Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE(2), 6-keto-PGF1(α,) TxB(2)), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(−1) h(−1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE(2) excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB(2) excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users

Homopolymer tract length dependent enrichments in functional regions of 27 eukaryotes and their novel dependence on the organism DNA (G+C)% composition

BACKGROUND: DNA homopolymer tracts, poly(dA).poly(dT) and poly(dG).poly(dC), are the simplest of simple sequence repeats. Homopolymer tracts have been systematically examined in the coding, intron and flanking regions of a limited number of eukaryotes. As the number of DNA sequences publicly available increases, the representation (over and under) of homopolymer tracts of different lengths in these regions of different genomes can be compared. RESULTS: We carried out a survey of the extent of homopolymer tract over-representation (enrichment) and over-proportional length distribution (above expected length) primarily in the single gene documents, but including some whole chromosomes of 27 eukaryotics across the (G+C)% composition range from 20 – 60%. A total of 5.2 × 10(7 )bases from 15,560 cleaned (redundancy removed) sequence documents were analyzed. Calculated frequencies of non-overlapping long homopolymer tracts were found over-represented in non-coding sequences of eukaryotes. Long poly(dA).poly(dT) tracts demonstrated an exponential increase with tract length compared to predicted frequencies. A novel negative slope was observed for all eukaryotes between their (G+C)% composition and the threshold length N where poly(dA).poly(dT) tracts exhibited over-representation and a corresponding positive slope was observed for poly(dG).poly(dC) tracts. Tract size thresholds where over-representation of tracts in different eukaryotes began to occur was between 4 – 11 bp depending upon the organism (G+C)% composition. The higher the GC%, the lower the threshold N value was for poly(dA).poly(dT) tracts, meaning that the over-representation happens at relatively lower tract length in more GC-rich surrounding sequence. We also observed a novel relationship between the highest over-representations, as well as lengths of homopolymer tracts in excess of their random occurrence expected maximum lengths. CONCLUSIONS: We discuss how our novel tract over-representation observations can be accounted for by a few models. A likely model for poly(dA).poly(dT) tract over-representation involves the known insertion into genomes of DNA synthesized from retroviral mRNAs containing 3' polyA tails. A proposed model that can account for a number of our observed results, concerns the origin of the isochore nature of eukaryotic genomes via a non-equilibrium GC% dependent mutation rate mechanism. Our data also suggest that tract lengthening via slip strand replication is not governed by a simple thermodynamic loop energy model

Double Blind Study Investigating the Effect of Different Voice Prostheses on Ease of Swallowing and Residue Post Laryngectomy.

Voice prostheses have been examined for their effect on voice production but there is little datum on their effect on swallow function. This study investigated the difference between six commonly available voice prostheses in terms of swallowing. Laryngectomy patients had up to six voice prostheses placed in a random order over two visits. Swallowing was evaluated for each prosthesis using FEES (Fibreoptic Endoscopic Evaluation of Swallowing). After each prosthesis trial, patients self-evaluated their experience of swallowing. Three independent experts indicated which prosthesis they considered best for swallowing for each patient and judged residue on the voice prosthesis and in the upper esophagus. Raters were blinded to participant details, voice prosthesis type and scores of other raters. On patient self-evaluation, scores were equally distributed across all prostheses for swallowing. Experts most frequently chose the Blom Singer Low pressure and Blom Singer Classic Indwelling voice prostheses as best for swallowing but consensus was poor for most patients. Experts found that the Blom Singer Classic Indwelling and the Provox Vega had least residue on the voice prosthesis on thin liquid (p ≤ 0.001) and soft (p = 0.001), respectively. Experts also found that the Blom Singer Low Pressure had least residue in the upper esophagus on soft consistency (p ≤ 0.001). While self-evaluation by patients did not identify a consistently preferred prosthesis for swallow, many patients expressed personal preferences, suggesting benefits to involving patients in the choice of prosthesis. Some voice prostheses may be associated with lower levels of residue on the prosthesis and upper esophagus with certain consistencies

Dental therapy before and after radiotherapy–an evaluation on patients with head and neck malignancies

The present investigation evaluates the dental care situation of patients with head and neck cancer before and after radiotherapy. The situations of these patients in 1993 and 2005 were compared to detect similarities, differences and developments. In the years 1993 and 2005, 37 and 36 patients, respectively, with head and neck cancer treated by the local departments of otorhinolaryngology and of radiotherapy were examined consecutively according to their aftercare appointments. Time points of radiotherapy treatment of the patients evaluated in 1993 varied from 1984 to 1993. The patients evaluated in 2005 had received radiotherapy between 1998 and 2005. Therefore the applied radiotherapeutic regimen differed not only between the two groups of patients, but also within each group. The information for these investigations was provided anonymously. It was evaluated with descriptive statistics. The evaluation of the data shows distinct differences with respect to preventive and therapeutic dental care measures. In 2005, 35 out of 36 patients (97.2%) had a dental consultation before radiotherapy (1993, 65%). All 27 dentate patients (100%) obtained a splint for fluoride application (1993, none). 29% fewer edentulous patients were seen than in 1993. The number of teeth destroyed decreased from 19.2% (1993) to 7.8% in 2005. Mycoses due to Candida spp. and chronic failures in wound healing were rare (5.5%). In the course of the 12 years, prophylactic measures, such as the application of splints for fluoride treatment, were intensified. However, concepts for the dental care of patients undergoing radiotherapy, especially following the radiation, should be widened to avoid ruined teeth and long delayed wound healings

Repeated Training with Augmentative Vibrotactile Feedback Increases Object Manipulation Performance

Most users of prosthetic hands must rely on visual feedback alone, which requires visual attention and cognitive resources. Providing haptic feedback of variables relevant to manipulation, such as contact force, may thus improve the usability of prosthetic hands for tasks of daily living. Vibrotactile stimulation was explored as a feedback modality in ten unimpaired participants across eight sessions in a two-week period. Participants used their right index finger to perform a virtual object manipulation task with both visual and augmentative vibrotactile feedback related to force. Through repeated training, participants were able to learn to use the vibrotactile feedback to significantly improve object manipulation. Removal of vibrotactile feedback in session 8 significantly reduced task performance. These results suggest that vibrotactile feedback paired with training may enhance the manipulation ability of prosthetic hand users without the need for more invasive strategies

Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications

Sodium retention and edema are common features of nephrotic syndrome that are classically attributed to hypovolemia and activation of the renin–angiotensin–aldosterone system. However, numbers of clinical and experimental findings argue against this underfill theory. In this review we analyze data from the literature in both nephrotic patients and experimental models of nephrotic syndrome that converge to demonstrate that sodium retention is not related to the renin–angiotensin–aldosterone status and that fluid leakage from capillary to the interstitium does not result from an imbalance of Starling forces, but from changes of the intrinsic properties of the capillary endothelial filtration barrier. We also discuss how most recent findings on the cellular and molecular mechanisms of sodium retention has allowed the development of an efficient treatment of edema in nephrotic patients

Modeling the Adaptive Role of Negative Signaling in Honey Bee Intraspecific Competition

Collective decision making in the social insects often proceeds via feedback cycles based on positive signaling. Negative signals have, however, been found in a few contexts in which costs exist for paying attention to no longer useful information. Here we incorporate new research on the specificity and context of the negative stop signal into an agent based model of honey bee foraging to explore the adaptive basis of negative signaling in the dance language. Our work suggests that the stop signal, by acting as a counterbalance to the waggle dance, allows colonies to rapidly shut down attacks on other colonies. This could be a key adaptation, as the costs of attacking a colony strong enough to defend itself are significant

DRD4 Polymorphism Moderates the Effect of Alcohol Consumption on Social Bonding

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse

Early Embryonic Vascular Patterning by Matrix-Mediated Paracrine Signalling: A Mathematical Model Study

During embryonic vasculogenesis, endothelial precursor cells of mesodermal origin known as angioblasts assemble into a characteristic network pattern. Although a considerable amount of markers and signals involved in this process have been identified, the mechanisms underlying the coalescence of angioblasts into this reticular pattern remain unclear. Various recent studies hypothesize that autocrine regulation of the chemoattractant vascular endothelial growth factor (VEGF) is responsible for the formation of vascular networks in vitro. However, the autocrine regulation hypothesis does not fit well with reported data on in vivo early vascular development. In this study, we propose a mathematical model based on the alternative assumption that endodermal VEGF signalling activity, having a paracrine effect on adjacent angioblasts, is mediated by its binding to the extracellular matrix (ECM). Detailed morphometric analysis of simulated networks and images obtained from in vivo quail embryos reveals the model mimics the vascular patterns with high accuracy. These results show that paracrine signalling can result in the formation of fine-grained cellular networks when mediated by angioblast-produced ECM. This lends additional support to the theory that patterning during early vascular development in the vertebrate embryo is regulated by paracrine signalling

Crystal Structure of Reovirus Attachment Protein σ1 in Complex with Sialylated Oligosaccharides

Many viruses attach to target cells by binding to cell-surface glycans. To gain a better understanding of strategies used by viruses to engage carbohydrate receptors, we determined the crystal structures of reovirus attachment protein σ1 in complex with α-2,3-sialyllactose, α-2,6-sialyllactose, and α-2,8-di-siallylactose. All three oligosaccharides terminate in sialic acid, which serves as a receptor for the reovirus serotype studied here. The overall structure of σ1 resembles an elongated, filamentous trimer. It contains a globular head featuring a compact β-barrel, and a fibrous extension formed by seven repeating units of a triple β-spiral that is interrupted near its midpoint by a short α -helical coiled coil. The carbohydrate-binding site is located between β-spiral repeats two and three, distal from the head. In all three complexes, the terminal sialic acid forms almost all of the contacts with σ1 in an identical manner, while the remaining components of the oligosaccharides make little or no contacts. We used this structural information to guide mutagenesis studies to identify residues in σ1 that functionally engage sialic acid by assessing hemagglutination capacity and growth in murine erythroleukemia cells, which require sialic acid binding for productive infection. Our studies using σ1 mutant viruses reveal that residues 198, 202, 203, 204, and 205 are required for functional binding to sialic acid by reovirus. These findings provide insight into mechanisms of reovirus attachment to cell-surface glycans and contribute to an understanding of carbohydrate binding by viruses. They also establish a filamentous, trimeric carbohydrate-binding module that could potentially be used to endow other trimeric proteins with carbohydrate-binding properties