The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection

Abstract: During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin‐1 (IL‐1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic‐pituitary secretion that characterizes infection. IL‐2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin‐releasing hormone (CRH)‐secreting neurons and releases CRH. IL‐2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL‐1α blocks the NO‐induced release of luteinizing hormone‐releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle‐stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL‐1α and granulocyte macrophage colony‐stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on γ‐aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL‐1α inhibits growth hormone (GH) release by inhibiting GH‐releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL‐1α‐induced stimulation of PRL release is also mediated by intra‐hypothlamic action of NO, which inhibits release of the PRL‐inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase‐liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL‐1β, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.Fil: McCann, Samuel M.. Pennington Biomedical Research Center; Estados UnidosFil: Kimura, M.. Medical and Dental University; JapónFil: Karanth, S.. Pennington Biomedical Research Center; Estados UnidosFil: Yu, W. H.. Pennington Biomedical Research Center; Estados UnidosFil: Mastronardi, C. A.. Pennington Biomedical Research Center; Estados UnidosFil: Besuhli, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Enhancement of Medical Interns\u27 Levels of Clinical Skills Competence and Self-Confidence Levels via Video iPods: Pilot Randomized Controlled Trial

Background: Designing and delivering evidence-based medical practice for students requires careful consideration from medical science educators. Social Web (Web 2.0) applications are a part of today’s educational technology milieu; however, empirical research is lacking to support the impact of interactive Web 2.0 mobile applications on medical educational outcomes.Objectives: The aim of our study was to determine whether instructional videos provided by iPod regarding female and male urinary catheter insertion would increase students’ confidence levels and enhance skill competencies.Methods: We conducted a prospective study with medical trainee intern (TI) participants: 10 control participants (no technological intervention) and 11 intervention participants (video iPods). Before taking part in a skills course, they completed a questionnaire regarding previous exposure to male and female urinary catheterization and their level of confidence in performing the skills. Directly following the questionnaire, medical faculty provided a 40-minute skills demonstration in the Advanced Clinical Skills Centre (ACSC) laboratory at the University of Auckland, New Zealand. All participants practiced the skills following the demonstrations and were immediately evaluated by the same faculty using an assessment rubric. Following the clinical skill evaluation, participants completed a postcourse questionnaire regarding skill confidence levels. At the end of the skills course, the intervention group were provided video iPods and viewed a male and a female urinary catheterization video during the next 3 consecutive months. The control group did not receive educational technology interventions during the 3-month period. At the end of 3 months, participants completed a follow-up questionnaire and a clinical assessment of urinary catheterization skills at the ACSC lab.Results: The results indicate a decline in skill competency over time among the control group for both male and female catheterizations, whereas the competency level was stable among the experimental group for both procedures. Interaction results for competency scores indicate a significant level by group and time (P = .03) and procedure and group (P = .02). The experimental group’s confidence level for performing the female catheterization procedure differed significantly over time (P \u3c .001). Furthermore, confidence scores in performing female catheterizations increased for both groups over time. However, the confidence levels for both groups in performing the male catheterization decreased over time.Conclusions: Video iPods offer a novel pedagogical approach to enhance medical students’ medical skill competencies and self-confidence levels. The outcomes illustrate a need for further investigation in order to generalize to the medical school population

Control of Salivary Secretion by Nitric Oxide and Its Role in Neuroimmunomodulation

Abstract: In many in vivo systems exposure to endotoxins (LPS) leads to the co‐induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2), which is important to the regulation of the function of different systems during infection. In submandibular glands (SMG) neural (n)NOS is localized in neural terminals and in striated, granular convoluted and excretory ducts, endothelial (e) NOS in vascular endothelium and ducts, and iNOS in macrophages and in tubules and ducts. In normal adult male rats, injection of an inhibitor of NOS decreased the stimulated salivary secretion and a donor of NO potentiated it, indicating that NO exerts a stimulatory role. A single high dose of LPS (5 mg/kg, i.p.) induced an increase in NOS activity measured by the 14C‐citrulline method, increased PGE content almost 100% as measured by RIA, and blocked stimulated salivary secretion. The administration of a specific iNOS inhibitor, aminoguanidine (AG), with LPS not only decreased NOS activity but significantly decreased PGE content, indicating that NO triggered the activation of COX‐2. LPS increased conversion of labeled arachidonate to prostaglandins (PGs) showing that COX was induced. Since a PGE1 analogue blocked stimulated salivation, the LPS‐induced inhibition of salivation is probably due to release of PGs. Therefore, the use of inhibitors of iNOS and COX‐2 could be very useful to increase salivation during infection since saliva has antimicrobial actions.Fil: Besuhli, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Lomniczi, A.. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Elverdín, Juan Carlos. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Suburo, Angela Maria. Universidad Austral; ArgentinaFil: Faletti, Alicia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Franchi, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: McCann, Samuel M.. State University of Louisiana; Estados Unido

The effect of anandamide on prolactin secretion is modulated by estrogen

Recent research has revealed that endogenous cannabinoid receptors (CB1 and CB2) react with the active ingredient of marijuana, Δ9-tetrahydrocannabinol. Two endogenous ligands activate these receptors. The principal one, anandamide (AEA), activates CB1. AEA and CB1 are localized to various neurons within the brain. Because Δ9-tetrahydrocannabinol inhibited prolactin (Prl) secretion following its intraventricular injection into male rats, we hypothesized that AEA would have a similar effect. Estrogen modifies many hormonal responses and is known to increase Prl secretion. Therefore, we hypothesized that responses to intraventricular AEA would change depending on the gonadal steroid environment. Consequently, we evaluated the effects of lateral cerebral ventricular microinjection of AEA (20 ng) into male, ovariectomized (OVX), and estrogen-primed (OVX-E) rats. AEA decreased plasma Prl in male rats, had little effect in OVX females, and increased Prl in OVX-E rats. The results were at least partially mediated by changes in dopaminergic turnover, altering the inhibitory dopaminergic control of Prl release by the anterior pituitary gland. Thus, dopamine turnover was increased in the male rats and decreased significantly in OVX and in OVX-E rats. The changes in Prl may be caused not only by altered dopamine input to the anterior pituitary gland but also by effects of AEA on other transmitters known to alter Prl release. Importantly, in OVX-E rats, the elevated Prl release and the response to AEA were blocked by the AEA antagonist, indicating that AEA is a synaptic transmitter released from neurons that decrease inhibitory control of Prl release.Fil: Scorticati, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Mohn, Claudia Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: de Laurentiis, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Vissio, Paula Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Fernández Solari, José Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Seilicovich, Adriana. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: McCann, Samuel M.. Pennington Biomedical Research Center; Estados UnidosFil: Rettori, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Role of type IV collagen in prolactin release from anterior pituitaries of male rats

We previously demonstrated that laminin, a component of basement membranes, modulates pituitary hormone secretion. In the present study, we evaluated the effect of type IV collagen, another component of this membrane, on the release of prolactin (PRL) by anterior pituitary gland from adult male rats. Hemipituitaries were incubated for 3 h with type IV collagen or antibodies against it and PRL release was studied. Rabbit IgG to type IV collagen at concentrations of 10⁻⁷ - 10⁻⁵ M had a significant stimulatory effect on PRL release, in comparison to normal rabbit serum IgG or medium alone used as controls. Type IV collagen induced a significant inhibitory effect on basal release of PRL at a concentration of 30 µg/mL. A slight decrease in PRL release was detected in thyrotropin-releasing hormone-stimulated hemipituitaries incubated with type IV collagen at all concentrations used. These results suggest that type IV collagen, similar to laminin-1, modulates PRL released from hemipituitaries, in vitro.Instituto Multidisciplinario de Biología Celula

Quantum Resistance Standard Based on Epitaxial Graphene

We report development of a quantum Hall resistance standard accurate to a few parts in a billion at 300 mK and based on large area epitaxial graphene. The remarkable precision constitutes an improvement of four orders of magnitude over the best results obtained in exfoliated graphene and is similar to the accuracy achieved in well-established semiconductor standards. Unlike the traditional resistance standards the novel graphene device is still accurately quantized at 4.2 K, vastly simplifying practical metrology. This breakthrough was made possible by exceptional graphene quality achieved with scalable silicon carbide technology on a wafer scale and shows great promise for future large scale applications in electronics.Comment: Submitte

Endocannabinoids in TNF-α and Ethanol Actions

During marijuana and alcohol consumption as well as during inflammation the reproductive axis is inhibited, mainly through the inhibition of luteinizing hormone-releasing hormone release. In male rats, this inhibitory effect is mediated, at least in part, by the activation of hypothalamic cannabinoid type 1 receptors (CB1). During inflammation, this activation of the endocannabinoid system seems to be mediated by an increase in TNF-α production followed by anandamide augmentations, similarly the effect of intragastric administration of ethanol (3 g/kg) seems to be due to an increase in anandamide. On the other hand, a number of different actions mediated by the endocannabinoid system in various organs and tissues have been described. Both cannabinoid receptors, CB1 and CB2, are localized in the submandibular gland where they mediate the inhibitory effect of intrasubmandibular injections of the endocannabinoid anandamide (6 × 10–5M) on salivary secretion. Lipopolysaccharide (5 mg/kg/3 h) injected intraperitoneally and ethanol (3 g/kg/1 h) injected intragastrically inhibited the salivary secretion induced by the sialogogue metacholine; this inhibitory effect was blocked by CB1 and/or CB2 receptor antagonists. Similar to the hypothalamus, these effects seem to be mediated by increased anandamide. In summary, similar mechanisms mediate the inhibitory actions of endocannabinoids and cannabinoids in both hypothalamus and submandibular gland during drug consumption and inflammation.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Organic Complexation of U(VI) in Reducing Soils at a Natural Analogue Site : Implications for Uranium Transport

Understanding the long-term fate, stability, and bioavailability of uranium (U) in the environment is important for the management of nuclear legacy sites and radioactive wastes. Analysis of U behavior at natural analogue sites permits evaluation of U biogeochemistry under conditions more representative of long-term equilibrium. Here, we have used bulk geochemical and microbial community analysis of soils, coupled with X-ray absorption spectroscopy and mu-focus X-ray fluorescence mapping, to gain a mechanistic understanding of the fate of U transported into an organic-rich soil from a pitchblende vein at the UK Needle's Eye Natural Analogue site. U is highly enriched in the Needle's Eye soils (similar to 1600 mg kg(-1)). We show that this enrichment is largely controlled by U(VI) complexation with soil organic matter and not U(VI) bioreduction. Instead, organic-associated U(VI) seems to remain stable under microbially-mediated Fe(III)-reducing conditions. U(IV) (as non-crystalline U(IV)) was only observed at greater depths at the site (>25 cm); the soil here was comparatively mineral-rich, organic-poor, and sulfate-reducing/methanogenic. Furthermore, nanocrystalline UO2, an alternative product of U(VI) reduction in soils, was not observed at the site, and U did not appear to be associated with Fe-bearing minerals. Organicrich soils appear to have the potential to impede U groundwater transport, irrespective of ambient redox conditions. (C) 2020 The Authors. Published by Elsevier Ltd.Peer reviewe

CLIMB-COVID: continuous integration supporting decentralised sequencing for SARS-CoV-2 genomic surveillance.

Funder: Wellcome TrustIn response to the ongoing SARS-CoV-2 pandemic in the UK, the COVID-19 Genomics UK (COG-UK) consortium was formed to rapidly sequence SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of CLIMB-COVID, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network