From Liver to Brain: How MAFLD/MASLD Impacts Cognitive Function.

Metabolic dysfunction-associated fatty liver disease or metabolic dysfunction-associated steatotic liver disease (MAFLD/MASLD), is a common chronic liver condition affecting a substantial global population. Beyond its primary impact on liver function, MAFLD/MASLD is associated with a myriad of extrahepatic manifestations, including cognitive impairment. The scope of cognitive impairment within the realm of MAFLD/MASLD is a matter of escalating concern. Positioned as an intermediate stage between the normal aging process and the onset of dementia, cognitive impairment manifests as a substantial challenge associated with this liver condition. Insights from studies underscore the presence of compromised executive function and a global decline in cognitive capabilities among individuals identified as being at risk of progressing to liver fibrosis. Importantly, this cognitive impairment transcends mere association with metabolic factors, delving deep into the intricate pathophysiology characterizing MAFLD/MASLD. The multifaceted nature of cognitive impairment in the context of MAFLD/MASLD is underlined by a spectrum of factors, prominently featuring insulin resistance, lipotoxicity, and systemic inflammation as pivotal contributors. These factors interplay within the intricate landscape of MAFLD/MASLD, fostering a nuanced understanding of the links between hepatic health and cognitive function. By synthesizing the available evidence, exploring potential mechanisms, and assessing clinical implications, the overarching aim of this review is to contribute to a more complete understanding of the impact of MAFLD/MASLD on cognitive function.

Structural and biochemical alterations in dendritic spines as key mechanisms for severe mental illnesses.

Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.

Infecciones bacterianas durante el primer mes post trasplante hepático. Experiencia de 12 años en un único centro. Montevideo-Uruguay

Introducción: Las infecciones bacterianas en trasplante hepático (TH) son una de las principales causas de morbimortalidad. Objetivo: Caracterizar las complicaciones infecciosas bacterianas en el primer mes postrasplante. Pacientes y Métodos: Estudio retrospectivo entre los años 2009-2020. Resultados: 225 pacientes recibieron un TH. 80 (35,5%) desarrollaron al menos un episodio de infección bacteriana en el primer mes postrasplante hepático. Hubo 105 episodios de infección bacteriana con una incidencia de 46,6%. El foco más frecuente fue el abdominal (48,6%) y el microorganismo predominante fue Klebsiella spp. De los 104 aislamientos, el 57,6% presentaron un perfil MDR/XDR. Los pacientes que desarrollaron una complicación infecciosa presentaron menor sobrevida al alta hospitalaria en comparación con los que no la presentaron 87,5 versus 94,5% [OR 4,18 (IC 95%: 1,5-11,6)]. En el análisis multivariado la reintervención quirúrgica precoz [OR 4,286 (IC 95%: 1,911-9,61)], mostró un riesgo significativo de desarrollar una complicación infecciosa bacteriana en el primer mes postrasplante. Conclusiones: Tres de cada 10 pacientes presentaron una infección bacteriana en el primer mes postrasplante con una alta incidencia de bacilos gramnegativos MDR/XDR. Los pacientes que desarrollaron una complicación infecciosa presentaron una menor sobrevida al alta. La reintervención quirúrgica precoz se identificó como un factor predisponente de infección temprana.

Background: Bacterial infections are one of the main causes of morbidity and mortality in liver transplant recipients (LT). Aim: To characterize bacterial infectious complications in the first month an after a liver transplant. Methods: Retrospective analysis of a cohort of liver transplant recipients who presented at least one bacterial infectious complication in the first month after transplant between 2009 and 2020. Results: 225 patients were analyzed. 80 (35.5%) had a least one documented bacterial infection during the first month after transplant. 105 bacterial infections were documented, with an incidence of 46.6%. The most frequent origin was intra-abdominal (48.6%) and the predominant isolated microorganism was Klebsiella spp. Among 104 isolated microorganisms 57.6% showed MDR/XDR profile. Patients who developed a bacterial infectious complication had a shorter overall survival (OS) after discharge from hospital (87.5% vs 94.5%) [OR 4.18 (IC 95%: 1.5-11,6)]. When multivariate analysis of predisposing factors was performed early surgical reoperation was the only variable associated with an increased risk of developing a bacterial complication in the first month [OR 4.286 (IC 95%: 1.911-9.61)]. Conclusions: Three out of 10 patients developed a bacterial infectious complication during the first month after liver transplant with a high incidence of gram-negative bacillus MDR/XDR. Patients who presented infectious complications had a shorter OS after discharge, and early reoperation was identified as a predisposing factor of early infectious complications.

Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications.

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.

EPD1504: a novel µ-opioid receptor partial agonist attenuates obsessive-compulsive disorder (OCD)-like behaviors.

Low doses of µ-opioid receptor (MOR) agonists rapidly ameliorate symptoms in treatment-resistant obsessive-compulsive disorder (OCD) patients (10-50% of OCD patients). However, the utility of MOR agonists is limited by their safety liabilities. We developed a novel MOR partial agonist (EPD1540) that has an improved respiratory safety profile when compared to buprenorphine. Buprenorphine is a MOR partial agonist primarily used in the treatment of opiate-use disorder, which in investigator-led trials, has been shown to rapidly ameliorate symptoms in treatment-resistant OCD patients. In this study, we show that doses of EPD1504 and buprenorphine that occupy small fractions of MORs in the CNS (approximately 20%) are as effective as fluoxetine at ameliorating OCD-like behaviors in two different rat models (an operant probabilistic reversal task and marble burying). Importantly, effective doses of EPD1504 did not impair either locomotor activity, or respiration under normoxic or hypercapnic conditions. Additionally, EPD1504 had effects comparable to buprenorphine in the conditioned place preference assay. These results indicate that EPD1504 may provide a safer alternative to buprenorphine for the treatment of OCD patients.

The antipsychotic olanzapine reduces memory deficits and neuronal abnormalities in a male rat model of Autism.

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.

Olfactory bulbectomy induces nociceptive alterations associated with gliosis in male rats.

Major depressive disorder (MDD) is a major health concern worldwide with a wide array of symptoms. Emerging evidence suggests a high comorbidity between MDD and chronic pain, however, the relationship between these two diseases is not completely understood. Growing evidence suggests that glial cells play a key role in both disorders. Hence, we examined the effect of olfactory bulbectomy (OBX), a well-known model of depression-related behavior, on nociceptive behaviors and the number and morphology of astrocytes and glial cells in brain regions involved in the control of nociceptive processes in male rats. The brain regions analyzed included the basolateral amygdala (BLA), central amygdala (CeA), prefrontal cortex (PFC), and CA1 subregion of the hippocampus. A battery of behavioral tests, mechanical allodynia, thermal cold allodynia and mechanical hyperalgesia, was evaluated before and four weeks after OBX. Quantitative morphological analysis, as well as assessment of the number of glial fibrillary acidic protein (GFAP) and ionizing calcium-binding adaptor molecule 1 (Iba1) positive astrocytes and microglia were carried out to characterize glial remodeling and density, respectively. OBX caused mechanical and cold allodynia in an asynchronous pattern. The cold allodynia was noticeable one week following surgery, while mechanical allodynia became apparent two weeks after surgery. In the BLA, CeA and CA1, OBX caused significant changes in glial cells, such as hypertrophy and hypotrophy in GFAP-positive astrocytes and Iba1-positive microglia, respectively. Iba1-positive microglia in the PFC underwent selective hypotrophy due to OBX and OBX enhanced both GFAP-positive astrocytes and Iba1-positive microglia in the BLA. In addition, OBX increased the number of GFAP-positive astrocytes in the CeA and CA1. The amount of Iba1-positive microglia in the PFC also increased as a result of OBX. Furthermore, we found that there was a strong link between the observed behaviors and glial activation in OBX rats. Overall, our work supports the neuroinflammatory hypothesis of MDD and the comorbidity between pain and depression by demonstrating nociceptive impairment and significant microglial and astrocytic activation in the brain.

Neonatal olfactory bulbectomy induces anxiety-related behavior and modifies dopaminergic receptor expression in post-pubertal rats.

Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs (OB) send projections to various CNS regions including the nucleus accumbens (NAcc) and caudate-putamen (CPu). Both the NAcc and CPu receive important dopaminergic input. Emerging evidence suggests that dopamine (DA) is related to anxiety-related behaviors. Therefore, we aimed to investigate the consequences of neonatal olfactory bulbectomy (nOBX) to anxiety-related behavior as assayed in the elevated plus maze (EPM) as well as the expression of dopaminergic receptors (D1-like, D2-like, and D3) in the NAcc and CPu at pre- and post-pubertal ages in the rat. The results show that nOBX increased the number of entries in the open arm of the EPM post-pubertally, suggesting an anxiolytic-related effect. nOBX increased the D2-like binding in the NAcc shell and D3 binding in the NAcc core pre-pubertally. At post-pubertal ages, the D3 binding was reduced at the olfactory tubercle and islands of Calleja in nOBX rats. Alterations in the DA receptor expression may be one mechanism responsible for the observed behavioral modifications in nOBX rats.

Persistent peripheral inflammation and pain induces immediate early gene activation in supraspinal nuclei in rats.

Pain is a public health concern worldwide and can present simultaneously with anxiety and depression. c-Fos is a marker used to identify activated cells in response to various stimuli. Specifically, it can be used as a brain marker of pain. We examined whether peripheral inflammation produces mechanical allodynia, anxiety- and depression-related behaviors in male rats (Rattus norvegicus, Wistar strain) and if these behaviors can have an impact on c-Fos expression in the supraspinal nuclei involved in pain control. We assessed mechanical thresholds by von Frey monofilaments, depression-like behaviors in the forced swimming test (FST) and anxiety-related behaviors in the open field test (OFT) after the administration of the inflamogen Complete Freund´s Adjuvant (CFA) in rats. We found that CFA increased paw diameter is all rats, however, CFA treatment resulted in a subgroup of rats developing allodynia [CFA- mechanical allodynia (CFA-MA)] and a subgroup of rats not developing allodynia [CFA-no mechanical allodynia (CFA-NMA)]. The peak of tactile allodynia and inflammation were coupled with an increase in c-Fos expression in several supraspinal brain nuclei, i.e. basolateral amygdala, periaqueductal gray matter and rostroventromedial medulla in CFA-MA rats. Moreover, we found a correlation between c-Fos levels and mechanical thresholds. No modification in c-Fos expression was observed in CFA-NMA rats. CFA did not modulate behaviors in the OFT or FST. In summary, we show that mechanical allodynia but not peripheral inflammation activates c-Fos in several supraspinal nuclei, which sheds new light on brain regions involved in the control of pain following peripheral injury and decouples this effect from mere peripheral inflammation. This model may be used to study resistance to pain development in future studies.

Evidence for Endogenous Opioid Dependence Related to Latent Sensitization in a Rat Model of Chronic Inflammatory Pain.

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked.

Cellular mechanisms in brain aging: Focus on physiological and pathological aging.

Aging is a natural phenomenon characterized by accumulation of cellular damage and debris. Oxidative stress, cellular senescence, sustained inflammation, and DNA damage are the main cellular processes characteristic of aging associated with morphological and functional decline. These effects tend to be more pronounced in tissues with high metabolic rates such as the brain, mainly in regions such as the prefrontal cortex, hippocampus, and amygdala. These regions are highly related to cognitive behavior, and therefore their atrophy usually leads to decline in processes such as memory and learning. These cognitive declines can occur in physiological aging and are exacerbated in pathological aging. In this article, we review the cellular processes that underlie the triggers of aging and how they relate to one another, causing the atrophy of nerve tissue that is typical of aging. The main topic of this review to determine the central factor that triggers all the cellular processes that lead to cellular aging and discriminate between normal and pathological aging. Finally, we review how the use of supplements with antioxidant and anti-inflammatory properties reduces the cognitive decline typical of aging, which reinforces the hypothesis of oxidative stress and cellular damage as contributors of physiological atrophy of aging. Moreover, cumulative evidence suggests their possible use as therapies, which improve the aging population's quality of life.

Infecciones osteoarticulares: epidemiología, etiología y evolución clínica en un centro de referencia nacional

Introducción: la infección osteo-articular es una patología compleja, y su prevalencia esta en aumento. Conocer las principales características de su presentación clínica, etiología y evolución permite mejorar su abordaje. Material y métodos: estudio observacional, retrospectivo, período 01 de enero 2020 a 31 diciembre 2020 en el Instituto Nacional de Ortopedia y Traumatología. Se incluyeron todos los pacientes adultos ingresados con diagnóstico clínico de infección osteo-articular y que fueron asistido en conjunto por Enfermedades Infecciosas y Traumatología en el período de estudio. Todos los casos contaban con uno o más cultivos microbiológicos profundos. Resultados: hubo 132 pacientes con infección osteo-articular, la relación hombre-mujer fue 2 a 1 y una media de 53 años. La presentación clínica fue con dolor, fístula y signos fluxivos locales. Las infecciones más frecuentes fueron de fracturas y prótesis articulares. El 54% de las infecciones fue por cocos gram positivos, 31% por enterobacterias y 13% bacilos gram negativos no fermentadores. En cuanto al perfil de sensibilidad 33% de los cocos fueron meticilino resistentes y 43% de las enterobacterias multirresistentes. Conclusión: La patología mas frecuente en 2 de cada 3 ingresos fue la infección de fracturas y la asociada a material implantado. A la complejidad habitual del tratamiento quirúrgico y antimicrobiano de esta patología se suma que 3 de cada 10 microorganismos aislados fueron resistentes.

Introduction: osteoarticular infections are a complex condition that are gradually increasing in prevalence. Learning about its clinical presentation, etiology and evolution will enable improving its management. Method: observational, retrospective study of cases seen at the National Orthopedic and Traumatology Institute from January 1st, 2020 to December 31st, 2020. All adult patients admitted with clinical diagnosis of osteoarticular infection who were assisted jointly by the Infectious Diseases and Traumatology units in the above mentioned period were included in the study. All cases had at least one deep microbiological cultures. Results: there were 132 patients with osteoarticular infection, female to male ratio was 2-to-1 and average age was 53 years old. Clinical presentation was characterized by pain, fistula and local fluxiye signs. The most frequent infections were fracture and prosthetic joint infections. Fifty four percent of infections were caused by gram-positive coccus, 31% were caused by enterobacteria and 13% by nonfermenting gram-negative bacilli (NFGNB). As to the sensitivity profile, 33% of cocci were methicillin-resistant and 43% of enterobacteria were multidrug-resistant. Conclusions: the most frequent pathology in 2 out of three hospitalizations were fracture infection and infections in orthopedic-related devices. The usual complexity.

Introdução: a infecção osteoarticular é uma patologia complexa, e sua prevalência está aumentando. Conhecer as principais características da sua apresentação clínica, etiologia e evolução permite-nos melhorar a sua abordagem. Material e métodos: estudo observacional, retrospectivo, que inclui pacientes atendidos no período 1º de janeiro -a 31 de dezembro de 2020 no Instituto Nacional de Ortopedia e Traumatologia. Foram incluídos todos os pacientes adultos internados com diagnóstico clínico de infecção osteoarticular atendidos conjuntamente por especialistas em Infecciologia e Traumatologia. Em todos os casos foram realizadas uma ou mais culturas microbiológicas profundas. Resultados: foram incluídos 132 pacientes diagnosticados com infecção osteoarticular, a relação homem-mulher foi de 2 para 1 e a idade média foi 53 anos. A apresentação clínica foi: dor, fístula e sinais inflamatórios agudos locais. As infecções mais frequentes foram as associadas a fraturas e próteses articulares. 54% das infecções foram devidas a cocos Gram positivos, 31% a enterobactérias e 13% a bacilos Gram negativos não fermentadores. Em relação ao perfil de sensibilidade, 33% dos cocos eram resistentes à meticilina e 43% das enterobactérias eram multirresistentes. Conclusão: a patologia mais frequente em 2 dos 3 internamentos foi a infecção das fracturas e estava associada ao material implantado. Acrescenta-se à complexidade usual do tratamento cirúrgico e antimicrobiano desta doença o fato de que 3 em cada 10 microrganismos isolados eram resistentes.

Phenotypic screening with deep learning identifies HDAC6 inhibitors as cardioprotective in a BAG3 mouse model of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs using a phenotypic screen and deep learning. From a library of 5500 bioactive compounds and siRNA validation, we found that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiomyocyte-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. In BAG3cKO mice, TYA-018 protected against sarcomere damage and reduced Nppb expression. Based on integrated transcriptomics and proteomics and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate drug discovery, and they support developing novel therapies that address underlying mechanisms associated with heart disease.

A nutraceutical formulation combined with sclerofoam-assisted laser treatment ameliorates chronic venous insufficiency.

Chronic venous insufficiency has a high impact on the healthcare system due to its high incidence worldwide. We performed a study in 30 women with thigh and leg varices due to major saphenous vein valve incontinence with saphenous trunk reflux causing phlebo-lymphoedema to assess the efficacy of sclerofoam-assisted laser treatment combined with nutraceutical administration. The patients underwent endovascular combination sealing of the saphenous trunk with sclerofoam-assisted laser treatment technique into the major saphenous veins under low-volume tumescent anesthesia followed by intraoperative phlebectomies. Post-operatively, the patients received capsules containing Aesculus Hippocastanum, chondroitin sulphate, proanthocyanidins from Pinus pinaster Aiton, proanthocyanidins from Vitis vinifera L., hydrolysed marine collagen and carcinine dihydrochloride for 3 weeks. We evaluated the extracellular fluid volume of the lower limbs using bioimpedance spectroscopy pre- (T0) and post-surgery (T2) (impedance is a vector which is composed of two components, resistance [RES] and reactance [REA)]). In addition, we evaluated the following parameters pre- and post-surgery: pain, heaviness, paresthesia, itching, swelling, daily urine volume output and leg volume. Limb volume was significantly decreased at T2 compared to T0 (p < 0.01). RES and REA were significantly increased at T2 compared to T0 (p < 0.0001 and p < 0.01, respectively). A significant improvement in heaviness, paresthesia, pain, swelling and itch was also observed (all p < 0.0001) while no changes in terms of diuresis occurred. No adverse effects were observed. The present study shows a promising approach to the treatment of chronic venous insufficiency that warrants further clinical studies in larger cohorts of patients.

Curcumin induces cortico-hippocampal neuronal reshaping and memory improvements in aged mice.

Aging induces cognitive decline, reduces of synaptic plasticity and increases oxidative reactive species (ROS) in the central nervous system. Traditional medicine has long benefitted from naturally occurring molecules such as curcumin (diferuloymethane). Curcumin is extracted from the plant Curcuma longa and is known for its synaptic and antioxidant-related benefits. In this study, we tested the hypothesis that chronic curcumin treatment reduces cognitive and cellular effects of aging. Curcumin-treated mice showed improved learning and memory using the Morris Water Maze and novel object recognition task. In addition, using the Golgi-Cox stain, curcumin treatment increased spine density in all evaluated regions and increased dendritic arborization in the prefrontal cortex (PFC) layer 3 and CA3 subregion of the hippocampus. Moreover, chronic curcumin exposure increased synaptophysin and actin expression and reduced glial fibrillary acidic protein expression, a marker of astrocytes, in the hippocampus (CA1 and CA3 subregions), while simultaneously reducing the ROS-related molecule, metallothionein 3 expression in the PFC and hippocampus. Collectively, these novel findings suggest that curcumin reduces cognitive, neuronal and astrocytic signs of aging in mice.

Threshold for copulation-induced analgesia varies according to the ejaculatory endophenotypes in rats.

Analgesia may be modulated by multiple internal and external factors. In prior studies, copulatory-induced analgesia was demonstrated using the vocalization threshold to tail shock (VTTS) in male and female rats. Three ejaculatory endophenotypes have been characterized in male Wistar rats based upon their ejaculation latency (EL). Since intromissions and ejaculations produce analgesia, and these copulatory patterns are performed with different frequency depending on the male's ejaculatory endophenotype, we hypothesized that copulation-induced analgesia would vary in relation to these endophenotypes. In the present study, we used three groups according to the EL (medians): rapid ejaculators (236 s; n = 21), intermediate ejaculators (663.2 s; n = 20) and sluggish ejaculators (1582.2 s; n = 8). Our aim was to evaluate whether copulation-induced analgesia is related to the ejaculatory endophenotypes during two consecutive ejaculatory series (EJS). In the first EJS, the VTTS of the rapid ejaculators was significantly higher than that of intermediate and sluggish rats. At the onset of the second EJS, the VTTS of the rapid and intermediate ejaculators was significantly higher than that of the sluggish rats. No differences in VTTS were observed during the first or second post-ejaculatory intervals among the three groups. These findings provide evidence that the more intromissions that occurred per unit time, the higher was the level of analgesia.

Endogenous µ-opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain.

Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ-opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or ß-funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion, and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co-expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co-expressed tdTomato+ in Oprm1Cre ::tdTomato transgenic mice. CeA microinjection of naltrexone (1 µg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra-CeA injection of the MOR-selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain.

Antimicrobial stewardship programs in adult intensive care units in Latin America: Implementation, assessments, and impact on outcomes.

OBJECTIVE: To assess the impact of antimicrobial stewardship programs (ASPs) in adult medical-surgical intensive care units (MS-ICUs) in Latin America. DESIGN: Quasi-experimental prospective with continuous time series. SETTING: The study included 77 MS-ICUs in 9 Latin American countries. PATIENTS: Adult patients admitted to an MS-ICU for at least 24 hours were included in the study. METHODS: This multicenter study was conducted over 12 months. To evaluate the ASPs, representatives from all MS-ICUs performed a self-assessment survey (0-100 scale) at the beginning and end of the study. The impact of each ASP was evaluated monthly using the following measures: antimicrobial consumption, appropriateness of antimicrobial treatments, crude mortality, and multidrug-resistant microorganisms in healthcare-associated infections (MDRO-HAIs). Using final stewardship program quality self-assessment scores, MS-ICUs were stratified and compared among 3 groups: ≤25th percentile, >25th to <75th percentile, and ≥75th percentile. RESULTS: In total, 77 MS-ICU from 9 Latin American countries completed the study. Twenty MS-ICUs reached at least the 75th percentile at the end of the study in comparison with the same number who remain within the 25th percentile (score, 76.1 ± 7.5 vs 28.0 ± 7.3; P < .0001). Several indicators performed better in the MS-ICUs in the 75th versus 25th percentiles: antimicrobial consumption (143.4 vs 159.4 DDD per 100 patient days; P < .0001), adherence to clinical guidelines (92.5% vs 59.3%; P < .0001), validation of prescription by pharmacist (72.0% vs 58.0%; P < .0001), crude mortality (15.9% vs 17.7%; P < .0001), and MDRO-HAIs (9.45 vs 10.96 cases per 1,000 patient days; P = .004). CONCLUSION: MS-ICUs with more comprehensive ASPs showed significant improvement in antimicrobial utilization.

Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review.

BACKGROUND: Tuberculous meningitis (TBM) is the most frequent, severe, and disabling form of central nervous system (CNS) tuberculosis (TB). TBM paradoxical manifestations are characterized by clinical or paraclinical worsening after 1 month of effective anti-TB treatment in patients who initially responded to treatment despite the use of adjunctive corticosteroids. METHODS: Retrospective descriptive study of consecutive HIV-negative adult patients (≥ 18 years) with definitive TBM who developed a paradoxical manifestation following anti-TB in a tertiary-care hospital in Mexico from 2009 to 2019; we also conducted a literature review of published cases/series of paradoxical manifestations in HIV-negative patients from 1980 to 2020. RESULTS: We detected 84 cases of definitive TBM; 55 (68.7%) HIV-negative patients and 29 (36.3%) HIV-infected patients. Among HIV-negative patients, four (7.3%), three female and one male (19-49 years old), developed a paradoxical manifestation within 4-14 weeks following treatment initiation despite receiving adequate corticosteroid doses; Mycobacterium bovis was isolated from the cerebrospinal fluid of three cases and Mycobacterium tuberculosis in one more. Two patients developed vasculopathy-related cerebral infarctions, one severe basilar meningitis, and hydrocephalus, one more a tuberculoma. Two were treated with intravenous cyclophosphamide, and two with steroids. One of the patients treated with steroids died; patients who received cyclophosphamide had a good clinical response. CONCLUSIONS: This case series illustrates the diverse clinical/radiologic paradoxical manifestations of TBM in HIV-negative patients. Cyclophosphamide may be safe and effective in treating TBM-associated paradoxical manifestations. Specific diagnostic and care protocols for these patients are needed.