Cellular and Molecular Bases of the Initiation of Fever

All phases of lipopolysaccharide (LPS)-induced fever are mediated by prostaglandin (PG) E(2). It is known that the second febrile phase (which starts at ~1.5 h post-LPS) and subsequent phases are mediated by PGE(2) that originated in endotheliocytes and perivascular cells of the brain. However, the location and phenotypes of the cells that produce PGE(2) triggering the first febrile phase (which starts at ~0.5 h) remain unknown. By studying PGE(2) synthesis at the enzymatic level, we found that it was activated in the lung and liver, but not in the brain, at the onset of the first phase of LPS fever in rats. This activation involved phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) and transcriptional up-regulation of cyclooxygenase (COX)-2. The number of cells displaying COX-2 immunoreactivity surged in the lung and liver (but not in the brain) at the onset of fever, and the majority of these cells were identified as macrophages. When PGE(2) synthesis in the periphery was activated, the concentration of PGE(2) increased both in the venous blood (which collects PGE(2) from tissues) and arterial blood (which delivers PGE(2) to the brain). Most importantly, neutralization of circulating PGE(2) with an anti-PGE(2) antibody both delayed and attenuated LPS fever. It is concluded that fever is initiated by circulating PGE(2) synthesized by macrophages of the LPS-processing organs (lung and liver) via phosphorylation of cPLA(2) and transcriptional up-regulation of COX-2. Whether PGE(2) produced at the level of the blood–brain barrier also contributes to the development of the first phase remains to be clarified

Trends in the epidemiology of catheter-related bloodstream infections; towards a paradigm shift, Spain, 2007 to 2019

Altres ajuts: Departament de Salut. Generalitat de Catalunya ("Pla estratègic de recerca i innovació en salut (PERIS) 2019-2021"); Ministerio de Asuntos Económicos y Transformación Digital; Red Española de Investigación en Patología Infecciosa (REIPI).Background: Catheter-related bloodstream infections (CRBSI) are frequent healthcare-associated infections and an important cause of death. Aim: To analyse changes in CRBSI epidemiology observed by the Infection Control Catalan Programme (VINCat). Methods: A cohort study including all hospital-acquired CRBSI episodes diagnosed at 55 hospitals (2007-2019) in Catalonia, Spain, was prospectively conducted. CRBSI incidence rates were adjusted per 1,000patientdays. To assess the CRBSI rate trend per year, negative binomial models were used, with the number of events as the dependent variable, and the year as the main independent variable. From each model, the annual rate of CRBSI diagnosed per 1,000patientdays and the incidence rate ratio (IRR) with its 95% confidence intervals (CI) were reported. Results: During the study, 9,290 CRBSI episodes were diagnosed (mean annual incidence rate:0.20episodes/1,000patientdays). Patients' median age was 64.1years; 36.6% (3,403/9,290) were female. In total, 73.7% (n=6,845) of CRBSI occurred in non-intensive care unit (ICU) wards, 62.7% (n=5,822) were related to central venous catheter (CVC), 24.1% (n=2,236) to peripheral venous catheters (PVC) and 13.3% (n=1,232) to peripherally-inserted central venous catheters (PICVC). Incidence rate fell over the study period (IRR:0.94;95%CI:0.93-0.96), especially in the ICU (IRR:0.88;95%CI:0.87-0.89). As a whole, while episodes of CVC CRBSI fell significantly (IRR:0.88;95%CI:0.87-0.91), peripherally-inserted catheter CRBSI (PVC and PICVC) rose, especially in medical wards (IRR PICVC:1.08;95%CI:1.05-1.11; IRR PVC: 1.03; 95% 1.00-1.05). Conclusions: Over the study, CRBSIs associated with CVC and diagnosed in ICUs decreased while episodes in conventional wards involving peripherally-inserted catheters increased. Hospitals should implement preventive measures in conventional wards

Una aproximació neuroanatòmica a l'estudi de sistemes de neurotransmissors en els nuclis del rafe

La modulación de la actividad de las neuronas sertonérgicas localizadas en los núcleos del rafe (principalmente en el núcleo dorsal y en el medial) juega un papel muy importante en la regulación de diferentes aspectos fisiológicos, como el ciclo sueño-vigilia, la ingesta y aspectos comportamentales básicos. La presencia de diferentes receptores de neurotransmisores en los núcleos del rafe se ha propuesto mediante el uso de técnicas electrofisiológicas, de microdiálisis y, en algunos, casos mediante técnicas histoquímicas. Con la intención de dar validez anatómica a la presencia de determinados receptores en células de rafe, y para intentar determinar el fenotipo de las células que expresaban estos receptores para neurotransmisores nos propusimos: 1,- Estudiar la colocalización de diferentes mRNAs que codifican para receptores de neurotransmisores (5-HT1A, 5-HT1B, 5-HT2C, 5-ht5B, GABAB, alfa1B adrenoceptor) con los marcadores celulares serotonérgico (5-HTT mRNA) y/o GABAérgico (GAD mRNA) mediante la técnica de la doble hibridación in situ a difernetes niveles del eje rostrocaudal de los núcleos dorsal y medial del rafe. Estudiar el efecto que produce la destrucción selectiva de las células serotonérgicas sobre los mRNAs de los receptores de neurotransmisores antes mencionados. 2,- Estudiar el efecto del pindolol en los receptores 5-HT1A pre- y postsinápticos a nivel transuccional mediante estudios autorradiográficos de fijación de GTPgammaS marcado con [35S]. Para llevar a cabo este estudio se estimuló el receptor con 5-HT (ligando endógeno), y se bloqueó con un antagonista (pindolol). Se determinó la posibilidad que los receptores pre- y postsinápticos tuvieran propiedades transduccionales diferentes. 3,- Caracterizar neuroanatómicamente la conectividad de una subzona del núcleo medial del rafe, concretamente la zona ventral del núcleo.Peer Reviewe

Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei

We have used double in situ hybridization to examine the cellular localization of 5-HT2C receptor mRNA in relation to serotonergic and GABAergic neurons in the anterior raphe nuclei of the rat. In the dorsal and median raphe nuclei 5-HT2C receptor mRNA was not detected in serotonergic cells identified as those expressing serotonin (5-HT) transporter mRNA. In contrast, 5-HT2C receptor mRNA was found in most GABAergic cells, recognized by the presence of glutamic acid decarboxylase mRNA. Such 5-HT2C receptor-positive GABAergic neurons were mainly located in the intermediolateral and lateral portions of the dorsal raphe and lateral part of the median raphe. The present data give anatomical support to a previous hypothesis that proposed a negative-feedback loop involving reciprocal connections between GABAergic interneurons bearing 5-HT2A/2C receptors and 5-HT neurons in the dorsal raphe and surrounding areas. According to this model, the excitation of GABAergic interneurons through these 5-HT 2C (and also 5-HT2A) receptors would result in the suppression of 5-HT cell firing. © 2004 Elsevier B.V. All rights reserved.This work was supported by grants SAF97-0117 (CICYT) and SAF2000-0212 (‘‘Ministerio de Ciencia y Tecnología’’ (MCYT)). Support from DURSI ‘‘Generalitat de Catalunya’’ to the Department of Neurochemistry of IIBB–CSIC (IDIBAPS) as a ‘‘Grup de Recerca Consolidat’’ (5092-CSIC-01) is also acknowledged (Grant 2001-SGR-00355). Jordi Serrats has been recipient of a fellowship ‘‘Beca de Formació de Personal Investigador’’ from ‘‘Institut d’Investigacions Biomèdiques August Pi i Sunyer’’ (IDIBAPS)Peer Reviewe

An autoradiographic study of the influence of pindolol upon [35S]GTPgammaS binding in rat, guinea pig and human brain

The 5-HT1A/beta-adrenoceptor ligand (+/-)pindolol has been used in clinical trials to enhance the antidepressant effect of selective serotonin (5-HT) reuptake inhibitors (SSRIs). The accelerating effect of (+/-)pindolol is thought to derive from its blockade of the SSRI-induced, 5-HT1A autoreceptor-mediated inhibition of serotonergic cell firing and 5-HT release. However, controversial results have been reported in regard to its ability to antagonize the effect of 5-HT at such receptors. In the present study, we have analysed the effect of (+/-)pindolol on receptor-mediated G-protein activation by measuring guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTPgammaS) binding onto tissue sections from the hippocampus and dorsal raphe nucleus from rat, guinea pig and human brain. In these regions, enriched in 5-HT1A receptors, (+/-)pindolol antagonized the stimulation of [35S]GTPgammaS binding induced by 5-HT in a concentration-dependent manner. We found that in both rat and human brain the calculated pEC50 values were higher in the dorsal raphe nucleus than in hippocampus. This suggests a higher potency of (+/-)pindolol at somatodendritic 5-HT1A receptors compared to post-synaptic 5-HT1A sites. In the absence of 5-HT, (+/-)pindolol (up to 10(-3) M) did not modify [35S]GTPgammaS binding, which remained at basal levels, indicating that, in this assay, (+/-)pindolol acts as a neutral antagonist rather than a partial agonist as it has been observed in other experimental models. The present data are relevant for the understanding of the neurobiological basis of pindolol acceleration of the action of SSRI antidepressants.Peer reviewe

GABAB receptor mRNA in the raphe nuclei: co-expression with serotonin transporter and glutamic acid decarboxylase

We have used double-label in situ hybridization techniques to examine the cellular localization of GABAB receptor mRNA in relation to serotonin transporter mRNA and glutamic acid decarboxylase mRNA in the rat dorsal raphe, median raphe and raphe magnus nuclei. The degree of cellular co-localization of these markers notably varied among the different nuclei. In the dorsal raphe, cell bodies showing GABAB receptor mRNA were very abundant, the 85% being also labelled for serotonin transporter mRNA, and a low proportion (5%) showing glutamic acid decarboxylase mRNA. In the median raphe, the level of co-expression of GABAB receptor mRNA with serotonin transporter mRNA was significantly lower. Some cells were also identified that contained GABAB receptor mRNA in the absence of either one of the other mRNA species studied. Our results support the presence of GABAB receptors in serotonergic as well as GABAergic neurones in the dorsal and median raphe, providing the anatomical basis for the reported dual inhibitory/disinhibitory effect of the GABAB agonist baclofen on serotonergic function.Peer reviewe

5-ht5B Receptor mRNA in the Raphe Nuclei: Coexpression with Serotonin Transporter

We used double-label in situ hybridization to examine the cellular localization of 5-ht5B receptor mRNA in relation to serotonin transporter mRNA in the rat dorsal raphe (DR) and central superior nucleus (CS, median raphe nucleus). 5-ht5B receptor mRNA hybridization signal was often found on serotonin transporter mRNA-positive neuron profiles. The degree of cellular colocalization of these mRNAs notably varied among the different regions of the raphe nuclei. In the DR, cell bodies showing 5-ht5B receptor mRNA expression were abundant in the medial portions of the nucleus, all of them being also labeled for serotonin transporter mRNA. In contrast, in the ventrolateral regions (lateral wings) of the DR, we observed serotonin transporter mRNA-positive cells, but they were devoid of 5-ht5B receptor mRNA signal. In the CS, the level of coexpression of 5-ht5B receptor mRNA with serotonin transporter mRNA was high in the intermediate portions of the nucleus; however, we were unable to detect specific 5-ht 5B receptor mRNA hybridization signal in its caudal extent. Our results support the presence of 5-ht5B receptor in serotonergic neurons in the DR and CS, suggesting an autoreceptor role for this receptor subtype. © 2003 Wiley-Liss, Inc.Contract grant sponsor: >Ministerio de Ciencia y Tecnología> (MCYT); Contract grant numbers: SAF97-0117, SAF2000-0212; Contract grant sponsor: DURSI - >Generalitat de Catalunya> to the Department of Neurochemistry of IIBB-CSIC (IDIBAPS) as a >Grup de Recerca Consolidat> (5092-CSIC-01); Contract grant number: 2001-SGR-00355; Contract grant sponsors: >Institut d'Investigacions Biomèdiques August Pi i Synyer> (IDIBAPS) (fellowship >Beca de Formació de Personal Investigador> to JS), CIRIT (>Generalitt de Catalunya>) (fellowship to AR), the Ministerio de Ciencia y Tecnología (>Ramón y Cajal> contract to MTV)Peer Reviewe

Reversion of levodopa-induced motor fluctuations by the A2A antagonist CSC is associated with an increase in striatal preprodynorphin mRNA expression in 6-OHDA-lesioned rats

The molecular mechanisms involved in the reversion of levodopa-induced motor fluctuations by the adenosine A2A antagonist 8-(3-chlorostryryl) caffeine (CSC) were investigated in rats with a 6-hydrokydopamine (6-OHDA)-induced lesion and compared with the ones achieved by the kappa-opioid agonist, U50,488. Animals were treated with levodopa (50 mg/kg/day) for 22 days and for one additional week with levodopa + CSC (5 mg/kg/day), levodopa + U50,488 (1 mg/kg/day), or levodopa + vehicle. The reversion of the decrease in the duration of levodopa-induced rotations by CSC, but not by U50,488, was maintained until the end of the treatment and was associated with a further increase in levodopa-induced preprodynorphin mRNA in the lesioned striatum, being higher in the ventromedial striatum. The increase in striatal preprodynorphin expression, particularly in the ventromedial striatum, may be related to the reversion of levodopa-induced motor fluctuations in the CSC-treated animals, suggesting a role of the direct striatal output pathway activity in the ventromedial striatum in the pathophysiology of motor fluctuations. © 2006 Wiley-Liss, Inc.Contract grant sponser: Ministerio de Sanidad y Consumo; Contract grant number: FIS 01/1499; Contract sponser: Ministerio de Ciencia y Tecnología; Contract grant Number: SAF2000-0212; Contract grant sponser: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Peer Reviewe

Neuroprotection induced by the adenosine A2A antagonist CSC in the 6-OHDA rat model of parkinsonism: Effect on the activity of striatal output pathways

In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved. © Springer-Verlag 2005.This research was supported by grants from the Ministerio de Sanidad y Consumo (FIS 01/1499) and from the Ministerio de Ciencia y Tecnología (SAF2000–0212) of Spanish Government. J.B. and J.S. were supported by a grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Peer Reviewe