Morphological Characteristics of the Results of Experimental Modeling of Septic Peritonitis

SUMMARY: Experimental studies devoted to the study of the mechanisms of the pathogenesis of acute peritonitis and the development of new methods of medical and surgical treatment are becoming increasingly relevant. Today, experimental medicine knows many different ways to modeling septic peritonitis and eliminate it, but the role of the local immune system is underestimated, whereas it takes a direct part in inflammation. The objective of our work to study morphological features of results of experimental modeling of septic peritonitis in white rats. The study included 15 sexually mature white male rats weighing 276.75±6.56 grams. A simulation of septic peritonitis was performed by perforating the upper part of the cecum with four punctures with a G16 injection needle. As a result of the experiment, after examination of the peritoneal cavity, all 15 animals were diagnosed with omentum tamponade of perforated damage to the caecum. In 11 cases, the perforated wall of the caecum was covered by the greater omentum (73.34 %), and in the other 4 animals, tamponade was performed by one of the epididymal omentum (26.66 %). The initial stage of tamponade with the greater or epididymal omentums of a perforated caecum begins on the first day of the experiment and consists of tight interstitial consolidation between them, as well as in the invasion of blood vessels from the omentum side to the focus of infection, which ensure the delivery of the appropriate immunocompetent cells. As a result of this process, intensive lymphoid infiltrates are formed in this area, as well as the growth of adipose tissue, which isolates the inflammatory focus from the peritoneal cavity with a thick layer.

Las investigaciones experimentales dedicadas al estudio de los mecanismos de patogénesis de la peritonitis aguda y el desarrollo de nuevos métodos de tratamiento médico y quirúrgico son cada vez más relevantes. Hoy en día, la medicina experimental conoce muchas formas diferentes de modelar la peritonitis séptica y eliminarla, pero se subestima el papel del sistema inmunológico local, mientras que él participa directamente en la inflamación. El objetivo de nuestro trabajo fue estudiar las características morfológicas de los resultados del modelado experimental de peritonitis séptica en ratas blancas. El estudio incluyó 15 ratas macho blancas, sexualmente maduras que pesaban 276,75 ± 6,56 gramos. Se realizó una simulación de peritonitis séptica perforando la parte superior del ciego con cuatro punciones con una aguja de inyección G16. Como resultado del experimento, después del examen de la cavidad peritoneal, a los 15 animales se les diagnosticó taponamiento del omento o lesión perforada del ciego. En 11 casos, la pared perforada del ciego fue recubierta por el omento mayor (73,34 %), y en los otros 4 animales el taponamiento se realizó por uno de los epidídimos (26,66 %). La etapa inicial del taponamiento con omento mayor o epidídimo de un ciego perforado comienza el primer día del experimento y consiste en una estrecha consolidación intersticial entre ellos, así como en la invasión de los vasos sanguíneos desde el lado del omento hasta el foco de infección, que aseguran la entrega de las células inmunocompetentes apropiadas. Como resultado de este proceso, se forman intensos infiltrados linfoides en esta zona, así como el crecimiento de tejido adiposo, que aísla el foco inflamatorio de la cavidad peritoneal con una gruesa capa.

METTL3-mediated HPV vaccine enhances the effect of anti PD-1 immunotherapy to alleviate the development of cutaneous squamous cell carcinoma

Abstract Background Cutaneous squamous cell carcinoma (cSCC) develops from epithelial keratinocytes by dysregulation of self-renewal and differentiation. Recent studies have found that the size and number of cSCC tumors gradually decrease or even disappear after HPV vaccination. However, the role of the HPV vaccine in the cSCC mechanism is poorly understood. Objective The aim of this study is to investigate the effect and mechanism of the HPV vaccine in cSCC. Methods Immunofluorescence was used to study the immune infiltrating cells in the tumor tissues of patients with cSCC. The effects of the HPV vaccine on cSCC cells and tissues were studied by Cell Culture, Real-time PCR, Western Blot, Cytotoxicity Assay, Enzyme-linked Immunosorbent Assay, m6A Blotting, CCK-8 Assay, m6A Ribonucleic acid Methylation Quantification and tumor transplantation. Results The HPV vaccine enhanced the toxic effect of CD8+T cells on cSCC cells and promoted the secretion of multiple cytokines by CD8+T cells. In addition, HPV vaccines can increase tumor sensitivity to anti-PD-1 therapy by downregulating METTL3 in tumor tissue, with the combination of HPV vaccine and PD-1 monoclonal antibodies producing enhanced immune cell infiltration compared to PD-1 blockade alone. Study limitations It is important to note the limitations of this study, including the small sample size, the construction of the mouse model, and the choice of HPV vaccine and PD-1 monoclonal antibody, which may limit the generalization of our findings to a wider population. Conclusions It is hoped that this research will contribute to a deeper understanding of the role of the HPV vaccine in the treatment of cSCC. HPV vaccine is expected to become an important approach to alleviate the development of cSCC.

Deficiency in infiltration of CD8/CD3 positive lymphocytes and macrophages plays a role in lip carcinogenesis: an immunohistochemical study

Abstract Objective To evaluate the immunoexpression profile for CD8, CD3, CD20 and CD68 in the process and carcinogenesis of Carcinoma of the vermilion lip. Methods Average cell count with positive expression for CD3, CD8, CD20 and CD68. The CD8/CD3 ratio calculated in the region was based on the percentage of positive cells in a total of malignant cells. Kruska-Wallis/Dunn, Mann-Whitney and Spearman correlation tests (SPSS, p< 0.05) were used. Results In the Aquitic Cheilitis samples, there was an increase in intraepithelial CD8+ and CD68+. In LSCCs, there was an increase in peritumoral and intratumoral CD3+, CD8+, CD20+ and CD68+ cells. In peritumoral LSCC, CD3+ and CD8+ showed a direct correlation (p= 0.004), and CD68+ and CD8+ (p= 0.017). In the intraepithelial region, CD8+ correlated with CD20+ (p= 0.014) and CD68+ (p= 0.013). In the CAs, CD3 (p< 0.001) and CD8 (p= 0.025) correlated intraepithelial and subepithelial. In LSCC CD3+ (p= 0.002), CD8+ (p= 0.001) and CD68+ (p= 0.030) had intra and peritumoral correlation. Conclusion CD68+ is the first interacting cell with the greatest capacity to migrate to the tumor and interact with CD3, CD8 and CD20. Apparently, CD20 affects perineural invasion. Level of evidence: Level 2.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics

ABSTRACT Background: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. Methods: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. Results: A total of 202 PLWH with CD4 > 200 cells/μL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. Conclusions: 17DD was safe and well-tolerated in PLWH with CD4 > 200 cells/μL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

Humoral and Cellular Immunology in Human Prostate Cancer: Plasma Cells and T and B Lymphocytes / Inmunología Humoral y Celular en el Cáncer de Próstata Humano: Células Plasmáticas y Linfocitos T y B

SUMMARY: In solid and malignant tumors, innate and adaptive immunity are combined in antitumor responses. This study aimed to analyze the activation of plasma cells and the correlation between the infiltration of B and T lymphocytes with the degree of malignancy or Gleason grade in human prostate biopsies diagnosed with cancer. Prostate cancer biopsies were obtained from the Clinical Hospital of Universidad de Chile (n=70), according to the bioethical norms of the institution. Histological sections of 5µm thickness were processed for immunohistochemistry with primary antibodies against BL and total TL (HRP/DAB). Recognition and quantification were performed under a Leica DM750 optical microscope. Microsoft Excel and GraphPad software were used for the statistical study. Correlation coefficient (Pearson) and mean comparison tests (Kruskal-Wallis and Dunn) and p≤ 0.05 were developed. B and T lymphocyte populations were inversely interregulated in prostate cancer (Gleason) (r= -0.46). Their relationship with Gleason grade is variable according to lymphocyte type (LB vs. Gleason r= -0.0.47 and LT vs. Gleason r= -0.21). Histological diagnosis of prostate cancer correlates with a predominance of LT. The malignancy of the pathology correlates with a predominance of LTs, according to the Gleason grade. The increased knowledge of B and T lymphocyte infiltration and plasma cell activation could be used to better target clinical trials on treatments based on immune system responses. Immunotherapy could be a new paradigm to apply better antitumor therapy strategies.

En tumores sólidos y malignos, la inmunidad innata y adaptativa se combinan en respuestas antitumorales. Este estudio tuvo como objetivo analizar la activación de células plasmáticas y la correlación entre la infiltración de linfocitos B y T con el grado de malignidad o grado de Gleason en biopsias de próstata humana diagnosticadas con cáncer. Las biopsias de cáncer de próstata se obtuvieron del Hospital Clínico de la Universidad de Chile (n=70), de acuerdo con las normas bioéticas de la institución. Secciones histológicas de 5 µm de espesor fueron procesadas para inmunohistoquímica con anticuerpos primarios contra LB y LT total (HRP/DAB). El reconocimiento y las cuantificaciones se realizaron bajo un microscopio óptico Leica DM750. Para el estudio estadístico se utilizaron los programas Microsoft Excel y GraphPad. Se desarrollaron pruebas de coeficiente de correlación (Pearson) y comparación de medias (Kruskal-Wallis y Dunn) y p≤ 0.05. Los resultados muestran que las poblaciones de linfocitos B y T están inversamente interreguladas en el cáncer de próstata (r= -0,4578). Su relación con el grado de Gleason es variable según el tipo de linfocito (LB vs Gleason r= -0,47* y LT vs Gleason r= -0,21). Se concluye que la malignidad del cáncer de próstata se correlaciona con un predominio de LT, versus el grado de Gleason. El mayor conocimiento de la infiltración de linfocitos B y T y la activación de células plasmáticas podría aprovecharse para una mejor orientación de ensayos clínicos en tratamientos basados en las respuestas del sistema inmunitario. La inmunoterapia podría ser un nuevo paradigma para aplicar mejores estrategias de terapias antitumorales.

Linfocitopenia como biomarcador de gravedad en pacientes pediátricos con la COVID-19

Introducción: La COVID-19 en edades pediátricas presenta características singulares; un pequeño número de pacientes pediátricos desarrollan un estado clínico grave. Objetivos: Evaluar si la linfocitopenia es un predictor de gravedad en pacientes pediátricos con la COVID-19. Métodos: Se estudiaron en 706 pacientes, las variables edad, sexo, antecedentes patológicos personales de enfermedades crónicas de la infancia (asma bronquial, diabetes mellitus), comorbilidades, estado clínico, valores de linfocitos, conteo absoluto de linfocitos (≤ 1 x 109/L = linfocitopenia). De acuerdo con el estado clínico los pacientes se agruparon en 5 grupos, de asintomáticos a críticos. Se determinó la correlación entre el estado clínico y el conteo absoluto de linfocitos; de este se determinó su capacidad discriminativa para estimar el pronóstico. Resultados: La media de la edad fue 8,6 años; el 6,2 % de los pacientes evolucionó al estado grave o crítico; 74,6 % tuvo valores normales de linfocitos, el 16,14 % altos y el 9,2 % bajos. Linfocitopenia presentó el 4,2 %; se correlacionó significativamente con estado grave, área bajo la curva de 0,711 (IC 95 %: 0,595-0,827); 46 % de sensibilidad y 98 % de especificidad. Conclusiones: La linfocitopenia es un biomarcador que puede estimar el pronóstico en pacientes pediátricos con la COVID-19 que desarrollan un estado clínico grave.

Introduction: COVID-19 in pediatric ages presents unique features; a small number of pediatric patients develop severe clinical status. Objectives: To evaluate whether lymphocytopenia is a predictor of severity in pediatric patients with COVID-19. Methods: In 706 patients were studied the variables age, sex, personal pathological history of childhood chronic diseases (bronchial asthma, diabetes mellitus), comorbidities, clinical status, lymphocyte values, absolute lymphocyte count (≤ 1 x 109/L = lymphocytopenia). According to clinical status patients were grouped into 5 groups, from asymptomatic to critical. The correlation between clinical status and absolute lymphocyte count was determined; its discriminative capacity to estimate prognosis was determined. Results: The mean age was 8.6 years; 6.2% of patients progressed to severe or critical condition; 74.6% had normal lymphocyte values, 16.14% high and 9.2% low. Lymphocytopenia presented 4.2%; it was significantly correlated with severe condition, area under the curve of 0.711 (95% CI: 0.595-0.827); 46% sensitivity and 98% specificity. Conclusions: Lymphocytopenia is a biomarker that can estimate prognosis in pediatric patients with COVID-19 who develop severe clinical status.

Evaluation of lymphocyte count, T-cell subsets and neutrophil-to-lymphocyte ratio as early predictors for severity and outcome of COVID-19 disease-a report from a highly complex hospital in Brazil

ABSTRACT Introduction: Lymphopenia is a laboratory marker of poor prognosis and severity of disease in the SARS-CoV-2 infection. This study aims to describe the immune profile of a Brazilian population. Methods: A total of 121 consecutive patients with severe acute respiratory syndrome (SARS) were analyzed between April and June 2020. Routine peripheral blood counts and multiparametric flow cytometry were performed on admission to assess lymphocytes and subsets (CD3, CD4, CD8). Demographic, clinical and laboratory data were collected from hospital sources. Results: The total of 116 patients included 63 (54.3%) males; 76 (62.8%) COVID-19 patients were divided, based on clinical characteristics and mechanical ventilation (MV) use, into moderate (n = 41; no MV) and severe (n = 35; MV) groups. The control group (n = 40) was comprised of patients with SARS of different etiologies. All patients had lymphopenia, with overall lymphocyte counts and their subsets considerably lower in severe patients, when compared to the moderate and controls. Patients with a high neutrophil-to-lymphocyte ratio (> 15.2) and T-cell lymphopenia (CD3 < 593 cells/μL, CD4 < 326 cells/μL, CD8 < 121 cells/μL) had a higher risk of being intubated and progressing to death. A total of 39 patients (95.1%) in the moderate group and 54.3% (n = 19) in the severe group were discharged; 28 patients died. Conclusion: Laboratory assessment of the neutrophil/lymphocyte ratio and T-cell subsets may be predictive of mortality and may be useful for stratifying COVID-19 patients.

Programmed cell death protein 1 is a marker for neoadjuvant chemotherapy response in triple-negative breast cancer

SUMMARY OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.

Inflammation in Cardiovascular Disease: Current Status and Future Perspectives

Abstract Atherosclerosis has been defined as an inflammatory disease. Three decades of research have pointed to a pivotal role of interleukin 6 for many aspects of cardiovascular disease, not the least of which is atherosclerosis. In this review, experimental and clinical studies are reported on a timeline, exploring mechanisms and possible explanations that form the basis of current knowledge. Some successful clinical trials were proof of concept studies, showing that not only inflammatory biomarkers are related to cardiovascular outcomes, but also that decreasing inflammation can reduce cardiovascular events. Great advances have been made in the management of residual cardiovascular risk due to cholesterol, thrombosis, and metabolic diseases, but the next frontier now seems to be targeting inflammation. In the upcoming years, the importance of inflammation will be evaluated in high-risk patients with chronic kidney disease, after acute coronary heart disease or heart failure with preserved ejection fraction. Inflammation seems to precede the development of cardiovascular risk factors. Moreover, counseling for a heathy lifestyle and, when necessary, the use of cardiometabolic therapies capable of decreasing inflammation, might be important.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and prognosis after aneurysmal subarachnoid hemorrhage: a cohort study / Razão neutrófilos-linfócitos e razão plaquetas-linfócitos e o prognóstico de hemorragia subaracnóidea aneurismática: um estudo de coorte

Abstract Background Subarachnoid hemorrhage (SAH) prognosis remains poor. Vasospasm mechanism might be associated with inflammation. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied as inflammation markers and prognostic predictors. Objective We aimed to investigate NLR and PLR in admission as predictors of angiographic vasospasm and functional outcome at 6 months. Methods This cohort study included consecutive aneurysmal SAH patients admitted to a tertiary center. Complete blood count was recorded at admission before treatment. White blood cell count, neutrophil count, lymphocyte count, platelet count, NLR, and PLR were collected as independent variables. Vasospasm occurrence-modified Rankin scale (mRS), Glasgow outcome scale (GOS), and Hunt-Hess score at admission and at 6 months were recorded as dependent variables. Multivariable logistic regression models were used to adjust for potential confounding and to assess the independent prognostic value of NLR and PLR at admission. Results A total of 74.1% of the patients were female, with mean age of 55.6 ± 12.4 years. At admission, the median Hunt-Hess score was 2 (interquartile range [IQR] 1), and the median mFisher was 3 (IQR 1). Microsurgical clipping was the treatment for 66.2% of the patients. Angiographic vasospasm incidence was 16.5%. At 6 months, the median GOS was 4 (IQR 0.75), and the median mRS was 3 (IQR 1.5). Twenty-one patients (15.1%) died. Neutrophil-to-lymphocyte ratio and PLR levels did not differ between favorable and unfavorable (mRS > 2 or GOS < 4) functional outcomes. No variables were significantly associated with angiographic vasospasm. Conclusion Admission NLR and PLR presented no value for prediction of functional outcome or angiographic vasospasm risk. Further research is needed in this field.

Resumo Antecedentes O prognóstico da hemorragia subaracnoidea (HSA) permanece ruim. Vasoespasmo pode estar associado à inflamação. Razões neutrófilo-linfócito (NLR) e plaqueta-linfócito (PLR) têm sido estudadas como marcadores de inflamação e prognóstico. Objetivo Investigar NLR e PLR na admissão como preditores de vasoespasmo angiográfico e desfecho aos 6 meses. Métodos Este estudo de coorte incluiu pacientes consecutivos com HSA aneurismática de um centro terciário. Contagem de leucócitos, neutrófilos, linfócitos e plaquetas, proporção de neutrófilos para linfócitos e de plaquetas para linfócitos foram coletados como variáveis independentes. Ocorrência de vasoespasmo, escala de Rankin modificada, escala de desfecho de Glasgow e o escore de Hunt-Hess na admissão e 6 meses após a mesma foram registradas como variáveis dependentes. Modelos de regressão logística multivariável foram usados para ajustar potenciais fatores de confusão e avaliar valor prognóstico independente de NLR e PLR. Resultados Um total de 74,1% pacientes eram do sexo feminino, com idade média de 55,6 ± 12,4 anos. Na admissão, a pontuação média de Hunt-Hess foi de 2 (IQR 1) e a mediana de mFisher foi de 3 (IQR 1). Clipagem microcirúrgica foi o tratamento escolhido para 66,2% dos pacientes. A incidência de vasoespasmo angiográfico foi de 16,5%. Aos 6 meses, a escala de desfecho de Glasgow mediana era 4 (IQR 0,75) e a escala de Rankin modificada mediana era 3 (IQR 1,5). Vinte e um pacientes (15,1%) morreram. Os níveis de NLR e PLR não diferiram entre resultados funcionais favoráveis e desfavoráveis (mRS > 2 ou GOS < 4). Nenhuma variável foi significativamente associada ao vasoespasmo angiográfico. Conclusão Razão neutrófilo-linfócito e a PLR não apresentaram valor preditivo de desfecho funcional ou risco de vasoespasmo angiográfico. Mais pesquisas são necessárias neste campo.

Efecto de la inmunidad celular en el tratamiento de las úlceras del pie diabético con Heberprot-P® / Effect of cellular immunity in the treatment of diabetic foot ulcers with Heberprot-P®

Introducción: Los diabéticos muestran una disminuida función del sistema inmune. Su complicación más temida es la aparición de las úlceras del pie. El Heberprot-P® tiene efectos beneficiosos en la curación de estas úlceras. Objetivo: Evaluar el efecto de la inmunidad celular en el tratamiento de las úlceras del pie diabético con Heberprot-P®. Métodos: Se realizó un estudio observacional, prospectivo, de serie de casos, en 30 pacientes con úlcera de pie diabético, ingresados en el Instituto Nacional de Angiología y Cirugía Vascular. Se administraron 75 µg de Heberprot-P®, tres veces por semana, a través de vías peri- e intralesional, durante ocho semanas. Se evaluaron las variables edad, sexo, glucemia en ayunas, creatinina, urea, ácido úrico, prueba de hipersensibilidad retardada, porcentaje de granulación, tiempo de cierre de la lesión y localización de la úlcera, antes de comenzar el tratamiento, a las 4 y 8 semanas. Resultados: Se precisó un predominio del 60 por ciento en el sexo femenino y del color de piel blanca. Los niveles de glucemia y creatinina se comportaron más elevados en los anérgicos; la urea fue similar tanto en anérgicos como en reactivos; y el ácido úrico resultó mayor en hombres reactivos y en mujeres anérgicas. Hubo mayor proporción de reactivos (63,6 por ciento), que en la cuarta semana presentaron un tejido de granulación igual o mayor al 50 por ciento; y a la octava, igual o mayor al 70 por ciento. Conclusiones: La condición en los pacientes diabéticos de ser reactivo a las pruebas de hipersensibilidad retardada con úlcera de pie diabético de tipo neuropática, tratados con Heberprot-P®, está asociada directamente con una mejor respuesta en la cicatrización de sus lesiones, mediante la formación del tejido de granulación, que favorece el cierre total o parcial de la lesión. Esto no ocurrió con los pacientes anérgicos a dicha prueba(AU)

Introduction: Diabetics show decreased immune system function. Its most feared complication is the appearance of foot ulcers. Heberprot-P® has beneficial effects in healing these ulcers. Objective: To assess the effect of cellular immunity in the treatment of diabetic foot ulcers with Heberprot-P®. Methods: An observational, prospective, case series study was conducted in 30 patients with diabetic foot ulcer admitted to the National Institute of Angiology and Vascular Surgery. 75 µg of Heberprot-P®, three times a week, were administered through peri- and intralesional routes, during eight weeks. The variables age, sex, fasting blood glucose, creatinine, urea, uric acid, delayed hypersensitivity test, percentage of granulation, time of closure of the lesion and location of the ulcer, before starting treatment, at 4 and 8 weeks were evaluated. Results: A predominance of 60 % in females and white skin color were specified. Blood glucose and creatinine levels behaved higher in the anergics; urea was similar in both anergics and reagents; and uric acid was higher in reactive men and anergic women. There was a higher proportion of reagents (63.6 por ciento), which in the fourth week presented a granulation tissue equal to or greater than 50 por ciento; and at the eighth week, it was equal to or greater than 70 por ciento. Conclusions: The condition of being reactive to delayed hypersensitivity tests in diabetic patients with diabetic foot ulcer of neuropathic type, treated with Heberprot-P® is directly associated with a better response in the healing of their lesions, through the formation of granulation tissue, which favors the total or partial closure of the lesion. This did not occur with patients who were anergic to this test(AU)

TTYH3 is a prognostic biomarker and associates with immune cell infiltrations of lung adenocarcinoma / TTYH3 es un biomarcador pronóstico y se asocia con infiltraciones de células inmunitarias del adenocarcinoma de pulmón

SUMMARY: We investigated Tweety Family Member 3 (TTYH3) level in lung adenocarcinoma (LUAD) and its relationship with immune infiltration in tumors by bioinformatics. Differential expressions of TTYH3 in lung cancer were analyzed with Oncomine, TIMER, GEO, UALCAN and HPA. Relationship of TTYH3 mRNA/protein levels with clinical parameters was analyzed by UALCAN. Co-expressed genes of TTYH3 in LUAD were analyzed using Cbioportal. Its relationship with LUAD prognosis was analyzed by Kaplan-Meier plotter. GO and KEGG analysis were performed. Correlation between TTYH3 and tumor immune infiltration were tested by TIMER, TISIDB and GEPIA. We found that TTYH3 was significantly increased in LUAD tissues. TTYH3 high expression was closely related to poor overall survival, post progression survival and first progression in LUAD patients. TTYH3 mRNA/protein levels were significantly associated with multiple pathways. Specifically, TTYH3 up-regulation was mostly related to biological regulation, metabolic process, protein blinding, extracellular matrix organization and pathways in cancer. Moreover, TTYH3 was positively associated with immune cell infiltration in LUAD. Finally, TTYH3 was highly expressed in LUAD as revealed by meta-analysis. TTYH3 is closely related to the prognosis of LUAD and immune cell infiltration, and it can be used as a prognostic biomarker for LUAD and immune infiltration.

Investigamos por bioinformática el nivel de Tweety Family Member 3 (TTYH3) con adenocarcinoma de pulmón (LUAD) y su relación con la infiltración inmune en tumores. Las expresiones diferenciales de TTYH3 en cáncer de pulmón se analizaron con Oncomine, TIMER, GEO, UALCAN y HPA. Con UALCAN se analizó la relación de los niveles de ARNm/proteína de TTYH3 con los parámetros clínicos. Los genes coexpresados de TTYH3 en LUAD se analizaron utilizando Cbioportal. Su relación con el pronóstico LUAD se analizó mediante plotter de Kaplan- Meier. Se realizaron análisis GO y KEGG. TIMER, TISIDB y GEPIA probaron la correlación entre TTYH3 y la infiltración inmune tumoral. Encontramos que TTYH3 aumentó significativamente en los tejidos LUAD. La alta expresión de TTYH3 estuvo estrechamente relacionada con una supervivencia general deficiente, supervivencia posterior a la progresión y primera progresión en pacientes con LUAD. Los niveles de ARNm/ proteína de TTYH3 se asociaron significativamente con múltiples vías. Específicamente, la regulación positiva de TTYH3 se relacionó principalmente con la regulación biológica, el proceso metabólico, el cegamiento de proteínas, la organización de la matriz extracelular y las vías en el cáncer. Además, TTYH3 se asoció positivamente con la infiltración de células inmunitarias en LUAD. Finalmente, TTYH3 se expresó altamente en LUAD como lo reveló el metanálisis. TTYH3 está estrechamente relacionado con el pronóstico de LUAD y la infiltración de células inmunitarias, y se puede utilizar como biomarcador pronóstico para LUAD y la infiltración de células inmunitarias.

Linfoma em cão da raça cane corso: relato de caso / Lymphoma in a cane corso dog: case report / Linfoma en un perro cane corso: relato de un caso

Os linfócitos são células de defesa do organismo que funcionam como barreira contra infecções e células cancerígenas, elas circulam pelo sistema linfático e estão presentes por todo o organismo do animal, podem se proliferar de forma maligna, caracterizando o linfoma. Acometem em sua maioria, cães de raças de grande porte, animais de meia idade e idosos. Sendo uma doença de etiologia desconhecida, vários fatores podem contribuir para sua evolução, como deficiências autoimunes, bem como hábitos alimentares ao longo da vida do animal, ou até por predisposição genética. O presente relato de caso, tem o objetivo de mostrar a evolução gradual da doença, quais sinais clínicos o animal poderá apresentar, e como os exames laboratoriais podem nos auxiliar em seu diagnóstico.(AU)

The lymphocytes are defense cells of the body that act as a barrier against infection and cancer cells, they circulate through the lymphatic system and are present throughout the animal's body, and can proliferate in a malignant way, characterizing the lymphoma. They mostly affect large breed dogs, middle-aged and elderly animals. Being a disease of unknown etiology, several factors may contribute to its evolution, such as autoimmune deficiencies, as well as food habits throughout the animal's life, or even genetic predisposition. The present case report has the objective of showing the gradual evolution of the disease, which clinical signs the animal may present, and how laboratory tests can help us in its diagnosis.(AU)

Los linfocitos son células de defensa del organismo que actúan como barrera contra infecciones y células cancerígenas, circulan por el sistema linfático y están presentes en todo el organismo del animal, pudiendo proliferar de forma maligna, caracterizando el linfoma. Afectan sobre todo a perros de razas grandes, animales de mediana edad y ancianos. Siendo una enfermedad de etiología desconocida, varios factores pueden contribuir a su evolución, como deficiencias autoinmunes, así como hábitos alimentarios a lo largo de la vida del animal, o incluso predisposición genética. El presente caso clínico tiene como objetivo mostrar la evolución gradual de la enfermedad, qué signos clínicos puede presentar el animal y cómo las pruebas de laboratorio pueden ayudarnos en su diagnóstico.(AU)

Spleen regeneration after subcutaneous heterotopic autotransplantation in a mouse model

BACKGROUND: Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the spleen. Splenic autografts rapidly restore the regular splenic microanatomy in model animals. However, the functional competence of such regenerated autografts in terms of lympho- and hematopoietic capacity remains uncertain. Therefore, this study aimed to monitor the dynamics of B and T lymphocyte populations, the monocyte-macrophage system, and megakaryocytopoiesis in murine splenic autografts. METHODS: The model of subcutaneous splenic engraftment was implemented in C57Bl male mice. Cell sources of functional recovery were studied using heterotopic transplantations from B10-GFP donors to C57Bl recipients. The cellular composition dynamics were studied by immunohistochemistry and flow cytometry. Expression of regulatory genes at mRNA and protein levels was assessed by real-time PCR and Western blot, respectively. RESULTS: Characteristic splenic architecture is restored within 30 days post-transplantation, consistent with other studies. The monocyte-macrophage system, megakaryocytes, and B lymphocytes show the highest rates, whereas the functional recovery of T cells takes longer. Cross-strain splenic engraftments using B10-GFP donors indicate the recipient-derived cell sources of the recovery. Transplantations of scaffolds populated with splenic stromal cells or without them afforded no restoration of the characteristic splenic architecture. CONCLUSIONS: Allogeneic subcutaneous transplantation of splenic fragments in a mouse model leads to their structural recovery within 30 days, with full reconstitution of the monocyte-macrophage, megakaryocyte and B lymphocyte populations. The circulating hematopoietic cells provide the likely source for the cell composition recovery.

Actividad física y su relación con el sistema inmune / Physical activity and its relationship with the immune system

Introducción: El ejercicio mejora muchos aspectos de la salud humana, incluso, regula el sistema inmune. Se ha comprobado que el ejercicio moderado y regular ejerce efectos antiinflamatorios. Al mejorar las funciones inmunitarias, reduce la incidencia de enfermedades no transmisibles y la susceptibilidad a infecciones virales. Objetivo: Describir los efectos de la actividad física sobre el sistema inmune innato y adaptativo. Método: Para este manuscrito se usó la base de datos PubMed y Google Académico. Se utilizaron los términos ejercicios físicos, inmunidad, macrófago, neutrófilos, linfocitos e inmunoglobulinas, según el descriptor de Ciencias de la Salud. Se incluyeron 53 artículos en la revisión. Conclusiones: El ejercicio agudo (intensidad moderada a vigorosa, menos de 150 min) se considera un inmunoestimulante porque mejora la actividad antimicrobicida de los macrófagos e incrementa la síntesis de citocinas antiinflamatorias. Además, favorece el tráfico de neutrófilos, células NK, células T citotóxicas y células B inmaduras(AU)

Introduction: Exercise improves many aspects of human health, including, regulating the immune system. Moderate training has been shown to exert anti-inflammatory effects. By improving immune functions, it reduces the incidence of non-communicable diseases and susceptibility to viral infections. Objective: To describe the effects of physical activity on the innate and adaptive immune system. Methods: The PubMed and Google Scholar databases were used. The terms physical exercise, immunity, macrophage, neutrophils, lymphocytes and immunoglobulins were used, according to the Health Sciences descriptor (DeCS). Eighty-six articles were included in the review. Conclusions: Acute exercise (moderate to vigorous intensity, less than 150 min) is considered an immunostimulant because it enhances the antimicrobicidal activity of macrophages and increases the synthesis of anti-inflammatory cytokines. In addition, it favors the movement of neutrophils, NK cells, cytotoxic T cells and immature B cells(AU)

Tumoral inflammatory infiltrate does not predict metastases in thin primary cutaneous melanomas

Abstract Background In cutaneous melanomas in general, tumor inflammatory infiltrate (TII) can protect against distant metastases, but there is no consensus when only thin primary cutaneous melanomas (TPCM) are considered. Objective To investigate the presence of TII in TPCM and the relationship between TII and the occurrence of metastases. Methods Case-control study including 50 patients with TPCM, 22 metastatic (MC group) and 28 non-metastatic (NMC group). The presence of TII was evaluated and, if present, qualified as mild, moderate or marked. Results The mean age was 50.7 years in the MC and 56.2 years in the NMC group (p = 0.234), and the male sex predominated in the MC group (63.6%). The average Breslow thickness was higher in the MC when compared to that observed in the NMC (respectively 0.8 vs. 0.6 mm, p = 0.012). The presence of ulceration occurred in 22.7% of the MC and 17.9% of the NMC (p = 0.732). TII was present in all 50 TPCM, being marked or moderate in 67.9% of the NMC and 54.5% in the MC group (p = 0.503). In the multivariate analysis, the presence of moderate and marked TII had an Odds Ratio (OR) of 0.57 (95% Confidence Interval [CI]: 0.18‒1.8) and adjusted OR of 0.68 (95% CI 0.13‒3.99). Study limitations Small sample size. Conclusions TII was present in all TPCM (with and without metastases), and it was not possible to demonstrate a protective effect of TII against the appearance of metastases.

Determining reference ranges for immunological cells of healthy indigenous individuals from a region in Brazil

ABSTRACT Objective The establishment of reference values for a subset of leukocytes is common in clinical practice, and ethnic variations are strongly associated with disease development. In Brazil, indigenous people are vulnerable to infections, and few studies have described the health and disease conditions of this population. This study aimed to provide reference values for immunological cell subsets in indigenous Brazilians living in the state of Mato Grosso do Sul. Methods Flow cytometry and 4-color combinations of monoclonal antibodies were used to characterize cells. A total of 115 healthy adults, mostly females (72%), were included in the study. The results are presented as mean and median (2.5%-97.5% percentiles) for T and B lymphocytes, CD4+ T cells, CD8+ T cells, Natural Killer cells, monocytes, and dendritic cells, providing an average immunological profile for the population in question. Results The relative medians of CD3+, CD4+, and CD8+ T cells were significantly higher in women than in men in a healthy indigenous population. Conclusion To our knowledge, cell reference data from indigenous Brazilians are unknown in the literature. The immune cell results presented in this pioneering study will contribute to the clinical and laboratory evaluation of the Brazilian indigenous population, especially given the important differences when compared with other Brazilian ethnic groups.

Serum lymphocytes and cytokines: diagnostic value and influence on the immune status in patients with pulmonary tuberculosis / Linfócitos e citocinas séricas: valor diagnóstico e influência no estado imunológico de pacientes com tuberculose pulmonar

ABSTRACT Objective: To determine the absolute number of serum T lymphocytes and cytokine levels and the characteristics of patients with active pulmonary tuberculosis and to assess their effect on the immune status of these patients and their diagnostic and predictive value for tuberculosis. Methods: We included 1,069 patients with active tuberculosis, 51 patients with latent tuberculosis infection, and 600 health individuals. Absolute serum T-lymphocyte counts and cytokine levels were quantified. Results: T lymphocytes were significantly reduced in patients with active tuberculosis when compared with healthy individuals. The immune function of patients gradually decreased with age and was stronger in female patients than in males. Th1 cells expressed higher levels of cytokines than did Th2 cells. Logistic regression analysis showed that reduced CD3+ T, CD8+ T, and NK cell counts, as well as reduced IL-4 and IFN-g expression, were independent influencing factors for active tuberculosis. ROC analysis showed that the sensitivity and specificity of absolute CD3+ T and CD8+ T lymphocyte counts and combined factors were significantly higher than were those of IL-4 and IFN-g for diagnosing active tuberculosis. Conclusions: Serum T-lymphocyte counts and cytokine levels can assess the immune status of tuberculosis patients; they are also useful biomarkers for predicting and diagnosing tuberculosis.

RESUMO Objetivo: Determinar o número absoluto de linfócitos T séricos e os níveis de citocinas séricas, bem como as características, de pacientes com tuberculose pulmonar ativa e avaliar o efeito desses no estado imunológico desses pacientes e seu valor diagnóstico e preditivo para tuberculose. Métodos: Foram incluídos 1.069 pacientes com tuberculose ativa, 51 pacientes com tuberculose latente e 600 indivíduos saudáveis. Foram realizadas a contagem absoluta de linfócitos T séricos e a quantificação de citocinas séricas. Resultados: Os linfócitos T estavam significativamente reduzidos nos pacientes com tuberculose ativa em comparação com os indivíduos saudáveis. A função imunológica dos pacientes diminuiu gradativamente com a idade e mostrou-se mais forte nas mulheres do que nos homens. As células Th1 expressaram maiores níveis de citocinas do que as células Th2. A análise de regressão logística mostrou que contagens reduzidas de células T CD3+, T CD8+ e NK e expressão reduzida de IL-4 e IFN-g foram fatores de influência independentes para tuberculose ativa. A análise ROC mostrou que a sensibilidade e especificidade dos valores absolutos de linfócitos T CD3+ e T CD8+ e de fatores combinados foram significativamente maiores do que as da IL-4 e do IFN-g para o diagnóstico da tuberculose ativa. Conclusões: A contagem de linfócitos T séricos e os níveis de citocinas séricas podem avaliar o estado imunológico de pacientes com tuberculose; também são biomarcadores úteis na predição e diagnóstico da tuberculose.

Evaluation of the relationship between blood cell markers and inflammation, disease activity, and general health status in ankylosing spondylitis

SUMMARY OBJECTIVE: The aim of this study was to assess the relation of systemic immune inflammation index, systemic inflammation response index, and systemic inflammation aggregate index with disease activity, functional status, and general health status in ankylosing spondylitis. METHODS: Patients with ankylosing spondylitis and healthy volunteers were included in this cross-sectional study. Demographic data; disease activity measurements such as the Bath Ankylosing Spondylitis Disease Activity Index, the Ankylosing Spondylitis Disease Activity Score with C-reactive protein, and the Ankylosing Spondylitis Disease Activity Score with erythrocyte sedimentation rate; functional status such as the Bath Ankylosing Spondylitis Functional Index; and general health status such as the Assessment of Spondyloarthritis International Society Health Index of the patients were recorded. C-reactive protein, erythrocyte sedimentation rate, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, systemic immune inflammation index, systemic inflammation response index, and systemic inflammation aggregate index values were recorded. Patients were grouped as active and remission according to the Bath Ankylosing Spondylitis Disease Activity Index score and as inactive-low and high-very high disease activity according to the Ankylosing Spondylitis Disease Activity Score. The correlation of laboratory parameters with disease-related parameters was tested. RESULTS: The indexes were significantly higher in patients compared to controls (p<0.001, for platelet to lymphocyte ratio p=0.03). No significant differences existed in any blood cell-derived indexes among patient groups categorized by disease activity (p<0.05 for all). Systemic immune inflammation index was weakly correlated with Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ρ=0.197 and p=0.049) and Ankylosing Spondylitis Disease Activity Score-erythrocyte sedimentation rate (ρ=0.201 and p=0.045). Systemic immune inflammation index was not correlated with Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and Assessment of Spondyloarthritis International Society Health Index. No correlation was found between other indexes and disease-related variables. Platelet to lymphocyte ratio, systemic immune inflammation index, systemic inflammation response index, and systemic inflammation aggregate index showed a weak positive correlation with C-reactive protein and erythrocyte sedimentation rate (ρ=0.200-0.381). CONCLUSION: Systemic immune inflammation index, systemic inflammation response index, and systemic inflammation aggregate index can be used to indicate systemic inflammatory burden in ankylosing spondylitis patients. However, these indexes are not effective in indicating patients' disease activity, general health status, and functional status.

Proliferative verrucous leukoplakia mimicking oral lichen planus: case report and literature review

This report presents the clinical, microscopic and immunohistochemical aspects of a case of proliferative verrucous leukoplakia (PVL) mimicking oral lichen planus (OLP) in a 66-year-old woman. We also review the literature reporting cases of PVL mimicking OLP, where we found a higher prevalence in women who do not consume tobacco or alcohol. The initial manifestation of lichenoid areas was around the age of 59, with the diagnosis of PVL being established on average 6 years later, while malignant transformation occurred in 8 of the 22 cases at an average of 3.7 years after the final diagnosis of PVL. We emphasize the need for a close follow-up of any patient presenting white lesions of the oral mucosa. Lesions that are clinically and microscopically compatible with lichenoid reactions or OLP must be investigated and differentiated from PVL, which has a worse prognosis.

Este relato apresenta os aspectos clínicos, microscópicos e imuno-histoquímicos de um caso de leucoplasia verrucosa proliferativa (LPV) mimetizando líquen plano oral (LPO) em uma paciente do sexo feminino de 66 anos. Também revisamos a literatura relatando casos de LPV mimetizando LPO, onde encontramos maior prevalência em mulheres que não consomem tabaco ou álcool, com manifestação inicial de áreas liquenoides por volta dos 59 anos, sendo estabelecido o diagnóstico de LPV em média 6 anos depois, enquanto a transformação maligna ocorreu em 8 dos 22 casos em média 3,7 anos após o diagnóstico final de LPV. Ressaltamos a necessidade de acompanhamento rigoroso de qualquer paciente que apresente lesões brancas da mucosa oral, devendo ser investigadas lesões clinicamente e microscopicamente compatíveis com reações liquenóides ou LPO e diferenciadas da LPV, que tem pior prognóstico

Este reporte presenta los aspectos clínicos, microscópicos e inmunohistoquímicos de un caso de leucoplasia verrugosa proliferativa (LVP) simulando liquen plano oral (LPO) en una paciente de 66 años. También revisamos la literatura reportando casos de LVP simulando LPO, donde encontramos una mayor prevalencia en mujeres que no consumen tabaco ni alcohol, con una manifestación inicial de áreas liquenoides alrededor de los 59 años, estableciéndose el diagnóstico de LVP en promedio 6 años después, mientras que la transformación maligna ocurrió en 8 de los 22 casos en un promedio de 3,7 años después del diagnóstico final de LVP. Resaltamos la necesidad de un seguimiento estrecho de todo paciente que presente lesiones blanquecinas de la mucosa oral, que las lesiones clínica y microscópicamente compatibles con reacciones liquenoides o LPO deben ser investigadas y diferenciadas de la LVP, que tienen peor pronóstico.