Targeted Analysis of Tears Revealed Specific Altered Metal Homeostasis in Age-Related Macular Degeneration

PurposeSpecific altered metal homeostasis has been investigated in the tear film of age-related macular degeneration (AMD) patients considering that metal dyshomeostasis contributes to the production of free radicals, inflammation, and apoptosis and results in conformational changes of proteins.MethodsA multitargeted approach based on spectrophotometry and mass spectrometry techniques has been implemented to the multiplexed quantitation of lactoferrin (LF), S100 calcium binding protein A6 (S100A6), metallothionein 1A (MT1A), complement factor H (CFH), clusterin (CLU), amyloid precursor protein (APP), Mg, P, Na, Fe, Cu, Zn, and Ca, in the tear film from 60 subjects, 31 patients diagnosed with the dry form of AMD, and 29 healthy individualsResultsSignificant up-regulations of MT1A (1.9-fold) and S100A6 (1.4-fold) and down-regulations of LF (0.7-fold), Fe (0.6-fold), Mg (0.7-fold), and Cu (0.7-fold) were observed in AMD patients, when compared to control subjects. Of all the studied variables, only APP showed negative correlation with age in the AMD group. Also, positive correlations were observed for the variables Mg and Na, Cu and Mg, and P and Mg in both the AMD and control groups, whereas positive correlations were exclusively determined in the AMD group for Cu and LF, Na and Ca, and Mg and Ca. The panel constituted of MT1A, Na, and Mg predicts AMD disease in 73% of cases.ConclusionsThe different levels of target metals and (metallo-)proteins in the tear film suggest altered metal homeostasis in AMD patients. These observed pathophysiological changes may be related with the anomalous protein aggregation in the macula.     

Cutaneous, pulmonary and bone aspergillosis in a patient presumed immunocompetent presenting subacute cutaneous lupus erythematosus

INTRODUCTION: We report a case of cutaneous, pulmonary and bone aspergillosis successfully treated after many years of progression in a patient presumed immunocompetent presenting subacute cutaneous lupus erythematosus. CASE-REPORT: A 43-year-old man, treated with thalidomide for subacute cutaneous lupus erythematosus, presented chest pain with haemoptysis and dyspnea. A pulmonary nodule was detected but the microbiological investigation was negative. The histological examination showed granuloma with round structures. No cause was found. Three years later, skin lesions appeared on the patient's face concomitantly with a pulmonary relapse. Histopathological examination of these lesions demonstrated septate hyphae. Aspergillus fumigatus was isolated in skin and lung. Disseminated aspergillosis was then diagnosed as spondylodiscitis developed. Treatment with combined voriconazole and caspofungin produced significant and rapid improvement of lesions. DISCUSSION: While aspergillosis is commonly seen in immunocompetent patients, angiotropic dissemination points to cellular immunodepression. Our patient, however, was not presenting immunodepression. We discuss the possible contributory role of thalidomide in dissemination of aspergillosis given that the literature to date contains only one reported case of cutaneous aspergillosis secondary to A. fumigatus in an immunocompetent patient. We would also point out the specific histopathological pattern of this disseminated aspergillosis with both septate hyphae and round structures. Invasive aspergillosis is highly lethal but the chances of recovery are now greater thanks to new antifungal agents.     

Huntington’s disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington’s disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule–positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.     

Adherence to Antidepressant Therapies in Patients with Depressive Disorders Attending an Outpatient Clinic in a Public Mental Health Hospital,Antioquia, Colombia in 2017

Psychiatric Quarterly - To evaluate the level of adherence to antidepressant therapies and associated factors in patients with depressive disorders. a cross-sectional analytical study was conducted...     

γ‐Aminobutyric acid‐ρ expression in ependymal glial cells of the mouse cerebellum

The ependymal glial cells (EGCs) from the periventricular zone of the cerebellum were studied to determine their distribution and the functional properties of their γ‐aminobutyric acid type A (GABA_A) receptors. EGCs were identified by the presence of ciliated structures on their ventricular surface and their expression of glial fibrillary acidic protein (GFAP). Interestingly, diverse cell types, including neurons, astrocytes, and other types of glia, were identified in the subventricular zone by their current profiles. Electron microscopy showed ciliated cells and myelinated axons in this zone, but we found no collateral connections to suggest the presence of functional synapses. GABA‐mediated currents were recorded from EGCs in cerebellar slices from postnatal days 13 to 35 (PN13–PN35). These currents were blocked by TPMPA (a highly specific GABA_Aρ subunit antagonist) and bicuculline (a selective antagonist for classic GABA_A receptors). Pentobarbital failed to modulate GABA_A‐mediated currents despite the expression of GABAα1 and GABAγ2 subunits. In situ hybridization, RT‐PCR, and immunofluorescence studies confirmed GABAρ1 expression in EGCs of the cerebellum. We conclude that cerebellar EGCs express GABAρ1, which is functionally involved in GABA_A receptor‐mediated responses that are unique among glial cells of the brain. © 2013 Wiley Periodicals, Inc.     

Integrative physiological assessment of cerebral hemodynamics and metabolism in acute ischemic stroke

Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)—termed cerebral autoregulation (CA)—bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to ‘identify novel therapeutic targets for treatment and management in acute ischemic stroke’. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.     

Technological insights： Combined impedance manometry for esophageal motility testing-current results and further implications

INTRODUCTION The basic function of the esophagus is the transport of the bolus from the pharynx into the stomach. Esophageal peristalsis is based on propulsive mechanisms along the axis of the organ, generated by a latency gradient that is modulated by th…     

Selective effect of conjugated linoleic acid isomers on atherosclerotic lesion development in apolipoprotein E knockout mice

Research suggests that conjugated linoleic acid (CLA) may inhibit atherosclerosis, but there are contradictory results in different animal models fed heterogeneous mixtures of CLA isomers. This study addressed the hypothesis that the individual CLA isomers may exert different atherogenic properties. ApoE(-/-) mice were fed isocaloric, isonitrogenous westernized diets containing 0.15% cholesterol and enriched with 1% (w/w) cis-9,trans-11-CLA (c9,t11-CLA), trans-10,cis-12-CLA (t10,c12-CLA) or linoleic acid (control diet) for 12 weeks. At the end of the dietary intervention, the effects of CLA isomers on the development of atherosclerotic vascular lesions, lipid metabolism, inflammation and oxidative stress were assessed. The t10,c12-CLA diet had a profound pro-atherogenic effect, whereas c9,t11-CLA impeded the development of atherosclerosis. En face aortic lesion assessment showed more dorsal and lumbar extensions presenting atherosclerotic foci after the t10,c12-CLA diet. Furthermore, animals fed t10,c12-CLA had pronounced hyperlipidemia, higher 8-iso-prostaglandin F(2alpha) levels, higher vulnerable atherosclerotic plaque with a lower smooth muscle and fibre contents and higher macrophage content and activation, assayed as plasma chitotriosidase compared to the control or c9,t11-CLA dietary groups. Plasma chitotriosidase activity was more closely associated with the extent of the plaque than with MOMA staining or than monocyte chemoattractant protein-1 levels. Our results demonstrate that CLA isomers differentially modulate the development of atherosclerosis, c9,t11-CLA impedes, whereas t10,c12-CLA promotes atherosclerosis. These opposing effects may be ascribed to divergent effects on lipid, oxidative, inflammatory and fibro muscular components of this pathology. Plasma chitotriosidase is a better indicator of dietary fat interventions that alter plaque monocyte activity in this murine model.