Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity / 药物分析学报

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed inde-pendently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endo-thelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

Checkmate ao rei: como reinventar o pai / King checkmate: how to reinvent the father

Este artigo tem como objetivo abordar a questão da paternidade na psicoterapia familiar. Uma revisão crítica das teorias sistêmicas e especialmente do pós-modernismo é oferecida, dentro da qual a "revelação da verdade" não parece ter recebido atenção adequada. Ao contrário, este trabalho pretende demonstrar a sua importância, principalmente, no engajamento dos pais na terapia, a fim de passar de um aspecto protetor em relação aos filhos, que nunca têm idade para saber a verdade, ao seu pleno respeito. Em seguida, aborda o problema da parentificação dos filhos e da imaturidade de alguns pais e descreve como intervir na psicoterapia, de modo a restaurar o equilíbrio emocional e a aceitação de responsabilidades por parte do pai. Para atingir esse objetivo, é útil incluir a história do desenvolvimento da família e da terceira geração como uma ponte entre pais e filhos na terapia.

This paper describes how to engage fathers in family therapy. It starts from a critical review of systems theory and postmodernism around the topic of the truth and family secrets. The Author describes how to challenge fathers' resistances and to motivate them to reveal the truth to their children in therapy. The fundamental passage from being protective to being respectful of children is outlined too. The process of immaturity transmitted through generations can bring children to perform adult and responsible roles instead of their fathers. Then, the third older generation can be activated and considered as an emotional bridge in connecting fathers and children in order to transform inverted roles and responsibilities.

Enterocolitis necrotizante / Necrotizing enterocolitis

Resumen La enterocolitis necrotizante (ECN) es la urgencia más frecuente en el periodo neonatal asociada al sistema digestivo; afectando principalmente a los neonatos pretérmino con muy bajo peso al nacer. La etiología continúa siendo desconocida, se considera una enfermedad multifactorial, donde la prematuridad es el principal factor de riesgo, todo esto relacionado con la inmadurez del tracto gastrointestinal, una motilidad disminuida que genera una mayor permeabilidad en la mucosa y con esto facilita la translocación bacteriana. Su diagnóstico suele ser muy complejo y suele pasar desapercibido en muchas ocasiones generando una mortalidad importante de hasta el 30% donde su principal complicación es la perforación intestinal y el consiguiente shock séptico. Las opciones terapéuticas se dividen en 2 grupos: médico y quirúrgico, ambos con complicaciones importantes que afectan el desarrollo de los niños que la padecen donde las más importantes abarcan desde alteraciones del crecimiento y neurodesarrollo hasta síndrome de intestino corto y desnutrición.

Abstract Necrotizing enterocolitis (NEC) is the most common emergency in the neonatal period associated with the digestive system; mainly affecting preterm neonates with very low birth weight. Etiology remains unknown, considered a multifactorial disease, all this related to the immaturity of the gastrointestinal tract, a decreased motility that generates greater permeability in the mucosa and with this facilitates bacterial translocation. Diagnosis is usually very complex and often goes unnoticed on many occasions leading to a significant mortality of up to 30% where its main complication is intestinal perforation and consequent septic shock. Therapeutic options are divided into 2 groups: medical and surgical, both with major complications affecting the development of children with it where the most important from growth and neurodevelopmental alterations to short bowel syndrome and malnutrition.

Retinal immaturity at first screening and retinopathy of prematurity: Image-based validation of 1202 eyes of premature infants to predict disease progression

Purpose: To use the extent of retinal immaturity at the first visit to predict progression to any stage and treatment-requiring retinopathy of prematurity (ROP). Methods: Retrospective, multicenter, nonrandomized, observational, clinical, validation study. In all, 601 Asian Indian preterm infants born < 2000 g and/or < 34 weeks of gestation completing ROP screening with RetCam images taken during each visit were included. A total of 1202 eyes of these infants were classified into three groups based on the retinal immaturity at the first screening visit into “mild” (Group 1), vessels reaching the posterior boundary of zone 3; “moderate” (Group 2), vessels entering zone 2 anterior; and “severe” (Group 3), vessels in zone 1 or zone 2 posterior. RetCam images at each subsequent visit were evaluated and the proportion of eyes that progressed to Type 1 or Type 2 ROP was correlated with the degree of retinal immaturity. Results: Of the 958 eyes in Group 1, 200 eyes in Group 2, and 44 eyes in Group 3, any stage ROP developed in 15% of eyes in Group 1, 46.5% of eyes in Group 2, and 100% of eyes in Group 3 (P < 0.001). Sixteen of 128 eyes (12.5%), 12 of 72 (16.6%), and 28 of 44 of eyes (63.6%) in Groups 1, 2, and 3, respectively, required treatment (P < 0.001). Conclusion: Retinal immaturity at first screening visit predicts Type 1 and Type 2 ROP. “Severe” immaturity is more likely to progress to “treatment-requiring” disease. This could be a useful tool for prognostication, counseling, and scheduling follow-up.

Hematological and biochemical indicators of maturity in foals and their relation to the placental features / Indicadores hematológicos e bioquímicos de maturidade em potros e relação com suas características placentárias

Newborn's health is directly related to gestational conditions and placental efficiency. The aims of this study were: (1) To evaluate hematological and biochemical parameters of foals born from mares with placentitis at birth and at 24h of age, (2) to verify if placental pathology had any influence on neonatal maturity degree through hematological and biochemical response of those foals. According to placental findings (control and placentitis) and neonatal maturity degree (mature and immature), foals were divided into three groups: (1) Control group (n=22), foals born from mares with placentitis and classified as (2) Mature (n=26), and (3) Immature (n=10). The hematocrit and plasma concentration of fibrinogen, total plasma protein, white blood cells count, lactate, glucose, creatinine, urea, albumin, bilirubin, triglyceride, cholesterol, calcium, phosphorus, magnesium, aspartate aminotransferase (AST), creatine kinase (CK), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) were measured. Placental features were significantly different between neonatal maturity degree (P=0.001). Mares that had acute placentitis foaled more immature neonates (n=8/10; 80%). Concentrations of fibrinogen (P=0.003), creatinine (P=0.021), total cholesterol (P=0.014), AST (P=0.001), GGT (P=0.002), total (P=0.001) and unconjugated bilirubin (P=0.010) were higher at birth in the Immature group, whereas albumin levels were lower (P=0.002). Foals born from mares with placentitis presented hyperlactatemia at 24h of age (P=0.002). Acute placentitis had an influence on the neonatal maturity, allowing an accelerated but incomplete fetal maturation. The monitoring of lactate, fibrinogen, creatinine, bilirubin, cholesterol, albumin, AST, and GGT levels, associated with clinical, physical, and behavior evaluation may contribute as indicators of neonatal maturity.(AU)

A saúde do neonato está diretamente relacionada às condições gestacionais e eficiência placentária. Os objetivos deste estudo foram: (1) avaliar parâmetros hematológicos e bioquímicos de potros nascidos de éguas com placentite ao nascimento e com 24h de vida e (2) verificar se a patologia placentária exerceu influência no grau de maturidade através da resposta hemato-bioquímica destes neonatos. De acordo com os resultados histopatológicos placentários (controle e placentite) e grau de maturidade neonatal (maturo e imaturo), os potros foram divididos em três grupos: grupo controle (n=22); e potros nascidos de éguas com placentite classificados como (2) maturos (n=26) e (3) imaturos (n=10). Foi avaliado hematócrito e concentrações sanguíneas de fibrinogênio, proteína plasmática total, leucócitos totais, lactato, glicose, creatinina, uréia, albumina, bilirrubinas, triglicerídeos, colesterol, cálcio, fósforo, magnésio, aspartato aminotransferase (AST), creatina quinase (CK), fosfatase alcalina (FA) e gama glutamiltranferase (GGT). As características placentárias foram significativamente diferentes entre os graus de maturidade neonatal (P=0.001). Éguas com placentite aguda produziram mais potros imaturos (n=8/10; 80%). No nascimento, os potros imaturos apresentaram maiores concentrações de fibrinogênio (P=0,003), creatinina (P=0,021), colesterol total (P=0,0014), AST (P=0,001), GGT (P=0,002), bilirrubina indireta (P=0,010) e total (P=0,001) e menor concentração de albumina (P=0,002). Os potros nascidos de éguas com placentite apresentaram hiperlactatemia com 24h de vida (P=0,002). A placentite aguda exerceu influência na maturidade neonatal, permitindo uma maturação fetal acelerada, porém, incompleta. Mensurações dos níveis sanguíneos de lactato, fibrinogênio, creatinina, colesterol total, AST, GGT, bilirrubinas e albumina, associado à avaliação clínica, física e comportamental, podem contribuir como indicadores de maturidade neonatal.(AU)

Application of nucleoprotein immature sperm percentage and sperm DNA damage rate detection in in vitro fertilization / 国际检验医学杂志

Objective To investigate the application value of sperm nucleoprotein immaturity and sperm DNA damage detection in in vitro fertilization(IVF).Methods From Mar.2015 to Feb.2016,routine sperm analysis,sperm nucleoprotein immaturity and sperm DNA damage detection were performed in 102 patients with infertility,and the correlation between these parameters were analyzed.Results Sperm DNA fragmentation rate was negatively correlated with IVF optimal embryos rate and sperm viability(P0.05).Sperm nucleoprotein immaturity rate was not correlated with IVF optimal embryos rate and fertility rate(P>0.05),while was negatively correlated with sperm concentration(P<0.05).Conclusion Sperm DNA fragmentation rate could be closely correlated with IVF optimal embryos rate,which might be with prediction value in IVF treatment.

Maturidade de potros nascidos de éguas com placentite / Maturity of foals from the mares with placentitis

Objetivou-se descrever a maturidade neonatal através da resposta clínica, comportamental e hematológica de potros nascidos de éguas com placentite. Participaram do estudo seis potros nascidos de éguas submetidas à indução experimental de placentite ascendente através da infusão intracervical de Streptococcus equi subespécie zooepidemicus e tratadas com Sulfa-trimetoprim e Flunixin meglumine. A formação dos grupos neonatais foi realizada de acordo com o grau de viabilidade e sobrevivência até 60 horas: Grupo Não Sobreviventes (n=2); Grupo Debilitados (n=2); Grupo Saudáveis (n=2). Foi considerado o tempo de gestação, período de intervalo inoculação-parto, avaliação comportamental, clínica e hematológica. O Grupo dos potros Saudáveis apresentou maior tempo de gestação (320±2 dias) e maior intervalo inoculação-parto (20,5±2,5 dias). Os Grupos Não Sobreviventes e Debilitados apresentaram atraso para decúbito esternal e reflexo de sucção. Foi observada bradicardia e hipotermia com 48h de vida no Grupo Não Sobreviventes. Os potros do Grupo Não Sobreviventes e Saudáveis apresentaram leucopenia no nascimento com discretas variações até as 48h. Os potros nascidos de éguas com placentite ascendente e tratadas demonstraram evolução clínica e respostas neonatais distintas. Conclui-se que, quanto maior o tempo de manutenção da gestação após a injúria placentária, melhor será a maturação fetal, o que refletirá em viabilidade e melhor capacidade de resposta neonatal...

The aim of this study was to describe the neonatal maturity through clinical, behavioral and hematologic response of foals born from mares with placentitis. Were used six foals born from mares subjected to experimentally induced ascending placentitis through intracervical infusion of Streptococcus equi subspecies zooepidemicus and treated with trimethoprim sulfametoxazole and flunixin meglumine. The neonatal groups were performed according to the viability and survival rate up to 60 hours: No Survivors group (n = 2); Debilitated group (n = 2); Healthy group (n = 2). Gestational length, the period between inoculation and delivery, and behavioral, clinical and hematologic evaluations were considered. The Healthy group showed longer gestation length (320±2 days) and longer inoculation-delivery interval (20.5±2.5 days). No Survivors and Debilitated groups showed delay in sternal recumbency and sucking reflex. Bradycardia and hypothermia was observed at 48 hours of life in No Survivors Group. Foals from No Survivors and Healthy groups showed leukopenia at birth with slight variations until 48h. Foals born from mares with ascending placentitis and treated showed distinct clinical and neonatal responses. It is concluded that the longer the maintenance of gestation after placental injury, better is the fetal maturation, which reflects in better viability and ability to neonatal response...

A Fetus with Persistent Hyperextended Neck Complicated with Ventriculomegaly and Pulmonary Immaturity in Third Trimester / 대한주산의학회잡지

Hyperextended neck of the fetal head is among the various fetal attitudes detected by prenatal sonography. Various etiologies may lead to hyperextension of the fetal head, including fetal anomalies such as structural abnormalities, conjoined twins and fetal neck masses, nuchal cord and uterine factors such as leiomyoma and uterine malformations. The importance of the precise prenatal diagnosis of this condition relates not only to the delivery mode, but also to the detection of associated conditions, as noted above. We report a case of a fetus whose persistent hyperextended neck was detected by midtrimester sonography, and who later demonstrated ventriculomegaly and lung immaturity in the 3rd trimester.

The Disease Spectrum in Premature Infants and the Progress of Pharmacological Treatment

Liveborn infants delivered before 37 week of postmenstrual age or less than 2,500g of birth weight are defined as premature infants. Recently, the unprecedented progress in neonatal practice has achieved remarkable improvements in the survival of extremely premature infants. However, immature organ function and the complication of therapy still contribute to the high mortality and morbidity from a spectrum of disease especially in extremely premature, low birth weight infants; respiratory distress syndrome, chronic lung disease, necrotizing enterocolitis, intraventricular hemorrhage, nosocomial infection, and prolonged hospitalization consist of the spectrum of disease in premature infants. To achieve further progress in neonatal-perinatal practice, randomized clinical trials should be employed not just to test the effectiveness of new therapies but also to evaluate competing strategies toward evidence-based, better clinical practice.