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Postoperative hemorrhage can severely affect the patients' neurological outcome after awake craniotomy. Higher postoperative blood pressure can increase the risk of postoperative hemorrhage. The aim of this study was to investigate the role of postoperative blood pressure and other common radiological and epidemiological features with the incidence of postoperative hemorrhage. In this retrospective analysis, we included patients who underwent awake surgery at our institution. We assessed the blood pressure both intra- and postoperatively as well as the heart rate for the first 12 h. We compared a cohort with postoperative hemorrhage, who required further treatment (surgical revision or intravenous antihypertensive therapy), with a cohort with no postoperative hemorrhage. We included 48 patients with a median age of 39 years. 9 patients (19%) required further treatment due to postoperative hemorrhage, which was surgery in 2 cases and intensive blood pressure measurements in 7 cases. However, with early treatment, no significant difference in Performance scores at follow-up could be found. Patients with postoperative hemorrhage showed significantly higher postoperative systolic blood pressure during the hours 3-12 (p < 0.05) as well as intraoperatively throughout the procedure (p < 0.05). In ROC and Youden Test, a strong impact of systolic blood pressure over 140mmHg during the early postoperative course could be shown. Postoperative hemorrhage is a rare but possible complication in awake surgery glioma patients. To avoid postoperative hemorrhage, treating physicians should aim strictly on systolic blood pressure of under 140mmHg for the postoperative course.
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Presión Sanguínea , Neoplasias Encefálicas , Craneotomía , Glioma , Hemorragia Posoperatoria , Vigilia , Humanos , Craneotomía/efectos adversos , Masculino , Glioma/cirugía , Glioma/complicaciones , Femenino , Adulto , Persona de Mediana Edad , Presión Sanguínea/fisiología , Neoplasias Encefálicas/cirugía , Vigilia/fisiología , Estudios Retrospectivos , Hemorragia Posoperatoria/epidemiología , Anciano , Adulto Joven , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/efectos adversosRESUMEN
Background Early treatment of intracranial lesions in the emergency department is crucial, but it can be challenging to differentiate between them. This differentiation is essential because the treatment of each type of lesion is different. Cerebral computed tomography perfusion (CTP) imaging can help visualize the vascularity of brain lesions and provide absolute quantification of physiological parameters. Compared to magnetic resonance imaging, CTP has several advantages, such as simplicity, wide availability, and reproducibility. Purpose This study aimed to assess the effectiveness of Hounsfield units (HU) in measuring the density of hypercellular lesions and the ability of CTP to quantify hemodynamics in distinguishing intracranial space-occupying lesions. Methods A retrospective study was conducted from March 2016 to March 2022. All patients underwent CTP and CT scans, and relative cerebral blood volume (rCBV) and HU were obtained for intracranial lesions. Results We included a total of 244 patients in our study. This group consisted of 87 (35.7%) individuals with glioblastomas (GBs), 48 (19.7%) with primary central nervous system lymphoma (PCNSL), 45 (18.4%) with metastases (METs), and 64 (26.2) with abscesses. Our study showed that the HUs for METs were higher than those for GB (S 57.4% and E 88.5%). In addition, rCBV values for PCNSL and abscesses were lower than those for GB and METs. The HU in PCNSL was higher than those in abscesses (S 94.1% and E 96.6%). Conclusion PCT parameters provide valuable information for diagnosing brain lesions. A comprehensive assessment improves accuracy. Combining rCBV and HU enhances diagnostic accuracy, making it a valuable tool for distinguishing between lesions. PCT's widespread availability allows for the use of both anatomical and functional information with high spatial resolution for diagnosing and managing brain tumor patients.
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Parkinson's disease (PD) is characterised neuropathologically by the degeneration of dopaminergic neurons in the ventral midbrain, the accumulation of α-synuclein (α-syn) aggregates in neurons, and chronic neuroinflammation. In the past two decades, in vitro, ex vivo and in vivo studies have consistently shown the involvement of inflammatory responses mediated by microglia and astrocytes, which may be elicited by pathological α-syn or signals from affected neurons and other cell types, and are directly linked to neurodegeneration and disease development. Besides the prominent immune alterations seen in the central nervous system (CNS), including the infiltration of T-cells into the brain, more recent studies have demonstrated important changes in the peripheral immune profile within both the innate and adaptive compartments, particularly involving monocytes, CD4+ and CD8+ T-cells. This review aims to integrate the consolidated understanding of immune-related processes underlying the pathogenesis of PD, focusing on both central and peripheral immune cells, neuron-glia crosstalk as well as the central-peripheral immune interaction during the development of PD. Our analysis seeks to provide a comprehensive view of the emerging knowledge of the mechanisms of immunity in PD and the implications of this for better understanding the overall pathogenesis of this disease.
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OBJECTIVE: This study aimed to identify clinical and surgical features associated with poor long-term postoperative outcomes in patients diagnosed with Type I Chiari Malformation (CMI) treated with posterior fossa decompression with duroplasty (PFDD), with or without tonsillar coagulation. METHODS: This retrospective, single-center study included 107 adult patients with CMI surgically treated between 2010 and 2021. The surgical technique involved a midline suboccipital craniectomy, C1 laminectomy, durotomy, arachnoid dissection, duroplasty, and tonsillar coagulation until 2014, after which tonsillar coagulation was discontinued. Postoperative outcomes were assessed using the Chicago Chiari Outcome Scale (CCOS) at a median follow-up of 35 months. Clinical, surgical, and neuroimaging data were analyzed using the Wilcoxon signed-rank test, Cox regression analysis, and Kaplan-Meier survival curves to identify predictors of poor functional outcomes. RESULTS: Of the 107 patients (mean age 43.9 years, SD 13), 81 (75.5â¯%) showed functional improvement, 25 (23.4â¯%) remained unchanged, and 1 (0.9â¯%) experienced worsened outcomes. Cephalalgia, bilateral motor weakness, and bilateral paresthesia were the most frequent initial symptoms. Tonsillar coagulation was performed in 31 cases (28.9â¯%) but was clinically associated with higher rates of unfavorable outcomes. The Wilcoxon signed-rank test indicated that long-term follow-up CCOS was significantly higher than postoperative CCOS (Z = -7.678, p < 0.000). Multivariate Cox analysis identified preoperative bilateral motor weakness (HR 6.1, 95â¯% CI 1.9-18.9; p = 0.002), hydrocephalus (HR 3.01, 95â¯% CI 1.3-6.9; p = 0.008), and unilateral motor weakness (HR 2.99, 95â¯% CI 1.1-8.2; p = 0.033) as significant predictors of poor outcomes on a long-term follow-up. CONCLUSION: This study highlights the high rate of functional improvement in CMI patients following PFDD. Preoperative motor weakness and hydrocephalus were significant predictors of poor long-term outcomes. Tonsillar coagulation did not demonstrate a clear clinical benefit and may be associated with worse outcomes. Our findings suggest that careful preoperative assessment and selection of surgical techniques are crucial for optimizing patient outcomes.
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Malformación de Arnold-Chiari , Humanos , Femenino , Masculino , Malformación de Arnold-Chiari/cirugía , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Estudios de Seguimiento , Resultado del Tratamiento , Descompresión Quirúrgica/métodos , Adulto JovenRESUMEN
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.
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Linfocitos T CD4-Positivos , Redes Reguladoras de Genes , Enfermedades Inflamatorias del Intestino , Animales , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Ratones , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Regulación de la Expresión GénicaRESUMEN
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.
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Acromegalia , Microcirugia , Humanos , Acromegalia/cirugía , Resultado del Tratamiento , Microcirugia/métodos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/cirugía , Endoscopía/métodos , Neoplasias Hipofisarias/cirugía , Adenoma/cirugía , Adenoma/patología , Hueso Esfenoides/cirugía , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/efectos adversos , Neuroendoscopía/métodosRESUMEN
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.
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Infecciones por VIH , Lactante , Humanos , Recién Nacido , Inmunoglobulina G , Incidencia , Recuento de Linfocito CD4 , Transmisión Vertical de Enfermedad InfecciosaRESUMEN
Abstract Introduction Anxiety, mood- and stress-related behaviors are regulated by sex hormones in pregnant and non-pregnant women. Very scarce information exists about the role of sex steroids in pregnant women displaying high levels of anxiety. Objective To determine sex hormones serum levels in pregnant women exhibiting high levels of anxiety symptoms. Method The Hamilton Anxiety Rating Scale (HARS/ HAM-A) was used to assess the intensity of anxiety symptoms in third-trimester pregnant women. Two groups were included in the study, pregnant women exhibiting severe anxiety (ANX; HARS scores ≥ 25; n = 101) and healthy control subjects (CTRL; n = 40) displaying lower scores for anxiety (HARS scores ≤ 7). Estradiol (E2), progesterone (P4), and testosterone (T) serum levels were measured using a standard chemiluminescent immunoassay. Bivariate and partial correlations were performed to detect significant associations between groups, clinical measures, biochemical data, and HARS scores. Results The anxiety group (ANX) showed an increase in E2 and T serum levels (p < .001) compared to CTRL. Conversely, significantly lower P4 levels were found in the symptomatic group (p < .001) as compared to the CTRL hormone values. The P4:E2 index was significantly reduced in pregnant women with high levels of anxiety (p < .001). Negative correlations between anxiety (HARS) scores, P4 serum levels (p = .02), and P4:E2 ratio (p = .04) were found in the symptomatic group. Conversely, T serum levels displayed a positive association (p = .001) with high levels of anxiety symptoms in the same group, after adjusting our data by clinical confounders. Discussion and conclusion Serum levels of sex-steroid hormones are altered in pregnant women exhibiting severe anxiety.
Resumen Introducción La ansiedad, el estado de ánimo y el estrés están regulados por diversos esteroides sexuales. Existe poca información sobre el papel que juegan estos esteroides en mujeres embarazadas con niveles elevados de ansiedad. Objetivo Determinar los niveles séricos de hormonas sexuales en mujeres embarazadas con altos índices de síntomas de ansiedad con respecto a mujeres gestantes sanas. Método Determinación de la intensidad de síntomas ansiosos empleando la escala de Hamilton de Ansiedad (HAM-A) en 141 mujeres embarazadas en el tercer trimestre de gestación. Cuantificación de los niveles séricos de estradiol (E2), progesterona (P4) y testosterona (T) por inmunoensayo estándar. Aplicación de las correlaciones de Pearson para detectar asociaciones entre parámetros clínicos y valores hormonales entre los grupos de estudio. Resultados Las mujeres con ansiedad severa (ANX; n = 101; HAM-A ≥ 25) mostraron niveles séricos más altos de E2 y T (p < .001), así como niveles más bajos de P4 (p < .001) en relación con el grupo control (CTRL, n = 40, HAM-A < 7). Se detectó una disminución significativa en el índice P4:E2 en el grupo de ANX (p < .001) y se observaron correlaciones negativas y positivas entre los puntajes elevados de ansiedad con los niveles circulantes de P4 (p = .02), en la taza P4:E2 (p = .04) y en los niveles séricos de T (p = .001) respectivamente, al ajustar nuestros datos con variables confusoras. Discusión y conclusión Los niveles circulantes de los esteroides sexuales se encontraron alterados en mujeres con ansiedad severa.
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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.
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Craneotomía , Nervio Facial , Humanos , Nervio Facial/cirugía , Nervio Facial/anatomía & histología , Craneotomía/métodos , Cabeza/cirugía , Procedimientos Neuroquirúrgicos , Disección , CadáverRESUMEN
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.
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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.
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Dolor Crónico , Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Disbiosis , Percepción del Dolor , Microbioma Gastrointestinal/fisiología , Neuronas DopaminérgicasRESUMEN
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.
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Adenoma , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patología , Microcirugia/métodos , Resultado del Tratamiento , Adenoma/cirugía , Adenoma/patología , Endoscopía/métodos , Estudios RetrospectivosRESUMEN
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.
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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.
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Neoplasias de la Vesícula Biliar , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Antígeno Carcinoembrionario/genética , Inmunoterapia Adoptiva/métodos , Antígeno B7-H1 , Neoplasias de la Vesícula Biliar/terapia , Inmunoterapia , Linfocitos TRESUMEN
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.
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Encefalomielitis Autoinmune Experimental , Receptores de Antígenos de Linfocitos T alfa-beta , Ratones , Animales , Autoinmunidad , Disbiosis , Sistema Nervioso Central , Glicoproteína Mielina-Oligodendrócito/toxicidad , Péptidos , Ratones Endogámicos C57BLRESUMEN
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.
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Leche Humana , Leche , Humanos , Lactante , Recién Nacido , Femenino , Animales , Embarazo , Lactancia/fisiología , Mama , Hormonas/fisiología , Inmunidad , MamíferosRESUMEN
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.
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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.
RESUMEN
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.