Memantine increases the dendritic complexity of hippocampal young neurons in the juvenile brain after cranial irradiation.

Introduction: Cranial irradiation (IR) negatively regulates hippocampal neurogenesis and causes cognitive dysfunctions in cancer survivors, especially in pediatric patients. IR decreases proliferation of neural stem/progenitor cells (NSPC) and consequently diminishes production of new hippocampal neurons. Memantine, an NMDA receptor antagonist, used clinically to improve cognition in patients suffering from Alzheimer's disease and dementia. In animal models, memantine acts as a potent enhancer of hippocampal neurogenesis. Memantine was recently proposed as an intervention to improve cognitive impairments occurring after radiotherapy and is currently under investigation in a number of clinical trials, including pediatric patients. To date, preclinical studies investigating the mechanisms underpinning how memantine improves cognition after IR remain limited, especially in the young, developing brain. Here, we investigated whether memantine could restore proliferation in the subgranular zone (SGZ) or rescue the reduction in the number of hippocampal young neurons after IR in the juvenile mouse brain. Methods: Mice were whole-brain irradiated with 6 Gy on postnatal day 20 (P20) and subjected to acute or long-term treatment with memantine. Proliferation in the SGZ and the number of young neurons were further evaluated after the treatment. We also measured the levels of neurotrophins associated with memantine improved neural plasticity, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Results: We show that acute intraperitoneal treatment with a high, non-clinically used, dose of memantine (50 mg/kg) increased the number of proliferating cells in the intact brain by 72% and prevented 23% of IR-induced decrease in proliferation. Long-term treatment with 10 mg/kg/day of memantine, equivalent to the clinically used dose, did not impact proliferation, neither in the intact brain, nor after IR, but significantly increased the number of young neurons (doublecortin expressing cells) with radial dendrites (29% in sham controls and 156% after IR) and enhanced their dendritic arborization. Finally, we found that long-term treatment with 10 mg/kg/day memantine did not affect the levels of BDNF, but significantly reduced the levels of NGF by 40%. Conclusion: These data suggest that the enhanced dendritic complexity of the hippocampal young neurons after treatment with memantine may contribute to the observed improved cognition in patients treated with cranial radiotherapy.

Stroma-derived IL-6, G-CSF and Activin-A mediated dedifferentiation of lung carcinoma cells into cancer stem cells.

Cancer stem cells (CSCs) are a small population of resistant cells inhabiting the tumors. Although comprising only nearly 3% of the tumor mass, these cells were demonstrated to orchestrate tumorigenesis and differentiation, underlie tumors' heterogeneity and mediate therapy resistance and tumor relapse. Here we show that CSCs may be formed by dedifferentiation of terminally differentiated tumor cells under stress conditions. Using a elegant co-culture cellular system, we were able to prove that nutrients and oxygen deprivation activated non-malignant stromal fibroblasts, which in turn established with tumor cells a paracrine loop mediated by Interleukine-6 (IL-6), Activin-A and Granulocyte colony-stimulating factor (G-CSF), that drove subsequent tumor formation and cellular dedifferentiation. However, by scavenging these cytokines from the media and/or blocking exosomes' mediated communication it was possible to abrogate dedifferentiation thus turning these mechanisms into potential therapeutic targets against cancer progression.

Kinetics of epsilon antitoxin antibodies in different strategies for active immunization of lambs against enterotoxaemia / Cinética dos anticorpos antitoxina epsilon em diferentes estratégias de imunização ativa em cordeiros contra a enterotoxemia

Enterotoxaemia, a common disease that affects domestic small ruminants, is mainly caused by the epsilon toxin of Clostridium perfringens type D. The present study tested four distinct immunization protocols to evaluate humoral response in lambs, a progeny of non-vaccinated sheep during gestation. Twenty-four lambs were randomly allocated into four groups according to age (7, 15, 30 and 45 days), receiving the first dose of epsilon toxoid commercial vaccine against clostridiosis with booster after 30 days post vaccination. Indirect ELISA was performed after the first vaccine dose and booster to evaluate the immune response of the lambs. Results showed that for the four protocols tested all lambs presented serum title considered protective (≥0.2UI/ml epsilon antitoxin antibodies) and also showed that the anticipation of primovaccination of lambs against enterotoxaemia conferred serum title considered protective allowing the optimization of mass vaccination of lambs.

Enterotoxemia, uma das mais comuns enfermidades que acomete os pequenos ruminantes domésticos, é causada principalmente pela toxina épsilon de Clostridium perfringens tipo D. O presente estudo avaliou a resposta humoral conferida por quatro protocolos distintos de primovacinação na progênie de ovelhas não vacinadas durante a gestação. Vinte e quatro cordeiros foram aleatoriamente divididos em quatro grupos de acordo com a idade (dias) que receberam a primeira dose da vacina comercial contra clostridiose contendo toxóide epsilon na sua formulação. Todos os cordeiros foram vacinados aos 7, 15, 30 ou 45 dias de idade e receberam um reforço da dose 30 dias após a vacinação. A avaliação sorológica dos cordeiros pelo teste de ELISA indireto foi realizada por ocasião da administração da primeira dose da vacina. Os resultados elucidaram não haver comprometimento da resposta imune de cordeiros vacinados tanto aos 7, 15, 30 ou 45 dias de idade associada ao reforço da dose 30 dias após, demonstrando assim que a antecipação da primeira vacinação conferiu proteção aos cordeiros contra a enterotoxemia, permitindo otimizar o planejamento da vacinação em massa dos cordeiros.

Fish oil supplementation for two generations increases insulin sensitivity in rats.

We investigated the effect of fish oil supplementation for two consecutive generations on insulin sensitivity in rats. After the nursing period (21 days), female rats from the same prole were divided into two groups: (a) control group and (b) fish oil group. Female rats were supplemented with water (control) or fish oil at 1 g/kg body weight as a single bolus for 3 months. After this period, female rats were mated with male Wistar rats fed on a balanced chow diet (not supplemented). Female rats continued to receive supplementation throughout gestation and lactation periods. The same treatment was performed for the next two generations (G1 and G2). At 75 days of age, male offspring from G1 and G2 generations from both groups were used in the experiments. G1 rats did not present any difference with control rats. However, G2 rats presented reduction in glycemia and lipidemia and improvement in in vivo insulin sensitivity (model assessment of insulin resistance, insulin tolerance test) as well as in vitro insulin sensitivity in soleus muscle (glucose uptake and metabolism). This effect was associated with increased insulin-stimulated p38 MAP kinase phosphorylation and lower n-6/n-3 fatty acid ratio, but not with activation of proteins from insulin signaling (IR, IRS-1 and Akt). Global DNA methylation was decreased in liver but not in soleus muscle. These results suggest that long-term fish oil supplementation improves insulin sensitivity in association with increased insulin-stimulated p38 activation and decreased n-6:n-3 ratio in skeletal muscle and decreased global DNA methylation in liver.

Back to basics: pitting edema and the optimization of hypertension treatment in incident peritoneal dialysis patients (BRAZPD).

Systemic arterial hypertension is an important risk factor for cardiovascular disease that is frequently observed in populations with declining renal function. Initiation of renal replacement therapy at least partially decreases signs of fluid overload; however, high blood pressure levels persist in the majority of patients after dialysis initiation. Hypervolemia due to water retention predisposes peritoneal dialysis (PD) patients to hypertension and can clinically manifest in several forms, including peripheral edema. The approaches to detect edema, which include methods such as bioimpedance, inferior vena cava diameter and biomarkers, are not always available to physicians worldwide. For clinical examinations, the presence of pitting located in the lower extremities and/or over the sacrum to diagnose the presence of peripheral edema in their patients are frequently utulized. We evaluated the impact of edema on the control of blood pressure of incident PD patients during the first year of dialysis treatment. Patients were recruited from 114 Brazilian dialysis centers that were participating in the BRAZPD study for a total of 1089 incident patients. Peripheral edema was diagnosed by the presence of pitting after finger pressure was applied to the edematous area. Patients were divided into 2 groups: those with and without edema according to the monthly medical evaluation. Blood arterial pressure, body mass index, the number of antihypertensive drugs and comorbidities were analyzed. We observed an initial BP reduction in the first five months and a stabilization of blood pressure levels from five to twelve months. The edematous group exhibited higher blood pressure levels than the group without edema during the follow-up. The results strongly indicate that the presence of a simple and easily detectable clinical sign of peripheral edema is a very relevant tool that could be used to re-evaluate not only the patient's clinical hypertensive status but also the PD prescription and patient compliance.

Cinética dos anticorpos de origem colostral contra a toxina épsilon de Clostridium perfringens tipo D em cordeiros / Kinetics of colostral antibodies against epsilon toxin produced by Clostridium perfringens type D in lambs

Enterotoxemia, uma das mais importantes enfermidades que acomete os pequenos ruminantes domésticos, é causada principalmente pela toxina épsilon de Clostridium perfringens tipo D. O presente estudo avaliou a cinética de anticorpos colostrais antitoxina épsilon em cordeiros nascidos de ovelhas submetidas a dois diferentes tipos de manejo sanitário. Um grupo de ovelhas prenhes (n=6) foi vacinado com uma dose única de vacina comercial polivalente contra clostridioses contendo toxóide épsilon na sua formulação cerca de 30 dias antes da data prevista para a parição. Outro grupo de ovelhas (n=6) de mesma idade gestacional não foi vacinado. Imediatamente após o parto, antes da ingestão do colostro, foram colhidas amostras sanguíneas dos respectivos cordeiros, bem como aos 30 e 60 dias de idade e submetidas à avaliação sorológica pelo teste de ELISA indireto. Os resultados encontrados permitem concluir que a vacinação de ovelhas prenhes 30 dias antes do parto contra a enterotoxemia causada pela toxina épsilon, com dose única de produto comercial, induz imunidade passiva em níveis considerados protetores (>0,5UI/ml) aos cordeiros por, no mínimo, 60 dias de idade.

Enterotoxemia, a disease that affect small ruminants, is caused mainly by the epsilon toxin from Clostridium perfringens type D. This study evaluated the kinetics of epsilon antitoxin colostral antibodies in lambs born to ewes submitted to two different types of health management. A group of pregnant ewes (n=6) was vaccinated with a single dose of commercial vaccine against polyvalent clostridial toxoid containing epsilon in its formulation some 30 days before the expected date of birth. Another group of ewes (n=6) of the same gestational age were not vaccinated. Immediately after birth, before intake of colostrum, blood samples were collected from their lambs as well as 30 and 60 days of age for serum evaluation by ELISA. The results allow to conclude that vaccination of pregnant ewes 30 days before parturition allowed the transfer of colostral antibodies specific enough to guarantee the immunity considered protective (0,5UI/ml) of the newborn lamb against enterotoxemia until its entry into the feedlot, with 60 days of age.

Efeito das estaçöes do ano sobre a produçäo de embriöes bovinos / Effect of the seasons year of the embryos of the production in cattle

Os dados para a realizaçäo desta pesquisa provieram de anotaçöes sobre transferência de embriöes realizadas no período de 1980 a 1985, pela Agropecuária Lagoa da Serra S/A, em fazendas ou na central, de 217 doadoras Bos taurus taurus (principalmente da raça Holandesa) e Bos taurus indicus (predominantemente da raça Nelore), com idade média de 6,64 anos. Foram avaliadas 528 colheitas, 2682 estruturas totais e 1038 (38,70%) embriöes viáveis. As análises estatísticas foram realizadas através do sistema one-way de análise de variância, baseado na soma dos quadrados mínimos, tendo os dados em percentagens sido transformados para arco/seno. Estudando os efeitos estacionais dentro dos animais Bos taurus indicus, verificou-se influência significativa (P<0,05) sobre o índice de estruturas näo fertilizadas, que foi mais elevado na primavera. Contudo, houve uma tendência de a produçäo de embriöes ser melhor no outono e inverno. Dentro do grupo de Bos taurus taurus, näo se observou efeito da estacionalidade (P>0,05), mas houve tendência de os resultados serem melhores no inverno e na primavera. Ao se analisar estaçöes do ano ou época seca e chuvosa, independentemente do tipo racial, näo se encontram efeitos (P>0,05) sobre a produçäo de embriöes em bovinos. Desta forma, pode-se concluir que, nas condiçöes deste estudo, näo houve influência consistente da estacionalidade sobre a produçäo de embriöes