Bax inhibitor 1 inhibits vascular calcification in mice by activating optic atrophy 1 expression / 南方医科大学学报

OBJECTIVE@#To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC).@*METHODS@#Mouse models of VC were established in ApoE-deficient (ApoE-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with Nε-carboxymethyl-lysine for 16 weeks. ApoE-/- mice (control group), ApoE-/- diabetic mice (VC group), ApoE-/- diabetic mice with BI-1 overexpression (VC + BI-1TG group), and ApoE-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1TG+OPA1-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining.@*RESULTS@#ApoE-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007).@*CONCLUSION@#BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells.

FOXC2-AS1 regulates phenotypic transition, proliferation and migration of human great saphenous vein smooth muscle cells

OBJECTIVES: In varicose veins, vascular smooth muscle cells (VSMCs) often shows phenotypic transition and abnormal proliferation and migration. Evidence suggests the FOXC2-Notch pathway may be involved in the pathogenesis of varicose veins. Here, this study aimed to explore the role of long non-coding RNA FOXC2-AS1 (FOXC2 antisense RNA 1) in phenotypic transition, proliferation, and migration of varicose vein-derived VSMCs and to explore whether the FOXC2-Notch pathway was involved in this process. METHODS: The effect of FOXC2-AS1 on the proliferation and migration of human great saphenous vein smooth muscle cells (SV-SMCs) was analyzed using MTT assay and Transwell migration assay, respectively. The levels of contractile marker SM22α and synthetic marker osteopontin were measured by immunohistochemistry and Western blot to assess the phenotypic transition. RESULTS: The human varicose veins showed thickened intima, media and adventitia layers, increased synthetic VSMCs, as well as upregulated FOXC2-AS1 and FOXC2 expression. In vitro assays showed that FOXC2-AS1 overexpression promoted phenotypic transition, proliferation, and migration of SV-SMCs. However, the effect of FOXC2-AS1 overexpression could be abrogated by both FOXC2 silencing and the Notch signaling inhibitor FLI-06. Furthermore, FOXC2-AS1 overexpression activated the Notch pathway by upregulating FOXC2. CONCLUSION: FOXC2-AS1 overexpression promotes phenotypic transition, proliferation, and migration of SV-SMCs, at least partially, by activating the FOXC2-Notch pathway.

Economic evaluation in the context of rare diseases: is it possible? / Evaluación económica en el contexto de enfermedades raras: ¿es posible? / Avaliação econômica no âmbito das doenças raras: isto é possível?

This study analyzes the available evidence on the adequacy of economic evaluation for decision-making on the incorporation or exclusion of technologies for rare diseases. The authors conducted a structured literature review in MEDLINE via PubMed, CRD, LILACS, SciELO, and Google Scholar (gray literature). Economic evaluation studies had their origins in Welfare Economics, in which individuals maximize their utilities based on allocative efficiency. There is no widely accepted criterion in the literature to weigh the expected utilities, in the sense of assigning more weight to individuals with greater health needs. Thus, economic evaluation studies do not usually weigh utilities asymmetrically (that is, everyone is treated equally, which in Brazil is also a Constitutional principle). Healthcare systems have ratified the use of economic evaluation as the main tool to assist decision-making. However, this approach does not rule out the use of other methodologies to complement cost-effectiveness studies, such as Person Trade-Off and Rule of Rescue.

El objetivo fue sistematizar las evidencias disponibles sobre la pertinencia de utilizar la evaluación económica para la incorporación/exclusión de tecnología en enfermedades raras. Se realizó una revisión sistemática de la literatura en MEDLINE vía PubMed, CRD, LILACS, SciELO y Google Académico (literatura gris). Los estudios de evaluación económica se originan de la Economía del Bienestar, en la que los individuos maximizan sus utilidades, basándose en la eficiencia de asignación. No existe un criterio ampliamente aceptado para examinar las utilidades, a fin de dar más peso a los individuos con mayores necesidades. Generalmente, los estudios no equilibran asimétricamente las utilidades, todas son consideradas iguales, lo que en Brasil es también un principio constitucional. Los sistemas de salud han ratificado el uso de la evaluación económica como la principal herramienta para ayudar en la toma de decisiones. Sin embargo, este abordaje no excluye el uso de otras metodologías complementarias a los estudios de coste-efectividad, como la técnica de compensación personal o la regla del rescate.

O objetivo deste estudo foi analisar as evidências disponíveis sobre a adequação do uso de avaliação econômica sobre incorporação/exclusão de tecnologias para doenças raras. Foi realizada uma revisão estruturada da literatura, nas bases MEDLINE, via PubMed, CRD, LILACS, SciELO e Google Acadêmico (literatura cinzenta). Os estudos de avaliação econômica têm origem na Economia do Bem-Estar, na qual os indivíduos maximizam suas utilidades, fundamentando-se na eficiência alocativa. Não há um critério amplamente aceito para ponderar as utilidades esperadas, no sentido de dar mais peso aos indivíduos com maiores necessidades em saúde. Geralmente não se ponderam assimetricamente as utilidades; todas são tratadas de forma igualitária, que, no caso brasileiro, também é um princípio constitucional. Os sistemas de saúde têm ratificado o uso de avaliação econômica como principal instrumento para auxiliar na tomada de decisão. No entanto, essa postura não exclui o uso de outras metodologias complementares aos estudos de custo-efetividade, como Person Trade-Off e regra de resgate.

The Juscelino Kubitschek government and the Brazilian Malaria Control and Eradication Working Group: collaboration and conflicts in Brazilian and international health agenda, 1958-1961 / O governo JK e o Grupo de Trabalho de Controle e Erradicação da Malária no Brasil: encontros e desencontros nas agendas brasileira e internacional de saúde, 1958-1961

Malaria, a disease which was under control in the beginning of Juscelino Kubitschek government, became the most important endemic disease in 1958, when Brazil made a commitment with the World Health Organization to convert its control programs into eradication programs. For this purpose a Malaria Control and Eradication Group was set up under the leadership of the malaria specialist Mário Pinotti. Malaria would become an important bargaining chip in the context of the development policies of Kubitschek. This article focuses on path of the Malaria Control and Eradication Working Group in Brazil, in its varying relationships with the arguments and guidelines established at international level.

A malária, doença que estava controlada no início do governo de Juscelino Kubitschek, torna-se a mais importante endemia em 1958, quando o Brasil assumiu o compromisso com a Organização Mundial da Saúde de converter seus programas de controle em programas de erradicação. Para isso foi instalado um Grupo de Controle e Erradicação da Malária sob a direção do malariologista Mário Pinotti. A malária seria uma importante moeda de negociação no contexto da política de desenvolvimento de Kubitschek. Este artigo tem como foco a trajetória do Grupo de Trabalho de Controle e Erradicação da Malária no Brasil, em suas diferentes relações com as discussões e normativas travadas e estabelecidas em âmbito internacional.

Sinusoidal Constriction and Vascular Hypertrophy in the Diabetes-Induced Rabbit Penis

Objective To assess the morphological changes of penile vascular structures and the corpus cavernosum area in alloxan-induced diabetic rabbits. Materials and Methods Twenty male rabbits (2 months old) were divided into two groups with 10 rabbits each, the control group (CG) and the diabetic group (DG). The animals from DG received an intravenous injection of alloxan (100mg/kg) to induce the diabetes. Ten weeks after the induction of diabetes, all animals were euthanized. Two fragments of the penile shaft were harvested and samples were processed and paraffin embedded. Sections (5µm) were cut and stained for histological and immunohistochemical markers. Results Nuclear protrusion toward the lumen, and cytoplasmic vacuolization were observed in the tunica intima of the dorsal artery of the penis in DG. The thicknesses of the tunica media increased significantly in DG (p = 0.0350). It was also observed a significant increase in the area of the tunica media (p = 0.0179). There was no significant change in smooth muscle cell density in the tunica media of the dorsal artery of the penis (p = 0.0855). The collagen fiber pattern of the tunica adventitia of the dorsal artery of the penis was different between the control and diabetic groups. There was a significant decrease in the area occupied by the cavernous sinuses in DG (p = 0.0013). Conclusion Alloxan-induced diabetes mellitus in rabbits promotes important changes in penile vascular structures, thereby decreasing blood supply and affecting penile hemodynamics, leading to erectile dysfunction. .

Structural analysis of testicular appendices in patients with cryptorchidism

Objectives Report the incidence and structure of testicular appendices (TAs) in patients with cryptorchidism, comparing their incidence with epididymal anomalies (EA) and patency of the vaginal process (PVP) and analyzes the structure of TAs. Material and Methods We studied 72 testes of patients with cryptorchidism (average of 6 years), and 8 testes from patients with hydroceles (average of 9 years). We analyzed the relations among the testis, epididymis and PVP and prevalence and histology of the TAs. The appendices of 10 patients with cryptorchidism and 8 with hydrocele were dissected and embedded in paraffin and stained with Masson trichrome; Weigert and Picro-Sirius Red with polarization and immunohistochemistry analysis of the collagen type III fibers to observe collagen. The stereological analysis was done with the software Image Pro and Image J, using a grid to determine volumetric densities (Vv). Means were statistically compared using the ANOVA and unpaired T test (p < 0.05). Results Of the 72 testes with cryptorchidism, 20 (27.77%) presented EA, 41 (56.9%) had PVP and 44 (61.1%) had TAs. Of the 44 testes with cryptorchidism and appendices, 30 (68.18%) presented PVP and 11 (25%) presented EA. There was no alteration of the epithelium in the appendices of patients in both groups. Stereological analysis documented the prevalence of ESFs (mean of 1.48%), prevalence of veins (mean of 10.11%) and decrease (p = 0.14) of SMCs in the TAs of patients with cryptorchidism (mean = 4.93%). Collagen III prevailed in the TAs of patients with cryptorchidism. Conclusion The testicular appendices presented significant structural alteration in the patients with cryptorchidism, indicating that TAs present a structural remodeling. .

Asthma: where is it going?: [review]

Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although our understanding of its pathophysiological mechanisms continues to evolve, the relative contributions of airway hyperresponsiveness and inflammation are still debated. The first mechanism identified as important for asthma was bronchial hyperresponsiveness. In a second step, asthma was recognized also as an inflammatory disease, with chronic inflammation inducing structural changes or remodeling. However, persistence of airway dysfunction despite inflammatory control is observed in chronic severe asthma of both adults and children. More recently, a potential role for epithelial-mesenchymal communication or transition is emerging, with epithelial injury often resulting in a self-sustaining phenotype of wound repair modulation by activation/reactivation of the epithelial-mesenchymal trophic unit, suggesting that chronic asthma can be more than an inflammatory disease. It is noteworthy that the gene-environmental interactions critical for the development of a full asthma phenotype involve processes similar to those occurring in branching morphogenesis. In addition, a central role for airway smooth muscle in the pathogenesis of the disease has been explored, highlighting its secretory function as well as different intrinsic properties compared to normal subjects. These new concepts can potentially shed light on the mechanisms underlying some asthma phenotypes and improve our understanding of the disease in terms of the therapeutic strategies to be applied. How we understand asthma and its mechanisms along time will be the focus of this overview.

The role of endogenous carbon monoxide in the hypoxic vascular remodeling of rat model of hypoxic pulmonary hypertension / 华中科技大学学报（医学）（英德文版）

We investigated the expression of heme oxygenase-1 (HO-1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin on the expression of HO-1 gene and pulmonary hypertension. A rat model of hypoxic pulmonary hypertension was recreated by exposure to intermittent normobaric hypoxic environment (10% O2). Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the level of HO-1 mRNA in the rat lung tissue and double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood. Cardiac catheterization was employed to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathological changes of the intra-acinar pulmonary arteries (IAPA). It was found that (1) There was a low level of HO-1 mRNA in normal rat lung tissue, but the level of HO-1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats (P<0.01). The quantity of COHb was 2-3 times those of control group (P<0.01 or P<0.05). These were accompanied by the increased of RVSP and the thickened IAPA; (2) Hemin could keep the HO-1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, thereby ameliorating the pathological changes of IAPA. In conclusion, the upregulation of the expression of HO-1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.