Role of a conserved glutamine in the function of voltage-gated Ca2+ channels revealed by a mutation in human CACNA1D.

J Biol Chem. 2018 Jul 27;:

Authors: Garza-Lopez E, Lopez JA, Hagen J, Sheffer R, Meiner V, Lee A

Abstract
Voltage-gated Cav Ca2+ channels play crucial roles in regulating gene transcription, neuronal excitability, and synaptic transmission. Natural or pathological variations in Cav channels have yielded rich insights into the molecular determinants controlling channel function. Here, we report the consequences of a natural, disease-associated mutation in the CACNA1D gene encoding the pore-forming Cav1.3 α1 subunit. The mutation causes a substitution of a glutamine residue that is highly conserved in the extracellular S1-S2 loop of domain II in all Cav channels with a histidine and was identified by whole-exome sequencing of an individual with moderate hearing impairment, developmental delay, and epilepsy. When introduced into the rat Cav1.3 cDNA, Q558H significantly decreased the density of Ca2+ currents in transfected HEK293T cells. Gating current analyses and cell-surface biotinylation experiments suggested that the smaller current amplitudes caused by Q558H were due to decreased numbers of functional Cav1.3 channels at the cell surface. The substitution also produced more sustained Ca2+ currents by weakening voltage-dependent inactivation. When inserted into the corresponding locus of Cav2.1, the substitution had similar effects as in Cav1.3. However, the substitution introduced in Cav3.1 reduced current density, but had no effects on voltage-dependent inactivation. Our results reveal a novel critical extracellular determinant of current density for all Cav family members and of voltage-dependent inactivation of Cav1.3 and Cav2.1 channels.

PMID: 30054272 [PubMed - as supplied by publisher]

Are diagnostic magnetic resonance patterns life-saving in children with biotin-thiamine-responsive basal ganglia disease?

Eur J Paediatr Neurol. 2018 Jul 09;:

Authors: Kamaşak T, Havalı C, İnce H, Eyüboğlu İ, Çebi AH, Sahin S, Cansu A, Aydin K

Abstract
BACKGROUND: Biotin-thiamine responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy that typically starts in early childhood. This study describes characteristic clinical and magnetic resonance imaging (MRI) findings of six cases of BTBGD diagnosed with newly identified mutations and genetically confirmed, with very early and different presentations compared to cases in the previous literature.
METHODS: Six patients referred from different centers with similar clinical findings were diagnosed with BTBGD with newly identified mutations in the SLC19A3 gene. Two novel mutations in the SLC19A3 gene were identified in two patients at whole exome sequencing analysis. The clinical characteristics, responses to treatment, and electroencephalography (EEG) and MRI findings of these patients were examined. The other four patients presented with similar clinical and cranial MRI findings. These patients were therefore started on high-dose biotin and thiamine therapy, and mutation analysis concerning the SLC19A3 gene was performed. Responses to treatment, clinical courses, EEG findings and follow-up MRI were recorded for all these patients.
RESULTS: Age at onset of symptoms ranged from 1 to 3 months. The first symptoms were generally persistent crying and restlessness. Seizures occurred in five of the six patients. Cranial magnetic resonance imaging revealed involvement in the basal ganglia, brain stem, and the parietal and frontal regions in general. The first two patients were siblings, and both exhibited a novel mutation of the SLC19A3 gene. The third and fourth patients were also siblings and also exhibited a similar novel mutation of the SLC19A3 gene. The fifth and sixth patients were not related, and a newly identified mutation was detected in both these subjects. Three novel mutations were thus detected in six patients.
CONCLUSION: BTBGD is a progressive disease that can lead to severe disability and death. Early diagnosis of treatable diseases such as BTBGD is important in order to prevent long-term complications and disability.

PMID: 30054086 [PubMed - as supplied by publisher]

A familial case of Galloway-Mowat syndrome due to a novel TP53RK mutation: a case report.

BMC Med Genet. 2018 Jul 27;19(1):131

Authors: Hyun HS, Kim SH, Park E, Cho MH, Kang HG, Lee HS, Miyake N, Matsumoto N, Tsukaguchi H, Cheong HI

Abstract
BACKGROUND: Galloway-Mowat syndrome (GAMOS) is a rare hereditary renal-neurological disease characterized by early-onset steroid-resistant nephrotic syndrome in combination with microcephaly and brain anomalies. Recently, novel causative mutations for this disease have been identified in the genes encoding the four KEOPS subunits: OSGEP, TP53RK, TPRKB, and LAGE3.
CASE PRESENTATION: We detected a novel homozygous TP53RK mutation (NM_033550, c.194A > T, p.Lys65Met) using whole exome sequencing in a familial case of GAMOS with three affected siblings. All three patients manifested similar phenotypes, including very early-onset nephrotic syndrome (8 days, 1 day, and 1 day after birth, respectively), microcephaly, dysmorphic faces, and early fatality (10 months, 21 days, and 25 days of age, respectively). One patient also showed hiatal hernia with gastric volvulus. Renal biopsy performed on one patient revealed focal segmental glomerulosclerosis with severe tubulo-interstitial changes.
CONCLUSION: We report on a familial case of GAMOS with three affected siblings carrying a novel homozygous TP53RK mutation. To our knowledge, this is only the second report on GAMOS in association with a TP53RK mutation.

PMID: 30053862 [PubMed - in process]

Euphorbia factor L2 alleviates lipopolysaccharide-induced acute lung injury and inflammation in mice through the suppression of NF-κB activation.

Biochem Pharmacol. 2018 Jul 25;:

Authors: Zhang Q, Zhu S, Cheng X, Lu C, Tao W, Zhang Y, Blackledge W, Cao X, Yi S, Liu Y, Zhao Y, Luo Y

Abstract
Acute respiratory distress syndrome threatens public health with high morbidity and mortality due to ineffective intervention whereby lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice provides a research model. The seeds of Euphorbia lathyris L. have a long history of usage in Traditional Chinese Medicine. Euphorbia factors L1-L11, extracted from this herb, have been reported to have anti-inflammation and anti-cancer effects. Here, we report the preventive and therapeutic potential of Euphorbia factor L2 (EFL2) on LPS-induced ALI in mice, where EFL2 attenuated pathological alterations in the lung and improved survival. Significant suppresson of the recruitment and transmigration of inflammatory cells, specifically neutrophils, by 40 mg/kg of EFL2 was observed. EFL2 exerted potent anti-inflammatory effects by decreasing the levels of interleukin-1β (IL-1 β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF- α), interleukin-8 (IL-8) and myeloperoxidase (MPO) in the lung and bronchioalveolar lavage fluid. Consistent with the findings in vivo, EFL2 also showed robust inhibitory effects on the production of IL-1 β, IL-6, TNF- α and IL-8 released from LPS-stimulated RAW264.7 cells in vitro. Interestingly, this effect appeared to be mediated by EFL2's inhibition of NF-κB signaling activation, but not the MAPK pathway. Not only phosphorylation of IKK α / β and IκBα was down-regulated, p65 translocation and its DNA-binding activity were also significantly suppressed by EFL2. Moreover, overexpression of p65 reversed the inhibitory effect of EFL2 in LPS-induced NF-κB activation and cytokines production. The observed anti-inflammatory bioactivity of EFL2 indicates its potential as a drug development candidate, particularly for LPS-mediated disorders of inflammation.

PMID: 30055150 [PubMed - as supplied by publisher]

Multi-model ensembles improve predictions of crop-environment-management interactions.

Glob Chang Biol. 2018 Jul 28;:

Authors: Wallach D, Martre P, Liu B, Asseng S, Ewert F, Thorburn PJ, van Ittersum M, Aggarwal PK, Ahmed M, Basso B, Biernath C, Cammarano D, Challinor AJ, De Sanctis G, Dumont B, Eyshi Rezaei E, Fereres E, Fitzgerald GJ, Gao Y, Garcia-Vila M, Gayler S, Girousse C, Hoogenboom G, Horan H, Izaurralde RC, Jones CD, Kassie BT, Kersebaum KC, Klein C, Koehler AK, Maiorano A, Minoli S, Müller C, Naresh Kumar S, Nendel C, O'Leary GJ, Palosuo T, Priesack E, Ripoche D, Rötter RP, Semenov MA, Stöckle C, Stratonovitch P, Streck T, Supit I, Tao F, Wolf J, Zhang Z

Abstract
A recent innovation in assessment of climate change impact on agricultural production has been to use crop multi model ensembles (MMEs). These studies usually find large variability between individual models but that the ensemble mean (e-mean) and median (e-median) often seem to predict quite well. However few studies have specifically been concerned with the predictive quality of those ensemble predictors. We ask what is the predictive quality of e-mean and e-median, and how does that depend on the ensemble characteristics. Our empirical results are based on five MME studies applied to wheat, using different data sets but the same 25 crop models. We show that the ensemble predictors have quite high skill and are better than most and sometimes all individual models for most groups of environments and most response variables. Mean squared error of e-mean decreases monotonically with the size of the ensemble if models are added at random, but has a minimum at usually 2-6 models if best-fit models are added first. Our theoretical results describe the ensemble using four parameters; average bias, model effect variance, environment effect variance and interaction variance. We show analytically that mean squared error of prediction (MSEP) of e-mean will always be smaller than MSEP averaged over models, and will be less than MSEP of the best model if squared bias is less than the interaction variance. If models are added to the ensemble at random, MSEP of e-mean will decrease as the inverse of ensemble size, with a minimum equal to squared bias plus interaction variance. This minimum value is not necessarily small, and so it is important to evaluate the predictive quality of e-mean for each target population of environments. These results provide new information on the advantages of ensemble predictors, but also show their limitations. This article is protected by copyright. All rights reserved.

PMID: 30055118 [PubMed - as supplied by publisher]

Transcriptomic Analysis of Hepatic Cells in Multicellular Organotypic Liver Models.

Sci Rep. 2018 Jul 27;8(1):11306

Authors: Tegge AN, Rodrigues RR, Larkin AL, Vu L, Murali TM, Rajagopalan P

Abstract
Liver homeostasis requires the presence of both parenchymal and non-parenchymal cells (NPCs). However, systems biology studies of the liver have primarily focused on hepatocytes. Using an organotypic three-dimensional (3D) hepatic culture, we report the first transcriptomic study of liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) cultured with hepatocytes. Through computational pathway and interaction network analyses, we demonstrate that hepatocytes, LSECs and KCs have distinct expression profiles and functional characteristics. Our results show that LSECs in the presence of KCs exhibit decreased expression of focal adhesion kinase (FAK) signaling, a pathway linked to LSEC dedifferentiation. We report the novel result that peroxisome proliferator-activated receptor alpha (PPARα) is transcribed in LSECs. The expression of downstream processes corroborates active PPARα signaling in LSECs. We uncover transcriptional evidence in LSECs for a feedback mechanism between PPARα and farnesoid X-activated receptor (FXR) that maintains bile acid homeostasis; previously, this feedback was known occur only in HepG2 cells. We demonstrate that KCs in 3D liver models display expression patterns consistent with an anti-inflammatory phenotype when compared to monocultures. These results highlight the distinct roles of LSECs and KCs in maintaining liver function and emphasize the need for additional mechanistic studies of NPCs in addition to hepatocytes in liver-mimetic microenvironments.

PMID: 30054499 [PubMed - in process]

Pairwise library screen systematically interrogates Staphylococcus aureus Cas9 specificity in human cells.

Nat Commun. 2018 Jul 27;9(1):2962

Authors: Tycko J, Barrera LA, Huston NC, Friedland AE, Wu X, Gootenberg JS, Abudayyeh OO, Myer VE, Wilson CJ, Hsu PD

Abstract
Therapeutic genome editing with Staphylococcus aureus Cas9 (SaCas9) requires a rigorous understanding of its potential off-target activity in the human genome. Here we report a high-throughput screening approach to measure SaCas9 genome editing variation in human cells across a large repertoire of 88,692 single guide RNAs (sgRNAs) paired with matched or mismatched target sites in a synthetic cassette. We incorporate randomized barcodes that enable whitelisting of correctly synthesized molecules for further downstream analysis, in order to circumvent the limitation of oligonucleotide synthesis errors. We find SaCas9 sgRNAs with 21-mer or 22-mer spacer sequences are generally more active, although high efficiency 20-mer spacers are markedly less tolerant of mismatches. Using this dataset, we developed an SaCas9 specificity model that performs robustly in ranking off-target sites. The barcoded pairwise library screen enabled high-fidelity recovery of guide-target relationships, providing a scalable framework for the investigation of CRISPR enzyme properties and general nucleic acid interactions.

PMID: 30054474 [PubMed - in process]

Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials.

Gynecol Oncol. 2018 Jul 24;:

Authors: Meagher NS, Schuster K, Voss A, Budden T, Pang CNI, deFazio A, Ramus SJ, Friedlander ML

Abstract
OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials.
METHODS: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance.
RESULTS: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors.
CONCLUSIONS: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.

PMID: 30054102 [PubMed - as supplied by publisher]

Evaluating model reduction under parameter uncertainty.

BMC Syst Biol. 2018 Jul 27;12(1):79

Authors: Frøysa HG, Fallahi S, Blaser N

Abstract
BACKGROUND: The dynamics of biochemical networks can be modelled by systems of ordinary differential equations. However, these networks are typically large and contain many parameters. Therefore model reduction procedures, such as lumping, sensitivity analysis and time-scale separation, are used to simplify models. Although there are many different model reduction procedures, the evaluation of reduced models is difficult and depends on the parameter values of the full model. There is a lack of a criteria for evaluating reduced models when the model parameters are uncertain.
RESULTS: We developed a method to compare reduced models and select the model that results in similar dynamics and uncertainty as the original model. We simulated different parameter sets from the assumed parameter distributions. Then, we compared all reduced models for all parameter sets using cluster analysis. The clusters revealed which of the reduced models that were similar to the original model in dynamics and variability. This allowed us to select the smallest reduced model that best approximated the full model. Through examples we showed that when parameter uncertainty was large, the model should be reduced further and when parameter uncertainty was small, models should not be reduced much.
CONCLUSIONS: A method to compare different models under parameter uncertainty is developed. It can be applied to any model reduction method. We also showed that the amount of parameter uncertainty influences the choice of reduced models.

PMID: 30053887 [PubMed - in process]

Pharmacogenomics of Sulfonylureas Response in Relation to rs7754840 Polymorphisms in Cyclin-Dependent Kinase 5 Regulatory Subunit-associated Protein 1-like (CDKAL1) Gene in Iranian Type 2 Diabetes Patients.

Adv Biomed Res. 2018;7:96

Authors: Soltani G, Hatefi Z, Salehi AR, Khosravi S, Ghiasi MR, Teke K, Aminorroaya A, Salehi R

Abstract
Background: Sulfonylureas are important drugs of choice for treatment of type 2 diabetes mellitus (T2DM). It is suggested that differential response to sulfonylureas from T2DM patients is under influence of single nucleotide polymorphisms in some of the target genes. In spite of favorable therapeutic effects, sulfonylureas are associated with some adverse side effects such as microvascular complications and stroke, especially in older patients. Therefore, for T2DM patients who are getting less benefit, sulfonylureas should be avoided. Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like (CDKAL1) gene variation is reported to be associated with sulfonylureas effectiveness. Due to the inconsistency of available data regarding association of rs7754840 in CDKAL1 gene with sulfonylureas response in T2DM patients, the present study is conducted.
Materials and Methods: Fifty-one diabetic patients sensitive to sulfonylureas and 51 patients resistant to sulfonylureas treatment were recruited to this study. After extraction of DNA from patients' peripheral blood samples, rs7754840 single-nucleotide polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism assay using MaeII (Tail) restriction enzyme.
Results: Frequency of G allele in resistant group was more than sensitive group (71, 6% vs. 57, 8%). Regression analysis was shown significant association between GG genotype and higher risk of resistance to sulfonylureas treatment (odds ratio = 2.250 [95% confidential intervals: 1.010-5.012]; P = 0.046).
Conclusion: Our data confirmed that genotypes of rs7754840 are significantly associated with sulfonylureas treatment response. rs7754840 in CDKAL1 gene in combination with other clinicopathological findings would help to move towards personalized therapy of T2DM patients.

PMID: 30050884 [PubMed]

Putting Out the Fire: The Relationship of Pharmacogenetics and Proton Pump Inhibitors for the Treatment of Gastroesophageal Reflux Disease.

Cureus. 2018 May 24;10(5):e2687

Authors: Zheng CL, Alzghari SK

Abstract
Proton pump inhibitors (PPIs) are a mainstay treatment for gastroesophageal reflux disease (GERD) and are mainly metabolized by CYP2C19 in the liver. However, several polymorphisms of CYP2C19 exist that affect the metabolism of PPIs. Due to the large variability of PPI pharmacokinetics among the polymorphisms, this has implications in the management of patients with refractory GERD who may be potentially undertreated. Herein, we discuss the role of CYP2C19 and its relation to PPI therapy, particularly in those with GERD.

PMID: 30050742 [PubMed]

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Susceptibility to R-pyocins of Pseudomonas aeruginosa clinical isolates from cystic fibrosis patients.

J Antimicrob Chemother. 2018 Jul 24;:

Authors: Redero M, López-Causapé C, Aznar J, Oliver A, Blázquez J, Prieto AI

Abstract
Background: The appearance and dissemination of MDR among pathogenic bacteria has forced the search for new antimicrobials. Bacteriocins have been proposed as potential alternatives for the treatment of infections due to multiresistant strains.
Objectives: To analyse the activity of R-pyocins against clinical isolates of Pseudomonas aeruginosa from patients with cystic fibrosis and other sources and evaluate them as a potential adjuvant or alternative to the current antibiotic treatment.
Methods: The activity of R-pyocins against 150 strains of P. aeruginosa isolated from patients with cystic fibrosis or bacteraemia was studied through spot assay. Interactions between R-pyocins and antipseudomonal agents were quantitatively studied by the chequerboard method.
Results: The proportion of P. aeruginosa isolates susceptible to R-pyocins was found to be higher in cystic fibrosis isolates compared with bacteraemia isolates (79.41% versus 50%). Moreover, no interactions were found between common antipseudomonal agents and R-pyocin susceptibility, except for the ST175 high-risk clone.
Conclusions: Our results highlight the possibility of using R-pyocins as therapeutic agents, alone or as adjuvants, against P. aeruginosa in cystic fibrosis.

PMID: 30052973 [PubMed - as supplied by publisher]

Relationship of Initial Pancreatic Enzyme Replacement Therapy Dose with Weight Gain in Infants with Cystic Fibrosis.

J Pediatr Gastroenterol Nutr. 2018 Jul 26;:

Authors: Schechter M, Michel S, Liu S, Seo BW, Kapoor M, Khurmi R, Haupt M

Abstract
OBJECTIVE: To test the hypothesis of a positive relationship between initial dose of pancreatic enzyme replacement therapy (PERT) in infants with cystic fibrosis (CF) and optimal weight gain over the first two years of life.
METHODS: Using the CF Foundation Patient Registry, we identified 502 children born in 2010 and used multivariable models to compare as our primary analysis their 2-year changes in weight-for-age z score (WAZ) and as our secondary analysis weight-for-length percentile (W/L%) by initial PERT dose. We focused on initial dose without reference to subsequent changes in treatment in order to avoid confounding by indication (severity).
RESULTS: Initial PERT dose demonstrated a linear relationship to change in WAZ and W/L% at age 2 years. An initial dose of >1500 lipase units/kg/largest meal resulted in a higher likelihood of attaining WAZ at 2 years at or above the birth WAZ (adjusted odds ratio [aOR] 1.87, 95% confidence interval [CI]: 1.22-2.86) and at the top quartile for improvement over 2 years in WAZ (aOR 1.90, 95% CI: 1.19-3.05).. There was no correlation between initial PERT dose and weight at initial PERT encounter (p = 0.35). Findings were similar for W/L% and when the cohort was restricted to infants who began PERT in the first 3 months of life.
CONCLUSION: Infants receiving higher initial PERT dose demonstrate better weight-related outcomes, as reflected by attainment of favorable changes in WAZ and W/L%, at age 2 years.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

PMID: 30052568 [PubMed - as supplied by publisher]

Treatment for chronic methicillin-sensitive Staphylococcus aureus pulmonary infection in people with cystic fibrosis.

Cochrane Database Syst Rev. 2018 Jul 27;7:CD011581

Authors: Ahmed MI, Mukherjee S

Abstract
BACKGROUND: Cystic fibrosis is an inherited life-threatening multisystem disorder with lung disease characterized by abnormally thick airway secretions and persistent bacterial infection. Chronic, progressive lung disease is the most important cause of morbidity and mortality in the condition and is therefore the main focus of clinical care and research. Staphylococcus aureus is a major cause of chest infection in people with cystic fibrosis. Early onset, as well as chronic, lung infection with this organism in young children and adults results in worsening lung function, poorer nutrition and increases the airway inflammatory response, thus leading to a poor overall clinical outcome. There are currently no evidence-based guidelines for chronic suppressive therapy for Staphylococcus aureus infection in cystic fibrosis such as those used for Pseudomonas aeruginosa infection. This is an update of a previously published review.
OBJECTIVES: To assess the evidence regarding the effectiveness of long-term antibiotic treatment regimens for chronic infection with methicillin-sensitive Staphylococcus aureus (MSSA) infection in people with cystic fibrosis and to determine whether this leads to improved clinical and microbiological outcomes.
SEARCH METHODS: Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, handsearching article reference lists and through contact with local and international experts in the field. Date of the last search of the Group's Cystic Fibrosis Trials Register: 09 February 2018.We also searched ongoing trials databases. Date of latest search: 20 May 2018.
SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials used as suppressive therapy for chronic infection with methicillin-sensitive Staphylococcus aureus compared with placebo or no treatment.
DATA COLLECTION AND ANALYSIS: The authors independently assessed all search results for eligibility. No eligible trials were identified.
MAIN RESULTS: The searches identified 58 trials, but none were eligible for inclusion in the current version of this review.
AUTHORS' CONCLUSIONS: No randomised controlled trials were identified which met the inclusion criteria for this review. Although methicillin-sensitive Staphylococcus aureus is an important and common cause of lung infection in people with cystic fibrosis, there is no agreement on how best to treat long-term infection. The review highlights the need to organise well-designed trials that can provide evidence to support the best management strategy for chronic methicillin-sensitive Staphylococcus aureus infection in people with cystic fibrosis.

PMID: 30052271 [PubMed - as supplied by publisher]

High rates of Mycobacterium fortuitum isolation in respiratory samples from Iranian patients with suspected tuberculosis: is it clinically important?

J Med Microbiol. 2018 Jul 27;:

Authors: Irandoost M, Zare Ghanbari M, Sakhaee F, Vaziri F, Rahimi Jamnani F, Siadat SD, Fateh A

Abstract
PURPOSE: Although Mycobacterium fortuitum (M. fortuitum) is not an organism rarely isolated from respiratory samples, its clinical importance is still not fully understood, which therefore prompted our current study.
METHODOLOGY: We evaluated respiratory samples from 6800 patients with suspected tuberculosis from May 2014 to May 2016, for the detection of M. fortuitum using phenotypic and genotyping methods.Results/Key findings. Of the 40 patients with M. fortuitum lung disease, 35 had two or more positive culture results. The mean age of these 35 patients was 50.7±18.4 years, and 20 (57.1 %) were men. Sputum (68.6 %), haemoptysis (51.4 %), cough (45.7 %) and gastroesophageal disease (22.9 %) were the major presenting symptoms. Cystic fibrosis, other bacterial lung diseases and lung cancer were the main underlying pulmonary diseases. Five patients (12.5 %) were human immunodeficiency virus (HIV) positive. The most common chest X-ray findings were reticulonodular opacities (53.3 %). Multivariate logistic regression analysis revealed that cigarette smoking history (OR 0.334, 95 % CI 0.125-0.843, P=0.048) and underlying lung disease (OR 0.393, 95 % CI 0.216-0.588, P=0.023) were significant predictors for positive M. fortuitum infection.
CONCLUSION: These results demonstrated the high frequency of M. fortuitum in respiratory samples and that this bacterium causes transient infection or colonization in patients with underlying pulmonary conditions, such as cystic fibrosis and cigarette smoking-induced. Additionally, it appears that infection with M. fortuitum is particularly common and may be important in patients with HIV.

PMID: 30052175 [PubMed - as supplied by publisher]

Dynamic changes of DNA methylation and lung disease in cystic fibrosis: lessons from a monogenic disease.

Epigenomics. 2018 Jul 27;:

Authors: Magalhães M, Tost J, Pineau F, Rivals I, Busato F, Alary N, Mely L, Leroy S, Murris M, Caimmi D, Claustres M, Chiron R, Sario A

Abstract
AIM: To assess whether DNA methylation levels account for the noninherited phenotypic variations observed among cystic fibrosis (CF) patients.
PATIENTS & METHODS: Using the 450 K BeadChip, we profiled DNA methylation in nasal epithelial cells collected from 32 CF patients and 16 controls.
RESULTS: We detected substantial DNA methylation differences up to 55% (median β change 0.13; IQR: 0.15-0.11) between CF patients and controls. DNA methylation levels differed between mild and severe CF patients and correlated with lung function at 50 CpG sites.
CONCLUSION: In CF samples, dynamic changes of DNA methylation occurred in genes responsible for the integrity of the epithelium and the inflammatory and immune responses, were prominent in transcriptionally active genomic regions and were over-represented in enhancers active in lung tissues. ( Clinicaltrials.gov NCT02884622).

PMID: 30052057 [PubMed - as supplied by publisher]

Prognostication and Risk Factors for Cystic Fibrosis via Automated Machine Learning.

Sci Rep. 2018 Jul 26;8(1):11242

Authors: Alaa AM, van der Schaar M

Abstract
Accurate prediction of survival for cystic fibrosis (CF) patients is instrumental in establishing the optimal timing for referring patients with terminal respiratory failure for lung transplantation (LT). Current practice considers referring patients for LT evaluation once the forced expiratory volume (FEV1) drops below 30% of its predicted nominal value. While FEV1 is indeed a strong predictor of CF-related mortality, we hypothesized that the survival behavior of CF patients exhibits a lot more heterogeneity. To this end, we developed an algorithmic framework, which we call AutoPrognosis, that leverages the power of machine learning to automate the process of constructing clinical prognostic models, and used it to build a prognostic model for CF using data from a contemporary cohort that involved 99% of the CF population in the UK. AutoPrognosis uses Bayesian optimization techniques to automate the process of configuring ensembles of machine learning pipelines, which involve imputation, feature processing, classification and calibration algorithms. Because it is automated, it can be used by clinical researchers to build prognostic models without the need for in-depth knowledge of machine learning. Our experiments revealed that the accuracy of the model learned by AutoPrognosis is superior to that of existing guidelines and other competing models.

PMID: 30050169 [PubMed - in process]

The overlap between bronchiectasis and chronic airways diseases: state of the art and future directions.

Eur Respir J. 2018 Jul 26;:

Authors: Polverino E, Dimakou K, Hurst J, Angel Martinez-Garcia M, Miravitlles M, Paggiaro P, Shteinberg M, Aliberti S, Chalmers JD

Abstract
Bronchiectasis is a clinical and radiological diagnosis associated with cough, sputum production and recurrent respiratory infections. The clinical presentation inevitably overlaps with other respiratory disorders such as asthma and COPD. In addition, 4% to 72% of patients with severe COPD are found to have radiological bronchiectasis on CT scanning, with similar frequencies (20-30%) now being reported in cohorts with severe or uncontrolled asthma. Co-diagnosis of bronchiectasis with another airways disease has been reported to be associated with increased lung inflammation, frequent exacerbations, worse lung function and higher mortality. In addition, many patients with all three disorders suffer from chronic rhinosinusitis and upper airway disease resulting in a complex "mixed airway" phenotype.The management of asthma, bronchiectasis, COPD and upper airway diseases has been traditionally outlined in separate guidelines for each individual disorder. Recognition that the majority of patients have one or more overlapping pathologies requires a re-evaluation of how we treat airway disease. The concept of treatable traits promotes a holistic, pathophysiology based approach to treatment rather than a syndromic approach and may be more appropriate for patients with overlapping features.Here we review the current clinical definition, diagnosis, management and future directions for the overlap between bronchiectasis and other airway diseases.

PMID: 30049739 [PubMed - as supplied by publisher]

Lung function in patients with Primary Ciliary Dyskinesia: an iPCD Cohort study.

Eur Respir J. 2018 Jul 26;:

Authors: Halbeisen FS, Goutaki M, Spycher BD, Amirav I, Behan L, Boon M, Hogg C, Casaulta C, Crowley S, Haarman EG, Karadag B, Koerner-Rettberg C, Loebinger MR, Mazurek H, Morgan L, Nielsen KG, Omran H, Santamaria F, Schwerk N, Thouvenin G, Yiallouros P, Lucas JS, Latzin P, Kuehni CE

Abstract
Primary ciliary dyskinesia (PCD) has been considered to be relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small.This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF. We calculated z-scores and percentage of predicted values for FEV1 and FVC using the Global Lung Function Initiative 2012 for 991 patients from the international PCD (iPCD) Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6-9 years had the smallest impairment (FEV1 z-score -0.84 [-1.03 to -0.65], FVC z-score -0.31 [-0.51 to -0.11]). Compared to CF patients, FEV1 was similarly reduced in children (age 6-9 years PCD, 91% [88-93%]; CF, 90% [88-91%]), but less impaired in young adults (age 18-21 years PCD, 79% [76-82%]; CF, 66% [65-68%]). The results suggest that PCD affects lung function from early in life, which emphasizes the importance of early, standardised care for all patients.

PMID: 30049738 [PubMed - as supplied by publisher]