Efficacy of nutrition therapy with food rich in methionine for treating nonalcoholic fatty liver / Eficacia de la terapia nutricional con alimentos ricos en metionina para el tratamiento de hígado graso no alcohólico

Non-Alcoholic Fatty Liver disease (NAFLD) can lead to Non Alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The treatment for NAFLD involves modification of caloric intake and physical activity. NAFLD has a pro-oxidant nature; therefore, it is logical to suppose that the antioxidant methionine can be used as a treatment for this disease. Aim. This study aimed to evaluate the effect of high-methionine dietary therapy on patients with NAFLD. Materials and methods. A randomized clinical study was conducted over three months. In this study, 121 NAFLD patients participated, and the age of the participants was ≥ 20 years (experimental group included 56 and control group 65), all of whom were randomized and matched by sex, recluted from the ISSSTE hospital in Xalapa, Mexico. The patients were instructed to consume food to cover the recommended methionine daily doses, and the daily amount consumed was calculated. Methionine effect was measured as NAFLD regression and quality of life improvement. Results. Nutritional therapy induced NAFLD regression and diminished central fat accumulation, blood pressure, and the fatty liver index. Some parameters, such as liver enzymes, did not changed. The quality of life of patients improved after treatment. Conclusions. In this study, we show a hepatoprotective effect induced only in three months of chances in the diet, thus, a longer diet may generate more relevant benefits in the resistant parameters of our study(AU)

La enfermedad del hígado graso no alcohólico (NAFLD) puede conducir a la esteatohepatitis no alcohólica (NASH), la cirrosis y el cáncer de hígado. El tratamiento para NAFLD es la modificación de la ingesta calórica y la actividad física. Debido a que NAFLD tiene una naturaleza pro-oxidante; es lógico suponer que el antioxidante metionina puede utilizarse en el tratamiento de esta enfermedad. Objetivo. el presente trabajo evaluó el papel de la terapia nutricional con alimentos ricos en metioninaen pacientes con NAFLD. Materiales y Métodos. Se realizó un ensayo clínico aleatorizado durante tres meses. Participaron en el estudio 121 pacientes con NAFLD con edad ≥ 20 años (56 en el grupo experimental y 65 en el control), todos aleatorizados y pareados por sexo, reclutados de la Clínica Hospital ISSTE en la ciudad de Xalapa, México, en el año 2015. Se instruyó a los pacientes en consumir los alimentos hasta completar la dosis diaria recomendada de metioninay se calculó la cantidad diaria consumida. Su efecto se midió como la regresión de NAFLD y la mejora de la calidad de vida. Resultados. La terapia nutricional retrocedió NAFLD; disminuyó la acumulación de grasa central, la presión arterial y el índice de hígado graso. Algunos parámetros, como las enzimas de la función hepática, no se modificaron con el tratamiento. Otro parámetro fue la mejora de la calidad de vida de los pacientes tratados. Conclusiones. En este trabajo mostramos un impacto hepatoprotector producido con tan solo tres meses de cambios en la dieta, por lo que una dieta más prolongada podría generar beneficios aún más significativos en los parámetros resistentes en nuestro protocolo(AU)

Sex Reversal Syndrome (SRS): A case of SRY-Positive 46,XX Testicular Disorder / Journal of the ASEAN Federation of Endocrine Societies

@#We report a case of an SRY-positive 46,XX Indian male who presented with small testis and phallus, poor beard and mustache development and gynecomastia at the age of 24 years. He was biochemically found to have hypergonadotropic hypogonadism. He had 46,XX karyotype and Quantitative Fluorescence-PCR (QF-PCR) identified the SRY gene on the X chromosome. SRY-positive 46 XX male SRS cases usually present as phenotypically male since birth but develop features of hypogonadism, poor testicular development, and infertility after puberty. Infertility, hypogonadism, external genital development, and psychological distress are the major concerns during the management of the patients. Testosterone therapy for hypogonadism, artificial reproductive technologies for fertility, surgical repair of hypospadias/cryptorchidism/under-virilized genitalia and psychological and genetic counseling are helpful for proper management of the patients.

Natural reversal of mandibular condylar cartilage histological damage caused by chronic unpredictable moderate stress in rats / 口腔疾病防治

Objective @#To investigate the histological damage recovery of temporomandibular joint condylar cartilage caused by chronic unpredictable moderate stress, aiming to provide an experimental basis for the prevention and treatment of temporomandibular disorder.@*Methods @#This animal experiment was approved by the Laboratory Animal Ethical Inspection, School of Stomatology, The Fourth Military Medical University (No. 2020081). 60 male SD rats were randomly divided into control group, stress group, and 2-, 4- and 8-week post-stress recovery groups. Rats were subjected to chronic unpredictable moderate stress (CUMS) for 8 weeks including damp sawdust for 24 hours, tilted cage for 12 hours, noise for 4 hours, light/dark cycle reversal, water immersion, tail clamp, and restraint stress. The serum assessment, behavioral tests, histological and ultrastructural observation were performed 2-, 4- and 8-weeks after stress factors were removed. Serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were determined with ELISA. The sucrose preference test (SPT) and the forced swim test (FST) were used to assess the depressive-like behavior. The expression level of interleukin-1α (IL-1α) and matrix metalloproteinases-3 (MMP-3) were determined by Immunohistochemistry and Western blot.@*Results @#At the end of 8 weeks of CUMS, the serum levels of CORT and ACTH were significantly higher in stress group compared with control group (P<0.01). The sucrose preference decreased significantly and the immobility time increased significantly in the stressed rats compared with those in the control group, indicating a successful establishment of CUMS. The condylar cartilage showed significant degenerative changes, with disorganized collagen fibers and reduced proteoglycan synthesis on the cartilage surface. IL-1α and MMP-3 were expressed in the intracellular and extracellular matrix of the condylar cartilage, and their expression levels were increased (P<0.01). After 2 weeks of stress removal, the serum levels of CORT and ACTH were decreased but higher than control group (P<0.01), and behavioral changes were still different from the control group (P<0.01); the loosened collagen fibers could still be seen on the surface of condylar cartilage, and some free cell areas were visible within the proliferative layer; additionally, IL-1α and MMP-3 expression in the condyle was reduced in all layers of cartilage when compared with the stress group, but was still higher than in the control group (P<0.01). After 4 weeks of stress removal, the serum levels of CORT and ACTH changes returned to normal levels and behavioral changes were still different from control group (P<0.05); a few collagen fibers could be seen on the surface of the condylar cartilage and the expressions of IL-1α and MMP-3 decreased significantly compared with the stress group (P<0.01), with the similar level of IL-1α (P>0.05) and higher expression of MMP-3 comparing with the control group (P<0.01). After 8 weeks of stress removal, behavioral changes returned to normal levels, with no statistically significant differences compared with the control group (P>0.05). The condylar collagen fibers increased and showed a corrugated pattern, and no serious subchondral bone damage as well as irreversible damage occurred. Both of the expression levels of IL-1α and MMP-3 approached those of the control group after 8 weeks of stress removal (P>0.05). @*Conclusion@# The behavioral changes and condylar cartilage damage caused by CUMS could be self-repaired. The decline in IL-1α and MMP-3 expression may be one of the intrinsic mechanisms of this self-repair process.

Application of Laparoscopic Surgery in Ileostomy Reversal / 肿瘤防治研究

In colorectal cancer surgery, loop ileostomy is sometimes necessary to prevent anastomotic leakage. Although ileostomy reversal is relatively simple, postoperative complication is inevitable. In recent years, laparoscopic surgery has been gradually applied in ileostomy reversal due to its small trauma, fast recovery, and low complications, exhibiting satisfactory short-term outcomes. This review analyzes the application of the laparoscopic technique in ileostomy surgery and explores the potential of total laparoscopic surgery, aiming to provide a new perspective for the clinical application of laparoscopic ileostomy reversal.

Histopathological evaluation of cirrhosis reversal / 中华肝脏病杂志

A normal liver can develop cirrhosis through long-term and repeated stimulation from various etiologies. Histological manifestations like the collapse of hepatic lobular structure (including microvascular structure) and the formation of pseudolobules can lead to portal hypertension and even decompensated cirrhosis. More and more evidence suggests that effective etiological treatment can not only delay but also reverse the progression of cirrhosis. The mechanism of cirrhosis reversal mainly includes the degradation of extracellular matrix, hepatocyte regeneration, and hepatic lobular remodeling. The "gold standard" for the evaluation of cirrhosis reversal at present is still a liver biopsy. Therefore, the histopathological evaluation of cirrhosis reversal is very important for determining the disease's prognosis, efficacy, and mechanism of exploration.

Research progress on cirrhosis reversal and recompensation / 中华肝脏病杂志

Previously, liver lesions in cirrhosis were considered irreversible, especially because the condition aggravated gradually after entering the decompensated phase, thus making it difficult to return to the compensated phase. At present, more and more evidence shows that some patients with decompensated liver cirrhosis can be recompensated after the cause is controlled and complications are managed. This article explores the research progress related to LC reversal and recompensation from three aspects: liver histopathology, liver function, and clinical complications.

Vasectomy reversal in China during the recent decade: insights from a multicenter retrospective investigation / 亚洲男科学杂志(英文版)

To date, there is little information about the demography of vasectomy reversal (VR) patients or the factors currently influencing VR effectiveness in China, especially after the universal two-child policy was released in 2015. In this research, demographic data and perioperative medical records of VR patients were extracted from seven major hospitals in different provinces or municipalities of China. Meanwhile, a telephone survey of the patients was conducted to collect follow-up information. Eventually, 448 VR cases from the past 13 years were included. The results were analyzed by stratified comparison to investigate factors that can influence postoperative vas deferens patency and pregnancy rate. Appropriately statistical methods were used, and all of the protocols were approved by the Ethics Committees of the institutes in this research. The results showed that the annual operation volume of VR quadrupled after the two-child policy was implemented. Nonmicrosurgery and a long duration of vasectomy were significantly associated with a lower patency rate. A follow-up survey showed that the general postoperative pregnancy rate was 27.2%. For female partners over the age of 35 years, the postoperative pregnancy rate showed a more severe decline, but only 35.5% of them had been given a fertility examination before their husbands' VR surgery. Our work revealed that more patients in China have been demanding VR in recent years. High-quality microsurgery and a short duration of vasectomy are crucial for restoring patency by VR. Clinical andrologists should perform a preoperative fertility evaluation of the patients' female partners.

Pais e filhos: uma rua de mão dupla / Parents and children: a two-way street / Padres e hijos: una calle de dos sentidos

Neste artigo são discutidos alguns aspectos da relação pais-filhos, focados na importância do filho no desenvolvimento dos pais. A relação filho-adulto e pais é abordada tanto em seu sentido criativo como complicado, gerador de patologia. A relação filhos-pais é associada a outra mão da mesma rua onde a psicologia bastante tem discutido a relação pais-filhos. Daí o título: "Pais e filhos: uma rua de mão dupla". A compreensão simbólica do ditado popular "filho criado, trabalho dobrado" é buscada. Esse "maior trabalho" dado pelo "filho criado" é associado ao trabalhoso processo de recolhimento necessário que os pais precisam fazer da depositação-projeção dos papéis parentais arquetípicos de filho, Fm e Fp, sobre os filhos. Também são discutidos a função da idealização cruzada e o consequente jogo de poder cruzado entre filhos e pais. Algumas complicações desse processo de retirada das depositações-projeções pelos pais sobre os filhos são enfocadas pela sua importância clínica, a saber: os riscos dos avós, o risco da inversão de papéis entre pais e filhos e a adolescência tardia. É chamada a atenção para a importância do tema, uma vez que, com o aumento da vida média, a população com mais idade cresceu e sua problemática precisa ser mais bem compreendida.

The author discusses some aspects of parents-children relationship, the so called "double way street". She emphasizes the importance of this theme because psychology has discussed enough parents-children relationship but children-parents relationship has been put aside. Archetypal parental-roles and crossed projections between children and parents are discussed as being an important aspect of the complexity of this issue, due to their clinical importance. Some process disorders are focused like: grand-parents' risks, archetypal parental roles inversion between parents and children and tardy adolescence. The symbolic understanding of the popular saying "Raised children, hell breaks lose" is sought in this article. The troubles with the "raised child" is linked to the painful process parents have to go through with projection archetypal parental roles of the child, Cm Cf over the children.

En este artículo se discuten algunos aspectos de la relación padre-hijo, enfocándose en la importancia del niño en el desarrollo de los padres. Se aborda la relación hijo-adulto y padres tanto en su sentido creativo como en su sentido complicado, generador de patologías. La relación padre-hijo está asociada con otra mano en la misma calle donde la psicología ha discutido durante mucho tiempo la relación padre-hijo. De ahí el título: "Padres e hijos: una calle de dos sentidos". Se busca la comprensión simbólica del dicho popular "hijo criado, trabajo duplicado". Este "trabajo mayor" dado por el "hijo criado" está asociado al laborioso proceso de recolección necesaria que los padres deben hacer a partir del depositación-proyección de los roles parentales arquetípicos del hijo, Hm e Hp (hijo de la madre e hijo del padre), en sus hijos. También se discute el papel de la idealización cruzada y el juego de poder cruzado resultante entre hijos y padres. Se destacan, por su importancia clínica, algunas complicaciones de este proceso de eliminación de depositaciones-proyecciones de los padres sobre sus hijos, a saber: los riesgos de los abuelos, el riesgo de inversión de roles entre padres e hijos y la adolescencia tardía. Se llama la atención sobre la importancia del tema, ya que, con el aumento del promedio de vida, la población de mayor edad ha crecido y es necesario comprender mejor sus problemas.

Reconstrucción poscirugía de Hartmann / Stoma reversal after the Hartmann's procedure

RESUMEN Antecedentes: la reconstrucciónn del tránsito intestinal luego de una operación de Hartmann es un procedimiento habitualmente complejo y con alta morbilidad. Objetivo: analizar la tasa de reconstrucción después de la cirugía de Hartmann y resultados posoperatorios en nuestra experiencia. Material y métodos: análisis retrospectivo de pacientes a los que se les practicó la reconstrucción del tránsito intestinal posterior a una cirugía de Hartmann en un período 16 años. Revisamos la bibliografía y nuestra base de datos. Luego traspasamos la información disponible a una grilla de datos construida con variables habitualmente analizadas en la literatura. Finalmente, analizamos los resultados mediante medidas básicas de tendencia central. Resultados: en 16 años realizamos 92 operaciones de Hartmann, de las cuales 69 (75%) llegaron a la reconstrucción. Edad promedio: 58 años. El 52% de los pacientes fueron hombres. La operación de Hartmann fue de urgencia en el 48% y 58% resultaron malignas. Tiempo transcurrido hasta la reconstrucción: en promedio, 9 meses, y el 90% (N 62) de los casos se realizó por vía laparoscópica. Morbilidad general 38% y ajustada a los grados III y IV de Clavien-Dindo fue 11,5%. No hubo mortalidad. Conclusión: los resultados obtenidos son semejantes a los publicados y nuestra experiencia nos motiva a continuar eligiendo el abordaje laparoscópico.

ABSTRACT Background: Background: Stoma reversal after Hartman's operation is usually a complex procedure and is associated high morbidity. Objective: To analyze the rate of reversal after the Hartmann's procedure and the postoperative outcomes in our experience. Material and methods: We conducted a retrospective analysis of patients undergoing reversal after the Hartmann's procedure over a 16-year period with review of the literature and of our database and transferred the available information to a data grid constructed with variables commonly analyzed in the literature. Finally, we analyzed the results using basic measures of central tendency. Results: Over a 16-year period, we performed 92 Hartmann's operations; 69 (75%) reached the reversal stage. Mean age was 58 years and 52% were men. Forty-eight percent of the Hartmann's procedures were emergency surgeries and 58% were due to cancer. Mean time to reversal was 9 months and 90% (n = 62) were laparoscopic procedures. Overall morbidity and adjusted for complications grade III and IV of the Clavien-Dindo classification were 38% and 11.5%, respectively. None of the patients died. Conclusion: The results obtained are similar to those published and our experience motivates us to continue choosing the laparoscopic approach.

Abordaje abierto versus laparoscópico para la reconstitución del tránsito luego de la cirugía de Hartmann: resultados de una experiencia de 10 años / Open versus laparoscopic approach for Hartmann's reversal: results of a 10-year retrospective cohort study

Resumen Objetivo: El objetivo de este estudio es comparar los resultados perioperatorios del abordaje abierto (AA) con el abordaje laparoscópico (AL) para la reconstitución de tránsito (RT), y determinar factores de riesgo asociados a morbilidad posoperatoria. Material y Métodos: Se estudiaron pacientes consecutivos sometidos a RT entre enero de 2007 y diciembre de 2016 en nuestro centro. Se excluyeron aquellos con grandes hernias incisionales que requirieran reparación abierta simultánea. Se consignaron variables demográficas y perioperatorias, y se compararon ambos grupos. Además, se realizó una regresión logística para la identificación de factores de riesgo asociados a morbilidad posoperatoria en la serie. Resultados: Se realizaron 101 RT en el período. Se excluyeron 14 casos por hernia incisional, por lo que se analizaron 87 casos (46 AA y 41 AL). Diez pacientes en el grupo AL (24,4%) requirieron conversión, principalmente por adherencias. La morbilidad total de la serie fue de 36,8%, siendo mayor en el AA (50% vs 21,9%, p = 0,007). Hubo una filtración anastomótica en cada grupo. La estadía posoperatoria fue de 5 (3-52) días para el AL y 7 (4-36) días para el AA (p < 0,001). En la regresión logística, sólo el AA fue un factor de riesgo independientemente asociado a morbilidad posoperatoria (OR 2,89, IC 95% 1,11-7,49; p = 0,029). Conclusión: El abordaje laparoscópico se asocia a menor morbilidad y estadía posoperatoria que el abordaje abierto para la reconstitución del tránsito pos-Hartmann. En nuestra serie, el abordaje abierto fue el único factor independientemente asociado a morbilidad posoperatoria.

Introduction: Hartmann's reversal (HR) is considered a technically demanding procedure and is associated with high morbidity rates. Aim: The aim of this study is to compare the perioperative results of the open approach (OA) with the laparoscopic approach (LA) for HR, and to determine the risk factors associated with postoperative morbidity. Material and Methods: Consecutive patients undergoing HR between January 2007 and December 2016 at a university hospital were included. Patients with large incisional hernias that required an open approach a priori were excluded from the analysis. Demographic and perioperative variables were recorded. Analytical statistics were carried out to compare both groups, and a logistic regression was performed to identify risk factors associated with postoperative morbidity in the series. Results: A hundred and one HR were performed during the study period. Fourteen cases were excluded due to large incisional hernias, so 87 cases (46 OA and 41 LA) were analyzed. Ten patients in the LA group (24.4%) required conversion, mainly due to adhesions. The total morbidity of the series was 36.8%, being higher in the OA group (50% vs. 21.9%, p = 0.007). There was one case of anastomotic leakage in each group. The length of stay was 5 (3-52) days for LA and 7 (4-36) days for OA (p < 0.001). In the logistic regression, the OA was the only independent risk factor associated with postoperative morbidity in HR (OR 2.89, IC 95% 1.11-7.49; p = 0.029). Conclusion: A laparoscopic approach is associated with less morbidity and a shorter length of stay compared to the open approach for Hartmann's reversal. An open approach was the only factor independently associated with postoperative morbidity in our series.

Mechanism of Chemotherapy Resistance of Hepatocellular Carcinoma and Intervention with Chinese Medicine： A Review / 中国实验方剂学杂志

Multidrug resistance （MDR） has been a main culprit behind the failure of chemotherapy in patients with malignant tumors and a major obstacle to improving the life quality and prolonging the survival of patients. Hepatocellular carcinoma cells， the innate drug-resistant cells， are generally insensitive to radiotherapy and chemotherapy. Moreover， as the early symptoms of hepatocellular carcinoma are atypical， most patients are diagnosed at the advanced stage， with short survival period and high recurrence rate. Thus， the sensitivity to chemotherapy drugs is decreased. This explains how MDR becomes one of the important reasons for the failure of primary hepatocellular carcinoma （PHC） treatment. Therefore， it is an urgent task to search for safe and effective chemosensitizers with little adverse effect in the research on the drug resistance of hepatocellular carcinoma. As Chinese medicine has been widely applied in the treatment of tumors， the mechanisms of compound Chinese medicine prescriptions， Chinese medicine injections， and single Chinese medicinal in reversing chemotherapy resistance in liver cancer have attracted the interest of scholars. According to previous reports， the mechanisms can be summarized as increasing intracellular drug concentration， influencing changes in enzyme activity， inducing apoptosis， reversing abnormalities in cellular signaling pathways， and regulating the tumor microenvironment. Traditional Chinese medicine reduces the chemotherapy resistance of hepatocellular carcinoma cells through multiple targets and multiple pathways， thereby improving the chemotherapy sensitivity of the cancer cells and enhancing the toxicity of chemotherapeutic drugs to hepatocellular carcinoma cells. Therefore， exploring the mechanism of MDR of hepatocellular carcinoma from the perspective of traditional Chinese medicine is important for reversing the MDR and is of great reference value for clinical treatment of hepatocellular carcinoma. However， there are few experimental types and adverse effects available. Thus， the multi-mechanism and multi-target experiments and clinical research should be carried out in the future.

Upside down words as initial clinical presentation of an underlying acute ischemic stroke

@#We report a diabetic patient who was diagnosed with an acute stroke who presented with a 3-day history of difficulty of reading, described as the words were turned upside down, as if the words were inverted horizontally with associated right homonymous hemianopia and multiple higher cortical function deficits (alexia without agraphia, achromatopsia, prosopagnosia). He has poorly controlled diabetes and hypertension. Cranial magnetic resonance imaging (MRI) revealed an acute infarct on the left posterior cerebral artery territory. The patient was managed as an acute ischemic stroke and follow up after 6 months revealed improvement of the visual field cut but with persistence of the higher cortical function deficits. To the best of our knowledge, we report the first rare occurrence reversal of vision metamorphopsia described as inverted words as the sole initial presentation of an underlying stroke.

Interpretation to the European clinical guidelines of psychological interventions for Tourette syndrome and other tic disorders in 2021 / 中华实用儿科临床杂志

Tic disorders are one of the common neurodevelopmental disorders in children, which are mainly managed by pharmacological and non-pharmacological treatment.Psychological interventions belong to the non-pharmacological treatment, which, however, have not yet been fully recognized and understood in China.The analyses on clinical effectiveness and availability to pediatric patients are limited.This study aims to interpret the clinical guidelines of psychological interventions for Tourette syndrome and other tic disorders by European Society for the Study of Tourette syndrome in the journal of European Child and Adolescent Psychiatry in 2021, aiming to provide reference for the psychological interventions of tic disorders in China.

MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors

Considering that photodynamic therapy (PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac (Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species (ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A (LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1α (HIF-1α) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.

Guidelines on muscle relaxants and reversal in anaesthesia / 中华麻醉学杂志

Objectives:To provide an update to the 1999 French guidelines on " Muscle relaxants and reversal in anaesthesia" , a consensus committee of sixteen experts was convened.A formal policy of declaration and monitoring of conflicts of interest (COI) was developed at the outset of the process and enforced throughout.The entire guidelines process was conducted independently of any industrial funding (i.e.pharmaceutical, medical devices). The authors were required to follow the rules of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE ?) system to assess the quality of the evidence on which the recommendations were based.The potential drawbacks of making strong recommendations based on low-quality evidence were stressed.Few of the recommendations remained ungraded. Methods:The panel focused on eight questions: (1) In the absence of difficult mask ventilation criteria, is it necessary to check the possibility of ventilation via a facemask before muscle relaxant injection? Is it necessary to use muscle relaxants to facilitate facemask ventilation? (2) Is the use of muscle relaxants necessary to facilitate tracheal intubation? (3) Is the use of muscle relaxants necessary to facilitate the insertion of a supraglottic device and management of related complications? (4) Is it necessary to monitor neuromuscular blockade for airway management? (5) Is the use of muscle relaxants necessary to facilitate interventional procedures, and if so, which procedures? (6) Is intraoperative monitoring of neuromuscular blockade necessary? (7) What are the strategies for preventing and treating residual neuromuscular blockade? (8) What are the indications and precautions for use of both muscle relaxants and reversal agents in special populations (e.g.electroconvulsive therapy, obese patients, children, neuromuscular diseases, renal/hepatic failure, elderly patients)? All questions were formulated using the Population, Intervention, Comparison and Outcome (PICO) model for clinical questions and evidence profiles were generated.The results of the literature analysis and the recommendations were then assessed using the GRADE ? system. Results:The summaries prepared by the SFAR Guideline panel resulted in thirty-one recommendations on muscle relaxants and reversal agents in anaesthesia.Of these recommendations, eleven have a high level of evidence (GRADE 1±) while twenty have a low level of evidence (GRADE 2±). No recommendations could be provided using the GRADE ? system for five of the questions, and for two of these questions expert opinions were given.After two rounds of discussion and an amendment, a strong agreement was reached for all the recommendations. Conclusion:Substantial agreement exists among experts regarding many strong recommendations for the improvement of practice concerning the use of muscle relaxants and reversal agents during anaesthesia.In particular, the French Society of Anaesthesia and Intensive Care (SFAR) recommends the use of a device to monitor neuromuscular blockade throughout anaesthesia.

Reversión del bypass gástrico: indicaciones y resultados quirúrgicos / Gastric bypass reversal: surgical indications and results

Resumen Introducción: Debido a su eficacia en el tratamiento de la obesidad mórbida, el bypass gástrico (BPG) sigue siendo una intervención realizada frecuentemente. Sin embargo, un grupo reducido de pacientes puede desarrollar complicaciones nutricionales y metabólicas que no logran controlarse con un tratamiento médico óptimo. En estos casos, puede ser necesario reestablecer la continuidad del tracto gastrointestinal por medio de la reversión del BPG (R-BPG). Objetivo: Presentar las indicaciones y resultados obtenidos en una serie de pacientes sometidos a una R-BPG. Materiales y Método: Identificación y evaluación retrospectiva de todos los pacientes sometidos a una R-BPG en nuestra institución de manera consecutiva. Se registraron las características demográficas y antropométricas de la cirugía original y al momento de la reversión. Las complicaciones se registraron de acuerdo con la clasificación de Clavien-Dindo. Resultados: Se identificaron 7 pacientes en los cuales se realizó una R-BPG. En 2 casos la reversión fue por síndrome de intestino corto, en 3 casos por hipoglicemias severas refractarias a manejo médico y en 2 casos por diarrea crónica. La mediana de edad al momento de la reversión fue de 55 años. La mediana de tiempo desde la cirugía original hasta el momento de la reversión fue de 77 meses. La mediana de estadía hospitalaria fue de 6 días. No hubo complicaciones Clavien-Dindo ≥ III. La R-BPG logró revertir en todos los casos las complicaciones nutricionales y metabólicas. Conclusión: La restauración de la continuidad del tracto gastrointestinal permite el control de las complicaciones nutricionales y metabólicas.

Introduction: Due to its efficacy in the treatment of morbid obesity, roux-en-y gastric bypass (RYGB) continues to be a frequently performed intervention. However, a small group of patients may develop nutritional and metabolic complications that cannot be controlled with optimal medical treatment. In these cases, it may be necessary to reestablish the continuity of the gastrointestinal tract by reversing the RYGB (R-RYGB). Aim: To present the indications and results obtained in a series of patients who underwent to R-RYGB. Materials and Method: Identification and retrospective evaluation of all patients who underwent consecutive R-RYGB in our institution. Demographic and anthropometric characteristics of the original surgery and at the time of the reversal were recorded. Complications were classified according to Clavien-Dindo classification. Results: Seven patients were identified in whom an R-RYGB was performed. In 2 cases the reversal was due to short bowel syndrome, in 3 cases due to severe hypoglycemia refractory to medical treatment and in 2 cases due to chronic diarrhea. The median age at the time of the reversal was 55 years. The median time from primary surgery to reversal was 77 months. The median hospital stay was 6 days. There were no Clavien-Dindo complications ≥ III. The R-RYGB was able to reverse nutritional and metabolic complications in all cases. Conclusion: Restoring the continuity of the gastrointestinal tract allows control of nutritional and metabolic complications.

Histology and structure of the testicles in three species of Atelopus frogs (Anura: Bufonidae) endemic to the Sierra Nevada de Santa Marta, Colombia / Histología y estructura de los testículos en tres especies de ranas Atelopus (Anura: Bufonidae) endémicas de la Sierra Nevada de Santa Marta, Colombia

Abstract Introduction: Testicular histology constitutes one of the least explored aspects in frogs of the genus Atelopus. This taxonomic group shows an alarming population decline; therefore, its reproductive biology is one of the greatest topics of interest for its conservation. Objective: To describe the testicular morphology and the spermatogenetic lineage cells in adult males of Atelopus laetissimus, Atelopus nahumae, and Atelopus carrikeri in the Sierra Nevada de Santa Marta, Colombia. Methods: During June - July 2017 and 2018, sampling was conducted in the localities of San Lorenzo and Páramo Cebolletas, Sierra Nevada de Santa Marta (SNSM), to collect 15 adult males, 5 per species. Testes samples were fixed in Bouin to be processed by the standard paraffin-embedding technique. Histological sections (3 μm) were stained with Hematoxylin-eosin and Mallory-Heidenhain-Azan-Gomori's. For the description and photographic register of the germ cells, the photonic microscopy technique was used with the differential interference contrast system. Results: The testes are oval organs, compact, light yellow color, and with little vascularization. Externally, they are surrounded by a thin albuginea tunic constituted by regular dense connective tissue. Inside this layer, they are composed of numerous seminiferous tubules of hexagonal contour, in which germ cell cysts are distinguished at different stages of spermatogenesis (spermatogonia I and II, spermatocyte I and II, and early and late spermatids) and spermiogenesis (spermatozoa in fascicles and free spermatozoa). Separating the seminiferous structures is the interstitial tissue in which Leydig cells and blood vessels stand out. Additionally, in the cranial part of the testis, the Bidder's organ was found, formed by two distinguishable regions, the cortex and the medulla. In the cortex, there are previtellogénic oocytes of different sizes surrounded by a monolayer of flat follicular cells. For its part, the medullary region is the connective tissue that nourishes the oocytes and is constituted by blood capillaries. Conclusions: The gonads of the three species analyzed present a cystic cellular organization similar to other anurans, where all stages of spermatogenesis and spermiogenesis were identified, possibly indicating a continuous reproductive activity. Likewise, the Bidder's organ is reported for the first time in the three Atelopus species, which allows suggesting a possible sexual reversion in case of a population decrease of females as a reproductive strategy.

Resumen Introducción: La histología testicular constituye uno de los aspectos menos explorados en las ranas del género Atelopus. Este grupo taxonómico ostenta un declive poblacional alarmarte, es por ello, que su biología reproductiva resulta uno de los temas de mayor interés para su conservación. Objetivo: Describir la morfología testicular y las células del linaje espermatogénico en machos adultos de Atelopus laetissimus, Atelopus nahumae y Atelopus carrikeri en la Sierra Nevada de Santa Marta, Colombia. Métodos: Durante Junio - Julio de 2017 y 2018 se realizaron muestreos en las localidades de San Lorenzo y Páramo Cebolletas, Sierra Nevada de Santa Marta (SNSM), para recolectar 15 machos adultos, 5 por especie. Las muestras de testículo se fijaron en Bouin para ser procesadas mediante la técnica estándar de inclusión en parafina. Las secciones histológicas (3 μm) se tiñeron con Hematoxilina-eosina y Mallory-Heidenhain-Azan-Gomori's. Para la descripción y registro fotográfico de las células germinales, se utilizó la técnica de microscopía fotónica con el sistema de contraste diferencial de interferencia. Resultados: Los testículos son órganos ovalados, compactos, de color amarillo claro y con poca vascularización. Externamente, están rodeados por una delgada túnica albugínea constituida por tejido conectivo denso regular. Al interior de esta capa se componen por numerosos túbulos seminíferos de contorno hexagonal, en los que se distinguen quistes de células germinativas en diferentes etapas de la espermatogénesis (espermatogonia I y II, espermatocito I y II y espermátidas tempranas y tardías) y espermiogénesis (espermatozoides en fascículos y espermatozoides libres). Separando las estructuras seminíferas se halla el tejido intersticial en el que se destacan las células de Leydig y los vasos sanguíneos. Adicionalmente, en la parte craneal del testículo se encontró el órgano de bidder formado por dos regiones diferenciables, la corteza y la medula. En la corteza se aprecian ovocitos previtelogénicos en diferente tamaño rodeados por una monocapa de células foliculares planas. Por su parte, la región medular es el tejido conectivo que nutre los ovocitos y está constituido por capilares sanguíneos. Conclusiones: Las gónadas de las tres especies analizadas presentan una organización celular quística de manera similar con otros anuros, donde se identificó todos los estadios de la espermatogénesis y espermiogénesis indicando posiblemente una actividad reproductiva continua. Así mismo, se reporta por primera vez el órgano de bidder en las tres especies de Atelopus, lo cual permite sugerir una posible reversión sexual en caso de una disminución poblacional de las hembras como una estrategia reproductiva.

Action of heparin and acetylcholine modulators on the neurotoxicity of the toad Rhinella schneideri (Anura: Bufonidae) in Brazil / Acción de la heparina y moduladores de acetilcolina en la neurotoxicidad del sapo Rhinella schneideri (Anura: Bufonidae) en Brasil

Abstract Introduction: Rhinella schneideri is a toad widely distributed in South America and its poison is characterized by inducing cardiotoxicity and neurotoxicity. Objective: In this work, we investigated pharmacological strategies to attenuate the peripheral neurotoxicity induced by R. schneideri poison in avian neuromuscular preparation. Methods: The experiments were carried out using isolated chick biventer cervicis preparation subjected to field stimulation for muscle twitches recordings or exposed to acetylcholine and potassium chloride for contracture responses. Results: Poison (10 μg/ml) produced complete neuromuscular blockade in chick biventer cervicis preparation within approximately 70 min incubation (times for 50 and 90 % blockade: 15 ± 3 min and 40 ± 2 min, respectively; P < 0.05, N= 5); contracture responses to exogenous acetylcholine and KCl were unaffected by poison indicating no specificity with postsynaptic receptors or myotoxicity, respectively. Poison (10 μg/ml)-induced neuromuscular blockade was not prevented by heparin (5 and 150 IU/ml) under pre- or post-treatment conditions. Incubation at low temperature (23-25 °C) abolished the neuromuscular blockade; after raising the temperature to 37 °C, the complete neuromuscular blockade was slightly slower than that seen in preparations directly incubated at 37 °C (times for 50 and 90 % blockade: 23 ± 2 min and 60 ± 2.5 min, respectively; P < 0.05, N= 4). Neostigmine (3.3 μM) did not reverse the neuromuscular blockade in BC preparation whereas 3,4-diaminopyridine (91.6 μM) produced a partial and sustained reversal of the twitch responses (29 ± 7.8 % of maximal reversal reached in approximately 40 min incubation; P < 0.05, N= 4). Conclusions: R. schneideri poison induces potent peripheral neurotoxicity in vitro which can be partially reversible by 3,4-diaminopyridine.

Resumen Introducción: Rhinella schneideri está ampliamente distribuida en Suramérica y su veneno es caracterizado por inducir cardiotoxicidad y neurotoxicidad. Objetivo: En este trabajo, investigamos estrategias farmacológicas para atenuar la neurotoxicidad periférica inducida por el veneno de R. schneideri en preparaciones neuromusculares de aves. Métodos: Los experimentos fueron realizados usando preparaciones de biventer cervicis de pollos sometidas a estimulación de campo para el registro de las contracciones musculares o expuestas a la acetilcolina y al cloruro de potasio para la respuesta contractural. Resultados: El veneno (10 µg/ml) provocó un bloqueo neuromuscular completo en las preparaciones después de aproximadamente 70 min de incubación (tiempos para 50 y 90 % de bloqueo: 15 ± 3 min y 40 ± 2 min, respectivamente; P < 0.05, N = 5); las contracturas en respuesta a la acetilcolina y el KCl exógenos no fueron afectadas por el veneno, indicando que no hay una interacción especifica con receptores postsinápticos o miotoxicidad respectivamente. El bloqueo neuromuscular causado por el veneno (10 µg/ml) no fue prevenido por la heparina (5 y 150 UI/ml) bajo condiciones pre y post-tratamiento. La incubación a bajas temperaturas (23-25 ºC) abolió el bloqueo neuromuscular; después de aumentar la temperatura a 37 ºC, el bloqueo neuromuscular total fue levemente más lento que el visto en preparaciones directamente incubadas a 37 ºC (tiempos para 50 y 90 % de bloqueo: 23 ± 2 min y 60 ± 2.5 min, respectivamente; P < 0.05, N= 4). Neostigmina (3.3 µM) no revirtió el bloqueo neuromuscular, mientras que 3.4-diaminopiridina (91.6 µM) produjo una reversión parcial y sostenida de las respuestas neuromusculares (29 ± 7.8 % de la reversión máxima alcanzada en aproximadamente 40 min de incubación; P < 0.05, N = 4). Conclusiones: El veneno de R. schneideri indujo neurotoxicidad periférica potente in vitro, el cual puede ser revertido por 3.4-diaminopiridina.