Efficient biomarkers for diabetic nephropathy (DN) have not been established. Using ELISA, we found previously that urinary levels of full-length megalin (C-megalin), a multiligand endocytic receptor in proximal tubules, was positively correlated with DN progression in patients with type 2 diabetes mellitus (T2DM). Here, we found that urinary extracellular vesicle (UEV) excretion and C-megalin content in UEVs or in their exosomal fraction increased along with the progression of the albuminuric stages in patients with T2DM. Cultured immortalized rat proximal tubule cells (IRPTCs) treated with fatty acid-free BSA or advanced glycation end product-modified BSA (AGE-BSA), endocytic ligands of megalin, increased EV excretion, and their C-megalin content. C-megalin excretion from IRPTCs via extracellular vesicles was significantly blocked by an exosome-specific inhibitor, GW4869, indicating that this excretion is mainly exocytosis-mediated. AGE-BSA treatment of IRPTCs caused apparent lysosomal dysfunction, which stimulated multivesicular body formation, resulting in increased exosomal C-megalin excretion. In a high-fat diet-induced, megalin-mediated kidney injury model in mice, urinary C-megalin excretion also increased via UEVs. Collectively, exocytosis-mediated urinary C-megalin excretion is associated with the development and progression of DN in patients with T2DM, particularly due to megalin-mediated lysosomal dysfunction in proximal tubules, and hence it could be a candidate biomarker linked with DN pathogenesis.

Oral administration of K71 can be useful in dogs with cAD as a complementary therapy, by providing a steroid-sparing effect.

Social stress has a high impact on many biological systems in the brain, including serotonergic (5-HT) system—a major drug target in the current treatment for depression. Hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and monoamine oxidase A (MAO-A) are well-known stress responses, which are involved in the central 5-HT system. Although, many MAO-A inhibitors have been developed and used in the therapeutics of depression, effective management of depression by modulating the activity of MAO-A has not been achieved. Identifying the molecular pathways that regulate the activity of MAO-A in the brain is crucial for developing new drug targets for precise control of MAO-A activity. Over the last few decades, several regulatory pathways of MAO-A consisting of Kruppel like factor 11 (KLF11), Sirtuin1, Ring finger protein in neural stem cells (RINES), and Cell division cycle associated 7-like protein (R1) have been identified, and the influence of social stress on these regulatory factors evaluated. This review explores various aspects of these pathways to expand our understanding of the roles of the HPA axis and MAO-A regulatory pathways during social stress. The first part of this review introduces some components of the HPA axis, explains how stress affects them and how they interact with the 5-HT system in the brain. The second part summarizes the novel regulatory pathways of MAO-A, which have high potential as novel therapeutic targets for depression.

No abstract

Dear Sir: Juvenile nasopharyngeal angiofibroma (JNA) is a benign, highly vascular tumor that predominantly affects prepubescent or pubescent males. JNA is an uncommon disease and its incidence is approximately 0.05 to 0.5% of head and neck tumors [2]. The specific point of origin of the JNA is presumed to be the posterolateral wall of the roof of the nose, where the sphenoid process of the palatine bone meets the horizontal ala of the vomer and the root of the medial pterygoid process [12]. Surgery remains the most effective method of treatment for JNA, but can be complicated by massive bleeding. Surgical approaches to tumors without intracranial invasion include lateral rhinotomy, sublabial degloving, and/or transpalatal or transzygomatic resections [6]. We employed a transnasal endoscopic technique for resection of a JNA with the KTP laser. Case reportA 13-year-old Japanese boy presented with left nasal obstruction and recurrent epistaxis that had worsened over the past year. Transnasal endoscopic examination revealed a smooth mass with engorging blood vessels on surface filling the posterior nasal cavity and extending medially and inferiorly to the posterior end of the middle turbinate ( Fig. 1). Magnetic resonance imaging (MRI) showed a well-enhanced mass, at the left posterior nasal cavity, extending to the nasopharynx (Fig. 2). External carotid arteriography demonstrated an intensely vascular mass supplied by the distal internal maxillary artery (Fig. 3). Findings were consistent with a JNA and the distal internal maxillary and ascending arteries were embolized with polyvinyl alcohol. A transnasal endoscopic approach was then used to remove the tumor 7 days after embolization.At surgery, the reduction of tumor was evident, and the anatomical relation between tumor and adjacent structures was visualized to show that tumor was adherent to the lateral nasal wall of the left posterior nasal cavity and nasopharynx. These origins were vaporized with a KTP laser and released piece by piece using a cutting forceps. Tumor was removed in two main parts. After removal of the bulk of the tumor, its base was vaporized with the KTP laser. Posterior nasal packing was placed with a Foley catheter and nasal tampon. Total operating time was about 2 h, and blood loss was approximately 20 cc. The patient was given antibiotics (Cefditoren pivoxil) for 1 week. Three days after the operation, the Foley balloon was deflated. On postoperative day 5, all of the nasal packing was removed. No bleeding occurred postoperatively, and the patient's course was unremarkable.Pathological examination of excised tumor showed proliferation of dilated capillary vessels and spindle fibroblasts in a subepithelial lesion, which was consistent with JNA ( Fig. 4). Endoscopic follow-up for the next 6 months and MRI scan 6 months postoperatively showed no evidence of recurrence or residual tumor (Fig. 5). CommentThe differential diagnosis of JNA includes inflammatory polyp with neovascularization, hemangioma and a well-vascularized granuloma [4]. CT sc...