Tejido adiposo epicárdico en personas que viven con VIH: ¿una ventana hacia el riesgo cardiovascular? / Epicardial adipose tissue in people living with HIV: a window towards cardiovascular risk?

Introducción: En las personas que viven con el virus de la inmunodeficiencia humana (PVVIH) se han descripto desregulaciones metabólicas que podrían vincularse a un mayor riesgo cardiovascular.Objetivo: Evaluar el espesor del tejido adiposo epicárdico (ETAE) y la relación del mismo con parámetros clínicos y bioquímicos de riesgo cardiovascular en adultos que viven con VIH, comparados con controles seronegativos.Materiales y métodos: Observacional, inclusión prospectiva. Se incluyeron PVVIH >18 años y controles seronegativos para VIH, a los cuales se les midió el espesor de TAE en dos ejes por ecocardiograma transtorácico, así como el espesor de íntima media carotídea por ecografía doppler color.Resultados: 75 pacientes, 58,7% del sexo masculino, edad de 36 años (RIQ 22). 50,7% con VIH (CD4+: 512 cél/mm3 RIQ 382; 80% indetectables). IMC de 25,2 kg/m2 (RIQ 5,3) y circunferencia de cintura de 88,5 cm (DS 12,4), sin diferencias. Las PVVIH tuvieron menor HDL, mayor proteína C reactiva, mayor dímero D y mayor glucemia en ayunas. El ETAE fue mayor en las PVVIH (4,05 vs. 3,49 mm p=0,021), y se correlacionó con la edad, glucemia en ayunas y dímero D. En las PVVIH, se correlacionó con insulinemia, índice HOMA2-IR, HDL-c y dímero D. El tratamiento con Efavirenz se asoció a un mayor ETAE.Conclusión: Las PVVIH presentaron mayor inflamación sistémica de bajo grado y un mayor espesor de TAE que los controles sanos, el cual se asoció en este grupo a insulinorresistencia

Introduction: For people living with Human Immunodeficiency Virus (PLHIV), metabolic deregulations have been described, which could be related to a higher cardiovascular risk.Objective: To assess the epicardial adipose tissue thickness (EATT), and the relationship between this value and clinical and biochemical parameters of cardiovascular risk in adults living with HIV, if compared to a healthy control group. Methods: Observational, with prospective inclusion. It included PLHIV >18 years and seronegative controls. All of them had their EAT measured in two axes by transthoracic echocardiogram, as well as the carotid intima-media thickness determined by color doppler ultrasound.Results: 75 patients, 58.7% male, age of 36 years (RIQ 22). 50.7% patients with HIV (CD4+ of 512 cells/mm3; and 80% undetectable). BMI was of 25.2 kg/m2 and waist circumference of 88.5 cm, without between-groups differences. PLHIV had lower HDL, higher C reactive protein, higher D-dimer and higher fasting blood glucose. EATT was higher in PLHIV (4.05 vs 3.49 mm, p=0.021), and this correlated with age, fasting blood glucose and D-dimer. In PLHIV, it correlated with insulinemia, HOMA2-IR index, HDL-c ; and D-dimer. Treatment with Efavirenz was associated with a higher EATT.Conclusion: PLHIV presented increased systemic inflammation of low grade and higher EATT than the seronegative control group. EATT was associated in PLHIV to insulin resistance

Hepatic pathological characteristics and factors influencing alanine transaminase value below twice the upper limit of normal in patients with chronic hepatitis B / 中华肝脏病杂志

Objective: To analyze the hepatic pathological characteristics and factors influencing an alanine transaminase value below twice the upper limit of normal in patients with chronic hepatitis B (CHB) and further explore the optimal ALT threshold strategy for initiating antiviral therapy. Methods: Clinical data of treatment-naïve CHB patients who underwent liver biopsies from January 2010 to December 2019 were retrospectively collected. Multiple regression models were used to explore the ALT levels and significant risk of hepatic histological changes (≥G2/S2). Receiver operating characteristic curve was used to evaluate the value of different models in diagnosing liver tissue inflammation≥G2 or fibrosis ≥ S2. Results: A total of 447 eligible CHB patients, with a median age of 38.0 years and 72.9% males, were included. During ALT normalization, there was significant liver inflammation (≥G2) and fibrosis (≥S2) in 66.9% and 53.0% of patients, respectively. With an ALT rise of 1-2×ULN, the proportions of liver inflammation≥G2 and fibrosis≥S2 were 81.2% and 60.0%, respectively. After adjusting for confounding factors, higher ALT levels (> 29 U/L) were found to be associated with significant liver inflammation (OR: 2.30, 95% CI: 1.11 ~ 4.77) and fibrosis (OR: 1.84, 95% CI: 1.10 ~ 3.09). After the measurement of glutamyltransferase-platelet ratio (GPR), the proportion of CHB patients with≥G2/S2 was significantly reduced under different treatment thresholds of ALT standards, and in particular, the erroneous evaluation of liver fibrosis≥S2 was significantly improved (33.5% to 57.5%). Conclusion: More than half of CHB patients have a normal ALT or one within 2 × ULN, regardless of whether or not there is apparent inflammation and fibrosis. GPR can significantly improve the precise assessment of different conditions of treatment thresholds for the ALT value in CHB patients.

Protective effect of intervention with cannabinoid type-2 receptor agonist JWH133 on pulmonary fibrosis in mice / 中华内科杂志

Objective: JWH133, a cannabinoid type 2 receptor agonist, was tested for its ability to protect mice from bleomycin-induced pulmonary fibrosis. Methods: By using a random number generator, 24 C57BL/6J male mice were randomly divided into the control group, model group, JWH133 intervention group, and JWH133+a cannabinoid type-2 receptor antagonist (AM630) inhibitor group, with 6 mice in each group. A mouse pulmonary fibrosis model was established by tracheal instillation of bleomycin (5 mg/kg). Starting from the first day after modeling, the control group mice were intraperitoneally injected with 0.1 ml of 0.9% sodium chloride solution, and the model group mice were intraperitoneally injected with 0.1 ml of 0.9% sodium chloride solution. The JWH133 intervention group mice were intraperitoneally injected with 0.1 ml of JWH133 (2.5 mg/kg, dissolved in physiological saline), and the JWH133+AM630 antagonistic group mice were intraperitoneally injected with 0.1 ml of JWH133 (2.5 mg/kg) and AM630 (2.5 mg/kg). After 28 days, all mice were killed; the lung tissue was obtained, pathological changes were observed, and alveolar inflammation scores and Ashcroft scores were calculated. The content of type Ⅰ collagen in the lung tissue of the four groups of mice was measured using immunohistochemistry. The levels of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in the serum of the four groups of mice were measured using enzyme-linked immunosorbent assay (ELISA), and the content of hydroxyproline (HYP) in the lung tissue of the four groups of mice was measured. Western blotting was used to measure the protein expression levels of type Ⅲ collagen, α-smooth muscle actin (α-SMA), extracellular signal regulated kinase (ERK1/2), phosphorylated P-ERK1/2 (P-ERK1/2), and phosphorylated ribosome S6 kinase type 1 (P-p90RSK) in the lung tissue of mice in the four groups. Real-time quantitative polymerase chain reaction was used to measure the expression levels of collagen Ⅰ, collagen Ⅲ, and α-SMA mRNA in the lung tissue of the four groups of mice. Results: Compared with the control group, the pathological changes in the lung tissue of the model group mice worsened, with an increase in alveolar inflammation score (3.833±0.408 vs. 0.833±0.408, P<0.05), an increase in Ashcroft score (7.333±0.516 vs. 2.000±0.633, P<0.05), an increase in type Ⅰ collagen absorbance value (0.065±0.008 vs. 0.018±0.006, P<0.05), an increase in inflammatory cell infiltration, and an increase in hydroxyproline levels [(1.551±0.051) μg/mg vs. (0.974±0.060) μg/mg, P<0.05]. Compared with the model group, the JWH133 intervention group showed reduced pathological changes in lung tissue, decreased alveolar inflammation score (1.833±0.408, P<0.05), decreased Ashcroft score (4.167±0.753, P<0.05), decreased type Ⅰ collagen absorbance value (0.032±0.004, P<0.05), reduced inflammatory cell infiltration, and decreased hydroxyproline levels [(1.148±0.055) μg/mg, P<0.05]. Compared with the JWH133 intervention group, the JWH133+AM630 antagonistic group showed more severe pathological changes in the lung tissue of mice, increased alveolar inflammation score and Ashcroft score, increased type Ⅰ collagen absorbance value, increased inflammatory cell infiltration, and increased hydroxyproline levels. Compared with the control group, the expression of α-SMA, type Ⅲ collagen, P-ERK1/2, and P-p90RSK proteins in the lung tissue of the model group mice increased, while the expression of type Ⅰ collagen, type Ⅲ collagen, and α-SMA mRNA increased. Compared with the model group, the protein expression of α-SMA (relative expression 0.60±0.17 vs. 1.34±0.19, P<0.05), type Ⅲ collagen (relative expression 0.52±0.09 vs. 1.35±0.14, P<0.05), P-ERK1/2 (relative expression 0.32±0.11 vs. 1.14±0.14, P<0.05), and P-p90RSK (relative expression 0.43±0.14 vs. 1.15±0.07, P<0.05) decreased in the JWH133 intervention group. The type Ⅰ collagen mRNA (2.190±0.362 vs. 5.078±0.792, P<0.05), type Ⅲ collagen mRNA (1.750±0.290 vs. 4.935±0.456, P<0.05), and α-SMA mRNA (1.588±0.060 vs. 5.192±0.506, P<0.05) decreased. Compared with the JWH133 intervention group, the JWH133+AM630 antagonistic group increased the expression of α-SMA, type Ⅲ collagen, P-ERK1/2, and P-p90RSK protein in the lung tissue of mice, and increased the expression of type Ⅲ collagen and α-SMA mRNA. Conclusion: In mice with bleomycin-induced pulmonary fibrosis, the cannabinoid type-2 receptor agonist JWH133 inhibited inflammation and improved extracellular matrix deposition, which alleviated lung fibrosis. The underlying mechanism of action may be related to the activation of the ERK1/2-RSK1 signaling pathway.

Pathological significance of plasma cell infiltration in diagnosing lymph node diseases / 中华病理学杂志

Objective: To investigate the value of plasma cells for diagnosing lymph node diseases. Methods: Common lymphadenopathy (except plasma cell neoplasms) diagnosed from September 2012 to August 2022 were selected from the pathological records of Changhai Hospital, Shanghai, China. Morphological and immunohistochemical features were analyzed to examine the infiltration pattern, clonality, and IgG and IgG4 expression of plasma cells in these lymphadenopathies, and to summarize the differential diagnoses of plasma cell infiltration in common lymphadenopathies. Results: A total of 236 cases of lymphadenopathies with various degrees of plasma cell infiltration were included in the study. There were 58 cases of Castleman's disease, 55 cases of IgG4-related lymphadenopathy, 14 cases of syphilitic lymphadenitis, 2 cases of rheumatoid lymphadenitis, 18 cases of Rosai-Dorfman disease, 23 cases of Kimura's disease, 13 cases of dermal lymphadenitis and 53 cases of angioimmunoblastic T-cell lymphoma (AITL). The main features of these lymphadenopathies were lymph node enlargement with various degrees of plasm cell infiltration. A panel of immunohistochemical antibodies were used to examine the distribution of plasma cells and the expression of IgG and IgG4. The presence of lymph node architecture could help determine benign and malignant lesions. The preliminary classification of these lymphadenopathies was based on the infiltration features of plasma cells. The evaluation of IgG and IgG4 as a routine means could exclude the lymph nodes involvement of IgG4-related dieases (IgG4-RD), and whether it was accompanied by autoimmune diseases or multiple-organ diseases, which were of critical evidence for the differential diagnosis. For common lesions of lymphadenopathies, such as Castleman's disease, Kimura's disease, Rosai-Dorfman's disease and dermal lymphadenitis, the expression ratio of IgG4/IgG (>40%) as detected using immunhistochemistry and serum IgG4 levels should be considered as a standard for the possibility of IgG4-RD. The differential diagnosis of multicentric Castleman's diseases and IgG4-RD should be also considered. Conclusions: Infiltration of plasma cells and IgG4-positive plasma cells may be detected in some types of lymphadenopathies and lymphomas in clinicopathological daily practice, but not all of them are related to IgG4-RD. It should be emphasized that the characteristics of plasma cell infiltration and the ratio of IgG4/IgG (>40%) should be considered for further differential diagnosis and avoiding misclassification of lymphadenopathies.

Liver macrophages show an immunotolerance phenotype in nonalcoholic fatty liver combined with Porphyromonas gingivalis-lipopolysaccharide infection / 华西口腔医学杂志

OBJECTIVES@#This study aimed to explore the functions and potential regulatory targets of local macrophages in nonalcoholic fatty liver combined with Porphyromonas gingivalis (P. gingivalis)infection.@*METHODS@#Single-cell RNA sequencing was used to analyze the phenotypes and functional changes in various cells in the liver tissue of nonalcoholic steatohepatitis (NASH) mice fed with P. gingivalis. Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, and immunofluorescence staining were applied to observe the inflammation and expression levels of macrophage antigen presenting functional markers in the NASH liver. Oil red staining was performed to observe the accumulation of local adipose tissue in the NASH liver. Results were verified through RT-PCRand RNA sequencing using P. gingivalis-lipopolysaccharide treated mouse peritoneal macrophages.@*RESULTS@#In comparison with healthy livers with Kupffer cells, the NASH liver combined with P. gingivalis infection-related macrophages showed significant heterogeneity. C1qb, C1qc, Mafb, Apoe, and Cd14 were highly expressed, but Cd209a, H2-Aa, H2-Ab1, and H2-DMb1, which are related to the antigen presentation function, were weakly expressed. Further in vivo and in vitro investigations indicated that the activation and infiltration of these macrophages may be due to local P. gingivalis-lipopolysaccharide accumulation.@*CONCLUSIONS@#P. gingivalis-lipopolysaccharide induces a local macrophage immunotolerance phenotype in nonalcoholic fatty liver, which may be the key mechanism of periodontitis pathogen infection that promotes NASH inflammation and pathogenesis. This study further clarifies the dysfunction and regulatory mechanisms of macrophages in the pathogenesis of P. gingivalis-infected NASH, thereby providing potential therapeutic targets for its clinical treatment.

Osteoimmunology research in rheumatoid arthritis: From single-cell omics approach / 中华医学杂志(英文版)

Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis (RA). Under the pathological conditions of RA, dysregulated inflammation and immune processes tightly interact with skeletal system, resulting in pathological bone damage via inhibition of bone formation or induction of bone resorption. Single-cell omics technologies are revolutionary tools in the field of modern biological research.They enable the display of the state and function of cells in various environments from a single-cell resolution, thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and biomarkers. Here, we summarize the latest findings of single-cell omics technologies in osteoimmunology research in RA. These results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling, providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.

Glia Connect Inflammation and Neurodegeneration in Multiple Sclerosis / 神经科学通报·英文版

Multiple sclerosis (MS) is regarded as a chronic inflammatory disease that leads to demyelination and eventually to neurodegeneration. Activation of innate immune cells and other inflammatory cells in the brain and spinal cord of people with MS has been well described. However, with the innovation of technology in glial cell research, we have a deep understanding of the mechanisms of glial cells connecting inflammation and neurodegeneration in MS. In this review, we focus on the role of glial cells, including microglia, astrocytes, and oligodendrocytes, in the pathogenesis of MS. We mainly focus on the connection between glial cells and immune cells in the process of axonal damage and demyelinating neuron loss.

Prognostic value of pre-operative peripheral inflammation markers in patients with squamous cell carcinoma of the external auditory canal / Valor prognóstico dos marcadores de inflamação periférica pré-operatórios em pacientes com carcinoma espinocelular do meato acústico externo

Abstract Introduction: Squamous cell carcinoma of the external auditory canal is a rare entity. Previous studies have suggested predictors for tumor recurrence. However, most of the prognostic factors were from the clinicopathological aspect. Objective: This study aims to analyze the correlation between pre-operative peripheral inflammation markers and survival outcomes, in order to identify prognostic biomarkers for patients with squamous cell carcinoma of the external auditory canal. Methods: We retrospectively analyzed patients diagnosed with squamous cell carcinoma of the external auditory canal who underwent surgery at our institute. The pre-operative circulating inflammatory markers, such as the neutrophil, lymphocyte, platelet, and monocyte counts were measured and their ratios including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio were calculated. The prognostic value of the measured hematologic parameters in relation to the survival outcomes was also evaluated. Results: A total of 83 patients were included, of which 26 patients showed tumor recurrence and 57 without recurrence. Neutrophil counts and neutrophil-to-lymphocyte ratio were closely connected with tumor stage. In the patients with recurrence, neutrophil counts, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were elevated (p< 0.0001, p< 0.0001 and p = 0.001), while lymphocyte counts and lymphocyte-to-monocyte ratio were decreased (p = 0.013 and p = 0.016, respectively). The receiver operating curve analysis indicated that pre-operative neutrophil-to-lymphocyte ratio is a potential prognostic marker for recurrence of squamous cell carcinoma of the external auditory canal (area under curve = 0.816), and the cut-off points was 2.325. Conclusions: Pre-operative neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte are significantly correlated with tumor recurrence in patients with external auditory canal squamous cell carcinoma. Furthermore, neutrophil-to-lymphocyte ratio may be unfavorable prognostic factors of this disease.

Resumo Introdução: O carcinoma espinocelular do meato acústico externo é uma doença rara. Estudos anteriores sugeriram preditores de recorrência do tumor. Entretanto, a maioria dos fatores prognósticos se originou do aspecto clínico-patológico. Objetivo: Analisar a correlação entre marcadores inflamatórios periféricos pré-operatórios e os desfechos de sobrevida e identificar biomarcadores prognósticos para pacientes com carcinoma espinocelular do meato acústico externo. Método: Analisamos retrospectivamente pacientes com diagnóstico de carcinoma espinocelular do meato acústico externo submetidos à cirurgia em nosso instituto. Os marcadores inflamatórios circulantes pré-operatórios, como as contagens de neutrófilos, linfócitos, plaquetas e monócitos, foram medidos e as suas relações calculadas, inclusive as relações neutrófilos/linfócitos, plaquetas/linfócitos e linfócitos/monócitos. O valor prognóstico dos parâmetros hematológicos medidos em relação aos desfechos de sobrevida também foi avaliado. Resultados: Foram incluídos 83 pacientes, entre os quais 26 apresentaram recorrência tumoral e 57 não apresentaram. A contagem de neutrófilos e a relação neutrófilo/linfócito estavam intimamente associadas ao estágio do tumor. Nos pacientes com recorrência, a contagem de neutrófilos, a relação neutrófilos/linfócitos e a relação plaquetas/linfócitos eram elevadas (p < 0,0001, p > 0,0001 e p = 0,001), enquanto a contagem de linfócitos e a relação linfócitos/monócitos estavam diminuídas (p = 0,012 ep = 0,016, respectivamente). A análise da curva, Receiver Operating Characteristic, indicou que a relação neutrófilos/linfócitos pré-operatória era um potencial marcador prognóstico para a recorrência de carcinoma espinocelular do meato acústico externo (Área sob a curva = 0,816) e o ponto de corte foi de 2,325. Conclusão: A contagem pré-operatória de neutrófilos e linfócitos, as relações neutrófilos/linfócitos, plaquetas/linfócitos e linfócitos/monócitos estão significativamente correlacionadas com a recorrência do tumor em pacientes com carcinoma espinocelular do meato acústico externo. Além disso, a relação neutrófilos/linfócitos pode ser um fator prognóstico desfavorável dessa doença.

Anti-inflammatory effects of aucubin in cellular and animal models of rheumatoid arthritis / 中国天然药物

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. It is known that aucubin (AU) exerts anti-inflammatory activity, but its effects and mechanisms in RA are unclear. This study investigated the anti-inflammatory effects and mechanisms of AU in vivo and in vitro. Human fibroblast-like synoviocyte cells from patients with RA (HFLS-RA), RAW264.7 cells, and MC3T3-E1 cells were used to evaluate the effects of AU on migration, invasion, apoptosis, osteoclast differentiation and production. Immunofluorescence was used to observe nuclear translocation of nuclear factor (NF)-κB, the double luciferase reporter gene method was used to observe NF-κB-p65 activity in AU-treated MC3T3-E1 cells. RT-qPCR was used to measure expression of bone metabolism and inflammation-related genes, and western blot was used to measure bone metabolism and NF-κB protein expression levels. Collagen-induced arthritis (CIA) rat model was used for pharmacodynamics study. Arthritis indexes were measured in the ankle and knee, histological staining and Micro-computed tomography were performed on the ankle joints. Also, inflammatory factor gene expression and the levels of NF-κB-related proteins were detected as in vitro. AU effectively inhibited HFLS-RA cell migration and invasion, promoted apoptosis, and inhibited RAW264.7 cell differentiation into osteoclasts, as well as inhibited NF-κB-p65 activity in MC3T3-E1 cells. Notably, AU significantly reduced the gene expression levels of three cell-related inflammatory factors and bone metabolism factors, effectively inhibited the expression of p-Iκκα β, p-IκBα, and p-p65 proteins. In vivo, AU relieved joint inflammation, reduced related inflammatory factors, and inhibited NF-κB signaling. It could be used to treat RA-related synovial inflammation and bone destruction through the NF-κB pathway.

Pathological features related to onco-immunity and their clinical significance of pancreatic ductal adenocarcinoma / 中华病理学杂志

Objective: To investigate the tumor immunity-related pathologic features and clinical significance in pancreatic ductal adenocarcinoma (PDAC). Methods: All pathologic materials and clinical information of 192 PDAC patients from the Cancer Hospital of the University of Chinese Academy of Sciences from January 2010 to December 2020 were collected. The onco-immune microenvironment associated morphologic features were evaluated, and MHC-Ⅰ, PD-L1, CD3, and CD8 expression were detected by immunohistochemistry (IHC). Then the correlation between the factors and their influence on prognosis was analyzed. Results: There were 163 cases of non-specific adenocarcinoma (163/192, 84.90%), 18 cases of adeno-squamous carcinoma (18/192, 9.37%), and 11 cases of other rare subtypes (11/192, 5.73%). Perineural invasion was observed in 110 cases (110/192, 57.29%) and vascular invasion in 86 cases (86/192, 44.79%). There were 84 cases (84/182, 46.15%) with severe chronic inflammation. Tumor infiltrating immune cell numbers (TII-N) were increased in 52 cases (52/192, 27.08%). Lymphocytes and plasma cells were the main infiltrating immune cells in 60 cases (60/192, 31.25%), whereas in 34 cases (34/192, 17.71%) the tumors were mainly infiltrated by granulocytes, and 98 cases (98/192, 51.04%) showed mixed infiltration. CD3+T cells were deficient in 124 cases (124/192, 66.31%). CD8+T cells were deficient in 152 cases (152/192, 79.58%). MHC-Ⅰ expression was down-regulated in 156 cases (156/192, 81.25%), and PD-L1 was positive (CPS≥1) in 46 cases (46/192, 23.96%). Statistical analysis showed that TII-N was negatively correlated with vascular invasion (P=0.035), perineural invasion (P=0.002), stage (P=0.004) and long-term alcohol consumption (P=0.039). The type of immune cells correlated positively with chronic pancreatic inflammation (P=0.002), and negatively with tumor differentiation (P=0.024). CD8+T cells were positively correlated with CD3+T cells (P=0.032), MHC-Ⅰ expression (P<0.001) and PD-L1 expression (P=0.001), and negatively correlated with long-term smoking (P=0.016). Univariate analysis showed that histological nonspecific type (P=0.013) and TII-N (P<0.001) were the factors for good prognosis. Vascular invasion (P=0.032), perineural invasion (P=0.001), high stage (P=0.003) and long-term alcohol consumption (P=0.004) were adverse prognostic factors. COX multivariate risk analysis found that TII-N was an independent favorable factor for PDAC, while perineural invasion was an independent adverse risk factor. Conclusions: TII-N is an independent superior prognostic factor for PDAC, and significantly correlated with many factors; chronic alcohol consumption and smoking may inhibit onco-immunity in PDAC patients.

Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice / 中国天然药物

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.

Gamma-glutamyl transpeptidase-platelet ratio, systemic immune inflammation index, and system inflammation response index in invasive Aspergillosis

SUMMARY OBJECTIVE: Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index are three systemic immune and inflammation indexes that were investigated for their diagnostic and prognostic proficiencies in cardiovascular diseases and cancers. However, their predictive values for invasive aspergillosis have not yet been studied. The aim of this study was to evaluate Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index levels and their diagnostic values in invasive aspergillosis. METHODS: A total of 23 patients with invasive aspergillosis and 23 sex- and age-matched healthy participants were included in this study. Complete blood count parameters and liver function tests were studied. Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index were calculated. RESULTS: Leukocyte, neutrophil, lymphocyte, and monocyte levels were statistically significantly higher in IA group (p=0.031, p=0.027, p=0.033, and p=0.001, respectively). In invasive aspergillosis group, platelets were numerically lower; Aspartate transaminase, alanine aminotransferase, and lactic dehydrogenase levels were numerically higher than those in control group but differences between levels were not statistically significant (p>0.05). The γ-glutamyl transpeptidase levels of patients were statistically significantly higher (p=0.007), and in addition, statistically significant differences were found between groups in terms of gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index (p<0.001, p=0.037, p=0.001, respectively). Receiver operating characteristic analysis was performed, and areas under the curves were evaluated. gamma-glutamyl transpeptidase-platelet ratio had the higher area under the curve than systemic immune inflammation index and system inflammation response index (AUC 0.849, 0.798, 0.693, respectively). The results from receiver operating characteristic analysis of the data suggested that the use of a cutoff value of 0.15 for gamma-glutamyl transpeptidase-platelet ratio would be optimum for clinical use to confirm independent predictors of patients with invasive aspergillosis. CONCLUSIONS: Gamma-glutamyl transpeptidase-platelet ratio is an independent, a useful predictor, and is superior to other evaluated markers in the diagnosis of inflammation in invasive aspergillosis. Gamma-glutamyl transpeptidase-platelet ratio may also be a helpful biomarker for clinicians to follow-up the inflammatory process of these patients.

Índices neutrófilo/linfocito, plaqueta/linfocito e inmunidad/inflamación sistémica en pacientes con neumonía por COVID-19 / Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index in patients with COVID-19-associated pneumonia

Resumen Introducción: Existen índices hematológicos que correlacionan la severidad y predicen la mortalidad, principalmente en estados sépticos y de inflamación. Objetivo: Correlacionar los índices neutrófilo/linfocito (INL), plaqueta/linfocito (IPL) e inmunidad/inflamación sistémica (IIIS) con la severidad de COVID-19. Método: Estudio descriptivo, analítico y retrospectivo de pacientes con neumonía por COVID-19, en quienes se analizaron INL, IPL e IIIS. Resultados: Se incluyeron 100 pacientes, 54 hombres y 46 mujeres, con una media de 49.4 ± 19.3 años. Las medias de INL, IPL e IIIS fueron 10.7 ± 10.9, 290.1 ± 229.2 y 2.6 ± 3.4 × 109, respectivamente. En 54 %, la neumonía fue leve y en 46 %, grave. En cuanto a los desenlaces hospitalarios, 75 % egresó por mejoría y 25 % falleció. Las medias de INL, IPL e IIIS de los pacientes que fallecieron versus las de los pacientes que mejoraron fueron 20.4 ± 16.9 versus 7.5 ± 4.9 (p = 0.001), 417.1 ± 379.7 versus 247.7 ± 127.4 (p = 0.038) y 4.8 ± 6.1 versus 1.9 ± 1.2 × 109 (p = 0.030), respectivamente. Conclusión: Los índices hematológicos en pacientes con neumonía por COVID-19 pueden ser empleados como predictores de severidad y pronóstico.

Abstract Introduction: There are hematological parameters that correlate severity and predict mortality mainly in septic and inflammatory states. Objective: To correlate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) with COVID-19 severity. Method: Descriptive, analytical, retrospective study of patients with COVID-19 pneumonia, in which NLR, PLR and SII were analyzed. Results: One-hundred patients were included, 54 men and 46 women, with a mean age of 49.4 ± 19.3 years. NLR, PLR and SII means were 10.7 ± 10.9, 290.1 ± 229.2, and 2.6 ± 3.4 × 109, respectively. In 54 %, pneumonia was mild, and in 46 %, severe. Regarding hospital outcomes, 75 % were discharged due to improvement and 25 % died. NLR, PLR and SII means of the patients who died versus the patients who improved were 20.4 ± 16.9 versus 7.5 ± 4.9 (p = 0.001), 417.1 ± 379.7 versus 247.7 ± 127.4 (p = 0.038) and 4.8 ± 6.1 versus 1.9 ± 1.2 × 109 (p = 0.030), respectively. Conclusion: Hematological parameters can be used in patients with COVID-19-associated pneumonia as predictors of severity and prognosis.

A Brazilian regional basic diet-induced chronic malnutrition drives liver inflammation with higher ApoA-I activity in C57BL6J mice

Malnutrition is still considered endemic in many developing countries. Malnutrition-enteric infections may cause lasting deleterious effects on lipid metabolism, especially in children living in poor settings. The regional basic diet (RBD), produced to mimic the Brazilian northeastern dietary characteristics (rich in carbohydrate and low in protein) has been used in experimental malnutrition models, but few studies have explored the effect of chronic RBD on liver function, a central organ involved in cholesterol metabolism. This study aimed to investigate whether RBD leads to liver inflammatory changes and altered reverse cholesterol metabolism in C57BL6/J mice compared to the control group, receiving a standard chow diet. To evaluate liver inflammation, ionized calcium-binding adapter protein-1 (IBA-1) positive cell counting, interleukin (IL)-1β immunohistochemistry, and tumor necrosis factor (TNF)-α and IL-10 transcription levels were analyzed. In addition, we assessed reverse cholesterol transport by measuring liver apolipoprotein (Apo)E, ApoA-I, and lecithin-cholesterol acyltransferase (LCAT) by RT-PCR. Furthermore, serum alanine aminotransferase (ALT) was measured to assess liver function. RBD markedly impaired body weight gain compared with the control group (P<0.05). Higher hepatic TNF-α (P<0.0001) and IL-10 (P=0.001) mRNA levels were found in RBD-challenged mice, although without detectable non-alcoholic fatty liver disease. Marked IBA-1 immunolabeling and increased number of positive-IBA-1 cells were found in the undernourished group. No statistical difference in serum ALT was found. There was also a significant increase in ApoA mRNA expression in the undernourished group, but not ApoE and LCAT, compared with the control. Altogether our findings suggested that chronic RBD-induced malnutrition leads to liver inflammation with increased ApoA-I activity.

Controlled release alginate-chitosan microspheres of tolmetin sodium prepared by internal gelation technique and characterized by response surface modeling

Tolmetin sodium (TS) is a powerful non-steroidal mitigating drug for the treatment of rheumatoid joint inflammation, osteoarthritis, and adolescent rheumatoid joint pain. In addition to its gastrointestinal (GIT) problems, TS has a short biological half-life (1 hr). In a trial to overcome these side effects and control the rate of (TS) release, chitosan coated alginate microspheres are recommended. A Box-Behnken experimental design was employed to produce controlled release microspheres of TS in the sodium alginate and chitosan copolymers (Alg-Ch) by emulsification internal gelation methodology. The effect of critical formulation variables namely, drug to polymer ratio (D:P ratio), speed of rotation and span 80% on drug encapsulation efficiency (% EE), drug release at the end of 2 hours (Rel2) and drug release at the end of 8 hours (Rel8) were analyzed using response surface modeling. The parameters were assessed using the F test and mathematical models containing only the significant terms were generated for each parameter using multiple linear regression analysis. The produced microspheres were spherical in shape with extensive pores at D:P ratio 1:1 and small pores at a drug to polymer ratio (D:P ratio) 1:3. Differential scanning calorimetry (DSC) affirmed the steady character of TS in microspheres and revealed their crystalline form. All formulation variables examined exerted a significant influence on the drug release, whereas the speed emerged as a lone factor significantly influencing % EE. Increasing the D: P ratio decreases the release of the drug after two and 8 hours. The increase in speed results in an increase in drug release after two and eight hours. The drug release from the microspheres followed zero order kinetics. TS Alg-Ch microspheres exhibited a significant anti-inflammatory effect on incited rat paw edema after eight hours. These results revealed that the internal gelation technique is a promising method to control TS release and eradicate GIT side effects using Alg-Ch copolymers.

Safe-by-design development of a topical patch for drug delivery

Few topical products have been developed specifically to treat acute and chronic arthritis and inflammation, using non-steroidal anti-inflammatory drugs (NSAIDs). The lack of dosing accuracy commonly found in locally applied semisolid products for cutaneous use is a critical issue that leads to treatment failure. The aim of the present work is to develop a differentiated and innovative topical patch based on a monolithic hydrogel for ibuprofen skin delivery, in order to provide a safer and accurate way of drug administration along with improved treatment compliance. Topical patches based on hydroxypropylmethylcellulose (HPMC) were optimized in composition, in terms of enhancer and adhesive, supported on a systematic assessment of in vitro release and permeation behavior and adhesion properties. Several mathematical models were used to scrutinize the release mechanisms from the patches. In vitro release kinetics was shown to be mainly driven by diffusion. However, other mechanisms seemed to be also present, supporting the feasibility of using patches for sustained drug delivery. PEG 200 provided the best permeation rate, with a permeation enhancement ratio of ca. 3 times higher, than the commercial reference. The addition of Eudragit L30D 55 to the formulation led to the best adhesion profile, thus achieving a successful development based on a safe-by-design concept.

Evaluation of the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats

Abstract INTRODUCTION: Sepsis is an important cause of mortality and morbidity, and inflammatory response and oxidative stress play major roles underlying its pathophysiology. Here, we evaluated the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats. METHODS: Twenty-eight adult Sprague Dawley rats were classified into Control (Group 1), Sepsis (Group 2), Sepsis+Cefazolin (Group 3), and Sepsis+Cefazolin+Etanercept (Group 4) groups. Kidney tissue and serum samples were obtained for biochemical and histopathological investigations and examined for the C reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), triggering receptor expressed on myeloid cells (TREM), and malondialdehyde (MDA) levels. RESULTS: The levels of TNF-α, TREM, and MDA in serum and kidney samples were significantly higher in rats from sepsis group than in rats from control group (p < 0.05). Group 3 showed a significant reduction in serum levels of TNF-α, CRP, and TREM as compared with Group 2 (p < 0.05). Serum TNF-α, CRP, TREM, and MDA levels and kidney TNF-α and TREM levels were significantly lower in Group 4 than in Group 2 (p < 0.05). Serum TNF-α and TREM levels in Group 4 were significantly lower than those in Group 3, and histopathological scores were significantly lower in Group 3 and Group 4 than in Group 2 (p < 0.05). Histopathological scores of Group 4 were significantly lower than those of Group 3 (p < 0.05). CONCLUSIONS: Etanercept, a TNF-α inhibitor, may ameliorate sepsis-induced oxidative stress, inflammation, and histopathological damage.

Tumor miofibroblástico inflamatorio: presentación variable de una misma patología / Inflammatory myofibroblastic tumor: variable presentation of the same pathology

INTRODUCCIÓN: El tumor miofibroblástico inflamatorio (TMI) es una neoplasia benigna infrecuente, de comportamiento clínico impredecible. OBJETIVOS: describir 3 casos de TMI diagnosticados entre marzo 2014 y enero 2018 en Hospital Clinico San Borja Arriaran, y realizar una revisión actualizada de la literatura. CASO 1: Adolescente de género masculino de 14 años de edad, hospitalizado por dolor abdominal, diagnosticado de invaginación yeyunoyeyunal secundaria a un tumor de pared intestinal. La histología fue compatible con un tumor miofibroblástico inflamatorio. CASO 2: Adolescente de género femenino, edad 12 años, hospitalizada por neumonía y dolor lumbar en estudio asociado a pérdida de peso. Se diagnosticó una masa retroperitoneal que comprometía el músculo psoas derecho, músculos paravertebrales, vértebras, riñón derecho y diafragma ipsilateral. Se efectuó biopsia por punción cuyo resultado fue compatible con un tumor miofibroblástico inflamatorio. CASO 3: Preadolescente de género femenino de 11 años de edad, hospitalizada para estudio de infección del tracto urinario a repetición. Se identificó un tumor vesical y la biopsia mostró ser compatible con tumor miofibroblástico inflamatorio. CONCLUSIÓN: Debido al comportamiento variable del tumor miofibroblástico inflamatorio, el manejo de este dependerá de la localización, la expresión del anaplasic like lymphoma (ALK), el comportamiento del tumor y la posibilidad de resección.

INTRODUCTION: The inflammatory myofibroblastic tumor is an infrequent benign neoplasm with unpredictable cli nical behavior. OBJECTIVES: to describe three clinical cases at the San Borja Arriarán Clinical Hospital between March 2014 and January 2018 and to carry out an updated review of the literature. CASE 1: 14-year-old male adolescent, hospitalized due to abdominal pain, diagnosed with jejunojejunal intus susception secondary to an intestinal wall tumor. The histology was compatible with an inflamma tory myofibroblastic tumor. CASE 2: 12-year-old female adolescent, hospitalized due to pneumonia and low-back pain under study associated with weight loss. A retroperitoneal mass was diagnosed involving the right psoas muscle, paravertebral muscles, vertebrae, right kidney, and ipsilateral dia phragm. A puncture biopsy was performed and the result was compatible with an inflammatory myofibroblastic tumor. CASE 3: 11-year-old female pre-adolescent, hospitalized to study recurrent urinary tract infection. A bladder tumor was identified, and the biopsy showed compatibility with inflammatory myofibroblastic tumor. CONCLUSION: Due to the variable behavior of the inflammatory myofibroblastic tumor, its management will depend on the location, expression of the anaplastic lymphoma kinase (ALK), tumor behavior, and the resection possibility.

Evaluation of the use of tacrolimus ointment for the prevention of hypertrophic scars in experimental model

Abstract BACKGROUND: Tacrolimus, for its activity on modulation of collagen production and fibroblast activity, may have a role in the prevention of hypertrophic scars. OBJECTIVES: Evaluate macroscopic, microscopic, metabolic, laboratory effects and side effects of the use of topical tacrolimus ointment, in different concentrations, in the prevention of hypertrophic scars. METHODS: Twenty-two rabbits were submitted to the excision of 2 fragments of 1 cm of each ear, 4 cm apart, down to cartilage. The left ear of the animals was standardized as control and Vaseline applied twice a day. The right ear received tacrolimus ointment, at concentrations of 0.1% on the upper wound and 0.03% on the lower wound, also applied twice a day. Macroscopic, microscopic, laboratory criteria and the animals' weight were evaluated after 30 days of the experiment. RESULTS: Wounds treated with tacrolimus, at concentrations of 0.1% and 0.03%, when compared to control, showed a lower average degree of thickening (p = 0.048 and p <0.001, respectively). The average of scar thickness and lymphocyte, neutrophil and eosinophil concentrations are lower in the treated wounds compared to the control (p <0.001, p=0.022, p=0.007, p=0.044, respectively). The mean concentration of lymphocytes is lower in wounds treated with a higher concentration of the drug (p=0.01). STUDY LIMITATIONS: experiment lasted only 30 days. CONCLUSIONS: Tacrolimus at the 2 concentrations evaluated reduced the severity of inflammatory changes and positively altered the macroscopic aspect of the scar in the short term. Its use was shown to be safe, with no evidence of systemic or local adverse effects.

Positive outcomes of phosphodiesterase type 5 inhibitor on histopathologic and biochemical changes induced by ureteral obstruction

SUMMARY OBJECTIVES: We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO). METHODS: The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T). RESULTS: Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-β decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T. CONCLUSION: The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-β in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.

RESUMO OBJETIVOS: Examinamos os efeitos do tadalafil em um dos inibidores da fosfodiesterase tipo 5 (PDE5) em um modelo de rato com obstrução ureteral unilateral parcial e completa (UUO). MÉTODOS: Os ratos foram divididos em cinco grupos: sham (n = 6), obstrução ureteral unilateral parcial (PUUO, n = 6), PUUO com tadalafil (PUUO T; Cialis, 10 mg/72 h, intragástrica; Lilly, Indianapolis, Indiana, EUA), completa obstrução ureteral unilateral (CUUO, n = 6) e CUUO com tratamento com tadalafil (CUUO T). RESULTADOS: Quinze dias após a UUO, o ureter apresentou alterações nas camadas de urotélio e infiltração significativa de células inflamatórias nos grupos PUUO e CUUO. Em comparação com os grupos sham, PUUO e CUUO, houve um aumento grave da infiltração de células inflamatórias. O epitélio urotelial exibiu degeneração e perda celular devido às células epiteliais inchadas, atróficas e desnudas nos grupos PUUO e CUUO. Nos grupos PUUO T e CUUO T, o urotélio revelou menor degeneração e perda de células epiteliais. Nós mostramos que a expressão da actina do músculo liso-α (α-SMA) e do fator de crescimento transformador-β (TGF-β) foram exibidas como sub-regulação nos grupos PUUO e CUUO. A expressão do TGF-β foi diminuída positivamente correlacionada com a da α-SMA nos grupos de terapia com tadalafil, PUUO T e CUUO T. CONCLUSÃO: O tadalafil do inibidor da fosfodiesterase tipo 5 reduziu as expressões α-SMA e TGF-β nos ureteres obstruídos, medidos por exames bioquímicos. Além disso, o tadalafil diminuiu a degeneração do urotélio devido à diminuição da perda de células epiteliais e da infiltração de células inflamatórias. Nossos resultados mostram que o tadalafil previne ou retarda o início da inflamação do ureter e degeneração urotelial em ratos com UUO.