Maculopatía paracentral aguda media y neurorretinopatía macular aguda

La neurorretinopatía macular aguda es una condición rara con patogenia microvascular. Se presenta con un inicio agudo con escotomas paracentrales correspondientes a lesiones paramaculares evidentes. Los avances en las imágenes multimodales permitieron caracterizar este trastorno de retina y crear nuevos conceptos. Serraf, en el 2013, identificó dos formas por medio de la tomografía de coherencia óptica dominio espectral: el tipo 1 conocido como maculopatía paracentral aguda media en la cual se observa una banda hiperreflectiva en la capa nuclear interna, y el tipo 2 en el cual la banda hiperreflectiva se ubica en la capa nuclear externa, que involucra la zona elipsoide y la zona de interdigitación con el epitelio pigmentario de la retina. Hasta el momento no existe cura; pero se puede actuar sobre los factores de riesgo. Por ser una condición rara y por no existir reportes hasta el momento en Cuba es que se presentan a continuación dos pacientes con cuadros clínicos similares de estas dos variantes; concluyendo la importancia que presentan las imágenes multimodales como medio auxiliar diagnóstico.

Acute macular neuroretinopathy is a rare condition with complex pathogenesis and microvascular cause. It appears with acute onset, with paracentral scotomas corresponding to obvious paramacular lesions. Advances in multimodal imaging made it possible to characterize this retinal disorder and to create new concepts. Serraf, in 2013, identified two forms by spectral domain optical coherence tomography: type 1, known as paracentral acute middle maculopathy, in which a hyperreflective band is observed in the inner nuclear layer; and type 2, in which the hyperreflective band is located in the outer nuclear layer, involving the ellipsoid zone and the zone of interdigitation with the retinal pigment epithelium. Up to this moment, there is no cure; but it is possible to act on the risk factors. Because it is a rare condition and because there are no reports so far in Cuba, two patients with similar clinical pictures of these two variants are presented; concluding the importance of multimodal images as an auxiliary diagnostic tool.

Bienestar subjetivo y satisfacciones de dominios en estudiantes universitarios colombianos / Subjective well-being and domain satisfactions in Colombian university students

Resumen El concepto de bienestar subjetivo se refiere a la forma global, positiva o negativa, en la que las personas evalúan sus vidas y experiencias. La búsqueda de factores que expliquen el bienestar subjetivo, actualmente uno de los temas de mayor interés en la psicología, condujo al concepto de satisfacciones de dominios, que se entienden como los juicios que las personas hacen al evaluar los mayores dominios de vida. Este estudio correlacional tuvo por objetivo establecer la relación de la satisfacción en los dominios económico, de pareja, familia, amigos, salud, vida universitaria y rendimiento académico, con los componentes cognitivo y emocional del bienestar subjetivo (satisfacción vital y felicidad, respectivamente), identificando cuáles de esos dominios lo predicen. La muestra, no probabilística, estuvo conformada por 344 estudiantes de una universidad pública colombiana (50.9 % mujeres y 49.1 % hombres) con edades entre 18 y 29 años (. = 20.89; DT = 2.52). Los resultados mostraron una fuerte relación de todos los dominios con el bienestar subjetivo. La satisfacción en los dominios económico, de pareja, familia, amigos y vida universitaria explicó la varianza de la satisfacción vital y la felicidad en forma diferenciada. Se concluye que: (a) el bienestar se afecta con la satisfacción de necesidades asociadas a los dominios cercanos e importantes para el individuo; (b) las satisfacciones de dominios impactan más el componente cognitivo del bienestar que el emocional; (c) el dominio económico satisface más necesidades cognitivas, la amistad suple necesidades emocionales, y la pareja, la familia y la vida universitaria satisfacen ambas.

Abstract The concept of subjective well-being refers to the overall positive or negative way in which people evaluate their lives and experiences. It is generally accepted that subjective well-being is made up of a cognitive component usually called satisfaction with life or life satisfaction and an emotional component usually referred to as happiness. The search for factors that explain subjective well-being is currently one of the most interesting topics in psychology and led to the concept of domain satisfactions, which are understood as the judgments that people make when evaluating the major domains of life. It refers to the perceived degree of satisfaction that we obtain from the way in which each of these main domains or areas of our lives are developed. This correlational study with predictive intent aimed at establishing the relationship of satisfaction in the economic, couple, family, friends, health, university life, and academic performance domains, with the cognitive and emotional components of subjective well-being (life satisfaction and happiness, respectively), identifying which of these domains predict well-being. The non-probabilistic sample, for convenience, was made up of 344 women and men (50.9 % and 49.1 % respectively) between 18 and 29 years of age (M = 20.89); SD = 2.52), students from an important Colombian public university based in the city of Palmira. The instruments, which include the Diener's life satisfaction and Lyubomirsky and Lepper's happiness scales, and simple items for each domain satisfaction studied (economic, couple, family, friends, health, university life, and academic performance) were answered in a format printed by 64 % of the participants and in virtual format by 36 %, according to their own choice. The results showed that all domain satisfactions were significantly related to both the cognitive and the emotional components of subjective well-being. The results also showed that except for satisfaction with health and academic performance, all other domain satisfactions predicted at least one of the components of subjective well-being. In general, domain satisfactions explained the variance of satisfaction and happiness much better than sociodemographic variables. Thus, it was confirmed that the psychological significance of events that occur in the main areas of people´s lives have much more relevance to well-being than situational factors such as sociodemographic ones. In a different sense, and order of impact, satisfaction with the economic domain, satisfaction with university life, and satisfaction with the couple emerged as the domains that had the greatest influence on life satisfaction, and satisfaction with friends and satisfaction with university life emerged as the strongest predictors of happiness. The results suggest that well-being is especially affected by the satisfaction of needs associated with the closest domains and more important to the individual. These would include the economic domain and relationships that involve affections, but also other domains that, for specific reasons, occupy a relevant place in the individual's internal hierarchy of importance, which may vary among cultures and even among people of the same culture. The above conclusion could explain, among other findings, the significant impact of satisfaction with university life on subjective well-being. The results also suggest that, in general, domain satisfactions have a greater impact on the cognitive component of well-being than on the emotional component, and that, in particular, domains such as economics fundamentally satisfy cognitive needs, friendship fundamentally satisfy emotional needs, and other domains such as couple, family and university life, satisfy both cognitive and emotional needs. This would demonstrate the importance of applying differentiated instruments to study the cognitive and emotional components of well-being.

Trends of humoral immune responses to heterologous antigenic exposure due to vaccination & omicron SARS-CoV-2 infection: Implications for boosting

Background & objectives: Vaccination and natural infection can both augment the immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how omicron infection has affected the vaccine-induced and hybrid immunity is not well studied in Indian population. The present study was aimed to assess the durability and change in responses of humoral immunity with age, prior natural infection, vaccine type and duration with a minimum gap of six months post-two doses with either ChAdOx1 nCov-19 or BBV152 prior- and post-emergence of the omicron variant. Methods: A total of 1300 participants were included in this observational study between November 2021 and May 2022. Participants had completed at least six months after vaccination (2 doses) with either ChAdOx1 nCoV-19 or an inactivated whole virus vaccine BBV152. They were grouped according to their age (? or ?60 yr) and prior exposure of SARS-CoV-2 infection. Five hundred and sixteen of these participants were followed up after emergence of the Omicron variant. The main outcome was durability and augmentation of the humoral immune response as determined by anti-receptor-binding domain (RBD) immunoglobulin G (IgG) concentrations, anti-nucleocapsid antibodies and anti-omicron RBD antibodies. Live virus neutralization assay was conducted for neutralizing antibodies against four variants – ancestral, delta and omicron and omicron sublineage BA.5. Results: Before the omicron surge, serum anti-RBD IgG antibodies were detected in 87 per cent participants after a median gap of eight months from the second vaccine dose, with a median titre of 114 [interquartile range (IQR) 32, 302] BAU/ml. The levels increased to 594 (252, 1230) BAU/ml post- omicron surge (P<0.001) with 97 per cent participants having detectable antibodies, although only 40 had symptomatic infection during the omicron surge irrespective of vaccine type and previous history of infection. Those with prior natural infection and vaccination had higher anti-RBD IgG titre at baseline, which increased further [352 (IQR 131, 869) to 816 (IQR 383, 2001) BAU/ml] (P<0.001). The antibody levels remained elevated after a mean time gap of 10 months, although there was a decline of 41 per cent. The geometric mean titre was 452.54, 172.80, 83.1 and 76.99 against the ancestral, delta, omicron and omicron BA.5 variants in the live virus neutralization assay. Interpretation & conclusions: Anti-RBD IgG antibodies were detected in 85 per cent of participants after a median gap of eight months following the second vaccine dose. Omicron infection probably resulted in a substantial proportion of asymptomatic infection in the first four months in our study population and boosted the vaccine-induced humoral immune response, which declined but still remained durable over 10 months

Scleral thickness in normal Indian eyes measured using spectral domain anterior segment optical coherence tomography

Purpose: To establish normative data on anterior scleral thickness using the spectral domain anterior segment optical coherence tomography (AS?OCT). Methods: In total, 200 eyes of 100 healthy subjects underwent AS?OCT scans in the temporal and nasal quadrants. The scleral + conjunctival complex thickness (SCT) was measured by a single examiner. Mean SCT was analyzed for differences across age groups, gender, and location (nasal versus temporal). Results: Mean age was 46.4 ± 18.3 (21–84) years; male to female ratio was 54:46. Mean SCT (nasal + temporal) of the right eye (RE) was 682.3 ± 64.2 ?m in males and 660.6 ± 57.1 ?m in females. In the left eye (LE), it was 684.6 ± 64.9 ?m in males and 661.8 ± 49.3 ?m in females. These differences between male and female for both eyes were statistically significant (P = 0.006 and P = 0.002). The mean SCT of temporal and nasal quadrants in the RE was 678.54 ± 57.50 and 666 ± 66.2 ?m, respectively. In the LE, the temporal mean SCT quadrant was 679.6 ± 55.8 ?m, and the nasal was 668.6 ± 63.6 ?m. Age had a negative correlation with SCT (?0.62 ?m/year; P = 0.03), and males had a higher temporal SCT than females (22 ?m higher; P = 0.03). After adjusting for age and gender in a multivariate analysis, temporal SCT was significantly (P < 0.001) higher than nasal SCT. Conclusion: In our study, mean SCT decreased with age and males had a higher temporal SCT. This is the first study to evaluate scleral thickness in the Indian population, and the data can be used as a baseline for comparing variations in scleral thickness in disease.

Study of heart rate variability to assess autonomic dysfunction in patients with chronic obstructive pulmonary disease of a tertiary care hospital of West Bengal: A cross-sectional comparative study

Background: Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality throughout the world. COPD and its complications also lead to a large number of deaths every year in our country. Cardiac arrhythmias and sudden cardiac death are the major complications of COPD leading to death and disability. Such cardiac complications are often a result of autonomic dysfunction. Aims and Objectives: This study aims to find out the autonomic dysfunction in moderate COPD patients by comparing their heart rate variability (HRV) parameters with age and sex matched healthy controls. Materials and Methods: After obtaining approval from the Institutional Ethics Committee, 48 patients of moderate COPD and 54 healthy subjects were assessed and compared with respect to their HRV parameters which included Mean RR, Mean HR, SDNN, NN50, pNN50, root mean square of successive differences (RMSSD), high frequency (HF), low frequency (LF), LF/HF ratio, and SD2/SD1 ratio. Results: It was found that in comparison to healthy controls, patients of moderate COPD had significant alteration in the following HRV parameters – Mean HR (P: 0.001), RMSSD (P: 0.002), SDNN (P: 0.015), NN50 (P: 0.001), pNN50 (P: 0.000), HF (NU/normalized unit) [P: 0.033], HF (%) [P: 0.002], LF (NU/normalized unit) [P: 0.033], LF (%) [P: 0.012], and LF/HF (P: 0.033). Conclusion: As there is a significant alteration of several HRV parameters in moderate COPD patients, we conclude that HRV measurement may subserve as a simple and non-invasive tool to assess autonomic dysfunction in patients of COPD at the earliest.

Síndrome uveomeningoencefálico Vogt Koyanagi-Harada con desprendimiento de la capa bacilar de la retina / Vogt Koyanagi-Barada uveomeningoencephalic syndrome with detachment of the bacillary layer of the retina

Introducción: El síndrome de Vogt-Koyanagi-Harada pertenece a los síndromes uveomeníngeos y es una de las principales enfermedades que amenazan la visión. Se caracteriza por una uveítis bilateral que se asocia frecuentemente con manifestaciones neurológicas, auditivas y tegumentarias. Recientemente un fenotipo particular de engrosamiento macular se ha descrito como desprendimiento bacilar asociado a esta enfermedad. Objetivo: Describir el desprendimiento bacilar de la retina mediante la tomografía de coherencia óptica de dominio espectral en un caso de Vogt Koyanagi Harada en fase uveítica. Presentación de caso: Paciente femenina de 46 años de edad atendida en el Instituto Cubano de Oftalmología "Ramón Pando Ferrer" con disminución de agudeza visual en ambos ojos y panuveitis bilateral. Fue diagnosticada con síndrome de Vogt-Koyanagi-Harada en su fase uveítica aguda con presencia de manifestaciones neurológicas y desprendimiento de la capa bacilar de la retina identificado mediante la tomografía de coherencia óptica de dominio espectral. Conclusiones: El síndrome de Vogt-Koyanagi-Harada aguda y el desprendimiento bacilar de la capa de la retina pueden diferenciarse de otros signos mediante la tomografía de coherencia óptica de dominio espectral. Su desaparición pudiera tener una relación con la mejoría de la agudeza visual(AU)

Introduction: Vogt-Koyanagi-Harada syndrome belongs to the uveomeningeal syndromes and is one of the major vision-threatening diseases. It is characterized by bilateral uveitis, which is frequently associated with neurological, auditory and integumentary manifestations. Recently a particular phenotype of macular thickening has been described as bacillary detachment associated with this disease. Objective: To describe bacillary retinal detachment using spectral domain optical coherence tomography in a case of Vogt Koyanagi Harada in uveitic phase. Case presentation: 46-year-old female patient attended at the Cuban Institute of Ophthalmology "Ramón Pando Ferrer" with decreased visual acuity in both eyes and bilateral panuveitis. She was diagnosed with Vogt-Koyanagi-Harada syndrome in its acute uveitic phase with presence of neurological manifestations and detachment of the bacillary layer of the retina identified by spectral domain optical coherence tomography. Conclusions: Acute Vogt-Koyanagi-Harada syndrome and bacillary retinal layer detachment can be differentiated from other signs using spectral-domain optical coherence tomography. Their disappearance could be related to the improvement of visual acuity(AU)

Polimorfismo no gene PNPLA3 e o consumo de carne vermelha aumentam o risco de fibrose em pacientes com DHGNA comprovado por biópsia em acompanhamento médico em um centro terciário no Sudoeste do Brasil / Pnpla3 gene polymorphism and red meat consumption increased fibrosis risk in nash biopsy-proven patients under medical follow-up in a tertiary center in southwest brazil

ABSTRACT Background: Recent studies show an increase in nonalcoholic fatty liver disease (NAFLD) in populations with higher consumption of red meat, processed and cooked at high temperatures. On the other hand, the single nucleotide polymorphism rs738409 in the Patatin-like phospholipase domain containing 3 (PNPLA3) gene has been implicated in susceptibility to NAFLD and liver fibrosis. However, the synergistic effect between red meat consumption and the PNPLA3 gene polymorphism in NAFLD has not yet been evaluated. Objective: To evaluate the association between the presence of the polymorphism in the PNPLA3 gene and the consumption of macronutrients, including meat consumption and its cooking method among NAFLD patients. Methods: This was a cross-sectional study with 91 patients diagnosed with NAFLD by liver biopsy with genotyping for the polymorphism in the PNPLA3 gene were included. The consumption of calories and macronutrients was verified using the semi-quantitative food frequency questionnaire and the specific questionnaire on meat consumption. PNPLA3 gene polymorphism was analyzed by real-time polymerase chain reaction (RT-PCR) and anthropometric evaluation was realized. Results: The mean BMI was 32.38±4.58 kg/m² and the waist circumference was 107±10 cm. On liver biopsy, 42% of patients had significant fibrosis (F≥2). The odds ratio of F≥2 was 2.12 for the GG group and 1.54 for the CG group, compared to the CC group. The mean caloric intake was 1170±463.20 kcal/d. The odds ratio in the CC group concerning high red meat consumption in comparison to low consumption was 1.33. For white meat, the odds ratio was 0.8 when comparing high and low intake, also in the CC group. Conclusion: High red meat intake and PNPLA3 gene polymorphism seem to synergistically affect NAFLD and liver fibrosis, requiring confirmation in a larger number of patients and in different populations.

RESUMO Contexto: Estudos recentes mostram um aumento da doença hepática gordurosa não alcoólica (DHGNA) em populações com maior consumo de carne vermelha, processada e cozida em altas temperaturas. Por outro lado, o polimorfismo rs738409 no gene Patatin-like fosfolipase contendo 3 (PNPLA3) tem sido implicado na suscetibilidade à DHGNA e fibrose hepática. No entanto, o efeito sinérgico entre o consumo de carne vermelha e o polimorfismo no gene PNPLA3 na DHGNA ainda não foi avaliado. Objetivo: Avaliar a associação entre a presença do polimorfismo no gene PNPLA3 e o consumo de macronutrientes, incluindo o consumo de carne e seu modo de cozimento em pacientes com DHGNA. Métodos: Realizamos um estudo transversal com 91 pacientes diagnosticados com DHGNA por biópsia hepática e genotipados para o polimorfismo no gene PNPLA3. O consumo de calorias e macronutrientes foi verificado por meio do questionário de frequência alimentar semi-quantitativo (QFA) e do questionário específico sobre consumo de carnes. O polimorfismo no gene PNPLA3 foi analisado por reação em cadeia da polimerase em tempo real (RT-PCR) e a avaliação antropométrica foi realizada. Resultados: O índice de massa corporal médio foi de 32,38±4,58 kg/m² e a circunferência da cintura foi de 107±10 cm. Na biópsia hepática, 42% dos pacientes apresentavam fibrose significativa (F≥2). O odds ratio de F≥2 foi de 2,12 para o grupo GG e 1,54 para o grupo GC, comparado ao grupo CC. A ingestão calórica média foi de 1.170±463,20 kcal/d. O odds ratio para alto consumo de carne vermelha no grupo CC em comparação ao baixo consumo foi de 1,33. Para a carne branca, este valor foi de 0,8 ao comparar o alto e o baixo consumo, também no grupo CC. Conclusão: A alta ingestão de carne vermelha e o polimorfismo no gene PNPLA3 parecem afetar sinergicamente a DHGNA e a fibrose hepática, necessitando de confirmação em maior número de pacientes e em diferentes populações.

Myopia, axial length, and optic coherence tomography characteristics of the macula in Indian children

Background: Myopia is a common condition affecting a significant proportion of the pediatric population in Asian countries. Aim and Objectives: This study was undertaken to investigate the associations of optical coherence tomography measurements of macular volume and macular thickness with refractive error and axial length in Indian children. Materials and Methods: The prospective observational study was carried out at MRA Medical College, Ambedkar Nagar, Uttar Pradesh. We enrolled 300 consecutive cases (190 cases and 110 controls) of pediatric age group (6–18 years) between January 2015 and December 2018. Pearson’s correlation was performed with refractive errors, axial length, macular thickness, and volume. Results: Children with myopia (SE ?0.5–?4.57 D) tended to have smaller total macular volume and thinner macular thickness as, compared to control. The correlation of macular thickness and macular volume was analyzed with spherical equivalent (SE) and axial length. Macular thickness had negative correlation with SE and positive with axial length, correlation coefficients being observed as (r = ?0.886 and 0.880, P ? 0.001). Total macular volume correlated negatively with SE, (r= ?0.771, P ?0.001) and positively with axial length (r = 0.764, P ?0.001). Conclusion: Increasing axial myopia was associated with increased macular volume and thickness. It establishes the importance of the fact that refractive error should be considered in the interpretation of macular thickness.

Bioinformatics-based design of a fusion vaccine with CTLA-4 variable region to combat Brucella

Brucellosis has become a global zoonotic disease, seriously endangering the health of people all over the world. Vaccination is an effective strategy for protection against Brucella infection in livestock in developed countries. However, current vaccines are pathogenic to humans and pregnant animals, which limits their use. Therefore, it is very important to improve the safety and immune protection of Brucella vaccine. In this study, different bioinformatics approaches were carried out to predict the physicochemical properties, T/B epitope, and tertiary structure of Omp2b and Omp31. Then, these two proteins were sequentially linked, and the Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) variable region was fused to the N-terminal of the epitope sequence. In addition, molecular docking was performed to show that the structure of the fusion protein vaccine had strong affinity with B7 (B7-1, B7-2). This study showed that the designed vaccine containing CTLA-4 had high potency against Brucella, which could provide a reference for the future development of efficient brucellosis vaccines.

In vitro immunogenic profile of recombinant SARS-CoV2 S1-RBD peptide in murine macrophage and microglial cells

BACKGROUND The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can infect common mice inducing significant pathological lung lesions and inflammatory responses. This substantially mimics coronavirus disease 19 (COVID-19) infection and pathogenesis in humans. OBJECTIVES To characterise the effects of recombinant SARS-CoV-2 S1 receptor-binding domain (RBD) peptide in murine macrophage and microglial cells' immune activation compared with classical PAMPs in vitro. METHODS Murine RAW 264.7 macrophages and BV2 microglial cells were exposed to increasing concentrations of the RBD peptide (0.01, 0.05, and 0.1 µg/mL), Lipopolysaccharide (LPS) and Poly(I:C) and evaluated after two and 24 h for significant markers of macrophage activation. We determined the effects of RBD peptide on cell viability, cleaved caspase 3 expressions, and nuclear morphometry analysis. FINDINGS In RAW cells, RBD peptide was cytotoxic, but not for BV2 cells. RAW cells presented increased arginase activity and IL-10 production; however, BV2 cells expressed iNOS and IL-6 after RBD peptide exposure. In addition, RAW cells increased cleaved-caspase-3, apoptosis, and mitotic catastrophe after RBD peptide stimulation but not BV2 cells. CONCLUSION RBD peptide exposure has different effects depending on the cell line, exposure time, and concentration. This study brings new evidence about the immunogenic profile of RBD in macrophage and microglial cells, advancing the understanding of SARS-Cov2 immuno- and neuropathology.

Correlation and clinical significance of VISTA expression and cervical squamous cell carcinoma / 中华肿瘤杂志

Objective: To explore the relationship between the expression of the T-cell activation suppressor-immunoglobulin variable region (VISTA) and the development of cervical squamous cell carcinoma (CSCC), and the impact on the prognosis of CSCC patients. Methods: Cervical tissue samples from 116 CSCC, including 23 cervical intraepithelial neoplasia (CIN) grade I, 23 CIN grade Ⅱ-Ⅲ, and 23 chronic cervicitis patients, were collected from the First Hospital of Soochow University between March 2014 and April 2019. The expression of VISTA in each group was detected by immunohistochemistry (IHC). Survival data of CSCC patients were obtained by follow-up. The survival analysis was performed by Kaplan-Meier method, and survival differences between groups were compared by Log rank test. Prognostic impact factors were analyzed using a multifactorial Cox proportional hazards model. Results: The positive rate of VISTA expression in CSCC group was 32.8% (38/116), and which of grade Ⅱ-Ⅲ was 17.4% (4/23). VISTA expression results showed no positive expression patients in the cervical intraepithelial neoplasia grade I and chronic cervicitis groups. The differences between the CSCC group and other groups were statistically significant (P<0.01). In 116 CSCC patients, VISTA expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis (P<0.01). The mean survival time of patients in the VISTA positive expression group was 30.7 months, and the 3-year survival rate was 44.7% (17/38). However, the mean survival time of the patients in the VISTA negative expression group was 49.1 months, and the 3-year survival rate was 87.2% (68/78). The Cox regression model found that VISTA expression positivity (P=0.001) and FIGO stage (P=0.047) were prognostic factors for CSCC, and patients with VISTA-positive CSCC had a 4.130-fold risk of death higher than those with VISTA-negative expression. Conclusions: The VISTA protein is highly expressed in CSCC tissues, and its expression level is closely related to the occurrence and development of CSCC. The expression of VISTA can be used as an independent predictor of CSCC prognosis and can provide a strong basis for the treatment of CSCC with immune checkpoint inhibitors.

Modified Wuhutang Alleviates Airway Inflammation and Down-regulates Expression of Muc5AC， STAT3， NF-κB， and NLRP3 in Lung Tissues of RSV-infected Asthmatic Mice / 中国实验方剂学杂志

ObjectiveTo explore effect of modified Wuhutang on airway inflammation and expression of mucin （Muc） 5AC， signal transducer and activator of transcription 3 （STAT3）， nuclear factor kappa B （NF-κB）， and NOD-like receptor thermal protein domain associated protein 3 （NLRP3） in respiratory syncytial virus （RSV）-infected asthmatic mice. MethodSeventy male BALB/c mice of 6-8 weeks old were randomized into normal control （CON）， asthma （ovalbumin， OVA）， RSV infection-induced asthma （OVA+RSV）， high-， medium-， and low-dose （4.08， 2.04， 1.02 g·kg-1·d-1， respectively） modified Wuhutang， and dexamethasone （Dxms， 0.1 g·kg-1d-1） groups （n=10）. The model of asthma was established by sensitization and atomization inhalation with OVA. The RSV infection-induced asthma model was established by three consecutive RSV nasal infusions （1.0 × 106 PFU·mL-1， 50 μL）. Wuhutang was administrated by gavage， and Dxms by intraperitoneal injection. The CON group was given the same amount of normal saline by gavage. The mice were anesthetized with 2.5% pentobarbital sodium 24 h after the last administration， and then the lung tissue was stained by hematoxylin-eosin （HE） and Van Gieson （VG） for observation of airway inflammation. The immunohistochemical assay was employed to detect the expression of Muc5AC. Western blot was employed to determine the protein levels of phosphorylated （p）-STAT3， STAT3， p-NF-κB， NF-κB， and NLRP3. ResultCompared with the CON group， the OVA group presented airway inflammatory cell infiltration， tissue hyperemia and edema， and collagen fiber deposition. The OVA+RSV group showed severer airway inflammatory cell infiltration and tissue hyperemia and edema than the OVA group. Compared with the OVA+RSV group， modified Wuhutang alleviated the airway inflammatory cell infiltration， tissue hyperemia and edema， and collagen fiber deposition， and the high-dose group had the best performance. Compared with the CON group， the OVA group and the OVA+RSV group showed increased expression level of Muc5AC （P<0.01）. Compared with the OVA+RSV group， modified Wuhutang reduced the expression level of Muc5AC， and the reduction was significant in the high-dose group （P<0.05）. Compared with the high-dose modified Wuhutang group， Dxms lowered the expression level of Muc5AC （P<0.05）. Compared with the CON group， the OVA and OVA+RSV groups showed up-regulated protein levels of p-STAT3， p-NF-κB， and NLRP3 （P<0.05， P<0.01）. Compared with the OVA+RSV group， modified Wuhutang down-regulated the protein levels of p-STAT3， p-NF-κB， and NLRP3 （P<0.01）. Compared with the high-dose modified Wuhutang group， the Dxms group showed up-regulated levels of p-STAT3， p-NF-κB proteins （P<0.01）. ConclusionModified Wuhutang can reduce airway inflammation and down-regulate the expression of Muc5AC， p-STAT3， p-NF-κB， and NLRP3 in RSV-infected asthmatic mice， which suggests that Wuhutang reduces airway inflammation in RSV-infected asthma by regulating the STAT3/NF-κB signaling pathway.

Mechanism of Buyang Huanwutang in Regulating Macrophage Cell Polarization Based on TLR4/NF-κB/NLRP3 Pathway / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Buyang Huanwutang in regulating macrophage polarization based on the Toll-like receptor 4 （TLR4） / nuclear factor-κB （NF-κB） / nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） pathway. MethodRAW264.7 macrophages were intervened with lipopolysaccharide （LPS） of different concentrations （0， 1.25， 2.5， 5， 10， 20， 40， and 80 mg·L-1） for 24 hours. Cell Counting Kit-8 （CCK-8） assay was used to determine the cell viability of RAW264.7 macrophages. The optimal concentration was chosen to establish an in vitro inflammation model induced by LPS. Cells were divided into a blank group （20% blank serum）， a model group （20% blank serum + 10 mg·L-1 LPS）， a model control group （20% FBS + 10 mg·L-1 LPS）， low-， medium-， and high-dose （5%， 10%， and 20%） Buyang Huanwutang-containing serum groups， a high-dose （20%） Buyang Huanwutang combined with NLRP3 inhibitor MCC950 （50 μmol·L-1） group， a high-dose （20%） Buyang Huanwutang combined with reactive oxygen species （ROS） inhibitor NAC （10 μmol·L-1） group， and a high-dose （20%） Buyang Huanwutang combined with NF-κB inhibitor PDTC （10 μmol·L-1） group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the expression of interleukin-1β （IL-1β）， interleukin-18 （IL-18）， and tumor necrosis factor-α （TNF-α） in RAW264.7 macrophages. Flow cytometry was employed to measure ROS levels in macrophages. Western blot was used to determine the protein expression of M1-type macrophage-related factors inducible nitric oxide synthase （iNOS） and TNF-α， M2-type macrophage-related factors arginase-1 （Arg-1） and interleukin-10 （IL-10）， as well as the proteins in the TLR4/NF-κB/NLRP3 pathway. ResultCCK-8 results indicated that under 10 mg·L-1 LPS stimulation， RAW264.7 macrophages exhibited the highest cell viability （P<0.01）. Compared with the blank group， the model group showed significantly increased levels of IL-1β， IL-18， and TNF-α （P<0.05，P<0.01）， increased ROS expression （P<0.05，P<0.01）， increased protein expression of M1-type macrophage factors iNOS and TNF-α （P<0.01）， decreased protein expression of M2-type macrophage factors Arg-1 and IL-10 （P<0.05，P<0.01）， and upregulated expression levels of TLR4， myeloid differentiation factor 88 （MyD88）， phosphorylated inhibitor of NF-κB （p-IκB）/NF-κB inhibitor （IκB）， phosphorylated NF-κB （p-NF-κB） p65/NF-κB p65， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， and pro-Caspase-1 （P<0.05， P<0.01）. Compared with the model group， all Buyang Huanwutang-treated groups and inhibitor groups significantly reduced levels of IL-1β， IL-18， and TNF-α （P<0.01）， suppressed the expression of inflammatory factors in RAW264.7 macrophages， decreased cellular ROS expression levels （P<0.01）， downregulated M1-type macrophages iNOS and TNF-α protein expression （P<0.01）， upregulated M2-type macrophages Arg-1 and IL-10 protein expression （P<0.01）， and lowered protein expression levels of TLR4， MyD88， p-IκB/IκB， p-NF-κB p65/NF-κB p65， NLRP3， ASC， and pro-Caspase-1 （P<0.05， P<0.01）. ConclusionBuyang Huanwutang can improve macrophage inflammation， potentially by reducing macrophage ROS levels， inhibiting RAW264.7 macrophage polarization， and downregulating the protein expression levels of the TLR4/NF-κB/NLRP3 pathway.

Progress of Research on Tumor Extracellular Matrix and Discoidin Domain Receptor 1 / 肿瘤防治研究

Tumor extracellular matrix (ECM) is the center component of tumor microenvironment (TME), ECM diversity constitutes the inherent heterogeneity of TME that contributes to tumor growth, dormancy, drug resistance, and metastasis. Discoidin domain receptor 1 is one of the ECM receptors that interact with multiple ECM ligands. It also regulates the occurrence and development of tumors. Accordingly, DDR1 plays an increasingly important role in the prevention, diagnosis, and treatment of cancer. In this review, we primarily summarize the research of ECM and its receptors with components, regulation, cell receptors, and signaling pathways in tumor progression.

Is the myonuclear domain ceiling hypothesis dead?

Muscle fibres are multinuclear cells, and the cytoplasmic territory where a single myonucleus controls transcriptional activity is called the myonuclear domain (MND). MND size shows flexibility during muscle hypertrophy. The MND ceiling hypothesis states that hypertrophy results in the expansion of MND size to an upper limit or MND ceiling, beyond which additional myonuclei via activation of satellite cells are required to support further growth. However, the debate about the MND ceiling hypothesis is far from settled, and various studies show conflicting results about the existence or otherwise of MND ceiling in hypertrophy. The aim of this review is to summarise the literature about the MND ceiling in various settings of hypertrophy and discuss the possible factors contributing to a discrepancy in the literature. We conclude by describing the physiological and clinical significance of the MND ceiling limit in the muscle adaptation process in various physiological and pathological conditions.

Influence of selection of domain shape on parameters of microdosimetric kinetic model / 中华放射医学与防护杂志

Objective:To calculate the single-event dose-averaged specific energy of particles delivered in spherical domains based on the track structure model and using triple integration, and to investigate the influence of the domain shape on the key model parameters of microdosimetric kinetic model (MKM) and its corresponding physical significance.Methods:The domains are assumed to be cylinders and spheres, respectively. With α 0, domain radius, rd, and nucleus radius, Rn, as undetermined coefficients, the nuclear charge numbers, kinetic energies and their corresponding LETs of three kinds of charged particles ( 3He, 12C, 20Ne) as independent variables, D10 as dependent variable, the mean value of squared residuals, J2, between the D10 calculated values and D10 experimental values as the optimization objective, the final fitting values of the above undetermined coefficients of human salivary gland (HSG) cells and Chinese hamster lung (V79) cells obtained after iteration by the robust least square method are the optimal model parameter values of MKM. Results:For HSG cells, cylindrical domain: α 0=0.073/Gy, rd=0.29 μm, Rn=4.1 μm, J2=0.039 7 Gy 2; spherical domain: α 0=0.023/Gy, rd=0.29 μm, Rn=4.4 μm, J2=0.039 3 Gy 2; For V79 cells, cylindrical domain: α 0=0.114/Gy, rd=0.25 μm, Rn=3.8 μm, J2=0.097 4 Gy 2; spherical domain: α 0=0.095/Gy, rd=0.26 μm, Rn=4.1 μm, J2=0.096 9 Gy 2. Conclusions:For the same type of cells, cylindrical and spherical domains were selected respectively, and there are significant differences in MKM parameters obtained by fitting. The fitting values of the domain radius, rd of the two shapes of domains show no significant difference, while the fitting values of α0 of spherical domains are smaller than those of cylindrical domains, the fitting values of nucleus radius, Rn, of spherical domain are larger than those of cylindrical domains, closer to the nucleus radius observed by fluorescence microscopy. In the low LET (<20 keV/μm) region, D10 calculated according to the parameters of the two different shapes of domains are different, so the selection of the domain shape will cause differences in the relative biological effectiveness(RBE) calculation of proton in the region near Bragg peak.

The role of NLRP3/GATA-4/VEGF signal pathway in neovascular age-related macular degeneration / 中国医师杂志

Objective:To explore the potential role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/GATA-binding protein 4 (GATA-4)/vascular endothelial growth factor (VEGF) signal pathway in neovascular age-related macular degeneration (nAMD).Methods:We applied the TRANSFAC Public database to search the human and mouse VEGF promoters and upstream transcription factors, analyzed the transcription factors that may influence the transcriptional activity of VEGF. The RAW264.7 cells were divided into control group and lipopolysaccharide (LPS) stimulated group (LPS group). Real time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the activation of NLRP3 inflammasome, and the mRNA levels of GATA-4 and VEGFA. Thus, we applied the specific small molecular NLRP3 inhibitor MCC950 pretreated RAW264.7 cells (LPS+ MCC950 group), and detected the gene expression of NLRP3, Caspase-1, interleukin 1β( IL-1β), GATA-4 and VEGFA.Results:There were multiple GATA transcription factor binding sites upstream of human and mouse VEGF promoters. Compared with the control group, mRNA expression of NLRP3, Caspase-1, IL-1β, GATA-4 and VEGFA in LPS group were increased (all P<0.05). Compared with LPS group, mRNA expression of NLRP3, Caspase-1, IL-1β, GATA-4 and VEGFA in LPS+ MCC950 group were significantly decreased (all P<0.05). Conclusions:NLRP3/GATA-4/VEGF signal pathway may play a significant role in the pathologic processes of nAMD.

Genetic inhibition of MLKL exerts protective effects against cognitive impairment and neuroinflammation in a cerebral small vessel disease model / 中国药理学与毒理学杂志

OBJECTIVE To identify the role of mixed lineage kinase domain like protein(MLKL)in cerebral small vessel disease(CSVD)and explore the underlying mechanism.METHODS Transient bilateral common carotid artery occlusion(tBCCAO)was used to establish a mouse model of CSVD.Immunofluorescence staining and Western blotting were used to observe the expres-sions of RIPK3/MLKL signaling molecules in brain tissues at 7,14 and 28 d after tBCCAO.Open field test,rotarod test,Y-maze and novel object recognition test were used to observe the effect of MLKL knockout on cognitive func-tion after tBCCAO.Blood-brain barrier(BBB)disruption was observed by sodium fluorescein permeability test and the expressions of tight junction proteins.Immunoflu-orescence staining and Western blotting were used to detect the expression of microglia marker Iba-1,astro-cyte marker GFAP,and NLRP3/Caspase-1 signaling mol-ecules in the hippocampus of CSVD mice.ELISA was used to detect the level of inflammatory factors(TNF-α,IL-1β,IL-18)in hippocampus.RESULTS The expres-sions of RIPK3/MLKL signaling molecules increased in cortex and hippocampus after tBCCAO,especially on day 14.The expression of pMLKL mainly increased in neurons,glia cells and endothelial cells in CSVD mice.MLKL knockout improved the cognitive functions such as motor learning,spatial learning and working memory,and object recognition ability in CSVD mice.MLKL knock-out alleviated the leakage of sodium fluorescein and attenuated the down-regulation of tight junction proteins at 1 d and 14 d after tBCCAO.At 14 d after tBCCAO,MLKL knock out inhibited the activations of microglia and astrocytes,attenuated the expressions of NLRP3/cas-pase-1 molecules,and decreased the levels of inflamma-tory factors in the hippocampus of mice.CONCLUSION Genetic inhibition of MLKL exerts protective effects against cognitive impairment by ameliorating BBB dam-age and neuroinflammation in a mouse cerebral small vessel disease model.

Role of P2X7/NLRP3 inflammasome pathway in cognitive impairment in sleep deprived mice / 中华行为医学与脑科学杂志

Objective:To investigate the possible role and mechanism of purinergic ligand-gated ion channel 7(P2X7)/nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3) inflammasome pathway in cognitive impairment induced by sleep deprivation (SD)mice.Methods:SPF grade male C57BL / 6J mice aged 6-8 weeks were randomly divided into 3 groups according to the random number table method with 6 mice in each group.They were normal control group (CC group), SD group and SD+ P2X7 receptor antagonist brilliant blue G(BBG) group (SD+ BBG group). Modified multiple platform method was used to establish a 5-day SD model in mice.During the SD intervention period, the mice in SD+ BBG group were injected with BBG(50 mg/kg) intraperitoneally once a day, while the mice in CC group and SD group were injected with the same volume of 0.9% sodium chloride solution.Morris water maze was conducted to evaluate the cognitive function of mice.The protein expression levels of P2X7, NLRP3, caspase-1, apoptosis-associated proteins(ASC) and interleukin-1β(IL-1β) in hippocampus were detected by Western blot.RT-qPCR was used to detect the mRNA expression levels of tumor necrosis factor-α(TNF-α), IL-1β, interleukin-18(IL-18) and microglial polarization surface markers CD206 and CD86 in hippocampus.Graph pad Prism 8.0 software and SPSS 25.0 software were used for statistical analysis and mapping.Results:(1) The interaction effect between time and groups of escape latency in three groups of mice was significant ( F=15.76, P<0.001). From the 2nd to 5th day, the escape latencies of mice in SD group were higher than those of CC group, while the escape latencies of mice in SD+ BBG group were lower than those of SD group (all P<0.05). (2)The results of the space exploration experiment showed that there were statistically significant differences in target quadrant residence time and the times of crossing the platform( F=6.65, P=0.009; F=12.39, P<0.001). The target quadrant residence time ((23.42±0.55) s) and times of crossing the platform ((17.67±0.71) times) of the SD group were both lower than those of the CC group ((29.48±1.78) s, (23.33±0.95) times) (both P<0.05), while the target quadrant residence time ((28.62±1.19) s) and the times of crossing the platforms ((21.33±0.76) times) of the SD+ BBG group were both higher than those of the SD group (both P<0.05). (3)There were statistically significant differences in the protein levels of inflammatory related proteins such as P2X7, NLRP3, caspase-1, ASC and IL-1β in the hippocampus of mice among the 3 groups( F=8.23, 8.97, 8.45, 54.42, 8.12, all P<0.05). Compared with CC group, the protein levels of P2X7 ((0.93±0.02), (0.71±0.04)), NLRP3 ((0.97±0.04), (0.62±0.09)), caspase-1 ((1.00±0.03), (0.76±0.07)), ASC ((0.96±0.02), (0.77±0.04)) and IL-1β ((0.85±0.07), (0.54±0.04)) in SD group were all higher (all P<0.05). Compared with SD group, the protein levels of P2X7 (0.74±0.05), NLRP3 (0.78±0.02), caspase-1 (0.74±0.04), ASC (0.67±0.02), IL-1β (0.53±0.07) in SD+ BBG group were all lower (all P<0.05). (4)There were statistically significant differences in the mRNA levels of IL-18, IL-1β, TNF-α, CD86 and CD206 in hippocampus among the three groups ( F=12.80, 12.28, 105.80, 7.06, 30.19, all P<0.05). The mRNA levels of IL-18, IL-1β, TNF-α, CD86 in SD group were all higher than those in CC group(all P<0.05), while the mRNA level of CD206 in SD group was lower than that in CC group( P<0.05). Compared with SD group, the mRNA levels of IL-18, IL-1β, TNF-α, CD86 were lower in SD+ BBG group (all P<0.05), while the CD206 mRNA level of SD+ BBG group was higher than that in SD group( P<0.05). Conclusion:SD intervention can lead to cognitive impairment and increased expression of P2X7 in hippocampus of mice, which may be related to the activation of P2X7/ NLRP3 inflammasome signaling pathway, promoting the polarization of microglia into pro-inflammatory type and up-regulating the expression of pro-inflammatory cytokines.Inhibition of P2X7 can improve the cognitive function of mice.

The curative effect and mechanism of magnetic hyperthermia in the treatment of knee osteoarthritis / 西安交通大学学报(医学版)

【Objective】 We combined the concept of traditional medicine with magnetic induction technology, originally brought up the research concept of magnetic hyperthermia to cure KOA, explored the mechanism and constructed a new treatment of KOA with modern medical features. 【Methods】 Through establishing a primary KOA model in rats and constructing ferrimagnetic vortex domain iron oxide nanorings (FVIOs) as a platform for highly efficient magnetic hyperthermia agent, the lesions of KOA were heated accurately under the low-intensity magnetic field. We confirmed the curative effect through the results of pain perception, histopathology, knee joint morphology and microscopic bone structure and the content of serum inflammatory factor, to study the therapeutic mechanism of magnetic hyperthermia for KOA. 【Results】 Compared with the model group, the recovery of mechanical pain threshold after magnetic hyperthermia improved by approximately 48.9%; the degree of hyperemia and edema of joint capsule and synovial tissue and the wear degree of joint cartilage surface, were significantly reduced; the Mankin and OARSI scores decreased by about 33% and 20%, respectively; the MicroCT results indicated that the degree of hardening of the subchondral bone also improved; the expression of inflammatory factors in the serum was reduced. 【Conclusion】 In this study, we utilized the FVIOs as a high-efficiency magnetic hyperthermia platform for the treatment of KOA. The efficacy of magnetic hyperthermia on KOA is clarified, and the mechanism is related to the inhibition of inflammatory factors.