Identification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis.

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1-/- mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD.

Disturbances in the IgG Antibody Profile in HIV-Exposed Uninfected Infants Associated with Maternal Factors.

Over the last 20 years, the incidence of vertical HIV transmission has decreased from 25%-42% to less than 1%. Although there are no signs of infection, the health of HIV-exposed uninfected (HEU) infants is notoriously affected during the first months of life, with opportunistic infections being the most common disease. Some studies have reported effects on the vertical transfer of antibodies, but little is known about the subclass distribution of these antibodies. We proposed to evaluate the total IgG concentration and its subclasses in HIV+ mothers and HEU pairs and to determine which maternal factors condition their levels. In this study, plasma from 69 HEU newborns, their mothers, and 71 control pairs was quantified via immunoassays for each IgG isotype. Furthermore, we followed the antibody profile of HEUs throughout the first year of life. We showed that mothers present an antibody profile characterized by high concentrations of IgG1 and IgG3 but reduced IgG2, and HEU infants are born with an IgG subclass profile similar to that of their maternal pair. Interestingly, this passively transferred profile could remain influenced even during their own antibody production in HEU infants, depending on maternal conditions such as CD4+ T-cell counts and maternal antiretroviral treatment. Our findings indicate that HEU infants exhibit an altered IgG subclass profile influenced by maternal factors, potentially contributing to their increased susceptibility to infections.

Surgical outcomes in patients with acromegaly: Microscopic vs. endoscopic transsphenoidal surgery.

Transsphenoidal resection of growth hormone-secreting pituitary neuroendocrine tumors remains the first-line treatment for acromegaly. This can be performed through microsurgery or endoscopic surgery. For the past decades, endoscopic surgery has become the preferred technique in an increasing number of centers worldwide. However, whether it offers superior clinical outcomes has yet to be determined. In this paper, we performed a narrative review of the literature comparing both techniques in the treatment of acromegaly. We critically assessed available comparative studies from an objective perspective to determine their suitability for defining superiority of either technique. Available evidence displays substantial methodological variations and reports conflicting findings. Although endoscopic surgery provides a wider exposure and enhanced visibility of the surgical field, this does not consistently translate into better clinical outcomes, as most tumors are equally accessible through both techniques. Postoperative outcomes such as remission and complication rates are similar between both techniques. The management of acromegaly should be performed by experienced pituitary neurosurgeons, regardless of the approach. The involvement of a multidisciplinary team in a dedicated pituitary center is critical to ensure optimal outcomes.

Novel Hybrid Technique for Preservation of Frontal Branch of Facial Nerve: Subgaleal Preinterfascial Dissection.

OBJECTIVE: The pterional approach is the workhorse of skull-base neurosurgery, which allows virtual access to any intracranial lesion around the circle of Willis. Preserving the frontotemporal branch of the facial nerve and conserving the temporal muscle's symmetry are fundamental objectives besides the access that can be obtained through this versatile neurosurgical technique. This manuscript proposes a subgaleal preinterfascial dissection, a novel hybrid technique that provides advantages of previously described temporal muscle dissection techniques while preserving the integrity of facial nerve branches and the unobstructed broad pterional region. We describe the subgaleal preinterfascial dissection as a safe and simple to technique to achieve preservation of the facial nerve frontal branches during anterolateral approaches. METHODS: Two cadaveric heads were skillfully dissected and studied to perform a proper subgaleal preinterfascial dissection on both sides of each cadaver. Afterward, the same technique was employed in 108 patients during a pterional approach for different neurosurgical diseases, with a postoperative follow-up of 6 months. RESULTS: None of the 108 patients presented postoperative frontotemporal branch palsy during postoperative follow-up. Likewise, no complications related to the proposed technique were present. CONCLUSIONS: The subgaleal preinterfascial dissection is a reliable, safe technique that may be employed during a pterional approach with an unobstructed surgical view and excellent cosmetic and functional results, preserving the frontotemporal branch of the facial nerve.

Consecuencias inmunológicas de la infección materna por VIH en el recién nacido no infectado / Immunologic consequences of maternal HIV infection in the uninfected newborn

Resumen Con la implementación de estrategias de cuidado perinatal, la tasa de transmisión vertical del virus de inmunodeficiencia humana (VIH) ha disminuido considerablemente en el mundo. A pesar de no mostrar cargas virales, los infantes expuestos al VIH no infectados (ENI) cursan en sus primeros meses de vida con mayores tasas de morbimortalidad. Esto se relaciona con enfermedades infecciosas por microorganismos oportunistas y menor respuesta a las vacunas en comparación con infantes sin exposición al virus, lo que sugiere alteraciones en su sistema inmunitario. En esta revisión abordamos diferentes evidencias de alteraciones en las respuestas inmunitarias innatas y adaptativas de infantes ENI que pudieran explicar esta disfuncionalidad inmunitaria. Adicionalmente, este conocimiento ayuda a entender cómo se desarrolla el sistema inmunitario desde los primeros momentos de gestación que servirán para encontrar alternativas de manejo y terapias para el bienestar de los infantes con esta condición.

Abstract With the implementation of perinatal care strategies, the rate of vertical transmission of human immunodeficiency virus (HIV) has decreased considerably worldwide. Despite the absence of viral loads, infants exposed to HIV not infected during gestation have higher morbidity and mortality rates. This is found to be related to infectious diseases by opportunistic microorganisms and lower response to vaccines in their first months of life compared to non-HIV exposed infants, suggesting alterations in their immune system. In this review we address different evidence of alterations in the innate and adaptive immune responses of HIV exposed infants that could explain their immune dysfunctionality. Additionally, this knowledge helps to understand how the immune system develops from the early stages of gestation and will serve to find management alternatives and therapies for the welfare of the infants with this condition.

Regulation of Pain Perception by Microbiota in Parkinson Disease.

Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.

Current and Future Perspectives of Microscopic and Endoscopic Transsphenoidal Surgery for Pituitary Adenomas: A Narrative Review.

Transsphenoidal resection remains the standard treatment for most pituitary adenomas. However, the ideal surgical approach to safely access these lesions, either microsurgical or endoscopic, continues to be debated. Since the introduction of endoscopic transsphenoidal surgery, centers around the world have increasingly adopted this technique, experiencing a shift away from the conventional microsurgical approach. Large series reporting the efficacy and safety of endoscopic surgery have fueled a growing interest in comparing clinical outcomes between both approaches. Still, proving superiority of either surgical approach remains an elusive task due to the inherent drawbacks of surgical observational studies, as we are still faced with a growing body of evidence reporting conflicting results. Thus, a comprehensive discussion regarding the reach and limitations of both techniques becomes necessary. In this narrative review, we perform a critical appraisal of the literature and provide an expert opinion on the state-of-the-art in transsphenoidal surgery for pituitary adenomas. The advantages and limitations of each approach are assessed and compared from a technical standpoint, and their reported outcomes evaluated in the framework of this transition phase. Available evidence should be interpreted in light of individual patient characteristics and within the context of each medical center, taking into consideration the known impact that surgical expertise and multidisciplinary management hold on clinical outcomes.

MoS2 Photoelectrodes for Hydrogen Production: Tuning the S-Vacancy Content in Highly Homogeneous Ultrathin Nanocrystals.

Tuning the electrocatalytic properties of MoS2 layers can be achieved through different paths, such as reducing their thickness, creating edges in the MoS2 flakes, and introducing S-vacancies. We combine these three approaches by growing MoS2 electrodes by using a special salt-assisted chemical vapor deposition (CVD) method. This procedure allows the growth of ultrathin MoS2 nanocrystals (1-3 layers thick and a few nanometers wide), as evidenced by atomic force microscopy and scanning tunneling microscopy. This morphology of the MoS2 layers at the nanoscale induces some specific features in the Raman and photoluminescence spectra compared to exfoliated or microcrystalline MoS2 layers. Moreover, the S-vacancy content in the layers can be tuned during CVD growth by using Ar/H2 mixtures as a carrier gas. Detailed optical microtransmittance and microreflectance spectroscopies, micro-Raman, and X-ray photoelectron spectroscopy measurements with sub-millimeter spatial resolution show that the obtained samples present an excellent homogeneity over areas in the cm2 range. The electrochemical and photoelectrochemical properties of these MoS2 layers were investigated using electrodes with relatively large areas (0.8 cm2). The prepared MoS2 cathodes show outstanding Faradaic efficiencies as well as long-term stability in acidic solutions. In addition, we demonstrate that there is an optimal number of S-vacancies to improve the electrochemical and photoelectrochemical performances of MoS2.

GPR43 stimulation on TCRαß+ intraepithelial colonic lymphocytes inhibits the recruitment of encephalitogenic T-cells into the central nervous system and attenuates the development of autoimmunity.

INTRODUCTION: Gut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity. METHODS: To induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG35-55 peptide). To address the effects of GPR43 stimulation on colonic TCRαß+ T-cells upon CNS autoimmunity, mucosal lymphocytes were isolated and stimulated with a selective GPR43 agonist ex vivo and then transferred into congenic mice undergoing EAE. Several subsets of lymphocytes infiltrating the CNS or those present in the gut epithelium and gut lamina propria were analysed by flow cytometry. In vitro migration assays were conducted with mucosal T-cells using transwells. RESULTS: Our results show a sharp and selective reduction of intestinal propionate at the peak of EAE development, accompanied by increased IFN-γ and decreased IL-22 in the colonic mucosa. Further analyses indicated that GPR43 was the primary SCFAs receptor expressed on T-cells, which was downregulated on colonic TCRαß+ T-cells upon CNS autoimmunity. The pharmacologic stimulation of GPR43 increased the anti-inflammatory function and reduced the pro-inflammatory features in several TCRαß+ T-cell subsets in the colonic mucosa upon EAE development. Furthermore, GPR43 stimulation induced the arrest of CNS-autoreactive T-cells in the colonic lamina propria, thus avoiding their infiltration into the CNS and dampening the disease development. Mechanistic analyses revealed that GPR43-stimulation on mucosal TCRαß+ T-cells inhibits their CXCR3-mediated migration towards CXCL11, which is released from the CNS upon neuroinflammation. CONCLUSIONS: These findings provide a novel mechanism involved in the gut-brain axis by which bacterial-derived products secreted in the gut mucosa might control the CNS tropism of autoreactive T-cells. Moreover, this study shows GPR43 expressed on T-cells as a promising therapeutic target for CNS autoimmunity.

Preclinical evaluation of chimeric antigen receptor T cells targeting the carcinoembryonic antigen as a potential immunotherapy for gallbladder cancer.

Gallbladder cancer (GBC) is commonly diagnosed at late stages when conventional treatments achieve only modest clinical benefit. Therefore, effective treatments for advanced GBC are needed. In this context, the administration of T cells genetically engineered with chimeric antigen receptors (CAR) has shown remarkable results in hematological cancers and is being extensively studied for solid tumors. Interestingly, GBC tumors express canonical tumor-associated antigens, including the carcinoembryonic antigen (CEA). However, the potential of CEA as a relevant antigen in GBC to be targeted by CAR-T cell-based immunotherapy has not been addressed. Here we show that CEA was expressed in 88% of GBC tumors, with higher levels associated with advanced disease stages. CAR-T cells specifically recognized plate-bound CEA as evidenced by up-regulation of 4-1BB, CD69 and PD-1, and production of effector cytokines IFN-γ and TNF-α. In addition, CD8+ CAR-T cells up-regulated the cytotoxic molecules granzyme B and perforin. Interestingly, CAR-T cell activation occurred even in the presence of PD-L1. Consistent with these results, CAR-T cells efficiently recognized GBC cell lines expressing CEA and PD-L1, but not a CEA-negative cell line. Furthermore, CAR-T cells exhibited in vitro cytotoxicity and reduced in vivo tumor growth of GB-d1 cells. In summary, we demonstrate that CEA represents a relevant antigen for GBC that can be targeted by CAR-T cells at the preclinical level. This study warrants further development of the adoptive transfer of CEA-specific CAR-T cells as a potential immunotherapy for GBC.

The hormonal physiology of immune components in breast milk and their impact on the infant immune response.

During pregnancy, the maternal body undergoes a considerable transformation regarding the anatomy, metabolism, and immune profile that, after delivery, allows for protection and nourishment of the offspring via lactation. Pregnancy hormones are responsible for the development and functionality of the mammary gland for breast milk production, but little is known about how hormones control its immune properties. Breast milk composition is highly dynamic, adapting to the nutritional and immunological needs that the infant requires in the first months of life and is responsible for the main immune modeling of breastfed newborns. Therefore, alterations in the mechanisms that control the endocrinology of mammary gland adaptation for lactation could disturb the properties of breast milk that prepare the neonatal immune system to respond to the first immunologic challenges. In modern life, humans are chronically exposed to endocrine disruptors (EDs), which alter the endocrine physiology of mammals, affecting the composition of breast milk and hence the neonatal immune response. In this review, we provide a landscape of the possible role of hormones in the control of passive immunity transferred by breast milk and the possible effect of maternal exposure to EDs on lactation, as well as their impacts on the development of neonatal immunity.

Lysolecithin-derived feed additive improves feedlot performance, carcass characteristics, and muscle fatty acid profile of Bos indicus-influenced cattle fed in a tropical environment.

Lysolecithin might increase ruminal and intestinal emulsification, leading to increased digestibility, but there is minimum information about which is the most appropriate phase to start supplementation and its impacts on feedlot performance and muscle fatty acid profile. Two experiments were conducted to evaluate the effects of phase-feeding of Lysoforte™ eXtend (LYSO). In the first experiment, 1,760 predominantly Bos indicus bullocks (initial body weight of 400 ± 0.561 kg) were allocated in a complete randomized block design. LYSO was supplemented at 1 g/1% of ether extract from the diet. Treatments were no LYSO supplementation (NON); LYSO starting during the growing period and continuing during the finishing period; LYSO starting during the finishing period (FIN); and LYSO during adaptation, growing, and finishing periods (ALL). In the second experiment, the same treatments were evaluated with 96 bullocks (64 Nellore and 32½ Nellore × ½ Angus) in a 4 × 2 factorial arrangement (treatments × genotype). For both studies, intake and average daily gain were accessed; carcass characteristics were evaluated in the first experiment, while digestibility of nutrients and profile of muscle fatty acids were measured in the second experiment. In the first experiment, LYSO increased final body weight (P < 0.022) and average daily gain (GRO and FIN; P < 0.05). In the second study, a treatment × breed × feeding phase interaction was observed with Nellore having a greater average daily gain (P < 0.05) than crossbreds in every feeding phase that LYSO was introduced to the diet. A treatment × feeding phase interaction was observed for digestibility, such that LYSO increased total dry matter (P = 0.004), crude protein (P = 0.043), and NDF (P = 0.001) digestibility during the finishing period. A treatment × breed × day classification was observed (P < 0.05). During the finishing phase, crossbreds treated with LYSO had greater DMI (P < 0.05) on very hot days than NON. Also, animals treated with LYSO presented a greater C18:3 n3 concentration (P = 0.047) in the longissimus. Overall, feeding LYSO during GRO and FIN enhanced feedlot performance and should lead to higher intakes during very hot days of the finishing feeding period.

Ruminal fermentation pattern of acidosis-induced cows fed either monensin or polyclonal antibodies preparation against several ruminal bacteria.

This study was designed to evaluate a spray-dried multivalent polyclonal antibody preparation (PAP) against lactate-producing bacteria as an alternative to monensin (MON) to control ruminal acidification. Holstein cows (677 ± 98 kg) fitted with ruminal cannulas were allocated in an incomplete Latin square design with two 20 days period. Cows were randomly assigned to control (CTL), PAP, or MON treatments. For each period, cows were fed a forage diet in the first 5 days (d-5 to d-1), composed of sugarcane, urea and a mineral supplement, followed by a 74% concentrate diet for 15 days (d 0 to d 14). There were no treatment main effects (P > 0.05) on dry matter intake (DMI) and microbial protein synthesis. However, there was a large peak (P < 0.01) of intake on d 0 (18.29 kg), followed by a large decline on d 1 (3.67 kg). From d2, DMI showed an increasing pattern (8.34 kg) and stabilized around d 8 (12.96 kg). Higher mean pH was measured (P < 0.01) in cattle-fed MON (6.06 vs. PAP = 5.89 and CTL = 5.91). The ruminal NH3-N concentration of CTL-fed cows was lower (P < 0.01) compared to those fed MON or PAP. The molar concentration of acetate and lactate was not affected (P > 0.23) by treatments, but feeding MON increased (P = 0.01) propionate during the first 4 days after the challenge. Feeding MON and PAP reduced (P = 0.01) the molar proportion of butyrate. MON was effective in controlling pH and improved ruminal fermentation of acidosis-induced cows. However, PAP was not effective in controlling acidosis. The acidosis induced by the challenge was caused by the accumulation of SCFAs. Therefore, the real conditions for evaluation of this feed additive were not reached in this experiment, since this PAP was proposed to work against lactate-producing bacteria.

Economically sustainable shade design for feedlot cattle.

Provision of shade reduces radiant heat load on feedlot cattle, thus reducing demand of water and energy for thermoregulation. While the positive effects of shade on animal welfare are widely known, the literature lacks data on the magnitude of its economic impacts. In this study, we propose the concept of novel shade design to prove that a correctly oriented and dimensioned roof structure, which optimizes shade to be displaced within the pens, motivates cattle to seek shade, protect them from short-wave solar radiation, and is resilient to counteract weather adverse conditions. The beneficial outcome is improvement in animal welfare and productive performance, as well as increments on financial return and sustainability. To attest these benefits, eight hundred B. indicus × Bos taurus bulls were randomly assigned in pens with or without shade from a galvanized steel-roof structure. Performance data (e.g., dry matter intake, body weight gain, feed efficiency and hot carcass weight) and heat stress indicators (e.g., subcutaneous temperature, body-surface temperature, respiratory rate and water intake) were assessed along the study period. The economic outcomes derived from shade implementation were determined using the net present value. Meteorological variables were also monitored every 1 min, and grouped in a thermal comfort index for feedlot cattle, the InComfort Index (InCI). The shade structure efficiently reduced radiant heat load on cattle in pens with shade. According to the classification of the InCI, during very hot days (InCI > 0.6; around noon with mean solar radiation above 800 W m-2 and mean air temperature above 33°C), greater proportion (80%) of animals in shaded pens were using shade. Under such circumstances, cattle in shade had water intake reduced by 3.4 L per animal, body temperature was lower by 5°C, subcutaneous temperature was lower by 1°C and respiration rate was lower by 10 breaths min-1 compared to animals in pens without shade (P = 0.0001). Although dry matter intake was similar (P = 0.6805), cattle in pens with shade had higher average daily gain reflected in a heavier hot carcass weight (8 kg animal-1; P = 0.0002). Considering an initial investment of $90 per animal to build a structure that lasts 15 years, the expected payback time is four finishing cycles (~110 days per cycle). In conclusion, this study confirms that the proposed novel shade design is economically profitable, improves performance, and enhances animal welfare.

Assessing the Malignancy Risk of a Meningioma by Its Location.

BACKGROUND: Meningiomas represent 30% of primary intracranial tumors. The current incidence is up to 4.5 cases per 100,000 habitants worldwide. Although there is no prognostic difference among benign histopathological subtypes, atypical meningiomas and malignant meningiomas (WHO grade II and III respectively) may extend to the adjacent brain parenchyma, dura mater, and osseous tissue with a recurrence score (21-49%). This manuscript analyzes the malignancy risk according to neoplastic localization through a logistic retrospective analysis from a total sample of 452 patients with grade I, II, and III (WHO) meningiomas. METHODS: Detailed data collection through a three-year retrospective analysis (January 2008 to December 2011) was applied at Mexico's National Neurology and Neurosurgery Institute including patients with intracranial or spinal-cord meningioma, preoperative imaging study availability and post-surgical histopathological diagnosis. Formal written consent was not required with a waiver by the appropriate national research ethics committee in accordance with the provisions of the regulations of the general health law of Mexico. RESULTS: Convexity lesions displayed an increased risk of malignancy turning for non-benign meningiomas with an odds ratio of 3.1 (95% CI 1.6 to 5.7, p=0.0002) meanwhile skull-base meningiomas present an inverse risk with an odds ratio of 0.4 (95% CI 0.2 to 0.9, p=0.02), as well as spinal-cord meningiomas with an odds ratio of 0.3 (95% CI 0.1 to 0.9). CONCLUSION: Skull base and spinal cord meningiomas usually have benign behavior, meanwhile grade II or III meningiomas within this location are rare. The present work provides an additional criterion for decision making, according to the meningioma's location.

Dopaminergic Signalling Enhances IL-2 Production and Strengthens Anti-Tumour Response Exerted by Cytotoxic T Lymphocytes in a Melanoma Mouse Model.

Dopamine has emerged as an important regulator of immunity. Recent evidence has shown that signalling through low-affinity dopamine receptors exerts anti-inflammatory effects, whilst stimulation of high-affinity dopamine receptors potentiates immunity in different models. However, the dopaminergic regulation of CD8+ T-cells in anti-tumour immunity remains poorly explored. Here, we studied the role of dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in the function of CD8+ T-cells and its consequences in the anti-tumour immune response. We observed that the deficiency of Drd3 (the gene encoding DRD3) in CD8+ T-cells limits their in vivo expansion, leading to an impaired anti-tumour response in a mouse melanoma model. Mechanistic analyses suggest that DRD3 stimulation favours the production of interleukin 2 (IL-2) and the surface expression of CD25, the α-chain IL-2 receptor, which are required for expansion and effector differentiation of CD8+ T-cells. Thus, our results provide genetic and pharmacologic evidence indicating that DRD3 favours the production of IL-2 by CD8+ T-cells, which is associated with higher expansion and acquisition of effector function of these cells, promoting a more potent anti-tumour response in a melanoma mouse model. These findings contribute to understanding how dopaminergic signalling affects the cellular immune response and represent an opportunity to improve melanoma therapy.

Characteristics and Long-Term Outcome of Cerebellar Strokes in a Single Health Care Facility in Mexico.

Objective The purpose of this study was to analyze and discuss the clinical characteristics, long-term outcome, and prognostic factors of cerebellar strokes treated in a single health care facility in Mexico. Methods We retrospectively reviewed the medical records of adult patients admitted to our hospital with diagnosis of cerebellar ischemic and hemorrhagic stroke between 2018 and 2020. Baseline data included sociodemographic and radiological variables, treatment (surgical versus conservative), and Glasgow Coma Scale on arrival (GCSOA). The final neurological outcome was evaluated with the Glasgow Outcome Scale (GOS) six months after hospital discharge. Results Ten patients (seven male and three female) with a mean age of 57.9 ± 9.3 years were included, six with cerebellar ischemic infarction and four with cerebellar hemorrhage. Out of the 10 patients, four underwent surgery (suboccipital decompressive craniectomy {SDC} ± ventriculostomy). The outcome was favorable in four cases (40%) and unfavorable in six (60%). Patients who underwent surgical treatment fared worse with all four cases associating poor outcome. The comparison between good and poor outcome groups showed significant differences in the presence of obstructive hydrocephalus (one versus six, p = 0.05) and poorer GCSOA (6.16 ± 1.72 versus 12.5 ± 3.6, p = 0.05), associating poorer outcome. Conclusion There is still controversy regarding the appropriate management of cerebellar strokes. The presence of obstructive hydrocephalus and poorer GCSOA are associated to worse outcomes.

Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein.

Parkinson's disease is a neurodegenerative disorder that involves the death of the dopaminergic neurons of the nigrostriatal pathway and, consequently, the progressive loss of control of voluntary movements. This neurodegenerative process is triggered by the deposition of protein aggregates in the brain, which are mainly constituted of α-synuclein. Several studies have indicated that neuroinflammation is required to develop the neurodegeneration associated with Parkinson's disease. Notably, the neuroinflammatory process involves microglial activation as well as the infiltration of peripheral T cells into the substantia nigra (SN). This work analyzes a mouse model of Parkinson's disease that recapitulates microglial activation, T-cell infiltration into the SN, the neurodegeneration of nigral dopaminergic neurons, and motor impairment. This mouse model of Parkinson's disease is induced by the stereotaxic delivery of adeno-associated viral vectors encoding the human wild-type α-synuclein (AAV-hαSyn) into the SN. The correct delivery of viral vectors into the SN was confirmed using control vectors encoding green fluorescent protein (GFP). Afterward, how the dose of AAV-hαSyn administered in the SN affected the extent of hαSyn expression, the loss of nigral dopaminergic neurons, and motor impairment were evaluated. Moreover, the dynamics of hαSyn expression, microglial activation, and T-cell infiltration were determined throughout the time course of disease development. Thus, this study provides critical time points that may be useful for targeting synuclein pathology and neuroinflammation in this preclinical model of Parkinson's disease.

Dopaminergic inhibition of human neutrophils is exerted through D1-like receptors and affected by bacterial infection.

Dopamine (DA) affects immune functions in healthy subjects (HS) and during disease by acting on D1-like (D1 and D5) and D2-like (D2, D3 and D4) dopaminergic receptors (DR); however, its effects on human polymorphonuclear leukocytes (PMN) are still poorly defined. We investigated DR expression in human PMN and the ability of DA to affect cell migration and reactive oxygen species (ROS) production. Experiments were performed on cells from HS and from patients (Pts) with bacterial infections as well, during the acute phase and after recovery. Some experiments were also performed in mice knockout (KO) for the DRD5 gene. PMN from HS express both D1-like and D2-like DR, and exposure to DA results in inhibition of activation-induced morphological changes, migration and ROS production which depend on the activation of D1-like DR. In agreement with these findings, DA inhibited migration of PMN obtained from wild-type mice, but not from DRD5KO mice. In Pts with bacterial infections, during the febrile phase D1-like DRD5 on PMN were downregulated and DA failed to affect PMN migration. Both D1-like DRD5 expression and DA-induced inhibition of PMN migration were however restored after recovery. Dopaminergic inhibition of human PMN is a novel mechanism which is likely to play a key role in the regulation of innate immunity. Evidence obtained in Pts with bacterial infections provides novel clues for the therapeutic modulation of PMN during infectious disease.