2,060 research outputs found
Preclinical discovery of duloxetine for the treatment of depression
Introduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases areIntroduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several newantidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD.
Areas covered: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine.
Expert opinion: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD. associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD
Induced Dipoles and Possible Modulation of Wireless Effects in Implanted Electrodes. Effects of Implanting Insulated Electrodes on an Animal Test to Screen Antidepressant Activity
There is evidence that Deep Brain Stimulation (DBS) produces health benefits in patients even before initiating stimulation. Furthermore, DBS electrode insertion in rat infralimbic cortex (ILC) provokes antidepressant-like effects before stimulation, due to local inflammation and astrogliosis. Consequently, a significant effect of implanting electrodes is suspected. External fields, similar in magnitude to the brain's endogenous fields, induce electric dipoles in conducting materials, in turn influencing neural cell growth through wireless effects. To elucidate if such dipoles influence depressive-like behavior, without external stimulation, the comparative effect of conducting and insulated electrodes along with the glial response is studied in unstressed rats. Naive and implanted rats with electrically insulated or uninsulated steel electrodes were evaluated in the modified forced swimming test and expression of ILC-glial markers was assessed. An antidepressant-like effect was observed with conducting but not with insulated electrodes. Gliosis was detected in both groups, but astroglial reactivity was larger near uninsulated electrodes. Thus, induced dipoles and antidepressant-like effects were only observed with conducting implants. Such correlation suggests that dipoles induced in electrodes by endogenous fields in turn induce neuron stimulation in a feedback loop between electrodes and neural system. Further research of the effects of unwired conducting implants could open new approaches to regulating neuronal function, and possibly treat neurological disorders.This study was also supported by grants co-financed by the "Fondo Europeo de Desarrollo Regional" (FEDER)-UE "A way to build Europe" from the "Ministerio de Economia y Competitividad" (MINECO: RTI2018-099778-B-I00 (to E.B.), RTI2018-098269-B-I00 (to J.N.) and RTI2018-097753-B-I00 (to N.C.P.) and "Juan de la Cierva Formacion" postdoctoral grant FJC2018-037958-I (to L.P.C.)) and PID2019-108562GB-I00 (to V.T.M); the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia" (CTS-510, to E.B.); the Severo Ochoa Program CEX2019-000917-S (to N.C.P.) and the "Centro de Investigacion Biomedica en Red de Salud Mental-CIBERSAM" (CB/07/09/0033 and CB/07/09/0006
Glucocorticoid-based pharmacotherapies preventing PTSD
Altres ajuts: Swiss National Science Foundation (SNSF) [NCCR Synapsy grant: 51NF40-158776 and â 185897]Posttraumatic stress disorder (PTSD) is a highly disabling psychiatric condition that may arise after exposure to acute and severe trauma. It is a highly prevalent mental disorder worldwide, and the current treatment options for these patients remain limited due to low effectiveness. The time window right after traumatic events provides clinicians with a unique opportunity for preventive interventions against potential deleterious alterations in brain function that lead to PTSD. Some studies pointed out that PTSD patients present an abnormal function of the hypothalamic-pituitary-adrenal axis that may contribute to a vulnerability toward PTSD. Moreover, glucocorticoids have arisen as a promising option for preventing the disorder's development when administered in the aftermath of trauma. The present work compiles the recent findings of glucocorticoid administration for the prevention of a PTSD phenotype, from human studies to animal models of PTSD. Overall, glucocorticoid-based therapies for preventing PTSD demonstrated moderate evidence in terms of efficacy in both clinical and preclinical studies. Although clinical studies point out that glucocorticoids may not be effective for all patients' subpopulations, those with adequate traits might greatly benefit from them. Preclinical studies provide precise insight into the mechanisms mediating this preventive effect, showing glucocorticoid-based prevention to reduce long-lasting behavioral and neurobiological abnormalities caused by traumatic stress. However, further research is needed to delineate the precise mechanisms and the extent to which these interventions can translate into lower PTSD rates and morbidity
Geodiversity influences limnological conditions and freshwater ostracode species distributions across broad spatial scales in the northern Neotropics
Geodiversity is recognized as one of the most important drivers of ecosystem characteristics and biodiversity globally. However, in the northern Neotropics, the contribution of highly diverse landscapes, environmental conditions, and geological history in structuring large-scale patterns of aquatic environments and aquatic species associations remains poorly understood. We evaluated the relationships among geodiversity, limnological conditions, and freshwater ostracodes from southern Mexico to Nicaragua. A cluster analysis (CA), based on geological, geochemical, mineralogical, and water-column physical and chemical characteristics of 76 aquatic ecosystems (karst, volcanic, tectonic) revealed two main limnological regions: (1) karst plateaus of the YucatĂĄn Peninsula and northern Guatemala, and (2) volcanic terrains of the Guatemalan highlands, mid-elevation sites in El Salvador and Honduras, and the Nicaraguan lowlands. In addition, seven subregions were recognized, demonstrating a high heterogeneity of aquatic environments. Principal component analysis (PCA) identified water chemistry (ionic composition) and mineralogy as most influential for aquatic ecosystem classification. Multi-parametric analyses, based on biological data, revealed that ostracode species associations represent disjunct faunas. Five species associations, distributed according to limnological regions, were recognized. Structural equation modeling (SEM) revealed that geodiversity explains limnological patterns of the study area. Limnology further explained species composition, but not species richness. The influence of conductivity and elevation were individually evaluated in SEM and were statistically significant for ostracode species composition, though not for species richness. We conclude that geodiversity has a central influence on the limnological conditions of aquatic systems, which in turn influence ostracode species composition in lakes of the northern Neotropical region
Fluoxetine: a case history of its discovery and preclinical development
Introduction: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine.
Areas covered: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment.
Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetineâs effects on depressive-like behaviour,
anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine.
Expert opinion: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new
age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved
Insulin allergy and resistance successfully treated by desensitisation with Aspart insulin
A 25-year-old, with type I Diabetes Mellitus with a previous diagnosis of Protamine Allergy but not to human Insulin, started to notice anaphylactic reactions inmmediatly after bolus with Insulin. Skin prick and intradermal test were positive to all insulins. Skin tests to other potential allergens resulted negative. Examination after bolus of Human Insulin revealed urticaria. Daily insulin requirement were around 2-2,4 U/Kg/day. Slow desensitisation with Aspart insulin, the insulin with lowest size of skin test, was performed using subcutaneous insulin pump. Six months after the end of desensitisation his daily insulin requirement decreased to 0.8 U/Kg/day and oral corticosteroids are being reduced with no symptoms
Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity
TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5Îą but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations
Role for Maternal Asthma in Severe Human Metapneumovirus Lung Disease Susceptibility in Children
Background: Severity of human metapneumovirus (hMPV) lower respiratory illness (LRTI) is considered similar to that observed for respiratory syncytial virus (RSV). However, differences in severity between these pathogens have been noted, suggesting the degree of illness may vary in different populations. Moreover, a potential association between hMPV and asthma also suggests that hMPV may preferentially affect asthmatic subjects. Methods: In a population-based surveillance study in children aged <2 years admitted for severe LRTI in Argentina, nasopharyngeal aspirates were tested by RT-PCR for hMPV, RSV, influenza A, and human rhinovirus. Results: Of 3947 children, 383 (10%) were infected with hMPV. The hospitalization rate for hMPV LRTI was 2.26 per 1000 children (95% confidence interval [CI], 2.04-2.49). Thirty-nine (10.2%) patients infected with hMPV experienced life-threatening disease (LTD; 0.23 per 1000 children; 95% CI,. 16-.31/1000), and 2 died (mortality rate 0.024 per 1000; 95% CI,. 003-.086). In hMPV-infected children birth to an asthmatic mother was an increased risk for LTD (odds ratio, 4.72; 95% CI, 1.39-16.01). We observed a specific interaction between maternal asthma and hMPV infection affecting risk for LTD. Conclusions: Maternal asthma increases the risk for LTD in children <2 years old hospitalized for severe hMPV LRTI.Fil: Libster, Romina Paula. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂŠcnicas; ArgentinaFil: Esteban, Ignacio. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Bianchi, Alejandra Silvina. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Alva Grimaldi, Luciano. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Doctor Lucio Melendez.; ArgentinaFil: DueĂąas, Karina. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos Evita.; ArgentinaFil: Sancillo, Andrea. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos Evita.; ArgentinaFil: Rodriguez, Andrea. Gobierno de la Provincia de Buenos Aires. Hospital Provincial Evita Pueblo.; ArgentinaFil: Ferrero, Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de NiĂąos Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Stein, Katherine. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Acosta, Patricio Leandro. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂŠcnicas; ArgentinaFil: Ferolla, Fausto MartĂn. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂŠcnicas; ArgentinaFil: Bergel, Eduardo. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Caballero, Mauricio TomĂĄs. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂŠcnicas; ArgentinaFil: Polack, Fernando Pedro. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Pellegrino, Gustavo. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Fernandez Gago, Guadalupe. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Pozzolo, Cecilia. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Castro, Laura. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Almeida, Rodrigo Egues. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Rebec, Beatriz. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: GonzĂĄlez, Mariela. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Calvo, Mariel. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Henrichsen, Julieta. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Nocito, Celina. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Barbero, Guillermo. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Ves Losada, Juan. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Bonina, Angel. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Flamenco, Edgardo. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Rodriguez Perez, Alberto. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Kobylarz, Alicia. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Raggio, Mirta. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Schavlosky, Graciela. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Caria, Adriana. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Barboza, Edgar. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; ArgentinaFil: Sastre, Gustavo. FundaciĂłn para la InvestigaciĂłn en InfectologĂa Infantil; Argentin
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma
Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs).
EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated.
High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUCÂ = 0.947; odds ratio [OR]Â =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUCÂ = 0.992; ORÂ = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUCÂ = 0.941; ORÂ = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients' survival, respectively.
Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine.
The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.Spanish Carlos III Health Institute (ISCIII
Standalone vertex ďŹnding in the ATLAS muon spectrometer
A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at âs = 7 TeV collected with the ATLAS detector at the LHC during 2011
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