Brief environmental enrichment elicits metaplasticity on the insular cortex in vivo and reduces the strength of conditioned taste aversion.

Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.

Calcineurin requirement for in vivo insular cortex LTD and CTA-extinction.

Currently, it is widely accepted that memory extinction involves the formation of a new associative memory rather than unlearning of the information previously acquired. Nonetheless, the cellular and molecular mechanisms underlying this process are still unclear. In this regard, it has been suggested that while kinases modulate conditioning and LTP, phosphatases are relevant for extinction and LTD. In particular, the protein phosphatase calcineurin (CaN) has been involved in the extinction of some behavioral tasks along with LTD. Indeed, studies of our research group have demonstrated that induction of LTD in the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) pathway facilitates the extinction of conditioned taste aversion (CTA), while the induction of LTP in this pathway slows it down. In addition, we have shown that the extinction of CTA elicits an increase of CaN. The aim of the present study was to evaluate the participation of calcineurin in the extinction of CTA and in the expression of in vivo LTD in the Bla-IC pathway. For this purpose, we chemically inhibited calcineurin in the IC of adult male Wistar rats, either during CTA-extinction or thirty minutes after LTD induction in the Bla-IC pathway. Our results show that calcineurin inhibition slows down the CTA-extinction and blocks the maintenance of LTD. Furthermore, we show that CaN levels increase after LTD induction. These findings support the idea that calcineurin is a key molecular actor for both CTA extinction and LTD expression in the IC, a highly relevant neocortical area for the processing of aversively motivated learning tasks, suggesting that both processes are associated at a molecular level.

Culturally Sensitive OCD Research: Lessons from the U.S.-Mexico Border.

This paper explores culturally-related concerns that arose during a multi-year study of obsessive-compulsive disorder (OCD) along the U.S.-Mexico border and describes adaptations made to better connect the research process to study participants. The purpose of this exploration is two-fold: (1) to offer suggestions for culturally sensitive borderland mental health research; and (2) to enhance dialog focused on culture, mental health research and the U.S.-Mexico border. Systematic coding of the written record of weekly research team meetings identified six recurring cultural concerns: emotionally charged and poorly understood terminology; differing meanings of ethnicity and acculturation; quality of life-regional variation and uncertainty; overlap of research and care; hopeful but hesitant; and fatalism. We conclude that diligence in the initial planning phase of a study is only part of the challenge in doing culturally sensitive research. Equally important is an ongoing process of evaluation to make explicit cultural concerns that arise during research, as well as a readiness to implement culturally sensitive research adaptations.

Environmental enrichment attenuates conditioned taste aversion through the restoration of BDNF levels in the insular cortex.

It has been shown that exposure to an enriched environment (EE) can modulate the physiological impact of aversive stimuli in animals, promoting adaptive attitudes, as well as the development of resilience to stressful situations. These changes are known to be related to increased levels of some trophic factors, such as brain-derived neurotrophic factor (BDNF), which has been considered a regulatory protein for synaptic plasticity in the adult brain. Our previous studies have demonstrated that in the insular cortex (IC), a brain region of the temporal lobe implicated in the acquisition, consolidation, and retention of conditioned taste aversion (CTA) task, BDNF can reverse the CTA memory deficit caused by a protein synthesis inhibitor. Likewise, our research group have also shown that BDNF is required for the maintenance of CTA long-term memory. Here we evaluate the effects of the exposure to an enriched environment on the CTA memory strength, using a weak and strong version of this paradigm. The exposure to an EE for 21 days was able to attenuate the strong-CTA response through the restoration of BDNF levels in the IC of adult rats. These results provide evidence that environmental enrichment is capable of reducing the strength of an aversive memory trace, restoring the BDNF levels in a neocortical region of the adult brain.

Environmental enrichment: dissociated effects between physical activity and changing environmental complexity on anxiety and neurogenesis in adult male Balb/C mice.

Several factors, including environmental modifications, stimulate neuroplasticity. One type of neuroplasticity consists in the generation of new neurons in the dentate gyrus of the hippocampus. Neurogenesis is modulated by environmental enrichment (ENR, tunnels plus running wheel) and affected by the time of exposure to ENR. Despite the wide use of ENR to stimulate neuroplasticity, the degree to which ENR variations modeled by temporally changing the level of environmental complexity affect hippocampal neurogenesis and anxiety is still unclear. Thus, we investigated the effects of five housing conditions on young adult male Balb/C mice exposed for 42 days. The groups were as follows: standard conditions without ENR, constant ENR complexity, gradual increase of ENR complexity followed by a gradual decrease of ENR complexity, gradual increase of ENR complexity followed by constant ENR complexity, and constant ENR complexity followed by a gradual decrease of ENR complexity. On day 44, mice were exposed to the elevated plus-maze to evaluate anxiety. Further, we analyzed neurogenesis and quantified corticosterone levels. In an additional experiment, we explored the effect of voluntary physical activity on anxiety, neurogenesis, and corticosterone during the variations in ENR complexity. Our results showed that any change in ENR complexity over time reduced anxiety. Also, voluntary physical activity alone or in the context of a complex environment increased doublecortin cell maturation in the granular cell layer of the hippocampus. Finally, our study supports that physical activity acts proneurogenic, whereas any change in environmental complexity decreases anxiety-like behavior. However, the decrease in corticosterone levels elicited by physical activity was lower than the decrease produced by the decrement in environmental complexity.

Modifiable lifestyle behaviors, but not a genetic risk score, associate with metabolic syndrome in evening chronotypes.

Evening chronotype associates with health complications possibly via lifestyle factors, while the contribution of genetics is unknown. The aim was to study the relative contributions of genetics, lifestyle, and circadian-related physiological characteristics in metabolic risk of evening chronotype. In order to capture a biological contribution to chronotype, a genetic-risk-score (GRS), comprised of 15 chronotype-related variants, was tested. Moreover, a wide range of behavioral and emotional eating factors was studied within the same population. Chronotype, lifestyle, and metabolic syndrome (MetS) outcomes were assessed (n = 2,126), in addition to genetics (n = 1,693) and rest-activity/wrist-temperature rhythms (n = 100). Evening chronotype associated with MetS and insulin resistance (P < 0.05), and several lifestyle factors including poorer eating behaviors, lower physical activity and later sleep and wake times. We observed an association between higher evening GRS and evening chronotype (P < 0.05), but not with MetS. We propose a GRS as a tool to capture the biological component of the inter-individual differences in chronotype. Our data show that several modifiable factors such as sedentary lifestyle, difficulties in controlling the amount of food eaten, alcohol intake and later wake and bed times that characterized evening-types, may underlie chronotype-MetS relationship. Our findings provide insights into the development of strategies, particularly for evening chronotype.

Las Topográfias Médicas: una aportación de la Medicina Rural a la Salud Pública / Medical Topographies: A Contribution of Rural Medicine to Public Health

Las Topografías Médicas (TM) o Geografías Médicas, son un género de la literatura médica, cuyos orígenes pueden encontrarse en el tratado de Hipócrates, Sobre los aires, aguas y lugares. El objetivo básico de las TM fue simplemente describir la salud de la población de un lugar determinado, aunque pronto ampliaron su campo de acción, para investigar la influencia del entorno físico y social en las enfermedades que padece la población en zonas geográficas o localidades. El inicio de su desarrollo tiene lugar en el contexto de la Medicina de la Ilustración, y adquirirán su mayoría de edad durante el siglo xix y las primeras décadas del siglo xx, para finalizar su producción en los años setenta del pasado siglo. Las Reales Academias de Medicina tuvieron una importancia decisiva en el desarrollo de las TM, proponiendo una metodología y un contenido homogéneo para la redacción de las mismas y estableciendo premios anuales para las obras galardonadas, lo que permitió mejorar su calidad y homogeneidad. El texto de las TM incluía generalmente un esbozo histórico de la población, la geografía de la zona, la descripción de la flora y de la fauna, con frecuencia de forma muy detalladas, el estudio del clima, de las vías públicas y las viviendas, la descripción de las enfermedades más frecuentes y epidemias, así como la demografía y situación socioeconómica de la población, entre otros. ... En el presente artículo se describe la evolución histórica de las TM, sus contenidos principales, su distribución por autonomías y años, y algunos personajes ilustres relacionados con ellas; aportándose alguna iconografía y copias de los documentos más interesantes por su valor médico o artístico. (AU)

Medical Topographies (TM) or Medical Geographies, are a genre of medical literature, whose origins can be found in Hippocrates’ treatise, On Airs, Waters and Places. The initial objective of TM was simply to describe the health of the population of given place, although they soon expanded their field of action to investigate the influence of the physical and social environment on the diseases suffered by the population in geographical areas or localities. The beginning of their development took place in the context of Enlightenment Medicine, and they came of age during the 19th century and the first decades of the 20th century, ending their production in the seventies of the last century. The Royal Academies of Medicine had a decisive importance in the development of TM, proposing a methodology and homogeneous content for their writing and establishing annual prizes for the award-winning works, which allowed them to improve their quality and homogeneity. The text of the TM generally included a historical outline of the population, the geography of the area, the description of the flora and fauna, often in very detailed form, the study of the climate, public roads and homes, the description of the most frequent diseases and epidemics, as well as the demographics and socio-economic situation of the population, among others. ... This article describes the historical evolution of the TM, its main contents, its distribution by autonomies and years, and some illustrious people related to them, providing some iconography and copies of the most interesting documents due to their medical or artistic value. (AU)

Protective vascular effects of quercitrin in acute TNBS-colitis in rats: the role of nitric oxide.

Quercitrin (quercetin 3-rhamnoside) is a bioflavonoid with anti-inflammatory activity in experimental colitis. Several studies have suggested that vascular injury might be a primary process in Crohn's disease, but there is no information about the function of the mesenteric bed in the experimental models of colitis. The aims of this study were to analyse whether the reactivity to vasoconstrictor agents is altered in the mesenteric vascular bed from animals with colitis induced by administration of trinitrobenzenesulfonic acid (TNBS) in the early stages of this pathology, and to determine the effects of quercitrin on such vascular alterations. Contraction of mesenteric beds produced by vasoconstrictor agents such as noradrenaline and KCl is reduced in rats in the early stages of experimental TNBS-induced colitis. This alteration was partially reverted by non-selective nitric oxide synthase (NOS) inhibition with N-nitro-l-arginine methylester, and enhanced by non-selective cyclooxygenase (COX) inhibition with indomethacin. However, the endothelium-dependent relaxant responses to acetylcholine were not significantly altered. iNOS, COX-2, NOX-1, tumor necrosis factor α (TNFα) and interleukin 1ß (IL1ß) expressions were higher in the mesenteric arteries from TNBS-treated rats, without changes in both eNOS expression and eNOS-Ser1177 phosphorylation. The in vivo pre-treatment with 5 mg kg-1 of the flavonoid quercitrin reverts both the early hyporesponse of mesenteric arteries to noradrenaline and the up-regulation of iNOS, COX2, NOX1, TNFα and IL1ß in colitic rats. In conclusion, quercitrin improves the impaired mesenteric vascular reactivity in the acute phase of this colitis model, at least in part by reducing NO overproduction from iNOS.

Serotonin-transporter promoter polymorphism modulates the ability to control food intake: Effect on total weight loss.

SCOPE: The biggest challenge for losing weight is the ability to control the amount of food eaten; the tendency to overeat is called disinhibition. Our aims were to determine whether (a) the SLC6A4-promoter variant (5-HTTLPR) relates to disinhibition; (b) this association could affect total weight-loss during a behavioral/dietary treatment for obesity. METHODS AND RESULTS: A total of 2961 subjects attended voluntarily five weight-loss clinics; a subsample (n = 624) was recruited for SLC6A4 genotyping. Total weight-loss, emotional-eating-score and disinhibition-score were examined. We observed that: (a) the reduced ability to control food intake (disinhibition) is implicated in the impairment to lose weight; (b) SLC6A4-promoter variant is implicated in disinhibition. S carriers (low-expressing) of the SLC6A4-promoter variant had a lower inhibition capacity and showed more failure (1.6 times) to control the amount of food eaten than LL (p < 0.05); other factors such as eating while bored, overeating after work at night, or craving for specific foods were associated to the SLC6A4 genotype (p < 0.05); (c) The combination of disinhibition (high disinhibition) and genetics (S carrier) had a higher impact on total weight loss than each factor separately. CONCLUSIONS: SLC6A4-promoter variant is associated with the ability to control food intake and interacts with emotional eating to modulate total weight loss.

De la Higiene a la Salud pública. Apuntes para la historia / From Hygiene to Public Health. Notes for history

La Higiene ha sido motivo de preocupación para el hombre desde la más remota antigüedad, focalizándose en las enfermedades infecciosas, que fueron siempre un verdadero azote para el ser humano. Sólo en los últimos siglos ha derivado en la moderna Salud Pública, al incorporar los programas frente al resto de patologías e incorporar elementos de desarrollo y promoción de la salud. En la edad antigua, destacan las figuras de Moisés (siglo XIV a. de C.), Licurgo (siglo VII a C) e Hipócrates (siglo V a. de C.) que, desde distintas perspectivas, fueron desarrollando la Higiene y contribuyeron a su avance. El Imperio Romano supo incorporar el conocimiento de todas las naciones conquistadas, por lo que conoció un esplendor nunca visto en materia de organización social y sanitaria que. Sin embargo, sufrió un serio retroceso en el 313 de nuestra era con el Edicto de Milán y la visión resignada de la enfermedad y de la muerte que aportaba el cristianismo. La Edad Media, supone un largo periodo de oscurantismo, donde prácticas como la quiromancia, la influencia de los astros o las panaceas, entre otras, estuvieron muy arraigadas en la sociedad de la época. La invasión musulmana, aportó de nuevo a España un gran desarrollo de la Higiene y de las ciencias, al confluir en ella el saber grecolatino, hebreo y oriental. Es un periodo de terribles epidemias, como las de lepra y la de la peste de 1346, en la que falleció alrededor de la cuarta parte de la población de Europa. El descubrimiento de América supuso un incremento extraordinario del comercio y de los viajes, y la invención de la imprenta permitió una gran difusión del conocimiento. Al principio de la Edad Moderna, el Renacimiento supone un periodo brillante en la historia de España, con gran desarrollo de las ciencias y de la Medicina, la cual experimenta grandes avances en la Anatomía, al tiempo que Fracastoro funda la Epidemiología moderna.(AU)

Hygiene has been a matter of concern for mankind since ancient times, with its focus mainly on infectious diseases, which have always been a true scourge for human beings. Only in recent centuries has it derived in modern Public Health, by incorporating programs against other pathologies and incorporating elements of development and health promotion In ancient times, the figures of Moses (14th century BC), Licurgo (4th century BC) and Hippocrates (5th century BC) stand out, who, from different perspectives, developed the hygiene and contributed to its advancement. The Roman Empire knew how to incorpórate the knowledge of all the conquered nations, and as a consequence knew a splendor never seen before in terms of social and healthorganization. However, it suffered a serious setback in 313 AD. C. with the Edict of Milan and Christianity’s compliant view of illness and death. The Middle Ages, supposes a long period of obscurantism, where practices such as palmistry, the influence of the stars or panaceasamong others, were deeply rooted in the society of the time. The Muslim invasion once again brought to Spain a great development of hygiene and science, as Greco-Latin, Hebrew and Oriental knowledge converged in it. It is a period of terrible epidemics, such as leprosy and the plague of 1346, in which around a quarter of the population of Europe died. The discovery of America meant an extraordinary increase in trade and travel, and the invention of the printing press allowed for a great spread of knowledge. At the beginning of the Modern Age, the Renaissance represents a brilliant period in the history of Spain, with great development ofscience and Medicine, which experienced great advances in anatomy, at the time that Fracastoro founded modern epidemiology. Some private hygiene works are published, only intended for high society or the nobility. The 17th and 18th centuries brought exceptional progress to the medical sciences.(AU)

Lunch eating predicts weight-loss effectiveness in carriers of the common allele at PERILIPIN1: the ONTIME (Obesity, Nutrigenetics, Timing, Mediterranean) study.

BACKGROUND: We propose that eating lunch late impairs the mobilization of fat from adipose tissue, particularly in carriers of PERILIPIN1 (PLIN1) variants. OBJECTIVE: The aim was to test the hypothesis that PLIN1, a circadian lipid-stabilizing protein in the adipocyte, interacts with the timing of food intake to affect weight loss. DESIGN: A total of 1287 overweight and obese subjects [229 men and 1058 women; mean ± SD body mass index (in kg/m2): 31 ± 5] who attended outpatient obesity clinics were enrolled in the ONTIME (Obesity, Nutrigenetics, Timing, Mediterranean) study. Timing of food intake was estimated with a validated questionnaire. Anthropometric variables and PLIN1 genotypes were analyzed, including 6209T>C (rs2289487), 11482G>A (rs894160), 13041A>G (rs2304795), and 14995A>T (rs1052700). The main outcomes were effectiveness of the program and weight-loss progression during 28 wk of treatment. RESULTS: The PLIN1 locus was associated with variability in response to a weight-loss program. Specifically, carrying the minor C allele at the PLIN1 6209T>C was associated with better weight-loss response (P = 0.035). The probability of being a better responder [percentage of weight loss ≥7.5% (median)] was 33% higher among C than among TT carriers (OR: 1.32; 95% CI: 1.05, 1.67; P = 0.017). We found an interaction of PLIN1 × food timing between the 14995A>T variant and timing of lunch eating for total weight loss (P = 0.035). Among AA carriers, eating late was associated with less weight loss (P < 0.001), whereas time of eating did not influence weight loss among TT carriers (P = 0.326). CONCLUSIONS: Variability at the PLIN1 locus is associated with variability in weight loss. Moreover, eating late is related to lower weight-loss effectiveness among carriers of the AA genotype at the PLIN1 14995A>T variant. These results contribute to our ability to implement more precise and successful obesity treatments. The ONTIME study was registered at clinicaltrials.gov as NCT02829619.

Association of education with occurrence of delirium in patients from an emergency department.

BACKGROUND: Delirium is a neuropsychiatric syndrome with multiple etiological factors. Evaluation of delirium in different settings, especially the Emergency Department (ED) pertaining to different regions of the world with patients from different cultural and educational backgrounds is needed. OBJECTIVE: To determine the prevalence of delirium and its association with education in an ED in Brazil during a 6-month period. Methods: Patients aged >18 years were randomly selected from ED admissions. The instruments Confusion Assessment. METHOD: (CAM) scale, Mini-Mental State Examination (MMSE), Wechsler Logical Memory (WLM) and Charlson comorbidity score were applied to evaluate delirium, cognitive status, and comorbidities. RESULTS: The prevalence of delirium was10.7%. Delirium patients had significantly lower education, MMSE and WLM (immediate and delayed) scores, with 97.4% presenting episodic memory impairment. Patients with delirium had more history of neurological disorders. Three logistic regression models evaluating the association of variables with delirium were developed. Age and MMSE were retained in the first model, WLM scores in the second, and education in the third. CONCLUSION: To the best of our knowledge, this is the first study estimating the prevalence of delirium in a Brazilian ED. Lower education was associated with the occurrence of delirium.

INTRODUÇÃO: Delirium é uma síndrome neuropsiquiátrica, com fatores etiológicos múltiplos. A avaliação de delirium em diferentes ambientes, especialmente no Serviço de Emergência (SE) de diferentes regiões do mundo e com diferentes características culturais e educacionais é necessária. OBJETIVO: Determinar a prevalência de delirium e associação com educação em um SE no Brasil, durante seis meses. MÉTODOS: Foram randomizados aleatoriamente no SE os pacientes com idade acima de 18 anos. Escala Confusion Assessment Method (CAM), Mini Exame do Estado Mental (MEEM), o teste de Memória Lógica de Wechsler (MLW), e o escore de comorbidade de Charlson foram aplicados para avaliar delirium, status cognitivo, e comorbidades. RESULTADOS: A prevalência de delirium foi 10,7%. Os pacientes com delirium apresentaram significativamente menor escolaridade, escores mais baixos no MEEM e MLW (imediato e tardio), sendo que 97,4% apresentava comprometimento de memória episódica. Pacientes com delirium apresentaram mais história de transtorno neurológico prévio. Três modelos de regressão logística para delirium foram realizados. No primeiro, idade e MEEM foram mantidos no modelo final. No segundo, MLW imediato e tardio; e no terceiro, apenas educação. CONCLUSÃO: Este é o primeiro estudo brasileiro, de acordo com nosso melhor conhecimento, a estimar a prevalência de delirium em serviço de emergência. Nível educacional mais baixo foi associado com ocorrência de delirium.

Correction: Characterization of the Antiglioma Effect of the Oncolytic Adenovirus VCN-01.

[This corrects the article DOI: 10.1371/journal.pone.0147211.].

Characterization of the Antiglioma Effect of the Oncolytic Adenovirus VCN-01.

Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.

The Oncolytic Adenovirus VCN-01 as Therapeutic Approach Against Pediatric Osteosarcoma.

PURPOSE: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Despite aggressive chemotherapy, more than 30% of patients do not respond and develop bone or lung metastasis. Oncolytic adenoviruses engineered to specifically destroy cancer cells are a feasible option for osteosarcoma treatment. VCN-01 is a replication-competent adenovirus specifically engineered to replicate in tumors with a defective RB pathway, presents an enhanced infectivity through a modified fiber and an improved distribution through the expression of a soluble hyaluronidase. The aim of this study is to elucidate whether the use of VCN-01 would be an effective therapeutic strategy for pediatric osteosarcoma. EXPERIMENTAL DESIGN: We used osteosarcoma cell lines established from patients with metastatic disease (531MII, 678R, 588M, and 595M) and a commercial cell line (143B). MTT assays were carried out to evaluate the cytotoxicity of VCN-01. Hexon assays were used to evaluate the replication of the virus. Western blot analysis was performed to assess the expression levels of viral proteins and autophagic markers. The antitumor effect of VCN-01 was evaluated in orthotopic and metastatic osteosarcoma murine animal models. RESULTS: This study found that VCN-01, a new generation genetically modified oncolytic adenovirus, administered locally or systemically, had a potent antisarcoma effect in vitro and in vivo in mouse models of intratibial and lung metastatic osteosarcoma. Moreover, VCN-01 administration showed a safe toxicity profile. CONCLUSIONS: These results uncover VCN-01 as a promising strategy for osteosarcoma, setting the bases to propel a phase I/II trial for kids with this disease. Clin Cancer Res; 22(9); 2217-25. ©2015 AACR.

Endoplasmic reticulum stress-inducing drugs sensitize glioma cells to temozolomide through downregulation of MGMT, MPG, and Rad51.

BACKGROUND: Endoplasmic reticulum (ER) stress results from protein misfolding imbalance and has been postulated as a therapeutic strategy. ER stress activates the unfolded protein response which leads to a complex cellular response, including the upregulation of aberrant protein degradation in the ER, with the goal of resolving that stress. O(6)-methylguanine DNA methyltransferase (MGMT), N-methylpurine DNA glycosylase (MPG), and Rad51 are DNA damage repair proteins that mediate resistance to temozolomide in glioblastoma. In this work we sought to evaluate whether ER stress-inducing drugs were able to downmodulate DNA damage repair proteins and become candidates to combine with temozolomide. METHODS: MTT assays were performed to evaluate the cytotoxicity of the treatments. The expression of proteins was evaluated using western blot and immunofluorescence. In vivo studies were performed using 2 orthotopic glioblastoma models in nude mice to evaluate the efficacy of the treatments. All statistical tests were 2-sided. RESULTS: Treatment of glioblastoma cells with ER stress-inducing drugs leads to downregulation of MGMT, MPG, and Rad51. Inhibition of ER stress through pharmacological treatment resulted in rescue of MGMT, MPG, and Rad51 protein levels. Moreover, treatment of glioblastoma cells with salinomycin, an ER stress-inducing drug, and temozolomide resulted in enhanced DNA damage and a synergistic antitumor effect in vitro. Of importance, treatment with salinomycin/temozolomide resulted in a significant antiglioma effect in 2 aggressive orthotopic intracranial brain tumor models. CONCLUSIONS: These findings provide a strong rationale for combining temozolomide with ER stress-inducing drugs as an alternative therapeutic strategy for glioblastoma.

Chemical structure and anticoagulant activity of highly pyruvylated sulfated galactans from tropical green seaweeds of the order Bryopsidales.

Sulfated and pyruvylated galactans were isolated from three tropical species of the Bryopsidales, Penicillus capitatus, Udotea flabellum, and Halimeda opuntia. They represent the only important sulfated polysaccharides present in the cell walls of these highly calcified seaweeds of the suborder Halimedineae. Their structural features were studied by chemical analyses and NMR spectroscopy. Their backbone comprises 3-, 6-, and 3,6-linkages, constituted by major amounts of 3-linked 4,6-O-(1'-carboxy)ethylidene-d-galactopyranose units in part sulfated on C-2. Sulfation on C-2 was not found in galactans from other seaweeds of this order. In addition, a complex sulfation pattern, comprising also 4-, 6-, and 4,6-disulfated galactose units was found. A fraction from P. capitatus, F1, showed a moderate anticoagulant activity, evaluated by general coagulation tests and also kinetics of fibrin formation was assayed. Besides, preliminary results suggest that one of the possible mechanisms involved is direct thrombin inhibition.

Nutritional status, food intake and cardiovascular disease risk in individuals with schizophrenia in southern Brazil: a case-control study.

OBJECTIVES: To verify food consumption patterns and presence of risk anthropometric parameters in schizophrenic patients, trying to assess some modifiable cardiovascular risk. METHOD: Twenty-five schizophrenic outpatients, attended at the Hospital de Clínicas de Porto Alegre, Brazil, and 25 healthy controls matched by sex, age and body mass index (BMI) were included. Demographic (age, sex and socioeconomic status), anthropometric (weight, height and waist circumference), clinical (antipsychotics) and dietary consumption data (food frequency questionnaire) were obtained. RESULTS: There was a 40% frequency of overweight and 40% of obesity as verified by BMI, and 80% of increased risk of metabolic complications as measured by waist circumference. Most of the patients (68%) used atypical antipsychotics and no association was found between the distribution of the nutritional status according to BMI and type of antipsychotic used. There was a higher intake of total calories, calories and protein per kilogram of body weight, percentage of carbohydrates, and lower intake of omega-6, phytosterols, vitamin A and α-tocopherol by cases. Cholesterol and sodium intake did not differ between groups (365 ± 152 mg of cholesterol in cases and 313 ± 146 mg in controls; (3499 ± 1695 mg sodium by cases and 2874 ± 800 by controls). CONCLUSION: In this sample of schizophrenic patients there was a higher intake of calories and lower consumption of α-tocoferol and phitosterols, compared to controls. There was also elevated sodium, and cholesterol intake, and high frequency of overweight and central obesity.

The oncolytic adenovirus Δ24-RGD in combination with cisplatin exerts a potent anti-osteosarcoma activity.

Osteosarcoma is the most common malignant bone tumor in children and adolescents. The presence of metastases and the lack of response to conventional treatment are the major adverse prognostic factors. Therefore, there is an urgent need for new treatment strategies that overcome both of these problems. Our purpose was to elucidate whether the use of the oncolytic adenovirus Δ24-RGD alone or in combination with standard chemotherapy would be effective, in vitro and in vivo, against osteosarcoma. Our results showed that Δ24-RGD exerted a potent antitumor effect against osteosarcoma cell lines that was increased by the addition of cisplatin. Δ24-RGD osteosarcoma treatment resulted in autophagy in vitro that was further enhanced when combined with cisplatin. Of importance, administration of Δ24-RGD and/or cisplatin, in novel orthotopic and two lung metastatic models in vivo resulted in a significant reduction of tumor burden meanwhile maintaining a safe toxicity profile. Together, our data underscore the potential of Δ24-RGD to become a realistic therapeutic option for primary and metastatic pediatric osteosarcoma. Moreover, this study warrants a future clinical trial to evaluate the safety and efficacy of Δ24-RGD for this devastating disease.

Examen clínico: un método diagnóstico con dificultades en estudiantes de tercer año de la carrera de medicina / Clinical Method: a diagnosis tool with difficulties in students of third year of the medicine career

Introducción: el método clínico es un proceder científico y sistematizado que el médico ha empleado desde sus inicios y continúa vigente, es el arma primordial para el ejercicio de su profesión, considerado como un sistema de pensamiento lógico, ordenado y científico con la finalidad de establecer un diagnóstico e instaurar un tratamiento. Objetivo: comprobar el dominio y aplicación del método clínico de los estudiantes de tercer año de la carrera de Medicina en Moa, durante la rotación de Propedéutica, durante el curso escolar 2015-2016. Método: se realizó un estudio descriptivo observacional, con una muestra integrada por 52 estudiantes, los que constituyeron el 100% de la población estudiada. Se consideraron los resultados por los estudiantes en los exámenes prácticos de la asignatura de Propedéutica. Resultados: El 36,5% obtuvo resultados insatisfactorios en los exámenes, con un índice de calidad del 42,4%; el 65,3% presentó dificultades en el interrogatorio, el 57,6% en el examen físico y el 50,0% de los profesores valoró de regular la interrelación entre: interrogatorio, examen físico, resumen sindromológico y complementarios, considerando que el local de los exámenes tenía buena privacidad en el 85,7%, higiene en el 78,5% e iluminación en el 71,4%. Conclusiones: se demostró que existen dificultades en los estudiantes de tercer año de la carrera de medicina para desarrollar habilidades que reflejen dominio y aplicación del método clínico.

Introduction: the clinical method is a systematized and scientific practice; the doctor has ever used it up to nowadays. This method is of high importance, since it denotes a system of logical, well-ordered and scientific thought to make a diagnosis and give the treatment. Objective: to check the mastery and application of the clinical method of the students of third year of the career of Medicine in Moa, in the Propaedeutic cycle in 2015-2016 school year. Method: an observational descriptive study was carried out, with a sample of 52 students who represented the 100% of the population. The students´ results achieved in the practical exams of the Propaedeutic subject were considered. Results: insufficient results were obtained in the exam in 36.5% of the students, with an index of quality of 42.4%, 65.3% presented difficulties in the medical interview, 57.6% in the physical exam and. The interrelation among medical interview, physical exam, syndromological summary and complementary were assessed as medium by 50.0% of the professors, considering that the place where the exams were developed had good privacy in 85.7%, hygiene in 78.5% and illumination in 71.4%. Conclusions: the study demonstrated that there were difficulties in the students of third year of the medicine career, to develop abilities that show knowledge and use of the clinical method.