Nicotinamide, an acetylcholinesterase uncompetitive inhibitor, protects the blood‒brain barrier and improves cognitive function in rats fed a hypercaloric diet.

Oxidative stress and inflammation induced by abundant consumption of high-energy foods and caloric overload are implicated in the dysfunction of the blood‒brain barrier (BBB), cognitive impairment, and overactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These enzymes hydrolyse acetylcholine, affecting anti-inflammatory cholinergic signalling. Our aim was to evaluate whether nicotinamide (NAM) attenuates the impairment of the BBB and cognitive function, improving cholinergic signalling. Forty male rats were distributed into five groups: one group was fed a standard diet, and the remaining groups were fed a high-fat diet and a beverage with 40% sucrose (HFS; high-fat sucrose). In three of the HFS groups, the carbohydrate was replaced by drinking water containing different concentrations of NAM for 5 h every morning for 12 weeks. The biochemical profile, levels of stress and inflammation markers, cholinesterase activities, BBB permeability, and cognitive capacity were evaluated. The results showed that the HFS diet disturbed the metabolism of carbohydrates and lipids, causing insulin resistance. Simultaneously, AChE and BChE activities, levels of proinflammatory cytokines, oxidation of proteins and lipoperoxidation increased along with decreased antioxidant capacity in serum. In the hippocampus, increased activity of cholinesterases, protein carbonylation and lipoperoxidation were associated with decreased antioxidant capacity. Systemic and hippocampal changes were reflected in increased BBB permeability and cognitive impairment. In contrast, NAM attenuated the above changes by reducing oxidative stress and inflammation through decreasing cholinesterase activities, especially by uncompetitive inhibition. NAM may be a potential systemic and neuroprotective agent to mitigate cognitive damage due to hypercaloric diets.

¿Qué pasa durante y después del síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2? / What happens during and after multisystem inflammatory syndrome in children associated with SARS-CoV-2?

Objetivo. Analizar las características clínicas y analíticas de los pacientes diagnosticados de síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2 (SIM-PedS) en la Comunidad Autónoma del Principado de Asturias, durante su ingreso y en los seis meses posteriores. Material y métodos. Estudio descriptivo, observacional, prospectivo (diciembre 2020 - junio 2022). Se incluyeron los pacientes menores de 18 años diagnosticados de SIM-PedS en la Comunidad Autónoma del Principado de Asturias. Se recogieron datos demográficos, clínicos y analíticos durante el ingreso y en los seis meses posteriores. Resultados. Durante el periodo de estudio, se incluyeron 16 pacientes (11 varones, edad mediana 10,6 años). Todos los pacientes tuvieron fiebre, 12 clínica gastrointestinal y 12 exantema. Todos los pacientes presentaron elevación de reactantes de fase aguda, 13 elevación de la porción N-terminal del pro-péptido natriurético tipo B, 10 linfopenia y 6 trombopenia. En la evaluación cardiológica durante el ingreso se encontraron alteraciones en seis pacientes. Todos los pacientes recibieron inmunoglobulinas, 14 corticoides y 6 inotrópicos. Nueve pacientes precisaron ingreso en la Unidad de Cuidados Intensivos Pediátricos (UCIP), con una estancia mediana de cuatro días. Un paciente falleció. No se han observado alteraciones reseñables ni en la clínica ni en la analítica ni en la evaluación cardiaca durante los seis meses posteriores al alta. Conclusiones. Los casos recogidos han mostrado las características clínicas y analíticas descritas en la literatura sobre el SIM-PedS, requiriendo más de la mitad ingreso en UCIP y recibiendo en todos los casos tratamiento con inmunoglobulinas. Presentaron frecuentemente afectación cardiológica, falleciendo un paciente. A los seis meses del episodio, ningún paciente ha mostrado afectación clínica, analítica ni de la función cardiaca (AU)

Aim. To analyze the clinical and analytical characteristics of patients diagnosed with Multisystem Inflammatory Syndrome in Children associated with SARS-CoV-2 (MIS-C) in the autonomous community of the Principality of Asturias, during their admission and in the subsequent six months. Material and methods. Descriptive, observational, prospective study (December 2020 - June 2022). Patients under 18 years of age diagnosed with MIS-C in the autonomous community of the Principality of Asturias were included. Demographic, clinical and analytical data were collected during admission and in the following six months. Results. During the study period, 16 patients were included (11 males, median age 10.6 years). All patients had fever, 12 had gastrointestinal symptoms and 12 had rash. All patients presented elevation of acute phase reactants, 13 elevation of the N-terminal portion of B-type natriuretic pro-peptide, 10 lymphopenia and 6 thrombopenia. In the cardiological evaluation during admission, alterations were found in six patients. All patients received immunoglobulins, 14 corticosteroids and 6 inotropes. Nine patients required admission to the Pediatric Intensive Care Unit (PICU), with a median stay of four days. One patient died. No notable alterations have been observed either in clinical symptoms, laboratory tests or cardiac evaluation during the six months after discharge. Conclusions. The cases collected have shown the clinical and analytical characteristics described in the literature on MIS-C, with more than half requiring admission to the PICU and receiving treatment with immunoglobulins in all cases. They frequently presented cardiological involvement, with one patient dying. Six months after the episode, no patient has shown clinical, analytical or cardiac function impairment (AU)

Synchronous enteroid adenocarcinoma at the ureteral implantation site after ureterosigmoidostomy.

Ureterosigmoidostomy is considered to be the oldest urinary diversion technique performed for the first time in the 19th Century in patients with urinary malformations. However, the high rate of complications as well as the significant risk of developing tumors in the colonic portion of the ureteral anastomosis have given rise to other new intestinal urinary diversion techniques. We present the case of a patient with two synchronous enteroid adenocarcinomas, with a latency period of 66 years, at the site of both ureterocolonic anastomoses after ureterosigmoidostomy performed during childhood owing to bladder exstrophy.

Neurotransmitters, neuropeptides and their receptors interact with immune response in healthy and psoriatic skin.

Psoriasis is a chronic inflammatory disease with a multifactorial origin that affects the skin. It is characterized by keratinocyte hyperproliferation, which results in erythemato-squamous plaques. Just as the immune system plays a fundamental role in psoriasis physiopathology, the nervous system maintains the inflammatory process through the neuropeptides and neurotransmitters synthesis, as histamine, serotonin, calcitonin gene-related peptide, nerve growth factor, vasoactive intestinal peptide, substance P, adenosine, glucagon-like peptide, somatostatin and pituitary adenylate cyclase polypeptide. In patients with psoriasis, the systemic or in situ expression of these chemical mediators and their receptors are altered, which affects the clinical activity of patients due to its link to the immune system, provoking neurogenic inflammation. It is important to establish the role of the nervous system since it could represent a therapeutic alternative for psoriasis patients. The aim of this review is to offer a detailed review of the current literature about the neuropeptides and neurotransmitters involved in the physiopathology of psoriasis.

The yin/yang of inflammatory status: Blood-brain barrier regulation during sleep.

Sleep loss induces a low-grade inflammatory status characterized by a subtle but sustained increase of pro-inflammatory mediators, which are key regulators of blood-brain barrier function. To investigate the influence of inflammatory status on blood-brain barrier dysfunction induced by sleep restriction we performed an experiment using two strains of mice with different immunological backgrounds, C57BL/6 mice that have a predominant pro-inflammatory response and BALB/c mice that have a predominant anti-inflammatory response. Mice were sleep-restricted during 10 days using the flowerpot technique during 20 h per day with 4 h of daily sleep opportunity. The systemic inflammatory status, blood-brain barrier permeability, and the hippocampal expression of neuroinflammatory markers were characterized at the 10th day. Serum levels of TNF and IFN-γ increased in sleep-restricted C57BL/6 but not in BALB/c mice; no changes in other cytokines were found. Sleep restriction increased blood-brain barrier permeability in C57BL/6 strain but not in BALB/c. The hippocampus of sleep-restricted C57BL/6 mice exhibited an increase in the expression of the neuroinflammatory markers Iba-1, A2A adenosine receptor, and MMP-9; meanwhile in sleep-restricted BALB/c mice the expression of this markers was lesser than the control group. These data suggest that cytokines may be playing a key role in modulating blood-brain barrier function during sleep restriction, and probably the effects are related to Iba-1, MMP-9 and A2A adenosine receptor overexpression.

Chronic sleep restriction disrupts interendothelial junctions in the hippocampus and increases blood-brain barrier permeability.

Chronic sleep loss in the rat increases blood-brain barrier permeability to Evans blue and FITC-dextrans in almost the whole brain and sleep recovery during short periods restores normal blood-brain barrier permeability. Sleep loss increases vesicle density in hippocampal endothelial cells and decreases tight junction protein expression. However, at the ultrastructural level the effect of chronic sleep loss on interendothelial junctions is unknown. In this study we characterised the ultrastructure of interendothelial junctions in the hippocampus, the expression of tight junction proteins, and quantified blood-brain barrier permeability to fluorescein-sodium after chronic sleep restriction. Male Wistar rats were sleep restricted using the modified multiple platform method during 10 days, with a daily schedule of 20-h sleep deprivation plus 4-h sleep recovery at their home-cages. At the 10th day hippocampal samples were obtained immediately at the end of the 20-h sleep deprivation period, and after 40 and 120 min of sleep recovery. Samples were processed for transmission electron microscopy and western blot. Chronic sleep restriction increased blood-brain barrier permeability to fluorescein-sodium, and decreased interendothelial junction complexity by increasing the frequency of less mature end-to-end and simply overlap junctions, even after sleep recovery, as compared to intact controls. Chronic sleep loss also induced the formation of clefts between narrow zones of adjacent endothelial cell membranes in the hippocampus. The expression of claudin-5 and actin decreased after chronic sleep loss as compared to intact animals. Therefore, it seems that chronic sleep loss disrupts interendothelial junctions that leads to blood-brain barrier hyperpermeability in the hippocampus.

Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link.

Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

Altered functional development of the blood-brain barrier after early life stress in the rat.

This study investigated the effect of early life stress on blood-brain barrier functional development in an altricial mammal, the Wistar rat. Forced swimming between gestational days 10-20 was used as a stress procedure in pregnant rats. After delivery, half of the control litters underwent 180 min maternal separation from postnatal day 2-20. Controls were kept without any stress manipulations. At sacrifice between postnatal days 1-30 subjects were given intracardiac Evans blue or the lectin wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). Evans blue-stained brain slices were photographed and optical density quantified. WGA-HRP stained brains were processed for ultrastructural analysis. Plasma corticosterone at embryonic day 20 and postnatal days 1, 10, 20 and 30 was quantified by radioimmunoassay. At postnatal day 10, postnatal stress increased Evans blue entry to the neocortex, hippocampus, diencephalon, basal ganglia, olfactory bulb, brain stem, cerebellum, and spinal cord. At postnatal day 20, prenatal stress increased Evans blue concentration in the same regions as those affected after postnatal stress. Between postnatal days 10-20, both stress groups showed increased WGA-HRP caveolae-mediated transport in the hippocampal capillaries. By postnatal day 30, the blood-brain barrier was functionally mature in both control and stressed pups. Plasma corticosterone concentration was higher in pregnant stressed dams as compared to controls. Postnatal stress increased plasma corticosterone at postnatal days 10 and 20. The findings suggest that chronic perinatal stress alters blood-brain barrier functional development by increasing caveolae-mediated transport in brain endothelial cells.

DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship.

DNA double-strand breaks (DSBs) arise in cells from endogenous and exogenous attacks on the DNA backbone, but also as a direct consequence of replication failures. Proper repair of all these DSBs is essential for genome stability. Repair of broken chromosomes is a challenge for dividing cells that need to distribute equal genetic information to daughter cells. Consequently, eukaryotic organisms have evolved multi-potent and efficient mechanisms to repair DSBs that are primarily divided into two types of pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR). Here we briefly describe how eukaryotic cells sense DSBs and trigger cell cycle arrest to allow repair, and we review the mechanisms of both NHEJ and HR pathways and the choice between them. (Part of a Multi-author Review).