Regulation of cardiac allograft immune responses by microRNA-155.

INTRODUCTION: A better understanding of the immune mechanisms involved in allograft rejection after transplantation is urgently needed to improve patient outcomes. As microRNA-155 (miR155) plays a critical role in inflammation, we postulated that a deficiency of miR155 will improve cardiac allograft survival and enhance tolerance induction after heart transplantation. METHODS: We developed an acute rejection mouse model through heterotopic BALB/c cardiac transplantation to C57BL/6 (wild-type) and C57BL/6 miR155 knock-out (miR155KO) mice. Further, we induced tolerance in both groups through a costimulatory blockade with CTLA4-Ig (200 µg; post-transplant day 2) and MRI antibodies (250 µg; post-transplant day 0), targeting CD28/B7 and CD40/CD154 signals, respectively. Finally, we examined the effects of injecting 100 µg of small extracellular vesicles (sEVs) isolated from wild-type mice undergoing rejection into tolerant miR155KO mice. RESULTS: Mean survival time (MST) of the cardiac allografts in wild-type and miR155KO mice was 7 and 15 days, respectively (p < 0.0001). Costimulatory blockade increased MST to 65 days and > 100 days in the wild-type and miR155KO recipients, respectively (p < 0.001). Injection of sEVs isolated from wild-type mice undergoing rejection into tolerant miR155KO mice decreased the allograft survival to 9 days, significantly lower than the tolerant miR155KO mice without injection of sEVs (>100 days; p < 0.0001). CONCLUSION: miR155KO mice have improved cardiac allograft survival and enhanced induction of tolerance after heterotopic cardiac transplantation. Injection of sEVs from wild-type mice undergoing rejection into the miR155KO mice reversed these benefits.

Enhanced enrichment of extracellular vesicles for laboratory and clinical research from drop-sized blood samples.

In the realm of biomedical advancement, extracellular vesicles (EVs) are revolutionizing our capacity to diagnose, monitor, and predict disease progression. However, the comprehensive exploration and clinical application of EVs face significant limitations due to the current isolation techniques. The size exclusion chromatography, commercial precipitation reagents, and ultracentrifugation are frequently employed, necessitating skilled operators and entailing challenges related to consistency, reproducibility, quality, and yields. Notably, the formidable challenge of extracellular vesicle isolation persists when dealing with clinical samples of limited availability. This study addresses these challenges by aiming to devise a rapid, user-friendly, and high-recovery EVs isolation technique tailored for blood samples. The NTI-EXO precipitation method demonstrated a 5-fold increase in the recovery of serum EVs compared to current methodologies. Importantly, we illustrate that a mere two drops of blood (∼100 µL) suffice for the recovery of enriched EVs. The integrity and quality of these isolated EVs were rigorously assessed for the size, purity, and contaminants. This method was validated through the successful isolation of EVs from organ transplant recipients to detect disease-specific exosomal markers, including LKB1, SARS-CoV-2 spike protein, and PD-L1. In conclusion, NTI-EXO method can be used for small clinical samples, thereby advancing discoveries in the EV-centric domain and propelling the frontiers of biomedical research and clinical applications.

Cytotoxic Activity of Lepidium virginicum L. Methanolic Extract on Human Colorectal Cancer Cells, Caco-2, through p53-Mediated Apoptosis.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Its treatment options have had a limited impact on cancer remission prognosis. Therefore, there is an ongoing need to discover novel anti-cancer agents. Medicinal plants have gained recognition as a source of anti-cancer bioactive compounds. Recently, ethanolic extract of L. virginicum stems ameliorated dinitrobenzene sulfonic acid (DNBS)-induced colitis by modulating the intestinal immune response. However, no scientific study has demonstrated this potential cytotoxic impact on colon cancer cells. The objective of this study was to evaluate the cytotoxic effect of the methanolic extract of L. virginicum (ELv) on a human colorectal adenocarcinoma cell line (Caco-2) and to identify and quantify the phenolic compounds present in ELv extracts by liquid chromatography-mass spectrometry analysis. The cytotoxic activity was assessed using cell viability assays by reduction in the compound 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH). MTT and LDH assays revealed that the ELv decreases cell viability in the Caco-2 cell line in a concentration-dependent manner. Cell death was a result of DNA fragmentation and p53-mediated apoptosis. Eight phenolic acids and five flavonoids were identified and quantified in the stems. In conclusion, our findings demonstrate that the extract of L. virginicum possesses cytotoxic properties on Caco-2 cell line, suggesting that it could be a potential source of new drugs against CRC.

Predictive model to differentiate chronic histaminergic angioedema and chronic spontaneous urticaria with angioedema.

Background: Chronic histaminergic angioedema (CHA) may be classified as a separate acquired angioedema (AE) or as an endotype of chronic spontaneous urticaria (CSU). A recent study suggested them to be independent pathologies. Objective: We carried out an exhaustive analysis between CHA and AE-CSU to explore the possible differentiation between them on the bases of a series of predictors. Methods: An observational, retrospective, cross-sectional, and exploratory study was designed. Fifty-six CHA and 40 AE-CSU patients were included. Data were extracted from the year before and year after time of diagnosis. A predictive model was generated by logistic regression, and its discriminatory power was assessed using the area under the receiver operating characteristic curve. Results: The average frequency of AE attacks per year turned out to be higher in the AE-CSU group than in the CHA group, both before (median [interquartile range] 12 [43] vs 8 [16]) and after (24.3 [51.2] vs 2 [4.25]) diagnosis, respectively. The uvula was more frequently affected in CHA. No other differences were found. However, using 7 clinical characteristics of the patients, a multiple logistic regression model was able to predict, with a specificity of 86.4%, a sensitivity of 92.3%, and an area under the curve of 95.1% (P = .024), that CHA and AE-CSU behaved differently. Conclusion: CHA has similar characteristics to AE-CSU, although they slightly differed in the frequency of attacks and their location. Despite its similarities, a multiple logistic regression model that used clinical and evolutionary characteristics allowed the differentiation of both pathologies and supports the idea that these 2 entities are independent.

Gene expression alterations of purinergic signaling components in obesity-associated intestinal low-grade inflammation in type 2 diabetes.

Intestinal low-grade inflammation induced by a high-fat diet has been found to detonate chronic systemic inflammation, which is a hallmark of obesity, and precede the apparition of insulin resistance, a key factor for developing type 2 diabetes (T2D). Aberrant purinergic signaling pathways have been implicated in the pathogenesis of inflammatory bowel disease and other gastrointestinal diseases. However, their role in the gut inflammation associated with obesity and T2D remains unexplored. C57BL/6 J mice were fed a cafeteria diet for 21 weeks and received one injection of streptozotocin in their sixth week into the diet. The gene expression profile of purinergic signaling components in colon tissue was assessed by RT-qPCR. Compared to control mice, the treated group had a significant reduction in colonic length and mucosal and muscular layer thickness accompanied by increased NF-κB and IL-1ß mRNA expression. Furthermore, colonic P2X2, P2X7, and A3R gene expression levels were lower, while the P2Y2, NT5E, and ADA expression levels increased. In conclusion, these data suggest that these purinergic signaling components possibly play a role in intestinal low-grade inflammation associated with obesity and T2D and thus could represent a novel therapeutic target for the treatment of the metabolic complications related to these diseases.

Navigating the transition of care in patients with inborn errors of immunity: a single-center's descriptive experience.

The transition from pediatric to adult care is a critical milestone in managing children, especially in those with complex chronic conditions. It involves ensuring the patient and family adapt correctly to the new phase, maintaining continuity of ongoing treatments, and establishing an appropriate follow-up plan with specialists. Patients with Inborn error of immunity (IEI), formerly known as Primary Immune Disorders (PID) are part of a group of disorders characterized by alterations in the proper functioning of the immune system; as the diagnostic and treatment tools for these entities progress, life expectancy increases, and new needs emerge. These children have special needs during the transition. Particularly important in the group of children with PID and syndromic features, who often present multiple chronic medical conditions. In these cases, transition planning is a significant challenge, involving not only the patients and their families but also a wide range of specialists. To achieve this, a multidisciplinary transition team should be established between the pediatric specialists and the adult consultants, designing a circuit in which communication is essential. As few transition care guidelines in the field of PID are available, and to our knowledge, there is no specific information available regarding patients with PID associated with syndromic features, we share our experience in this issue as a Primary Immunodeficiencies Unit that is a National Reference Center for PID, and propose a guide to achieve an adequate and successful transition to adulthood in these patients, especially in those with associated syndromic features.

Primer Consenso Nacional Intersociedades de Inmunización del Adulto. 2023

Las vacunas previenen millones de muertes cada año y su eficacia y seguridad han sido ampliamente establecidas. En términos económicos, la vacunación es una de las intervenciones sanitarias más costo efectivas, generando un importante ahorro y crecimiento económico que supone a largo plazo. Se ha demostrado que la vacunación de adultos disminuye la morbilidad y la mortalidad asociadas a enfermedades infecciosas prevenibles, reduciendo las complicaciones y las hospitalizaciones, incluidos los ingresos a las unidades de cuidados intensivos. Hemos elaborado este documento de consenso con el objeto de diseñar un esquema de vacunación pragmático, accesible y estandarizado del adulto, según categoría de riesgo y edad, sobre la base de la evidencia disponible de vacunas accesibles y nuevas vacunas habiendo utilizado el Tercer Consenso de la Sociedad Paraguaya de Infectología del 2019 como base para las recomendaciones finales.

SUMMARY Vaccines prevent millions of deaths each year, and their efficacy and safety have been widely established. In economic terms, vaccination is one of the most cost-effective health interventions, generating significant savings and long-term economic growth. Adult vaccination has been shown to decrease morbidity and mortality associated with preventable Infectious diseases, reducing complications and hospitalizations, including admissions to intensive care units. We have prepared this consensus document in order to design a pragmatic, accessible and standardized vaccination scheme for adults, according to risk category and age, based on the available evidence of available vaccines and new vaccines, having used the third consensus of the Paraguayan Infectious Diseases Society of 2019 as a basis for the final recommendations.

Extracellular vesicles: a potential new player in antibody-mediated rejection in lung allograft recipients.

Identification of recipients with pre-existing antibodies and cross-matching of recipient sera with donor lymphocytes have reduced the incidence of antibody-mediated rejection (AMR) after human lung transplantation. However, AMR is still common and requires not only immediate intervention but also has long-term consequences including an increased risk of chronic lung allograft dysfunction (CLAD). The mechanisms resulting in AMR remain largely unknown due to the variation in clinical and histopathological features among lung transplant recipients; however, several reports have demonstrated a strong association between the development of antibodies against mismatched donor human leucocyte antigens [donor-specific antibodies (DSAs)] and AMR. In addition, the development of antibodies against lung self-antigens (K alpha1 tubulin and collagen V) also plays a vital role in AMR pathogenesis, either alone or in combination with DSAs. In the current article, we will review the existing literature regarding the association of DSAs with AMR, along with clinical diagnostic features and current treatment options for AMR. We will also discuss the role of extracellular vesicles (EVs) in the immune-related pathogenesis of AMR, which can lead to CLAD.

TNF-α enhances sensory DRG neuron excitability through modulation of P2X3 receptors in an acute colitis model.

Previous studies have demonstrated that acute colonic inflammation leads to an increase in dorsal root ganglia (DRG) neuronal excitability. However, the signaling elements implicated in this hyperexcitability have yet to be fully unraveled. Extracellular adenosine 5'-triphosphate (ATP) is a well-recognized sensory signaling molecule that enhances the nociceptive response after inflammation through activation of P2X3 receptors, which are expressed mainly by peripheral sensory neurons. The aim of this study is to continue investigating how P2X3 affects neuronal hypersensitivity in an acute colitis animal model. To achieve this, DNBS (Dinitrobenzene sulfonic acid; 200 mg/kg) was intrarectally administered to C57BL/6 mice, and inflammation severity was assessed according to the following parameters: weight loss, macroscopic and microscopic scores. Perforated patch clamp technique was used to evaluate neuronal excitability via measuring changes in rheobase and action potential firing in T8-L1 DRG neurons. A-317491, a well-established potent and selective P2X3 receptor antagonist, served to dissect their contribution to recorded responses. Protein expression of P2X3 receptors in DRG was evaluated by western blotting and immunofluorescence. Four days post-DNBS administration, colons were processed for histological analyses of ulceration, crypt morphology, goblet cell density, and immune cell infiltration. DRG neurons from DNBS-treated mice were significantly more excitable compared with controls; these changes correlated with increased P2X3 receptor expression. Furthermore, TNF-α mRNA expression was also significantly higher in inflamed colons compared to controls. Incubation of control DRG neurons with TNF-α resulted in similar cell hyperexcitability as measured in DNBS-derived neurons. The selective P2X3 receptor antagonist, A-317491, blocked the TNF-α-induced effect. These results support the hypothesis that TNF-α enhances colon-innervating DRG neuron excitability via modulation of P2X3 receptor activity.

CD19+ lineage chimerism, an early biomarker after anti-CD19 CAR-T cell therapy in patients previously receiving a hematopoietic stem cell transplantation.

Treatment targeting CD19 by a chimeric antigen receptor expressed on T cells (anti-CD19 CAR-T) has led to a breakthrough in the management and treatment of relapsed and refractory B- cell acute lymphoblastic leukemia (B-ALL). After infusion, the efficacy of anti-CD19 CAR-T is monitored by bone marrow negative minimal residual disease and the absence of peripheral CD19+ B lymphocytes (B-cell aplasia). In patients who have received an allogenic Hematopoietic Stem Cell Transplantation (HSCT) prior to treatment with anti-CD19 CAR-T, monitoring lineage-specific chimerism could be helpful. We found that on 4 patients who received anti-CD19 CAR-T cells after HSCT and achieved early complete response, CD19+ lineage mixed chimerism but not CD3+ lineage mixed chimerism monitored by molecular techniques anticipated earlier than B-cell aplasia determined by flow cytometry, lack of effectiveness of anti-CD19 CAR-T and leukemia relapse. Donor lymphocyte infusions (DLIs) did not prevent relapse but recovered CD3+ full donor chimerism. We suggest that continuous lineage chimerism analysis should be done routinely in patients who receive anti-CD19 CAR-T cells after HSCT and achieve complete remission because it can support early treatment intervention. However, the role of DLI in this setting is unclear, so further prospective studies should be developed.

Biological and Biochemical Characterization of Coronado Island Rattlesnake (Crotalus helleri caliginis) Venom and Antivenom Neutralization.

The Baja California Peninsula has over 250 islands and islets with many endemic species. Among them, rattlesnakes are the most numerous but also one of the least studied groups. The study of island rattlesnake venom could guide us to a better understanding of evolutionary processes and the description of novel toxins. Crotalus helleri caliginis venom samples were analyzed to determine possible ontogenetic variation with SDS-PAGE in one and two dimensions and with RP-HPLC. Western Blot, ELISA, and amino-terminal sequencing were used to determine the main components of the venom. The biological and biochemical activities demonstrate the similarity of C. helleri caliginis venom to the continental species C. helleri helleri, with both having low proteolytic and phospholipase A2 (PLA2) activity but differing due to the absence of neurotoxin (crotoxin-like) in the insular species. The main components of the snake venom were metalloproteases, serine proteases, and crotamine, which was the most abundant toxin group (30-35% of full venom). The crotamine was isolated using size-exclusion chromatography where its functional effects were tested on mouse phrenic nerve-hemidiaphragm preparations in which a significant reduction in muscle twitch contractions were observed. The two Mexican antivenoms could neutralize the lethality of C. helleri caliginis venom but not the crotamine effects.

A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications.

INTRODUCTION: Migraine involves neurovascular, functional, and anatomical alterations. Migraineurs experience an intense unilateral and pulsatile headache frequently accompanied with vomiting, nausea, photophobia, etc. Although there is no ideal preventive medication, frequency in migraine days may be partially decreased by some prophylactics, including antihypertensives, antidepressants, antiepileptics, and CGRPergic inhibitors. However, the mechanisms of action involved in antimigraine prophylaxis remain elusive. AREAS COVERED: This review recaps some of the main neurovascular phenomena related to migraine and currently available preventive medications. Moreover, it discusses the major mechanisms of action of the recommended prophylactic medications. EXPERT OPINION: In the last three years, migraine prophylaxis has evolved from nonspecific to specific antimigraine treatments. Overall, nonspecific treatments  mainly involve neural actions, whereas specific pharmacotherapy (represented by CGRP receptor antagonists and CGRPergic monoclonal antibodies) is predominantly mediated by neurovascular mechanisms that may include, among others: (i) reduction in the cortical spreading depression (CSD)-associated events; (ii) inhibition of pain sensitization; (iii) blockade of neurogenic inflammation; and/or (iv) increase in cranial vascular tone. Accordingly, the novel antimigraine prophylaxis promises to be more effective, devoid of significant adverse effects (unlike nonspecific treatments), and more beneficial for the quality of life of migraineurs.

Design, assembly and validation of a low-cost, high-fidelity simulator for heart exploration.

INTRODUCTION: Heart exploration is an essential clinical competence that requires continuous training and exposure. Low availability and accessibility to patients with heart disease constitutes a barrier to acquiring this competence. Inadequate cardiac auscultation skills in medical students, residents, and graduate physicians have been documented. OBJECTIVE: To develop and validate a low-cost, high-fidelity simulator for heart exploration. METHODS: A low-cost, high-fidelity heart examination simulator capable of reproducing normal cardiac sounds was designed and developed. Subsequently, the simulator was validated by a group of experts who gave their opinion according to a Likert scale. RESULTS: Ninety-four percent agreed that the simulator motivates the learning of heart exploration, and 92 % considered it to be a realistic model; 91 % considered that the simulator is an attractive tool to reinforce learning and 98 % recommended its further use. CONCLUSIONS: The use of the simulator facilitates the acquisition of skills and stimulates learning in the student, which can be attributed to repeated practice, longer exposure time and cognitive interaction.

INTRODUCCIÓN: La exploración cardiaca es una competencia clínica fundamental que requiere exposición o entrenamiento continuo. La baja disponibilidad y accesibilidad de pacientes con patología cardiaca constituye una barrera para adquirir esta competencia. Se han documentado inadecuadas habilidades de auscultación cardiaca en estudiantes de medicina, residentes y médicos graduados. OBJETIVO: Elaborar y validar un simulador de alta fidelidad y bajo costo para exploración cardiaca. MÉTODOS: Se diseñó y elaboró un simulador para exploración cardiaca, realista y de bajo costo capaz de reproducir ruidos cardiacos normales. Posteriormente se realizó la validación del simulador por un grupo de expertos que emitieron su opinión de acuerdo con una escala tipo Likert. RESULTADOS: El 94 % afirmó que el simulador motiva el aprendizaje de la exploración cardiaca y 92 % lo consideró un modelo realista; 91 % consideró que el simulador es una herramienta atractiva para fortalecer el aprendizaje y 98 % recomendó seguir utilizándolo. CONCLUSIONES: El uso del simulador facilita la adquisición de competencias y estimula el aprendizaje en el estudiante, lo cual puede ser atribuido a la práctica deliberada, a un mayor tiempo de exposición y a la interacción cognitiva.

Deshidratación en el paciente adulto / Dehydration in Adult Patients

Resumen: La deshidratación es un estado clínico como consecuencia de la pérdida de agua y solutos, las causas en adultos son diversas, entre ellas están las pérdidas gastrointestinales, renales, alteraciones en la piel (quemaduras) o secuestro del tercer espacio (fracturas). El diagnóstico es clínico, los signos y síntomas determinan el grado de deshidratación y el tratamiento a implementar. En este trabajo se hace una revisión sobre la fisiología, fisiopatología, cuadro clínico, y manejo terapéutico del paciente adulto, ya que existe escasa literatura dirigida a este grupo etario.

Abstract: Dehydration is a clinical state due to the loss of water and solutes; in adults the causes of this clinical state are diverse: gastrointestinal and renal losses, skin alterations (burns) or sequestration of the third space (fractures). The diagnosis is clinical, the signs and symptoms determine the degree of dehydration and the treatment to be implemented. In this work a review is made on the physiology, pathophysiology, clinical picture and therapeutic treatment of the adult patient, since there is little literature directed to this age group.

Diseño, elaboración y validación de un simulador realista y de bajo costo para exploración cardiaca / Design, assembly and validation of a low-cost, high-fidelity simulator for heart exploration

Resumen Introducción: La exploración cardiaca es una competencia clínica fundamental que requiere exposición o entrenamiento continuo. La baja disponibilidad y accesibilidad de pacientes con patología cardiaca constituye una barrera para adquirir esta competencia. Se han documentado inadecuadas habilidades de auscultación cardiaca en estudiantes de medicina, residentes y médicos graduados. Objetivo: Elaborar y validar un simulador de alta fidelidad y bajo costo para exploración cardiaca. Métodos: Se diseñó y elaboró un simulador para exploración cardiaca, realista y de bajo costo capaz de reproducir ruidos cardiacos normales. Posteriormente se realizó la validación del simulador por un grupo de expertos que emitieron su opinión de acuerdo con una escala tipo Likert. Resultados: El 94 % afirmó que el simulador motiva el aprendizaje de la exploración cardiaca y 92 % lo consideró un modelo realista; 91 % consideró que el simulador es una herramienta atractiva para fortalecer el aprendizaje y 98 % recomendó seguir utilizándolo. Conclusiones: El uso del simulador facilita la adquisición de competencias y estimula el aprendizaje en el estudiante, lo cual puede ser atribuido a la práctica deliberada, a un mayor tiempo de exposición y a la interacción cognitiva.

Abstract Introduction: Heart exploration is an essential clinical competence that requires continuous training and exposure. Low availability and accessibility to patients with heart disease constitutes a barrier to acquiring this competence. Inadequate cardiac auscultation skills in medical students, residents, and graduate physicians have been documented. Objective: To develop and validate a low-cost, high-fidelity simulator for heart exploration. Methods: A low-cost, high-fidelity heart examination simulator capable of reproducing normal cardiac sounds was designed and developed. Subsequently, the simulator was validated by a group of experts who gave their opinion according to a Likert scale. Results: Ninety-four percent agreed that the simulator motivates the learning of heart exploration, and 92 % considered it to be a realistic model; 91 % considered that the simulator is an attractive tool to reinforce learning and 98 % recommended its further use. Conclusions: The use of the simulator facilitates the acquisition of skills and stimulates learning in the student, which can be attributed to repeated practice, longer exposure time and cognitive interaction.

Functional expression of P2X1, P2X4 and P2X7 purinergic receptors in human monocyte-derived macrophages.

This study sought to examine the co-expression of the following purinergic receptor subunits: P2X1, P2X1del, P2X4, and P2X7 and characterize the P2X response in human monocyte-derived macrophages (MDMs). Single-cell RT-PCR shows the presence of P2X1, P2X1del, P2X4, and P2X7 mRNA in 40%, 5%, 20%, and 90% of human MDMs, respectively. Of the studied human MDMs, 25% co-expressed P2X1 and P2X7 mRNA; 5% co-expressed P2X4 and P2X7; and 15% co-expressed P2X1, P2X4, and P2X7 mRNA. In whole-cell patch clamp recordings of human MDMs, rapid application of ATP (0.01 mM) evoked fast current activation and two different desensitization kinetics: 1. a rapid desensitizing current antagonized by PPADS (1 µM), reminiscent of the P2X1 receptor's current; 2. a slow desensitizing current, insensitive to PPADS but potentiated by ivermectin (3 µM), similar to the P2X4 receptor's current. Application of 5 mM ATP induced three current modalities: 1. slow current activation with no desensitization, similar to the P2X7 receptor current, present in 69% of human macrophages and antagonized by A-804598 (0.1 µM); 2. fast current activation and fast desensitization, present in 15% of human MDMs; 3. fast activation current followed by biphasic desensitization, observed in 15% of human MDMs. Both rapid and biphasic desensitization kinetics resemble those observed for the recombinant human P2X1 receptor expressed in oocytes. These data demonstrate, for the first time, the co-expression of P2X1, P2X4, and P2X7 transcripts and confirm the presence of functional P2X1, P2X4, and P2X7 receptors in human macrophages.

Advances in Neurobiology and Pharmacology of GPR12.

GPR12 is a G protein-coupled orphan receptor genetically related to type 1 and type 2 cannabinoid receptors (CB1 and CB2) which are ancient proteins expressed all over the body. Both cannabinoid receptors, but especially CB1, are involved in neurodevelopment and cognitive processes such as learning, memory, brain reward, coordination, etc. GPR12 shares with CB1 that both are mainly expressed into the brain. Regrettably, very little is known about physiology of GPR12. Concerning its pharmacology, GPR12 seems to be endogenously activated by the lysophospholipids sphingosine-1-phosphate (S1P) and sphingosyl-phosphorylcholine (SPC). Exogenously, GPR12 is a target for the phytocannabinoid cannabidiol (CBD). Functionally, GPR12 seems to be related to neurogenesis and neural inflammation, but its relationship with cognitive functions remains to be characterized. Although GPR12 was initially suggested to be a cannabinoid receptor, it does not meet the five criteria proposed in 2010 by the International Union of Basic and Clinical Pharmacology (IUPHAR). In this review, we analyze all the direct available information in PubMed database about expression, function, and pharmacology of this receptor in central nervous system (CNS) trying to provide a broad overview of its current and prospective neurophysiology. Moreover, in this mini-review we highlight the need to produce more relevant data about the functions of GPR12 in CNS. Hence, this work should motivate further research in this field.

Outcome of Severe Bacterial Pneumonia in the Era of Pneumococcal Vaccination.

Introduction: After the introduction of pneumococcal conjugate vaccines, community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae has decreased whereas Staphylococcus aureus and Streptococcus pyogenes could be increasing. These bacteria have been associated with high rates of complications. Aims: (1) To describe the characteristics of pediatric bacterial CAP requiring hospitalization. (2) To compare outcomes according to causative microorganisms. (3) To analyze changes in bacterial CAP rate and etiology over time. Patients and Methods: Retrospective single-center study of inpatients aged 1 month-16 years with culture-confirmed bacterial CAP in 2010-2018 in Madrid, Spain. Results: We included 64 cases (42 S. pneumoniae, 13 S. pyogenes and 9 S. aureus). Culture-confirmed CAP represented 1.48-2.33/1,000 all-cause pediatric hospital admissions, and its rate did not vary over time. However, there was a significant decrease in pneumococcal CAP in the last 3 years of the study (78% of CAP in 2010-2015 vs. 48% in 2016-18, p = 0.017). Median hospital stay was 10.5 days (interquartile range 5-19.5), 38 patients (59%) developed complications and 28 (44%) were admitted to the intensive care unit. Outcomes were similar among children with S. pneumoniae and S. aureus CAP, whereas S. pyogenes was associated with a higher risk for complications (OR 8 [95%CI 1.1-57.2]) and ICU admission (OR 7.1 [95%CI 1.7-29.1]) compared with pneumococcal CAP. Conclusion: In a setting with high PCV coverage, culture-confirmed bacterial CAP did not decrease over time and there was a relative increase of S. pyogenes and S. aureus. Children with CAP caused by S. pyogenes were more likely to develop complications.