Disposition of d‐penicillamine,a promising drug for preventing alcohol‐relapse. Influence of dose,chronic alcohol consumption and age: studies in rats

Pharmacokinetic studies concerning d ‐penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d ‐penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d ‐penicillamine disposition in order to guide future clinical studies on the anti‐relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d ‐penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of d ‐penicillamine were performed using young or adult ethanol‐naïve rats or adult ethanol‐experienced (subjected to a long‐term ethanol self‐administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalized AUC₀^∞, V₁ and k₁₀ revealed that disposition, in the range plasma concentrations assayed, is non‐linear both in young ethanol‐naïve and in adult ethanol‐experienced rats. Notably, no significant changes in t_1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t_1/2. d ‐Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non‐linear, the lack of significant alterations of the t_1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters d ‐penicillamine disposition but, again, does not modify t_1/2. Copyright © 2014 John Wiley & Sons, Ltd.     

Epigenetics in Adipose Tissue,Obesity, Weight Loss,and Diabetes

Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them.     

T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy

The origin of T cells after highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus 1 (HIV-1) is now under discussion. The possibility of renewed lymphopoiesis in aged thymuses is still controversial. In this work we combine the analysis of na?ve T cells, T-cell receptor excision circles (TRECs), and computed tomography scanning of thymic tissue to further assess whether the thymus is involved in immune reconstitution. Fifteen antiretroviral-na?ve HIV-1-infected patients were evaluated during 48 weeks of HAART. At baseline, significant correlation was present among age and both thymic volume and TRECs, and between na?ve T cells and TRECs. After starting HAART, there was a significant increase at week 12 in na?ve CD4(+) and CD8(+) T cells, TRECs, and thymic volume. The initial net increases in na?ve T cells and TREC counts were significantly correlated. Changes in thymic volume and TRECs were also indirectly related; splitting the population into 2 groups of high and low baseline TREC levels, only the group with low TREC levels had significant increases in both TRECs and thymic volume. Thus, the increase in thymic volume might be functional, in response to depleted TREC levels. Taken together, our data strongly suggest a thymic role in immune reconstitution, at least in patients with depleted baseline TREC levels. (Blood. 2002;99:3702-3706)     

The genome of Bacillus coahuilensis reveals adaptations essential for survival in the relic of an ancient marine environment

The Cuatro Ciénegas Basin (CCB) in the central part of the Chihuahan desert (Coahuila, Mexico) hosts a wide diversity of microorganisms contained within springs thought to be geomorphological relics of an ancient sea. A major question remaining to be answered is whether bacteria from CCB are ancient marine bacteria that adapted to an oligotrophic system poor in NaCl, rich in sulfates, and with extremely low phosphorus levels (<0.3 μM). Here, we report the complete genome sequence of Bacillus coahuilensis, a sporulating bacterium isolated from the water column of a desiccation lagoon in CCB. At 3.35 Megabases this is the smallest genome sequenced to date of a Bacillus species and provides insights into the origin, evolution, and adaptation of B. coahuilensis to the CCB environment. We propose that the size and complexity of the B. coahuilensis genome reflects the adaptation of an ancient marine bacterium to a novel environment, providing support to a “marine isolation origin hypothesis” that is consistent with the geology of CCB. This genomic adaptation includes the acquisition through horizontal gene transfer of genes involved in phosphorous utilization efficiency and adaptation to high-light environments. The B. coahuilensis genome sequence also revealed important ecological features of the bacterial community in CCB and offers opportunities for a unique glimpse of a microbe-dominated world last seen in the Precambrian.     

Comparación de los efectos inducidos sobre la calciuria por tiazidas y diferentes dosis de sal en la dieta: implicaciones en la práctica clínica

Introduction

Both dietary restriction of sodium chloride (NaCl) and treatment with thiazides have been used in hypercalciuric patients.

The retained antrum, its endoscopic diagnosis and clinical significance]

A 65-year-old man was admitted to our hospital with gastrointestinal bleeding. Seventeen years previously, he had a Billroth II procedure for a bleeding duodenal ulcer. A gastroscopy performed on admission showed a stomal ulcer with signs of recent haemorrhage. In the proximal end of the afferent loop, we saw retained gastric mucosa. Histological evaluation confirmed the existence of antrum gastric mucosa. Other diagnostic test for retained gastric antrum were normal. The different approaches in the diagnosis of retained gastric antrum, the importance of our findings and the clinic implications are discussed. We conclude that endoscopic management may be the first diagnostic method in the assessment of retained gastric antrum, and it's possible to find gastric mucosa in the proximal end of the afferent loop (antrum retained), without clinic manifestations.