Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment.

Curr Opin Neurol. 2017 Feb 15;:

Authors: Symonds JD, Zuberi SM, Johnson MR

Abstract
PURPOSE OF REVIEW: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery.
RECENT FINDINGS: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery.
SUMMARY: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy's relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery.

PMID: 28212175 [PubMed - as supplied by publisher]

New applications for known drugs: Human glycogen synthase kinase 3 inhibitors as modulators of Aspergillus fumigatus growth.

Eur J Med Chem. 2016 Jun 30;116:281-9

Authors: Sebastián V, Manoli MT, Pérez DI, Gil C, Mellado E, Martínez A, Espeso EA, Campillo NE

Abstract
Invasive aspergillosis (IA) is one of the most severe forms of fungi infection. IA disease is mainly due to Aspergillus fumigatus, an air-borne opportunistic pathogen. Mortality rate caused by IA is still very high (50-95%), because of difficulty in early diagnostics and reduced antifungal treatment options, thus new and efficient drugs are necessary. The aim of this work is, using Aspergillus nidulans as non-pathogen model, to develop efficient drugs to treat IA. The recent discovered role of glycogen synthase kinase-3 homologue, GskA, in A. fumigatus human infection and our previous experience on human GSK-3 inhibitors focus our attention on this kinase as a target for the development of antifungal drugs. With the aim to identify effective inhibitors of colonial growth of A. fumigatus we use A. nidulans as an accurate model for in vivo and in silico studies. Several well-known human GSK-3β inhibitors were tested for inhibition of A. nidulans colony growth. Computational tools as docking studies and binding site prediction was used to explain the different biological profile of the tested inhibitors. Three of the five tested hGSK3β inhibitors are able to reduce completely the colonial growth by covalent bind to the enzyme. Therefore these compounds may be useful in different applications to eradicate IA.

PMID: 27131621 [PubMed - indexed for MEDLINE]

Pharmacogenomic Characterization and Isobologram Analysis of the Combination of Ascorbic Acid and Curcumin-Two Main Metabolites of Curcuma longa-in Cancer Cells.

Front Pharmacol. 2017;8:38

Authors: Ooko E, Kadioglu O, Greten HJ, Efferth T

Abstract
Curcuma longa has long been used in China and India as anti-inflammatory agent to treat a wide variety of conditions and also as a spice for varied curry preparations. The chemoprofile of the Curcuma species exhibits the presence of varied phytochemicals with curcumin being present in all three species but AA only being shown in C. longa. This study explored the effect of a curcumin/AA combination on human cancer cell lines. The curcumin/AA combination was assessed by isobologram analysis using the Loewe additivity drug interaction model. The drug combination showed additive cytotoxicity toward CCRF-CEM and CEM/ADR5000 leukemia cell lines and HCT116p53(+/+) and HCT116p53(-/-) colon cancer cell line, while the glioblastoma cell lines U87MG and U87MG.ΔEGFR showed additive to supra-additive cytotoxicity. Gene expression profiles predicting sensitivity and resistance of tumor cells to induction by curcumin and AA were determined by microarray-based mRNA expressions, COMPARE, and hierarchical cluster analyses. Numerous genes involved in transcription (TFAM, TCERG1, RGS13, C11orf31), apoptosis-regulation (CRADD, CDK7, CDK19, CD81, TOM1) signal transduction (NR1D2, HMGN1, ABCA1, DE4ND4B, TRIM27) DNA repair (TOPBP1, RPA2), mRNA metabolism (RBBP4, HNRNPR, SRSF4, NR2F2, PDK1, TGM2), and transporter genes (ABCA1) correlated with cellular responsiveness to curcumin and ascorbic acid. In conclusion, this study shows the effect of the curcumin/AA combination and identifies several candidate genes that may regulate the response of varied cancer cells to curcumin and AA.

PMID: 28210221 [PubMed - in process]

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

"cystic fibrosis"

These pubmed results were generated on 2017/02/18

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.

How the EUCERD Joint Action supported initiatives on Rare Diseases.

Eur J Med Genet. 2017 Mar;60(3):185-189

Authors: Lynn S, Hedley V, Atalaia A, Evangelista T, Bushby K, EUCERD Joint Action

Abstract
Joint Actions are successful initiatives from the European Commission (EC) that have helped to raise awareness and to bring significant benefit to those suffering from a rare disease (RD). In this paper, we will focus on the activities developed by the EUCERD Joint Action (EJA) and by the Orphanet Joint Action ("Orphanet Europe"). EUCERD Joint Action was co-funded by the EC and the Member States between 2012 and 2015 to help to define the activities and policies in the field of RD and foster exchange of experiences amongst Member States. This project is the continuation of previous efforts to turn RD a priority in the EC Health Programmes. "Orphanet Europe" was a Joint Action co-funded by INSERM, the French Directorate General for Health and the EC to address the need for a common portal that would gather the most update information regarding RD. This need was identified in the European Commission report "Rare Diseases: Europe's challenge" and in the Recommendation of the Council for a European RD portal. These joint actions have supported the policy development work of the European Commission, through the support of their committees for rare diseases. In this paper, the authors aim to raise awareness of the work done by the EUCERD Joint Action on behalf of the rare disease community and the policies established.

PMID: 28087401 [PubMed - indexed for MEDLINE]

Subcorneal Pustular Dermatosis: A Review of 30 Years of Progress.

Am J Clin Dermatol. 2016 Dec;17(6):653-671

Authors: Watts PJ, Khachemoune A

Abstract
Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a rare, benign yet relapsing pustular dermatosis. Its incidence and prevalence have not been well studied. It characteristically presents as hypopyon pustules on the trunk and intertriginous areas of the body. SPD is similar to two other disease entities. Both SPD-type immunoglobulin (Ig)-A pemphigus and annular pustular psoriasis clinically and histologically present similarly to SPD. Immunologic studies separate SPD-type IgA pemphigus from SPD and pustular psoriasis. However, there is still an unclear designation as to whether SPD is its own entity distinct from pustular psoriasis, as the once thought characteristic histologic picture of psoriasis does not hold true for pustular psoriasis. SPD has been reported to occur in association with several neoplastic, immunologic, and inflammatory conditions. Dapsone remains the first-line treatment for SPD, although dapsone-resistant cases have been increasingly reported. Other therapies have been used singly or as adjunctive therapy with success, such as corticosteroids, immunosuppressive agents, tumor necrosis factor inhibitors, and ultraviolet light therapy. This article provides a review of the last 30 years of available literature, with a focus on successful treatment options and a suggestion for reappraisal of the classification of SPD.

PMID: 27349653 [PubMed - indexed for MEDLINE]

Parent Recommendations for Family Functioning With Prader-Willi Syndrome: A Rare Genetic Cause of Childhood Obesity.

J Pediatr Nurs. 2016 Jan-Feb;31(1):47-54

Authors: Vitale SA

Abstract
UNLABELLED: Prader-Willi syndrome (PWS) is the most common genetic cause of childhood obesity. Neonates have hypotonia and may fail to growth and develop. Within a few years, behavioral problems occur along with insatiable hunger (hyperphagia) and the potential for excessive weight gain. The purpose of this study was to identify how families function when they have a child with PWS.
DESIGN AND METHODS: This qualitative descriptive study was based on 20 face-to-face, audio-taped interviews with parents. They were asked to identify family responses to PWS and offer recommendations. Data were transcribed, coded and analyzed for commonalities and themes.
RESULTS: There were twelve identified themes with two overarching themes of 1) taking action and 2) caring for oneself and family. Taking action was focused on achieving what was best for the child with PWS. Caring for oneself and family attempted to assure that all in the family were healthy, content, and living a fulfilling life under their circumstances.
CONCLUSIONS: This study revealed parental insight as to how they learned to creatively cope with a stressful family life. There was a recognition of inevitable sacrifice and the need for changes in expectations so as to help the child with PWS flourish while also focusing on the needs of all the members of the family.
PRACTICE IMPLICATIONS: Nursing and health care providers should be aware of these issues in the provision of anticipatory guidance to families contending with this genetic disorder.

PMID: 26684080 [PubMed - indexed for MEDLINE]

Epigenetic Landscape during Coronavirus Infection.

Pathogens. 2017 Feb 15;6(1):

Authors: Schäfer A, Baric RS

Abstract
Coronaviruses (CoV) comprise a large group of emerging human and animal pathogens, including the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) strains. The molecular mechanisms regulating emerging coronavirus pathogenesis are complex and include virus-host interactions associated with entry, replication, egress and innate immune control. Epigenetics research investigates the genetic and non-genetic factors that regulate phenotypic variation, usually caused by external and environmental factors that alter host expression patterns and performance without any change in the underlying genotype. Epigenetic modifications, such as histone modifications, DNA methylation, chromatin remodeling, and non-coding RNAs, function as important regulators that remodel host chromatin, altering host expression patterns and networks in a highly flexible manner. For most of the past two and a half decades, research has focused on the molecular mechanisms by which RNA viruses antagonize the signaling and sensing components that regulate induction of the host innate immune and antiviral defense programs upon infection. More recently, a growing body of evidence supports the hypothesis that viruses, even lytic RNA viruses that replicate in the cytoplasm, have developed intricate, highly evolved, and well-coordinated processes that are designed to regulate the host epigenome, and control host innate immune antiviral defense processes, thereby promoting robust virus replication and pathogenesis. In this article, we discuss the strategies that are used to evaluate the mechanisms by which viruses regulate the host epigenome, especially focusing on highly pathogenic respiratory RNA virus infections as a model. By combining measures of epigenome reorganization with RNA and proteomic datasets, we articulate a spatial-temporal data integration approach to identify regulatory genomic clusters and regions that play a crucial role in the host's innate immune response, thereby defining a new viral antagonism mechanism following emerging coronavirus infection.

PMID: 28212305 [PubMed - in process]

KIWI: A technology for public health event monitoring and early warning signal detection.

Online J Public Health Inform. 2016;8(3):e208

Authors: Mukhi SN

Abstract
OBJECTIVES: To introduce the Canadian Network for Public Health Intelligence's new Knowledge Integration using Web-based Intelligence (KIWI) technology, and to pefrom preliminary evaluation of the KIWI technology using a case study. The purpose of this new technology is to support surveillance activities by monitoring unstructured data sources for the early detection and awareness of potential public health threats.
METHODS: A prototype of the KIWI technology, adapted for zoonotic and emerging diseases, was piloted by end-users with expertise in the field of public health and zoonotic/emerging disease surveillance. The technology was assessed using variables such as geographic coverage, user participation, and others; categorized by high-level attributes from evaluation guidelines for internet based surveillance systems. Special attention was given to the evaluation of the system's automated sense-making algorithm, which used variables such as sensitivity, specificity, and predictive values. Event-based surveillance evaluation was not applied to its full capacity as such an evaluation is beyond the scope of this paper.
RESULTS: KIWI was piloted with user participation = 85.0% and geographic coverage within monitored sources = 83.9% of countries. The pilots, which focused on zoonotic and emerging diseases, lasted a combined total of 65 days and resulted in the collection of 3243 individual information pieces (IIP) and 2 community reported events (CRE) for processing. Ten sources were monitored during the second phase of the pilot, which resulted in 545 anticipatory intelligence signals (AIS). KIWI's automated sense-making algorithm (SMA) had sensitivity = 63.9% (95% CI: 60.2-67.5%), specificity = 88.6% (95% CI: 87.3-89.8%), positive predictive value = 59.8% (95% CI: 56.1-63.4%), and negative predictive value = 90.3% (95% CI: 89.0-91.4%).
DISCUSSION: Literature suggests the need for internet based monitoring and surveillance systems that are customizable, integrated into collaborative networks of public health professionals, and incorporated into national surveillance activities. Results show that the KIWI technology is well posied to address some of the suggested challenges. A limitation of this study is that sample size for pilot participation was small for capturing overall readiness of integrating KIWI into regular surveillance activities.
CONCLUSIONS: KIWI is a customizable technology developed within an already thriving collaborative platform used by public health professionals, and performs well as a tool for discipline-specific event monitoring and early warning signal detection.

PMID: 28210429 [PubMed - in process]

Closantel; a veterinary drug with potential severe morbidity in humans.

BMC Ophthalmol. 2016 Nov 29;16(1):207

Authors: Tabatabaei SA, Soleimani M, Mansouri MR, Mirshahi A, Inanlou B, Abrishami M, Pakrah AR, Masarat H

Abstract
BACKGROUND: Closantel is a halogenated salicylanilide with a potent anti parasitic activity. It is widely used in management of parasitic infestation in animals, but is contraindicated in humans.
CASE PRESENTATION: A 34-year-old man with depression was referred to our center with progressive loss of vision in both eyes 10 days after unintentional ingestion of three 500 mg tablets of Closantel. On fundus examination, left optic disc margin was blurred. His bilateral visual acuity was no light perception (NLP) despite prescribed IV erythropoietin injections 20,000 units daily for 3 days and 1gr intravenous methylprednisolone acetate for 3 days followed by 1 mg/kg oral prednisolone. On macular optical coherence tomography (OCT), a disruption in outer retina was observed. Electroretinogram and visual evoked potential tests showed visual pathway involvement.
CONCLUSIONS: Destruction of neurosensory retina and visual pathways after accidental Closantel use is related to severe visual loss. This case alerts us about the destructive effect of this drug on humans even in low dosage which necessitates preventive efforts to reduce the chance of this morbid side effect.

PMID: 27899086 [PubMed - indexed for MEDLINE]

Assessment of tissue damage due to percutaneous nephrolithotomy using serum concentrations of inflammatory mediators.

Actas Urol Esp. 2015 Jun;39(5):283-90

Authors: Pérez-Fentes D, Gude F, Blanco-Parra M, Morón E, Ulloa B, García C

Abstract
OBJECTIVES: To determine the percutaneous nephrolithotomy (PCNL) effects on the tissues using the quantification of inflammatory mediators, and to assess their impact on the development of postoperative complications.
PATIENTS AND METHODS: Prospective observational non-randomized study on 40 patients underwent to PCNL. 50 patients with kidney stone who were treated by extracorporeal shock wave lithotripsy (ESWL) were used as control group. Interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) were determined at baseline (T0: before treatment), and at 2, 6 and 24hours after (T1, T2 and T3).
RESULTS: No relevant changes on IL-1β and TNF-α were found. IL-6 showed two peaks at 2 and 6hours post-PCNL (median 17.8 and 15.8 pg/mL, respectively). At 24hours CRP had reached its peak value (3.4mg/L). The group treated with ESWL no showed significant changes in any of the markers. The serum concentration of IL-6 and CRP at 24hours post-NLP is different depending on the occurrence of complications (P=.001 and P=.039, respectively). IL-6 showed a good predictive power for the development of complications (AUC .801).
CONCLUSIONS: Tissue damage caused by the PCNL is low. This damage increases significantly in those cases showing postoperative complications. IL-6 at 24hours has been shown to be a good predictive tool for the development of complications.

PMID: 25667173 [PubMed - indexed for MEDLINE]

Semantics-based plausible reasoning to extend the knowledge coverage of medical knowledge bases for improved clinical decision support.

BioData Min. 2017;10:7

Authors: Mohammadhassanzadeh H, Van Woensel W, Abidi SR, Abidi SS

Abstract
BACKGROUND: Capturing complete medical knowledge is challenging-often due to incomplete patient Electronic Health Records (EHR), but also because of valuable, tacit medical knowledge hidden away in physicians' experiences. To extend the coverage of incomplete medical knowledge-based systems beyond their deductive closure, and thus enhance their decision-support capabilities, we argue that innovative, multi-strategy reasoning approaches should be applied. In particular, plausible reasoning mechanisms apply patterns from human thought processes, such as generalization, similarity and interpolation, based on attributional, hierarchical, and relational knowledge. Plausible reasoning mechanisms include inductive reasoning, which generalizes the commonalities among the data to induce new rules, and analogical reasoning, which is guided by data similarities to infer new facts. By further leveraging rich, biomedical Semantic Web ontologies to represent medical knowledge, both known and tentative, we increase the accuracy and expressivity of plausible reasoning, and cope with issues such as data heterogeneity, inconsistency and interoperability. In this paper, we present a Semantic Web-based, multi-strategy reasoning approach, which integrates deductive and plausible reasoning and exploits Semantic Web technology to solve complex clinical decision support queries.
RESULTS: We evaluated our system using a real-world medical dataset of patients with hepatitis, from which we randomly removed different percentages of data (5%, 10%, 15%, and 20%) to reflect scenarios with increasing amounts of incomplete medical knowledge. To increase the reliability of the results, we generated 5 independent datasets for each percentage of missing values, which resulted in 20 experimental datasets (in addition to the original dataset). The results show that plausibly inferred knowledge extends the coverage of the knowledge base by, on average, 2%, 7%, 12%, and 16% for datasets with, respectively, 5%, 10%, 15%, and 20% of missing values. This expansion in the KB coverage allowed solving complex disease diagnostic queries that were previously unresolvable, without losing the correctness of the answers. However, compared to deductive reasoning, data-intensive plausible reasoning mechanisms yield a significant performance overhead.
CONCLUSIONS: We observed that plausible reasoning approaches, by generating tentative inferences and leveraging domain knowledge of experts, allow us to extend the coverage of medical knowledge bases, resulting in improved clinical decision support. Second, by leveraging OWL ontological knowledge, we are able to increase the expressivity and accuracy of plausible reasoning methods. Third, our approach is applicable to clinical decision support systems for a range of chronic diseases.

PMID: 28203277 [PubMed]

Targeted therapy for chronic respiratory disease: a new paradigm.

Med J Aust. 2017 Feb 20;206(3):136-140

Authors: Gibson PG, Peters MJ, Wainwright CE

Abstract
Targeted therapy has emerged as a highly effective treatment approach for chronic respiratory diseases. Many of these conditions have dismal outcomes; however, targeted therapy shows great results for the subgroup who respond. This represents a new way to approach these conditions and offers great promise as a future treatment direction. In severe eosinophilic asthma, therapy that targets the interleukin-5 pathway with monoclonal antibodies leads to a 50% reduction in asthma exacerbations in previously refractory disease. In cystic fibrosis, lung function improves with therapy that targets specific molecular abnormalities in the cystic fibrosis transmembrane conductance regulator to increase the probability that this chloride channel is open. In lung cancer, specifically adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and overexpression of EGFR tyrosine kinase, therapy that inhibits EGFR tyrosine kinase gives better outcomes than conventional chemotherapy.

PMID: 28208047 [PubMed - in process]

Faecal Calprotectin in Cystic Fibrosis and IT'S Relation to Disease Parameters - a Longitudinal Analysis Over 12 Years.

J Pediatr Gastroenterol Nutr. 2017 Feb 15;:

Authors: Ellemunter H, Engelhardt A, Schüller K, Steinkamp G

Abstract
OBJECTIVES: Faecal calprotectin (FC) is a marker of inflammation in the intestinal tract. We assessed FC levels longitudinally in patients with cystic fibrosis (CF) and evaluated the relation between FC results and relevant markers of disease.
METHODS: Calprotectin was measured in faecal samples starting in 2003 and values were stored in the centre's patient database. In this retrospective analysis we searched for associations of FC concentrations with disease severity and progression. Linear mixed effects models were used to model the logarithm of FC levels.
RESULTS: A total of 171 patients (0-61 years) had 2434 FC measurements between 2003 and 2015, with a total observation period of 1686 patient years. Median (IQR) FC concentrations were 60.9 (75.9) μg/g and 61% of the samples showed elevated FC concentrations (>50 μg/g). Despite some statistically significant effects, there was no clinically relevant association between FC and sex, age, FEV1 z-score, or BMI z-score. Pancreatic insufficiency (i.e. faecal elastase < 100 μg/g stool) was associated with considerably higher FC values compared to normal pancreatic function (median FC 68 vs. 29 μg/g, p < 0.0001). F508del homozygous subjects showed a trend to higher FC values than heterozygous patients (median 71 vs. 62 μg/g, p = 0.173). In addition, a significant association with increasing serum CRP concentrations (p < 0.0001) was observed.
CONCLUSIONS: FC was elevated in two thirds of stool specimens. Increased FC was more common in patients with pancreatic insufficiency. Whether increased faecal calprotectin reflects intestinal inflammation in patients with cystic fibrosis remains to be determined.

PMID: 28207476 [PubMed - as supplied by publisher]

Molecular modeling in the age of clinical genomics, the enterprise of the next generation.

J Mol Model. 2017 Mar;23(3):75

Authors: Prokop JW, Lazar J, Crapitto G, Smith DC, Worthey EA, Jacob HJ

Abstract
Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation. In agreement with the clinical tests performed on the C203Y patient, protein modeling and molecular dynamics suggest that direct interactions with RIPK2 and Caspase3 are altered by the C203Y mutation and subsequent loss of Zn coordination in the second BIR domain of XIAP. Interestingly, the variant does not appear to alter interactions with SMAC, resulting in further damage to the caspase and NOD2 pathways. To expand the computational strategy designed when studying XIAP, we have applied the molecular modeling tools to a list of 140 variants seen in CFTR associated with cystic fibrosis, and a list of undiagnosed variants in 17 different genes. This paper shows the exciting applications of molecular modeling in the classification and characterization of genetic variants identified in next generation sequencing. Graphical abstract XIAP in Caspase 3 and NOD2 signaling pathways.

PMID: 28204942 [PubMed - in process]

High incidence of non-tuberculous mycobacteria-positive cultures among adolescent with cystic fibrosis.

J Cyst Fibros. 2017 Feb 12;:

Authors: Cavalli Z, Reynaud Q, Bricca R, Nove-Josserand R, Durupt S, Reix P, Perceval M, de Montclos MP, Lina G, Durieu I

Abstract
BACKGROUND: We evaluated the prevalence of non-tuberculous mycobacteria (NTM)-positive cultures among our cystic fibrosis (CF) center patients, reviewed risk factors for NTM positivity, and determined its impact on lung function evolution.
METHODS: From 2009 to 2014, CF adults and children attending the CF center of Lyon (France) and having at least one positive NTM isolate were included. Each case was matched by age and gender with two CF patients with no NTM isolate (controls).
RESULTS: 48 CF patients with NTM-positive isolates were matched to 96 controls. The age group for whom incident NTM was higher was young adolescents aged 13 to 17. A significant association for NTM positivity was found with Staphylococcusaureus in multivariate analysis and with allergic bronchopulmonary aspergillosis, corticosteroid and itraconazole in univariate analysis. Mean annual FEV1 decline was faster for NTM-positive patients compared to controls.
CONCLUSION: These data highlight the high incidence of NTM-positive cultures among young adolescents with CF.

PMID: 28202251 [PubMed - as supplied by publisher]

Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning.

J Psychopharmacol. 2017 Jan 01;:269881117691467

Authors: Powell TR, Murphy T, Lee SH, Price J, Thuret S, Breen G

Abstract
Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. 'Connectivity mapping' is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram). We identified mRNA changes common to both drugs to create an 'antidepressant mRNA signature'. We used this signature to probe the Library of Integrated Network-based Cellular Signatures (LINCS) and to identify other compounds that elicit similar changes to mRNA in neural progenitor cells. Results from LINCS revealed that the tricyclic antidepressant clomipramine elicited mRNA changes most similar to our mRNA signature, and we identified W-7 and vorinostat as functionally relevant drug candidates, which may have repositioning potential. Our results are encouraging and represent the first attempt to use connectivity mapping for drug repositioning in MDD.

PMID: 28208023 [PubMed - as supplied by publisher]

A review and update on orphan drugs for the treatment of noninfectious uveitis.

Clin Ophthalmol. 2017;11:257-265

Authors: You C, Sahawneh HF, Ma L, Kubaisi B, Schmidt A, Foster CS

Abstract
INTRODUCTION: Uveitis, a leading cause of preventable blindness around the world, is a critically underserved disease in regard to the medications approved for use. Multiple immunomodulatory therapy (IMT) drugs are appropriate for uveitis therapy but are still off-label. These IMT agents, including antimetabolites, calcineurin inhibitors, alkylating agents, and biologic agents, have been designated as "orphan drugs" and are widely used for systemic autoimmune diseases or organ transplantation.
AREA COVERED: The purpose of this paper is to comprehensively review and summarize the approved orphan drugs and biologics that are being used to treat systemic diseases and to discuss drugs that have not yet received approval as an "orphan drug for treating uveitis" by the US Food and Drug Administration (FDA).
OUR PERSPECTIVE: IMT, as a steroid-sparing agent for uveitis patients, has shown promising clinical results. Refractory and recurrent uveitis requires combination IMT agents. IMT is continued for a period of 2 years while the patient is in remission before considering tapering medication. Our current goals include developing further assessments regarding the efficacy, optimal dose, and safety in efforts to achieve FDA approval for "on-label" use of current IMT agents and biologics more quickly and to facilitate insurance coverage and expand access to the products for this orphan disease.

PMID: 28203051 [PubMed - in process]

A 36-Year-Old Female with Recurrent Left Sided Pleural Effusion: A Rare Case of Mediastinal Lymphangioma.

Am J Case Rep. 2016 Oct 28;17:799-804

Authors: Swarnakar RN, Hazarey JD, Dhoble C, Vaghani B, Ainsley AS, Khargie JF, Likaj L

Abstract
BACKGROUND Lymphangioma is an atypical non-malignant, lymphatic lesion that is congenital in origin. Lymphangioma is most frequently observed in the head and neck, but can occur at any location in the body. About 65% of lymphangiomas are apparent at birth, while 80-90% are diagnosed by two years of age. Occurrence in adults is rare, as evidenced by less than 100 cases of adult lymphangiomas reported in the literature. CASE REPORT A 36-year-old Indian woman with a medical history of recurrent pleural effusions presented with chief complaints of dyspnea on exertion for one year and a low-grade fever for one month. A thorax CT revealed left-sided pleural effusion with thin internal septations. Thoracoscopy revealed a large cystic lesion arising from the mediastinum from the hilum surrounding the mediastinal great vessels. The diagnosis of lymphangioma was confirmed via histopathologic examination of the cyst. It was managed with partial cystectomy along with the use of a sclerosing agent (talc). CONCLUSIONS The size and location of lymphangiomas can vary, with some patients presenting with serious problems like respiratory distress, while others may be asymptomatic. Complete cyst resection is the gold standard treatment for mediastinal cystic lymphangioma. Partial cyst resection along with the use of sclerosing agents can be an effective option when complete cystectomy is not possible. Although lymphangioma is a rare patient condition, it should be included in the differentials for patients presenting with pleural effusions. Also, a biopsy should be done at the earliest opportunity to differentiate lymphangioma from other mediastinal malignant tumors.

PMID: 27789902 [PubMed - indexed for MEDLINE]

Integrated multidisciplinary care for the management of chronic conditions in adults: an overview of reviews and an example of using indirect evidence to inform clinical practice recommendations in the field of rare diseases.

Haemophilia. 2016 Jul;22 Suppl 3:41-50

Authors: Yeung CH, Santesso N, Zeraatkar D, Wang A, Pai M, Sholzberg M, Schünemann HJ, Iorio A

Abstract
BACKGROUND: Integrated care models have been adopted for individuals with chronic conditions and for persons with rare diseases, such as haemophilia.
OBJECTIVE: To summarize the evidence from reviews for the effects of integrated multidisciplinary care for chronic conditions in adults and to provide an example of using this evidence to make recommendations for haemophilia care.
SEARCH METHODS: We searched MEDLINE, EMBASE, CINAHL and Cochrane Database of Systematic Reviews up to January 2016, and reviewed reference lists of retrieved papers.
SELECTION CRITERIA: Systematic reviews of at least one randomized study, on adults with non-communicable chronic conditions.
DATA COLLECTION AND ANALYSIS: Two investigators independently assessed eligibility and extracted data. Quality of reviews was assessed using ROBIS, and the evidence assessed using GRADE.
RESULTS: We included seven reviews reporting on three chronic conditions. We found low to high quality evidence. Integrated care results in a reduction in mortality; likely a reduction in emergency visits and an improvement in function; little to no difference in quality of life, but shorter hospital stays; and may result in little to no difference in missed days of school or work. No studies reported educational attainment, or patient adherence and knowledge. When used for haemophilia, judgment about the indirectness of the evidence was driven by disease, intervention or outcome characteristics.
CONCLUSION: This overview provides the most up to date evidence on integrated multidisciplinary care for chronic conditions in adults, and an example of how it can be used for guidelines in rare diseases.

PMID: 27348400 [PubMed - indexed for MEDLINE]