Effects of Weight Loss on Adipose Tissue, Liver and Heart Metabolism in Humans

Obesity has become the leading cause of many chronic diseases, such as type 2 diabetes and cardiovascular diseases. The prevalence of obesity is high in developed countries and it is also a major cause of the use of health services. Ectopic fat accumulation in organs may lead to metabolic disturbances, such as insulin resistance.Weight loss with very-low-energy diet is known to be safe and efficient. Weight loss improves whole body insulin sensitivity, but its effects on tissue and organ level in vivo are not well known. The aims of the studies were to investigate possible changes of weight loss in glucose and fatty acid uptake and perfusion and fat distribution at tissue and organ level using positron emission tomography and magnetic resonance imaging and spectroscopy in 34 healthy obese subjects. The results showed that whole-body insulin sensitivity increased after weight loss with very-low-energy diet and this is associated with improved skeletal muscle insulin-stimulated glucose uptake, but not with adipose tissue, liver or heart glucose uptake. Liver insulin resistance decreased after weight loss. Liver and heart free fatty acid uptakes decreased concomitantly with liver and heart triglyceride content. Adipose tissue and myocardial perfusion decreased. In conclusion, enhanced skeletal muscle glucose uptake leads to increase in whole-body insulin sensitivity when glucose uptake is preserved in other organs studied. These findings suggest that lipid accumulation found in the liver and the heart in obese subjects without co-morbidies is in part reversible by reduced free fatty acid uptake after weight loss. Reduced lipid accumulation in organs may improve metabolic disturbances, e.g. decrease liver insulin resistance. Keywords: Obesity, weight loss, very-low-energy diet, adipose tissue metabolism, liver metabolism, heart metabolism, positron emission tomography

Role of human hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) in steroid-dependent diseases in females –novel indications for HSD17B1 inhibitors. Phenotypic analysis of transgenic mice overexpressing human HSD17B1.

Hormone-dependent diseases, e.g. cancers, rank high in mortality in the modern world, and thus, there is an urgent need for new drugs to treat these diseases. Although the diseases are clearly hormone-dependent, changes in circulating hormone concentrations do not explain all the pathological processes observed in the diseased tissues. A more inclusive explanation is provided by intracrinology – a regulation of hormone concentrations at the target tissue level. This is mediated by the expression of a pattern of steroid-activating and -inactivating enzymes in steroid target tissues, thus enabling a concentration gradient between the blood circulation and the tissue. Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form a family of enzymes that catalyze the conversion between low active 17-ketosteroids and highly active 17beta-hydroxysteroids. HSD17B1 converts low active estrogen (E1) to highly active estradiol (E2) with high catalytic efficiency, and altered HSD17B1 expression has been associated with several hormone-dependent diseases, including breast cancer, endometriosis, endometrial hyperplasia and cancer, and ovarian epithelial cancer. Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered to be a promising drug target for estrogen-dependent diseases. A few studies have indicated that the enzyme also has androgenic activity, but they have been ignored. In the present study, transgenic mice overexpressing human HSD17B1 (HSD17B1TG mice) were used to study the effects of the enzyme in vivo. Firstly, the substrate specificity of human HSD17B1 was determined in vivo. The results indicated that human HSD17B1 has significant androgenic activity in female mice in vivo, which resulted in increased fetal testosterone concentration and female disorder of sexual development appearing as masculinized phenotype (increased anogenital distance, lack of nipples, lack of vaginal opening, combination of vagina with urethra, enlarged Wolffian duct remnants in the mesovarium and enlarged female prostate). Fetal androgen exposure has been linked to polycystic ovary syndrome (PCOS) and metabolic syndrome during adulthood in experimental animals and humans, but the genes involved in PCOS are largely unknown. A putative mechanism to accumulate androgens during fetal life by HSD17B1 overexpression was shown in the present study. Furthermore, as a result of prenatal androgen exposure locally in the ovaries, HSD17B1TG females developed ovarian benign serous cystadenomas in adulthood. These benign lesions are precursors of low-grade ovarian serous tumors. Ovarian cancer ranks fifth in mortality of all female cancers in Finland, and most of the ovarian cancers arise from the surface epithelium. The formation of the lesions was prevented by prenatal antiandrogen treatment and by transplanting wild type (WT) ovaries prepubertally into HSD17B1TG females. The results obtained in our non-clinical TG mouse model, together with a literature analysis, suggest that HSD17B1 has a role in ovarian epithelial carcinogenesis, and especially in the development of serous tumors. The role of androgens in ovarian carcinogenesis is considered controversial, but the present study provides further evidence for the androgen hypothesis. Moreover, it directly links HSD17B1-induced prenatal androgen exposure to ovarian epithelial carcinogenesis in mice. As expected, significant estrogenic activity was also detected for human HSD17B1. HSD17B1TG mice had enhanced peripheral conversion of E1 to E2 in a variety of target tissues, including the uterus. Furthermore, this activity was significantly decreased by treatments with specific HSD17B1 inhibitors. As a result, several estrogen-dependent disorders were found in HSD17B1TG females. Here we report that HSD17B1TG mice invariably developed endometrial hyperplasia and failed to ovulate in adulthood. As in humans, endometrial hyperplasia in HSD17B1TG females was reversible upon ovulation induction, triggering a rise in circulating progesterone levels, and in response to exogenous progestins. Remarkably, treatment with a HSD17B1 inhibitor failed to restore ovulation, yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment. We also demonstrate that HSD17B1 is expressed in normal human endometrium, hyperplasia, and cancer. Collectively, our non-clinical data and literature analysis suggest that HSD17B1 inhibition could be one of several possible approaches to decrease endometrial estrogen production in endometrial hyperplasia and cancer. HSD17B1 expression has been found in bones of humans and rats. The non-clinical data in the present study suggest that human HSD17B1 is likely to have an important role in the regulation of bone formation, strength and length during reproductive years in female mice. Bone density in HSD17B1TG females was highly increased in femurs, but in lesser amounts also in tibias. Especially the tibia growth plate, but not other regions of bone, was susceptible to respond to HSD17B1 inhibition by increasing bone length, whereas the inhibitors did not affect bone density. Therefore, HSD17B1 inhibitors could be safer than aromatase inhibitors in regard to bone in the treatment of breast cancer and endometriosis. Furthermore, diseases related to improper growth, are a promising new indication for HSD17B1 inhibitors.

Argilas especiais: argilas quimicamente modificadas - uma revisão

The simultaneous use of the specific values of some structural and chemical properties of clay minerals, such as kaolinite, montmorillonite and talc, allows the development of new properties for these materials, especially in relation to the external and internal microcrystal surfaces. These developments are very diversified for montmorillonite, due to the high specific surface area, expansible basal spacings, easy intercalation inside the 2:1 structural layers and a reversible and high cation exchance capacity. The review presents examples of chemical modifications on kaolins, montmorillonites (bentonites) and talcs.

Dinâmica complexa no sistema bromato/hipofosfito/acetona/manganês e ferroína

New chemical systems have been recently designed for the study of complex phenomena such as oscillatory dynamics in the temporal domain and spatiotemporal pattern formation. Systems derived from oscillators based on the chemistry of bromate are the most extensively studied, with the celebrated Belousov-Zhabotinsky (BZ) reaction being the most popular example. Problems such as the formation of bubbles (CO2) and solid precipitate in the course of the reaction and the occurrence of simply short-lived oscillations under batch conditions are very common and, in some cases, compromise the use of some of these systems. It is investigated in this paper the dynamic behavior of the bromate/hypophosphite/acetone/dual catalyst system, which has been sugested as an interesting alternative to circumvent those inconvenients. In this work, manganese and ferroin are employed as catalysts and the complete system (BrO3-/H2PO2-/acetone/Mn(II)-ferroin) is studied under batch conditions. Temporal symmetry breaking was studied in a reactor under agitation by means of simultaneous records of the potential changes of platinum and Ag/AgBr electrodes, both measured versus a reversible hydrogen electrode. Additionally, spatio-temporal formation of target patterns and spiral waves were obtained when the oscillating mixture was placed in a quasi two-dimensional reactor.

Estudi sobre la qualitat de vida de les persones amb demència ateses a la Unitat d'avaluació de deteriorament cognitiu de l'Hospital de la Santa Creu

OBJECTIU: determinar la qualitat de vida de les persones amb demència ateses en una unitat avaluadora de deteriorament cognitiu. MÈTODE: estudi descriptiu transversal amb una mostra consecutiva no probabilística, formada per 42 persones amb demència tipus Alzheimer lleu o moderada i els seus cuidadors. La Qualitat de Vida (QV) es va avaluar amb el qüestionari QoL-AD (Quality of Life Alzheimer’s Disease) en les versions per al pacient (QoL-ADp) i per al cuidador (QoL-ADc). RESULTATS: la mitjana de puntuació del QoL-ADp va ser de 35,38 punts (DE = 5,24) i del QoL-Adc, de 30,60 (DE 5,33). La diferència entre aquests resultats és significativa (p<0,001). Els pacients amb simptomatologia depressiva i els seus cuidadors van puntuar significativament més baix el QoL-AD (p<0,001). En les freqüències per ítems del QoL-ADp s’observa que: més del 75% van valorar com a bona/excel·lent les condicions de vida, família, matrimoni/relació estreta, vida social, situació financera i vida en general; el 61% valoraren bona/excel·lent la capacitat per realitzar tasques a casa; prop del 50% pensava que l’estat d’ànim, l’energia, la salut física, la capacitat per fer coses per diversió i la visió de si mateixos era dolenta/regular, i el 85,7% opinava que la seva memòria era dolenta/regular. CONCLUSIONS: els resultats obtinguts en el QoL-AD no difereixen dels obtinguts en altres investigacions. Suggereixen que les intervencions que genera l’avaluació de la QV en la pràctica clínica inclouen aspectes centrats pròpiament en la malaltia i aspectes vinculats amb les relacions socials.

Anestésicos locais: interação com membranas biológicas e com o canal de sódio voltagem-dependente

Many theories about the mechanism of action of local anesthetics (LA) are described in the literature. Two types of theories can be distinguished: those that focus on the direct effects of LA on their target protein in the axon membranes, i.e. the voltage-gated sodium channel and the ones that take into account the interaction of anesthetic molecules with the lipid membrane phase for the reversible nerve blockage. Since there is a direct correlation between LA hydrophobicity and potency, it is crucial to take this physico-chemical property into account to understand the mechanism of action of LA, be it on the sodium channel protein, lipid(s), or on the whole membrane phase.

A primeira lei da termodinâmica dos processos homogêneos

Thermodynamics of homogeneous processes, which corresponds to the very special situation in thermodynamics of continuous media, is used to discuss the first law. An important part of this work is the exposition of some typical mathematical errors, frequently found in the traditional presentation of thermodynamics. The concepts of state and process functions are discussed, as well as reverse and reversible processes, temporality and its implications on thermodynamics, energy reservoirs and symmetry. Our proposal is to present the first law by using a time dependent viewpoint coherent with mechanics and the foundations of that viewpoint.

O experimento de Clement-Desormes no século XXI

The Clement-Desormes experiment is reviewed. By reason of a finite difference between the pressure within the system and its surroundings, Bertrand and McDonald have criticized the usual consideration of the adiabatic expansion as reversible. Garland, Nibler and Shoemaker oppose, defining regions through virtual boundaries where the surroundings do not operate. For Holden, the use of virtual boundaries is expendable. Experiments cannot support a hypothesis testing due to experiment's intrinsic uncertainty. The role of polytropy in uncertainty is discussed. Both thermodynamic definitions and kinetic model depict the real processes as irreversible phenomena and the reversible ones as a limiting hypothetical case.

Electrochemical study, on mercury, of a Meta-nitroarylamine derivative of nor-β-lapachone, an antitumor and trypanocidal compound

The electrochemistry of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2- b]furan-4,5-dione ([Q]-PhNO2), on mercury was investigated. The first peak is consistent with a quasi-reversible one-electron reduction of the ortho-quinone, forming [Q•-]-PhNO2, while the second one, bielectronic, corresponds to the simultaneous reduction of the latter radical to a dianion and the nitro group to a nitro radical anion. The second order rate constant, k disp, for the decay of [Q•-]-PhNO2 is 15.188 x 10³ ± 827 mol"1 L s"1 and the t1/2 equals 0.06 s. E¹7Ic values for [Q]-PhNO2 and its precursor, nor-β-lapachone, are similar. The ease of semiquinone generation and its stability are parameters statistically relevant in the correlation biochemical/theoretical aspects.

Condições de equilíbrio termodinâmico: a função disponibilidade

The thermodynamic equilibrium is a state defined by conditions which depend upon some characteristics of the system. It requires thermal, mechanical, chemical and phase equilibrium. Continuum thermodynamics, its radical restriction usually called homogeneous processes thermodynamics, as well as the classical thermodynamic science of reversible processes, each of them defines equilibrium in a differing way. But these definitions lead to the same physical contents.

MCMC Analysis Of Classical Time Series Algorithms

Identification of order of an Autoregressive Moving Average Model (ARMA) by the usual graphical method is subjective. Hence, there is a need of developing a technique to identify the order without employing the graphical investigation of series autocorrelations. To avoid subjectivity, this thesis focuses on determining the order of the Autoregressive Moving Average Model using Reversible Jump Markov Chain Monte Carlo (RJMCMC). The RJMCMC selects the model from a set of the models suggested by better fitting, standard deviation errors and the frequency of accepted data. Together with deep analysis of the classical Box-Jenkins modeling methodology the integration with MCMC algorithms has been focused through parameter estimation and model fitting of ARMA models. This helps to verify how well the MCMC algorithms can treat the ARMA models, by comparing the results with graphical method. It has been seen that the MCMC produced better results than the classical time series approach.

Influência do eletrólito na eletrodeposição de nanopartículas de Cu sobre eletrodo de diamante dopado com boro

This paper presents the electrolyte influence on deposition and dissolution processes of Cu nanoparticles on boron doped diamond electrodes (BDD). Morphological, structural and electrochemical analysis showed BDD films with good reproducibility, quality and reversible in a specific redox system. Electrodeposition of Cu nanoparticles on DDB electrodes in three different solutions was influenced by pH and ionic strength of the electrolytic medium. Analyzing the process as function of the scan rate, it was verified a better efficiency in 0,5 mol L-1 Na2SO4 solution. Under the influence of the pH and ionic strength, Cu nanoparticles on DDB may be obtained with different morphologies and it was important for defining the desired properties.

Voltammetric determination of sibutramine in beverages and in pharmaceutical formulations

A simple and sensitive method has been proposed for the determination of sibutramine-HCl in energy drinks, green tea and pharmaceutical formulations using differential pulse voltammetry performed on a hanging mercury drop electrode. In the chosen experimental condition (Mcllvaine pH 4.0 buffer, 50 mV pulse amplitude and 40 mV s-1 scan velocity), sibutramine-HCl presented a reversible behavior and a peak maximum at -80 mV. Detection limit was 0.4 mg L-1 and the working linear range extended up to 33.3 mg L-1 (r = 0.99). Analysis of real and fortified samples enabled recoveries between 91 and 102%. The electroanalytical method was compared with a HPLC method which indicated it accuracy.

Construção de eletrodo de grafite retirado de pilha comum: aplicações didáticas

This paper presents a proposal for using recycled graphite electrodes obtained from exhausted commercial 1.5 V batteries and its application in electroanalysis. The electrode could be prepared by the students and applied in the simple didactic experiments suggested, such as determination of active electrode area, cyclic voltammetry and useful potential range (also called "potential window"), demonstration and effect of scan rate on cyclic voltammograms. The possibility of using the graphite electrode in quantitative analysis was also demonstrated using the ferricyanide/ferrocyanide reversible redox couple ([Fe(CN)6]3-/[Fe(CN)6]4-) as an electrochemical probe by the dependence of peak current with the analyte concentration and flow injection analysis with amperometric detection.

ALCALOIDES ACRIDÔNICOS INIBEM CATEPSINA L E V

Cathepsins represent a class of enzymes that has the primary function of randomly degrading proteins in the lysosomes, although are also involved in different pathologies. The aim of this paper was to evaluate the capacity of acridone alkaloids isolated from Swinglea glutinosa (Rutaceae) to inhibit cathepsin L in vitro . The IC50 values found were in the 0.8-57 µM range and the most promising compounds were alkaloids 1 and 2, with IC50 of 0.9 and 0.8 µM, respectively. Enzyme kinetics revealed that they are reversible competitive inhibitors with respect to the substrate Z-FR-MCA. This small series of acridone alkaloids showed low selectivity for both cathepsins, but represent promising lead candidates for the further development of competitive cathepsin L and V inhibitors.