ABSTRACT
BACKGROUND: Reproduction is tightly coupled to body energy and metabolic status. GnRH neurons, master elements and final output pathway for the brain control of reproduction, directly or indirectly receive and integrate multiple metabolic cues to regulate reproductive function. Yet, the molecular underpinnings of such phenomenon remain largely unfolded. AMP-activated protein kinase (AMPK), the fundamental cellular sensor that becomes activated in conditions of energy deficit, has been recently shown to participate in the control of Kiss1 neurons, essential gatekeepers of the reproductive axis, by driving an inhibitory valence in situations of energy scarcity at puberty. However, the contribution of AMPK signaling specifically in GnRH neurons to the metabolic control of reproduction remains unknown. METHODS: Double immunohistochemistry (IHC) was applied to evaluate expression of active (phosphorylated) AMPK in GnRH neurons and a novel mouse line, named GAMKO, with conditional ablation of the AMPK α1 subunit in GnRH neurons, was generated. GAMKO mice of both sexes were subjected to reproductive characterization, with attention to puberty and gonadotropic responses to kisspeptin and metabolic stress. RESULTS: A vast majority (>95%) of GnRH neurons co-expressed pAMPK. Female (but not male) GAMKO mice displayed earlier puberty onset and exaggerated LH (as surrogate marker of GnRH) responses to kisspeptin-10 at the prepubertal age. In adulthood, GAMKO females retained increased LH responsiveness to kisspeptin and showed partial resilience to the inhibitory effects of conditions of negative energy balance on the gonadotropic axis. The modulatory role of AMPK in GnRH neurons required preserved ovarian function, since the differences in LH pulsatility detected between GAMKO and control mice subjected to fasting were abolished in ovariectomized animals. CONCLUSIONS: Altogether, our data document a sex-biased, physiological role of AMPK signaling in GnRH neurons, as molecular conduit of the inhibitory actions of conditions of energy deficit on the female reproductive axis.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Energy Metabolism/physiology , Gonadotropin-Releasing Hormone/metabolism , Luteinizing Hormone/blood , Neurons/metabolism , Reproduction/physiology , AMP-Activated Protein Kinases/genetics , Animals , Estrous Cycle/metabolism , Female , Kisspeptins/pharmacology , Male , Malnutrition/metabolism , Mice , Mice, Knockout , Neurons/drug effects , Phosphorylation , Sex Characteristics , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
In order to discriminate general from aetiology-specific risk factors for immune reconstitution inflammatory syndrome (IRIS), we followed up, during six months, 99 patients with advanced HIV infection commencing antiretroviral therapy (ART) without active opportunistic infections or evident inflammation. IRIS predictors were determined by univariate analysis using clinical data from 76 ART-responding patients either completing follow-up or developing IRIS, and by multivariate analysis of inflammation, disease progression and nutrition status variables. We identified 23 primary IRIS events (30.3%). Univariate predictors for all IRIS events were higher platelet counts and lower CD4/CD8 ratio, whereas subclinical inflammation was the multivariate predictor. Platelets, alkaline phosphatase levels and %CD8 T-cells in univariate analysis also predicted mycobacteria-associated IRIS independently, remaining elevated during follow-up. Herpesvirus IRIS was predicted by platelets and inflammation. Indicators of advanced HIV disease and subclinical inflammation jointly predict IRIS, and some are specific of the underlying microbial aetiology, possibly explaining previous reports.
Subject(s)
Anti-Retroviral Agents/therapeutic use , Antiretroviral Therapy, Highly Active/methods , HIV Infections/drug therapy , Immune Reconstitution Inflammatory Syndrome/epidemiology , Immune Reconstitution Inflammatory Syndrome/etiology , Adult , CD4-CD8 Ratio , Female , Herpesviridae/immunology , Herpesviridae/pathogenicity , Herpesviridae Infections/immunology , Herpesviridae Infections/pathology , Humans , Immune Reconstitution Inflammatory Syndrome/microbiology , Immune Reconstitution Inflammatory Syndrome/virology , Male , Mycobacterium/immunology , Mycobacterium/pathogenicity , Platelet Count , Risk Factors , Tuberculosis/immunology , Tuberculosis/pathologyABSTRACT
BACKGROUND: Central retinal vein occlusion (CRVO) is a disorder with potentially blinding complications, particularly when associated with retinal ischemia. There is no reliable treatment for ischemic CRVO. METHODS: We developed a new approach for ischemic cases of CRVO consisting of vitrectomy, posterior hyaloid detachment, and four erbium:YAG laser-induced chorioretinal anastomoses, one in each quadrant. RESULTS: We report two cases of ischemic CRVO treated with this approach, with initial visual acuity of count fingers at 30 cm and hand movements respectively. After the surgery, there was resolution of hemorrhages and macular edema and visual improvement to 20/400 in the first case and to 20/180 in the second case. In both cases, there was successful creation of chorioretinal anastomoses, and there was no anterior segment neovascularization or other complications related to the surgery. CONCLUSION: This treatment shows promise in the management of the ischemic cases of CRVO, and further evaluation is justified.
