Effects of usual yoga practice on the diaphragmatic contractility: A cross-sectional controlled study.

Objectives: The aim of this study is to observe and compare the effects of regular yoga practice on the main inspiratory muscle, the diaphragm, by analyzing its thickness, excursion, velocity and contraction time, using ultrasound. Design: A Cross-Sectional Controlled Study. Participants: 80 healthy subjects (40 habitual yoga practitioners and 40 non-practitioners), without previous respiratory pathology participated in this study. During maximum diaphragmatic breathing, the diaphragmatic thickness (at rest and after maximum inspiration), excursion, velocity and contraction time were measured by ultrasound. Results: in the experimental group, practicing yoga, statistically significant differences (p < 0.001) were observed compared to the control group, not practicing, in the thickness of the diaphragm at rest (0.26 ± 0.02 vs 0.22 ± 0.01 cm); the diaphragmatic thickness in maximum inspiration (0.34 ± 0.03 vs 0.28 ± 0.03 cm); contraction velocity (1.54 ± 0.54 vs 2.23 ± 0.86 cm/s), contraction time (3.28 ± 0.45 vs 2.58 ± 0.49 s) and Borg scale of perceived exertion (1.05 ± 1.6 vs 1.70 ± 1.34), p = 0.05. However, the diaphragmatic excursion was greater in the control group (5.45 ± 1.42 vs 4.87 ± 1.33 cm) with no statistically significant differences (p = 0.06). Conclusions: the regular practice of yoga improves the parameters of diaphragm thickness, speed and contraction time measured in ultrasound and the sensation of perceived exertion during a maximum inspiration. So it can be considered as another method for training the inspiratory muscles in clinical practice.

Real-time ultrasound evaluation of CORE muscle activity in a simultaneous contraction in subjects with non-specific low back pain and without low-back pain. Protocol of an observational case-control study.

Non-specific low back pain represents 90-95% of all cases of low back pain and it has a prevalence of 18% in the adult population, assuming a great socioeconomic impact. The main objective of this observational case-control study study is to evaluate if there are differences in the simultaneous contraction of the core muscles between nonspecific low back pain and healthy subjects. This study will be carried out in the Physiotherapy department of the University of Alcalá. Eighty-two participants <18 years old, will be recruited, paired with NSLBP (n = 41) and healthy (n = 41). The main outcome will be the onset muscle contraction of lateral abdominal wall (internal oblique, external oblique and transversus abdominis), pelvic floor, lumbar multifidus and respiratory diafragm. The maneuvers that the subjects will perform will be abdominal drawing in maneouver, contralateral arm lift, valsalva, and voluntary pelvic floor contraction in sitting and standing. As a secondary objective, to analyze the amount of contraction of each muscle group and the capacity of the diaphragms to be excreted in both groups of subjects. Finally, to relate pain and disability.

Underage Problem Gambling: With Whom, Where and Why

BACKGROUND: Underage gambling is a widespread phenomenon with its own characteristics that differentiate it from adult gambling. In addition, problem gambling has shown a remarkable prevalence in previous studies. The present study examines underage gambling behaviour, studying its characteristics, as well as motivational and contextual aspects, and estimating the volume of problem gambling and possible moderating variables. METHOD: A sample of 9,681 students aged between 12 and 17 years old reported their involvement in gambling and filled in the Brief Adolescent Gambling Screen (BAGS), with 4,617 of them completing a questionnaire about gambling behaviours. RESULTS: Almost a quarter (23.5%) of the students reported having gambled in their lifetime (16.2% in-person, 1.4% online and 6% in both modalities), and 1.9% presented symptoms of problem gambling (BAGS ≥ 4). In-person gamblers preferred sport-betting machines, usually gambled in bars, and did not have their age checked. Online gamblers reported mainly sports betting, doing so on websites and paying with PayPal-like services and credit cards. Most gambled with friends and to win money. Problem gamblers were similar but gambled more frequently. CONCLUSIONS: These results present an image of the gambling situation among minors and, more importantly, of its context and related variables.

Inspiratory muscle strength and function in mechanically ventilated COVID-19 survivors 3 and 6†months after intensive care unit discharge.

Background: Knowledge regarding the long-term impact of invasive mechanical ventilation on the inspiratory muscles and functional outcomes in COVID-19 survivors is limited. Methods: In this single-centre prospective cohort study, we evaluated invasively ventilated patients with COVID-19 pneumonia 3 and 6 months post-intensive care unit (ICU) discharge. Outcomes included: maximal inspiratory pressure (MIP), ultrasound parameters for diaphragm function, 6-min walk distance (6MWD), dyspnoea and quality of life. We evaluated associations between MIP and duration of mechanical ventilation with follow-up outcomes. Results: 50 COVID-19 survivors discharged from ICU between 15 October 2020 and 1 April 2021 were enrolled. Overall, survivors showed a recovery trajectory over time. However, impaired MIP remained in 24 (48%) and 12 (24%) at 3 and 6 months, respectively. Diaphragm dysfunction was not observed. At 3 months, 23 (46%) had impaired functional capacity versus 10 (20%) at 6 months. Dyspnoea persisted in 44 (88%) patients at 3 months and 38 (76%) at 6 months. Quality of life was slightly decreased at 3 months with further improvements at 6 months. MIP was correlated to 6MWD, 6MWD % predicted, dyspnoea across follow-up, and quality of life at 3 months. The duration of invasive ventilation was correlated with 6MWD and 6MWD % predicted. Conclusion: In invasively ventilated COVID-19 survivors, inspiratory muscle strength impairments persisted 6 months after ICU discharge, while maintaining normal diaphragm function. Decreased functional capacity, dyspnoea and slightly reduced health status were observed. Early screening of survivors is of utmost importance to identify those with impairments and at risk of delayed or incomplete recovery.

Underage Problem Gambling: With Whom, Where and Why / El Juego de Azar Problemático en Menores de Edad: Con Quién, Dónde y Por Qué

Background: Underage gambling is a widespread phenomenon with its own characteristics that differentiate it fromadult gambling. In addition, problem gambling has shown a remarkable prevalence in previous studies. The presentstudy examines underage gambling behaviour, studying its characteristics, as well as motivational and contextualaspects, and estimating the volume of problem gambling and possible moderating variables. Method: A sample of 9,681students aged between 12 and 17 years old reported their involvement in gambling and filled in the Brief AdolescentGambling Screen (BAGS), with 4,617 of them completing a questionnaire about gambling behaviours. Results:Almost a quarter (23.5%) of the students reported having gambled in their lifetime (16.2% in-person, 1.4% online and6% in both modalities), and 1.9% presented symptoms of problem gambling (BAGS ≥ 4). In-person gamblers preferredsport-betting machines, usually gambled in bars, and did not have their age checked. Online gamblers reported mainlysports betting, doing so on websites and paying with PayPal-like services and credit cards. Most gambled with friendsand to win money. Problem gamblers were similar but gambled more frequently. Conclusions: These results present animage of the gambling situation among minors and, more importantly, of its context and related variables.(AU)

Antecedentes: La participación de menores de edad en juegos de azar es un fenómeno extendido con característicasdiferenciales respecto a las personas adultas y muestra una elevada prevalencia. El presente estudio examina la conductade juego en menores, estudiando sus características, aspectos motivacionales y contextuales, el volumen de juegoproblemático y las posibles variables moderadoras. Método: La muestra está compuesta por 9.681 estudiantes de 12 a17 años que cumplimentaron el Brief Adolescent Gambling Screen (BAGS), 4.617 adolescentes completaron ademásun cuestionario sobre hábitos. Resultados: El 23,5% ha apostado alguna vez en su vida (presencial: 16,2%; online:1,4%; ambas: 6%) y el 1,9% presenta síntomas de juego problemático (BAGS≥4). Quienes juegan presencialmenteprefieren las máquinas de apuestas deportivas; suelen apostar en bares y generalmente sin acreditar su edad. Quienesjuegan online principalmente hacen apuestas deportivas, a través de páginas web y pagan con servicios tipo PayPal ytarjetas de crédito. Suelen apostar con amigos y para ganar dinero, aunque mayoritariamente reconocen que es pocoprobable que esto llegue a ocurrir. Los/as jugadores/as problemáticos muestran características similares, pero apuestancon mayor frecuencia. Conclusiones: Estos resultados muestran la situación del juego en menores y permite determinarsus variables contextuales relacionadas.(AU)

Core Synergies Measured with Ultrasound in Subjects with Chronic Non-Specific Low Back Pain and Healthy Subjects: A Systematic Review.

Low back pain represents the leading cause of disability since 1990. In 90% of cases, it is classified as non-specific low back pain, being chronic in 10% of subjects. Ultrasound has proven to be an effective measurement tool to observe changes in the activity and morphology of the abdominal muscles. This article reviews which core synergies are studied with ultrasound in healthy subjects and with chronic non-specific low back pain. A systematic review was conducted on studies analyzing synergies between two or more core muscles. Publications from 2005 until July 2021 were identified by performing structured searched in Pubmed/MEDLINE, PEDro and WOS. Fifteen studies were eligible for the final systematic review. A total of 56% of the studies established synergies between the core muscles and 44% between the homo and contralateral sides of the core muscles. The most studied core synergies were transversus abdominis, internal oblique and external oblique followed by the rectus abdominis and the lumbar multifidus. No studies establishing synergies with diaphragm and pelvic floor were found. Eight studies were conducted in healthy subjects, five studies in subjects with chronic non-specific low back pain compared to healthy subjects and two studies in subjects with chronic non-specific low back pain.

Menores y consumo de cannabis: un análisis por género y edad / Minors and cannabis use: an analysis by gender and age

El consumo de cannabis sigue constituyendo a día de hoy uno de los principales problemas de salud pública en la población juvenil tanto española como europea. A las elevadas prevalencias de consumo actuales se unen nuevos formatos y nuevos rituales de consumo, niveles de THC significativamente mayores y edades de inicio especialmente tempranas, lo cual suscita una creciente preocupación social, especialmente cuando nos referimos a adolescentes. El presente trabajo, llevado a cabo con una muestra de casi 4.000 estudiantes de 12 a 17 años de la comunidad gallega, no sólo permite constatar los elevados niveles de consumo existentes a edades tempranas y tasas de consumo problemático alarmantes, sino que evidencia la interesante interacción entre las variables género y edad, que se da en las fases iniciales del consumo. Asumir que en términos generales puede haber o no diferencias de género en el consumo de cannabis implica ignorar el papel de las normas y roles de género en los procesos de socialización de las y los adolescentes. De forma más concreta, se ha constatado niveles de consumo y consumo problemático (evaluado a través del CAST) significativamente mayores entre las chicas a los 14-15 años, produciéndose una progresiva masculinización del consumo de cannabis a partir de dicha edad. Estos resultados poseen interesantes implicaciones a la hora de diseñar nuevas estrategias y políticas de prevención. (AU)

Cannabis use continues to be one of the main public health problems in the Spanish and European youth population. The current high prevalence of consumption is compounded by new formats and new consumption rituals, significantly higher THC levels and particularly early age of onset, which is of growing social concern, especially when referring to adolescents. The present study, carried out with a sample of almost 4,000 students aged 12 to 17 years in the Galician community, not only allows us to confirm the high levels of consumption at early ages and alarming rates of problematic consumption, but also shows the interesting interaction between gender and age variables, which occurs in the initial phases of consumption. Assuming that in general terms there may or may not be gender differences in cannabis use implies ignoring the role of gender norms and roles in the socialization processes of adolescents. More specifically, significantly higher levels of consumption and problematic use (assessed through the CAST) have been found among girls at 14-15 years of age, with a progressive masculinization of cannabis use from that age onwards. These results have interesting implications for the design of new prevention strategies and policies. (AU)

Scientific Productivity and Cancer-Related Mortality: A Case Study of a Positive Association in Colombia.

PURPOSE: Cancer morbidity represents an increasing public health issue; this worldwide phenomenon also is true for emerging upper-middle-income countries, such as Colombia. The main purpose of this study was to uncover the relationship between scientific productivity and cancer-related mortality in our setting. METHODS: We conducted a temporal-trend ecologic study by means of bibliometric analysis from records of publications from SCOPUS database with Colombian institutional affiliations between 2000 and 2015. Productivity and overall mortality were estimated and compared using econometric modeling to identify potential correlations. Additional exploratory analyses per six most frequent cancer sites were performed. RESULTS: Of 2,645 publication records retrieved, 1,464 (55.3%) met selection criteria to be classified as Colombian scientific production (interobserver agreement, 92.96%; κ = 0.859; 95% CI, 0.800 to 0.918). Overall, 79.6% of the records corresponded to original or in-press articles; furthermore, almost half (49.7%) embodied descriptive study designs. Selected records reported a median of five authors and three different affiliations per publication; 66% had been cited at least once up to September 2017. The most-studied cancer-specific locations were cervix (16.1%), breast (11.5%), and stomach (9.8%), but nonspecific locations had the largest combined participation (23.4%). An increasing trend in scientific productivity was correlated to decreasing trend in overall cancer mortality, which was reported as an inverse proportional relationship in the linear regression modeling (r = -0.958; P < .001). Graphic analyses per cancer-specific sites revealed heterogeneous behaviors of this relationship. CONCLUSION: Colombian cancer-specific scientific productivity demonstrated a steady growth as opposed to a decreasing mortality trend in the recent years. The research output is predominantly descriptive with relatively low interinstitutional partnership and low impact in the international scientific community.

Kernicterus in a boy with ornithine transcarbamylase deficiency: A case report.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle defect associated with severe and usually fatal hyperammonemia. This study describes a patient with early onset lethal OTCD due to a known pathogenic variant (c.298+1G>A), as well as the novel autopsy finding of kernicterus with relatively low blood concentration of unconjugated bilirubin (UCB) (11.55 mg/dL). The patient was a full-term male with a family history of two previous male siblings who died as newborns after acute neurologic deterioration. The patient's symptoms began at 24 h of life with lethargy that rapidly progressed to coma upon admission to the neonatal intensive care unit. Although hyperammonemia and hyperbilirubinemia were documented, hemofiltration could not be performed. OTCD diagnosis was biochemically established. Despite nutritional intervention and treatment for hyperammonemia, the patient died on the sixth day of life. At autopsy, external brain examination revealed a marked yellow pigmentation typical of kernicterus that included gray matter, particularly the thalamus and basal ganglia; dentate nuclei of the cerebellum and brain stem gray matter were also affected. Microscopic findings were consistent with the classical description of tissue damage in OTCD, including the presence of Alzheimer type II astrocytes in basal ganglia, necrosis, neuronal loss with spongiform degeneration and macrophage infiltration surrounded by astroglia. This condition may be an important comorbidity in newborns with hyperammonemia.

Tumor neuroectodérmico primitivo de la pared torácica: tumor de Askin en niños / Primitive neuroectodermal tumor of the chest wall: Askin tumor in children

Resumen Antecedentes. El tumor neuroectodérmico primitivo (TNEP) de la pared torácica o Tumor de Askin, es un tumor maligno clasificado dentro de los TNEP periféricos y perteneciente a los tumores de la familia del sarcoma de Ewing (FSE). Este tipo de neoplasia de la región toracopulmonar es muy poco frecuente y suele presentarse con mayor frecuencia en la población pediátrica. Objetivo. Describir algunas características de pacientes con Tumor de Askin de la Fundación Hospital La Misericordia. Materiales y métodos. Se realizó un análisis retrospectivo de los casos atendidos en una sola institución, Fundación Hospital de la Misericordia, en un lapso de 16 años. Resultados. Se encontraron 8 pacientes, 7 varones, 4 con metástasis al diagnóstico, 2 en pulmón y 2 en hueso, a 2 se les hizo resección quirúrgica completa del tumor al diagnóstico, los demás pacientes fueron llevados a biopsia y quimioterapia citoreductora previa a la cirugía para resección tumoral. Todos recibieron quimioterapia con protocolos para Sarcoma de Ewing y radioterapia en 6 casos. A la fecha están vivos 5 pacientes (62%) con una mediana de seguimiento de 32 meses; 3 de ellos tenían metástasis en el diagnóstico. De los 3 pacientes muertos, 2 no tenían metástasis en el diagnóstico, ambos recayeron y fallecieron por progresión de enfermedad; el otro abandonó el tratamiento a los 6 meses del diagnóstico. Dos pacientes en recaída recibieron quimioterapia de 2 líneas a altas dosis con rescate autólogo, uno está vivo y el otro falleció por progresión de la enfermedad. Conclusión. Se describieron las características clínicas, de laboratorio, diagnóstico, tratamiento y pronóstico de este grupo de pacientes.

Summary Background. The primitive neuroectodermal tumor (TNEP) of the chest wall, or Askin tumor, is a malignant neoplasia classified within the Ewing family of tumours (FSE). This particular type of malignancy of the chest wall is rare and usually appears in the pediatric population. Objective. Describe some characteristics of patients with Askin tumor of the Fundacion Hospital de La Misericordia. Materials and methods. A retrospective analysis of cases treated at a single institution, Fundación Hospital de la Misericordia, in a 16 years period was performed. Results. 8 patients were found, 7 boys, 4 with metastases at the diagnosis, 2 in lungs and 2 in bone, 2 underwent surgery at diagnosis. For the other 6 patients surgical resection was done after chemotherapy. All patients received chemotherapy and 6 received radiotherapy. To date, 5 patients are alive (62 %) with a median follow up of 32 months; 3 of them had metastases at diagnosis. 3 patients died, 2 of which had no metastases in the diagnosis, both relapsed and died of disease progression, the other abandoned treatment at 6 months after diagnosis. Other 2 patients that relapsed received chemotherapy plus autologous transplant, one is alive and the other one died due to disease progression. Conclusion. Clinical, laboratory, diagnosis, treatment and prognosis characteristics of this patient group were described.

LIGHT (TNFSF14/CD258) is a decisive factor for recovery from experimental autoimmune encephalomyelitis.

The TNF superfamily ligand LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator [HVEM], a receptor expressed by T lymphocytes) has been shown to play a role in T cell costimulation and be involved in apoptosis of mononuclear cells. As both T cells and monocytes are key components in the development and progression of experimental autoimmune encephalomyelitis (EAE), we studied the role of LIGHT in EAE. Following immunization with myelin oligodendrocyte glycoprotein peptide (35-55), LIGHT-deficient mice developed severe EAE that resulted in an atypically high mortality rate. Histological examinations revealed intensive activation of microglia/macrophages in the CNS and higher numbers of apoptotic cells within the CNS parenchyma of LIGHT-deficient mice. However, myelin oligodendrocyte glycoprotein peptide-specific CD4(+) T cells from LIGHT-deficient mice showed reduced IFN-γ and IL-17 production and migration. Serum levels of reactive nitrogen intermediates and CNS transcripts of several proinflammatory cytokines and chemokines were also substantially decreased in the absence of LIGHT. EAE adoptive transfer experiments and bone marrow chimeras indicated that expression of LIGHT on donor cells is not required for disease induction. However, its expression on CNS host cells is a decisive factor to limit disease progression and tissue damage. Together, these data show that LIGHT expression is crucially involved in controlling activated macrophages/microglia during autoimmune CNS inflammation.

Central nervous system expression and PET imaging of the translocator protein in relapsing-remitting experimental autoimmune encephalomyelitis.

UNLABELLED: Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111. METHODS: RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction. RESULTS: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE. CONCLUSION: PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies.

Demyelination caused by the copper chelator cuprizone halts T cell mediated autoimmune neuroinflammation.

Myelin reactive T cells are central in the development of the autoimmune response leading to CNS destruction in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis (EAE). Investigations on the mechanisms underlying the activation and expansion of myelin reactive T have stressed the importance of non-autoimmune conditions impinging the autoimmune repertoire potentially involved in the disease. Here, we show that CNS injury caused by the toxic cuprizone results in the generation of immunoreactivity towards several myelin components. Paradoxically, exposure to CNS injury does not increase the susceptibility to develop EAE, but render mice protected to the pathogenic autoimmune response against myelin antigens.

The innate immune response to adjuvants dictates the adaptive immune response to autoantigens.

To elucidate the role of innate immunity in susceptibility to the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we induced EAE by immunization with spinal cord homogenate (SCH) plus complete Freund adjuvant or carbonyl iron in 3 inbred rat strains. Lewis are considered "susceptible," PVG/c-Rt7a (PVG) as "semisusceptible," and Brown Norway (BN) as "resistant" to EAE. Immunization with SCH-carbonyl iron resulted in clinical disease in all 3 strains, but the pathologic features of EAE in the resistant BN and the semisusceptible PVG rats differed from those in the Lewis and PVG model of EAE induced with SCH-complete Freund adjuvant. In BN and PVG rats, there were numerous inflammatory lesions with prominent involvement of microglia and, to a lesser extent, perivascular macrophages. These data suggest that different levels of activation of the innate immune system by different adjuvants determine whether EAE will or will not develop. Accordingly, the widely accepted scale of susceptibility to EAE development (Lewis > PVG > BN) should be revised because it does not take into account the important contribution of the composition of the adjuvant to the quality and quantity of the innate immune response and, consequently, to the generation and extent of the pathogenic T-cell-mediated, that is, adaptive, autoimmune disease.

The contribution of nitric oxide and interferon gamma to the regulation of the neuro-inflammation in experimental autoimmune encephalomyelitis.

Nitric oxide (NO) is a key messenger involved in physiological functions including endothelium-dependent vascular relaxation, inhibition of platelet adhesion and aggregation and regulation of inflammatory and immune responses. Here we briefly introduce NO and its functions and then describe our work over the past several years examining the role of NO in EAE in both the rat and the mouse. We show that NO plays a significant role in determining the resistance or susceptibility to EAE in various strains and or sexes of animals. We demonstrate that NO down-regulates several aspects of CNS inflammation but also has a dual role in that it is required for inflammation in some situations.

Neuronal nitric oxide synthase plays a key role in CNS demyelination.

Nitric oxide (NO) is a small, short-lived molecule released from a variety of cells that is implicated in a multitude of biological processes. In pathological conditions, overproduction of NO may lead to the generation of highly reactive species, such as peroxynitrite and stable nitrosothiols, that may cause irreversible cell damage. Accordingly, several studies have suggested that NO may be involved in the pathogenesis of various neuroinflammatory/degenerative diseases. Increased concentrations of NO in the CNS in such cases are usually attributed to an increase in the inducible isoform of NO synthase (iNOS) usually produced by inflammatory cells. However, recent reports have suggested that the constitutive isoforms of NOS, neuronal (nNOS) and endothelial (eNOS), can also play a role. Here we examined the role that the constitutive isoforms of NOS might play in the cuprizone-induced model of demyelination/remyelination. Our results demonstrate that demyelination was greatly prevented in mice lacking nNOS. Protection was associated with a dramatic increase in mature oligodendrocyte survival and a decrease in apoptosis. Moreover, nNOS-/- mice did not respond to cuprizone with the extensive recruitment of microglia/macrophages and astrocytes, which is a typical feature in wild-type mice. Although demyelinating less, nNOS-/- mice exhibited a delay in remyelination. In eNOS-/- mice, demyelination progressed to the same extent as in wild type, but they showed a slight delay in spontaneous remyelination. In conclusion, this study highlights the importance of considering the source of NO when assessing its role in neuroinflammation/degeneration and emphasizes the differing pathological effects driven by the different NOS isoforms.

A BAFF antagonist suppresses experimental autoimmune encephalomyelitis by targeting cell-mediated and humoral immune responses.

BAFF [B cell-activating factor of the tumour necrosis factor (TNF) family] and APRIL (a proliferation-inducing ligand) are two TNF family members with shared receptors. While, physiological roles for APRIL are not fully understood, BAFF is critical for B cell homeostasis and also acts as a co-stimulator of T cells. Using a B and T cell-mediated mouse model of multiple sclerosis (MS), myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), we observed that a BAFF/APRIL antagonist (soluble BCMA-Fc) inhibited central nervous system inflammation and demyelination such that it suppressed the onset and progression of clinical symptoms of EAE. In addition to dramatically reducing the titre of MOG-specific auto-antibodies, this treatment also induced a switch in the subtype of the T(h) cell population characterized by marked alterations in cytokine production following re-stimulation with MOG in vitro. Indeed, hBCMA-Fc therapy led to significant increases in the level of transforming growth factor beta, while the levels of T(h)1 cytokines were markedly diminished. These results not only identify BAFF as a critical factor in maintaining humoral immunity in EAE but also support its role in T lymphocyte responses. Our findings demonstrate that hBCMA-Fc acts on both effector arms of the immune response in EAE, a characteristic that may be of significant therapeutic value in the treatment of MS.

Deleterious role of IFNgamma in a toxic model of central nervous system demyelination.

Interferon-gamma (IFNgamma) is a pleiotropic cytokine that plays an important role in many inflammatory processes, including autoimmune diseases such as multiple sclerosis (MS). Demyelination is a hallmark of MS and a prominent pathological feature of several other inflammatory diseases of the central nervous system, including experimental autoimmune encephalomyelitis, an animal model of MS. Accordingly, in this study we followed the effect of IFNgamma in the demyelination and remyelination process by using an experimental autoimmune encephalomyelitis model of demyelination/remyelination after exposure of mice to the neurotoxic agent cuprizone. We show that demyelination in response to cuprizone is delayed in mice lacking the binding chain of IFNgamma receptor. In addition, IFNgammaR(-/-) mice exhibited an accelerated remyelination process after cuprizone was removed from the diet. Our results also indicate that the levels of IFNgamma were able to modulate the microglia/macrophage recruitment to the demyelinating areas. Moreover, the accelerated regenerative response showed by the IFNgammaR(-/-) mice was associated with a more efficient recruitment of oligodendrocyte precursor cells in the demyelinated areas. In conclusion, this study suggests that IFNgamma regulates the development and resolution of the demyelinating syndrome and may be associated with toxic effects on both mature oligodendrocytes and oligodendrocyte precursor cells.

Single-step purification and refolding of recombinant mouse and human myelin oligodendrocyte glycoprotein and induction of EAE in mice.

The extracellular domain of human and rat MOG (ED-MOG) induces experimental autoimmune encephalomyelitis (EAE) when injected into susceptible animals. EAE is a T cell-mediated disease of the central nervous system commonly used as an animal model for human multiple sclerosis. Here, we describe a straightforward procedure for the purification and refolding of mouse and human ED-MOG overexpressed in Escherichia coli as inclusion bodies. Following solubilization and purification using Ni-NTA resin chromatography under denaturing conditions, a column-based refolding proceeded in renaturation buffer supplemented with a glutathione redox buffer system. Using this approach up to 33 mg of highly pure soluble proteins was obtained per liter of expression culture. The ability of purified proteins to induce EAE was evaluated in three strains of mice. We believe that the strategy described here would facilitate researchers to carry out encephalitogenic as well as structure-function studies of this autoantigen. Additionally, we show for the first time that mouse ED-MOG induces severe disease in mice.

Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Although the etiology of MS remains unknown, studies in experimental autoimmune encephalomyelitis (EAE) have suggested that foreign molecules, which show molecular mimicry with myelin antigens, may play an important role as causative agents of the human disease. In this study, we investigate the molecular mimicry between the extracellular Ig-like domain of the cow's milk protein butyrophilin (BTN) and the extracellular domain of myelin oligodendrocyte glycoprotein (MOG), a candidate autoantigen in MS. Interestingly, we found that as a result of a non-pathogenic cross-reactivity that is localized to a subdominant region of MOG, treatment of C57BL/6 mice with BTN either before or after immunization with MOG was shown to prevent and also suppress the clinical manifestations of EAE. BTN treatment resulted in a significant reduction in both proliferation and production of Th1-related cytokines (IFN-gamma, IL-2, IL-12 and granulocyte macrophage colony stimulating factor) in response to MOG. This specific inhibition was consistently associated with an up-regulation in IL-10 secretion. Furthermore, adoptive transfer of BTN-specific T cells prior to active immunization with MOG resulted in a transitory reduction of the clinical symptoms. Our results suggest that the clinical improvement associated with BTN treatment involved the combination of both anergy and regulatory cells secreting high levels of IL-10. In conclusion, we show that despite the traditional link between molecular mimicry and pathogenic immune response, environmental agents that share homology with autoantigens may also represent a source of cells with a protective phenotype.