29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Decreased Transcription Factor Binding Levels Nearby Primate Pseudogenes Suggest Regulatory Degeneration.

Mol Biol Evol. 2016 Jun;33(6):1478-85

Authors: Douglas GM, Wilson MD, Moses AM

Abstract
Characteristics of pseudogene degeneration at the coding level are well-known, such as a shift toward neutral rates of nonsynonymous substitutions and gain of frameshift mutations. In contrast, degeneration of pseudogene transcriptional regulation is not well understood. Here, we test two predictions of regulatory degeneration along a pseudogenized lineage: 1) Decreased transcription factor (TF) binding and 2) accelerated evolution in putative cis-regulatory regions.We find evidence for decreased TF binding levels nearby two primate pseudogenes compared with functional liver genes. However, the majority of TF-bound sequences nearby pseudogenes do not show evidence for lineage-specific accelerated rates of evolution. We conclude that decreases in TF binding level could be a marker for regulatory degeneration, while sequence degeneration in primate cis-regulatory modules may be obscured by background rates of TF binding site turnover.

PMID: 26882985 [PubMed - indexed for MEDLINE]

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Repurposing of Potent Drug Candidates for Multiparasite Targeting.

Trends Parasitol. 2017 Mar;33(3):158-161

Authors: Jain V, Sharma A

Abstract
Parasite-directed drug discovery efforts require sustained and substantial scientific resources. Many eukaryotic parasites share similarities in metabolic pathways and housekeeping genes, as evident from their underlying protein sequences. Their subsequent structural congruence within enzyme active sites can thus be leveraged for multiparasite targeting using similar or identical drug probes. This bodes well for delivering new anti-infectives.

PMID: 28081985 [PubMed - indexed for MEDLINE]

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Database of Optimized Proteomic Quantitative Methods for Human Drug Disposition-Related Proteins for Applications in Physiologically Based Pharmacokinetic Modeling.

CPT Pharmacometrics Syst Pharmacol. 2017 Apr;6(4):267-276

Authors: Vrana M, Whittington D, Nautiyal V, Prasad B

Abstract
The purpose of this study was to create an open access repository of validated liquid chromatography tandem mass spectrometry (LC-MS/MS) multiple reaction monitoring (MRM) methods for quantifying 284 important proteins associated with drug absorption, distribution, metabolism, and excretion (ADME). Various in silico and experimental approaches were used to select surrogate peptides and optimize instrument parameters for LC-MS/MS quantification of the selected proteins. The final methods were uploaded to an online public database (QPrOmics; www.qpromics.uw.edu/qpromics/assay/), which provides essential information for facile method development in triple quadrupole mass spectrometry (MS) instruments. To validate the utility of the methods, the differential tissue expression of 107 key ADME proteins was characterized in the tryptic digests of the pooled subcellular fractions of human liver, kidneys, intestines, and lungs. These methods and the data are critical for development of physiologically based pharmacokinetic (PBPK) models to predict xenobiotic disposition.

PMID: 28074615 [PubMed - indexed for MEDLINE]

Related Articles

Antidepressants in the Treatment of Functional Dyspepsia: A Systematic Review and Meta-Analysis.

PLoS One. 2016;11(6):e0157798

Authors: Lu Y, Chen M, Huang Z, Tang C

Abstract
BACKGROUND: Antidepressants have been empirically used in the treatment of functional dyspepsia (FD). However, results from recent clinical trials investigating their efficacy are conflicting. The aim of this study is to evaluate the efficacy of antidepressants in the management of FD in adults.
METHODS: Databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and BIOSIS Previews were searched for all randomized controlled trials (RCT) investigating efficacy of antidepressants in the management of FD in adult patients. Data of overall symptom unimproved and adverse events were compared between the antidepressants and placebo group.
RESULTS: The search strategy identified 432 citations. Of those, eight RCTs met the inclusion criteria and were included in the meta-analysis. The pooled relative risk (RR) of symptom unimproved with tricyclic antidepressants (TCAs) versus placebo was 0.76 (95% CI: 0.62 to 0.94, P = 0.01; I2 = 0%, P = 0.39). By contrast, selective serotonin reuptake inhibitors (SSRIs) did not show a benefit over placebo (RR = 1.00, 95% CI: 0.86 to 1.17, P = 0.95; I2 = 0%, P = 0.82). Adverse events were significantly more frequent among patients receiving antidepressants than those receiving placebos (RR = 1.64, 95% CI: 1.14 to 2.35, P = 0.007).
CONCLUSION: TCAs but not SSRIs, are effective in the treatment of FD, but antidepressants were also associated with more adverse events compared with placebo.

PMID: 27310135 [PubMed - indexed for MEDLINE]

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Vinblastine as a second rescue for the treatment of canine multicentric lymphoma in 39 cases (2005 to 2014).

J Small Anim Pract. 2016 Aug;57(8):429-34

Authors: Lenz JA, Robat CS, Stein TJ

Abstract
OBJECTIVES: The objective of this study was to retrospectively evaluate response and outcome of dogs with multicentric lymphoma treated with single-agent vinblastine as a second rescue.
METHODS: Medical records from 39 client-owned dogs receiving vinblastine rescue treatment (having relapsed on or following completion of UW-Madison and CCNU/L-asparaginase protocols), between 2005 and 2014, were reviewed for information regarding clinical presentation, diagnostic testing, drug dosage, number of treatments, side effects, response and outcome.
RESULTS: The median starting dose of vinblastine was 2·6 mg/m(2) (1·7 to 2·8 mg/m(2) ), administered weekly until disease progression. Of the 39 dogs treated, 3 dogs (7·7%) achieved a complete remission, 7 dogs (17·9%) achieved a partial response, 18 dogs (46·2%) maintained stable disease and 11 (28·2%) had progressive disease. Ten dogs (25·6%) developed a grade III or IV neutropenia, and 4 dogs (10·3%) developed grade III or IV thrombocytopenia (one dog in both categories). After starting vinblastine, the median progression-free survival was 29·5 days (0 to 77 days) and overall median survival time was 46 days (4 to 250 days). Duration of first remission was identified as a positive predictor of outcome.
CLINICAL SIGNIFICANCE: Single-agent vinblastine is well tolerated in dogs with relapsed or refractory lymphoma. Responses were incomplete and short-lasting.

PMID: 27251593 [PubMed - indexed for MEDLINE]

Related Articles

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

PLoS One. 2016;11(5):e0155530

Authors: Davis AP, Wiegers TC, King BL, Wiegers J, Grondin CJ, Sciaky D, Johnson RJ, Mattingly CJ

Abstract
Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

PMID: 27171405 [PubMed - indexed for MEDLINE]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2017/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Funding Opportunity RFA-HL-18-018 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support investigators performing research to identify the barriers and facilitators to implementation of an evidence-based practice(s) for heart, lung, blood, and sleep (HLBS) diseases in the inpatient setting. NHLBI is seeking applications that will utilize an implementation research framework to develop an implementation strategy (or strategies) to be tested during a subsequent hybrid effectiveness-implementation trial. During this grant, investigators will measure the baseline or usual care practice with respect to the evidence-based practice(s) of interest and plan for the subsequent trial. This FOA intends to support applications that propose a multidisciplinary research team that includes both inpatient clinical research expertise and implementation research expertise. At the conclusion of this U01, awardees and other qualified applicants may be ready to apply to a separate NHLBI-funded FOA, described in NOT-HL-17-493, to support the trial.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

N-Chlorotaurine, a Promising Future Candidate for Topical Therapy of Fungal Infections.

Mycopathologia. 2017 Jul 12;:

Authors: Nagl M, Arnitz R, Lackner M

Abstract
N-Chlorotaurine (NCT) is a mild long-lived oxidant that can be applied to sensitive body regions as an endogenous antiseptic. Enhancement of its microbicidal activity in the presence of proteinaceous material because of transchlorination, a postantibiotic/postantifungal effect and antitoxic activity renders it interesting for treatment of fungal infections, too. This is confirmed by first case applications in skin and mucous membranes of different body sites. Recent findings of good tolerability of inhaled NCT suggest further investigations of this substance for treatment of bronchopulmonary diseases, where microorganisms play a role, particularly multi-resistant ones. The availability of a well-tolerated and effective inhaled antiseptic with anti-inflammatory properties could be a significant progress, in particular for chronic pulmonary diseases, such as chronic obstructive pulmonary disease or cystic fibrosis.

PMID: 28702855 [PubMed - as supplied by publisher]

Related Articles

Defective CFTR leads to aberrant β-catenin activation and kidney fibrosis.

Sci Rep. 2017 Jul 12;7(1):5233

Authors: Zhang JT, Wang Y, Chen JJ, Zhang XH, Dong JD, Tsang LL, Huang XR, Cai Z, Lan HY, Jiang XH, Chan HC

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl(-) channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/β-catenin signaling pathways, whereas the β-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of β-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher β-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/β-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.

PMID: 28701694 [PubMed - in process]

Related Articles

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.

Diabetes Care. 2017 Jul 12;:

Authors: Shields BM, Shepherd M, Hudson M, McDonald TJ, Colclough K, Peters J, Knight B, Hyde C, Ellard S, Pearson ER, Hattersley AT, UNITED study team

Abstract
OBJECTIVE: Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes.
RESEARCH DESIGN AND METHODS: We studied patients diagnosed aged 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes.
RESULTS: A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95%CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a one-in-five detection rate for the pathway. The negative predictive value was 99.9%.
CONCLUSIONS: The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed aged 30 years or younger.

PMID: 28701371 [PubMed - as supplied by publisher]

Related Articles

AJRCCM: 100-Year Anniversary. Homeward Bound: A Centenary of Home Mechanical Ventilation.

Am J Respir Crit Care Med. 2017 May 01;195(9):1140-1149

Authors: Hind M, Polkey MI, Simonds AK

Abstract
The evolution of home mechanical ventilation is an intertwined chronicle of negative and positive pressure modes and their role in managing ventilatory failure in neuromuscular diseases and other chronic disorders. The uptake of noninvasive positive pressure ventilation has resulted in widespread growth in home ventilation internationally and fewer patients being ventilated invasively. As with many applications of domiciliary medical technology, home ventilatory support has either led or run in parallel with acute hospital applications and has been influenced by medical and societal shifts in the approach to chronic care, the creation of community support teams, a preference of recipients to be treated at home, and economic imperatives. This review summarizes the trends and growing evidence base for ventilatory support outside the hospital.

PMID: 28459325 [PubMed - indexed for MEDLINE]

Related Articles

Swine models, genomic tools and services to enhance our understanding of human health and diseases.

Lab Anim (NY). 2017 Mar 22;46(4):167-172

Authors: Walters EM, Wells KD, Bryda EC, Schommer S, Prather RS

Abstract
The pig is becoming increasingly important as a biomedical model. Given the similarities between pigs and humans, a greater understanding of the underlying biology of human health and diseases may come from the pig rather than from classical rodent models. With an increasing need for swine models, it is essential that the genomic tools, models and services be readily available to the scientific community. Many of these are available through the National Swine Resource and Research Center (NSRRC), a facility funded by the US National Institutes of Health at the University of Missouri. The goal of the NSRRC is to provide high-quality biomedical swine models to the scientific community.

PMID: 28328880 [PubMed - indexed for MEDLINE]

Related Articles

Former Very Preterm Infants Show an Unfavorable Cardiovascular Risk Profile at a Preschool Age.

PLoS One. 2016;11(12):e0168162

Authors: Posod A, Odri Komazec I, Kager K, Pupp Peglow U, Griesmaier E, Schermer E, Würtinger P, Baumgartner D, Kiechl-Kohlendorfer U

Abstract
Cardiovascular disease is the leading cause of death worldwide. Evidence points towards an unfavorable cardiovascular risk profile of former preterm infants in adolescence and adulthood. The aim of this study was to determine whether cardiovascular risk predictors are detectable in former very preterm infants at a preschool age. Five- to seven-year-old children born at <32 weeks' gestational age were included in the study. Same-aged children born at term served as controls. Basic data of study participants were collected by means of follow-up databases and standardized questionnaires. At study visit, anthropometric data, blood pressure readings and aortic intima-media thickness were assessed. Blood samples were obtained after an overnight fast. In comparison to children born at term, former preterm infants had higher systolic and diastolic blood pressure readings (odds ratio [95% confidence interval] per 1-SD higher blood pressure level 3.2 [2.0-5.0], p<0.001 and 1.6 [1.1-1.2], p = 0.008), fasting glucose levels (OR [95% CI] 5.2 [2.7-10.1], p<0.001), homeostasis model assessment index (OR [95% CI] 1.6 [1.0-2.6], p = 0.036), and cholesterol levels (OR [95% CI] 2.1 [1.3-3.4], p = 0.002). Systolic prehypertension (23.7% vs. 2.2%; OR [95% CI] 13.8 [3.1-60.9], p = 0.001), elevated glucose levels (28.6% vs. 5.9%; OR [95% CI] 6.4 [1.4-28.8], p = 0.016), and hypercholesterolemia (77.4% vs. 52.9%; OR [95% CI] 3.0 [1.3-7.1], p = 0.010) were significantly more prevalent in the preterm group. As former very preterm infants display an unfavorable cardiovascular risk profile already at a preschool age, implementation of routine cardiovascular follow-up programs might be warranted.

PMID: 27959909 [PubMed - indexed for MEDLINE]

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Spirometry Reference Equations for Indian Children: Create Local or Go Global?

Indian Pediatr. 2016 Sep 08;53(9):779-780

Authors: Guglani L, Weiner DJ

PMID: 27771644 [PubMed - indexed for MEDLINE]

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Mucolytic Effectiveness of Tyloxapol in Chronic Obstructive Pulmonary Disease - A Double-Blind, Randomized Controlled Trial.

PLoS One. 2016;11(6):e0156999

Authors: Koppitz M, Eschenburg C, Salzmann E, Rosewich M, Schubert R, Zielen S

Abstract
OBJECTIVE: Mucoactive drugs should increase the ability to expectorate sputum and, ideally, have anti-inflammatory properties. The aim of the study was to evaluate the mucolytic activity of Tyloxapol compared to saline (0.9%) in COPD.
DESIGN: A randomized, placebo-controlled, double-blinded crossover, clinical trial was carried out. Patients were randomly assigned to either inhale 5 ml Tyloxapol 1% or saline 0.9% solution three times daily for 3 weeks and vice versa for another 3 weeks. 28 patients (18 male, 10 female, 47 to 73 years old, median age 63.50) were screened, 21 were treated and 19 patients completed the study per protocol.
RESULTS: A comparison of the two treatment phases showed that the primary endpoint sputum weight was statistically significant higher when patients inhaled Tyloxapol (mean 4.03 g, 95% CI: 2.34-5.73 g at week 3) compared to saline (mean 2.63 g, 95% CI: 1.73-3.53 g at week 3). The p-value at three weeks of treatment was 0.041 between treatment arms. Sputum cells decreased during the Tyloxapol treatment after 3 weeks, indicating that Tyloxapol might have some anti-neutrophilic properties. Lung function parameters (FVC, FEV1, RV, and RV/TLC) remained stable during the study, and no treatment effect was shown. Interestingly, there was a mean increase in all inflammatory cytokines (IL-1β, IL-6, and IL-8) during the saline treatment from day 1 to week 3, whereas during the Tyloxapol treatment, all cytokines decreased. Due to the small sample size and the large individual variation in sputum cytokines, these differences were not significant. However, analyses confirmed that Tyloxapol has significant anti-inflammatory properties in vitro. Despite the high number of inhalations (more than 1000), only 27 adverse events (20 during the Tyloxapol and seven during saline) were recorded. Eleven patients experienced AEs under Tyloxapol and six under saline treatment, which indicates that inhalation of saline or Tyloxapol is a very safe procedure.
CONCLUSION: Our study demonstrated that inhalation of Tyloxapol by patients with COPD is safe and superior to saline and has some anti-inflammatory effects.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02515799.

PMID: 27308826 [PubMed - indexed for MEDLINE]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Greenhouse gas emissions from dung pats vary with dung beetle species and with assemblage composition.

PLoS One. 2017;12(7):e0178077

Authors: Piccini I, Arnieri F, Caprio E, Nervo B, Pelissetti S, Palestrini C, Roslin T, Rolando A

Abstract
Cattle farming is a major source of greenhouse gases (GHGs). Recent research suggests that GHG fluxes from dung pats could be affected by biotic interactions involving dung beetles. Whether and how these effects vary among beetle species and with assemblage composition is yet to be established. To examine the link between GHGs and different dung beetle species assemblages, we used a closed chamber system to measure fluxes of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) from cattle dung pats. Targeting a total of four dung beetle species (a pat-dwelling species, a roller of dung balls, a large and a small tunnelling species), we ran six experimental treatments (four monospecific and two mixed) and two controls (one with dung but without beetles, and one with neither dung nor beetles). In this setting, the overall presence of beetles significantly affected the gas fluxes, but different species contributed unequally to GHG emissions. When compared to the control with dung, we detected an overall reduction in the total cumulative CO2 flux from all treatments with beetles and a reduction in N2O flux from the treatments with the three most abundant dung beetle species. These reductions can be seen as beneficial ecosystem services. Nonetheless, we also observed a disservice provided by the large tunneler, Copris lunaris, which significantly increased the CH4 flux-an effect potentially traceable to the species' nesting strategy involving the construction of large brood balls. When fluxes were summed into CO2-equivalents across individual GHG compounds, dung with beetles proved to emit less GHGs than did beetle-free dung, with the mix of the three most abundant species providing the highest reduction (-32%). As the mix of multiple species proved the most effective in reducing CO2-equivalents, the conservation of diverse assemblages of dung beetles emerges as a priority in agro-pastoral ecosystems.

PMID: 28700590 [PubMed - in process]