Are Cushing's disease patients curable?

Treatment of Cushing's disease remains a challenge. Whereas pituitary surgery can “cure” the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences which ultimately require alternate therapeutic approaches. These are numerous, but so are their drawbacks, and all appear to be “default options”. For the future, pituitary adenoma has to remain the “reasonable obsession” of efficient and optimistic therapists…     

Bone formation in axial spondyloarthritis: Is disease modification possible?

Axial spondyloarthritis (SpA) is a chronic disease characterised by new bone formation (NBF) in the axial skeleton as well as at peripheral entheseal sites. NBF is thought to arise in areas of previous inflammation or osteitis visualised on MRI, with mechanical stress playing a role in disease pathogenesis. The interface between bone and immune cells is complex with the RANKL-OPG system being key to NBF. The IL-17/23 axis and other cytokines such as TNFα and MIF are thought to play a central role. The transition from inflammation to NBF is mediated via the Wnt, BMP and Hedgehog signalling pathways. An altered microbiome has been reported in SpA, which is a potential trigger of NBF in SpA. There is now data to show that treatment with TNF inhibitors prevents NBF and hence modifies disease progression. More research into identifying newer targets for disease modification is needed to alter the course of the disease.     

Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome

Irritable bowel syndrome(IBS)is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role.The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors,interacting with peripheral/central neuroendocrine and immune changes,may induce symptoms of IBS,modulate symptom severity,influence illness experience and quality of life,and affect outcome.The present review focuses on the role of negative affects,including depression,anxiety,and anger,on pathogenesis and clinical expression of IBS.The potential role of the autonomic nervous system,stress-hormone system,and immune system in the pathophysiology of both negative affects and IBS are taken into account.Psychiatric comorbidity and subclinical variations in levels of depression,anxiety,and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS,such as sensorimotor functions,gut microbiota,inflammation/immunity,and symptom reporting.     

Prise en charge des grossesses à risque dans un contexte d’incompatibilité fœto-maternelle plaquettaire et/ou d’allo-immunisation : avis du groupe d’experts du GFHT (Groupe français d’études sur l’hémostase et la thrombose)

IntroductionFetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, seen in 1/800–1000 neonates. FNAIT is the most common cause of early-onset isolated severe neonatal thrombocytopenia in maternity wards. A working group on fetomaternal platelet alloimmunization was created in 2017, under the auspices on the French Group of Thrombosis and Hemostasis (GFHT).ObjectivesThe objective was to survey clinical practices for management of high-risk pregnancies in a context of suspected or confirmed FNAIT.MethodsRecommendations published by the ICTMG were translated in French, and discussed (Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. British J of Haematology, 2019, 185, 549–562).ResultsThe study involved centers from France, Switzerland and Belgium: Angers, Besançon, Bordeaux, Brest, Créteil/Clamart, Genève, Grenoble, Liège, Lille, Lyon, Marseille, Nantes, Nîmes, Paris (hôpitaux Necker, Robert Debré et Trousseau), Poitiers, Rennes, Saint-Etienne, Strasbourg, Toulouse, Tours.ConclusionsExpert opinion was validated on September 23, 2020 (consensus ≥ 90%).     

Early-life stress leads to sex-dependent changes in pubertal timing in rats that are reversed by a probiotic formulation

Puberty marks the beginning of a period of dramatic physical, hormonal, and social change. This instability has made adolescence infamous as a time of “storm and stress” and it is well-established that stress during adolescence can be particularly damaging. However, prior stress may also shape the adolescent experience. In the present series of experiments, we observed sex-specific effects of early-life maternal separation stress on the timing of puberty onset in the rat. Specifically, stressed females exhibited earlier pubertal onset compared to standard-reared females, whereas stressed males matured later than their standard-reared counterparts. Further, we demonstrated that a probiotic treatment restores the normative timing of puberty onset in rodents of both sexes. These results are in keeping with previous findings that probiotics reverse stress-induced changes in learned fear behaviors and stress hormone levels, highlighting the remarkable and wide-ranging restorative effects of probiotics in the context of early-life stress.     

Immune-pineal axis protects rat lungs exposed to polluted air

Environmental pollution in the form of particulate matter <2.5 μm (PM_2.5) is a major risk factor for diseases such as lung cancer, chronic respiratory infections, and major cardiovascular diseases. Our goal was to show that PM_2.5 eliciting a proinflammatory response activates the immune-pineal axis, reducing the pineal synthesis and increasing the extrapineal synthesis of melatonin. Herein, we report that the exposure of rats to polluted air for 6 hours reduced nocturnal plasma melatonin levels and increased lung melatonin levels. Melatonin synthesis in the lung reduced lipid peroxidation and increased PM_2.5 engulfment and cell viability by activating high-affinity melatonin receptors. Diesel exhaust particles (DEPs) promoted the synthesis of melatonin in a cultured cell line (RAW 264.7 cells) and rat alveolar macrophages via the expression of the gene encoding for AANAT through a mechanism dependent on activation of the NFκB pathway. Expression of the genes encoding AANAT, MT1, and MT2 was negatively correlated with cellular necroptosis, as disclosed by analysis of Gene Expression Omnibus (GEO) microarray data from the human alveolar macrophages of nonsmoking subjects. The enrichment score for antioxidant genes obtained from lung gene expression data (GTEx) was significantly correlated with the levels of AANAT and MT1 but not the MT2 melatonin receptor. Collectively, these data provide a systemic and mechanistic rationale for coordination of the pineal and extrapineal synthesis of melatonin by a standard damage-associated stimulus, which activates the immune-pineal axis and provides a new framework for understanding the effects of air pollution on lung diseases.     

Hypothalamic insulin and glucagon-like peptide-1 levels in an animal model of depression and their effect on corticotropin-releasing hormone promoter gene activity in a hypothalamic cell line

Background

In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex – brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions.

B cell and B cell-related pathways for novel cancer treatments

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, −21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies.