Evaluación de resultados tras la aplicación de esteroides epidurales caudales no particulados en pacientes con dolor lumbar, experiencia en un hospital militar / Evaluation of results after the application of non-particulated flowring epidural steroids in patients with lumbar pain, experience in a military hospital

Introducción: El dolor lumbar es uno de los principales motivos de consulta en diferentes escenarios clínicos; entre las causas más frecuentes de dolor lumbar se encuentra el canal lumbar estrecho, discopatía y radiculopatías, por lo que se han establecido diferentes modalidades de tratamiento que incluyen medidas invasivas, como las inyecciones de esteroides epidurales vía caudal. Objetivo: Evaluar la mejoría del dolor lumbar después de la aplicación de esteroides epidurales caudales no particulados en la población con dolor crónico lumbar bajo secundario a canal lumbar estrecho, discopatía y radiculopatía lumbar de un hospital en Bogotá, Colombia. Metodología: Se realizó un estudio observacional retrospectivo en el que se evaluó la reducción del dolor, en pacientes con diagnóstico de dolor lumbar crónico secundario a canal lumbar estrecho, radiculopatía, discopatía, mediante escala visualanáloga del dolor EVA seis meses después de la aplicación de dexametasona 8 mg vía epidural caudal en 147 pacientes en un período de 2 años. Resultados: Se evaluaron 147 pacientes con dolor lumbar crónico, de los cuales 58.32% eran mujeres y 47.76% hombres, con edades entre 44 y 77 años, de los cuales 50% eran mayores o igual a 65 años y 75% mayor o igual a 77 años. En la evaluación inicial del dolor lumbar, se encontró que el 50% de los pacientes tenían una EVA inicial mayor o igual a 8/10 y el 75% informó un EVA inicial 10/10. Se encontró que el canal lumbar estrecho fue la principal causa de dolor lumbar en el 53,06% de los pacientes, seguido de la enfermedad del disco lumbar el 49,66% y en el tercer lugar, los pacientes con radiculopatía lumbar correspondieron al 19.73% de la población. Sobre la mejoría del dolor de una manera particular, se encontró una mayor reducción del dolor en pacientes con enfermedad de disco lumbar 48,21%, seguido de estrecho canal lumbar estrecho 41,37% y radiculopatías lumbares 33,3%. En el análisis comparativo por patología aislada, la intervención no presentó una mejora considerable, sin embargo, cuando más de una de las entidades estudiadas coexistieron en el mismo paciente, hubo una mejoría significativa del dolor, por lo que en el 66,5% de los pacientes diagnosticados con un canal lumbar estrecho y radiculopatía, la mejoría de la lumbalgia y la radiculopatía disminuyó, de la misma forma que los pacientes que presentaron discopatía y radiculopatía tuvieron un alivio del dolor del 66% y, finalmente, aquellos con discopatía y canal lumbar estrecho, 60% tuvieron una reducción del dolor después del procedimiento. Conclusión: La aplicación de esteroides no particulados vía epidural caudal proporciona una mejora sintomática significativa en un porcentaje considerable de pacientes sometidos al procedimiento, especialmente en aquellos que tienen más de una de las causas de dolor lumbar crónico expuesta, por lo que se constituye en una medida invasiva de tratamiento efectivo para el dolor lumbar en este tipo de pacientes.

Introduction: Low back pain is one of the main reasons for consultation in different clinical scenarios; among the most frequent causes of low back pain is the narrow lumbar canal, discopathy and radiculopathies, which is why different modalities have been established of treatment including invasive measures such as injections of epidural steroids caudal via. Objective: To evaluate the improvement of lumbar pain after application of non-particulate caudal epidural steroid via in the population with chronic low lumbar pain in the narrow lumbar canal, discopathy and lumbar radiculopathy of a military hospital in Bogotá, Colombia. Methodology: A retrospective observational study was performed in which the pain reduction measured by visual analogous scale of pain VAS was evaluated six months after the application of dexamethasone 8 mg caudal epidural via in 147 patients in a period of 2 years Results: 147 patients with chronic low back pain were evaluated, of which 58.32% were women and 47.76% men, with ages between 44 and 77 years, of which 50% were greater than or equal to 65 years and 75 % greater than or equal to 77 years. Concerning the initial evaluation of lumbar pain, it was found that 50% of the patients had an initial VAS greater than or equal to 8/10 and 75% reported an initial VAS 10/10. Regarding the prevalence of causes of low back pain in the evaluated patients, it was found that the narrow lumbar canal was the main cause in 53.06% of the patients, followed by lumbar disc disease 49.66% and in the third place patients with lumbar radiculopathy corresponded 19.73% of the population. About pain improvement in a particular way, greater pain reduction was found in patients with lumbar disc disease 48.21%, followed by narrow lumbar canal 41.37% and lumbar radiculopathies 33.3%. In the comparative analysis due to isolated pathology, the intervention did not present a considerable improvement, however, when more than one of the entities studied coexisted in the same patient, there was a significant improvement in pain, thus 66.5% of the patients diagnosed with a canal. Narrow lumbar and radiculopathy improved, in the same way those patients who presented with discopathy and radiculopathy 66% had relief of pain and finally those with discopathy and narrow lumbar canal 60% had pain reduction after the procedure. Conclusion: The application of non-particulate steroid via caudal epidural provides significant symptomatic improvement in a considerable percentage of patients undergoing the procedure, especially in those who have more than one of the causes of chronic low back pain exposed and evaluated, thus being able to constitute an invasive measure of effective treatment for low back pain in this type of patients.

Examining the factors that affect structural repetition in question answering.

We present two experiments that examine structural priming in the single-trial phone-call paradigm introduced by Levelt and Kelter (Cognitive psychology, 14 (1), 78-106, 1982). Experimenters called businesses and asked either What time do you close? or At what time do you close? Participants were more likely to produce a prepositional response (At 7 o'clock vs. 7 o'clock) following a prepositional question than following a non-prepositional question. Experiments 1 and 2 attempted to strengthen the priming effect by having the experimenters engage in a brief interaction with the participant before asking the What time…? question. The interactions did not reliably affect the observed priming effect. An analysis across experiments demonstrated that the priming effect found in this paradigm is generally smaller than the average structural priming effect (as reported in Mahowald, James, Futrell, & Gibson, Journal of Memory and Language, 91, 5-27, 2016), but within the range of the effects that are observed in different structural priming paradigms.

Cavß2 transcription start site variants modulate calcium handling in newborn rat cardiomyocytes.

In the heart, the main pathway for calcium influx is mediated by L-type calcium channels, a multi-subunit complex composed of the pore-forming subunit CaV1.2 and the auxiliary subunits CaVα2δ1 and CaVß2. To date, five distinct CaVß2 transcriptional start site (TSS) variants (CaVß2a-e) varying only in the composition and length of the N-terminal domain have been described, each of them granting distinct biophysical properties to the L-type current. However, the physiological role of these variants in Ca(2+) handling in the native tissue has not been explored. Our results show that four of these variants are present in neonatal rat cardiomyocytes. The contribution of those CaVß2 TSS variants on endogenous L-type current and Ca(2+) handling was explored by adenoviral-mediated overexpression of each CaVß2 variant in cultured newborn rat cardiomyocytes. As expected, all CaVß2 TSS variants increased L-type current density and produced distinctive changes on L-type calcium channel (LTCC) current activation and inactivation kinetics. The characteristics of the induced calcium transients were dependent on the TSS variant overexpressed. Moreover, the amplitude of the calcium transients varied depending on the subunit involved, being higher in cardiomyocytes transduced with CaVß2a and smaller in CaVß2d. Interestingly, the contribution of Ca(2+) influx and Ca(2+) release on total calcium transients, as well as the sarcoplasmic calcium content, was found to be TSS-variant-dependent. Remarkably, determination of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) messenger RNA (mRNA) abundance and cell size change indicates that CaVß2 TSS variants modulate the cardiomyocyte hypertrophic state. In summary, we demonstrate that expression of individual CaVß2 TSS variants regulates calcium handling in cardiomyocytes and, consequently, has significant repercussion in the development of hypertrophy.

Increases in reactive oxygen species enhance vascular endothelial cell migration through a mechanism dependent on the transient receptor potential melastatin 4 ion channel.

A hallmark of severe inflammation is reactive oxygen species (ROS) overproduction induced by increased inflammatory mediators secretion. During systemic inflammation, inflammation mediators circulating in the bloodstream interact with endothelial cells (ECs) raising intracellular oxidative stress at the endothelial monolayer. Oxidative stress mediates several pathological functions, including an exacerbated EC migration. Because cell migration critically depends on calcium channel-mediated Ca(2+) influx, the molecular identification of the calcium channel involved in oxidative stress-modulated EC migration has been the subject of intense investigation. The transient receptor potential melastatin 4 (TRPM4) protein is a ROS-modulated non-selective cationic channel that performs several cell functions, including regulating intracellular Ca(2+) overload and Ca(2+) oscillation. This channel is expressed in multiple tissues, including ECs, and contributes to the migration of certain immune cells. However, whether the TRPM4 ion channel participates in oxidative stress-mediated EC migration is not known. Herein, we investigate whether oxidative stress initiates or enhances EC migration and study the role played by the ROS-modulated TRPM4 ion channel in oxidative stress-mediated EC migration. We demonstrate that oxidative stress enhances, but does not initiate, EC migration in a dose-dependent manner. Notably, we demonstrate that the TRPM4 ion channel is critical in promoting H2O2-enhanced EC migration. These results show that TRPM4 is a novel pharmacological target for the possible treatment of severe inflammation and other oxidative stress-mediated inflammatory diseases.

Endotoxin-induced vascular endothelial cell migration is dependent on TLR4/NF-κB pathway, NAD(P)H oxidase activation, and transient receptor potential melastatin 7 calcium channel activity.

Endothelial dysfunction is decisive and leads to the development of several inflammatory diseases. Endotoxemia-derived sepsis syndrome exhibits a broad inflammation-induced endothelial dysfunction. We reported previously that the endotoxin, lipopolysaccharide (LPS), induces the conversion of endothelial cells (ECs) into activated fibroblasts, showing a myofibroblast-like protein expression profile. Enhanced migration is a hallmark of myofibroblast function. However, the mechanism involved in LPS-induced EC migration is no totally understood. Some studies have shown that the transient receptor potential melastatin 7 (TRPM7) ion channel is involved in fibroblast and tumor cell migration through the regulation of calcium influx. Furthermore, LPS modulates TRPM7 expression. However, whether TRPM7 is involved in LPS-induced EC migration remains unknown. Here, we study the participation of LPS as an inducer of EC migration and study the mechanism underlying evaluating the participation of the TRPM7 ion channel. Our results demonstrate that LPS induced EC migration in a dose-dependent manner. Furthermore, this migratory process was mediated by the TLR-4/NF-κB pathway and the generation of ROS through the PKC-activated NAD(P)H oxidase. In addition, LPS increased the intracellular calcium level and the number of focal adhesion kinase (FAK)-positive focal adhesions in EC. Finally, we demonstrate that using TRPM7 blockers or suppressing TRPM7 expression through siRNA successfully inhibits the calcium influx and the LPS-induced EC migration. These results point out TRPM7 as a new target in the drug design for several inflammatory diseases that impair vascular endothelium function.

Lipopolysaccharide induces a fibrotic-like phenotype in endothelial cells.

Endothelial dysfunction is crucial in endotoxaemia-derived sepsis syndrome pathogenesis. It is well accepted that lipopolysaccharide (LPS) induces endothelial dysfunction through immune system activation. However, LPS can also directly generate actions in endothelial cells (ECs) in the absence of participation by immune cells. Although interactions between LPS and ECs evoke endothelial death, a significant portion of ECs are resistant to LPS challenge. However, the mechanism that confers endothelial resistance to LPS is not known. LPS-resistant ECs exhibit a fibroblast-like morphology, suggesting that these ECs enter a fibrotic programme in response to LPS. Thus, our aim was to investigate whether LPS is able to induce endothelial fibrosis in the absence of immune cells and explore the underlying mechanism. Using primary cultures of ECs and culturing intact blood vessels, we demonstrated that LPS is a crucial factor to induce endothelial fibrosis. We demonstrated that LPS was able and sufficient to promote endothelial fibrosis, in the absence of immune cells through an activin receptor-like kinase 5 (ALK5) activity-dependent mechanism. LPS-challenged ECs showed an up-regulation of both fibroblast-specific protein expression and extracellular matrix proteins secretion, as well as a down-regulation of endothelial markers. These results demonstrate that LPS is a crucial factor in inducing endothelial fibrosis in the absence of immune cells through an ALK5-dependent mechanism. It is noteworthy that LPS-induced endothelial fibrosis perpetuates endothelial dysfunction as a maladaptive process rather than a survival mechanism for protection against LPS. These findings are useful in improving current treatment against endotoxaemia-derived sepsis syndrome and other inflammatory diseases.

Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death.

AIMS: Endothelial dysfunction is decisive in the progression of cardiovascular diseases. Lipopolysaccharide (LPS)-induced reactive oxygen species (ROS)-mediated endothelial cell death is a main feature observed in inflammation secondary to endotoxaemia, emerging as a leading cause of death among critically ill patients in intensive care units. However, the molecular mechanism underlying LPS-induced endothelial cell death is not well understood. Transient receptor protein melastatin 4 (TRPM4) is an ion channel associated with cell death that is expressed in endothelium and modulated by ROS. Here, we investigate the role of TRPM4 in LPS-induced endothelial cell death, testing whether suppression of the expression of TRPM4 confers endothelial cell resistance to LPS challenge. METHODS AND RESULTS: Using primary cultures of human umbilical vein endothelial cells (HUVEC), we demonstrate that TRPM4 is critically involved in LPS-induced endothelial cell death. HUVEC exposed to LPS results in Na(+)-dependent cell death. Pharmacological inhibition of TRPM4 with 9-phenanthrol or glibenclamide protects endothelium against LPS exposure for 48 h. Furthermore, TRPM4-like currents increase in cells pre-treated with LPS and inhibited with glibenclamide. Of note, suppression of TRPM4 expression by siRNA or suppression of its activity in a dominant negative mutant is effective in decreasing LPS-induced endothelial cell death when cells are exposed to LPS for 24-30 h. CONCLUSION: TRPM4 is critically involved in LPS-induced endothelial cell death. These results demonstrate that either pharmacological inhibition of TRPM4, suppression of TRPM4 expression, or inhibition of TRPM4 activity are able to protect endothelium against LPS injury. These results are useful in sepsis drug design and development of new strategies for sepsis therapy.

Increased expression of the transient receptor potential melastatin 7 channel is critically involved in lipopolysaccharide-induced reactive oxygen species-mediated neuronal death.

AIMS: To assess the mechanisms involved in lipopolysaccharide (LPS)-induced neuronal cell death, we examined the cellular consequences of LPS exposure in differentiated PC12 neurons and primary hippocampal neurons. RESULTS: Our data show that LPS is able to induce PC12 neuronal cell death without the participation of glial cells. Neuronal cell death was mediated by an increase in cellular reactive oxygen species (ROS) levels. Considering the prevalent role of specific ion channels in mediating the deleterious effect of ROS, we assessed their contribution to this process. Neurons exposed to LPS showed a significant intracellular Ca(2+) overload, and nonselective cationic channel blockers inhibited LPS-induced neuronal death. In particular, we observed that both LPS and hydrogen peroxide exposure strongly increased the expression of the transient receptor protein melastatin 7 (TRPM7), which is an ion channel directly implicated in neuronal cell death. Further, both LPS-induced TRPM7 overexpression and LPS-induced neuronal cell death were decreased with dithiothreitol, dipheniliodonium, and apocynin. Finally, knockdown of TRPM7 expression using small interference RNA technology protected primary hippocampal neurons and differentiated PC12 neurons from the LPS challenge. INNOVATION: This is the first report showing that TRPM7 is a key protein involved in neuronal death after LPS challenge. CONCLUSION: We conclude that LPS promotes an abnormal ROS-dependent TRPM7 overexpression, which plays a crucial role in pathologic events, thus leading to neuronal dysfunction and death.