Clinical Management of COPD in a Real-World Setting. A Big Data Analysis

ObjectiveThe aim of this study was to evaluate the quality of diagnosis and treatment of COPD using Big Data methodology on the Savana Manager 2.1 clinical platform.Materials and methodsA total of 59,369 patients with a diagnosis of COPD were included from a population of 1,219,749 adults over 40 years of age.ResultsIn total, 78% were men. Spirometry data were available for only 26,453 (43.5%) subjects. Disease severity was classified in 18,172 patients: 4396 mild, 7100 moderate, and 6676 severe, although only 27%, 34%, and 28%, respectively, presented obstructive spirometry. The clinical management of COPD is mainly the responsibility of the primary care and pulmonology departments, while internal medicine and, to a lesser extent, geriatrics also participate. Drug treatment was based on bronchodilators and inhaled corticosteroids (ICS). A marked decline in the use of long-acting beta-2 agonists (LABA) in monotherapy and a slight reduction in ICS/LABA combinations, associated with a long-acting anticholinergic (LAMA) in 74% of cases, were observed. All-cause in-hospital mortality among the overall population was 5.6% compared to 1% of the general population older than 40 years. In total, 35% were admitted to hospital, with an average stay of 6.6 days and an in-hospital mortality rate in this group of 10.74%.DiscussionThis study identifies the main features of an unselected COPD population and the main errors made in the management of the disease.     

Human renalase: a review of its biology,function, and implications for hypertension

Renalase is a novel flavoprotein, highly expressed in kidney and heart, which metabolizes catecholamines and catecholamine-like substances via a superoxide (O2^–)-dependent mechanism using nicotinamide adenine dinucleotide (NADH) as a cofactor. Its mechanism of action is distinct from that of monoaminooxidases A and B, because it oxidizes catecholamines (epinephrine>>L-DOPA>dopamine = norepinephrine) to aminochrome, and the reaction rate increases ～4- to 6-fold in presence of NADH. Tissue and plasma renalase levels are decreased in animal models of chronic kidney disease, and renalase deficiency is associated with increased blood pressure and elevated circulating catecholamines. Renalase plasma levels, measured by enzyme-linked immunosorbent assay, are reported to be ～ 5-fold higher in patients with end-stage renal disease than in normal control subjects. They were also increased in kidney and heart transplant recipients, and inversely correlated with estimated glomerular filtration rate. Renalase has potential therapeutic applications. Experimental models demonstrate that the chronic administration of renalase decreases ambulatory blood pressure and prevents the development of cardiac hypertrophy in rats, and that its acute administration decreases ischemic acute kidney injury in mice. Here we provide a detailed review of renalase biology including its mechanism of action, secretion into blood, interaction with the renal dopamine and epinephrine system, and early studies evaluating its association with outcomes related to hypertension and target-organ injury.     

Quality Assessment of Mixed and Ceramic Recycled Aggregates from Construction and Demolition Wastes in the Concrete Manufacture According to the Spanish Standard ?

Construction and demolition waste (CDW) constitutes an increasingly significant problem in society due to the volume generated, rendering sustainable management and disposal problematic. The aim of this study is to identify a possible reuse option in the concrete manufacturing for recycled aggregates with a significant ceramic content: mixed recycled aggregates (MixRA) and ceramic recycled aggregates (CerRA). In order to do so, several tests are conducted in accordance with the Spanish Code on Structural Concrete (EHE-08) to determine the composition in weight and physic-mechanical characteristics (particle size distributions, fine content, sand equivalent, density, water absorption, flakiness index, and resistance to fragmentation) of the samples for the partial inclusion of the recycled aggregates in concrete mixes. The results of these tests clearly support the hypothesis that this type of material may be suitable for such partial replacements if simple pretreatment is carried out. Furthermore, this measure of reuse is in line with European, national, and regional policies on sustainable development, and presents a solution to the environmental problem caused by the generation of CDW.     

Decreased functional brain connectivity in individuals with early-treated phenylketonuria: evidence from resting state fMRI

Previous histological and neuroimaging studies have documented structural abnormalities in the white matter of the brain in individuals with early-treated phenylketonuria (ETPKU). It remains unclear, however, the extent to which the function of the brain's interconnections are impacted by this condition. Presently, we utilized functional magnetic resonance imaging (fMRI) to evaluate the synchronization of neural signals (i.e., functional connectivity) among brain regions comprising the default mode network (DMN) in a sample of 11 individuals with ETPKU and 11 age- and gender-matched neurologically intact controls. The DMN is a group of interconnected brain regions that are known to be generally more active during rest than during task performance. Data analysis revealed decreased functional connectivity among DMN regions for the ETPKU group compared with the control group. Within the PKU group, we also found a significant relationship between blood phenylalanine (phe) levels and the functional connectivity between select regions of the DMN. In conjunction with findings from another recent fMRI study (Christ, Moffitt et al. 2010), the present results suggest that ETPKU-related deficiencies in functional connectivity are pervasive. The current findings also provide initial evidence that the extent of such impairment may be moderated in part by blood phe levels.     

Reduced response of Cystathionine Beta-Synthase (CBS) to S-Adenosylmethionine (SAM): Identification and functional analysis of CBS gene mutations in Homocystinuria patients

A reduced response of cystathionine beta-synthase (CBS) to its allosteric activator S-adenosylmethionine (SAM) has been reported to be a cause of CBS dysfunction in homocystinuria patients. In this work we performed a retrospective analysis of fibroblast data from 62 homocystinuria patients and found that 13 of them presented a disturbed SAM activation. Their genotypic background was identified and the corresponding CBS mutant proteins were produced in E. coli. Nine distinct mutations were detected in 22 independent alleles: the novel mutations p.K269del, p.P427L, p.S500L and p.L540Q; and the previously described mutations p.P49L, p.C165Rfs*2, p.I278T, p.R336H and p.D444N. Expression levels and residual enzyme activities, determined in the soluble fraction of E. coli lysates, strongly correlated with the localization of the affected amino acid residue. C-terminal mutations lead to activities in the range of the wild-type CBS and to oligomeric forms migrating faster than tetramers, suggesting an abnormal conformation that might be responsible for the lack of SAM activation. Mutations in the catalytic core were associated with low protein expression levels, decreased enzyme activities and a higher content of high molecular mass forms. Furthermore, the absence of SAM activation found in the patients’ fibroblasts was confirmed for all but one of the characterized recombinant proteins (p.P49L). Our study experimentally supports a deficient regulation of CBS by SAM as a frequently found mechanism in CBS deficiency, which should be considered not only as a valuable diagnostic tool but also as a potential target for the development of new therapeutic approaches in classical homocystinuria.     

Calcium consumption and insulin resistance syndrome parameters. Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR)

Background and aimA number of studies have investigated the role of dietary calcium in lipid metabolism and weight regulation, and the influence of dairy products on the incidence of insulin resistance syndrome. In this study we have examined the relationship between dietary calcium and the established parameters of the insulin resistance syndrome.Methods and resultsThe study population (n = 4372) was taken from the DESIR (Data from the Epidemiological Study on the Insulin Resistance Syndrome) cohort. Data for parameters relating to the syndrome were recorded, including glucose, serum insulin, triglycerides, HDL-cholesterol, waist circumference and blood pressure. Total energy, calcium and alcohol intake were estimated using a food-frequency questionnaire. Relationships between dietary calcium density and the above parameters were analyzed by multiple linear regression models, adjusted for age, smoking, alcohol consumption and physical activity. From one quartile of calcium density to the next, mean systolic and diastolic blood pressures and insulin concentrations decreased in women by 0.9 mmHg, 0.5 mmHg and 2.4%, respectively, and HDL-cholesterol increased by 0.007 mmol/l (all p < 0.05) after adjustment for age, smoking, alcohol intake and physical activity. In men, there was an increase of 0.2 kg/m² in the body mass index(BMI) and a decrease of 0.4 mmHg in diastolic blood pressure (both p < 0.05).ConclusionsThese results confirm a beneficial association between dietary calcium and arterial blood pressure, insulin and HDL-cholesterol levels in women, whereas in men there was only a beneficial association with diastolic blood pressure.     

Isolation and characterization of microsatellite loci in blesbok (Damaliscus pygargus phillipsi)

Eight microsatellite markers were developed via pyrosequencing for the blesbok (Damaliscus pygargus phillipsi). These microsatellite loci and microsatellite loci from two cross species markers displayed two to four alleles with an expected heterozygosity range between 0.2899 and 0.6268 and an observed heterozygosity between 0.2083 and 0.6667. The high level of polymorphisms observed in the microsatellite markers indicates that they can be used to strongly improve our knowledge of the genetic structure and relatedness of these animals.     

Inhibiting signal transduction: recent advances in the development of receptor tyrosine kinase and Ras inhibitors

Since aberrant cell signaling is implicated in the initiation, growth, and progression of cancer, proteins involved in signal transduction are rational therapeutic targets. Receptor tyrosine kinases (RTK) and Ras oncoprotein are examples of critical signaling proteins that mediate the processes of cellular growth and differentiation. Agents presently being evaluated as inhibitors of signal transduction include both natural and synthetic compounds, monoclonal antibodies, and antisense oligonucleotides. Preclinical studies of compounds which inhibit RTK and Ras have shown that these targets can be blocked, while side effects in animal models are minimal. Early clinical trials reveal that, in general, treatment with these compounds is both feasible and tolerable. However, many issues about STI remain unresolved including how to optimize schedule, how long to continue treatment, specific mechanisms of action, and how to optimize combinations of STI with standard therapeutic modalities. Addressing these issues may require a shift in the traditional paradigm of drug development, as conventional endpoints may not adequately capture the potential benefits from agents believed to act in a cytostatic vs. cytotoxic manner. This review will discuss the rationale and application of inhibiting signal transduction using inhibitors of RTK and Ras as prototypes of this class of agents.