Epithelial Sodium Channel ENaC is a Modifier of the Long Term Non-progressive Phenotype Associated with F508del CFTR Mutations.

Am J Respir Cell Mol Biol. 2017 Jul 14;:

Authors: Agrawal PB, Wang R, Li HL, Schmitz-Abe K, Simone-Roach C, Chen J, Shi J, Louie T, Sheng S, Towne MC, Brainson CF, Matthay MA, Kim CF, Bamshad M, Emond MJ, Gerard NP, Kleyman TR, Gerard C

Abstract
BACKGROUND: Cystic Fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability of clinical phenotype and survival, even among patients harboring the same genotype. We identified five CF patients with a homozygous F508del mutation in the CFTR gene living in their 5th or 6th decade of life, all with minimal change in lung function over longitudinal period of more than 20 years. Because of the rarity of this long-term non-progressive phenotype, we hypothesized those individuals may carry rare genetic variants in modifier genes that ameliorate disease severity.
METHODS: Individuals at the extremes of survival time and lung function trajectory underwent whole exome sequencing, and the data was filtered for missense, stopgain, indel, and splicing variants present with mean allele frequency <0.2%, and their potential impact on protein function was evaluated. The mutations in δ-ENaC were generated via site-directed mutagenesis, and expressed to carry out Xenopus oocyte assay.
RESULTS: Four of the five individuals carried extremely rare or never reported variants in the SCNN1D and SCNN1B genes of the epithelial sodium channel (ENaC). Separately, an independently enriched rare variant in SCNN1D was identified in the exome variant server database associated with a milder pulmonary disease phenotype. Functional analysis using Xenopus oocytes revealed two of the three variants in δ-ENaC encoded by SCNN1D exhibited hypomorphic channel activity.
CONCLUSION: Our data suggest a potential role of δ-ENaC in control of the sodium reabsorption in the airways, and advance the plausibility of ENaC as a therapeutic target in CF.

PMID: 28708422 [PubMed - as supplied by publisher]

Association of Antibiotics, Airway Microbiome and Inflammation in Infants with Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Jul 14;:

Authors: Pittman JE, Wylie KM, Akers K, Storch GA, Hatch J, Quante J, Frayman KB, Clarke N, Davis M, Stick SM, Hall GL, Montgomery G, Ranganathan S, Davis SD, Ferkol TW, AREST CF

Abstract
RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation.
OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF.
METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin-8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid.
RESULTS: Thirty-two infants (mean age 4.7 months) underwent BAL and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, though community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily anti-staphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated strongly with lower interleukin-8 concentration and absolute neutrophil count.
CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.

PMID: 28708417 [PubMed - as supplied by publisher]

Immunomodulatory Cell Therapy to Target Cystic Fibrosis Inflammation.

Am J Respir Cell Mol Biol. 2017 Jul 14;:

Authors: Khoury O, Barrios C, Ortega V, Atala A, Murphy SV

Abstract
Cystic fibrosis (CF) is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, airway mucus obstruction, bronchiectasis and loss of lung function. This hyper-inflammatory phenotype appears to be caused by an imbalance between the pro- and anti-inflammatory regulatory pathways, with heightened pro-inflammatory stimuli, a decreased counter-regulatory response, and reduced effectiveness of immune cell function and inflammatory resolution. Thus, therapies that can target this inflammatory environment would have a major impact in preventing the progression of lung disease. Due to the complex phenotype of CF inflammation, current anti-inflammatory regimens have proven to be inadequate for the targeting of these multiple dysregulated pathways and effects. Several approaches utilizing cell therapies have shown potential therapeutic benefit for the treatment of CF inflammation. This review provides an overview of the immune dysfunctions in CF and current therapeutic regimens and explores the field of cell therapy as a treatment for CF inflammation, and focuses on the various cell types utilized, their immunomodulatory functions, and the current approaches to mitigate the inflammatory response and reduce the long-term damage for CF patients.

PMID: 28707978 [PubMed - as supplied by publisher]

Mycobacterium abscessus in patients with cystic fibrosis: low impact of inter-human transmission in Italy.

Eur Respir J. 2017 Jul;50(1):

Authors: Tortoli E, Kohl TA, Trovato A, Baldan R, Campana S, Cariani L, Colombo C, Costa D, Cristadoro S, Di Serio MC, Manca A, Pizzamiglio G, Rancoita PMV, Rossolini GM, Taccetti G, Teri A, Niemann S, Cirillo DM

PMID: 28705942 [PubMed - in process]

Characterisation of eppin function: expression and activity in the lung.

Eur Respir J. 2017 Jul;50(1):

Authors: Scott A, Glasgow A, Small D, Carlile S, McCrudden M, McLean D, Brown R, Doherty D, Lundy FT, Hamid UI, O'Kane CM, McAuley DF, Brodlie M, Tunney M, Elborn JS, Irwin CR, Timson DJ, Taggart CC, Weldon S

Abstract
Eppin is a serine protease inhibitor expressed in male reproductive tissues.The aim of this study was to investigate the localisation and regulation of eppin expression in myeloid and epithelial cell lines, and explore its potential role as a multifunctional host defence protein.Using immunohistochemistry and Western blotting, eppin was detected in the lungs of patients with acute respiratory distress syndrome and cystic fibrosis lung disease. Expression of eppin in monocytic cells was unaffected by stimulation with Toll-like receptor agonists, cytokines and hormone receptor agonists. However, upregulated expression and secretion of eppin was observed following treatment of monocytes with epidermal growth factor. Incubation of recombinant eppin with monocytic cells resulted in significant inhibition of lipopolysaccharide-induced chemokine production. Furthermore, eppin inhibited lipopolysaccharide-induced NF-κB activation by a mechanism which involved accumulation of phosphorylated IκBα. In an in vivo model of lung inflammation induced by lipopolysaccharide, eppin administration resulted in decreased recruitment of neutrophils to the lung with a concomitant reduction in the levels of the neutrophil chemokine macrophage inflammatory protein-2.Overall, these results suggest a role for eppin outside of the reproductive tract and that eppin may have a role in the innate immune response in the lung.

PMID: 28705940 [PubMed - in process]

Clinical characteristics of bacteraemia caused by burkholderia cepacia complex species and antimicrobial susceptibility of the isolates in a medical centre in taiwan.

Int J Antimicrob Agents. 2017 Jul 10;:

Authors: Chien YC, Liao CH, Sheng WH, Chien JY, Huang YT, Yu CJ, Hsueh PR

Abstract
This study investigated the clinical characteristics and outcomes of bacteraemia due to Burkholderia cepacia complex (BCC) species among 54 patients without cystic fibrosis from January 2013 to February 2015. BCC isolates were identified to the species level by the Bruker Biotyper MALDI-TOF MS system and by sequencing analysis of the 16S rRNA and recA genes. Antimicrobial susceptibilities of the isolates were determined by the agar dilution method. Sequencing of the recA gene in the 54 blood isolates revealed 37 (68.5%) isolates of B. cenocepacia, 9 (16.7%) B. cepacia, 4 (7.4%) isolates of B. multivorans and one isolate each of B. arboris, B. pseudomultivorans, B. seminalis, and B. vietnamiensis. The overall performance of the Bruker Biotyper MALDI-TOF MS system for correctly identifying the 54 BCC isolates to the species level was 79.6% that was better than that (16.7%) by 16S RNA sequencing analysis. Bacteraemic pneumonia (n=23, 42.6%) and catheter-related bacteraemia (n=21, 38.9%) were the most common types of infection. Higher rates of ceftazidime and meropenem resistance were found in B. cepacia isolates (33.3% and 22.2%, respectively) than in isolates of B. cenocepacia (21.6% and 10.8%, respectively) and other species (12.5% and 12.5%, respectively). Overall, the 30-day mortality rate was 38.9% (21/54). Bacteraemia caused by BCC species other than B. cenocepacia and B. cepacia (adjusted odds ratio [aOR] 20.005, P=0.024) and high SOFA score (aOR 1.412, P=0.003) were predictive of higher 30-day mortality. Different BCC complex species are associated with different outcomes of bacteraemia and exhibit different susceptibility patterns.

PMID: 28705667 [PubMed - as supplied by publisher]

Monitoring clinical and microbiological evolution of a cystic fibrosis patient over 26 years: experience of a Brazilian CF Centre.

BMC Pulm Med. 2017 Jul 14;17(1):100

Authors: da Costa Ferreira Leite C, Folescu TW, de Cássia Firmida M, Cohen RWF, Leão RS, de Freitas FAD, Albano RM, da Costa CH, Marques EA

Abstract
BACKGROUND: Burkholderia cepacia complex is a group of opportunistic pathogens in cystic fibrosis (CF) patients believed to be associated with poor prognosis and patient-to-patient transmissibility. Little is known about clinical outcomes after B. vietnamiensis chronic colonization/infection.
CASE PRESENTATION: A 33 yo male patient had diagnosis of CF by 7 yo, after recurrent pneumonia during infancy and lobectomy (left upper lobe) at 6 yo. Burkholderia cepacia complex (Bcc) was first isolated by 13 yo, and the patient fulfilled the criteria for chronic colonization by 15 yo. In the following 16 years (1997-2013), there was intermittent isolation of P. aeruginosa and continuous isolation of Bcc, identified as B. vietnamiensis. There was clinical and laboratorial stability for 16 years with annual rate of decline in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) of 1.61 and 1.35%, respectively. From 2013 to 2015, there was significant clinical and lung function deterioration: annual rate of decline in FEV1 and FVC was 3 and 4.1%, respectively while body mass index decreased from 18.1 to 17.1. Episodes of hemoptysis and respiratory exacerbations (with hospital admissions) became more frequent. CF related diabetes was diagnosed (fasting glycemia: 116 mg/dL, oral glucose tolerance test: 305 mg/dL). Because of the severity of the disease in the last years, in addition to traditional microbiological surveillance, microbiome analysis by next generation sequencing (NGS) was performed on respiratory secretions. The NGS showed that 97% of the sequencing data were attributed to genus Burkholderia.
CONCLUSIONS: We report the case of a 33-year-old male CF patient known to have chronic infection with B. vietnamiensis who remained clinically stable for 16 years and presented recent clinical and laboratorial deterioration. Microbiome analysis of respiratory secretions was performed in 3 samples collected in 2014-2015. Clinical deterioration overlapped with cystic fibrosis-related diabetes and microbiome composition revealed no significant differences when compared microbiome results to culture dependent methods.

PMID: 28705217 [PubMed - in process]

Premature Thelarche and the PURA Syndrome.

Obstet Gynecol. 2017 Jun;129(6):1037-1039

Authors: Rezkalla J, Von Wald T, Hansen KA

Abstract
BACKGROUND: Premature thelarche is a self-limited condition characterized by Tanner stage II-III breast development in girls younger than 8 years of age with no evidence of advancing puberty. Evaluation concentrates on excluding central or peripheral causes of precocious puberty.
CASE: A girl aged 2 years 4 months with profound hypotonia and delayed developmental milestones presented with Tanner II breast development, elevated follicle-stimulating hormone levels, suppressed luteinizing hormone level, normal growth and skeletal development, and prepubertal uterine length and ovarian volume. Monitoring until 8 years of age revealed no pubertal progression. Whole exome sequencing at 8 years revealed an autosomal-dominant mutation in the purine-rich element-binding protein A (PURA) gene. Previous patients with PURA syndrome have had pituitary dysfunction and precocious puberty.
CONCLUSION: Purine-rich element-binding protein A syndrome can be associated with premature thelarche.

PMID: 28486374 [PubMed - indexed for MEDLINE]

Medical treatment of erectile dysfunction: too many medical prescriptions?

Urologia. 2017 Jul 05;:0

Authors: Capogrosso P, Ventimiglia E, Oreggia D, Salonia A, Montorsi F

Abstract
Erectile dysfunction (ED) is a worldwide commonly reported condition; epidemiological data showed a prevalence ranging from 2.3 to 53.4% within different population subsets. In this context, the advent of phosphodiesterase type 5 inhibitors (PDE5is) in the second mid of 1990s has deeply changed the treatment scenario of this bothersome condition. Being user-friendly compounds with an excellent overall safety profile, PDE5is emerged as the first-line treatment for ED, thus overcoming topical alprostadil and intracavernous injections (ICIs). However, available data on treatment-utilization patterns and medical prescriptions of PDE5is showed a range of as wide as 22-78% of patients reporting to purchase PDE5is even without a proper medical prescription. Moreover, an increase in the recreational use of PDE5is among young men has been observed in the last decades, with a worrisome diffusion of potential health-risky behaviours associated with this habit. Indeed, treatment of ED should carefully follow internationally based clinical guidelines to avoid inappropriate drug prescriptions, which may eventually expose treated patients to drug-related side effects. Thereof, a careful assessment of the so-called modifiable and reversible ED risk factors along with a patient-tailored screening for potential contraindications to the treatment itself should be performed in every case. Lastly, although conclusive data still lack, the potential association between life-risky PDE5is side effects (i.e. cardiovascular adverse events, melanoma skin cancer and worsening of prostate cancer outcomes) should be carefully taken into account when counselling patients for ED treatment.

PMID: 28708203 [PubMed - as supplied by publisher]

The British National Formulary.

Nurs Stand. 2016 Nov 02;31(10):64-65

Authors: Tallo D

Abstract
What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article introduced the revised format of the British National Formulary (BNF) and explained how the information it contains may be accessed. It discussed the importance of developing healthcare professionals' knowledge and understanding of the BNF to enable safe and effective prescribing, dispensing, administration and monitoring of medicines.

PMID: 27861054 [PubMed - indexed for MEDLINE]

Life threatening torsades de pointes due to abiraterone-induced hypokaelemia in a patient with metastatic prostate cancer.

N Z Med J. 2016 Nov 18;129(1445):124-127

Authors: Khan A, Kneale B

Abstract
We present a case of a 77 year-old gentleman with previous coronary artery bypass grafting, admitted to hospital with recurrent torsades de pointes (TdP) due to abiraterone-induced hypokalaemia and prolonged QTc. The patient was on abiraterone and prednisone for metastatic prostate cancer. He required multiple defibrillations for recurrent TdP. Abiraterone is a relatively novel drug used in metastatic prostate cancer and we discuss this potential adverse effect and its management in this unusual presentation.

PMID: 27857247 [PubMed - indexed for MEDLINE]

Adverse drug reactions: classification, susceptibility and reporting.

Nurs Stand. 2016 Aug 10;30(50):53-63

Authors: Kaufman G

Abstract
Adverse drug reactions (ADRs) are increasingly common and are a significant cause of morbidity and mortality. Historically, ADRs have been classified as type A or type B. Type A reactions are predictable from the known pharmacology of a drug and are associated with high morbidity and low mortality. Type B reactions are idiosyncratic, bizarre or novel responses that cannot be predicted from the known pharmacology of a drug and are associated with low morbidity and high mortality. Not all ADRs fit into type A and type B categories; therefore, additional categories have been developed. These include type C (continuing), type D (delayed use), and type E (end of use) reactions. Susceptibility to ADRs is influenced by age, gender, disease states, pregnancy, ethnicity and polypharmacy. Drug safety is reliant on nurses and other healthcare professionals being alert to the possibility of ADRs, working with patients to optimise medicine use and exercising vigilance in the reporting of ADRs through the Yellow Card Scheme.

PMID: 27507394 [PubMed - indexed for MEDLINE]

Safety of Drugs during Pregnancy and Breastfeeding in Cystic Fibrosis Patients.

Respiration. 2016;91(4):333-48

Authors: Panchaud A, Di Paolo ER, Koutsokera A, Winterfeld U, Weisskopf E, Baud D, Sauty A, Csajka C

Abstract
Health management of cystic fibrosis (CF) patients should be maximized during pregnancy and breastfeeding because of its significant impact on the maternal and newborn outcomes. Thus, numerous drugs will have to be continued during pregnancy and lactation. Most of the drugs representing CF treatment lines cross the placenta or are excreted into human milk. Research addressing the risks and benefits of drugs used in CF patients during pregnancy and lactation is often incomplete or challenged by limited methodology, which often leads to conflicting or inconclusive results. Yet, potential treatment benefits for CF pregnant patients most often outbalance potential risks for the unborn child.

PMID: 26942733 [PubMed - indexed for MEDLINE]

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

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

"systems biology"

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

These pubmed results were generated on 2017/07/14

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

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

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

Authors: Douglas GM, Wilson MD, Moses AM

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

PMID: 26882985 [PubMed - indexed for MEDLINE]

Repurposing of Potent Drug Candidates for Multiparasite Targeting.

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

Authors: Jain V, Sharma A

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

PMID: 28081985 [PubMed - indexed for MEDLINE]

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

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

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

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

PMID: 28074615 [PubMed - indexed for MEDLINE]