Coronary artery bypass grafting and sensorineural hearing loss, a cohort study

BACKGROUND: Sudden sensorineural hearing loss is routinely encountered by the otologist. The etiology is varied and often identifiable. One of the relatively less frequent causes is surgery. Apart from being an established entity with otological surgeries, sensorineural hearing loss has also been known to occur after non-otological procedures under general anesthesia. Commonest amongst these procedures is cardiopulmonary bypass, an association that has long been recognized. However, despite the proposition of diverse hypotheses in the past, the pathophysiology remains unclear. METHODS: The study is a prospective matched cohort study that will be carried out in Aga Khan University Hospital, Karachi, Pakistan. Participants among exposed would include all those patients who would be undergoing coronary artery bypass surgery in the hospital who fall under the criteria for inclusion. Unexposed group would comprise of patients undergoing a non-bypass procedure of similar duration under the same type of anesthesia who meet the selection criteria. Both these groups will undergo audiometric testing at our hospital on three different occasions during the course of this study. Initially before the procedure to test the baseline hearing capacity; then one week after the procedure to assess any changes in hearing ability following the surgery; and finally a third audiogram at six weeks follow-up to assess further changes in any hearing deficits noted during the second phase of testing. Certain variables including the subjects' demographics and those concerning the procedure itself will be noted and used later for risk factors analysis. A detailed past medical and surgical history will also be obtained. Data analysis would include calculation of relative risk and significance of the results, by running the chi-square test. Other statistical tests like Fisher exact test may then be employed to facilitate data interpretation. Continuous scale may then be employed and multivariate linear regression used. DISCUSSION: This study is planned to obtain a better understanding of the correlation between sudden sensorineural hearing loss and cardiopulmonary bypass. Being the first major cohort trial in this line of investigation, the project is designed to identify the existence of any significant relationship between cardiopulmonary bypass and sensorineural hearing deficit

Validation of Results from Knowledge Discovery: Mass Density as a Predictor of Breast Cancer

The purpose of our study is to identify and quantify the association between high breast mass density and breast malignancy using inductive logic programming (ILP) and conditional probabilities, and validate this association in an independent dataset. We ran our ILP algorithm on 62,219 mammographic abnormalities. We set the Aleph ILP system to generate 10,000 rules per malignant finding with a recall >5% and precision >25%. Aleph reported the best rule for each malignant finding. A total of 80 unique rules were learned. A radiologist reviewed all rules and identified potentially interesting rules. High breast mass density appeared in 24% of the learned rules. We confirmed each interesting rule by calculating the probability of malignancy given each mammographic descriptor. High mass density was the fifth highest ranked predictor. To validate the association between mass density and malignancy in an independent dataset, we collected data from 180 consecutive breast biopsies performed between 2005 and 2007. We created a logistic model with benign or malignant outcome as the dependent variable while controlling for potentially confounding factors. We calculated odds ratios based on dichomotized variables. In our logistic regression model, the independent predictors high breast mass density (OR 6.6, CI 2.5–17.6), irregular mass shape (OR 10.0, CI 3.4–29.5), spiculated mass margin (OR 20.4, CI 1.9–222.8), and subject age (β = 0.09, p < 0.0001) significantly predicted malignancy. Both ILP and conditional probabilities show that high breast mass density is an important adjunct predictor of malignancy, and this association is confirmed in an independent data set of prospectively collected mammographic findings

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

What traits are carried on mobile genetic elements, and why?

Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes

Targeting the EGFR in ovarian cancer with the tyrosine kinase inhibitor ZD1839 (“Iressa”).

The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 (‘Iressa’) on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-α stimulated growth was completely inhibited by concentrations of ZD 1839 ⩾0.3 μM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-α stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-α was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-α, EGF and amphiregulin mRNAs were detected by RT–PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(−1) day(−1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit. British Journal of Cancer (2002) 86, 456–462. DOI: 10.1038/sj/bjc/6600058 www.bjcancer.com © 2002 The Cancer Research Campaig

The interaction between the proliferating macroalga Asparagopsis taxiformis and the coral Astroides calycularis induces changes in microbiome and metabolomic fingerprints

Mediterranean Sea ecosystems are considered as hotspots of biological introductions, exposed to possible negative effects of non-indigenous species. In such temperate marine ecosystems, macroalgae may be dominant, with a great percentage of their diversity represented by introduced species. Their interaction with temperate indigenous benthic organisms have been poorly investigated. To provide new insights, we performed an experimental study on the interaction between the introduced proliferative red alga Asparagopsis taxiformis and the indigenous Mediterranean coral Astroides calycularis. The biological response measurements included meta-barcoding of the associated microbial communities and metabolomic fingerprinting of both species. Significant changes were detected among both associated microbial communities, the interspecific differences decreasing with stronger host interaction. No short term effects of the macroalga on the coral health, neither on its polyp activity or its metabolism, were detected. In contrast, the contact interaction with the coral induced a change in the macroalgal metabolomic fingerprint with a significant increase of its bioactivity against the marine bacteria Aliivibrio fischeri. This induction was related to the expression of bioactive metabolites located on the macroalgal surface, a phenomenon which might represent an immediate defensive response of the macroalga or an allelopathic offense against coral.ERA-NET Biome project "SEAPROLIF"; CNRS; Provence Alpes Cote d'Azur Region; TOTAL Fundation; Fundacao para a Ciencia e a Tecnologia (FCT) [Netbiome/0002/2011]; FCT fellowships [SFRH/BPD/63703/2009, SFRH/BPD/107878/2015]info:eu-repo/semantics/publishedVersio

Pentalogy of Cantrell: two patients and a review to determine prognostic factors for optimal approach

Two patients with incomplete pentalogy of Cantrell are described. The first was a girl with a large omphalocele with evisceration of the heart, liver and intestines with an intact sternum. Echocardiography showed profound intracardiac defects. The girl died 33 h after birth. The second patient was a female fetus with ectopia cordis (EC) without intracardiac anomalies; a large omphalocele with evisceration of the heart, stomach, spleen and liver; a hypoplastic sternum and rib cage; and a scoliosis. The pregnancy was terminated. A review of patients described in the literature is presented with the intention of finding prognostic factors for an optimal approach to patients with the pentalogy of Cantrell. In conclusion the prognosis seems to be poorer in patients with the complete form of pentalogy of Cantrell, EC, and patients with associated anomalies. Intracardial defects do not seem to be a prognostic factor

Adhesion Molecules Associated with Female Genital Tract Infection

Altres ajuts: Marie Curie Career Integration Grant i una beca Fundació Dexeus Salut de la DonaEfforts to develop vaccines that can elicit mucosal immune responses in the female genital tract against sexually transmitted infections have been hampered by an inability to measure immune responses in these tissues. The differential expression of adhesion molecules is known to confer site-dependent homing of circulating effector T cells to mucosal tissues. Specific homing molecules have been defined that can be measured in blood as surrogate markers of local immunity (e.g. α4β7 for gut). Here we analyzed the expression pattern of adhesion molecules by circulating effector T cells following mucosal infection of the female genital tract in mice and during a symptomatic episode of vaginosis in women. While CCR2, CCR5, CXCR6 and CD11c were preferentially expressed in a mouse model of Chlamydia infection, only CCR5 and CD11c were clearly expressed by effector T cells during bacterial vaginosis in women. Other homing molecules previously suggested as required for homing to the genital mucosa such as α4β1 and α4β7 were also differentially expressed in these patients. However, CD11c expression, an integrin chain rarely analyzed in the context of T cell immunity, was the most consistently elevated in all activated effector CD8+ T cell subsets analyzed. This molecule was also induced after systemic infection in mice, suggesting that CD11c is not exclusive of genital tract infection. Still, its increase in response to genital tract disorders may represent a novel surrogate marker of mucosal immunity in women, and warrants further exploration for diagnostic and therapeutic purposes

Probenecid Inhibits the Human Bitter Taste Receptor TAS2R16 and Suppresses Bitter Perception of Salicin

Bitter taste stimuli are detected by a diverse family of G protein-coupled receptors (GPCRs) expressed in gustatory cells. Each bitter taste receptor (TAS2R) responds to an array of compounds, many of which are toxic and can be found in nature. For example, human TAS2R16 (hTAS2R16) responds to β-glucosides such as salicin, and hTAS2R38 responds to thiourea-containing molecules such as glucosinolates and phenylthiocarbamide (PTC). While many substances are known to activate TAS2Rs, only one inhibitor that specifically blocks bitter receptor activation has been described. Here, we describe a new inhibitor of bitter taste receptors, p-(dipropylsulfamoyl)benzoic acid (probenecid), that acts on a subset of TAS2Rs and inhibits through a novel, allosteric mechanism of action. Probenecid is an FDA-approved inhibitor of the Multidrug Resistance Protein 1 (MRP1) transporter and is clinically used to treat gout in humans. Probenecid is also commonly used to enhance cellular signals in GPCR calcium mobilization assays. We show that probenecid specifically inhibits the cellular response mediated by the bitter taste receptor hTAS2R16 and provide molecular and pharmacological evidence for direct interaction with this GPCR using a non-competitive (allosteric) mechanism. Through a comprehensive analysis of hTAS2R16 point mutants, we define amino acid residues involved in the probenecid interaction that result in decreased sensitivity to probenecid while maintaining normal responses to salicin. Probenecid inhibits hTAS2R16, hTAS2R38, and hTAS2R43, but does not inhibit the bitter receptor hTAS2R31 or non-TAS2R GPCRs. Additionally, structurally unrelated MRP1 inhibitors, such as indomethacin, fail to inhibit hTAS2R16 function. Finally, we demonstrate that the inhibitory activity of probenecid in cellular experiments translates to inhibition of bitter taste perception of salicin in humans. This work identifies probenecid as a pharmacological tool for understanding the cell biology of bitter taste and as a lead for the development of broad specificity bitter blockers to improve nutrition and medical compliance