Belfast Agar-a simple laboratory medium to separate Pseudomonas aeruginosa from pan-resistant Burkholderia cenocepacia isolated from the sputum of patients with cystic fibrosis (CF).

Br J Biomed Sci. 2018 Mar 07;:1-3

Authors: Caskey S, Moore JE, McCaughan J, Rendall JC

PMID: 29513134 [PubMed - as supplied by publisher]

Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice.

Exp Biol Med (Maywood). 2018 Mar;243(5):496-503

Authors: Strandvik B, O Neal WK, Ali MA, Hammar U

Abstract
Low linoleic acid concentration is a common finding in patients with cystic fibrosis and associated with severe clinical phenotype. Low docosahexaenoic and arachidonic acids are more inconsistently found in patients, but arachidonic/docosahexaenoic ratio is usually high. In animal models with cftr mutations or KO animals for the cftr gene, linoleic acid deficiency has not been consistently reported and some report docosahexaenoic deficiency as the major fatty acid abnormality. We hereby describe fatty acid profile in a severe clinical cystic fibrosis phenotype in mice with a duplication of exon 3 generated in the cystic fibrosis gene of C57B1/6J mice ( cftrm1Bay allele). In 43/50 animals, plasma phospholipid fatty acids were repeatedly analyzed (mean three times/animal) covering ages between 7 and 235 days. Linoleic acid concentrations were significantly lower in cftr-/- mice compared to heterozygotes ( P = 0.03) and wild type mice ( P < 0.001). Females had significantly lower linoleic acid than males, not related to age. Arachidonic acid did not differ but docosahexaenoic acid was higher in cftr-/- than in wild type mice ( P < 0.001). The arachidonic/docosahexaenoic acid ratio did not differ but arachidonic/linoleic acid ratio was higher in cftr-/- mice compared to wild type mice ( P = 0.007). Similar to clinical studies, type of mutation is important for lipid abnormality with low linoleic acid most consistently found in the animals. Rodents differ in metabolism by synthesizing docosahexaenoic acid more efficiently comparing to humans, suggesting greater influence by diet. Precaution seems important when comparing animal and humans. Impact statement In translational research, animal models are important to investigate the effect of genetic mutations in specific diseases and their metabolism. Special attention has to be given to differences in physiology and metabolism between species and humans, which otherwise can hazard the conclusions. Our work illustrates that the different synthesis capacity in mice and humans for DHA would explain different results in different models for cystic fibrosis and different influences of diets. To avoid disappointing clinical results, these facts have to be considered before extensive clinical studies are started based on results from single animal studies.

PMID: 29513100 [PubMed - in process]

Isavuconazole Pharmacokinetics in a Patient with Cystic Fibrosis Following Bilateral Orthotopic Lung Transplantation.

Transpl Infect Dis. 2018 Mar 07;:

Authors: Kabulski GM, MacVane SH

Abstract
Previous studies of patients with cystic fibrosis (CF) treated with azole antifungals have shown altered pharmacokinetics relative to healthy patients. Data regarding the pharmacokinetic profile of isavuconazole in patients with CF undergoing lung transplantation is currently not available. Serum trough concentrations assessed in a single CF patient following transplant revealed significantly lower values relative to available literature. Larger studies are required to validate CF population pharmacokinetics of isavuconazole. This article is protected by copyright. All rights reserved.

PMID: 29512930 [PubMed - as supplied by publisher]

Outcome evaluation of a pharmacy-based therapy management program for patients with cystic fibrosis.

Pediatr Pulmonol. 2018 Mar 07;:

Authors: Kirkham HS, Staskon F, Hira N, McLane D, Kilgore KM, Parente A, Kim S, Sawicki GS

Abstract
OBJECTIVE: To compare medication adherence, pulmonary exacerbations, healthcare utilization, and costs for patients with cystic fibrosis (CF) who utilized a pharmacy-based therapy management program to a matched control group. We hypothesized that patient management services would be associated with better medication adherence, and thus require fewer visits to the emergency room or hospitalizations.
METHODS: This retrospective, observational cohort study used claims data from the MORE2 claims Registry®. The sample consisted of CF patients, aged 6+, who had ≥1 pharmacy claim for inhaled tobramycin, inhaled aztreonam, ivacaftor, or dornase alfa from 6/2/2014-5/31/2015. Adherence was measured as proportion of days covered (PDC). Propensity score matching and multivariable regression techniques were used to compare outcomes in program participants to matched controls.
RESULTS: Of the 236 intervention and 724 control patients meeting selection criteria, 202 were propensity-matched from each cohort. Relative to the control cohort, program patients had 23% higher mean PDC for tobramycin (IRR = 1.23, P = 0.01) and were twice as likely to be adherent to tobramycin (PDC ≥ 80%) than matched controls (OR = 2.14, P = 0.04). Program patients had fewer ER visits (IRR = 0.52, P < 0.01) and slightly lower ER costs (IRR = 0.66, P = 0.06) than the control patients.
CONCLUSION: A pharmacy-based therapy management program for CF patients was associated with higher adherence to inhaled tobramycin and lower ER rates. Pharmacies that provide therapy management can support effective CF care management.

PMID: 29512893 [PubMed - as supplied by publisher]

CFTR ameliorates high glucose-induced oxidative stress and inflammation by mediating the NF-κB and MAPK signaling pathways in endothelial cells.

Int J Mol Med. 2018 Mar 07;:

Authors: Fei Y, Sun L, Yuan C, Jiang M, Lou Q, Xu Y

Abstract
Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive production of oxidative stress and pro-inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regulator (CFTR). However, little information is available about the role of CFTR in hyperglycemia‑induced endothelial cell oxidative stress and inflammation. In the present study, a high glucose‑treatment was applied in human umbilical vein endothelial cells with CFTR overexpression or inhibition, and the oxidative and inflammatory characteristics were measured. It was shown that CFTR protein and mRNA expression were reduced by glucose in a concentration‑dependent manner. Overexpression of CFRT via adenoviral infection significantly inhibited the production of reactive oxygen species and inflammatory biomediators induced by high glucose. Conversely, pharmacological inhibition of CFTR led to the opposite effects. Mechanistically, nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinase (MAPK) signaling were activated following high glucose treatment, which were inhibited by CFTR overexpression and enhanced by CFTR inhibition. The pro‑inflammatory effect of CFTR inhibition was abolished by pharmacological inhibition of the NF‑κB or MAPK pathways. Moreover, inhibition of MAPK abrogated CFTR inhibition‑induced NF‑κB nuclear translocation, whereas NF‑κB inhibitor produced no effects on MAPK activation. Additionally, antioxidant treatment inhibited the high glucose‑induced decrease in CFTR expression and the increase in inflammatory responses. Collectively, these findings revealed that CFTR attenuates high glucose‑induced endothelial cell oxidative stress and inflammation through inactivation of NF‑κB and MAPK signaling, indicating that elevation of CFRT expression may be a novel strategy in preventing endothelial dysfunction in diabetes.

PMID: 29512777 [PubMed - as supplied by publisher]

Use of extracorporeal membrane oxygenation in cystic fibrosis in an Australian cystic fibrosis centre.

Intern Med J. 2018 Mar;48(3):340-343

Authors: Sivam S, Dentice R, Reddy N, Moriarty C, Yozghatlian V, Mellis C, Torzillo P, Glanville A, Gattas D, Bye P

Abstract
Extracorporeal membrane oxygenation (ECMO) support is used in selected patients with cystic fibrosis (CF) as a bridge to transplantation. Our aim was to describe briefly treatment and outcomes of six CF patients who received ECMO. One patient received a lung transplant and another recovered from acute respiratory failure. Four died despite ECMO support. Lack of timely availability of suitable donor lungs and patient selection are contributing factors.

PMID: 29512325 [PubMed - in process]

Related Articles

Detection of drug-responsive B lymphocytes and antidrug IgG in patients with β-lactam hypersensitivity.

Allergy. 2017 Jun;72(6):896-907

Authors: Amali MO, Sullivan A, Jenkins RE, Farrell J, Meng X, Faulkner L, Whitaker P, Peckham D, Park BK, Naisbitt DJ

Abstract
BACKGROUND: Delayed-type β-lactam hypersensitivity develops in subset of patients. The cellular immunological processes that underlie the drug-specific response have been described; however, little is known about involvement of the humoral immune system. Thus, the aim of this study was to utilize piperacillin hypersensitivity as an exemplar to (i) develop cell culture methods for the detection of drug-specific B-cell responses, (ii) characterize drug-specific IgG subtypes and (iii) assess reactivity of IgG antibodies against proteins modified to different levels with piperacillin haptens.
METHODS: IgG secretion and CD19+ CD27+ expression on B cells were measured using ELISPOT and flow cytometry, respectively. A piperacillin-BSA adduct was used as an antigen in ELISA antibody binding studies. Adducts generated using different ratios of drug to protein were used to determine the degree of conjugation required to detect IgG binding.
RESULTS: B cells from hypersensitive patients, but not controls, were stimulated to secrete IgG and increase CD27 expression when cultured with soluble piperacillin. A piperacillin-BSA adduct with cyclized and hydrolysed forms of the hapten bound to eight lysine residues was used to detect hapten-specific IgG 1-4 subclasses in patient plasma. Hapten inhibition and the use of structurally unrelated hapten-BSA adducts confirmed antigen specificity. Antibody binding was detected with antigens generated at piperacillin/BSA ratios of 10:1 and above, which corresponded to a minimum epitope density of 1 for antibody binding.
CONCLUSION: These data show that antigen-specific B lymphocytes and T lymphocytes are activated in piperacillin-hypersensitive patients. Further work is needed to define the role different IgG subtypes play in regulating the iatrogenic disease.

PMID: 27861994 [PubMed - indexed for MEDLINE]

Utility of whole exome sequencing in detecting novel compound heterozygous mutations in COL7A1 among families with severe recessive Dystrophic Epidermolysis Bullosa in India - implications on diagnosis, prognosis and prenatal testing.

J Eur Acad Dermatol Venereol. 2018 Mar 06;:

Authors: Mahajan R, Vellarikkal SK, Handa S, Verma A, Jayarajan R, Kumar A, De D, Kaur J, Panigrahi I, VSl V, Sivasubbu S, Scaria V

Abstract
Epidermolysis Bullosa (EB) encompasses a number of genetic conditions caused by mutations in genes involved in the formation of basement membrane resulting in blistering of the epidermis on trauma or pressure. At least 18 genes and 30 distinct subtypes of the disease are presently known[1]. Here-in, we report two un-related children with recessive dystrophic EB (RDEB) with novel compound heterozygous variations in collagen VII, one of whom had a fatal outcome and the other with a better sequel. This article is protected by copyright. All rights reserved.

PMID: 29512197 [PubMed - as supplied by publisher]

Whole-Exome Sequencing Identified a Novel Compound Heterozygous Mutation of LRRC6 in a Chinese Primary Ciliary Dyskinesia Patient.

Biomed Res Int. 2018;2018:1854269

Authors: Liu L, Luo H

Abstract
Primary ciliary dyskinesia (PCD) is a clinical rare peculiar disorder, mainly featured by respiratory infection, tympanitis, nasosinusitis, and male infertility. Previous study demonstrated it is an autosomal recessive disease and by 2017 almost 40 pathologic genes have been identified. Among them are the leucine-rich repeat- (LRR-) containing 6 (LRRC6) codes for a 463-amino-acid cytoplasmic protein, expressed distinctively in motile cilia cells, including the testis cells and the respiratory epithelial cells. In this study, we applied whole-exome sequencing combined with PCD-known genes filtering to explore the genetic lesion of a PCD patient. A novel compound heterozygous mutation in LRRC6 (c.183T>G/p.N61K; c.179-1G>A) was identified and coseparated in this family. The missense mutation (c.183T>G/p.N61K) may lead to a substitution of asparagine by lysine at position 61 in exon 3 of LRRC6. The splice site mutation (c.179-1G>A) may cause a premature stop codon in exon 4 and decrease the mRNA levels of LRRC6. Both mutations were not present in our 200 local controls, dbSNP, and 1000 genomes. Three bioinformatics programs also predicted that both mutations are deleterious. Our study not only further supported the importance of LRRC6 in PCD, but also expanded the spectrum of LRRC6 mutations and will contribute to the genetic diagnosis and counseling of PCD patients.

PMID: 29511670 [PubMed - in process]

Whole exome sequencing in three families segregating a pediatric case of sarcoidosis.

BMC Med Genomics. 2018 Mar 06;11(1):23

Authors: Calender A, Rollat Farnier PA, Buisson A, Pinson S, Bentaher A, Lebecque S, Corvol H, Abou Taam R, Houdouin V, Bardel C, Roy P, Devouassoux G, Cottin V, Seve P, Bernaudin JF, Lim CX, Weichhart T, Valeyre D, Pacheco Y, Clement A, Nathan N, in the frame of GSF (Groupe Sarcoïdose France)

Abstract
BACKGROUND: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology.
METHODS: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) ( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST - 2 - REF IRB 00009118 - September 21, 2016).
RESULTS: We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis.
CONCLUSIONS: Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.

PMID: 29510755 [PubMed - in process]

Related Articles

Does low-dose methotrexate deserve more respect from clinicians?

JAAPA. 2017 May;30(5):12-15

Authors: Luu B, Rodway GW

Abstract
Medical errors associated with low-dose methotrexate may be life-threatening. Prescribers should be cognizant of the medication's toxicities and the persistent challenges in preventing adverse events. This article reviews the properties of methotrexate and its common drug-drug interactions. Best practices from the Institute for Safe Medication Practices, aimed at reducing methotrexate errors, are highlighted.

PMID: 28441215 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-AI-18-002 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications to participate in the NIAID Autoimmunity Centers of Excellence (ACE), a cooperative network intended to improve the understanding, prevention, and treatment of autoimmune diseases (www.autoimmunitycenters.org). The ACE was founded on the premise that collaborations among basic and clinical scientists can accelerate both fundamental and applied research. The ACE combines Basic and Clinical research programs. This FOA solicits applications for the Basic research program; a companion FOA solicits applications for the Clinical research program. Members of the Basic research program will conduct innovative studies of human autoimmunity within Principal, Pilot, and Collaborative Projects. Members of the Basic and Clinical ACE will work together to design and conduct studies of autoimmune disease pathogenesis and mechanisms of action of immune-modulating agents being tested in ACE clinical trials.

Funding Opportunity RFA-AI-18-003 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications to participate in the NIAID Autoimmunity Centers of Excellence (ACE), a cooperative network intended to improve the understanding, prevention, and treatment of autoimmune diseases (www.autoimmunitycenters.org). The ACE program was founded on the premise that collaborations among basic and clinical scientists can accelerate both fundamental and applied research. The ACE combines Basic and Clinical research programs. This FOA solicits applications for the Clinical research program; a companion FOA solicits applications for the Basic research program. Members of the Clinical research program will conduct innovative studies of human autoimmunity within Clinical and Collaborative Projects. Members of the Basic and Clinical ACE will work together to design and conduct studies of autoimmune disease pathogenesis and mechanisms of action of immune-modulating agents being tested in ACE clinical trials.

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