Anti-CGRP in cluster headache therapy

Abstract

Cluster headache is a primary headache characterized by recurring excruciating pain and autonomic signs, leading to significant suffering and derangement of patients' life. Efficacious new preventive treatments are needed. The pathophysiology of cluster headache comprises mechanisms both in the peripheral and central nervous system, involving the trigeminovascular system, the trigemino-parasympathetic reflex, and central modulating systems. Calcitonin gene–related peptide (CGRP) has an active role throughout these systems. It is increased during spontaneous and provoked attacks, and itself can induce attacks. Recently, drugs against this neuropeptide have been developed for the treatment of different headache disorders. In particular, monoclonal antibodies vs CGRP as galcanezumab and fremanezumab have been tested in cluster headache, with promising results for the episodic form. Considering the relevance of central mechanisms in CH, drugs interfering with the CGRP pathway in the central nervous system can enlarge the therapeutic armamentarium against this highly disabling condition.

https://ift.tt/2StbaMV

AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3

Abstract

Epithelial-mesenchymal transition (EMT) in peritoneum was induced during peritoneal dialysis (PD), which finally caused progressive fibrosis. However, the underlying mechanisms were not well elucidated. We established advanced glycation end-products (AGEs)-induced EMT model using primary human peritoneal mesothelial cells (HPMCs). The working concentration and time of AGEs were optimized. Then the expression and activation signal transducer and activator of transcription 3 (STAT3), a key factor of EMT in cancer, were detected. The regulation of STAT3 by miRNA was also explored. 50 μg/ml AGEs treatment for 24 h can successfully induce EMT in HPMCs. AGEs treatment upregulated and activated STAT3. miRNA-454, potentially targeting STAT3, was down-regulated in AGEs-treated HPMCs. Overexpression of miRNA-454 prevented AGEs- induced EMT in HPMCs. AGEs induce epithelial to mesenchymal transformation of Human peritoneal mesothelial cells via upregulation of STAT3.

https://ift.tt/2NwQgvC

Body Contouring Following Massive Weight Loss: the Evolving Role of Plastic Surgeons and Risk Stratification Tools

https://ift.tt/2GPkcCA

Effects of Preventive Treadmill Exercise on the Recovery of Metabolic and Mitochondrial Factors in the 6-Hydroxydopamine Rat Model of Parkinson’s Disease

Abstract

Metabolic and mitochondrial dysfunction has been implicated in Parkinson's disease, while exercise can induce essential pathways of mitochondrial biogenesis. Here, we tested whether long-term preventive treadmill training (16 weeks, 21 m/min, and 0° inclinations for 50 min/d, 5 d/week) effects the mitochondrial and neurodegeneration markers, in the striatum of rats in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Following 16 weeks of exercise or no exercise period (n = 16 rats per group), the animals were divided into four experimental groups (n = 8 per group): (1) no exercise and saline (SED), (2) exercise and saline (EX), (3) no exercise and 6-OHDA (SED + 6-OHDA), and (4) exercise and 6-OHDA (EX + 6-OHDA). For the model, 8 μg of 6-OHDA (2 μg/μL prepared in a solution of 0.2% ascorbic acid and 0.9% saline) was injected into the right medial forebrain bundle. Exposure to 6-OHDA resulted in a significant reduction (P < 0.05) of mitochondrial factors AMP-activated protein kinase, peroxisome proliferator-activated receptor gamma coactivator-1 alpha, and tyrosine hydroxylase, and increased expression of silent information regulator T1, mitochondrial transcription factor A, and p53 in the SED + 6-OHDA group relative to SED group. By contrast, gene and protein expressions upon exercise were higher and p53 protein level was lower in the EX + 6-OHDA group compared with SED + 6-OHDA. Further, exercise reduced the extent of weight loss associated with the 6-OHDA injection. In conclusion, exercise might be used to reduce mitochondrial disorders in Parkinson's disease.

https://ift.tt/2tGyCMP

Salicylate-Induced Ototoxicity of Spiral Ganglion Neurons: Ca 2+ /CaMKII-Mediated Interaction Between NMDA Receptor and GABA A Receptor

Abstract

Sodium salicylate (SS) is one of the nonsteroidal anti-inflammatory drugs and widely used in clinical practice. Therefore, we aimed to investigate the potential ototoxicity mechanism of sodium salicylate: the influence of Ca²⁺/calmodulin-dependent protein kinase II (Ca²⁺/CaMKII) in interaction between NMDA receptors (NMDAR) and GABA_A receptors (GABA_AR) in rat cochlear spiral ganglion neurons (SGNs). After treatment with SS, NMDA, and an NMDAR inhibitor (APV), the changes of GABA_AR β3 (GABR β3) mRNA, surface and total protein, and GABA_AR currents in SGNs were assessed by quantitative PCR, Western blot, and whole-cell patch clamp. Mechanistically, SS and/or NMDA increased the GABR β3 mRNA expression, while decreased GABR β3 surface protein levels and GABA_AR-mediated currents. Moreover, application of SS and/or NMDA showed promotion in phosphorylation levels at S383 of GABR β3. Collectively, Ca²⁺ chelator (BAPTA) or Ca²⁺/CaMKII inhibitor (KN-93) reversed the effects of SS and/or NMDA on GABA_AR. Therefore, we hypothesize that the interaction between NMDAR and GABA_AR is involved in the SGNs damage induced by SS. In addition, the underlying molecular mechanism is related to Ca²⁺/CaMKII-mediated signaling pathway, which suggests that the interaction between calcium signal-regulated receptors mediates SS ototoxicity.

https://ift.tt/2H8Jg6L

Chylous fistula: management of a rare complication following right anterior cervical spine approach

Abstract

Purpose

Chylorrhea resulting from injury of the lymphatic system during neck dissection is a well-known complication. It is an uncommon occurrence in spinal surgery, and only one case after right anterior cervical spine surgery has been described so far. Despite its rarity, chylous leakage deserves a particular attention since it may become a serious and occasionally fatal complication if not detected early and managed appropriately.

Methods

We report the case of a 42-year-old man who underwent a standard anterior cervical discectomy and fusion according to Cloward approach for a C6–C7 disk herniation. The patient developed a delayed prevertebral chyle collection on postoperative day 5, presenting with mild breathing and swallowing difficulties.

Results

He was managed with conservative care, including bed rest, low-fat diet and drainage pouch positioning, which led to the complete resolution of the fluid collection.

Conclusions

Knowledge of the normal anatomy of the lymphatic system and of its variations is essential when planning an anterior spinal procedure, and represents the first measure to be adopted in order to avoid such complication. The prompt identification of a postoperative chylous fistula and the applicability of an individually based management's protocol may help in the majority of the cases to reduce the potential morbidity, without significant long-term effects.

https://ift.tt/2ElKdWi

Thermally stable and dielectric nanocomposite based on poly(arylene ether nitrile) and BaTiO 3 functionalized by modified mussel-inspired route

Abstract

Easy and efficient surface functionalization is critical for obtaining high-performance barium titanate (BaTiO₃) based dielectric polymer composites. We here demonstrated the easy surface functionalization of barium titanate via modified mussel-inspired method, using dopamine and silane coupling agent KH550 as reactive precursors. As-modified BaTiO₃ hybrid presented core-shell structure, which was further compounded with thermally stable poly(arylene ether nitrile)(PEN) via simple solution casting method, thus obtaining dielectric nanocomposite films. As a result, the dielectric constant of PEN was enhanced from 3.5 to 10.7 at 1 KHz by addition of 40 wt% BaTiO₃ hybrid, due to good dispersion of BaTiO₃ nanoparticles and its interfacial interaction with PEN matrix. Furthermore, as-prepared PEN composites exhibited low dielectric loss, which fluctuated in the range of 0.03 to 0.11 at 1 KHz. Besides, the thermal stability of PEN was significantly improved, and the tensile strength was well maintained even the weight ratio of BaTiO₃ hybrid reached 40 wt%. Therefore, thermally stable and dielectric PEN composite films show promising application in special area where high thermal stability, high strength, and high dielectric constant are needed.

https://ift.tt/2EhajKd