Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bia

NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial-to-hematopoietic transition in mouse hematopoietic stem cell specification.

Hematopoietic stem cells (HSCs) sustain life-long hematopoiesis and emerge during mid-gestation from hemogenic endothelial progenitors via an endothelial-to-hematopoietic transition (EHT). The full scope of molecular mechanisms governing this process remains unclear. The NR4A subfamily of orphan nuclear receptors act as tumor suppressors in myeloid leukemogenesis and have never been implicated in HSC specification. Here, we report that Nr4a1 and Nr4a2 expression is upregulated in hemogenic endothelium during EHT. Progressive genetic ablation of Nr4a gene dosage results in a gradual decrease in numbers of nascent c-Kit+ hematopoietic progenitors in developing embryos, c-Kit+ cell cluster size in the dorsal aorta, and a block in HSC maturation, revealed by an accumulation of pro-HSCs and pre-HSC-type I cells and decreased numbers of pre-HSC-type II cells. Consistent with these observations, cells isolated from embryonic day 11.5 Nr4a1-/-; Nr4a2-/- aorta-gonads-mesonephros are devoid of in vivo long-term hematopoietic repopulating potential. Molecularly, employing spatial transcriptomic analysis we determined that the genetic ablation of Nr4a1 and Nr4a2 prevents Notch signaling from being downregulated in intra-aortic clusters and thus for pro-HSCs to mature into HSCs. Interestingly, this defect is partially rescued by ex vivo culture of dissected aorta-gonads-mesonephros with SCF, IL3 and FLT3L, which may bypass Notch-dependent regulation. Overall, our data reveal a role for the NR4A family of orphan nuclear receptors in EHT

Potential plasma markers of type 1 and type 2 leprosy reactions: a preliminary report

<p>Abstract</p> <p>Background</p> <p>The clinical management of leprosy Type 1 (T1R) and Type 2 (T2R) reactions pose challenges mainly because they can cause severe nerve injury and disability. No laboratory test or marker is available for the diagnosis or prognosis of leprosy reactions. This study simultaneously screened plasma factors to identify circulating biomarkers associated with leprosy T1R and T2R among patients recruited in Goiania, Central Brazil.</p> <p>Methods</p> <p>A nested case-control study evaluated T1R (n = 10) and TR2 (n = 10) compared to leprosy patients without reactions (n = 29), matched by sex and age-group (+/- 5 years) and histopathological classification. Multiplex bead based technique provided profiles of 27 plasma factors including 16 pro inflammatory cytokines: tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), interleukin (IL)- IL12p70, IL2, IL17, IL1 β, IL6, IL15, IL5, IL8, macrophage inflammatory protein (MIP)-1 alpha (MIP1α), 1 beta (MIP1β), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractrant protein 1 (MCP1), CC-chemokine 11 (CCL11/Eotaxin), CXC-chemokine 10 (CXCL10/IP10); 4 anti inflammatory interleukins: IL4, IL10, IL13, IL1Rα and 7 growth factors: IL7, IL9, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), platelet-derived growth factor BB (PDGF BB), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF).</p> <p>Results</p> <p>Elevations of plasma CXCL10 (P = 0.004) and IL6 (p = 0.013) were observed in T1R patients compared to controls without reaction. IL6 (p = 0.05), IL7 (p = 0.039), and PDGF-BB (p = 0.041) were elevated in T2R. RANTES and GMCSF were excluded due to values above and below detection limit respectively in all samples.</p> <p>Conclusion</p> <p>Potential biomarkers of T1R identified were CXCL10 and IL6 whereas IL7, PDGF-BB and IL6, may be laboratory markers of TR2. Additional studies on these biomarkers may help understand the immunopathologic mechanisms of leprosy reactions and indicate their usefulness for the diagnosis and for the clinical management of these events.</p

Transcultural adaptation and validation of the Stanford Presenteeism Scale for the evaluation of presenteeism for Brazilian Portuguese

OBJETIVO: descrever o processo de adaptação transcultural e validação para o português brasileiro do Stanford Presenteeism Scale. MÉTODOS: trata-se de estudo metodológico de adaptação cultural e validação de instrumento que envolveu 153 trabalhadores de enfermagem, incluindo seis aspectos de equivalência, obtidos pelas seguintes etapas: tradução, primeira versão de consenso, retrotradução, comitê de especialistas, pré-teste, estudo de confiabilidade teste/reteste e validade dimensional. RESULTADOS: a estabilidade dos itens variou de moderado a quase perfeito e da escala foi quase perfeito. Dois fatores foram identificados pela análise fatorial exploratória: o primeiro incluiu os aspectos físicos - trabalho finalizado e o segundo incluiu os aspectos psicológicos - distração evitada. CONCLUSÕES: os resultados sugerem adequação do instrumento na versão em português brasileiro, indicando seu uso no contexto da população de estudo e em populações semelhantes, contribuindo para o estudo de evidências que embasem estratégias que favoreçam as condições de saúde dos trabalhadores.OBJETIVO: describir el proceso de adaptación transcultural y validación para el portugués brasileño del Stanford Presenteeism Scale. MÉTODOS: se trata de un estudio metodológico de adaptación cultural y validación de instrumento en que participaron 153 trabajadores de enfermería, incluyendo seis aspectos de equivalencia obtenidos en las siguientes etapas: traducción, primera versión de consenso, retrotraducción, comité de especialistas, prueba piloto, estudio de confiabilidad prueba-reprueba y validez dimensional. RESULTADOS: La estabilidad de los ítems varió de moderado a casi perfecto y el de la escala fue casi perfecto. Dos factores fueron identificados por el análisis factorial exploratorio: el primero incluye los aspectos físicos - trabajo finalizado y el segundo a los aspectos psicológicos - concentración mantenida. CONCLUSIONES: los resultados sugieren que el instrumento es adecuado en la versión en portugués brasileño, indicando su uso en el contexto de la población de estudio y en poblaciones semejantes, contribuyendo así para el estudio de evidencias que contienen estrategias que favorezcan las condiciones de salud de los trabajadores.OBJECTIVE: describe the process of transcultural adaptation and validation of the Stanford Presenteeism Scale for Brazilian Portuguese. METHODS: Methodological study of the cultural adaptation and validation of the tool which involved 153 nursing staff and included six aspects of equivalence, obtained through the following stages: translation, first version of consent, retranslation, specialist committee, pre-test, study of test-retest credibleness and dimensional validity. RESULTS: The stability of the items varied from moderate to almost perfect and the sequence constancy was almost perfect. Two factors were identified through the exploratory fact analysis: the first one included the physical aspects - completing work; and the second one the psychological aspects - avoided distraction . CONCLUSIONS: the results suggest adequacy of the tool in the Brazilian Portuguese version, indicating its use in the context of the study group and in similar groups, contributing to the study of evidences which consolidate strategies that favor the health conditions of the jobholders