Myostatin and CXCL11 promote nervous tissue macrophages to maintain osteoarthritis pain.

Pain is the most debilitating symptom of knee osteoarthritis (OA) that can even persist after total knee replacement. The severity and duration of pain do not correlate well with joint tissue alterations, suggesting other mechanisms may drive pain persistence in OA. Previous work identified that macrophages accumulate in the dorsal root ganglia (DRG) containing the somas of sensory neurons innervating the injured knee joint in a mouse OA model and acquire a M1-like phenotype to maintain pain. Here we aimed to unravel the mechanisms that govern DRG macrophage accumulation and programming. The accumulation of F4/80+iNOS+ (M1-like) DRG macrophages was detectable at day 3 after mono-iodoacetate (MIA)-induced OA in the mouse. Depletion of macrophages prior to induction of OA resolved pain-like behaviors by day 7 without affecting the initial development of pain-like behaviors. Analysis of DRG transcript identified CXCL11 and myostatin. CXCL11 and myostatin were increased at 3 weeks post OA induction, with CXCL11 expression partially localized in satellite glial cells and myostatin in sensory neurons. Blocking CXCL11 or myostatin prevented the persistence of OA pain, without affecting the initiation of pain. CXCL11 neutralization reduced the number of total and F4/80+iNOS+ DRG macrophages, whilst myostatin inhibition diminished the programming of F4/80+iNOS+ DRG macrophages. Intrathecal injection of recombinant CXCL11 did not induce pain-associated behaviors. In contrast, intrathecal myostatin increased the number of F4/80+iNOS+ DRG macrophages concurrent with the development of mechanical hypersensitivity that was prevented by macrophages depletion or CXCL11 blockade. Finally, myostatin inhibition during established OA, resolved pain and F4/80+iNOS+ macrophage accumulation in the DRG. In conclusion, DRG macrophages maintain OA pain, but are not required for the induction of OA pain. Myostatin is a key ligand in neuro-immune communication that drives the persistence of pain in OA through nervous tissue macrophages and represent a novel therapeutic target for the treatment of OA pain.

NLRP3 inflammasome activation in sensory neurons promotes chronic inflammatory and osteoarthritis pain.

Pain is one of the most debilitating symptoms in rheumatic diseases. Pain often persists after total knee replacement in osteoarthritis, or when inflammation is minimal/absent in rheumatoid arthritis. This suggests that pain transitions to a chronic state independent of the original damage/inflammation. Mitochondrial dysfunction in the nervous system promotes chronic pain and is linked to NLRP3 inflammasome activation. Therefore, we investigated the role of mitochondrial dysfunction and NLRP3 inflammasome activation in the transition from acute to persistent inflammation-induced nociplastic pain and in persistent monoiodoacetate-induced osteoarthritis pain. Intraplantar injection of carrageenan in mice induced transient inflammatory pain that resolved within 7 days. A subsequent intraplantar PGE2 injection induced persistent mechanical hypersensitivity, while in naive mice it resolved within one day. Thus, this initial transient inflammation induced maladaptive nociceptor neuroplasticity, so-called hyperalgesic priming. At Day 7, when mice were primed, expression of NLRP3 inflammasome pathway components was increased, and dorsal root ganglia (DRG) neurons displayed signs of activated NLRP3 inflammasome. Inhibition of NLRP3 inflammasome with MCC950 prevented the transition from acute to chronic pain in this hyperalgesic priming model. In mice with persistent monoiodoacetate-induced osteoarthritis pain, DRG neurons displayed signs of mitochondrial oxidative stress and NLRP3 inflammasome activation. Blocking NLRP3 inflammasome activity attenuated established osteoarthritis pain. In males, NLPR3 inhibition had longer-lasting effects than in females. Overall, these data suggest that NLRP3 inflammasome activation in sensory neurons, potentially caused by neuronal oxidative stress, promotes development of persistent inflammatory and osteoarthritis pain. Therefore, targeting NLRP3 inflammasome pathway may be a promising approach to treat chronic pain.

Thermal Behavior of Graphene Oxide Deposited on 3D-Printed Polylactic Acid for Photothermal Therapy: An Experimental-Numerical Analysis.

The present work evaluates the thermal behavior of graphene oxide (GO) when deposited on 3D-printed polylactic acid (PLA), in order to develop a medical device for photothermal therapy applications. An experimental-numerical analysis was performed to assess the photothermal conversion capacity, based on the power emitted by a NIR (785 nm) laser, and the subsequent temperature distribution on the GO-PLA material. The influence of the deposited mass of GO and the PLA thickness was studied through 40 different scenarios. The results estimated a value of photothermal conversion efficiency of up to 32.6%, achieved for the lower laser power density that was tested (0.335 mW/mm²), and a high mass value of deposited GO (1.024 × 10-3 mg/mm²). In fact, an optimal mass of GO in the range of 1.024-2.048 × 10-3 mg/mm2 is proposed, in terms of absorption capacity, since a higher mass of GO would not increase the conversion efficiency. Moreover, the study allowed for an estimation of the thermal conductivity of this specific biomaterial (0.064 W/m·K), and proved that a proper combination of GO mass, PLA thickness, and laser power can induce ablative (>60 °C, in a concentrated area), moderate (50 °C), and mild (43 °C) hyperthermia on the bottom face of the biomaterial.

Numerical modelling of osteocyte growth on different bone tissue scaffolds.

The most common solution for the regeneration or replacement of damaged bones is the implantation of prostheses comprising ceramic or metallic materials. However, these implants are known to cause problems such as post-operative infections, collapse of the prosthesis, and lack of osseointegration. Consequently, bone tissue engineering was established because of the limitations of such implants. Osteogenic implants offer promising solutions for bone regeneration; however, three-dimensional scaffolds should be used as supportive structures. It is challenging to correctly design these structures and their compositions or properties to provide a microenvironment that promotes tissue regeneration and expedites bone formation. Computational fluid dynamics can be used to model the main phenomena that occur in bioreactors, such as cell metabolism, nutrient transport, and cell culture growth, or to model the influence of several key mechanisms related to the fluid medium, in particular, the wall shear stress. In this work, a new numerical bone cell growth model was developed, which considered the oxygen and nutrient consumption as well as the wall shear stress effect on cell proliferation. The model was implemented using 35 three-dimensional scaffolds of different porosities, and the effect of the main geometrical parameters involved in each scaffold type was analysed. The porosity plays an important role, however, a similar porosity did not guarantee similar shear stress or cell growth among the scaffolds. Randomised trabecular scaffolds, that more closely resembled trabecular bone, showed the highest cell growth values, so these are the best candidates for cell growth in a bioreactor.

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain.

The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking. Here, we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain.

Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain.SIGNIFICANCE STATEMENT In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.

Experiencia inicial en un centro único del uso de neocuerdas preformadas en reparación mitral / Experience with Premeasured Chordal Loops for Mitral Valve Repair: A Uselful and Reproducible Technique?

RESUMEN Introducción: La reparación de la válvula mitral ha demostrado superioridad por sobre el reemplazo valvular en el tratamiento de la insuficiencia mitral degenerativa. Objetivo: El propósito de este trabajo es demostrar la utilización de neocuerdas de politetrafluoroetileno expandido preformadas para la realización de una plástica mitral exitosa. Material y métodos: Entre marzo y diciembre del 2018 se intervinieron 13 pacientes con insuficiencia mitral grave quirúrgica por enfermedad degenerativa con criterios quirúrgicos a los cuales se les implantó cuerdas nuevas preformadas para la reparación mitral en el Hospital Universitario Austral. Resultados: Se repararon en forma exitosa la insuficiencia mitral grave a los 13 pacientes colocando neocuerdas preformadas en la valva posterior en 6 pacientes; en la valva anterior, en 4 pacientes; y, en ambas valvas, en 3 pacientes. Conclusiones: Las neocuerdas de politetrafluoroetileno permitieron realizar la plástica reparadora de la insuficiencia mitral en forma satisfactoria, segura y reproducible para el prolapso de cualquier segmento valvular mitral.

ABSTRACT Background: Mitral valve repair has demonstrated better outcomes compared with valve replacement for the treatment of degenerative mitral regurgitation. Objective: The aim of this study is to show the experience with premeasured expanded polytetrafluoroethylene chordal loops for successful mitral valve repair. Methods: Between May and December 2018, 13 patients with severe mitral regurgitation caused by degenerative disease with indication for surgery underwent mitral valve repair at the Hospital Universitario Austral. Results: The procedure was successful in the 13 patients. Chordal loops were applied to the anterior leaflet in 4 patients, to the posterior leaflet in 6 patients and to both anterior and posterior leaflets in 3 patients.

Is the second internal thoracic artery better than the radial artery in total arterial off-pump coronary artery bypass grafting? A propensity score-matched follow-up study.

OBJECTIVE: The aim of our study was to evaluate the long-term outcome of patients exclusively undergoing total arterial revascularization off-pump coronary artery bypass grafting and to compare the performance of the radial artery and the right internal thoracic artery as a second conduit. METHODS: We studied a consecutive series of 1700 patients undergoing off-pump coronary artery bypass grafting, receiving a radial artery or right internal thoracic artery as a second graft for total arterial revascularization, between 2003 and 2010. A total of 1447 patients (85.11%) received bilateral internal thoracic artery grafting, and 253 patients (14.89%) received left internal thoracic artery and radial artery grafting. A propensity score-matched analysis was performed to compare the 2 groups, bilateral internal thoracic artery and left internal thoracic artery and radial artery, relative to overall survival, morbidity, and combined end points event-free survival. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were estimated by Cox regression. RESULTS: In the full unmatched patient population, the postoperative survival (HR, 0.59; 95% CI, 0.38-0.92; P = .021), incidence of reintervention/readmission (HR, 0.42; 95% CI, 0.28-0.61; P < .001), and combined end points (HR, 0.47; 95% CI, 0.35-0.63; P < .001) were significantly better in the bilateral internal thoracic artery group. In the propensity score-matched patient population, the incidence of reintervention/readmission (HR, 0.40; 95% CI, 0.18-0.88; P = .02) and combined end points (HR, 0.54; 95% CI, 0.32-0.92; P = .02) were significantly better in the bilateral internal thoracic artery group compared with the left internal thoracic artery-radial artery group. CONCLUSIONS: The results of our study provide evidence for the superiority of the right internal thoracic artery graft compared with the radial artery as a second conduit in total arterial revascularization off-pump coronary artery bypass grafting.

Medicina para el aeropasajero colombiano / Medicine for the colombian air passenger. If Not Now, When?

En las últimas décadas el tráfico aéreo se ha incrementado, y con ello la cantidad de pasajeros que diariamente atraviesan el mundo usando este medio de trasporte quienes se exponen cada vez más a un ambiente hostil y confinado. Este ambiente puede exacerbar enfermedades subyacentes o actuar como detonante en la aparición de otras, incluyendo la transmisión de enfermedades infecciosas en muy corto tiempo. Estas adversidades en su gran mayoría son prevenibles y a bajo costo, tanto para las empresas aéreas como para los sistemas de salud. Sin embargo, a la fecha, en Colombia no se tiene información que permita plantear intervenciones preventivas sobre esta población expuesta a riesgos que, en numerosas ocasiones derivan de una práctica inexistente de la medicina del viajero, pudiendo esto generar grandes problemas, en la salud pública local y mundial.