What does immunology have to do with brain development and neuropsychiatric disorders?

Introdução: O desenvolvimento neural é um processo extremamente complexo e dinâmico. Tao pronto se inicia o desenvolvimento do cérebro, as "células imunológicas" desempenham um papel fundamental em vários processos, incluindo a formação e aperfeiçoamento de circuitos neurais, bem como a diferenciação sexual. Há um crescente corpo de evidências de que o sistema imunológico também desempenha um papel importante na fidiopatologia de diversos transtornos neurodesenvolvimentais e neuropsiquiátricos. Objetivo: O objetivo deste artigo é revisar os dados atualmente disponíveis sobre o papel do "sistema imunológico" em relação ao desenvolvimento normal do cérebro, bem como a fisiopatogenia dos transtornos de neurodesenvolvimento e neuropsiquiátricos. Metodologia: Foi realizada uma pesquisa bibliográfica tradicional para localizar artigos de revisão relevantes. Resultados: Os processos celulares e moleculares que compõem o nosso "sistema imunológico" são cruciais para o desenvolvimento normal do cérebro e a formação e manutenção de circuitos neurais. É cada vez mais evidente que o sistema imunológico e neuroinflamação desempenham papéis importantes na etiopatogenia de pelo menos um subconjunto de indivíduos com autismo, esquizofrenia, transtorno obsessivo-compulsivo, síndrome de Tourette, depressão e transtornos do humor, bem como distúrbios autoimunes e neurodegenerativos. Evidências emergentes também apontam para a importância do eixo intestino-cerebral e do microbioma de um indivíduo em relação à sua saúde e bem-estar somático e mental. Conclusões: Existem interconexões multidirecionais entre múltiplos sistemas biológicos em nossos cérebros e corpos que são mediados em parte pelo sistema imunológico. No momento, no entanto, a "promessa" desse campo continua sendo maior do que os "resultados finais". O tempo dirá se novas intervenções serão desenvolvidas que farão uma diferença positiva no cuidado de nossos pacientes. Também é possível que surjam biomarcadores válidos que orientarão uma abordagem mais personalizada ao tratamento.Introduction: Neural development is an enormously complex and dynamic process. From very early in brain development ‘immune cells’ play a key role in a number of processes including the formation and refinement of neural circuits, as well as sexual differentiation. There is a growing body of evidence that the immune system also plays an important role in the pathobiology of several neurodevelopmental and neuropsychiatric disorders. Objective: The goal of this article is to review the currently available data concerning the role of the ‘immune system’ in normal brain development, as well as its role in the pathobiology of neurodevelopmental and neuropsychiatric disorders. Methodology: We conducted a traditional literature search using PubMed and recent special issues of journals to locate relevant review articles. Results: The cellular and molecular processes that make up our ‘immune system’ are crucial to normal brain development and the formation and maintenance of neural circuits. It is also increasingly evident that the immune system and neuroinflammation play important roles in the pathobiology of at least a subset of individuals with Autism Spectrum Disorder (ASD), schizophrenia, obsessive-compulsive disorder, Tourette syndrome and mood disorders, such as depression, as well as autoimmune and neurodegenerative disorders. Emerging evidence also points to the importance of the ‘gut-brain axis’ and an individual’s microbiome, which can impact an individual’s somatic and mental well-being. Conclusions: There are multidirectional interconnections across multiple biological systems in our brains and bodies that are mediated in part by the immune system. At present, however, the ‘promise’ of this field remains greater than the ‘deliverables.’ Time will tell whether novel interventions will be developed that will make a positive difference in the care of our patients. It is also possible that valid biomarkers will emerge that will guide a more personalized approach to treatment

Microembolization during carotid artery stenting in patients with high-risk, lipid-rich plaque: A randomized trial of proximal versus distal cerebral protection

Objectives: The goal of this study was to compare the rate of cerebral microembolization during carotid artery stenting (CAS) with proximal versus distal cerebral protection in patients with high-risk, lipid-rich plaque. Background: Cerebral protection with filters partially reduces the cerebral embolization rate during CAS. Proximal protection has been introduced to further decrease embolization risk. Methods: Fifty-three consecutive patients with carotid artery stenosis and lipid-rich plaque were randomized to undergo CAS with proximal protection (MO.MA system, n = 26) or distal protection with a filter (FilterWire EZ, n = 27). Microembolic signals (MES) were assessed by using transcranial Doppler during: 1) lesion wiring; 2) pre-dilation; 3) stent crossing; 4) stent deployment; 5) stent dilation; and 6) device retrieval/deflation. Diffusion-weighted magnetic resonance imaging was conducted before CAS, after 48 h, and after 30 days. Results: Patients in the MO.MA group had higher percentage diameter stenosis (89 \ub1 6% vs. 86 \ub1 5%, p = 0.027) and rate of ulcerated plaque (35% vs. 7.4%; p = 0.019). Compared with use of the FilterWire EZ, MO.MA significantly reduced mean MES counts (p < 0.0001) during lesion crossing (mean 18 [interquartile range (IQR): 11 to 30] vs. 2 [IQR: 0 to 4]), stent crossing (23 [IQR: 11 to 34] vs. 0 [IQR: 0 to 1]), stent deployment (30 [IQR: 9 to 35] vs. 0 [IQR: 0 to 1]), stent dilation (16 [IQR: 8 to 30] vs. 0 [IQR: 0 to 1]), and total MES (93 [IQR: 59 to 136] vs. 16 [IQR: 7 to 36]). The number of patients with MES was higher with the FilterWire EZ versus MO.MA in phases 3 to 5 (100% vs. 27%; p < 0.0001). By multivariate analysis, the type of brain protection was the only independent predictor of total MES number. No significant difference was found in the number of patients with new post-CAS embolic lesion in the MO.MA group (2 of 14, 14%) as compared with the FilterWire EZ group (9 of 21, 42.8%). Conclusions: In patients with high-risk, lipid-rich plaque undergoing CAS, MO.MA led to significantly lower microembolization as assessed by using MES counts. (Carotid Stenting in Patients With High Risk Carotid Stenosis ["Soft Plaque"] [MOMA]; NCT01274676) \ua9 2011 American College of Cardiology Foundation

Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study

Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan–Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8–91.5%) at month 12, 78.8% (95% CI: 78.8–85.2%) at month 24, 63.8% (95% CI: 55.1–73.8%) at month 36, and 59.9% (95% CI: 55.1–73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988–June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994–1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted