The gating of the CFTR channel

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed in the apical membrane of epithelia. Mutations in the CFTR gene are the cause of cystsic fibrosis. CFTR is the only ABC-protein that constitutes an ion channel pore forming subunit. CFTR gating is regulated in complex manner as phosphorylation is mandatory for channel activity and gating is directly regulated by binding of ATP to specific intracellular sites on the CFTR protein. This review covers our current understanding on the gating mechanism in CFTR and illustrates the relevance of alteration of these mechanisms in the onset of cystic fibrosis.

http://ift.tt/2dQ5a0K

Brain natriuretic peptide for prevention of contrast-inducednephropathy: a meta-analysis of randomized controlled trials

Abstract

Purpose

Contrast-induced nephropathy (CIN) is a serious complication and associated with poor clinical outcomes. The protective value of brain natriuretic peptide (BNP) administration on CIN is still controversial in patients undergoing percutaneous coronary intervention (PCI) or coronary angiography (CAG). We performed a meta-analysis of randomized controlled trials (RCTs) for BNP in preventing CIN.

Methods

We systematically searched PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov for RCTs comparing administration of BNP versus non-BNP for preventing CIN. Publication bias was assessed by funnel plots. Relative risk (RR) was calculated for incidence of CIN and major adverse cardiovascular events (MACEs) using the random or fixed effect model according to heterogeneity analysis.

Results

There were five RCTs with 1441 patients in this analysis. BNP treatment was associated with lower incidence of CIN (RR = 0.38, 95 % CI 0.27–0.54, p < 0.001) and MACEs (RR = 0.47, 95 % CI 0.24–0.95, p = 0.034) with no significant heterogeneity (I ² = 0 %, p = 0.701; I ² = 60 %, p = 0.113, respectively). Similar results were seen in subgroup analysis. Prophylactic BNP significantly decreased the incidence of CIN after cardiac catheterization in the studies of regarding sodium chloride as placebo (I ² = 0 %, RR = 0.39, 95 % CI 0.27–0.56, p < 0.001) or JADAD score > 3 (I ² = 0 %, RR = 0.38, 95 % CI 0.21–0.68, p = 0.001).

Conclusions

Preprocedural BNP treatment significantly decreased the incidence of CIN and short-term MACEs in patients undergoing PCI or CAG.

http://ift.tt/2dxZkgE

Molecular analysis of the role of osmolyte transporters opuCA and betL in Listeria monocytogenes after cold and freezing stress

Abstract

Listeria monocytogenes is a food-borne pathogen of humans and other animals. The striking ability to survive several stresses usually used for food preservation makes L. monocytogenes one of the biggest concerns to the food industry. This ubiquity can be partly explained by the ability of the organism to grow and persist at very low temperatures, a consequence of its ability to accumulate cryoprotective compound called osmolytes. A quantitative RT-PCR assay was used to measure mRNA transcript accumulation for the stress response genes opuCA and betL (encoding carnitine and betaine transporters, respectively) and the housekeeping gene 16S rRNA. Assays were conducted on mid-exponential phase L. monocytogenes cells exposed to conditions reflecting cold and freezing stress, conditions usually used to preserve foods. We showed that expression of the two cold-adapted genes encoded the transporters of the cryoprotectants carnitine and betaine in ATCC 19115 and the food-isolated L. monocytogenes S1 is induced after cold and freezing stress exposure. Furthermore, transcriptional analysis of the genes encoding opuCA and betL revealed that each transporter is induced to different degrees upon cold shock of L. monocytogenes ATCC 19115 and S1. Our results confirm an increase in carnitine uptake at low temperatures more than in betaine after cold-shocked temperature compared to the non-stress control treatment. It was concluded the use of carnitine and betaine as cryoprotectants is essential for rapid induction of the tested stress response under conditions typically encountered during food preservation.

http://ift.tt/2dQ2hxg

Third issue of volume 12

http://ift.tt/2dAWecA

SBRISK: speed-up binary robust invariant scalable keypoints

Abstract

Keypoint generation, including detection, description and matching is the basis of a broad range of applications. A more efficient and effective keypoint generation method is always of interest. In this paper, we propose the speed-up BRISK (SBRISK), a variant of the binary robust invariant scalable keypoint (BRISK). SBRISK not only inherits the high speed of BRISK in the keypoint detection, but also adopts a nearly circular symmetric constellation to describe the pattern of keypoint. To adapt to the characteristic orientation of keypoint, SBRISK shifts the binary vector rather than rotating the image pattern or constellation like many other descriptors have done. It abandons interpolation to get intensity at sub-pixel position, since the constellation does not strictly restrict to circular symmetric. Different from BRISK, SBRISK classifies keypoints into bright patterns and dark patterns. Comparison is conducted only within the same class. Meanwhile, a special refinement scheme is imposed upon the initial matching results to improve the match precision. Experiments show that SBRISK has a faster and better performance than BRISK with less memory consumption.

http://ift.tt/2dhmj4T

Low-energy motion estimation architecture using quadrant-based multi-octagon (QBMO) algorithm

Abstract

The H.264 video-coding standard is a great improvement on its predecessor in that it is able to save 50 % of the bit-rate while maintaining the same quality as MPEG-4. However, its high computational complexity means the standard consumes large amounts of energy to process a video sequence, especially during motion estimation (ME) searches. To overcome this problem, a low-energy ME architecture is proposed in this paper that utilizes a quadrant-based multi-octagon search algorithm as one of its fast-search motion-estimation techniques. The proposed architecture is able to reduce the clock cycle needed to perform the search by 42 % compared to the original conventional algorithm. This clock cycle reduction reduces energy consumption by up to 43 %.

http://ift.tt/2dAUDTQ

Fast star centroid extraction algorithm with sub-pixel accuracy based on FPGA

Abstract

Spacecraft's attitude information plays an important role in celestial navigation. The attitude is mainly determined by matching the star's centroid in the obtained image with its corresponding information in star catalog. Generally, the star image can be regarded as a spot with a diameter <5 pixels. Therefore, it is very difficult to extract the star centroid with sub-pixel accuracy, especially in the hardware system, such as FPGAs. The existing spot centroid extraction methods with high accuracy require plenty of pixels to realize the complex computations. Limited to the star's diameter and hardware requirements, such methods are not suitable for star centroid extraction in hardware system. To solve the problem, a two-step extraction method for star centroid with sub-pixel accuracy is proposed. The maximum pixel-level center can be located through zero crossing of the first derivative in a small region. Taking the pixel-level center as the middle of the window with fixed size, the sub-pixel offsets to the sub-pixel center can be calculated using fixed window weighted centroid method. The sub-pixel center of the star is then obtained by adding the offsets to the pixel-level center. This method can be implemented in hardware to increase processing speed, using Verilog hardware description languages. A simulation is performed on computer and FPGA. Experimental results show the excellent performance in accuracy and processing speed of two-step method. In addition, two-step method has strong ability of resisting noise and good robustness compared to other methods.

http://ift.tt/2dhnjpK

The Role of Autophagy in the Maintenance of Stemness and Differentiation of Mesenchymal Stem Cells

Abstract

Regulated self-consumption, also known as autophagy, is an evolutionary conserved process that degrades cellular components by directing them to the lysosomal compartment of eukaryotic cells. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining and remodeling cellular homeostasis during normal cellular and tissue development. Recent studies have demonstrated that autophagy is necessary for the maintenance of cellular stemness and for a number of differentiation processes, including the lineage determination of mesenchymal stem cells. These are multipotent progenitor cells with self-renewal capacities that can give rise to a subset of tissues and thus hold a consistent potential in regenerative medicine. Here, we review the current literature on the complex liaison between autophagy induced by various extra- or intracellular stimuli and the molecular targets that affect mesenchymal stem cells proliferation and differentiation.

http://ift.tt/2cUt8GI

Electrophysiology, immunophenotype, and gene expression characterization of senescent and cryopreserved human amniotic fluid stem cells

Abstract

We characterized human amniotic fluid stem cells (AFSC) in senescent cultures (6 weeks) versus cryopreserved cells using whole-cell patch-clamp, immunophenotyping, and differential gene expression profiling for senescence genes. We evidenced five ion current components (outward rectifier, A-type, inward rectifier, and big conductance Ca²⁺-dependent K⁺ currents, fast voltage-dependent Na⁺ currents). Senescent AFSC showed reduced expression of CD90, CD44, CD133, over 500-fold increase of interferon gamma and telomerase reverse transcriptase genes, increased cycle-dependent kinase 4 inhibitors, p53-binding protein 1, and decreased calreticulin and CD44. HLA-ABC immune expression was similar, and HLA-DR expression very low in both cell types. A subset of cryopreserved AFSC featured large inward rectifier K⁺ currents, voltage-dependent Na⁺ currents, and neural progenitor markers evidenced by immunophenotyping and RT-PCR. In all AFSC, in both culture conditions, at patch rupture the outward currents were very low, and they increased progressively over several minutes upon cytoplasm dialysis with pipette solution.

http://ift.tt/2cJE77z

Neuronal circuits and physiological roles of the basal ganglia in terms of transmitters, receptors and related disorders

Abstract

The authors have reviewed recent research advances in basal ganglia circuitry and function, as well as in related disorders from multidisciplinary perspectives derived from the results of morphological, electrophysiological, behavioral, biochemical and molecular biological studies. Based on their expertise in their respective fields, as denoted in the text, the authors discuss five distinct research topics, as follows: (1) area-specific dopamine receptor expression of astrocytes in basal ganglia, (2) the role of physiologically released dopamine in the striatum, (3) control of behavioral flexibility by striatal cholinergic interneurons, (4) regulation of phosphorylation states of DARPP-32 by protein phosphatases and (5) physiological perspective on deep brain stimulation with optogenetics and closed-loop control for ameliorating parkinsonism.

http://ift.tt/2dmiloh

Different rate-limiting activities of intracellular pH regulators for HCO 3 − secretion stimulated by forskolin and carbachol in rat parotid intralobular ducts

Abstract

Intracellular pH (pH_i) regulation fundamentally participates in maintaining HCO₃⁻ release from HCO₃⁻-secreting epithelia. We used parotid intralobular ducts loaded with BCECF to investigate the contributions of a carbonic anhydrase (CA), anion channels and a Na⁺–H⁺ exchanger (NHE) to pH_i regulation for HCO₃⁻ secretion by cAMP and Ca²⁺ signals. Resting pH_i was dispersed between 7.4 and 7.9. Forskolin consistently decreased pH_i showing the dominance of pH_i-lowering activities, but carbachol gathered pH_i around 7.6. CA inhibition suppressed the forskolin-induced decrease in pH_i, while it allowed carbachol to consistently increase pH_i by revealing that carbachol prominently activated NHE via Ca²⁺-calmodulin. Under NHE inhibition, forskolin and carbachol induced the remarkable decreases in pH_i, which were slowed predominantly by CA inhibition and by CA or anion channel inhibition, respectively. Our results suggest that forskolin and carbachol primarily activate the pH_i-lowering CA and pH_i-raising NHE, respectively, to regulate pH_i for HCO₃⁻ secretion.

http://ift.tt/2cJD9YI

Disorders of the Abdominal Aorta and Major Branches

Abstract

Pediatric vascular disease is heterogenous, rare, and requires an interdisciplinary approach to management. Definitive diagnosis and medical stabilization of the underlying disease process should be obtained preoperatively when feasible. Autologous grafts are the preferred conduit for reconstruction, but synthetic or allografts are acceptable, readily available, and may be sized to specification. Aneurysmal disease should be treated early to prevent complications of rupture, occlusive dissection, thrombosis, or embolization. Stenotic disease can usually be treated conservatively with medical management of hypertension, though vascular reconstruction is indicated for hypertension refractory to medical therapy, end-organ damage of the kidneys or heart, stroke, claudication, limb-length discrepancy, or intestinal ischemia.

http://ift.tt/2dxHFWp

Fenestrated Aortic Endografts in the Last 3 Years: An Update

Abstract

Purpose of Review

Fenestrated endovascular aortic aneurysm repair (FEVAR) is an accepted treatment option for patients who are not suitable for conventional endovascular aortic aneurysm repair or open surgical repair (OSR). Five years ago, the FDA approved the use of FEVAR in patients with inadequate infrarenal aortic seal zones (short necks). This procedural paradigm continues to gain in popularity compared to OSR for complex aortic disease. We seek to define the current state of fenestrated endovascular repair by reviewing relevant literature over the past 3 years.

Recent Findings

FEVAR continues to prove to be efficacious with reasonable durability as a therapy for patients who are not candidates for OSR. As a second-line treatment, FEVAR is less morbid in the short-term with trade-off of high reintervention rates in the follow-up period. Mid- to long-term outcomes have proven to be comparable to OSR in selected patients with persistent excellent patency of the visceral target vessels. Recent publications have thrust FEVAR into consideration as the primary interventional modality in juxtarenal abdominal aortic aneurysms, a traditional indication for OSR.

Summary

As FEVAR continues to evolve from surgeon-modified devices to custom built and eventually off-the-shelf grafts, it is anticipated to be employed widely for managing complex aortic aneurysms. Compared to OSR, FEVAR carries a low risk of perioperative morbidity while demonstrating continued safety and durability in early to mid-term reports.

http://ift.tt/2dIYjDu

Bradyarrythmias in the obstructive sleep apnea sundrome: a dangerous complication or defense mechanism?

Abstract

Sleep is characterized by cycling and consecutive alternation of different phases and stages, each of which features intrinsic changes in autonomic regulation with heart rate oscillations; this may cause heart rhythm disorders, especially in the presence of comorbidities. This review addresses the issues of interrelationship between cardiac conduction disorders and obstructive sleep apnea. It is shown that some mechanisms of bradyarrythmia emergence (first of all, features of autonomic regulation with increases in parasympathetic tone) under respiratory arrest during sleep are also inherent to human divers as well as aquatic or para-aquatic mammals that have to hold their breath when diving or staying under water for a long time. These mechanisms may fulfill the defense function.

http://ift.tt/2dFQT7R

Regulation of antimicrobial peptide synthesis in larvae of Calliphora vicina (Diptera, Calliphoridae): a dose-dependent effect of ecdysteroids

Abstract

Ecdysteroids are multifunctional hormones regulating virtually all morphogenetic events in insects. Their role in stress and immune response regulation is not well researched. Here we study the effect of 20-hydroxyecdysone on antimicrobial peptide synthesis in the larvae of Calliphora vicina. An inverse correlation was observed between the 20-hydroxyecdysone titer and antimicrobial peptide concentration in the hemolymph of naïve and bacteria challenged maggots. High and low doses of 20-hydroxyecdysone, injected simultaneously with bacterial cells, had an opposite effect on antimicrobial peptide synthesis in the diapausing larvae. Morphogenetically effective doses of 20-hydroxyecdysone demonstrated immunosuppressive activity. A low dose of 20-hydroxyecdysone, on the contrary, moderately stimulated antimicrobial peptide synthesis. The data suggest that ecdysteroids are directly involved in the regulation of the immune system activity and that the final effect is dose-dependant.

http://ift.tt/2dhP6Ds

Effects of 5-HT3 receptor blockade on visceral nociceptive neurons in the ventrolateral reticular field of the rat medulla oblongata

Abstract

The caudal ventrolateral reticular formation of the medulla oblongata is the first layer of visceral nociceptive processing. In experiments on rats, neuronal responses in this zone to nociceptive stimulation of the large intestine were examined and the effects of selective blockade of 5-HT3 receptors on these responses were assessed. By the character of responses to nociceptive colorectal stimulation (CRS), the recorded medullary neurons were divided into three groups—excited, inhibited and indifferent. Intravenous injection of 5-HT3 antagonist granisetron (1 and 2 mg/kg) as well as local application of this agent on the surface of the medulla oblongata (1.25 and 2.5 nmole) suppressed the background and evoked firing of CRS-excited reticular neurons in a dose-dependent manner but did not exert as pronounced influence on the cells inhibited by visceral nociceptive stimulation. Spike activity in the group of CRS-indifferent neurons under similar conditions was 5-HT3-independent. The results obtained provide evidence that 5-HT3 receptors mediate the facilitating effect of serotonin on supraspinal transmission of the abdominal nociceptive stimulus which, at least in part, is realized via selective activation of visceral medullary nociceptive neurons. A shutdown of this mechanism may underlie the analgesic effect of 5-HT3 antagonists in abdominal pain syndromes.

http://ift.tt/2dFRdDn

Indicators of pituitary-thyroid system and lipid metabolism in female representatives of the Buryat ethnos and Europeoids

Abstract

Specific features of indicators of the thyroid status and blood serum lipoprotein level were revealed in girls and women of the Buryat ethnos and Europeoid race. Buryat versus Europeoid females develop adaptive responses of the pituitary-thyroid part of the neuroendocrine regulatory system (increased free T3 levels in girls and decreased TTH levels in women). Changes in lipid metabolism indicators consist in lower levels of atherogenic cholesterol fractions in Buryat girls and higher levels of cholesterol-containing blood components in Europeoid adolescents. At the older ages, an inverse tendency is observed, characterized by a higher activity of lipid metabolism in females of the indigenous nationality.

http://ift.tt/2dhPnpQ

Taste attractiveness of free amino acids and their physicochemical and biological properties (as exemplified by fishes)

Abstract

Using fishes (32 species, 11 families) as an example, the relationship between the taste attractiveness of free amino acids (L-isomers) and their physicochemical and biological properties was analyzed. It was shown that essential amino acids, most nutritionally required for an organism, have lower taste attractiveness for fishes than nonessential amino acids. Only in 6 of the 32 tested species (sunbleak Leucaspius delineatus, European minnow Phoxinus phoxinus, dace Leuciscus leuciscus, chub Leuciscus cephalus, blue gourami Trichopodus trichopterus, pearl gourami Trichopodus leerii) the relationship between the taste attractiveness and molecular weight of amino acids was supported statistically, being negative in all cases. Only in 2 species, a statistically significant correlation between the taste properties of amino acids and the dissociation constant (K₁) was found, positive in the stone loach Barbatula barbatula and negative in the lake char Salvelinus namaycush. A positive correlation between taste preferences and the magnitude of the isoelectric point (pI) of amino acids was found in one species (roach Rutilus rutilus) and a negative correlation in 2 species (brown trout Salmo trutta and Arctic char Salvelinus alpinus erythrinus). A statistically significant correlation between the taste attractiveness and water solubility of amino acids was revealed in 2 species (chum salmon Oncorhynchus keta and navaga Eleginus nawaga), negative in both cases. The flavor, which stimulates food intake, was found to be more often intrinsic to acidic and polar uncharged than basic and nonpolar amino acids, L- than D-isomers, amino acids with an amino group at the α- than β-position. Amino acids are more attractive than their salts. Aromatic amino acids are much less attractive than S-containing or acyclic amino acids. Thus, in most fish species there is no or weak relationship between the taste attractiveness of free amino acids and many of their physical, chemical and biological properties, suggesting a mediated character of this relationship and/or its poor detectability.

http://ift.tt/2dFRmqG

Blood–brain barrier and evolution of peptide regulation of physiological functions

Abstract

Literature and own data on central effects of regulatory peptides (155 substances from 32 families) have been analyzed. Peptides produced by peripheral tissues affect the brain through the almost impermeable for them blood–brain barrier and evoke numerous central effects. The mechanisms of this impact are as follows: peptides bind to specific receptors located on vagal afferent terminals and in the circumventricular organs as well as (to a lesser extent) penetrate into the brain with the aid of specific transport systems or by simple diffusion. The number of these trans-barrier communications depends on the evolutionary age of the regulated physiological function: the more ancient the function is, the greater number of peripheral peptides are involved in such trans-barrier communications.

http://ift.tt/2dhRNoa

Effect of food deprivation on transformation of carotenoids in the bivalve mollusc Anadara kagoshimensis (Tokunaga, 1906)

Abstract

The composition and content of carotenoids in tissues of Anadara kagoshimensis (Tokunaga, 1906) were analyzed under food deprivation over 30 days. By the end of the experiment, a little and uneven decrease in the total carotenoid level was observed in the foot, hepatopancreas, gills, and tissue remainder. Initially, β-carotine, pectenolon, zeaxanthine, diatoxanthine, alloxanthine and the ethers of the latter four carotenoids were detected in tissue extracts. The qualitative carotenoid composition in the tissues under study was similar. During the experiment, changes common to all tissues were found both in the composition and content of carotenoids. β-carotene disappeared on days 3–4, the level of pectenolon, zeaxanthine, diatoxanthine and alloxanthine ethers decreased over 30 days, while the pectenolon and alloxanthine levels increased. Tissue specificity was revealed. Specifically, in the foot and hepatopancreas, a considerable increase was observed in the pectenolon and alloxanthine levels parallel to the decreasing total level of carotenoid esthers and increasing level of diatoxanthine and zeaxanthine; in the gills and lump of the remaining tissues, at the similar increase in the pectenolon and alloxanthine levels, those of diatoxanthine and zeaxanthine remained intact or even a little below the initial level. The diagram of carotenoid transformation in Anadara kagoshimensis is supplemented.

http://ift.tt/2dFQoug

Managing the Complex Esophagus

Abstract

Complex esophageal problems in children are uncommon and mainly include long-gap esophageal atresia, injuries due to caustic ingestion, and failed attempts at repair of congenital esophageal abnormalities. These complex problems require detailed investigation with imaging and endoscopy before decisions about surgical management can be made. The aim of treatment is to salvage the native esophagus and optimize esophageal function. If salvage is not achieved, esophageal replacement is considered. The two most commonly used replacement techniques are gastric transposition and colonic interposition. The evidence for which technique is superior remains equivocal, but we favor gastric transposition. Preclinical studies suggest tissue engineering may be useful for esophageal replacement in the future. Care of the pediatric patient with complex esophageal disease should be centralized in experienced centers with experienced surgeons.

http://ift.tt/2dFH8qh

Pediatric Combat Trauma

Abstract

Purpose of review

Military physicians have amassed tremendous experience treating children with combat-related injuries in Iraq and Afghanistan. This review will present several treatment principles adapted from adult trauma care that were applied to children in war and consider their selective application in civilian practice.

Recent findings

Many standard practices of adult trauma care were applied to the management of war-injured children. Initial reports of tourniquet use, tranexamic acid administration, and balanced blood transfusion suggest a benefit to the pediatric population. Constraints of providing intensive care in an austere environment required a shift in management toward aggressive limb salvage over amputation, and early palliation for severe brain injury or extensive burns.

Summary

Despite the obstacles that may limit the direct translation of trauma care principals to civilian settings, these wartime experiences offer robust and excellent preliminary data that might inform future investigations in the field of pediatric trauma care.

http://ift.tt/2dPwDju

Synthetic Fractal Modelling of Heterogeneous and Anisotropic Reservoirs for Use in Simulation Studies: Implications on Their Hydrocarbon Recovery Prediction

Abstract

Optimising production from heterogeneous and anisotropic reservoirs challenges the modern hydrocarbon industry because such reservoirs exhibit extreme inter-well variability making them very hard to model. Reasonable reservoir models can be obtained using modern geostatistical techniques, but all of them rely on significant variability in the reservoir only occurring at a scale at or larger than the inter-well spacing. In this paper we take a different, generic approach. We have developed a method for constructing realistic synthetic heterogeneous and anisotropic reservoirs which can be made to represent the reservoir under test. The main physical properties of these synthetic reservoirs are distributed fractally. The models are fully controlled and reproducible and can be extended to model multiple facies reservoir types. This paper shows how the models can be constructed and how they have been tested. Reservoir simulation results of a number of generated 3-D heterogeneous and anisotropic models show that heterogeneity, in terms of only the geometric distribution of reservoir properties, has a little effect on oil production from high and moderate quality reservoirs. However, if the effect of heterogeneity on capillary pressure is taken into account, the effect becomes striking, where varying the heterogeneity of reservoirs properties can lead to a 70 % change in the predicted oil production rate and a significant early shift of water breakthrough time. Hence, it is the heterogeneity consequences that are really substantial if not taken into account. These are very significant uncertainties for a hydrocarbon company if the heterogeneity of their reservoir is not well defined.

http://ift.tt/2dI2MGv

Erratum to: Three-Dimensional Simulations for Convection in a Porous Medium with Internal Heat Source and Variable Gravity Effects

http://ift.tt/2dijsGm

Giant pulmonary artery aneurysm and surgical repair

Abstract

We present a 70-year old patient who had congenital quadricuspid pulmonary valve and a giant 8.2-cm pulmonary artery (PA) aneurysm who underwent successful surgical repair under normothermic, beating heart cardiopulmonary bypass. We utilize computed axial tomography with three-dimensional reconstructions to diagnose and follow these patients. This case highlights our perioperative management and technique of repairing giant PA aneurysms.

http://ift.tt/2cJYbla

Natural structural diversity within a conserved cyclic peptide scaffold

Abstract

We recently isolated and described the evolutionary origin of a diverse class of small single-disulfide bonded peptides derived from Preproalbumin with SFTI-1 (PawS1) proteins in the seeds of flowering plants (Asteraceae). The founding member of the PawS derived peptide (PDP) family is the potent trypsin inhibitor SFTI-1 (sunflower trypsin inhibitor-1) from Helianthus annuus, the common sunflower. Here we provide additional structures and describe the structural diversity of this new class of small peptides, derived from solution NMR studies, in detail. We show that although most have a similar backbone framework with a single disulfide bond and in many cases a head-to-tail cyclized backbone, they all have their own characteristics in terms of projections of side-chains, flexibility and physiochemical properties, attributed to the variety of their sequences. Small cyclic and constrained peptides are popular as drug scaffolds in the pharmaceutical industry and our data highlight how amino acid side-chains can fine-tune conformations in these promising peptides.

http://ift.tt/2d4JIBh

Interest in Collaborative, Practice-Based Research Networks in Pediatric Refugee Health Care

Abstract

Over the last decade, approximately 200,000 refugee children have resettled across the United States. This population is dispersed, resulting in limited data. Collaborative research networks, where clinicians across distinct practice sites work together to answer research questions, can improve the evidence base regarding clinical care. We distributed a web-based survey to pediatric refugee providers around North America to assess priorities, perceived barriers and benefits to collaborative research. We recruited 57 participants. Of respondents, 89 % were interested in collaborative research, prioritizing: (1) access to health care (33 %), (2) mental health (24 %) and (3) nutrition/growth (24 %). Perceived benefits were "improving clinical practice" (98 %) and "raising awareness about the needs of pediatric refugees" (94 %). Perceived barriers were "too many other priorities" (89 %) and "lack of funding for data entry" (78 %). There is widespread interest in collaborative networks around pediatric refugee healthcare. A successful network will address barriers and emphasize priorities.

http://ift.tt/2cT8S8i

Taxonomical and functional microbial community dynamics in an Anammox-ASBR system under different Fe (III) supplementation

Abstract

In the present study, we explored the metabolic versatility of anaerobic ammonium oxidation (anammox) bacteria in a variety of Fe (III) concentrations. Specifically, we investigated the impacts of Fe (III) on anammox growth rates, on nitrogen removal performance, and on microbial community dynamics. The results from our short-term experiments revealed that Fe (III) concentrations (0.04–0.10 mM) significantly promote the specific anammox growth rate from 0.1343 to 0.1709 d⁻¹. In the long-term experiments, the Anammox-anaerobic sequencing batch reactor (ASBR) was operated over 120 days and achieved maximum NH₄⁺-N, NO₂⁻-N, and TN efficiencies of 90.98 ± 0.35, 93.78 ± 0.29, and 83.66 ± 0.46 %, respectively. Pearson's correlation coefficients between anammox-(narG + napA), anammox-nrfA, and anammox-FeRB all exceeded r = 0.820 (p < 0.05), confirming an interaction and ecological association among the nitrogen and iron-cycling-related microbial communities. Illumina MiSeq sequencing indicated that Chloroflexi (34.39–39.31 %) was the most abundant phylum in an Anammox-ASBR system, followed by Planctomycetes (30.73–35.31 %), Proteobacteria (15.40–18.61 %), and Chlorobi (4.78–6.58 %). Furthermore, we found that higher Fe (III) supplementation (>0.06 mM) could result in the community succession of anammox species, in which Candidatus Brocadia and Candidatus Kuenenia were the dominant anammox bacteria species. Combined analyses indicated that the coupling of anammox, dissimilatory nitrogen reduction to ammonium, and iron reduction accounted for nitrogen loss in the Anammox-ASBR system. Overall, the knowledge gained in this study provides novel insights into the microbial community dynamics and metabolic potential of anammox bacteria under Fe (III) supplementation.

http://ift.tt/2cJbQsA

Uncertainty assessment of gamma-aminobutyric acid concentration of different brain regions in individual and group using residual bootstrap analysis

Abstract

The aim of this work is to quantify individual and regional differences in the relative concentration of gamma-aminobutyric acid (GABA) in human brain with in vivo magnetic resonance spectroscopy. Spectral editing Mescher–Garwood point resolved spectroscopy (MEGA-PRESS) sequence and GABA analysis toolkit (Gannet) were used to detect and quantify GABA in anterior cingulate cortex (ACC) and occipital cortex (OCC) of healthy volunteers. Residual bootstrap, a model-based statistical analysis technique, was applied to resample the fitting residuals of GABA from the Gaussian fitting model (referred to as GABA₊ thereafter) in both individual and group data of ACC and OCC. The inter-subject coefficient of variation (CV) of GABA₊ in OCC (20.66 %) and ACC (12.55 %) with residual bootstrap was lower than that of a standard Gaussian model analysis (21.58 % and 16.73 % for OCC and ACC, respectively). The intra-subject uncertainty and CV of OCC were lower than that of ACC in both analyses. The residual bootstrap analysis thus provides a more robust uncertainty estimation of individual and group GABA₊ detection in different brain regions, which may be useful in our understanding of GABA biochemistry in brain and its use for the diagnosis of related neuropsychiatric diseases.

http://ift.tt/2dtPT5k

Microscopic histological characteristics of soft tissue sarcomas: analysis of tissue features and electrical resistance

Abstract

Tissue electrical conductivity is correlated with tissue characteristics. In this work, some soft tissue sarcomas (STS) excised from patients have been evaluated in terms of histological characteristics (cell size and density) and electrical resistance. The electrical resistance has been measured using the ex vivo study on soft tissue tumors electrical characteristics (ESTTE) protocol proposed by the authors in order to study electrical resistance of surgical samples excised by patients in a fixed measurement setup. The measurement setup includes a voltage pulse generator (700 V, 100 µs long at 5 kHz, period 200 µs) and an electrode with 7 needles, 20 mm-long, with the same distance arranged in a fixed hexagonal geometry. In the ESTTE protocol, the same voltage pulse sequence is applied to each different tumor mass and the corresponding resistance has been evaluated from voltage and current recorded by the equipment. For each tumor mass, a histological sample of the volume treated by means of voltage pulses has been taken for histological analysis. Each mass has been studied in order to identify the sarcoma type. For each histological sample, an image at 20× or 40× of magnification was acquired. In this work, the electrical resistance measured for each tumor has been correlated with tissue characteristics like the type, size and density of cells. This work presents a preliminary study to explore possible correlations between tissue characteristics and electrical resistance of STS. These results can be helpful to adjust the pulse voltage intensity in order to improve the electrochemotherapy efficacy on some histotype of STS.

http://ift.tt/2d4uSL8

Addiction, Compulsion, and Persistent Temptation

Abstract

Addicts sometimes engage in such spectacularly self-destructive behavior that they seem to act under compulsion. I briefly review the claim that addiction is not compulsive at all. I then consider recent accounts of addiction by Holton and Schroeder, which characterize addiction in terms of abnormally strong motivations. However, this account can only explain the apparent compulsivity of addiction if we assume—contrary to what we know about addicts—that the desires are so strong as to be irresistible. I then consider accounts that invoke the phenomenon of "ego depletion," according to which a person can resist temptation for a while, but not indefinitely. Implicit in this account is the assumption that addiction-related desires persist long enough to deplete the addict's willpower. The balance of the paper argues that the persistence of the desire to consume drugs is a significant form of dysfunction in its own right, and that it makes an important and independent contribution to the compulsivity of addiction. I argue that addiction involves dysfunction in a mechanism that normally prevents a person from being tempted to do something that would invite disaster.

http://ift.tt/2dOX60j

Optimal Transducer Level for Atrial and Pulmonary Arterial Pressure Measurement in Patients with Functional Single Ventricle

Abstract

This study aimed to investigate the optimal transducer level for accurate measurement of atrial and pulmonary arterial pressures in the supine position for patients with functional single ventricle. Contrast-enhanced chest computed tomographic images of 108 patients who underwent either the bidirectional cavopulmonary shunt (BCPS) placement or the Fontan procedure were reviewed. Vertical distances from the skin of the back to the uppermost levels of fluid in the single atrium or the pulmonary artery confluence and their ratios to the greatest anteroposterior (AP) diameter of the thoracic cage were determined. In patients who underwent BCPS, the ratios of the uppermost levels of blood in the atrium and pulmonary artery confluence to the greatest AP diameter of the thorax were 76.0 ± 8.1 and 56.3 ± 5.5 %, respectively. The distance (mm) between these two levels was calculated as 24.2 + 0.31 × age (years) (r ² = 0.08, P < 0.03). In patients who underwent the Fontan procedure, the ratios were 79.3 ± 10.0 and 58.3 ± 5.8 %, respectively. The distance (mm) between these two levels was calculated as 31.1 + 0.44 × age (years) (r ² = 0.05, P < 0.11). The optimal transducer levels for measuring atrial and pulmonary arterial pressures in the supine position are 75–80 and 55–60 % of the AP diameter of the thorax, respectively, in patients with functional single ventricle. We should consider the difference of the pressure when atrial and pulmonary arterial pressures were measured with the same level of transducers.

http://ift.tt/2dkTXmi

Waypoint-Based Trajectory Planning of Fixed-Wing MAVs in 3D Space

Abstract

The paper addresses the problem of trajectory generation of a fixed-wing miniature aerial vehicle (MAV), constrained by a bounded turn rate, which is required to fly along a path defined by a series of waypoints in three-dimensional space. The generated trajectory named as γ-trajectory, transits between two consecutive waypoint segments in a "smooth" manner. For this trajectory the shortest distance from the waypoint can also be set to a desired value based on the limited capacity of the sensor mounted on the MAV. Subsequently, a loop-trajectory is generated, which is important if the vehicle is required to track the entire waypoint segments as well as the waypoints. Since the trajectory is composed of circles of minimum turn radius and straight lines, this is computationally fast and real-time implementable. Finally, the implementation of generated trajectory is illustrated in an environment cluttered with obstacles and several aspects of the generated trajectory are compared with those of the trajectories obtained using techniques available in the literature.

http://ift.tt/2dyJFCL

Parallel algorithm for convection–diffusion system based on least-squares procedure

Combining subspace correction method with least-squares finite element procedure, we construct a new overlapping domain decomposition parallel algorithm for solving the first-order time-dependent convection–di...

http://ift.tt/2dlGivU

A straight pin foreign body in a child: ingested or aspirated?

Though foreign body (FB) aspiration or ingestion is not uncommon in children, a straight pin as the culprit FB is rarely seen. The nature of such a FB makes it sometimes difficult to diagnose and deal with, es...

http://ift.tt/2cIYPUK

Determinants of marketing performance: empirical study at National Commercial Bank in Jakarta Indonesia

Indonesian banking industry has experienced up and down as can be seen after Pakto '88, in which the number of new banks grew rapidly, but after the 1997–1998 financial crisis, a lot of banks were liquidated d...

http://ift.tt/2dlFjf3

Determinants of adaptation choices to climate change by sheep and goat farmers in Northern Ethiopia: the case of Southern and Central Tigray, Ethiopia

The livestock sector serves as a foremost source of revenue for rural people, particularly in many developing countries. Among the livestock species, sheep and goats are the main source of livelihood for rural...

http://ift.tt/2cIXJsc

Screening for intermediate CGG alleles of FMR1 gene in male Iranian patients with Parkinsonism

Abstract

Male carriers of an expansion of CGG alleles (with 55–200 CGG repeats) in the FMR1 gene are affected with Fragile X-associated tremor/ataxia syndrome (FXTAS). On the other hand, individuals with Parkinson's disease (PD) or Parkinsonism spectrum disorders may have some clinical features that overlap with FXTAS. To investigate the possible association between PD and FMR1 expanded alleles, we screened a total of 154 male PD patients and 190 gender- and age-matched healthy control subjects from Iran. Eleven intermediate allele carriers (7.14 %) were detected among PD patients, compared with three carriers (1.57 %) among the controls (P = 0.01). No pre-mutation carriers were identified. Our results indicate that there is a potential association between FMR1 intermediate expanded alleles and PD.

http://ift.tt/2cJqHn0

Early rehabilitation: benefits in patients with severe acquired brain injury

Abstract

Establish the best time to start rehabilitation by means of scientific evidence. Observational study in patients with a diagnosis of Severe Brain Injury who received intensive inpatient rehabilitation after acute care. 1470 subjects enrolled: 651 with Traumatic Brain Injury (TBI) and 819 with Non-TBI. Male gender was prevalent in the population study, but sex distribution was not different among groups, with a prevalence of male gender in both populations. This project involved 29 rehabilitation facilities for Severe ABI. The registry was an electronic database, remained active only during the period of data collection. The patients were divided into three different categories according to the time interval from brain injury to inpatient rehabilitation admission and demographic and clinical data were collected. Etiology, time interval from injury to inpatient rehabilitation, disability severity, the presence of tracheostomy at admission to the rehabilitation facility, rehabilitation length of stay and transfer back to acute care wards because of medical, surgical or neurosurgical complications. The interval from brain injury to rehabilitation facilities admission increases along with age, brain injury severity according to DRS scores, the presence of a tracheal tube and the percentage of transfers back to acute care wards from rehabilitation facilities, because of medical, surgical or neurosurgical complications. The better recovery and more positive outcomes, reported as resulting from early rehabilitation, may be due more to less severity of brain injury and fewer complications in the acute and post-acute phase than to when the rehabilitation starts.

http://ift.tt/2dzEQcB

A Review of Insulin Degludec/Insulin Aspart: Pharmacokinetic and Pharmacodynamic Properties and Their Implications in Clinical Use

Abstract

Insulin degludec/insulin aspart (IDegAsp; 70 % IDeg and 30 % IAsp) is a soluble combination of two individual insulin analogues in one product, designed to provide mealtime glycaemic control due to the IAsp component and basal glucose-lowering effect from the IDeg component. The pharmacokinetic and pharmacodynamic characteristics of IDegAsp have been investigated in a series of clinical pharmacology studies with generally comparable designs, methodologies and patient inclusion/exclusion criteria. The glucose-lowering effect profile of IDegAsp during once-daily dosing at steady state shows distinct and clearly separated action from the prandial and basal components of IDegAsp. The IAsp component provides rapid onset and peak glucose-lowering effect followed by a flat glucose-lowering effect lasting beyond 30 h due to IDeg. During twice-daily dosing, the distinct peak effect and the flat basal effect are retained following each dose. The pharmacological properties of IDegAsp are maintained in the elderly, children, adolescents, Japanese patients and those with hepatic or renal impairment. The potential clinical benefits associated with the pharmacological properties of IDegAsp have been verified in phase III clinical trials comparing IDegAsp with three other currently available treatment options: premixed insulin, basal-bolus regimens and basal-only therapy. IDegAsp shows favourable clinical benefits compared with biphasic insulin aspart 30 and is a viable alternative to basal-bolus and basal-only therapy. This review presents the results from clinical pharmacology studies conducted with IDegAsp to date, and extrapolates these results to clinical use of IDegAsp in the context of findings from the IDegAsp clinical therapeutic studies.

http://ift.tt/2dzBSA7

Diversities of H-type anorectal malformation: a systematic review on a rare variant of the Krickenbeck classification

Abstract

Congenital H-type fistula is a rare congenital rectourogenital connection with an external anal opening in a normal or ectopic position. A systematic review was done to study the anatomical types of congenital H-type fistula, embryology, clinical presentation, relative gender distribution, associated anomalies, investigative modalities, and recent advances in treatment of these lesions. A PubMed search included H-type anorectal malformation; H-type anorectal malformations; H-type anorectal; and H-type congenital anorectal that gave 9;43;76;26 abstracts, respectively. Relevant studies and cited articles were studied omitting duplicate search. The reported incidence is 0.1–16 % of all anorectal malformation. The H-type anorectal malformation is 2.5–6 times more common in females and usually associated with a normal anus. In males, the anomaly is usually a variant with an ectopic anus or a perineal fistula. Anatomical types include anovestibular; rectovestibular; rectovaginal fistula in females and rectourethral (bulbar, prostatic, bladder neck) and rectovesical fistula in males. Variants identified include H-type fistula with perineal fistula, perineal groove, H-type sinus, H-type canal, and acquired H-type fistula. This review compiles the available literature over last six decades. Various surgical corrective procedures have been described. The high recurrence decreases with a learning curve and experience.

http://ift.tt/2dwpwIu

Modified PATIO repair for urethrocutaneous fistula post-hypospadias repair: operative technique and outcomes

Abstract

Background

To describe a modification of PATIO repair for urethrocutaneous fistula repair and evaluate its outcome.

Methods

We studied 15 boys who underwent modified PATIO repair from Jan 2010 to Sept 2015. Parameters studied included age, type of hypospadias, age at first urethroplasty, hypospadias repair technique, number of urethroplasties required, location of fistula, time gap between urethroplasty and fistula repair, method of fistula repair, and outcome of fistula repair.

Results

Mean age of the studied patients was 67.6 months (38–139). Type of hypospadias was Coronal = 3, subcoronal = 8, mid-penile = 2, prominal penile = 1, and penoscrotal = 1. Ten patients had single urethroplasty, while two patients had two urethroplasties, details not available for three patients. Average age at urethroplasty was 43.4 months (18–110). 12 patients had Snodgrass repair, Mathieu = 1 patient, tubularised plate repair = 1 patient, and unknown = 1 patient. Location of fistula was coronal in nine patients and subcoronal in six patients. Average operative time was 47.2 min (30–68). Follow-up is available for 12 patients out of which 2 patients had recurrent fistula, one of which was successfully treated by the redo modified PATIO method.

Conclusion

Modified PATIO method is technically easy method for urethrocutaneous fistula repair, with less operating time and good postoperative outcomes.

http://ift.tt/2cTrbdm

The Impact of Soil Heterogeneity on Nitrate Dynamic and Losses in Tile-Drained Arable Fields

Abstract

Intensive agriculture and the related application of fertilizers are one of the main sources for diffuse nitrate (NO₃–N) inputs into surface- and groundwater. It is assumed that especially subsurface tile drainage is an essential source. To examine the impact of heterogeneous soil properties on NO₃–N leaching via drains, field experiments in the northern Altmark region in Saxony-Anhalt (Germany) were realized on two neighboring, tile-drained arable fields with adjusted agronomic conditions but different soil physical properties from 1 November 2013 until 31 October 2015. Field campaigns, the implemented measuring technology, and numerical simulations provided the detailed characterization of the subsurface, the flow regime, and the NO₃–N dynamic. The results revealed that field I was groundwater influenced and dominated by ponding and surface runoff, whereas at field II, the whole amount of seepage water percolated freely to the drains. Thus, the amount of drained water and discharged NO₃–N loads differed significantly between both sites although their comparable size (field I/field II, 17.1 mm and 2.5 kg N ha⁻¹/150.2 mm and 40.4 kg N ha⁻¹). Furthermore, NO₃–N accumulated in the top soil of field I; whereas, this site showed a huge denitrification potential due to long hydraulic residence times. These aspects could not be reproduced at field II. A site-specific N management is absolutely required to reduce further N losses at field II as a requirement to fulfill the objectives of the European water protection policy.

http://ift.tt/2dg3L4W

Interleukin-35: a Potential Therapeutic Agent for Autoimmune Diseases

Abstract

Autoimmune diseases contain a large number of pathologies characterized by various factors that contribute to a breakdown in self-tolerance. Cytokine-mediated immunity plays an essential role in the pathogenesis of varieties of autoimmune diseases. Recent studies reveal that interleukin-35 (IL-35), a newly identified cytokine of IL-12 family, is implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), etc. In this review, we will discuss the biological features of IL-35 and summarize recent advances in the role of IL-35 in the development and pathogenesis of autoimmune diseases; the discoveries gained from these findings might translate into future therapies for these diseases.

http://ift.tt/2dvBYrO

The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer

Abstract

Background

Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored.

Methods

We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3–4 months and 6–8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR).

Results

At the 3–4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6–8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected.

Conclusions

Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.

http://ift.tt/2cILQgV

Clinicians should not be forced to use likelihood ratios when comparing tests

http://ift.tt/2dyT9K1

Editorial foreword to the Special Issue of Journal of Computational Particle Mechanics “Particle modeling of powder-based processes in advanced manufacturing”

http://ift.tt/2cI4BGk

Mortality-related risk factors and long-term survival after 4460 liver resections in Sweden—a population-based study

Abstract

Purpose

The objectives of this study were to analyze the outcome after hepatectomy and to identify contributing factors to mortality and long-term survival in a population-based setting.

Method

A retrospective, nationwide register study was performed. All patients who underwent hepatectomy in Sweden between 2002 and 2011 were identified in the Swedish Hospital Discharge Registry using their unique personal identification numbers. This cohort was linked to the National Cancer Registry (cancer diagnosis), the National Registry of Causes of Death, and the Migration Registry. Survival analysis by Kaplan-Meier method was performed to assess long-term outcome. A Cox regression model was used to analyze risk factors affecting long-term survival.

Results

Overall, 4460 hepatectomies were performed. The 30- and 90-day mortalities were 1.8 and 3.1 %, respectively. The overall 5- and 10-year survival rates for all diagnoses were 45 and 38 %, respectively. Independent risk factors for 5-year mortality were as follows: patient age, comorbidity, male gender, intrahepatic/extrahepatic cholangiocarcinoma, gallbladder cancer, extent of hepatectomy, and hepatectomies performed at non-university hospitals. Re-resection (78.1 % with diagnosis "metastasis") was performed on 374 patients. In these patients, mortality risk decreased by >50 % (HR 0.42; 95 %, CI 0.33–0.53).

Conclusion

In a population-based analysis, liver resections are done with a low mortality risk and good long-term outcome. Patients who underwent resection at a University Hospital showed a significant better outcome compared to patients resected at non-University Hospitals. These results support further centralization of liver surgery. Re-resection should be performed if feasible.

http://ift.tt/2dyVgx8

A machine-learned computational functional genomics-based approach to drug classification

Abstract

Objective

The public accessibility of "big data" about the molecular targets of drugs and the biological functions of genes allows novel data science-based approaches to pharmacology that link drugs directly with their effects on pathophysiologic processes. This provides a phenotypic path to drug discovery and repurposing. This paper compares the performance of a functional genomics-based criterion to the traditional drug target-based classification.

Methods

Knowledge discovery in the DrugBank and Gene Ontology databases allowed the construction of a "drug target versus biological process" matrix as a combination of "drug versus genes" and "genes versus biological processes" matrices. As a canonical example, such matrices were constructed for classical analgesic drugs. These matrices were projected onto a toroid grid of 50 × 82 artificial neurons using a self-organizing map (SOM). The distance, respectively, cluster structure of the high-dimensional feature space of the matrices was visualized on top of this SOM using a U-matrix.

Results

The cluster structure emerging on the U-matrix provided a correct classification of the analgesics into two main classes of opioid and non-opioid analgesics. The classification was flawless with both the functional genomics and the traditional target-based criterion. The functional genomics approach inherently included the drugs' modulatory effects on biological processes. The main pharmacological actions known from pharmacological science were captures, e.g., actions on lipid signaling for non-opioid analgesics that comprised many NSAIDs and actions on neuronal signal transmission for opioid analgesics.

Conclusions

Using machine-learned techniques for computational drug classification in a comparative assessment, a functional genomics-based criterion was found to be similarly suitable for drug classification as the traditional target-based criterion. This supports a utility of functional genomics-based approaches to computational system pharmacology for drug discovery and repurposing.

http://ift.tt/2cIHqHe

How the reference values for serum parathyroid hormone concentration are (or should be) established?

Abstract

Well-validated reference values are necessary for a correct interpretation of a serum PTH concentration. Establishing PTH reference values needs recruiting a large reference population. Exclusion criteria for this population can be defined as any situation possibly inducing an increase or a decrease in PTH concentration. As recommended in the recent guidelines on the diagnosis and management of asymptomatic primary hyperparathyroidism, PTH reference values should be established in vitamin D-replete subjects with a normal renal function with possible stratification according to various factors such as age, gender, menopausal status, body mass index, and race. A consensus about analytical/pre-analytical aspects of PTH measurement is also needed with special emphasis on the nature of the sample (plasma or serum), the time and the fasting/non-fasting status of the blood sample. Our opinion is that blood sample for PTH measurement should be obtained in the morning after an overnight fast. Furthermore, despite longer stability of the PTH molecule in EDTA plasma, we prefer serum as it allows to measure calcium, a prerequisite for a correct interpretation of a PTH concentration, on the same sample. Once a consensus is reached, we believe an important international multicentre work should be performed to recruit a very extensive reference population of apparently healthy vitamin D-replete subjects with a normal renal function in order to establish the PTH normative data. Due to the huge inter-method variability in PTH measurement, a sufficient quantity of blood sample should be obtained to allow measurement with as many PTH kits as possible.

http://ift.tt/2dHeQIh

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

Abstract

Since 2008, the direct-acting oral anticoagulants (DOACs) have expanded the therapeutic options of cardiovascular diseases with recognized clinical and epidemiological impact, such as non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and also in the preventive setting of orthopedic surgical patients. The large body of evidence, not only from pivotal clinical trials but also from 'real-world' postmarketing observational findings (e.g. analytical epidemiological studies and registry data) gathered to date allow for a first attempt at verifying a posteriori whether or not the pharmacological advantages of the DOACs actually translate into therapeutic innovation, with relevant implications for clinicians, regulators and patients. This review aims to synthesize the risk–benefit profile of DOACs in the aforementioned consolidated indications through an 'evidence summary' approach gathering the existent evidence-based data, particularly systematic reviews with meta-analyses of randomized controlled trials, as well as observational studies, comparing DOACs with vitamin K antagonists. Clinical evidence will be discussed and compared with major international guidelines to identify whether an update is needed. Controversial clinically relevant safety issues will be also examined in order to highlight current challenges and unsettled questions (e.g. actual bleeding risk in susceptible populations). It is anticipated that the large number of publications on NVAF or VTE (44 systematic reviews with meta-analyses and 12 observational studies retained in our analysis) suggests the potential existence of overlapping studies and calls for common criteria to qualitatively and quantitatively assess discordances, thus guiding future research.

http://ift.tt/2dht2t4

Imaging of cerebrovascular disease. A practical guide

http://ift.tt/2d3jYp2

Contemporary Controversies in Digoxin Use in Systolic Heart Failure

Abstract

Digoxin remains one of the oldest therapies for heart failure; however, its safety and efficacy have been controversial since its initial use. Questions that remain include the clinical efficacy of digoxin when added to contemporary medical therapy, when and if it should be added, and how to minimize adverse effects. In this review, we will summarize recent data on the use of digoxin in systolic heart failure and address some of the controversies regarding the role of digoxin in the modern era of heart failure treatment.

http://ift.tt/2cHYlON