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BACKGROUND: Belimumab was the first biological drug approved for the treatment of systemic lupus erythematosus (SLE) patients. Phase II/III randomized controlled trials and real-life studies identified patients with musculoskeletal involvement as best responders. OBJECTIVES: To evaluate the effectiveness of belimumab in SLE-related joint involvement. METHODS: The cohort comprised SLE patients receiving belimumab for musculoskeletal indications. Belimumab was intravenously administrated according to protocols; all the patients were evaluated at baseline (T0) and after 3 (T1), 6 (T2), and 12 (T3) months. We assessed joint activity by disease activity score 28, simple disease activity index (SDAI), clinical disease activity index (CDAI), and swollen tender ratio. Each patient underwent musculoskeletal ultrasound of 34 joints to assess synovial effusion synovial hypertrophy, and power Doppler; by using a semi-quantitative scale (0-3) we obtained the total inflammatory score (0-216). RESULTS: We evaluated 20 patients (males/females 1/19, median age 45 years [interquartile range (IQR) 12], median disease duration 144 months [IQR 144]). CDAI and SDAI significantly decreased at T1 (P = 0.02 and P = 0.01 respectively) and this improvement was maintained at the following time-points (CDAI: T2 P = 0.008, T3 P = 0.004; SDAI: T2 P = 0.006, T3 P = 0.01). A significant reduction of median ultrasound score was identified at T1 (T0 20.5 [IQR 13.5] vs. T1 7.5 [IQR 4.7], P < 0.001), and maintained at T2 (7.0 [IQR 5], P < 0.0001), and T3 (7.0 [IQR 9.0], P < 0.0001). CONCLUSIONS: Belimumab induces a sustained improvement of ultrasound-detected inflammatory status at the articular level.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunosupresores/uso terapéutico , Artropatías/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Femenino , Humanos , Artropatías/diagnóstico por imagen , Estudios Longitudinales , Lupus Eritematoso Sistémico/diagnóstico por imagen , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Kidney biopsy is the gold standard for the diagnosis of lupus nephritis (LN). Conventional biomarkers of disease activity or renal function, such as complement levels, anti-dsDNA, serum creatinine, urinary sediment and proteinuria, do not have a sensitive diagnostic and prognostic value, therefore new biomarkers are needed to help predict or monitor LN. Osteopontin (OPN) is a pro-inflammatory molecule detectable in serum and renal tissue. The aim of this study was to evaluate OPN as a biomarker of renal involvement in patients with systemic lupus erythematosus (SLE) and correlate its levels with disease activity and laboratory features. METHODS: OPN was measured in the serum and urine of SLE patients with active LN (n=14), LN in remission (n=20), SLE without kidney involvement (n=22) and age- and sex-matched healthy controls (HC, n=20). RESULTS: OPN levels were significantly higher in urine than in serum in both groups of patients and controls (p<0.001). Serum OPN levels were higher in the LN patients than in HC and in SLE patients without renal involvement (p<0.0001 and 0.0032, respectively), regardless of the phase of renal activity. SLE patients without renal involvement and controls showed similar serum levels. We detected a direct correlation between low complement levels and OPN serum levels in patients with LN (p=0.014; R=0.438). Moreover, a higher percentage of patients with LN, compared to SLE without LN and HC, showed abnormal serum OPN. CONCLUSIONS: Our data suggest that serum OPN could be considered a biomarker of renal involvement, without differentiating between active and remission LN.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Osteopontina/fisiología , Biomarcadores/sangre , Humanos , Riñón , Lupus Eritematoso Sistémico/sangre , Nefritis Lúpica/sangre , Osteopontina/sangreRESUMEN
Patients treated with the TNF antagonist adalimumab develop anti-therapeutic antibodies (ATA), the prevalence of which varies depending on the assay used. Most assays are compromised due to the presence of adalimumab in the clinical samples. Our objective was to develop an antibody assay, applicable for clinical testing, which overcomes the limitation of therapeutic interference and to further determine the relationship between ATA development, adalimumab levels and disease activity in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Use of an electrochemiluminescence platform permitted development of fit-for-purpose immunoassays. Serum samples from patients, taken prior to and at 12 and 24â¯weeks of treatment, were retrospectively analysed for levels of adalimumab and ATA. Overall, the antibody prevalence was 43.6% at 12â¯weeks and 41% at 24â¯weeks of treatment. Disruption of immune complexes by acid dissociation, a strategy often adopted for this purpose, only marginally increased the antibody prevalence to 48.7% and 46% at 12 and 24â¯weeks respectively. We found that antibody formation was associated with decreasing levels of circulating adalimumab, but no direct effect on disease activity was evident as assessed using DAS28 for RA patients and BASDAI for PsA and AS patients. However, a negative correlation of free adalimumab trough levels with disease activity scores was observed. Data showed that adalimumab levels can serve as an indicator of ATA development which can then be confirmed by ATA testing. Monitoring of both therapeutic and antibodies should be considered during adalimumab therapy to allow clinicians to personalise treatments for maximal therapeutic outcomes.
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Adalimumab/efectos adversos , Antiinflamatorios/efectos adversos , Anticuerpos Antiidiotipos/análisis , Anticuerpos Antiidiotipos/biosíntesis , Anticuerpos Monoclonales Humanizados/efectos adversos , Adalimumab/administración & dosificación , Adalimumab/sangre , Adalimumab/uso terapéutico , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/inmunología , Antiinflamatorios/uso terapéutico , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/sangre , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Complejo Antígeno-Anticuerpo , Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Técnicas Electroquímicas , Femenino , Humanos , Inmunoensayo/instrumentación , Inmunoensayo/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Espondilitis Anquilosante/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Patients treated with the TNF antagonist adalimumab develop anti-therapeutic antibodies (ATA), the prevalence of which varies depending on the assay used. Most assays are compromised due to the presence of adalimumab in the clinical samples. Our objective was to develop an antibody assay, applicable for clinical testing, which overcomes the limitation of therapeutic interference and to further determine the relationship between ATA development, adalimumab levels and disease activity in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). Use of an electrochemiluminescence platform permitted development of fit-for-purpose immunoassays. Serum samples from patients, taken prior to and at 12 and 24weeks of treatment, were retrospectively analysed for levels of adalimumab and ATA. Overall, the antibody prevalence was 43.6% at 12weeks and 41% at 24weeks of treatment. Disruption of immune complexes by acid dissociation, a strategy often adopted for this purpose, only marginally increased the antibody prevalence to 48.7% and 46% at 12 and 24weeks respectively. We found that antibody formation was associated with decreasing levels of circulating adalimumab, but no direct effect on disease activity was evident as assessed using DAS28 for RA patients and BASDAI for PsA and AS patients. However, a negative correlation of free adalimumab trough levels with disease activity scores was observed. Data showed that adalimumab levels can serve as an indicator of ATA development which can then be confirmed by ATA testing. Monitoring of both therapeutic and antibodies should be considered during adalimumab therapy to allow clinicians to personalise treatments for maximal therapeutic outcomes.
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Adalimumab/inmunología , Adalimumab/uso terapéutico , Anticuerpos Antiidiotipos/sangre , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/administración & dosificación , Adalimumab/efectos adversos , Adulto , Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Técnicas Electroquímicas , Femenino , Humanos , Inmunoglobulina G/sangre , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The striatum is a large brain nucleus with an important role in the control of movement and emotions. Medium spiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains poorly understood. Here, we implicate the Wnt binding receptor Frizzled3 in several uncharacterized aspects of MSN pathway formation [i.e., anterior-posterior guidance of MSN axons in the striatum and their subsequent growth into the globus pallidus (GP), an important (intermediate) target]. In Frizzled3 knock-out mice, MSN axons fail to extend along the anterior-posterior axis of the striatum, and many do not reach the GP. Wnt5a acts as an attractant for MSN axons in vitro, is expressed in a posterior high, anterior low gradient in the striatum, and Wnt5a knock-out mice phenocopy striatal anterior-posterior defects observed in Frizzled3 mutants. This suggests that Wnt5a controls anterior-posterior guidance of MSN axons through Frizzled3. Axons that reach the GP in Frizzled3 knock-out mice fail to enter this structure. Surprisingly, entry of MSN axons into the GP non-cell-autonomously requires Frizzled3, and our data suggest that GP entry may be contingent on the correct positioning of "corridor" guidepost cells for thalamocortical axons by Frizzled3. Together, these data dissect MSN pathway development and reveal (non)cell-autonomous roles for Frizzled3 in MSN axon guidance. Further, they are the first to identify a gene that provides anterior-posterior axon guidance in a large brain nucleus and link Frizzled3 to corridor cell development. SIGNIFICANCE STATEMENT: Striatal axon pathways mediate complex physiological functions and are an important therapeutic target, underscoring the need to define how these connections are established. Remarkably, the molecular programs regulating striatal pathway development remain poorly characterized. Here, we determine the embryonic ontogeny of the two main striatal pathways (striatonigral and striatopallidal) and identify novel (non)cell-autonomous roles for the axon guidance receptor Frizzled3 in uncharacterized aspects of striatal pathway formation (i.e., anterior-posterior axon guidance in the striatum and axon entry into the globus pallidus). Further, our results link Frizzled3 to corridor guidepost cell development and suggest that an abnormal distribution of these cells has unexpected, widespread effects on the development of different axon tracts (i.e., striatal and thalamocortical axons).
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Axones/fisiología , Polaridad Celular/genética , Cuerpo Estriado/citología , Receptores Frizzled/metabolismo , Vías Nerviosas/embriología , Neuronas/citología , Animales , Células Cultivadas , Cuerpo Estriado/embriología , Embrión de Mamíferos , Femenino , Receptores Frizzled/genética , Globo Pálido/citología , Células HEK293 , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Neurofibromatosis type I and multiple sclerosis, when considered separately, are associated with a higher risk of cerebrovascular accident. The coexistence of neurofibromatosis type I and multiple sclerosis may lead to a further increase in cerebrovascular risk; however, this has not been reported in the literature. We report the case of a 37-year-old woman affected by both neurofibromatosis type I and multiple sclerosis: she was referred to our rehabilitation department because of a recent event of ischemic stroke. Moreover, we provide a comprehensive and updated review of all published cases reporting the coexistence of neurofibromatosis type I and multiple sclerosis to gather information regarding their association with cerebrovascular accidents.
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Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that is characterized by new bone formation in the axial musculoskeletal system, with X-ray discriminating between radiographic and non-radiographic forms. Current therapeutic options include non-steroidal anti-inflammatory drugs in addition to biological disease-modifying anti-rheumatic drugs that specifically target tumor necrosis factor-alpha (TNFα) or interleukin (IL)-17. Pain is the most critical symptom for axSpA patients, significantly contributing to the burden of disease and impacting daily life. While the inflammatory process exerts a major role in determining pain in the early phases of the disease, the symptom may also result from mechanical and neuromuscular causes that require complex, multi-faceted pharmacologic and non-pharmacologic treatment, especially in the later phases. In clinical practice, pain often persists and does not respond further despite the absence of inflammatory disease activity. Cytokines involved in axSpA pathogenesis interact directly/indirectly with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascade, a fundamental component in the origin and development of spondyloarthropathies. The JAK/STAT pathway also plays an important role in nociception, and new-generation JAK inhibitors have demonstrated rapid pain relief. We provide a comprehensive review of the different pain types observed in axSpA and the potential role of JAK/STAT signaling in this context, with specific focus on data from preclinical studies and data from clinical trials with JAK inhibitors.
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Espondiloartritis Axial , Inhibidores de las Cinasas Janus , Humanos , Quinasas Janus/metabolismo , Transducción de Señal , Inhibidores de las Cinasas Janus/uso terapéutico , Factores de Transcripción STAT/metabolismo , DolorRESUMEN
The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factor Tal1. This study characterizes the behavioral and neurochemical changes caused by the absence of Tal1 function. The Tal1cko mutant mice are hyperactive, impulsive, hypersensitive to reward, have learning deficits and a habituation defect in a novel environment. Only minor changes in their dopaminergic system were detected. Amphetamine induced striatal dopamine release and amphetamine induced place preference were normal in Tal1cko mice. Increased dopamine signaling failed to stimulate the locomotor activity of the Tal1cko mice, but instead alleviated their hyperactivity. Altogether, the Tal1cko mice recapitulate many features of the attention and hyperactivity disorders, suggesting a role for Tal1 regulated developmental pathways and neural structures in the control of motivation and movement.
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Trastorno por Déficit de Atención con Hiperactividad , Tronco Encefálico/citología , Neuronas Dopaminérgicas , Proteína 1 de la Leucemia Linfocítica T Aguda/genética , Anfetamina/farmacología , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Mesencéfalo , RatonesRESUMEN
Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.
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Neuronas GABAérgicas/metabolismo , Ácido Glutámico/metabolismo , Rombencéfalo/metabolismo , Tegmento Mesencefálico/metabolismo , Animales , Diferenciación Celular , Linaje de la Célula , Proteínas de Unión al ADN/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Embrión de Mamíferos/citología , Femenino , Proteína Forkhead Box O1/metabolismo , Proteínas de Homeodominio/metabolismo , Masculino , Ratones Endogámicos C57BL , Células-Madre Neurales/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Notch/metabolismo , Factores de Transcripción SOXB2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 de la Leucemia Linfocítica T Aguda/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial function. In patients with systemic lupus erythematosus (SLE), the numerical reduction and functional impairment of EPCs contribute to the endothelial dysfunction. Through ex vivo and in vitro studies, we aimed at evaluating the effects of B lymphocyte stimulator (BLyS) on EPC colonies and endothelial cells and also investigating BLyS receptor expression on these cells. METHODS: EPCs were isolated from peripheral blood mononuclear cells (PBMC). In order to evaluate their ability to form colonies, EPCs were cultured on fibronectin-coated dishes and incubated with BlyS alone or BlyS and belimumab. Apoptosis of EPCs and endothelial cell line EA.hy926 was evaluated after 6, 12, and 24 h of incubation with BLyS and after 6 h with BLyS and belimumab. The expression of B cell activating factor-receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) on EPCs and EA.hy926 was analyzed by cytofluorimetry. RESULTS: The number of EPC colonies was lower in patients than in controls. Moreover, the colonies from SLE patients were poorly organized compared to controls; the addition of belimumab restored the colony structure. Incubation with BLyS induced apoptosis of EPCs and EA.hy926 that was inhibited by the co-incubation with belimumab. BAFF-R and BCMA were expressed on both EPCs and EA.hy926, while TACI was expressed only on EPCs. CONCLUSIONS: EPCs and endothelial cells preferentially express BAFF-R which could be involved in the pro-apoptotic effect of BlyS. Belimumab administration seems to restore the quantitative and qualitative changes of EPC colonies both ex vivo and in vitro.
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Anticuerpos Monoclonales Humanizados/farmacología , Factor Activador de Células B/farmacología , Células Progenitoras Endoteliales/efectos de los fármacos , Lupus Eritematoso Sistémico/metabolismo , Adulto , Apoptosis/efectos de los fármacos , Receptor del Factor Activador de Células B/metabolismo , Antígeno de Maduración de Linfocitos B/metabolismo , Recuento de Células , Línea Celular , Células Cultivadas , Células Progenitoras Endoteliales/citología , Células Progenitoras Endoteliales/metabolismo , Femenino , Humanos , Inmunosupresores/farmacología , Lupus Eritematoso Sistémico/patología , Persona de Mediana Edad , Células Madre/efectos de los fármacos , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs). They interact with native KAR subunits to modulate multiple aspects of receptor function. Variation in KAR genes has been associated with psychiatric disorders in humans, and in mice, knockouts of the Grik1 gene have increased, while Grik2 and Grik4 knockouts have reduced anxiety-like behavior. To determine whether the NETO proteins regulate anxiety and fear through modulation of KARs, we undertook a comprehensive behavioral analysis of adult Neto1-/- and Neto2-/- mice. We observed no differences in anxiety-like behavior. However, in cued fear conditioning, Neto2-/-, but not Neto1-/- mice, showed higher fear expression and delayed extinction compared to wild type mice. We established, by in situ hybridization, that Neto2 was expressed in both excitatory and inhibitory neurons throughout the fear circuit including the medial prefrontal cortex, amygdala, and hippocampus. Finally, we demonstrated that the relative amount of synaptosomal KAR GLUK2/3 subunit was 20.8% lower in the ventral hippocampus and 36.5% lower in the medial prefrontal cortex in Neto2-/- compared to the Neto2+/+ mice. The GLUK5 subunit abundance was reduced 23.8% in the ventral hippocampus and 16.9% in the amygdala. We conclude that Neto2 regulates fear expression and extinction in mice, and that its absence increases conditionability, a phenotype related to post-traumatic stress disorder and propose that this phenotype is mediated by reduced KAR subunit abundance at synapses of fear-associated brain regions.
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Amígdala del Cerebelo/metabolismo , Extinción Psicológica/fisiología , Miedo/fisiología , Hipocampo/metabolismo , Proteínas de la Membrana/genética , Corteza Prefrontal/metabolismo , Animales , Condicionamiento Clásico/fisiología , Aprendizaje por Laberinto/fisiología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinaptosomas/metabolismoRESUMEN
A variety of environmental agents has been found to influence the development of autoimmune diseases; in particular, the studies investigating the potential association of systemic autoimmune rheumatic diseases with environmental micro and nano-particulate matter are very few and contradictory. In this study, the role of diesel exhaust particles (DEPs), one of the most important components of environment particulate matter, emitted from Euro 4 and Euro 5 engines in altering the Normal Human Bronchial Epithelial (NHBE) cell biological activity was evaluated. NHBE cells were exposed in vitro to Euro 4 and Euro 5 particle carbon core, sampled upstream of the typical emission after-treatment systems (diesel oxidation catalyst and diesel particulate filter), whose surfaces have been washed from well-assessed harmful species, as polycyclic aromatic hydrocarbons (PAHs) to: (1) investigate their specific capacity to affect cell viability (flow cytometry); (2) stimulate the production of the pro-inflammatory cytokine IL-18 (Enzyme-Linked ImmunoSorbent Assay -ELISA-); (3) verify their specific ability to induce autophagy and elicit protein citrullination and peptidyl arginine deiminase (PAD) activity (confocal laser scanning microscopy, immunoprecipitation, Sodium Dodecyl Sulphate-PolyAcrylamide Gel Electrophoresis -SDS-PAGE- and Western blot, ELISA). In this study we demonstrated, for the first time, that both Euro 4 and Euro 5 carbon particles, deprived of PAHs possibly adsorbed on the soot surface, were able to: (1) significantly affect cell viability, inducing autophagy, apoptosis and necrosis; (2) stimulate the release of the pro-inflammatory cytokine IL-18; (3) elicit protein citrullination and PAD activity in NHBE cells. In particular, Euro 5 DEPs seem to have a more marked effect with respect to Euro 4 DEPs.
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Autofagia , Bronquios/citología , Citrulinación , Células Epiteliales/metabolismo , Material Particulado/efectos adversos , Emisiones de Vehículos , Contaminantes Atmosféricos/efectos adversos , Apoptosis , Enfermedades Autoinmunes/etiología , Supervivencia Celular , Células Cultivadas , Humanos , Interleucina-18/metabolismo , Necrosis , Tamaño de la Partícula , Hidrocarburos Policíclicos Aromáticos/efectos adversos , Desiminasas de la Arginina Proteica/metabolismoRESUMEN
RESULTS: Anti-CarP antibodies were detected in 117 patients with RA (37.9%), ACPA in 190 patients (61.4%) and RF in 202 patients (65.3%). Two (2.04%) of the NHS were positive for anti-CarP, one NHS (1.02%) was positive for ACPA and three NHS were positive for RF (3.06%). Among disease controls, anti-CarP antibodies were detected in 33 patients (16.5%), ACPA in 29 patients (14.5%) and RF in 64 patients (32%). In particular, 16.8% of patients with systemic lupus erythematosus and 31.1% of patients with Sjögren syndrome were positive for anti-CarP. The sensitivity of anti-CarP, ACPA and RF was 46.8, 61.8 and 64.4%, respectively and specificity was 91.95, 89.93 and 76.51%, respectively.
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BACKGROUND: Antibodies against carbamylated proteins (anti-CarP) have been recently identified in the sera of patients with rheumatoid arthritis (RA). The objective of the study was to evaluate the prevalence, sensitivity and specificity of anti-CarP compared to anti-citrullinated peptide antibodies (ACPA) and rheumatoid factor (RF), replicating the existing data in a large cohort of Italian patients with RA and extending the evaluation to other autoimmune rheumatic diseases (AIRDs). METHODS: Serum samples (n = 607) from 309 patients with RA, 200 disease controls and 98 normal healthy subjects (NHS) were evaluated. Anti-CarP were detected using carbamylated fetal calf serum as the antigen. ACPAs were detected using second-generation ELISA and IgM RF was assessed as part of routine analysis. RESULTS: Anti-CarP antibodies were detected in 117 patients with RA (34.4%), ACPA in 190 patients (61.4%) and RF in 202 patients (65.3%). Two (2.04%) of the NHS were positive for anti-CarP, one NHS (1.02%) was positive for ACPA and three NHS were positive for RF (3.06%). Among disease controls, anti-CarP antibodies were detected in 33 patients (16.5%), ACPA in 29 patients (14.5%) and RF in 64 patients (32%). In particular, 16.8% of patients with systemic lupus erythematosus and 31.1% of patients with Sjögren syndrome were positive for anti-CarP. The sensitivity of anti-CarP, ACPA and RF was 46.8%, 61.8% and 64.4%, respectively and specificity was 91.95%, 89.93% and 76.51%, respectively. CONCLUSIONS: The present study extends the knowledge of anti-CarP antibodies, confirming previous data on the diagnostic accuracy of anti-CarP in RA in a large cohort of Italian patients. Anti-CarP antibodies demonstrated relatively low sensitivity and slightly higher specificity compared to ACPA and RF. Even if predominantly present in RA, anti-CarP was detected in a variable percentage of patients with other autoimmune rheumatic diseases and their generation could be attributed to the inflammatory status; the clinical relevance of anti-CarP antibodies in these latter patients should be further determined.
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Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Adulto , Anciano , Área Bajo la Curva , Autoanticuerpos/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Enfermedades Reumáticas/diagnóstico , Enfermedades Reumáticas/inmunología , Sensibilidad y EspecificidadRESUMEN
For regulation of voluntary movement and motivation the midbrain dopaminergic system receives input from a variety of brain regions. Often this input is mediated by local non-dopaminergic neurons within or closely associated with the dopaminergic nuclei. In addition to the dopaminergic neurons, some of these non-dopaminergic neurons also send functionally important output from the ventral midbrain to forebrain targets. The aim of this review is to introduce subtypes of GABAergic and glutamatergic neurons, which are located in the dopaminergic nuclei or the adjacent brainstem and are important for the regulation of the dopaminergic pathways. In addition, we discuss recent studies beginning to reveal mechanisms for their development, which may hold the key to understanding the diversity of these neurons.
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Encéfalo/fisiología , Neuronas Dopaminérgicas/fisiología , Neuronas GABAérgicas/fisiología , Animales , Encéfalo/citología , Humanos , Transmisión SinápticaRESUMEN
In the present study, we performed a retrospective study on the indication, efficacy and causes of withdrawal of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE). Moreover, a review of the literature concerning the use of MMF in the real life was performed. We recorded data about indications, mean dosage, duration of treatment and reasons for drug withdrawal. The efficacy was evaluated according to changes in SLE Disease Activity Index 2000 (SLEDAI-2K), renal SLEDAI-2K and daily proteinuria, after 4 and 12 months of treatment. Six hundred and nine SLE patients were evaluated; among them, 109 patients (17.9 %) were treated with MMF (mean treatment duration 33.9 ± 31.2 months, mean dosage 28.1 ± 10.6 mg/kg). The most frequent indications for using MMF were lupus nephritis (55.9 %) and musculoskeletal manifestations (33.0 %). After 4 and 12 months, a significant reduction of mean SLEDAI-2K, renal SLEDAI and daily proteinuria, compared with baseline, was demonstrated. Thirty-one patients (28.4 %) discontinued MMF therapy (mean treatment duration at the time of discontinuation 17.5 ± 21.2 months). The incidence risks of MMF discontinuation due to inefficacy and side effects were 0.09 and 0.1, respectively. Patients with disease duration longer than 36 months (70.6 %) had a significant increased risk of MMF withdrawal (RR 0.4, P = 0.03). The results of the present study demonstrated that MMF should be considered a treatment option for SLE manifestation other than renal involvement in daily clinical practice.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Adolescente , Adulto , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Midbrain dopamine (mdDA) neurons project via the medial forebrain bundle towards several areas in the telencephalon, including the striatum(1). Reciprocally, medium spiny neurons in the striatum that give rise to the striatonigral (direct) pathway innervate the substantia nigra(2). The development of these axon tracts is dependent upon the combinatorial actions of a plethora of axon growth and guidance cues including molecules that are released by neurites or by (intermediate) target regions(3,4). These soluble factors can be studied in vitro by culturing mdDA and/or striatal explants in a collagen matrix which provides a three-dimensional substrate for the axons mimicking the extracellular environment. In addition, the collagen matrix allows for the formation of relatively stable gradients of proteins released by other explants or cells placed in the vicinity (e.g. see references 5 and 6). Here we describe methods for the purification of rat tail collagen, microdissection of dopaminergic and striatal explants, their culture in collagen gels and subsequent immunohistochemical and quantitative analysis. First, the brains of E14.5 mouse embryos are isolated and dopaminergic and striatal explants are microdissected. These explants are then (co)cultured in collagen gels on coverslips for 48 to 72 hours in vitro. Subsequently, axonal projections are visualized using neuronal markers (e.g. tyrosine hydroxylase, DARPP32, or ßIII tubulin) and axon growth and attractive or repulsive axon responses are quantified. This neuronal preparation is a useful tool for in vitro studies of the cellular and molecular mechanisms of mesostriatal and striatonigral axon growth and guidance during development. Using this assay, it is also possible to assess other (intermediate) targets for dopaminergic and striatal axons or to test specific molecular cues.
Asunto(s)
Técnicas de Cultivo/métodos , Disección/métodos , Neuronas Dopaminérgicas/citología , Neostriado/citología , Neostriado/cirugía , Animales , Técnicas de Cultivo de Célula/métodos , Colágeno/aislamiento & purificación , Femenino , Mesencéfalo/citología , Mesencéfalo/cirugía , Ratones , Ratas , Cola (estructura animal)/química , Técnicas de Cultivo de Tejidos/métodosRESUMEN
In mammals, reproduction is dependent on specific neurons secreting the neuropeptide gonadotropin hormone-releasing hormone-1 (GnRH-1). These cells originate during embryonic development in the olfactory placode and migrate into the forebrain, where they become integral members of the hypothalamic-pituitary-gonadal axis. This migratory process is regulated by a wide range of guidance cues, which allow GnRH-1 cells to travel over long distances to reach their appropriate destinations. The Semaphorin4D (Sema4D) receptor, PlexinB1, is highly expressed in the developing olfactory placode, but its function in this context is still unknown. Here, we demonstrate that PlexinB1-deficient mice exhibit a migratory defect of GnRH-1 neurons, resulting in reduction of this cell population in the adult brain. Moreover, Sema4D promotes directional migration in GnRH-1 cells by coupling PlexinB1 with activation of the Met tyrosine kinase (hepatocyte growth factor receptor). This work identifies a function for PlexinB1 during brain development and provides evidence that Sema4D controls migration of GnRH-1 neurons.