Pharmacological Reversal Agents in Dental Practice: Keys to Patient Safety.

Compend Contin Educ Dent. 2016 Nov/Dec;37(10):681-687; quiz 688

Authors: Donaldson M, Goodchild JH

Abstract
Though uncommon, medical emergencies in the dental office are harrowing occurrences that can be the result of adverse drug reactions. Pharmacological antagonists have been developed for administration as reversal agents in emergency situations in which patients may have an untoward effect, typically caused by too much medication. Dental practitioners should be familiar with these agents to keep patients safe and help mitigate drug-induced medical emergencies. This article reviews the pharmacokinetic and pharmacodynamic principles of pharmacological antagonists; it emphasizes six specific reversal agents as they relate to the clinical practice of dentistry: naloxone, flumazenil, epinephrine, diphenhydramine, phentolamine, and atropine. Outside of emergency situations, the pharmacological antagonist phentolamine has been developed to reverse the effects of the vasoconstrictor in dental local anesthesia preparations when the effects of the agonist medication are no longer required. Such newer reversal agents are being considered for more routine use once the dental procedure is complete. This article is intended to assist dental practitioners who are familiar with pharmacological antagonists to be better able to help mitigate drug-induced medical emergencies should they occur.

PMID: 27875053 [PubMed - indexed for MEDLINE]

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Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil.

Anthropol Med. 2018 Apr;25(1):11-29

Authors: Gibbon S, Aureliano W

Abstract
Within the context of a globalising agenda for genetic research where 'global health' is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases 'rarenesss' has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the 'judicialisation' of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities.

PMID: 29533091 [PubMed - indexed for MEDLINE]

Bullous morphoea: a retrospective study.

Clin Exp Dermatol. 2017 Jul;42(5):532-535

Authors: Venturi M, Pinna AL, Pilloni L, Atzori L, Ferreli C, Rongioletti F

Abstract
Bullous morphoea is a rare variant of localized scleroderma whose pathogenesis has been widely discussed. We retrospectively reviewed the records of all histopathologically confirmed cases of morphoea followed from 2005 to 2015 at the Dermatology Clinic and Pathology Institute of the University of Cagliari, Sardinia, Italy. Among 137 patients with morphoea, 2 cases of the bullous variant were identified, which were successfully treated with methotrexate. Thus, the bullous form comprised 1.4% of all cases of morphoea, which is much lower than the 7.5% previously reported. In one of the cases, histopathological examination revealed a peculiar 'stretching' pattern of basal keratinocytes attached to the epidermal roof of the bulla, together with increased lymphatic vessels, which were either collapsed or dilated, stressing the role of lymphatics and possibly of excessive skin trauma and friction in the development of bullous lesions.

PMID: 28543394 [PubMed - indexed for MEDLINE]

Comprehensive mapping of Cystic Fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site.

Proteins. 2018 Mar 23;:

Authors: Molinski SV, Shahani VM, Subramanian AS, MacKinnon SS, Woollard G, Laforet M, Laselva O, Morayniss LD, Bear CE, Windemuth A

Abstract
Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, of which over 2000 have been reported to date. Mutations have yet to be analyzed in aggregate to assess their distribution across the tertiary structure of the CFTR protein, an approach that could provide valuable insights into the structure-function relationship of CFTR. In addition, the binding site of Class I correctors (VX-809, VX-661, C18) is not well understood. In this study, exonic CFTR mutations and mutant allele frequencies described in three curated databases (ABCMdb, CFTR1 and CFTR2, comprising >130,000 data points) were mapped to two different structural models: a homology model of full-length CFTR protein in the open-channel state, and a cryo-electron microscopy core-structure of CFTR in the closed-channel state. Accordingly, residue positions of six high-frequency mutant CFTR alleles were found to spatially co-localize in CFTR protein, and a significant cluster was identified at the NBD1:ICL4 interdomain interface. In addition, immunoblotting confirmed the approximate binding site of Class I correctors, demonstrating that these small molecules act via a similar mechanism in vitro, and in silico molecular docking generated binding poses for their complex with the cryo-electron microscopy structure to suggest the putative corrector binding site is a multi-domain pocket near residues F374-L375. These results confirm the significance of interdomain interfaces as susceptible to disruptive mutation, and identify a putative corrector binding site. The structural pharmacogenomics approach of mapping mutation databases to protein models shows promise for facilitating drug discovery and personalized medicine for monogenetic diseases. This article is protected by copyright. All rights reserved.

PMID: 29569753 [PubMed - as supplied by publisher]

Future directions in pharmacogenomics discovery in cardiovascular disease.

Pharmacogenomics. 2018 Mar 23;:

Authors: Friede KA, Voora D

PMID: 29569527 [PubMed - as supplied by publisher]

Pharmacogenetics and the treatment of chronic myeloid leukemia: how relevant clinically? An update.

Pharmacogenomics. 2018 Mar 23;:

Authors: Ankathil R, Azlan H, Dzarr AA, Baba AA

Abstract
Despite the excellent efficacy and improved clinical responses obtained with imatinib mesylate (IM), development of resistance in a significant proportion of chronic myeloid leukemia (CML) patients on IM therapy have emerged as a challenging problem in clinical practice. Resistance to imatinib can be due to heterogeneous array of factors involving BCR/ABL-dependent and BCR/ABL-independent pathways. Although BCR/ABL mutation is the major contributory factor for IM resistance, reduced bio-availability of IM in leukemic cells is also an important pharmacokinetic factor that contributes to development of resistance to IM in CML patients. The contribution of polymorphisms of the pharmacogenes in relation to IM disposition and treatment outcomes have been studied by various research groups in numerous population cohorts. However, the conclusions arising from these studies have been highly inconsistent. This review encompasses an updated insight into the impact of pharmacogenetic variability on treatment response of IM in CML patients.

PMID: 29569526 [PubMed - as supplied by publisher]

Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations.

Mol Med Rep. 2018 Mar 16;:

Authors: Zhu YB, Luo JW, Jiang F, Liu G

Abstract
Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual). Targeted exome sequencing was used to screen exons and adjacent splice sites of 61 inherited arrhythmia‑associated genes, to detect pathogenic genes and variant sites in the proband. Family members were sequenced by Sanger sequencing and protein functions predicted by Polyphen‑2 software. A total of three rare variants were identified in the family, including two missense variants in calcium voltage‑gated channel subunit alpha1 C (CACNA1C) (gi:193788541, NM_001129843), c.1786G>A (p.V596M) and c.5344G>A (p.A1782T), and one missense variant in titin (TTN) c.49415G>A (p.R16472H) (gi:291045222, NM_003319). The variants p.V596M and p.R16472H were predicted to be deleterious and resulted in alterations in the amino acid type and sequence of the polypeptide chain, which may partially or completely inactivate the encoded protein. The comparison of literature, gene database, and pedigree phenotype analysis suggests that p.V596M or p.R16472H variants are pathogenic. The complex overlapping variants at three loci lead to a more severe phenotype in the proband, and may increase the susceptibility of individuals to atrial fibrillation. The simultaneous occurrence of V596M and R16472H may increase the severity of early repolarization. Various family members may have carried heterozygous mutants of p.A1782T and p.R16472H due to genetic heterogeneity, however did not exhibit clinical signs of cardiac electrophysiological alterations, potentially attributable to the low vagal tone. To the best of the author's knowledge, this is the first study to suggest the involvement of the novel missense CACNA1C c.1786G>A and TTN c.49415G>A variants in the inheritance of symptomatic bradycardia and development of SSS.

PMID: 29568937 [PubMed - as supplied by publisher]

Evaluation of CYP2C9- and VKORC1-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

Future Sci OA. 2018 Mar;4(3):FSO276

Authors: Ayesh BM, Abu Shaaban AS, Abed AA

Abstract
Aim: To evaluate applicability of CYP2C9*2, *3 and VKORC1-1639G > A based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients.
Patients & methods: Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD.
Results: Frequency of CYP2C9*2, *3 and VKORC1-1639G > A alleles is 13.6, 0.0 and 46.5% respectively. The international warfarin pharmacogenetics consortium algorithm was more reliable (MAE = 8.9 ± 1.4; R2 = 0.350) than both the clinical algorithm (MAE = 10.4 ± 1.4; R2 = 0.128;) and the fixed-dose algorithm (MAE = 11.1 ± 1.7).
Conclusion: The international warfarin pharmacogenetics consortium algorithm can be reliably applied for predicting the WSD in Palestinian population.

PMID: 29568565 [PubMed]

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Neuron. 2018 Mar 21;97(6):1268-1283.e6

Authors: Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt JJFA, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A, ITALSGEN Consortium, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L, Genomic Translation for ALS Care (GTAC) Consortium, Moreno CAM, Kamalakaran S, Goldstein DB, ALS Sequencing Consortium, Gitler AD, Harris T, Myers RM, NYGC ALS Consortium, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC, Answer ALS Foundation, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J, SLAGEN Consortium, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C, French ALS Consortium, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, Sidle KC, Malaspina A, Hardy J, Singleton AB, Johnson JO, Arepalli S, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Al-Sarraj S, King A, Troakes C, Vance C, de Belleroche J, Baas F, Ten Asbroek ALMA, Muñoz-Blanco JL, Hernandez DG, Ding J, Gibbs JR, Scholz SW, Floeter MK, Campbell RH, Landi F, Bowser R, Pulst SM, Ravits JM, MacGowan DJL, Kirby J, Pioro EP, Pamphlett R, Broach J, Gerhard G, Dunckley TL, Brady CB, Kowall NW, Troncoso JC, Le Ber I, Mouzat K, Lumbroso S, Heiman-Patterson TD, Kamel F, Van Den Bosch L, Baloh RH, Strom TM, Meitinger T, Shatunov A, Van Eijk KR, de Carvalho M, Kooyman M, Middelkoop B, Moisse M, McLaughlin RL, Van Es MA, Weber M, Boylan KB, Van Blitterswijk M, Rademakers R, Morrison KE, Basak AN, Mora JS, Drory VE, Shaw PJ, Turner MR, Talbot K, Hardiman O, Williams KL, Fifita JA, Nicholson GA, Blair IP, Rouleau GA, Esteban-Pérez J, García-Redondo A, Al-Chalabi A, Project MinE ALS Sequencing Consortium, Rogaeva E, Zinman L, Ostrow LW, Maragakis NJ, Rothstein JD, Simmons Z, Cooper-Knock J, Brice A, Goutman SA, Feldman EL, Gibson SB, Taroni F, Ratti A, Gellera C, Van Damme P, Robberecht W, Fratta P, Sabatelli M, Lunetta C, Ludolph AC, Andersen PM, Weishaupt JH, Camu W, Trojanowski JQ, Van Deerlin VM, Brown RH, van den Berg LH, Veldink JH, Harms MB, Glass JD, Stone DJ, Tienari P, Silani V, Chiò A, Shaw CE, Traynor BJ, Landers JE

Abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

PMID: 29566793 [PubMed - in process]

Contractile reserve and the response to cardiac resynchronization therapy.

Int J Cardiol. 2018 02 01;252:234-235

Authors: Bristow MR

PMID: 29249434 [PubMed - indexed for MEDLINE]

Impact of BCL2 polymorphisms on survival in transitional cell carcinoma of the bladder.

J Cancer Res Clin Oncol. 2017 Sep;143(9):1659-1670

Authors: Hess J, Stelmach P, Eisenhardt A, Rübben H, Reis H, Schmid KW, Bachmann HS

Abstract
PURPOSE: To evaluate the impact of three BCL2 single-nucleotide polymorphisms, i.e., c.-938C>A (rs2279115), c.21G>A (rs1801018), and c.*2203A>G (rs4987853) on survival in patients with transitional cell carcinoma of the bladder.
METHODS: We analyzed 179 patients who underwent surgical treatment for bladder cancer at the Clinic of Urology, University Hospital Essen, Germany. Genomic DNA was extracted and genotyped for the polymorphisms. For all polymorphisms, linkage analysis was performed. Kaplan-Meier and Cox regression analyses were used to determine the putative impact of the three polymorphisms on outcome.
RESULTS: c.-938C>A and c.21G>A, but not c.*2203A>G, are in strong linkage disequilibrium (D' 0.96). We found a significant association between c.-938C>A and relapse-free survival (p = 0.024) with an allele dose effect. In the same way, c.21G>A had a significant impact on both relapse-free survival (p = 0.009) and progression-free survival (p = 0.012), as well as a pronounced allele dose effect. Regression analysis proved c.21G>A and c.-938C>A, to be an independent risk factor in univariate and multivariable analyses.
CONCLUSIONS: In our cohort, both c.-938C>A and c.21G>A showed a significant impact on outcome with TCC of the bladder. Due to the linkage disequilibrium of both SNPs, maybe, only one of them could mediate this effect. In multivariable analysis, however, both proved to be independently associated with overall survival. Contrary to other findings which found the c.-938C>A mainly influencing outcome, our data may suggest that the main effect on TCC could be due to the c.21G>A polymorphism.

PMID: 28417194 [PubMed - indexed for MEDLINE]

Comprehensive mapping of Cystic Fibrosis mutations to CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site.

Proteins. 2018 Mar 23;:

Authors: Molinski SV, Shahani VM, Subramanian AS, MacKinnon SS, Woollard G, Laforet M, Laselva O, Morayniss LD, Bear CE, Windemuth A

Abstract
Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, of which over 2000 have been reported to date. Mutations have yet to be analyzed in aggregate to assess their distribution across the tertiary structure of the CFTR protein, an approach that could provide valuable insights into the structure-function relationship of CFTR. In addition, the binding site of Class I correctors (VX-809, VX-661, C18) is not well understood. In this study, exonic CFTR mutations and mutant allele frequencies described in three curated databases (ABCMdb, CFTR1 and CFTR2, comprising >130,000 data points) were mapped to two different structural models: a homology model of full-length CFTR protein in the open-channel state, and a cryo-electron microscopy core-structure of CFTR in the closed-channel state. Accordingly, residue positions of six high-frequency mutant CFTR alleles were found to spatially co-localize in CFTR protein, and a significant cluster was identified at the NBD1:ICL4 interdomain interface. In addition, immunoblotting confirmed the approximate binding site of Class I correctors, demonstrating that these small molecules act via a similar mechanism in vitro, and in silico molecular docking generated binding poses for their complex with the cryo-electron microscopy structure to suggest the putative corrector binding site is a multi-domain pocket near residues F374-L375. These results confirm the significance of interdomain interfaces as susceptible to disruptive mutation, and identify a putative corrector binding site. The structural pharmacogenomics approach of mapping mutation databases to protein models shows promise for facilitating drug discovery and personalized medicine for monogenetic diseases. This article is protected by copyright. All rights reserved.

PMID: 29569753 [PubMed - as supplied by publisher]

Cellular mechanism for herbal medicine Junchoto to facilitate intestinal Cl-/water secretion that involves cAMP-dependent activation of CFTR.

J Nat Med. 2018 Mar 22;:

Authors: Numata T, Sato-Numata K, Okada Y, Inoue R

Abstract
Constipation is a common symptom frequently compromising the quality of daily life. Several mechanistically different drugs have been used to mitigate constipation, including Japanese herbal (Kampo) medicines. However, the mechanisms of their actions are often not well understood. Here we aimed to investigate the molecular mechanisms underlying the effects of Junchoto (JCT), a Kampo medicine empirically prescribed for chronic constipation. Cl- channel activity was measured by the patch-clamp method in human cystic fibrosis transmembrane conductance regulator (CFTR)-expressing HEK293T cells and human intestinal Caco-2 cells. cAMP was measured by a luciferase-based assay. Cell volume change was measured by a particle-sizing and particle-counting analyzer and video-microscopic measurement. In both CFTR-expressing HEK293T and Caco-2 cells, JCT dose-dependently induced whole-cell currents showing typical biophysical and pharmacological features of CFTR. Robust expression of CFTR was confirmed by RT-PCR and Western blotting in Caco-2 cells. Luciferase-based measurement revealed that JCT increases intracellular cAMP levels. Administration of the adenylate cyclase inhibitor SQ22536 or CFTR inhibitor-172, or treatment with small interfering RNAs (siRNA) targeting CFTR, abolished JCT-induced whole-cell currents, suggesting that elevated intracellular cAMP by JCT causes activation of CFTR in Caco-2 cells. Finally, blockade of CFTR activity by CFTR inhibitor-172 or siRNA-knockdown of CFTR or application of SQ22536 markedly reduced the degree of cell volume decrease induced by JCT. JCT can induce a Cl- efflux through the CFTR channel to promote water secretion, and this effect is likely mediated by increased cAMP production.

PMID: 29569221 [PubMed - as supplied by publisher]

CT features of diffuse lung disease in infancy.

Radiol Med. 2018 Mar 22;:

Authors: Toma P, Secinaro A, Sacco O, Curione D, Cutrera R, Ullmann N, Granata C

Abstract
Diffuse lung disease in infancy includes a wide range of very rare and peculiar pulmonary conditions usually not seen in older children, in whom diffuse lung disease has much greater overlap with adult disorders. The acronym chILD (childhood Interstitial Lung Disease) commonly defines these disorders, although air spaces, airways, alveolar epithelium, vasculature, pleura, and pleural spaces can also be involved, besides the pulmonary interstitium. chILD can be caused by diffuse developmental disorders, alveolar growth abnormalities, surfactant dysfunction disorders, and other specific conditions of poorly understood etiology. Chest CT imaging studies play a pivotal role in the evaluation of chILD. In some conditions CT findings can be specific, and thus make it possible avoiding further testing. In other disorders, findings are nonspecific, although they may suggest a diagnostic pattern and guide further testing. Nevertheless, chILD disorders often remain unrecognized on imaging studies, as they are very rare. The aim of this article is to review the CT patterns of lung involvement in a series of infants with chILD.

PMID: 29569218 [PubMed - as supplied by publisher]

Neutrophil extracellular traps promote lipopolysaccharide-induced airway inflammation and mucus hypersecretion in mice.

Oncotarget. 2018 Mar 02;9(17):13276-13286

Authors: Zou Y, Chen X, Xiao J, Bo Zhou D, Xiao Lu X, Li W, Xie B, Kuang X, Chen Q

Abstract
Bacterial lipopolysaccharide (LPS) contributes to airway inflammation and mucus hypersecretion in chronic airway inflammatory diseases, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Neutrophil extracellular traps (NETs) are extracellular meshworks composed of DNA fibers and antimicrobial proteins. Although NET formation has been detected in COPD and CF patients, how NETs contribute to these diseases is poorly understood. This study was performed to clarify the effects and mechanisms of action of NETs in airway inflammation and mucus hypersecretion. We created a murine model of LPS-induced airway inflammation and mucus hypersecretion, and found that LPS-induced NET formation was degraded by aerosolized DNase I treatment in mice. Degradation of NETs by aerosolized DNase I reduced LPS-induced airway inflammation and mucus hypersecretion in mice, this reduction correlated with suppression of TLR4/NF-κB signaling pathway. More importantly, NETs promoted LPS-induced production of IL-1β, IL-6 and TNF-α in macrophages. These results suggest NET degradation using aerosolized DNase I is a potential new therapeutic strategy for treating COPD and CF.

PMID: 29568356 [PubMed]

The evaluation of selected insomnia predictors in adolescents and young adults with cystic fibrosis.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018 Mar 21;:

Authors: Tomaszek L, Cepuch G, Pawlik L

Abstract
AIMS AND BACKGROUND: The purpose of the study was to assess the incidence of insomnia in adolescents and young adults with cystic fibrosis and its impact on the quality of life, and to examine whether demographic and clinical factors and negative emotional states are predictors of insomnia in these patients.
METHODS: The study was conducted among 95 cystic fibrosis patients aged 14-25 years. The study used a personal questionnaire survey, the Athens Insomnia Scale, the Cystic Fibrosis Quality of Life Questionnaire, the Hospital Anxiety and Depression Scale, and the Numeric Rating Scale.
RESULTS: Insomnia was diagnosed in 38% of cystic fibrosis patients. In patients with insomnia, the level of anxiety (Me: 10 vs. 4; P=0.000) and depression (Me: 6.5 vs. 2; P=0.000) was significantly higher than in the good sleep quality group. The risk of insomnia increases as anxiety (OR: 4.31; 95% CI: 2.20 to 8.41) and depressive symptoms exacerbate (OR: 4.98; 95% CI: 1.84 to 13.43). Insomnia significantly worsens the quality of life in cystic fibrosis patients (ß =-0.5, P=0.000).
CONCLUSION: Insomnia affects a large percentage of cystic fibrosis patients, and anxiety and depression are factors that increase the risk of insomnia. Insomnia decreases the quality of life in cystic fibrosis patients.

PMID: 29568122 [PubMed - as supplied by publisher]

Sputum active polymyxin lipopeptides: Activity against Cystic Fibrosis Pseudomonas aeruginosa isolates and their interactions with sputum biomolecules.

ACS Infect Dis. 2018 Mar 22;:

Authors: Schneider-Futschik EK, Paulin OKA, Hoyer D, Roberts KD, Ziogas J, Baker MA, Karas J, Li J, Velkov T

Abstract
The mucoid biofilm mode of growth of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients makes eradication of infections with antibiotic therapy very difficult. The lipopeptide antibiotics polymyxin B and colistin are currently the last-resort therapies for infections caused by multidrug-resistant P. aeruginosa. In the present study, we investigated the antibacterial activity of a series of polymyxin lipopeptides (polymyxin B, colistin, FADDI-003, octapeptin A3 and polymyxin A2) against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa cystic fibrosis isolates grown under planktonic or biofilm conditions in artificial sputum, and their interactions with sputum component biomolecules. In sputum media under planktonic conditions, the lipopeptides FADDI-003 and octapeptin A3 displayed very promising activity against the polymyxin-resistant isolate FADDI-PA066 (polymyxin B MIC = 32 mg/L), while retaining their activity against the polymyxin-sensitive strains FADDI-PA021 (polymyxin B MIC = 1 mg/L) and FADDI-PA020 (polymyxin B MIC = 2 mg/L). Polymyxin A2 was only effective against the polymyxin-sensitive isolates. However, under biofilm growth conditions, the hydrophobic lipopeptide FADDI-003 was inactive compared to the more hydrophilic lipopeptides, octapeptin A3 and polymyxin A2, polymyxin B and colistin. Moreover, transmission electron micrographs revealed octapeptin A3 reduced the cell numbers in biofilm as well as causing 'anti-biofilm' activity/biofilm disruption. We therefore assessed the interactions of the lipopeptides with the component sputum biomolecules, mucin, DNA, surfactant, f-actin, lipopolysaccharide and phospholipids. We observed the general trend that sputum biomolecules reduce lipopeptide antibacterial activity. Collectively, our data suggests that in the airways, lipopeptide binding to component sputum biomolecules may reduce antibacterial efficacy and is dependent on the physicochemical properties of the lipopeptide.

PMID: 29566483 [PubMed - as supplied by publisher]

Novel putative drivers revealed by targeted exome sequencing of advanced solid tumors.

PLoS One. 2018;13(3):e0194790

Authors: Pannuti A, Filipovic A, Hicks C, Lefkowitz E, Ptacek T, Stebbing J, Miele L

Abstract
Next generation sequencing (NGS) is becoming increasingly integrated into oncological practice and clinical research. NGS methods have also provided evidence for clonal evolution of cancers during disease progression and treatment. The number of variants associated with response to specific therapeutic agents keeps increasing. However, the identification of novel driver mutations as opposed to passenger (phenotypically silent or clinically irrelevant) mutations remains a major challenge. We conducted targeted exome sequencing of advanced solid tumors from 44 pre-treated patients with solid tumors including breast, colorectal and lung carcinomas, neuroendocrine tumors, sarcomas and others. We catalogued established driver mutations and putative new drivers as predicted by two distinct algorithms. The established drivers we detected were consistent with published observations. However, we also detected a significant number of mutations with driver potential never described before in each tumor type we studied. These putative drivers belong to key cell fate regulatory networks, including potentially druggable pathways. Should our observations be confirmed, they would support the hypothesis that new driver mutations are selected by treatment in clinically aggressive tumors, and indicate a need for longitudinal genomic testing of solid tumors to inform second line cancer treatment.

PMID: 29570743 [PubMed - in process]

A new nonsense mutation in the POGLUT1 gene in two sisters with Dowling-Degos disease.

J Eur Acad Dermatol Venereol. 2018 Mar 23;:

Authors: Duchatelet S, Clerc H, Machet L, Gaboriaud P, Miskinyte S, Kervarrec T, Hovnanian A

Abstract
Dowling-Degos disease (DD) (OMIM: 179850, 615327, 615674, 615696) is a rare autosomal-dominant genetic disorder belonging to the spectrum of reticulated pigmented dermatitis(1). Galli-Galli disease is considered as being a variant of DD, harboring all clinical, histological and genetics features of DD in association with acantholysis (2). In 2006, exome sequencing revealed loss-of-function mutations in KRT5 (cytokeratin 5) (p.Ile140fsAsnfs*39, p.Ser5*) in 8 of 10 DD cases (3). Since then, mutations in POGLUT1, encoding O-glucosylosyltransferase 1 enzyme, were reported in Galli-Galli cases (4). Loss-of-function mutations in POFUT1, encoding fucosyltransferase 1, were identified in cases of DD showing overlap with Kitamura disease (5) and finally, mutations in PSENEN (presenilin enhancer gamma-secretase subunit) were found in DD associated with acne inversa or Hidradenitis suppurativa (6). This article is protected by copyright. All rights reserved.

PMID: 29569780 [PubMed - as supplied by publisher]