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Introduction: The aim of this study was to document clinical practice in Portugal regarding the use of electronic cardiac devices in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF)., Methods: The Síncrone study was an observational prospective multicenter registry conducted in 16 centers in Portugal between 2006 and 2014. It included adult patients with a diagnosis of HF, LVEF <35% and indication for implantable cardioverter-defibrillator (ICD) and/or cardiac resynchronization therapy (CRT) devices, according to the recommendations of the European Society of Cardiology at the beginning of the study. Patients were followed for one year according to the practice of each center., Results: A total of 486 patients were included in the registry, half of whom received an ICD and the other half a CRT pacemaker (CRT-P) or CRT defibrillator (CRT-D). Mean age was 65±12 years and the most frequent causes of HF were ischemic (47%) and idiopathic dilated cardiomyopathy (28%). Overall mortality at one year was 3.6% and the hospitalization rate was 11%, significantly higher in patients with CRT-P/CRT-D than with ICD (17% vs. 5.6%, p<0.001). Patients who received CRT-P/CRT-D experienced significant reductions in QRS duration (160±21 vs. 141±24 ms, p<0.001) as well as improvement in New York Heart Association functional class., Conclusion: The Síncrone study shows that the use of implantable devices in HF with reduced LVEF in Portugal is in accordance with international recommendations and that patients presented functional improvement and reduced one-year mortality., (Copyright © 2019. Publicado por Elsevier España, S.L.U.)

Introduction: The CAD-RADS TM classification was recently introduced in an attempt to standardize coronary computed tomography angiography (CCTA) reports and to provide recommendations for further management. The aim of this study was to assess how additional cardiac investigations were being ordered before the introduction of the CAD-RADS classification in a tertiary hospital's CCTA reports., Methods: We conducted a single-center retrospective analysis of 200 patients (103 women, mean age 59±13 years) who underwent CCTA for suspected or known coronary artery disease prior to the systematic introduction of the CAD-RADS classification in the reports. For each case, we assessed whether further cardiac investigation was requested after CCTA and what type of test was performed (functional testing, invasive coronary angiography or viability testing)., Results: The majority of patients (n=158; 79%) were classified as CAD-RADS 0-2. In patients with lower (0-2) or higher (4 or 5) scores, further testing was in accordance with CAD-RADS recommendations in 98% of cases (n=168). In patients with CAD-RADS 3 (intermediate stenosis), functional testing was requested as recommended in only 36% of cases (n=5), while 50% (n=7) proceeded directly to invasive coronary angiography. In patients in whom CCTA was non-diagnostic, most did not undergo further cardiac investigation., Conclusion: In patients with CAD-RADS classifications at the ends of the spectrum, additional cardiac investigation after CCTA was almost always in accordance with the recommendations. However, in patients with intermediate scores, invasive coronary angiography prevailed over functional testing., (Copyright © 2019 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background/aims: Vascular complications contribute significantly to the extensive morbidity and mortality rates observed in people with diabetes. Despite well known that the diabetic kidney and heart exhibit imbalanced angiogenesis, the mechanisms implicated in this angiogenic paradox remain unknown. In this study, we examined the angiogenic and metabolic gene expression profile (GEP) of endothelial cells (ECs) isolated from a mouse model with type1 diabetes mellitus (T1DM)., Methods: ECs were isolated from kidneys and hearts of healthy and streptozocin (STZ)-treated mice. RNA was then extracted for molecular studies. GEP of 84 angiogenic and 84 AMP-activated Protein Kinase (AMPK)-dependent genes were examined by microarrays. Real time PCR confirmed the changes observed in significantly altered genes. Microvessel density (MVD) was analysed by immunohistochemistry, fibrosis was assessed by the Sirius red histological staining and connective tissue growth factor (CTGF) was quantified by ELISA., Results: The relative percentage of ECs and MVD were increased in the kidneys of T1DM animals whereas the opposite trend was observed in the hearts of diabetic mice. Accordingly, the majority of AMPK-associated genes were upregulated in kidneys and downregulated in hearts of these animals. Angiogenic GEP revealed significant differences in Tgfβ, Notch signaling and Timp2 in both diabetic organs. These findings were in agreement with the angiogenesis histological assays. Fibrosis was augmented in both organs in diabetic as compared to healthy animals., Conclusion: Altogether, our findings indicate, for the first time, that T1DM heart and kidney ECs present opposite metabolic cues, which are accompanied by distinct angiogenic patterns. These findings enable the development of innovative organ-specific therapeutic strategies targeting diabetic-associated vascular disorders., Competing Interests: No conflict of interest., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

We present a case report of a 42 year old female, diagnosed at the age of 3 with Juvenile Dermatomyositis. The clinical course was severe and refractory to immunosuppressive therapy. Currently, she is mostly affected by severe muscle atrophy, large joint contractures, calcinosis, and a lipodystrophy associated metabolic syndrome with hypertriglyceridemia, insulin resistance, high total testosterone and hepatic steatosis. She developed Hodgkin´s lymphoma in the course of her disease. Personalized therapeutic choices are discussed as regards juvenile dermatomyositis complications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Galectin-3 (Gal3) expression is associated with accumulation of Advanced Glycation End products (AGE), a common feature in diabetes mellitus (DM). The role of Gal3 in oxidative stress is, however, controversial, being considered in the literature to play either a protective role or exacerbating disease., Methods: Herein, we examined the interplay between Gal3 and oxidative stress in a high-fat diet -induced type 2 DMC57Bl/6 mice model. Because natural polyphenols are known to play antioxidant and anti-inflammatory roles and to modulate metabolic activity, we further evaluated the effect of xanthohumol and 8-prenylnaringenin polyphenols in this crosstalk., Results: Gal3 expression was accompanied by 3-nitrotyrosine and AGE production in liver and kidney of diabetic mice compared to healthy animals (fed with standard diet). Oral supplementation with polyphenols decreased the levels of these oxidative biomarkers as evaluated by immunohistochemistry and western blotting. Interestingly, blocking Gal3 by incubating human microvascular endothelial cells with modified citrus pectin increased 3-nitrotyrosine protein expression., Conclusions: These findings imply that Gal3 overexpression is probably controlling oxidative stress in endothelial cells. In conclusion, our results indicate that supplementation with 8-prenylnaringenin or xanthohumol reverses diabetes-associated oxidation in liver and kidney, and consequently decreases this diabetic biomarker that predispose to cardiovascular complications., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.The authors report no conflicts of interest., (Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of PBJ-Associação Porto Biomedical/Porto Biomedical Society. All rights reserved.)

The purpose of this study is to present an fMRI paradigm, based on the Williams inhibition test (WIT), to study attentional and inhibitory control and their neuroanatomical substrates. We present an index of the validity of the proposed paradigm and test whether the experimental task discriminates the behavioral performances of healthy participants from those of individuals with acquired brain injury. Stroop and Simon tests present similarities with WIT, but this latter is more demanding. We analyze the BOLD signal in 10 healthy participants performing the WIT. The dorsolateral prefrontal cortex, the inferior prefrontal cortex, the anterior cingulate cortex, and the posterior cingulate cortex were defined for specified region of interest analysis. We additionally compare behavioral data (hits, errors, reaction times) of the healthy participants with those of eight acquired brain injury patients. Data were analyzed with GLM-based random effects and Mann-Whitney tests. Results show the involvement of the defined regions and indicate that the WIT is sensitive to brain lesions. This WIT-based block design paradigm can be used as a research methodology for behavioral and neuroimaging studies of the attentional and inhibitory components of executive functions.

The goal of this study was to propose a new functional magnetic resonance imaging (fMRI) paradigm using a language-free adaptation of a 2-back working memory task to avoid cultural and educational bias. We additionally provide an index of the validity of the proposed paradigm and test whether the experimental task discriminates the behavioural performances of healthy participants from those of individuals with working memory deficits. Ten healthy participants and nine patients presenting working memory (WM) deficits due to acquired brain injury (ABI) performed the developed task. To inspect whether the paradigm activates brain areas typically involved in visual working memory (VWM), brain activation of the healthy participants was assessed with fMRIs. To examine the task's capacity to discriminate behavioural data, performances of the healthy participants in the task were compared with those of ABI patients. Data were analysed with GLM-based random effects procedures and t-tests. We found an increase of the BOLD signal in the specialized areas of VWM. Concerning behavioural performances, healthy participants showed the predicted pattern of more hits, less omissions and a tendency for fewer false alarms, more self-corrected responses, and faster reaction times, when compared with subjects presenting WM impairments. The results suggest that this task activates brain areas involved in VWM and discriminates behavioural performances of clinical and non-clinical groups. It can thus be used as a research methodology for behavioural and neuroimaging studies of VWM in block-design paradigms., (© 2015 The British Psychological Society.)

We analyzed the GlobalFiler short tandem repeat (STR) loci for 152 and 70 unrelated individuals from Angolan and Guinean immigrant populations inhabiting Southern Portugal, respectively. After Bonferroni correction, no significant deviations from the Hardy-Weinberg equilibrium and linkage disequilibrium were detected for either population. For the Angolan population, SE33 was the most informative marker. In contrast, D5S818 and D13S317 were the least informative loci. The combined power of discrimination was 99.9999999999999999999999961907%. For the Guinean population, SE33 and D21S1 were the most informative loci, while D13S317 was the least. The combined power of discrimination was 99.99999999999999999999997915%. No significant differences were observed between Angolan, Guinean, and Afro-American populations for any of the analyzed STRs. The South African population presented significant differences at D22S1045 and D10S1248 when compared to Angola, and at D22S1045 when compared to Guinea-Bissau. The MDS plot and neighbor-joining tree analysis revealed that Angolan and Guinean populations are genetically close to African-American and South African populations, and genetically different from Korean, Mexican, European (including American-Caucasian), and Middle Eastern populations.

Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease with multiple presentations, whose management presents many challenges. Many disease modifying or immunosuppressive drugs have been used with limited success, especially in patients with more severe disease activity. Belimumab is the first drug to be approved specifically for the treatment of SLE in more than 50 years. By blocking the B-cell activating factor, it interferes in B-cell differentiation and survival. Here we consider the results of the clinical trials that led to its approval, as well as the post-hoc analyses, follow-up studies and the current trials., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Genetic variability is one of the important criteria for species conservation decisions. This study aimed to analyze the genetic diversity and the population differentiation of two natural populations of Arapaima gigas, a species with a long history of being commercially exploited. We collected 87 samples of A. gigas from Grande Curuai Lake and Paru Lake, located in the Lower Amazon region of Amazônia, Brazil, and genotyped these samples using a multiplex panel of microsatellite markers. Our results showed that the populations of A. gigas analyzed had high levels of genetic variability, which were similar to those described in previous studies. These two populations had a significant population differentiation supported by the estimates of F ST and R ST (0.06), by Bayesian analysis (K = 2), and by population assignment tests, which revealed a moderate genetic distance.

Colossoma macropomum is the second largest scaled fish of the Amazon. It is economically important for commercial fisheries and for aquaculture, but few studies have examined the diversity and genetic structure of natural populations of this species. The aim of this study was to investigate the levels of genetic variability and connectivity that exist between three natural populations of C. macropomum from the Amazon basin. In total, 247 samples were collected from the municipalities of Tefé, Manaus, and Santarém. The populations were genotyped using a panel of 12 multiplex microsatellite markers. The genetic diversity found in these populations was high and similar to other populations described in the literature. These populations showed a pattern of high gene flow associated with the lack of a genetic structure pattern, indicating that the number of migrants per generation and recent migration rates are high. The values of the FST, RST, and exact test of differentiation were not significant for pairwise comparisons between populations. The Bayesian population clustering analysis indicated a single population. Thus, the data provide evidence for high genetic diversity and high gene flow among C. macropomum populations in the investigated region of the Amazon basin. This information is important for programs aiming at the conservation of natural populations.

Purified microglial cells in culture are frequently used to model brain inflammatory responses but obtaining large yields of these cells on a routine basis can be quite challenging. Here, we demonstrate that it is possible to achieve high-yield isolation of pure microglial (MAC-1(+) /Fcrls(+) /Ccr2(-) ) cells from postnatal brain tissue through a simple culture procedure that mainly relies on the adhesion preference of these cells to the polycation polyethyleneimine (PEI) in serum-supplemented DMEM medium. Accordingly, other synthetic or biological substrates failed to mimic PEI effects under the same culture conditions. Replacement of DMEM by DMEM/F12 nutrient mixture did not permit microglial cell isolation on PEI coating, indicating that PEI effects were context-dependent. Remarkably, the lack of culture feeding during progression of microglial cell isolation strongly improved cell yield, suggesting that nutritional deprivation was required to optimize this process. When generated in large culture flasks coated with PEI, cultures of microglial cells were easily recovered by trypsin proteolysis to produce subcultures for functional studies. These cultures responded to lipopolysaccharide (LPS, 1-10 ng/ml) treatment by secreting pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β and by generating nitric oxide and reactive oxygen species. Most interestingly, this response was curtailed by appropriate reference drugs. Microglial cells were also strongly responsive to the mitogenic cytokine GM-CSF, which confirms that the functional repertoire of these cells was well preserved. Because of its high yield and simplicity, we believe that the present method will prove to be especially convenient for mechanistic studies or screening assays. GLIA 2016;64:1912-1924., (© 2016 Wiley Periodicals, Inc.)

Background: Different cardiovascular risk calculators and risk-based thresholds for initiating statin therapy are currently in use. Using coronary computed tomography angiography, we sought to compare the Pooled-Cohort Equation [atherosclerotic cardiovascular disease (ASCVD) score] with the Systematic COronary Risk Evaluation (SCORE) in the identification of patients with high coronary atherosclerotic burden., Methods: In a single-center prospective registry of patients undergoing coronary computed tomography angiography, we identified individuals aged 40-75 years without diabetes or known cardiovascular disease. Cardiovascular risk and eligibility for statin therapy were determined individually on the basis of the two calculators and the guidelines that endorse them. Coronary atherosclerotic burden was assessed by coronary calcium score, presence of stenosis greater than or equal to 50%, and several measures of plaque severity and extension., Results: In the 327 patients assessed (181 men, mean age 59±9 years), the median SCORE and ASCVD values were 2.6 and 9.7%, respectively. Compared with SCORE, the ASCVD calculator showed greater discriminative power to identify patients with calcium score greater than or equal to 300 [C-statistic 0.74, 95% confidence interval (CI) 0.67-0.82 vs. 0.69, 95% CI 0.61-0.78, P=0.008] and showed a trend toward better identification of patients with obstructive stenosis (C-statistic 0.72, 95% CI 0.64-0.80 vs. 0.68, 95% CI 0.60-0.76, P=0.053). The proportion of statin-eligible patients would be higher with the SCORE-based criteria, particularly among individuals with little or no detectable coronary atherosclerosis., Conclusion: The SCORE calculator seems to be less discriminative than the ASCVD equation in identifying patients with high atherosclerotic burden. Current SCORE-based criteria would assign statin therapy to a larger proportion of patients with low-risk features, which could result in a lower yield of cholesterol-reducing strategies.

We describe the case of a 68-year-old man, who presented with an ischemic stroke due to cardiac embolization related to mitral valve endocarditis. Blood cultures were always negative and post-operative valve histology did not show microorganisms. The patient also presented further recurrent peripheral embolic events. These clinical aspects were the first sign of a pancreas adenocarcinoma, which was only diagnosed in the clinical autopsy. In conclusion, these clinical findings of recurrent thromboembolic events with no microorganisms isolated suggests the diagnostic of a marantic endocarditis., Learning Points: Marantic endocarditis is characterized by the deposition of fibrin and thrombi on heart valves in the absence of microorganisms.Is associated with higher incidence of thromboembolic events and most commonly found in patients with neoplasia in post-mortem studies.It is a diagnostic challenge to distinguish from infective endocarditis and a high clinical suspicion is crucial to confirm the diagnosis., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests.

High-density accumulation of voltage-gated sodium (Nav) channels at nodes of Ranvier ensures rapid saltatory conduction along myelinated axons. To gain insight into mechanisms of node assembly in the CNS, we focused on early steps of nodal protein clustering. We show in hippocampal cultures that prenodes (i.e., clusters of Nav channels colocalizing with the scaffold protein ankyrinG and nodal cell adhesion molecules) are detected before myelin deposition along axons. These clusters can be induced on purified neurons by addition of oligodendroglial-secreted factor(s), whereas ankyrinG silencing prevents their formation. The Nav isoforms Nav1.1, Nav1.2, and Nav1.6 are detected at prenodes, with Nav1.6 progressively replacing Nav1.2 over time in hippocampal neurons cultured with oligodendrocytes and astrocytes. However, the oligodendrocyte-secreted factor(s) can induce the clustering of Nav1.1 and Nav1.2 but not of Nav1.6 on purified neurons. We observed that prenodes are restricted to GABAergic neurons, whereas clustering of nodal proteins only occurs concomitantly with myelin ensheathment on pyramidal neurons, implying separate mechanisms of assembly among different neuronal subpopulations. To address the functional significance of these early clusters, we used single-axon electrophysiological recordings in vitro and showed that prenode formation is sufficient to accelerate the speed of axonal conduction before myelination. Finally, we provide evidence that prenodal clusters are also detected in vivo before myelination, further strengthening their physiological relevance.

To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-protein-coupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype, N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala(11), d-Leu(15)]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of α-bungarotoxin-sensitive (presumably α7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: To determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10%) combined with estriol (0.1%) + estradiol (0.25%) for relieving postmenopausal symptoms., Methods: A total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512., Results: An improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05) after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04±4.9 to 57.12±4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol., Conclusion: The nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women.

The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes., (© 2013 International Society for Neurochemistry.)

Parkinson disease (PD) is a degenerative brain disorder characterized by motor symptoms that are unequivocally associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although our knowledge of the mechanisms that contribute to DA cell death in both hereditary and sporadic forms of the disease has advanced significantly, the nature of the pathogenic process remains poorly understood. In this review, we present evidence that neurodegeneration occurs when the electrical activity and excitability of these neurons is reduced. In particular, we will focus on the specific need these neurons may have for stimulation in order to survive and on the molecular and cellular mechanisms that may be compromised when this need is no longer met in PD.

Epidemiological and experimental evidence indicates that nicotine is protective for Parkinson disease vulnerable dopamine neurons, but the underlying mechanism of this effect remains only partly characterized. To address this question, we established rat midbrain cultures maintained in experimental conditions that favor the selective and spontaneous loss of dopamine neurons. We report here that nicotine afforded neuroprotection to dopamine neurons (EC(50)=0.32 μM) but only in a situation where cytosolic Ca(2+) (Ca(2+)(cyt)) was slightly and chronically elevated above control levels by concurrent depolarizing treatments. By a pharmacological approach, we demonstrated that the rise in Ca(2+)(cyt) was necessary to sensitize dopamine neurons to the action of nicotine through a mechanism involving α-bungarotoxin-sensitive (presumably α7) nicotinic acetylcholine receptors (nAChRs) and secondarily T-type voltage-gated calcium channels. Confirming the role played by α7 nAChRs in this effect, nicotine had no protective action in midbrain cultures prepared from genetically engineered mice lacking this receptor subtype. Signaling studies revealed that Ca(2+)(cyt) elevations evoked by nicotine and concomitant depolarizing treatments served to activate a survival pathway involving the calcium effector protein calmodulin and phosphatidylinositol 3-kinase. Collectively, our data support the idea that the protective action of nicotine for dopamine neurons is activity-dependent and gated by Ca(2+)(cyt).

Methylxanthines of either natural or synthetic origin have a number of interesting pharmacological features. Proposed mechanisms of methylxanthine-induced pharmacological effects include competitive antagonism of G-coupled adenosine A(1) and A(2A) receptors and inhibition of phosphodiesterases. A number of studies have indicated that methylxanthines also exert effects through alternative mechanisms, in particular via activation of sarcoplasmic reticulum or endoplasmic reticulum ryanodine receptor (RyR) channels. More specifically, RyR channel activation by methylxanthines was reported (1) to stimulate the process of excitation coupling in muscle cells, (2) to augment the excitability of neurons and thus their capacity to release neurotransmitters, and also (3) to improve their survival. Here, we address the mechanisms by which methylxanthines control RyR activation and we consider the pharmacological consequences of this activation, in muscle and neuronal cells.

Obesity prevalence is increasing all over the world. Most affected are people changing from a traditional lifestyle to an environment with both availability of high energy diet and less physical activity. Glycemic index (GI) is a measure of dietary glycemic carbohydrates, representing their ability to raise blood glucose concentrations. It refers to the postprandial blood glucose response expressed as a percentage of the response to a reference food (glucose or white bread) containing the same carbohydrate content. Given the present high consumption of sugary drinks, the putative contribution of these products to obesity deserves investigation. The aim of this study was to determine the GI of some drinks from the Portuguese market. Postprandial glycemia after ingestion of apple Frutis, peach Frutis, Green tea Frutea, green tea, black tea, lupin infusion, rooibos infusion, raftilose solution or bran solution has been determined for two hours in a caucasian population of young adults of any sex, 17 to 24 years of age. Apple Frutis GI was found to be 54.3, i.e., a low GI; Frutea Green tea had a GI of 64.7, considered as a moderate GI; peach Frutis showed a high GI, 86.6. Green and Black teas as well as rooibos and lupin infusions, all with added glucose (25 g), did not change glycemic response in comparison with the reference solution (water with 25 g glucose). No differences were seen after raftilose and bran solutions by comparison with the reference solution. GI information may help the choice of carbohydrates to include in a healthy diet. Formerly considered as a parameter of interest to diabetic patients, it may actually interest anybody concerned with a healthy diet. This study has been performed by medical and nutritional science students, who observed glycemic excursions in themselves, after drink ingestion. This experiment allowed them to see the impressive rise of glycemia after ingestion of a sugary drink, by comparison with basal levels which would not rise if plain water or other nonsugary drink had been ingested.

While K(ATP) channels serve primarily as metabolic gatekeepers in excitable cells, they might also participate in other important cellular functions. Here, we demonstrate that K(ATP) channel blockade with the sulfonylurea derivative glibenclamide provided robust protection to dopamine neurons undergoing spontaneous and selective degeneration in midbrain cultures. Unexpectedly, glibenclamide operated not by a direct effect on dopamine neurons but instead by halting the proliferation of a population of immature glial cells lacking astrocytic and microglial markers. The antimitotic effect of glibenclamide appeared essential to unmask a prosurvival phosphoinositide 3-kinase (PI3K)/Akt-dependent signaling pathway that controlled shuttling of calcium from endoplasmic reticulum to mitochondria in dopamine neurons. Preventing integrin-ligand interactions with a decoy ligand, the Arg-Gly-Asp-Ser sequence peptide, reproduced survival promotion by glibenclamide via a mechanism that also required PI3K/Akt-dependent regulation of mitochondrial calcium. Noticeably, Arg-Gly-Asp-Ser did not cause a reduction in glial cell numbers indicating that it prevented the death process downstream of the level at which glibenclamide intervenes. Based on these results, we propose that K(ATP) channel blockade protected dopamine neurons by inhibiting a glia-to-neuron signaling pathway that propagates through integrin/ligand interactions and ultimately disrupts PI3K/Akt-dependent signaling and mitochondrial calcium homeostasis.

Objective: Obesity is an important component of the metabolic syndrome in constituting a risk factor for cardiovascular disease, diabetes, and cancer. Estrogens influence lipid accumulation in adipocytes, acting indirectly or directly on adipose tissue. In this study we aimed to investigate the influence of red wine ingestion on the expression of aromatase (estrogen synthase) in adipose tissue., Methods: Red wine or ethanol solution, in the concentration found in red wine, was provided to Wistar rats as the sole drinking fluid for 8 wk. Food and drink intakes and body weight were monitored throughout treatment and adipocyte size and aromatase expression in the adipose tissue were determined at the end of the experimental period., Results: Red wine and ethanol increased aromatase expression in the adipose tissue and red wine decreased adipocyte size (P < 0.05). In addition, animals treated with red wine or ethanol had significantly lower weight gain than controls, despite a similar energy intake., Conclusion: Thus, the ingestion of red wine may alter the production of estrogens by adipose tissue, body weight gain, and adipocyte size. Some of these red wine effects are attributable to ethanol. This relation among estrogen availability, adipocyte biology, and weight gain is most interesting and deserves further study because it may lead to new strategies to reduce metabolic syndrome incidence.

High plasma levels of the end product of purine metabolism uric acid (UA) predict a reduced risk of developing Parkinson's disease suggesting that UA may operate as a protective factor for midbrain dopaminergic neurons. Consistent with this view, UA exerted partial but long-term protection in a culture model in which these neurons die spontaneously. The rescued neurons were functional as they accumulated dopamine, efficiently. The use of the fluorescent probe dihydrorhodamine-123 revealed that UA operated by an antioxidant mechanism. The iron chelating agent desferrioxamine, the H(2)O(2) scavenger enzyme catalase and the inhibitor of lipid peroxidation Trolox mimicked the effects of UA, suggesting that UA neutralized reactive oxygen species produced via a Fenton-type chemical reaction. UA was, however, not significantly accumulated into neurons, which indicates that the antioxidant effect occurred probably extracellularly. Structure - activity relationships among purine derivatives revealed that the antioxidant properties of UA resulted from the presence of a 8-one substituent in its chemical structure. Of interest, the stimulation of L-type Ca(2+) channels by high K(+)-induced depolarization and the ensuing activation of extracellular signal-regulated kinases 1/2 strongly improved the neuroprotective effect of UA whereas the depolarizing signal alone had no effect. In summary, our data indicate that UA may interfere directly with the disease's pathomechanism.

Mouse models of MPTP intoxication have been used extensively to explore the molecular mechanisms of Parkinson's disease. However, these models present some limitations since; (i) Dopaminergic (DA) cell death occurs rapidly in contrast to the presumably slow evolution of the disease process. (ii) Some of the key histological features of the disease such as Lewy body like inclusions and long-term inflammatory changes are lacking. Fornai et al. [Proc. Natl Acad. Sci. USA 102 (2005), 3413] suggested that continuous delivery of MPTP with Alzet osmotic minipumps may possibly circumvent these problems. Our results show, however, that MPTP infusion via Alzet osmotic minipumps (40 mg/kg/day) produces only a transient depletion in striatal dopamine (DA) without causing dopaminergic cell loss in the substantia nigra. Neuronal cell loss occurred, however, if MPTP was infused concomitantly with probenecid, an uricosuric agent which potentiates the effects of the toxin injected via the i.p. route. Even under these conditions, dopaminergic cell loss was moderate (-25%) and other neurodegenerative changes characteristic of Parkinson's disease remained undetectable.

Epidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection. The survival effect of PX was highly specific to dopaminergic neurons and independent of glial cell line-derived neurotrophic factor (GDNF). Nevertheless, PX had the potential to rescue dopaminergic neurons that had matured initially with and were then deprived of GDNF. The protective effect of PX was not mediated by blockade of adenosine receptors or by elevation of intracellular cAMP levels, two pharmacological effects typical of methylxanthine derivatives. Instead, it was attributable to a moderate increase in free cytosolic calcium via the activation of reticulum endoplasmic ryanodine receptor (RyR) channels. Consistent with these observations, PX and also ryanodine, the preferential agonist of RyRs, were protective in an unrelated paradigm of mitochondrial toxin-induced dopaminergic cell death. In conclusion, our data suggest that PX has a neuroprotective potential for diseased dopaminergic neurons.

Xanthohumol (XN), a natural polyphenol present in beer, is known to exert anti-cancer effects. However, its precise mechanisms are not yet clearly defined. The aim of this study was to investigate the effect of oral administration of XN in breast cancer xenografts in nude mice. Proliferation and apoptosis were first examined in MCF7 cell cultures after incubation with XN by trypan blue exclusion assay, [3H]-thymidine incorporation, KI67 immunostaining and TUNEL. Morphological and histological characteristics of tumours from XN-treated or control (vehicle-treated) mice were compared. Immunohistochemistry for proliferative, inflammatory and endothelial cell markers was performed and activation of nuclear factor kappa B (NFkappaB) pathway was assessed by ELISA. In vitro MCF7 cell proliferation decreased in a dose-dependent manner. Oral administration of XN to nude mice inoculated with MCF7 cells resulted in central necrosis within tumours, reduced inflammatory cell number, focal proliferation areas, increased percentage of apoptotic cells and decreased microvessel density. Anti-angiogenic effects of XN were further confirmed by immunoblotting for factor VIII expression in XN-treated tumours as compared to controls. Decreased immunostaining for NFkappaB, phosphorylated-inhibitor of kappa B and interleukin-1beta were also observed as well as a significant decrease in NFkappaB activity to 60% of control values. These novel findings indicate that XN is able to target both breast cancer and host cells, namely inflammatory and endothelial cells, suggesting its potential use as a double-edge anti-cancer agent.

Alkaline phosphatase (ALP) is important in calcification and its expression seems to be associated with the inflammatory process. We investigated the in vitro acute effects of compounds used for the prevention or treatment of cardiovascular diseases on total ALP activity from male Wistar rat heart homogenate. ALP activity was determined by quantifying, at 410 nm, the p-nitrophenol released from p-nitrophenylphosphate (substrate in Tris buffer, pH 10.4). Using specific inhibitors of ALP activity and the reverse transcription-polymerase chain reaction, we showed that the rat heart had high ALP activity (31.73 +/- 3.43 nmol p-nitrophenol.mg protein-1.min-1): mainly tissue-nonspecific ALP but also tissue-specific intestinal ALP type II. Both ALP isoenzymes presented myocardial localization (striated pattern) by immunofluorescence. ALP was inhibited a) strongly by 0.5 mM levamisole, 2 mM theophylline and 2 mM aspirin (91, 77 and 84%, respectively) and b) less strongly by 2 mM L-phenylalanine, 100 mL polyphenol-rich beverages and 0.5 mM progesterone (24, 21 to 29 and 11%, respectively). beta-estradiol and caffeine (0.5 and 2 mM) had no effect; 0.5 mM simvastatin and 2 mM atenolol activated ALP (32 and 36%, respectively). Propranolol (2 mM) tended to activate ALP activity and corticosterone activated (18%) and inhibited (13%) (0.5 and 2 mM, respectively). We report, for the first time, that the rat heart expresses intestinal ALP type II and has high total ALP activity. ALP activity was inhibited by compounds used in the prevention of cardiovascular pathology. ALP manipulation in vivo may constitute an additional target for intervention in cardiovascular diseases.

Dopaminergic neurons that constitute the nigrostriatal pathway are characterized by singular electrical properties that allow them to discharge in vivo spontaneously in a spectrum of patterns ranging from pacemaker to random and bursting modes. These electrophysiological features allow dopaminergic neurons to optimize the release of dopamine in their terminal fields. However, there is emerging evidence indicating that electrical activity might also participate in the control of dopaminergic neuron survival, not only during development, but also in the adult brain, thus raising the possibility that alterations in ionic currents could contribute actively to the demise of these neurons in Parkinson disease. This review focuses on the mechanisms by which activity-dependent mechanisms might modulate dopaminergic cell survival.

Objectives: To examine the effect of 17beta-estradiol and xanthohumol in alkaline phosphatase (ALP) expression and activity in breast cancer MCF-7 cells., Design and Methods: ALP isoenzymes expression was evaluated by RT-PCR and Western blotting. ALP activity was measured by spectrophotometry. Cell proliferation and apoptosis were examined by MTT and immunostaining for KI67 and TUNEL, respectively., Results: ALP isoenzymes expression and activity were decreased by 1 nM 17beta-estradiol. Pure estrogenic antagonist (ICI 182,780) reversed 17beta-estradiol-inhibiting effect in TNS-ALP expression. RNA and protein expression of IALP, but not TNS-ALP, was also decreased by incubation with 10 microM xanthohumol (IC(50)) and was accompanied by a significant reduction in ALP activity. Treatment with 17beta-estradiol enhanced cell proliferation and decreased apoptosis. Conversely, xanthohumol incubation inhibited cell viability and apoptosis., Conclusion: Estrogens and xanthohumol differently modulate ALP isoenzymes. ALP loss associated with increased cell proliferation. Modulation of this enzyme by 17beta-estradiol and xanthohumol might provide therapeutic strategies against hormone-dependent breast cancer.

Several studies indicate that progesterone exerts relevant effects in breast tissue. However, the exact role of this steroid in breast cancer development and progression has not been elucidated. Here, we show that platelet-derived growth factor (PDGF)-A is one of the progesterone target genes on breast cancer MCF7 and T47D cells. A paracrine role for PDGF-A was investigated, since its receptor expression was down-regulated from breast cancer cells. Progesterone increased PDGF-A protein release as evaluated by Western blotting and ELISA. Medium from Progesterone-treated MCF7 cells resulted in phosphorylation of smooth muscle cells PDGF receptor alpha. This effect was not observed after treatment with PDGF inhibitor. MCF7 cells-secreted PDGF-A was able to increase smooth muscle cell viability and proliferation and decrease apoptosis, effects that were prevented by the use of a PDGF-A neutralizing antibody. Notably, cell invasion was not influenced by PDGF-A secreted by MCF7 cells. Our results elucidated for the first time the cross talk between progesterone and PDGF signaling pathway. The fact that MCF7-secreted PDGF elicited crucial roles in vascular wall smooth muscle cells, suggested a paracrine pathway for progesterone. Targeting these progesterone-induced processes may provide novel therapeutic strategies for hormone-dependent human breast cancer., (2006 Wiley-Liss, Inc.)

Adrenal lipomas are extremely rarely occurring benign tumors being hormonally inactive. The patient described in this report underwent surgical excision of an adrenal lipoma because of the associated hypertension. The blood pressure decreased postoperatively to normal levels. This case report and the review of the literature consider diagnosis and therapy of the adrenal lipomas.

We conducted a prospective clinical trial of 154 patients with duodenal ulcer disease, which was divided in two different steps: healing phase and post-healing phase. In the first phase, the patients were randomly assigned to treatment with H2 blockers (Ranitidine 300 mg or Famotidine 40 mg), in a single bedtime dose. Endoscopy was performed after 4 and 12 weeks of treatment and the healing rate was 70% and 90%. There were no significant differences between the two drugs. After 12 weeks of treatment there were sixteen patients with non-healed duodenal ulcer, considered as refractory duodenal ulcer disease, in which we started therapy with a double dose of H2 receptor antagonists or sucralfate (4 gr/day). Endoscopic follow-up after 12 weeks of this regimen revealed ulcer healing in about half of them; the cummulative healing rate in 6 months was 96.4%. Persistent lesions after 6 months of follow-up were found in 5 patients. Omeprazole 40 mg, single dose, was given and all of them were healed during the first 4 weeks of treatment. In the second phase, 137 patients healed during the first 3 months of treatment, were followed for 12 months and randomized in two groups: 61, with maintenance therapy--ranitidine 150 mg or famotidine 20 mg; 76, without treatment. In the patients without maintenance therapy, the recurrence rate was significantly higher (p less than 0.55), than in the group with maintenance therapy. In this group several parameters were evaluated--clinical, biochemical and psychosocial--to try to identify some prognostic markers of healing, relapse.(ABSTRACT TRUNCATED AT 250 WORDS)