Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and in the anxiogenic response to ethanol withdrawal. Previously, we found that both ethanol and corticotropin releasing factor (CRF) increase GABAergic transmission in mouse and rat CeA neurons, in part by enhancing the release of GABA via activation of presynaptic CRF1 receptors. CRF1 receptors are coupled to the enzyme adenylyl cyclase (AC), which produces the second messenger cyclic AMP. There are nine isoforms of AC, but we recently found that CRF1 receptors in the pituitary were coupled to the Type 7 AC (AC7). Therefore, using an in vitro electrophysiological approach in brain slices, here we have investigated a possible role of the AC7 signaling pathway in ethanol and CRF effects on CeA GABAergic synapses of genetically modified mice with diminished brain Adcy7 activity (HET) compared to their littermate male wild-type (WT) mice. We found no significant differences in basal membrane properties, mean baseline amplitude of evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs), or paired-pulse facilitation (PPF) of GABAA-IPSPs between HET and WT mice. In CeA neurons of WT mice, ethanol superfusion significantly augmented (by 39%) GABAA-IPSPs and decreased PPF (by 25%), suggesting increased presynaptic GABA release. However, these effects were absent in HET mice. CRF superfusion also significantly augmented IPSPs (by 38%) and decreased PPF (by 23%) in WT CeA neurons, and still elicited a significant but smaller (by 13%) increase of IPSP amplitude, but no effect on PPF, in HET mice. These electrophysiological data suggest that AC7 plays an important role in ethanol and CRF modulation of presynaptic GABA release in CeA and thus may underlie ethanol-related behaviors such as anxiety and dependence

¿Podría ser la videolaringoscopia la técnica de elección para intubación con paciente despierto?

Awake fibreoptic intubation is often considered the technique of choice when a difficult airway is anticipated. However, videolaryngoscopes are being used more commonly. We searched the current literature and performed a meta-analysis to compare the use of videolaryngoscopy and fibreoptic bronchoscopy for awake tracheal intubation. Our primary outcome was the time needed to intubate the patient’s trachea. Secondary outcomes included: failed intubation; the rate of successful intubation at the first attempt; patient-reported satisfaction with the technique; and any complications resulting from intubation. Eight studies examining 429 patients were included in this review. The intubation time was shorter when videolaryngoscopy was used instead of fibreoptic bronchoscopy (seven trials, 408 participants, mean difference(95%CI) - 45.7 (- 66.0 to -25.4) s, p<0.0001, low-quality evidence). There was no significant difference between the two techniques in the failure rate (six studies, 355 participants, risk ratio (95%CI) 1.01 (0.24–4.35), p=0.99, low-quality evidence) or the first-attempt success rate (six studies, 391 participants, risk ratio (95%CI) 1.01 (0.95–1.06), p=0.8, moderate quality evidence). The level of patient satisfaction was similar between both groups. No difference was found in two reported adverse events: hoarseness/sore throat (three studies, 167 participants, risk ratio (95%CI) 1.07 (0.62–1.85), p=0.81, low-quality evidence),and low oxygen saturation (five studies, 337 participants, risk ratio (95%CI) 0.49 (0.22–1.12), p=0.09,low-quality evidence). In summary, videolaryngoscopy for awake tracheal intubation is associated with a shorter intubation time. It also seems to have a success rate and safety profile comparable to fibreoptic bronchoscopy.La intubación orotraqueal (IOT) con fibrobroncoscopio es a menudo considerada la técnica de elección cuando nos encontramos ante una vía aérea difícil prevista. Sin embargo, los videolaringoscopios se usan con más frecuencia. Se realizaron búsquedas en la literatura actual y se realizó un metaanálisis para comparar el uso de la videolaringoscopia y la fibrobroncoscopia para la intubación traqueal despierta.  El principal objetivo fue el tiempo necesario para intubación. Los objetivos secundarios incluyeron: intubación fallida; la tasa de intubación exitosa en el primer intento; satisfacción informada por el paciente con la técnica; y cualquier complicación resultante de la intubación. Ocho estudios donde se examinaron a 429 pacientes se incluyeron en esta revisión. El tiempo de intubación fue más corto cuando se utilizó la videolaringoscopia en lugar de la fibrobroncoscopia (siete ensayos, 408 participantes, diferencia significativa [IC del 95%] 45,7 (66,0 a 25,4) s, p <0,0001, bajo nivel de evidencia). No hubo diferencias significativas entre las dos técnicas en la tasa de fracaso (seis estudios, 355 participantes, riesgo relativo [IC 95%] 1,01 (0,24-4,35), p = 0,99, bajo nivel de evidencia) o la tasa de éxito de primer intento (seis estudios, 391 participantes, riesgo relativo (IC 95%) 1,01 (0,95-1,06), p = 0,8, nivel de evidencia moderado). El nivel de satisfacción del paciente fue similar entre ambos grupos. No se encontraron diferencias en los eventos adversos informados: ronquera / dolor de garganta (tres estudios, 167 participantes, riesgo relativo [IC 95%] 1,07 (0,62-1,85), p = 0,81, bajo nivel de evidencia) y baja saturación de oxígeno (cinco estudios, 337 participantes, riesgo relativo (IC 95%) 0,49 (0,22-1.12), p = 0,09, bajo nivel de evidencia). En resumen, la videolaringoscopia para la intubación traqueal despierta se asocia con un tiempo de intubación más corto. También parece tener una tasa de éxito y un perfil de seguridad comparable a la fibrobroncoscopia

Prácticas anestésicas seguras: ¿Sabemos que presión arterial intraoperatoria debemos mantener para evitar resultados postoperatorio desfavorables?

Intraoperative hypotension is a common side effect of general anesthesia and might lead to inadequate organ perfusion. However, the relationship between hypotension during non-cardiac surgery and unfavorable results is not clear. Methods: We searched in PubMed, Embase, Web of Science and CINAHL, classified the quality of retrieved articles according to the STROBE and CONSORT criteria. The strengths of association from high-quality studies were classified into end-organ specific injury risks: acute renal failure (ARF), myocardial injury, stroke and overall organ injury risks for various arterial blood pressure thresholds. Results: We present an overview of 42 articles on reported associations between various intraoperative hypotension and their associations with postoperative adverse outcomes after non-cardiac surgery. High risks of end-organ injury were reported for prolonged exposure (> 10 min) to mean blood pressures (MBP) <80 mmHg and for shorter durations <70 mmHg. Reported risks increase with increased durations for MBP <65-60 mmHg or for any exposure <55-50 mmHg. Conclusions: The reported associations suggest that organ injury might occur when MBP decreases <80 mmHg for> 10 min, and that this risk increases with the progressive decrease in blood pressure. Given the retrospective observational design of the studies reviewed, reflected by large variability in patient characteristics, hypotension definitions and outcomes, solid conclusions cannot be obtained about what blood pressure and under what circumstances are really dangerous. We provide recommendations for the design of future studies.La hipotensión intraoperatoria es un efecto secundario común de la anestesia general que puede producir una insuficiente perfusión de órganos. Sin embargo, no está clara la relación entre hipotensión durante cirugía no cardiaca y resultados desfavorables. Métodos: Buscamos en PubMed, Embase, Web of Science y CINAHL, clasificando la calidad de los artículos analizados según los criterios STROBE y CONSORT. Las fuerzas de asociación de los estudios de alta calidad se clasificaron en riesgos de lesiones orgánicas específicas: insuficiencia renal aguda (IRA), lesión miocárdica, accidente cerebrovascular y lesiones orgánicasgenerales para diferentes umbrales de presión arterial.  Resultados: Presentamos una revisión de 42 artículos sobre las asociaciones entre varias definiciones de hipotensión intraoperatoria, y su relación con resultados postoperatorios desfavorables tras cirugía no cardíaca. Se informaron riesgos elevados de lesión orgánica por exposición prolongada (>10 min) a presiones arteriales medias (PAM) <80 mmHg y para periodos más cortos <70 mmHg. Los riesgos informados aumentan con la duración de las PAM  <65-60 mmHg o para cualquier exposición con PAM <55-50 mmHg. Conclusiones: Las asociaciones reportadas sugieren que puede producirse lesión orgánica cuando disminuye la PAM <80 mmHg durante >10 min, y que este riesgo aumenta con la disminución progresiva de la presión arterial. Dado el diseño observacional retrospectivo de los estudios revisados, con gran variabilidad en las características del paciente, las definiciones de hipotensión y los resultados, no se pueden obtener conclusiones sólidas sobre qué presión arterial y bajo qué circunstancias son realmente peligrosas. Se ofrecen recomendaciones para el diseño de estudios futuros

Receptor subtype‐dependent galanin actions on gamma‐aminobutyric acidergic neurotransmission and ethanol responses in the central amygdala

The neuropeptide galanin and its three receptor subtypes (GalR1‐3) are expressed in the central amygdala (CeA), a brain region involved in stress‐ and anxiety‐related behaviors, as well as alcohol dependence. Galanin also has been suggested to play a role in alcohol intake and alcohol dependence. We examined the effects of galanin in CeA slices from wild‐type and knockout (KO) mice deficient of GalR2 and both GalR1 and GalR2 receptors. Galanin had dual effects on gamma‐aminobutyric acid (GABA)‐ergic transmission, decreasing the amplitudes of pharmacologically isolated GABAergic inhibitory postsynaptic potentials (IPSPs) in over half of CeA neurons but augmenting IPSPs in the others. The increase in IPSP size was absent after superfusion of the GalR3 antagonist SNAP 37889, whereas the IPSP depression was absent in CeA neurons of GalR1 × GalR2 double KO and GalR2 KO mice. Paired‐pulse facilitation studies showed weak or infrequent effects of galanin on GABA release. Thus, galanin may act postsynaptically through GalR3 to augment GABAergic transmission in some CeA neurons, whereas GalR2 receptors likely are involved in the depression of IPSPs. Co‐superfusion of ethanol, which augments IPSPs presynaptically, together with galanin caused summated effects of ethanol and galanin in those CeA neurons showing galanin‐augmented IPSPs, suggesting the two agents act via different mechanisms in this population. However, in neurons showing IPSP‐diminishing galanin effects, galanin blunted the ethanol effects, suggesting a preemptive effect of galanin. These findings may increase understanding of the complex cellular mechanisms that underlie the anxiety‐related behavioral effects of galanin and ethanol in CeA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92021/1/j.1369-1600.2011.00360.x.pd

Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents

Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABAA receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABAA receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target., SIGNIFICANCE STATEMENT Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence-driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets

Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report

<p>Abstract</p> <p>Background</p> <p><it>Fusarium </it>spp. is being isolated with increasing frequency as a pathogen in oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic activity against <it>Fusarium </it>spp.</p> <p>Case presentation</p> <p>We herein report a case of disseminated fusariosis diagnosed by chest CT scan and positive blood cultures to <it>Fusarium </it>spp. Because the patient's clinical condition deteriorated, CRP levels increased, and blood cultures continued to yield <it>Fusarium </it>spp. despite liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added. Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals, the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy, the patient remains in complete remission of her neoplastic disease with no signs of clinical activity of the <it>Fusarium </it>infection.</p> <p>Conclusion</p> <p>This is the first description of successful treatment of disseminated fusariosis in a pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed by oral suppressive therapy with voriconazole.</p

MICROELE. Píldoras de español. Creación de un canal de vídeos breves de gramática de español como lengua extranjera

Memoria ID-015. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2019-2020

MICROELE. Píldoras de español. Ampliación y diversificación del canal de vídeos breves de español como lengua extranjera

Memoria ID-030 Ayudas de la Universidad de Salamanca para la innovación docente, curso 2020-2021

Asesoría lingüística digital e internacional: prácticas online para futuros docentes de lengua española

Memoria ID-039. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2018-2019

Preclinical evidence implicating corticotropin-releasing factor signaling in ethanol consumption and neuroadaptation

The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF1) in EtOH-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with EtOH drinking, although additional data are needed. These results suggest that CRF1 antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.The authors were supported by the Department of Veterans Affairs; NIH NIAAA grants P60AA010760, R24AA020245 and U01AA013519 and NIH NIDA grant P50DA018165, during the writing of this manuscript. The authors have no financial conflict of interest to disclose