Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects.

Between 2.5 and 28% of people infected with SARS-CoV-2 suffer Long COVID or persistence of symptoms for months after acute illness. Many symptoms are neurological, but the brain changes underlying the neuropsychological impairments remain unclear. This study aimed to provide a detailed description of the cognitive profile, the pattern of brain alterations in Long COVID and the potential association between them. To address these objectives, 83 patients with persistent neurological symptoms after COVID-19 were recruited, and 22 now healthy controls chosen because they had suffered COVID-19 but did not experience persistent neurological symptoms. Patients and controls were matched for age, sex and educational level. All participants were assessed by clinical interview, comprehensive standardized neuropsychological tests and structural MRI. The mean global cognitive function of patients with Long COVID assessed by ACE III screening test (Overall Cognitive level - OCLz= -0.39± 0.12) was significantly below the infection recovered-controls (OCLz= +0.32± 0.16, p< 0.01). We observed that 48% of patients with Long COVID had episodic memory deficit, with 27% also impaired overall cognitive function, especially attention, working memory, processing speed and verbal fluency. The MRI examination included grey matter morphometry and whole brain structural connectivity analysis. Compared to infection recovered controls, patients had thinner cortex in a specific cluster centred on the left posterior superior temporal gyrus. In addition, lower fractional anisotropy (FA) and higher radial diffusivity (RD) were observed in widespread areas of the patients' cerebral white matter relative to these controls. Correlations between cognitive status and brain abnormalities revealed a relationship between altered connectivity of white matter regions and impairments of episodic memory, overall cognitive function, attention and verbal fluency. This study shows that patients with neurological Long COVID suffer brain changes, especially in several white matter areas, and these are associated with impairments of specific cognitive functions.

RND3 Potentiates Proinflammatory Activation through NOTCH Signaling in Activated Macrophages.

Macrophage activation is a complex process with multiple control elements that ensures an adequate response to the aggressor pathogens and, on the other hand, avoids an excess of inflammatory activity that could cause tissue damage. In this study, we have identified RND3, a small GTP-binding protein, as a new element in the complex signaling process that leads to macrophage activation. We show that RND3 expression is transiently induced in macrophages activated through Toll receptors and potentiated by IFN-γ. We also demonstrate that RND3 increases NOTCH signaling in macrophages by favoring NOTCH1 expression and its nuclear activity; however, Rnd3 expression seems to be inhibited by NOTCH signaling, setting up a negative regulatory feedback loop. Moreover, increased RND3 protein levels seem to potentiate NFκB and STAT1 transcriptional activity resulting in increased expression of proinflammatory genes, such as Tnf-α, Irf-1, or Cxcl-10. Altogether, our results indicate that RND3 seems to be a new regulatory element which could control the activation of macrophages, able to fine tune the inflammatory response through NOTCH.

NOTCH4 potentiates the IL-13 induced genetic program in M2 alternative macrophages through the AP1 and IRF4-JMJD3 axis.

IL-13 signaling polarizes macrophages to an M2 alternatively activated phenotype, which regulates tissue repair and anti-inflammatory responses. However, an excessive activation of this pathway leads to severe pathologies, such as allergic airway inflammation and asthma. In this work, we identified NOTCH4 receptor as an important modulator of M2 macrophage activation. We show that the expression of NOTCH4 is induced by IL-13, mediated by Janus kinases and AP1 activity, probably mediated by the IL-13Rα1 and IL-13Rα2 signaling pathway. Furthermore, we demonstrate an important role for NOTCH4 signaling in the IL-13 induced gene expression program in macrophages, including various genes that contribute to pathogenesis of the airways in asthma, such as ARG1, YM1, CCL24, IL-10, or CD-163. We also demonstrate that NOTCH4 signaling modulates IL-13-induced gene expression by increasing IRF4 activity, mediated, at least in part, by the expression of the histone H3K27me3 demethylase JMJD3, and by increasing AP1-dependent transcription. In summary, our results provide evidence for an important role of NOTCH4 signaling in alternative activation of macrophages by IL-13 and suggest that NOTCH4 may contribute to the increased severity of lesions in M2 inflammatory responses, such as allergic asthma, which points to NOTCH4 as a potential new target for the treatment of these pathologies.

NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling.

NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1. Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation.

NOTCH3 signaling is essential for NF-κB activation in TLR-activated macrophages.

Macrophage activation by Toll receptors is an essential event in the development of the response against pathogens. NOTCH signaling pathway is involved in the control of macrophage activation and the inflammatory processes. In this work, we have characterized NOTCH signaling in macrophages activated by Toll-like receptor (TLR) triggering and determined that DLL1 and DLL4 are the main ligands responsible for NOTCH signaling. We have identified ADAM10 as the main protease implicated in NOTCH processing and activation. We have also observed that furin, which processes NOTCH receptors, is induced by TLR signaling in a NOTCH-dependent manner. NOTCH3 is the only NOTCH receptor expressed in resting macrophages. Its expression increased rapidly in the first hours after TLR4 activation, followed by a gradual decrease, which was coincident with an elevation of the expression of the other NOTCH receptors. All NOTCH1, 2 and 3 contribute to the increased NOTCH signaling detected in activated macrophages. We also observed a crosstalk between NOTCH3 and NOTCH1 during macrophage activation. Finally, our results highlight the relevance of NOTCH3 in the activation of NF-κB, increasing p65 phosphorylation by p38 MAP kinase. Our data identify, for the first time, NOTCH3 as a relevant player in the control of inflammation.

Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming.

Inhibition of Notch signalling in T cells attenuates the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Growing evidence indicates that myeloid cells are also key players in autoimmune processes. Thus, the present study evaluates the role of the Notch1 receptor in myeloid cells on the progression of myelin oligodendrocyte glycoprotein (MOG)35-55 -induced EAE, using mice with a myeloid-specific deletion of the Notch1 gene (MyeNotch1KO). We found that EAE progression was less severe in the absence of Notch1 in myeloid cells. Thus, histopathological analysis revealed reduced pathology in the spinal cord of MyeNotch1KO mice, with decreased microglia/astrocyte activation, demyelination and infiltration of CD4+ T cells. Moreover, these mice showed lower Th1 and Th17 cell infiltration and expression of IFN-γ and IL-17 mRNA in the spinal cord. Accordingly, splenocytes from MyeNotch1KO mice reactivated in vitro presented reduced Th1 and Th17 activation, and lower expression of IL-12, IL-23, TNF-α, IL-6, and CD86. Moreover, reactivated wild-type splenocytes showed increased Notch1 expression, arguing for a specific involvement of this receptor in autoimmune T cell activation in secondary lymphoid tissues. In summary, our results reveal a key role of the Notch1 receptor in myeloid cells for the initiation and progression of EAE.

The Tetraspanin TSPAN33 Controls TLR-Triggered Macrophage Activation through Modulation of NOTCH Signaling.

The involvement of NOTCH signaling in macrophage activation by Toll receptors has been clearly established, but the factors and pathways controlling NOTCH signaling during this process have not been completely delineated yet. We have characterized the role of TSPAN33, a tetraspanin implicated in a disintegrin and metalloproteinase (ADAM) 10 maturation, during macrophage proinflammatory activation. Tspan33 expression increases in response to TLR signaling, including responses triggered by TLR4, TLR3, and TLR2 activation, and it is enhanced by IFN-γ. In this study, we report that induction of Tspan33 expression by TLR and IFN-γ is largely dependent on NOTCH signaling, as its expression is clearly diminished in macrophages lacking Notch1 and Notch2 expression, but it is enhanced after overexpression of a constitutively active intracellular domain of NOTCH1. TSPAN33 is the member of the TspanC8 tetraspanin subgroup more intensely induced during macrophage activation, and its overexpression increases ADAM10, but not ADAM17, maturation. TSPAN33 favors NOTCH processing at the membrane by modulating ADAM10 and/or Presenilin1 activity, thus increasing NOTCH signaling in activated macrophages. Moreover, TSPAN33 modulates TLR-induced proinflammatory gene expression, at least in part, by increasing NF-κB-dependent transcriptional activity. Our results suggest that TSPAN33 represents a new control element in the development of inflammation by macrophages that could constitute a potential therapeutic target.

Actualización de la Guía Mexicana para el Tratamiento Farmacológico de la Artritis Reumatoide del Colegio Mexicano de Reumatología / Update of the Mexican College of Rheumatology Guidelines for the Pharmacologic Treatment of Rheumatoid Arthritis

Antecedentes: El manejo de la artritis reumatoide ha tenido avances muy importantes en los últimos a˜nos. Las guías de práctica clínica requieren una actualización constante. Recientemente se han publicado diversas guías internacionales para el manejo farmacológico de la artritis reumatoide que difícilmente se adaptan a la realidad mexicana, en especial por la heterogénea disponibilidad de los medicamentos en las diversas instituciones del sector salud. Por ello, debido a la importancia de unificar el criterio de manejo con los tratamientos disponibles, el Colegio Mexicano de Reumatología decidió revisar las guías existentes e incorporar nueva evidencia actualizada y adaptada a la realidad del sistema de salud mexicano. Objetivo: Revisar, actualizar y adaptar la guía del manejo farmacológico de la artritis reumatoide y emitir recomendaciones adaptadas al sistema de salud de México, de acuerdo con manejos disponibles hasta diciembre de 2012. Método: Participaron en la elaboración de la guía 30 reumatólogos certificados con experiencia y juicio clínico. Las recomendaciones se basaron en niveles de evidencia de las guías de tratamiento previamente establecidas, ensayos clínicos controlados y guías estandarizadas para población adulta con artritis reumatoide. Resultados: Durante la conformación del documento, cada grupo de trabajo estableció la evidencia existente sobre los diferentes temas a tratar según su campo de mayor experiencia clínica, siendo enriquecida por la opinión de los demás expertos. Al final, toda la evidencia y las decisiones tomadas se unificaron en un manuscrito, se desarrolló un algoritmo de tratamiento y se resumieron en tablas estandarizadas por medicamento. onclusiones: La actualización de la Guía Mexicana para el Tratamiento Farmacológico de la Artritis Reumatoide integra la mejor información disponible para la toma de decisiones y contextualiza su empleo al complejo y heterogéneo sistema de salud mexicano (AU)

Background: The pharmacologic management of rheumatoid arthritis has progressed substantially over the past years. It is therefore desirable that existing information be periodically updated. There are several published international guidelines for the treatment of rheumatoid arthritis that hardly adapt to the Mexican health system because of its limited healthcare resources. Hence, it is imperative to unify the existing recommendations and to incorporate them to a set of clinical, updated recommendations;the Mexican College of Rheumatology developed these recommendations in order to offer an integral management approach of rheumatoid arthritis according to the resources of the Mexican health system. Objective: To review, update and improve the available evidence within clinical practice guidelines on the pharmacological management of rheumatoid arthritis and produce a set of recommendations adapted to the Mexican health system, according to evidence available through December 2012. Methods: The working group was composed of 30 trained and experienced rheumatologists with a high quality of clinical knowledge and judgment. Recommendations were based on the highest quality evidence from the previously established treatment guidelines, meta-analysis and controlled clinical trials for the adult population with rheumatoid arthritis. Results: During the conformation of this document, each working group settled the existing evidence from he different topics according to their experience. Finally, all the evidence and decisions were unified into a single document, treatment algorithm and drug standardization tables. Conclusions: This update of the Mexican Guidelines for the Pharmacologic Treatment of Rheumatoid Arthritis provides the highest quality information available at the time the working group undertook this review and contextualizes its use for the complex Mexican health system (AU)

Update of the Mexican College of Rheumatology guidelines for the pharmacologic treatment of rheumatoid arthritis.

BACKGROUND: The pharmacologic management of rheumatoid arthritis has progressed substantially over the past years. It is therefore desirable that existing information be periodically updated. There are several published international guidelines for the treatment of rheumatoid arthritis that hardly adapt to the Mexican health system because of its limited healthcare resources. Hence, it is imperative to unify the existing recommendations and to incorporate them to a set of clinical, updated recommendations; the Mexican College of Rheumatology developed these recommendations in order to offer an integral management approach of rheumatoid arthritis according to the resources of the Mexican health system. OBJECTIVE: To review, update and improve the available evidence within clinical practice guidelines on the pharmacological management of rheumatoid arthritis and produce a set of recommendations adapted to the Mexican health system, according to evidence available through December 2012. METHODS: The working group was composed of 30 trained and experienced rheumatologists with a high quality of clinical knowledge and judgment. Recommendations were based on the highest quality evidence from the previously established treatment guidelines, meta-analysis and controlled clinical trials for the adult population with rheumatoid arthritis. RESULTS: During the conformation of this document, each working group settled the existing evidence from the different topics according to their experience. Finally, all the evidence and decisions were unified into a single document, treatment algorithm and drug standardization tables. CONCLUSIONS: This update of the Mexican Guidelines for the Pharmacologic Treatment of Rheumatoid Arthritis provides the highest quality information available at the time the working group undertook this review and contextualizes its use for the complex Mexican health system.

Sarcomas sinoviales en el área sanitaria de Lugo en el período de 2002 a 2006 / Synovial sarcomas in Lugo between 2002–2006

Objetivo Estudiar las características epidemiológicas y clínicas de todos los pacientes adultos diagnosticados de sarcoma sinovial (SS) en el período de 2002 a 2006 en el Hospital Xeral-Calde de Lugo. Pacientes y método Estudio retrospectivo de todos los pacientes mayores de 18 años diagnosticados mediante estudio de anatomía patológica de SS desde enero de 2002 hasta diciembre de 2006. Este hospital da asistencia sanitaria a 250.000 habitantes. Resultados Un total de 4 casos (3 mujeres) cumplían los criterios establecidos para este estudio, con edades comprendidas entre los 22 y los 41 años (media de 35 años).El motivo de consulta fue tumoración (media de 6,7cm) y dolor predominantemente en las extremidades inferiores. El retraso diagnóstico promedio fue de 17 meses, aunque en algún caso se llegó a los 2,5 años. Excepto para el caso de SS de localización cervical, un mayor retraso al diagnóstico se correlacionó con un mayor tamaño del tumor y un estadio más avanzado. El seguimiento medio de los enfermos fue de 25,5 meses. Un paciente falleció al cabo de un año y medio del diagnóstico. Conclusiones El promedio de incidencia mínima estimada de los SS en mayores de 18 años en el área de Lugo fue de 0,32 por cada 105 habitantes al año. A pesar de su baja incidencia, ante una persona joven que presenta una masa, a veces dolorosa, en las extremidades inferiores, debe incluirse el SS en el diagnóstico diferencial. Un mayor índice de sospecha por parte de los médicos puede evitar un diagnóstico tardío (AU)

Objective To study the clinical and epidemiological characteristics of all adults patients as having synovial sarcoma in the Hospital Xeral-Calde (Lugo) between 2002 and 2006.Patients and method. We conducted a retrospective study of the case records of all adults patients diagnosed with synovial sarcoma from January 2002 through December 2006. Patients were considered to be adults if they were more than 18. In all cases a tissue-biopsy sample showing synovial sarcoma was required. The Hospital Xeral-Calde is the only referral center for a population of almost 250.000 people. Results Four cases (3 women) met the classification criteria for this study. The mean age was 35 years old (range, 22–41).The most common presentation was a palpable mass (mean 6.7cm.) associated with pain in lower extremities. The mean delay for the diagnosis was 17 months, but in one case has been noted as long as 2.5 years. Unlike the neck synovial sarcoma case, a long delay in the diagnosis implied a major tumor size and a higher histologic grade. The mean follow-up was 25.5 months; one patient died 1.5 years after the diagnosis. Conclusions The overall annual incidence rate of synovial sarcoma in the Lugo region between January 2002 and 2006 for the population older than 18 years was a minimum estimate 0.32/105. Better physician awareness may contribute to the progressive increase in the recognition of this condition, especially in young people presenting with palpable mass. A long delay at the diagnosis implied a poor prognosis (AU)

[Synovial sarcomas in Lugo between 2002-2006]. / Sarcomas sinoviales en el área sanitaria de Lugo en el período de 2002 a 2006.

OBJECTIVE: To study the clinical and epidemiological characteristics of all adults patients as having synovial sarcoma in the Hospital Xeral-Calde (Lugo) between 2002 and 2006. PATIENTS AND METHOD: We conducted a retrospective study of the case records of all adults patients diagnosed with synovial sarcoma from January 2002 through December 2006. Patients were considered to be adults if they were more than 18. In all cases a tissue-biopsy sample showing synovial sarcoma was required. The Hospital Xeral-Calde is the only referral center for a population of almost 250.000 people. RESULTS: Four cases (3 women) met the classification criteria for this study. The mean age was 35 years old (range, 22-41). The most common presentation was a palpable mass (mean 6.7cm.) associated with pain in lower extremities. The mean delay for the diagnosis was 17 months, but in one case has been noted as long as 2.5 years. Unlike the neck synovial sarcoma case, a long delay in the diagnosis implied a major tumor size and a higher histologic grade. The mean follow-up was 25.5 months; one patient died 1.5 years after the diagnosis. CONCLUSIONS: The overall annual incidence rate of synovial sarcoma in the Lugo region between January 2002 and 2006 for the population older than 18 years was a minimum estimate 0.32/10(5). Better physician awareness may contribute to the progressive increase in the recognition of this condition, especially in young people presenting with palpable mass. A long delay at the diagnosis implied a poor prognosis.