Treatment of cystic fibrosis-related diabetes.

Lancet Diabetes Endocrinol. 2018 Mar;6(3):167

Authors: Kessler L

PMID: 29475494 [PubMed - in process]

Treatment of cystic fibrosis-related diabetes - Authors' reply.

Lancet Diabetes Endocrinol. 2018 Mar;6(3):167-168

Authors: Ballmann M, Holl RW

PMID: 29475493 [PubMed - in process]

Ethical implications of digital communication for the patient-clinician relationship: analysis of interviews with clinicians and young adults with long term conditions (the LYNC study).

BMC Med Ethics. 2018 Feb 23;19(1):11

Authors: Ignatowicz A, Slowther AM, Elder P, Bryce C, Hamilton K, Huxley C, Forjaz V, Sturt J, Griffiths F

Abstract
BACKGROUND: Digital communication between a patient and their clinician offers the potential for improved patient care, particularly for young people with long term conditions who are at risk of service disengagement. However, its use raises a number of ethical questions which have not been explored in empirical studies. The objective of this study was to examine, from the patient and clinician perspective, the ethical implications of the use of digital clinical communication in the context of young people living with long-term conditions.
METHODS: A total of 129 semi-structured interviews, 59 with young people and 70 with healthcare professionals, from 20 United Kingdom (UK)-based specialist clinics were conducted as part of the LYNC study. Transcripts from five sites (cancer, liver, renal, cystic fibrosis and mental health) were read by a core team to identify explicit and implicit ethical issues and develop descriptive ethical codes. Our subsequent thematic analysis was developed iteratively with reference to professional and ethical norms.
RESULTS: Clinician participants saw digital clinical communication as potentially increasing patient empowerment and autonomy; improving trust between patient and healthcare professional; and reducing harm because of rapid access to clinical advice. However, they also described ethical challenges, including: difficulty with defining and maintaining boundaries of confidentiality; uncertainty regarding the level of consent required; and blurring of the limits of a clinician's duty of care when unlimited access is possible. Paradoxically, the use of digital clinical communication can create dependence rather than promote autonomy in some patients. Patient participants varied in their understanding of, and concern about, confidentiality in the context of digital communication. An overarching theme emerging from the data was a shifting of the boundaries of the patient-clinician relationship and the professional duty of care in the context of use of clinical digital communication.
CONCLUSIONS: The ethical implications of clinical digital communication are complex and go beyond concerns about confidentiality and consent. Any development of this form of communication should consider its impact on the patient-clinician-relationship, and include appropriate safeguards to ensure that professional ethical obligations are adhered to.

PMID: 29475437 [PubMed - in process]

Progress in defining the genetic contribution to type 2 diabetes susceptibility.

Curr Opin Genet Dev. 2018 Feb 21;50:41-51

Authors: Morris AP

Abstract
Candidate gene, genome-wide association, exome array and sequencing studies have identified more than 140 loci associated with type 2 diabetes (T2D) susceptibility. In this review, progress in understanding the genetic architecture of T2D susceptibility across diverse populations and in localising potential causal variants for the disease through fine-mapping studies is discussed. The additional insights gained from these genetic studies into novel molecular mechanisms and pathophysiology underlying T2D susceptibility are described, and the prospects for future genomic investigations of the disease are considered.

PMID: 29477131 [PubMed - as supplied by publisher]

Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis.

J Hum Genet. 2018 Feb 23;:

Authors: Suspitsin EN, Yanus GA, Dorofeeva MY, Ledashcheva TA, Nikitina NV, Buyanova GV, Saifullina EV, Sokolenko AP, Imyanitov EN

Abstract
Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease-causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity.

PMID: 29476190 [PubMed - as supplied by publisher]

Genetics of dementia in a Finnish cohort.

Eur J Hum Genet. 2018 Feb 23;:

Authors: Pasanen P, Myllykangas L, Pöyhönen M, Kiviharju A, Siitonen M, Hardy J, Bras J, Paetau A, Tienari PJ, Guerreiro R, Verkkoniemi-Ahola A

Abstract
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.

PMID: 29476165 [PubMed - as supplied by publisher]

MANAGEMENT OF ENDOCRINE DISEASE: Adrenocortical carcinoma: differentiating the good from the poor prognosis tumors.

Eur J Endocrinol. 2018 Feb 23;:

Authors: Jouinot A, Bertherat J

Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis, the five-years overall survival being below 40%. However there is great variability of outcomes and we have now a better view of the heterogeneity of tumor aggressiveness. The extent of the disease at the time of diagnosis, best assayed by the European Network for the Study of Adrenal Tumors (ENSAT) staging score, is a major determinant of survival. The tumor grade, including the mitotic count and the Ki67 proliferation index, also appears as a strong prognostic factor. The assessment of tumor grade, even by expert pathologists, still suffers from inter-observer reproducibility. The emergence of genomics in the last decade has revolutionized the knowledge of molecular biology and genetics of cancers. In ACC, genomic approaches -including pan-genomic studies of gene expression (transcriptome), recurrent mutations (exome or whole-genome sequencing), chromosome alterations, DNA methylation (methylome), miRNA expression (miRnome)- converge in a new classification of ACC, characterized by distinct molecular profiles and very different outcomes. Targeted measurements of a few discriminant molecular alterations have been developed in the perspective of clinical routine, and thus may help defining therapeutic strategy. By individualizing patients' prognosis and tumor biology, these recent progresses appear as an important step forward towards precision medicine.

PMID: 29475877 [PubMed - as supplied by publisher]

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

"systems biology"

These pubmed results were generated on 2018/02/25

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.

Representation of Time-Relevant Common Data Elements in the Cancer Data Standards Repository: Statistical Evaluation of an Ontological Approach.

JMIR Med Inform. 2018 Feb 22;6(1):e7

Authors: Chen HW, Du J, Song HY, Liu X, Jiang G, Tao C

Abstract
BACKGROUND: Today, there is an increasing need to centralize and standardize electronic health data within clinical research as the volume of data continues to balloon. Domain-specific common data elements (CDEs) are emerging as a standard approach to clinical research data capturing and reporting. Recent efforts to standardize clinical study CDEs have been of great benefit in facilitating data integration and data sharing. The importance of the temporal dimension of clinical research studies has been well recognized; however, very few studies have focused on the formal representation of temporal constraints and temporal relationships within clinical research data in the biomedical research community. In particular, temporal information can be extremely powerful to enable high-quality cancer research.
OBJECTIVE: The objective of the study was to develop and evaluate an ontological approach to represent the temporal aspects of cancer study CDEs.
METHODS: We used CDEs recorded in the National Cancer Institute (NCI) Cancer Data Standards Repository (caDSR) and created a CDE parser to extract time-relevant CDEs from the caDSR. Using the Web Ontology Language (OWL)-based Time Event Ontology (TEO), we manually derived representative patterns to semantically model the temporal components of the CDEs using an observing set of randomly selected time-related CDEs (n=600) to create a set of TEO ontological representation patterns. In evaluating TEO's ability to represent the temporal components of the CDEs, this set of representation patterns was tested against two test sets of randomly selected time-related CDEs (n=425).
RESULTS: It was found that 94.2% (801/850) of the CDEs in the test sets could be represented by the TEO representation patterns.
CONCLUSIONS: In conclusion, TEO is a good ontological model for representing the temporal components of the CDEs recorded in caDSR. Our representative model can harness the Semantic Web reasoning and inferencing functionalities and present a means for temporal CDEs to be machine-readable, streamlining meaningful searches.

PMID: 29472179 [PubMed]

19 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 2018/02/24

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.

14 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 2018/02/24

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.

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

"systems biology"

These pubmed results were generated on 2018/02/24

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.

14 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 2018/02/24

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.

Development of anti-fungal pesticides from protein kinase inhibitor-based anticancer agents.

Eur J Med Chem. 2018 Feb 15;148:349-358

Authors: Ma Y, Liang S, Zhang Y, Yang D, Wang R

Abstract
Repurposing the novel p21-activated protein kinase inhibitor compound 15 identified its antifungal activity against five selected species of phytopathogenic fungi. Lead optimization based on its structure gave rise to a focused library of 20 derivatives, among which compound 3c demonstrated increased activity over compound 15 and even comparable to that of some commercialized fungicides in the market including carbendazim, tebuconazole, and pyraclostrobin. This study showed that p21-activated protein kinase inhibitor compound 15 was able to serve as a molecular platform to develop effective fungicides against fungal phytopathogens and indicate that screening existing protein kinase inhibitors might be an effective way to identify lead compounds for antifungal pesticides development.

PMID: 29475155 [PubMed - as supplied by publisher]

Chronic Azithromycin Use in Cystic Fibrosis and Risk of Treatment-Emergent Respiratory Pathogens.

Ann Am Thorac Soc. 2018 Feb 23;:

Authors: Cogen JD, Onchiri F, Emerson J, Gibson RL, Hoffman LR, Nichols DP, Rosenfeld M

Abstract
RATIONALE: Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in cystic fibrosis patients. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens.
OBJECTIVES: To determine if chronic azithromycin use (defined as thrice weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens.
METHODS: We performed a new-user, propensity-score matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity-score matched 1:1 with contemporaneous non-users. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the two years prior to cohort entry.
RESULTS: After propensity score matching, mean age of the cohorts was ~12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, non-tuberculous mycobacteria, and Burkholderia cepacia complex compared to non-users. The risk of acquiring the remaining five pathogens was not significantly different between users and non-users.
CONCLUSIONS: Using an innovative new-user, propensity-score matched study design to minimize indication and selection biases, we found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. These results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric cystic fibrosis patients.

PMID: 29474110 [PubMed - as supplied by publisher]

Antimicrobial molecules in the lung: formulation challenges and future directions for innovation.

Future Med Chem. 2018 Feb 23;:

Authors: Woods A, Rahman KM

Abstract
Inhaled antimicrobials have been extremely beneficial in treating respiratory infections, particularly chronic infections in a lung with cystic fibrosis. The pulmonary delivery of antibiotics has been demonstrated to improve treatment efficacy, reduce systemic side effects and, critically, reduce drug exposure to commensal bacteria compared with systemic administration, reducing selective pressure for antimicrobial resistance. This review will explore the specific challenges of pulmonary delivery of a number of differing antimicrobial molecules, and the formulation and technological approaches that have been used to overcome these difficulties. It will also explore the future challenges being faced in the development of inhaled products and respiratory infection treatment, and identify future directions of innovation, with a particular focus on respiratory infections caused by multiple drug-resistant pathogens.

PMID: 29473765 [PubMed - as supplied by publisher]

Lipid shell-enveloped polymeric nanoparticles with high integrity of lipid shells improve mucus penetration and interaction with cystic fibrosis-related bacterial biofilms.

ACS Appl Mater Interfaces. 2018 Feb 23;:

Authors: Wan F, Nylander T, Klodzinska SN, Foged C, Yang M, Baldursdottir SG, Mørck Nielsen H

Abstract
Nanoparticle (NP) mediated drug delivery into viscous biomatrices, e.g., mucus and bacterial biofilms, is challenging. Lipid shell-enveloped polymeric NPs (Lipid@NPs), composed of a polymeric NP core coated with a lipid shell, represent a promising alternative to the current delivery systems. Here, we describe facile methods to prepare Lipid@NPs with high integrity of lipid shells and demonstrate the potential of Lipid@NPs in effective mucus penetration and interaction with cystic fibrosis-related bacterial biofilms. Lipid shell-enveloped polystyrene NPs with high integrity of lipid shells (cLipid@PSNPs) were prepared by using an electrostatically mediated layer-by-layer approach, where the model polystyrene NPs (PSNPs) were first modified with positively charged poly-L-lysine (PLL) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), followed by subsequent fusion with zwitterionic, PEGylated small unilamellar vesicles (SUVs). The interaction of the PSNPs with SUVs was significantly enhanced by modifying the PSNPs with PLL and DOTAP, which eventually resulted in the formation of cLipid@PSNPs, i.e. Lipid@PLL-PSNPs and Lipid@DOTAP-PSNPs. Improved mucus-penetrating property of cLipid@PSNPs was demonstrated by quartz crystal microbalance with dissipation monitoring measurements. Furthermore, fluorescence resonance energy transfer measurements showed that the interaction of the cLipid@PSNPs with bacterial biofilms was significantly promoted. In conclusion, we prepare cLipid@PSNPs via an electrostatically mediated layer-by layer approach. Our results suggest that the integrity of the lipid envelopes is crucial for enabling the diffusion of Lipid@PSNPs into the mucus layer and promoting the interaction of Lipid@PSNPs with a bacterial biofilm.

PMID: 29473725 [PubMed - as supplied by publisher]

Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics.

Curr Med Chem. 2018 Feb 21;:

Authors: Ghanem CI, Manautou JE

Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistance-associated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.

PMID: 29473496 [PubMed - as supplied by publisher]

The Antimicrobial Activity of a Carbon Monoxide Releasing Molecule (EBOR-CORM-1) Is Shaped by Intraspecific Variation within Pseudomonas aeruginosa Populations.

Front Microbiol. 2018;9:195

Authors: Flanagan L, Steen RR, Saxby K, Klatter M, Aucott BJ, Winstanley C, Fairlamb IJS, Lynam JM, Parkin A, Friman VP

Abstract
Carbon monoxide releasing molecules (CORMs) have been suggested as a new synthetic class of antimicrobials to treat bacterial infections. Here we utilized a novel EBOR-CORM-1 ([NEt4][MnBr2(CO)4]) capable of water-triggered CO-release, and tested its efficacy against a collection of clinical Pseudomonas aeruginosa strains that differ in infection-related virulence traits. We found that while EBOR-CORM-1 was effective in clearing planktonic and biofilm cells of P. aeruginosa strain PAO1 in a concentration dependent manner, this effect was less clear and varied considerably between different P. aeruginosa cystic fibrosis (CF) lung isolates. While a reduction in cell growth was observed after 8 h of CORM application, either no effect or even a slight increase in cell densities and the amount of biofilm was observed after 24 h. This variation could be partly explained by differences in bacterial virulence traits: while CF isolates showed attenuated in vivo virulence and growth compared to strain PAO1, they formed much more biofilm, which could have potentially protected them from the CORM. Even though no clear therapeutic benefits against a subset of isolates was observed in an in vivo wax moth acute infection model, EBOR-CORM-1 was more efficient at reducing the growth of CF isolate co-culture populations harboring intraspecific variation, in comparison with efficacy against more uniform single isolate culture populations. Together these results suggest that CORMs could be effective at controlling genetically diverse P. aeruginosa populations typical for natural chronic CF infections and that the potential benefits of some antibiotics might not be observed if tested only against clonal bacterial populations.

PMID: 29472912 [PubMed]

Can mean platelet volume and neutrophil-to-lymphocyte ratio be biomarkers of acute exacerbation of bronchiectasis in children?

Cent Eur J Immunol. 2017;42(4):358-362

Authors: Nacaroglu HT, Erdem SB, Karaman S, Yazici S, Can D

Abstract
Introduction: Bronchiectasis (BE) is a parenchymal lung disease evolving as a result of recurrent lung infections and chronic inflammation. Although it has been shown in adult studies that mean platelet volume (MPV) and neutrophil-to-lymphocyte ratio (NLR) can be used as biomarkers of airway inflammation, knowledge is limited in the paediatric age group. The aim of our study is to investigate the potential of MPV and NLR as biomarkers that may indicate acute exacerbations of non-cystic fibrosis BE in children.
Material and methods: Children with non-cystic fibrosis BE (n = 50), who were followed in the division of Paediatric Pulmonology of our hospital between June 2010 and July 2015, were involved in the present retrospective cross-sectional study. Haemogram values during acute exacerbations and non-exacerbation periods, and a control group were compared.
Results: In children with bronchiectasis, the average leukocyte count (p < 0.001), platelet count (p = 0.018), absolute neutrophil count (p < 0.001), and NLR (p < 0.001) were higher, as expected, when compared with the control group. NLR values, in the period of acute exacerbation were significantly higher than the values of both the non-exacerbation periods (p = 0.02) and the control group (p < 0.001). In contrast, MPV values in the period of acute exacerbation did not exhibit a significant difference from those of non-exacerbation periods (p = 0.530) and the control group (p = 0.103).
Conclusions: It was concluded that leukocyte count, platelet count, absolute neutrophil count, and NLR can be used to show chronic inflammation in BE, but only NLR and absolute neutrophil count can be used as biomarkers to show acute exacerbations.

PMID: 29472813 [PubMed]