Evaluation of Alcohol Preference and Drinking in msP Rats Bearing a Crhr1 Promoter Polymorphism

Alcoholism is a pervasive societal problem, yet available pharmacotherapies fail to treat most sufferers. The type 1 corticotropin-releasing factor (CRF1) receptor has received much attention for its putative role in the progression to alcohol dependence, although at present its success in clinical trials has been limited. Two single-nucleotide polymorphisms in the rat Crhr1 promoter have been identified in the Marchigian substrain of Sardinian alcohol-preferring (msP) rats. Unlike other Wistar-derived alcohol-preferring lines, nondependent msP rats reduce their alcohol self-administration in response to CRF1 antagonists and show increased brain CRF1 expression. The current study tested the hypotheses that the A alleles in the Crhr1 promoter polymorphisms are: (1) unique to msP (vs. CRF1 antagonist-insensitive) alcohol-preferring lines and (2) associate with greater alcohol preference or intake. Two related polymorphisms were observed in which both loci on a given chromosome were either mutant variant (A) or wild-type (G) alleles within the distal Crhr1 promoter of 17/25 msP rats (68%), as compared to 0/23 Indiana P rats, 0/20 Sardinian alcohol-preferring rats bred at Scripps (Scr:sP) and 0/21 outbred Wistar rats. Alcohol consumption in msP rats did not differ according to the presence of Crhr1 A alleles, but greater alcohol preference (98%) was observed in A allele homozygous msP rats (AA) compared to msP rats with wild-type (GG, 91%) or heterozygous (GA, 91%) genotypes. The greater alcohol preference reflected decreased water intake, accompanied by reduced total calories consumed by AA rats. The data show that msP rats differentially possess mutant A variant alleles in the polymorphic promoter region of the Crhr1 gene that may differentially regulate consumption

Eficacia y seguridad del cannabis medicinal en el tratamiento del dolor de origen oncológico: revisión y metaanálisis

Lorena Vecino: Estudiante de Medicina, Ciclo de Metodología Científica II, Facultad de Medicina, Universidad de la República, Uruguay.-- Joaquín Fontoura: Estudiante de Medicina, Ciclo de Metodología Científica II, Facultad de Medicina, Universidad de la República, Uruguay.-- Valentina Zorrilla: Estudiante de Medicina, Ciclo de Metodología Científica II, Facultad de Medicina, Universidad de la República, Uruguay.-- Jimena Varela: Estudiante de Medicina, Ciclo de Metodología Científica II, Facultad de Medicina, Universidad de la República, Uruguay.-- Erica Nieves: Estudiante de Medicina, Ciclo de Metodología Científica II, Facultad de Medicina, Universidad de la República, Uruguay.-- Sebastián Giménez: Estudiante de Medicina, Ciclo de Metodología Científica II, Facultad de Medicina, Universidad de la República, Uruguay.-- Javier Pintos: Docente supervisor. Departamento de Medicina Preventiva y Social, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.-- Emails de autores: Lorena Vecino: [email protected]; Joaquín Fontoura: [email protected]; Valentina Zorrilla: [email protected]; Jimena Varela: [email protected]; Erica Nieves: [email protected]; Sebastián Giménez: [email protected] los múltiples síntomas experimentados por los pacientes con cáncer, el dolor es uno de los que más afectan la calidad vida, y existen reportes de que algunos pacientes se benefician del uso de cannabis. El objetivo de este trabajo fue revisar la evidencia científica proveniente de Ensayos Clínicos Aleatorizados (ECAs) para evaluar los efectos del cannabis medicinal en el tratamiento del dolor de origen oncológico. Se definió una estrategia de búsqueda para identificar en la base de datos de PubMed todos los ECAs publicados en los últimos 15 años que compararon el efecto de derivados del cannabis (naturales, sintéticos o combinados) versus placebo en pacientes con dolor relacionado al cáncer. Se realizó un metaanálisis utilizando el programa RevMan. Un total de seis artículos cumplieron con los criterios de inclusión de la pregunta PICO. La calidad de evidencia de estos estudios fue en general pobre. Todos los ECAs reportaron una leve mejoría del dolor a favor del cannabis, aunque solo dos de ellos presentaron resultados estadísticamente significativos. El metaanálisis mostró un efecto muy leve de los derivados del cannabis: un descenso de 0,44 puntos (IC95%:0,25-0,63) en una escala de intensidad del dolor de 0 a 10. Los efectos adversos fueron en general leves y un poco más frecuentes en los grupos que recibieron cannabis. A pesar de que el efecto sobre el dolor de origen oncológico parece ser leve, es necesario identificar los componentes analgésicos del cannabis para desarrollar productos más eficaces para el tratamiento del dolor.Among the multiple symptoms experienced by cancer patients, pain is one of those that most affect the quality of life, and there are anecdotal reports that some patients benefit from the use of cannabis. The objective of this investigation was to review the scientific evidence produced by Randomized Clinical Trials (RCTs) to evaluate the effects of medical cannabis in the treatment of cancer-related pain. A search strategy was defined to identify in the PubMed database all RCTs published in the last 15 years that compared the effect of cannabis derivatives (natural, synthetic or combined) versus placebo in patients with cancer-related pain. A meta-analysis was performed using the RevMan program.Six articles met the inclusion criteria of the PICO question. The quality of evidence from these studies was generally poor. All RCTs reported a slight improvement in pain in favor of cannabis, although only two of them obtained statistically significant results. The metaanalysis showed a slight effect of medical cannabis: a decrease of 0.44 points (95% CI: 0.25-0.63) on a scale of pain intensity from 0 to 10. Adverse effects were generally mild and slightly more frequent in those groups that received cannabis. Despite the fact that the effect on cancer pain appears to be slight, it is necessary to identify the analgesic components of cannabis to develop more effective products for the treatment of pain

Development of benzodioxane-benzamides inhibitors of FtsZ as potent broad-spectrum antimicrobial agents

1 p.-1 graph. abst.Antimicrobial resistance is a serious worldwide health threat. The identification of novel potential antibiotic targets is one of the ways to slow down its worsening. FtsZ, one of the bacterial cell division machinery proteins, emerged in the last decade for its crucial role in bacterial replication and viability [1]. Benzamide compounds are the most studied and promising FtsZ inhibitors developed so far, due to their high anti-staphylococcal activity, their low cytotoxicity and the interesting results obtained in association with other antibiotic classes [2]. Along these lines, here we report our recent findings on a class of FtsZ inhibitors, containing a 2,6-difluoro-benzamide scaffold linked to a hydrophobically substituted 1,4-benzodioxane ring [3-6]. We firstly validated a robust computational model, which drove us to identify the structural features the 1,4-benzodioxane moiety and the alkoxy linker should possess, in order to perfectly fit the FtsZ binding pocket. We thus developed several interesting compounds, having submicromolar antibacterial activities and showing comparable inhibitory activities towards both Gram-positive (Staphylococcus aureus and Bacillus subtilis) [3,5] and Gram-negative (Escherichia coli) FtsZ. Nevertheless, these derivatives proved to be substrates of E. coli efflux pump AcrAB, thus affecting their potencies [4]. These surprising and novel results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. We set-up and performed different assays, to firstly validate FtsZ as the target of our class of compounds. Morphometric analysis and fluorescence microscopy let us evaluate the typical alterations of cell division and FtsZ inhibition, as well as the effects on FtsZ localization [6].Moreover, we took advantages of fluorescence anisotropy to investigate and assess the impact of our derivatives on the kinetics of disassembly of the GTP triggered FtsZ polymers. Furthermore, we used confocal microscopy, to evaluate the shape and the dimension of FtsZ polymers, when in presence or in absence of our compounds in solutions containing crowding agents mimicking the crowded environment in the cytoplasm.Peer reviewe

Consummatory, anxiety-related and metabolic adaptations in female rats with alternating access to preferred food

Avoidance of and relapse to palatable foods is a qualitative aspect of dieting, a putative risk factor for eating disorders or obesity. The present studies tested the hypotheses that rats with alternating access to highly preferred foods would show: (1) hypophagia, a function of the relative hedonic value of the underaccepted diet, (2) increased anxiety-like behavior and psychomotor arousal when preferred diet was unavailable, (3) obesity-like changes, and (4) stable individual differences in diet-switch-induced hypophagia. Preferences among three high-carbohydrate diets were determined in female Wistar rats (n = 16). Adolescent rats (n = 162) received the following weekly diet schedules: (1) continuous regular chow (7 days/week), (2) chow (5 days/week) followed by a more preferred diet (2 days/week), or (3) chow (5 days/week) followed by a less preferred chow (2 days/week). Some animals were yoke-restricted (75% calories) when provided chow to increase its rewarding properties. Diurnal locomotor activity was measured in a familiar environment, and anxiety-like behavior was assessed in the elevated plus-maze and defensive withdrawal tests. Rats withdrawn from the preferred diet showed hypophagia, anxiogenic-like behavior, increased locomotion, and weight loss. Chow hypophagia was progressive, individuat-specific in magnitude, (partly) non-homeostatic in nature, and blunted by previous chow restriction. Despite eating less, rats cycled with the preferred diet became heavier, fatter, and diurnally less active, with greater feed efficiency and proinflammatory adipokine levels than chow controls. The present diet cycling procedure may model consummatory, anxiety-related, and metabolic effects of qualitative dieting in humans. (C) 2008 Elsevier Ltd. All rights reserved

Intermittent access to preferred food reduces the reinforcing efficacy of chow in rats

Intermittent, extended access to preferred diets increases their intake. However, the effects of such access on the acceptance and reinforcing efficacy of otherwise satisfying alternatives is less known. To investigate the role of nonnutritional contributions to the hypophagia that follows removal of preferred food, male Wistar rats were fed a chow diet (Chow A/I), preferred to their regular chow (Chow), which was equally consumed under 1-choice conditions to an even more preferred chocolate-flavored, sucrose-rich diet (Preferred). Rats then learned to obtain Chow A/I pellets under a progressive ratio schedule of reinforcement and were assigned to two matched groups. Each week, one group (n = 15) was diet-cycled, receiving Chow A/I for 5 days followed by the Preferred diet for 2 days. Controls received Chow A/I daily (n = 14). Progressive ratio sessions were performed daily during the 5 days that all subjects received Chow A/I in the home cage. Across 5 wk, diet-cycled rats progressively ate less of the otherwise palatable Chow A/I diet. Hypophagia was not due to greater prior intake or weight gain, motor impairment, or facilitated satiation and was associated with changes in progressive ratio performance that suggested a reduced reinforcing efficacy of the Chow A/I diet in diet-cycled animals. By week 4, diet-cycled animals began to overeat the preferred diet, especially during the first 6 h of renewed access, resembling a deprivation effect. The results suggest that intermittent access to highly preferred food, as practiced by many restrained eaters, may progressively decrease the acceptability of less palatable foods, and may promote relapse to more rewarding alternatives

Sigma-1 receptor knockout mice display a depressive-like phenotype

Activation of sigma-1 receptors (Sig-1R) reportedly has antidepressant-like action. Limited data suggest that Sig-1Rs also modulate anxiety-related behaviors. The present experiments measured depressive-like, anxiety-like and motor behavior in Sig-1R knockout mice and their wildtype littermates. Sig-1R knockout mutants showed increased immobility in the forced swimming test, a depressive-like phenotype, but normal anxiety-like behavior in the elevated plus-maze and light/dark box tests and normal locomotor activity. The results further suggest that Sig-1Rs inversely modulate depressive-like behavior. (C) 2008 Elsevier B.V. All rights reserved

Selective reduction of alcohol drinking in Sardinian alcohol-preferring rats by a sigma-1 receptor antagonist

Sigma receptors have been implicated in appetitive effects of psychostimulants and in high levels of ethanol intake. This study tested the hypothesis that the sigma-1 receptor subtype (Sig-1R) may modulate ethanol intake. The effects of acute and repeated treatment with the potent, selective Sig-1R antagonist NE-100 on ethanol intake (10%) were studied in adult, male Sardinian alcohol-preferring (sP) rats, a model of genetic predisposition to high ethanol drinking. To assess the specificity of action, the acute effects of NE-100 on intake of an equally preferred sucrose solution and of a higher concentration of ethanol that sP rats did not prefer over water (28%), were determined. Finally, the ability of NE-100 administration to prevent the increased ethanol intake that occurs after deprivation was evaluated. Acute treatment with NE-100 dose-dependently (10-30 mg/kg) reduced 1- and 3-h intake of 10% ethanol solution in sP rats, while increasing concurrent water intake and not affecting food intake. NE-100 (17.8-30 mg/kg) comparably reduced intake of the 28% ethanol solution, while not suppressing 1.25% sucrose solution intake, suggesting selectivity of action against ethanol intake. Acute NE-100 (30 mg/kg) also prevented an increase in ethanol intake after a 7-day deprivation period. Repeated, daily NE-100 (30 mg/kg) treatment continued to reduce 24-h ethanol intake across 7 days of administration, with some, but incomplete, tolerance, evident by day 6. The results implicate the Sig-1R system in alcohol drinking, identifying a potential therapeutic target for the treatment of alcohol use disorders

Evaluación del uso del agua en PYMES de alimentos: caso de estudio en una planta de beneficio avícola en Colombia

Water resources and the food sector in developing countries are key elements in ensuring the goals of sustainable development. The challenge is even greater, considering that the 90% of companies in these countries are small and medium enterprises (SMEs). To evaluate water management in food SMEs in Colombia, a case study was conducted in a poultry processing plant. Operation was determined by technical visits, measurements and water balances and the performance was evaluated by a sensitivity analysis. Total water consumption was 206,2m3ꞏd-1 finding performances between 10,9 and 28,8 L.chicken-1. The areas of plucking and evisceration were responsible for 62% and cleaning for 19% of water use. Daily, a volume of 32,4m3 water was used as a means of transport. It was found that water consumption exceeds the recommended values of the Environmental Technology Best Practice Programme. Proposals for improvement in situ focused on prevention and minimization were suggested.El sector de alimentos y el agua en países en desarrollo, son elementos fundamentales para alcanzar los objetivos del desarrollo sostenible. Este reto a enfrentar es mayor cuando el 90% de las empresas son pequeñas y medianas (Pymes). Para evaluar cómo es el manejo del agua en las Pymes, un estudio de caso fue desarrollado en una planta de beneficio avícola colombiana. Visitas técnicas, monitoreos y balances de agua determinaron el funcionamiento. El desempeño fue evaluado por un análisis de sensibilidad. El consumo promedio de agua fue 206,2m3.d-1 hallando desempeños entre 10,9 y 28,8 L.pollo-1, con las áreas de desplume y evisceración responsables del 62% y la limpieza del 19%. Diariamente 32,4m3 de agua son empleados como medio de transporte. Se encontró que el consumo de agua excede los valores recomendados del Programa de Mejores Prácticas de Tecnología Ambiental. Propuestas de mejora enfocadas en prevención y minimización fueron planteadas

Evaluation of alcohol preference and drinking in msP rats bearing a Crhr1 promoter polymorphism

Alcoholism is a pervasive societal problem, yet available pharmacotherapies fail to treat most sufferers. The type 1 corticotropin-releasing factor (CRF1) receptor has received much attention for its putative role in the progression to alcohol dependence, although at present its success in clinical trials has been limited. Two single-nucleotide polymorphisms in the rat Crhr1 promoter have been identified in the Marchigian substrain of Sardinian alcohol-preferring (msP) rats. Unlike other Wistar-derived alcohol-preferring lines, nondependent msP rats reduce their alcohol self-administration in response to CRF1 antagonists and show increased brain CRF1 expression. The current study tested the hypotheses that the A alleles in the Crhr1 promoter polymorphisms are: (1) unique to msP (vs. CRF1 antagonist-insensitive) alcohol-preferring lines and (2) associate with greater alcohol preference or intake. Two related polymorphisms were observed in which both loci on a given chromosome were either mutant variant (A) or wild-type (G) alleles within the distal Crhr1 promoter of 17/25 msP rats (68%), as compared to 0/23 Indiana P rats, 0/20 Sardinian alcohol-preferring rats bred at Scripps (Scr:sP) and 0/21 outbred Wistar rats. Alcohol consumption in msP rats did not differ according to the presence of Crhr1 A alleles, but greater alcohol preference (98%) was observed in A allele homozygous msP rats (AA) compared to msP rats with wild-type (GG, 91%) or heterozygous (GA, 91%) genotypes. The greater alcohol preference reflected decreased water intake, accompanied by reduced total calories consumed by AA rats. The data show that msP rats differentially possess mutant A variant alleles in the polymorphic promoter region of the Crhr1 gene that may differentially regulate consumption