and comparison with literature data. Investigation of the antioxidant activity of the ethyl acetate fraction indicated its strong scavenging capacity for 1,1 -diphenyl-2-picrylhydrazyl (DPPH) radicals (SC50 3.1+/-0.82 microg/mL). Moreover, the treatment of different human cancer cell lines with the ethyl acetate fraction led to dose-dependant suppression in the proliferation of both breast carcinoma cells (MCF-7; IC50 59.09+/-4.1 microg/mL) and lymphoblastic leukemia cells (1301; IC50 53.1+/-2.9 microg/mL); however, it was found to have no effect on the growth of hepatocellular carcinoma cells (Hep G2).