Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS.

Beilstein J Org Chem. 2019;15:187-193

Authors: Thierbach S, Wienhold M, Fetzner S, Hennecke U

Abstract
Selectively methylated analogues of naturally occurring 2-heptyl-4(1H)-quinolones, which are alkaloids common within the Rutaceae family and moreover are associated with quorum sensing and virulence of the human pathogen Pseudomonas aeruginosa, have been prepared. While the synthesis by direct methylation was successful for 3-unsubstituted 2-heptyl-4(1H)-quinolones, methylated derivatives of the Pseudomonas quinolone signal (PQS) were synthesized from 3-iodinated quinolones by methylation and iodine-metal exchange/oxidation. The two N- and O-methylated derivatives of the PQS showed strong quorum sensing activity comparable to that of PQS itself. Staphylococcus aureus, another pathogenic bacterium often co-occurring with P. aeruginosa especially in the lung of cystic fibrosis patients, was inhibited in planktonic growth and cellular respiration by the 4-O-methylated derivatives of HQNO and HHQ, respectively.

PMID: 30745993 [PubMed]

HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants.

Hum Mol Genet. 2019 Feb 07;:

Authors: Anglès F, Hutt DM, Balch WE

Abstract
Understanding the role of the epigenome in protein misfolding diseases remains a challenge in light of genetic diversity found in the world-wide population revealed by human genome sequencing efforts and the highly variable response of the disease population to therapeutics. An ever-growing body of evidence has shown that histone deacetylase (HDAC) inhibitors (HDACi) can have significant benefit in correcting protein misfolding diseases that occur in response to both familial and somatic mutation. Cystic fibrosis (CF) is a familial autosomal recessive disease, caused by genetic diversity in the CF transmembrane conductance regulator (CFTR) gene, a cAMP-dependent chloride channel expressed at the apical plasma membrane of epithelial cells in multiple tissues. The potential utility of HDACi in correcting the phenylalanine 508 deletion (F508del) CFTR variant as well as the over 2000 CF-associated variants remains controversial. To address this concern, we examined the impact of FDA-approved HDACi on the trafficking and function of a panel of CFTR variants. Our data reveal that panobinostat (LBH-589) and romidepsin (FK-228) provide functional correction of Class II and III CFTR variants, restoring cell surface chloride channel activity in primary human bronchial epithelial (hBE) cells. We further demonstrate a synergistic effect of these HDACi with Vx809, that can significantly restore channel activity for multiple CFTR variants. These data suggest that HDACi can serve to level the cellular playing field for correcting CF-causing mutations, a leveling effect that might also extend to other protein misfolding diseases.

PMID: 30753450 [PubMed - as supplied by publisher]

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence.

Clin Infect Dis. 2019 Feb 07;:

Authors: Tan X, Coureuil M, Ramond E, Euphrasie D, Dupuis M, Tros F, Meyer J, Nemazanyy I, Chhuon C, Guerrera IC, Ferroni A, Sermet-Gaudelus I, Nassif X, Charbit A, Jamet A

Abstract
Background: Chronic lung infection of cystic fibrosis (CF) patients by Staphylococcus aureus is a well-established epidemiological fact. Indeed, S. aureus is the most commonly identified pathogen in the lungs of CF patients. Improving our understanding of the mechanisms associated with the persistence of S. aureus is therefore an important issue.
Methods: We selected pairs of sequential S. aureus isolates from 3 patients with CF and from one patient with non-CF chronic lung disease. We used a combination of genomic, proteomic and metabolomic approaches with functional assays for in-depth characterization of S. aureus long-term persistence.
Results: In this study, we show that late S. aureus isolates from CF patients have an increased ability for intracellular survival in CFBE-F508del cells compared to ancestral early isolates. Importantly, the increased ability to persist intracellularly was confirmed for S. aureus isolates within the own patient F508del epithelial cells. An increased ability to form biofilm was also demonstrated. Furthermore, we identified the underlying genetic modifications inducing altered protein expression profiles and notable metabolic changes. These modifications affect several metabolic pathways and virulence regulators that could constitute therapeutic targets.
Conclusions: Our results strongly suggest that the intracellular environment might constitute an important niche of persistence and relapse necessitating adapted antibiotic treatments.

PMID: 30753350 [PubMed - as supplied by publisher]

A decade of antimicrobial resistance in Staphylococcus aureus: A single center experience.

PLoS One. 2019;14(2):e0212029

Authors: Vicetti Miguel CP, Mejias A, Leber A, Sanchez PJ

Abstract
BACKGROUND: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) resulted in the recommended use of clindamycin and trimethoprim-sulfamethoxazole (TMP-SMX) for suspected S. aureus infections. The objective of this study was to determine the resistance to methicillin, clindamycin, and TMP-SMX in S. aureus isolates during a 10-year period.
METHODS: Retrospective review of the antimicrobial susceptibilities of all S. aureus isolates in the outpatient and inpatient settings at Nationwide Children's Hospital from 1/1/2005 to 12/31/2014. Duplicate isolates from the same site and year and those obtained for MRSA surveillance or from patients with cystic fibrosis were excluded.
RESULTS: Of the 57,788 S. aureus isolates from 2005-2014, 40,795 (71%) were included. In the outpatient setting, methicillin resistance decreased from 54% to 44% (p<0.001) while among inpatient isolates, no significant change was observed. From 2009-2014, resistance to clindamycin among outpatient isolates increased from 16% to 17% (p = 0.002) but no significant trend was observed among inpatient isolates (18% to 22%). Similarly, TMP-SMX resistance increased in outpatient S. aureus isolates from 2005-2014 (0.9% to 4%, p<0.001) but not among inpatient isolates. Among both inpatient and outpatient isolates, methicillin-susceptible S. aureus (MSSA) exhibited higher resistance to both clindamycin and TMP-SMX than MRSA. In addition, resistance to methicillin, clindamycin and TMP-SMX varied widely according to the site of specimen collection.
CONCLUSION: In a decade where >40,000 S. aureus isolates were identified at a large pediatric hospital, substantial changes in methicillin, clindamycin, and TMP-SMX resistance occurred. These findings highlight the importance of ongoing surveillance of the local antimicrobial resistance in S. aureus in order to guide empiric antimicrobial therapy.

PMID: 30753206 [PubMed - in process]

Semi-parametric Bayesian regression for subgroup analysis in clinical trials.

J Biopharm Stat. 2019 Feb 12;:1-19

Authors: Gamalo-Siebers M, Tiwari R

Abstract
Determining whether there are differential treatment effects in subgroups of trial participants remains an important topic in clinical trials as precision medicine becomes ever more relevant. Any assessment of differential treatment effect is predicated on being able to estimate the treatment response accurately while satisfying constraints of balancing the risk of overlooking an important subgroup with the potential to make a decision based on a false discovery. While regression models, such as marginal interaction model, have been widely used to improve accuracy of subgroup parameter estimates by leveraging the relationship between treatment and covariate, there is still a possibility that it can lead to excessively conservative or anti-conservative results. Conceivably, this can be due to the use of the normal distribution as a default prior, which forces outlying subjects to have their means over-shrunk towards the population mean, and the data from such subjects may be excessively influential in estimation of both the overall mean response and the mean response for each subgroup, or a model mis-specification. To address this issue, we investigate the use of nonparametric Bayes, particularly Dirichlet process priors, to create semi-parametric models. These models represent uncertainty in the prior distribution for the overall response while accommodating heterogeneity among individual subgroups. They also account for the effect and variation due to the unaccounted terms. As a result, the models do not force estimates to excessively shrink but still retain the attractiveness of improved precision given by the narrower credible intervals. This is illustrated in extensive simulations investigating bias, mean squared error, coverage probability and credible interval widths. We applied the method on a simulated data based closely on the results of a cystic fibrosis Phase 2 trial.

PMID: 30747568 [PubMed - as supplied by publisher]

Can paranasal sinus computed tomography (CT) screen for cystic fibrosis heterozygotes?

Panminerva Med. 2019 Feb 11;:

Authors: Malagutti N, Cogliandolo C, Franciosi D, Ferlini A, Rimessi P, Ravani A, Bianchini C, Ciorba A, Stomeo F, Pelucchi S

Abstract

PMID: 30747503 [PubMed - as supplied by publisher]

Impact of the Fontan operation on organ systems.

Cardiovasc Hematol Disord Drug Targets. 2019 Feb 11;:

Authors: Michel M, Zlamy M, Entenmann A, Pichler K, Scholl-Bürgi S, Karall D, Geiger R, Salvador C, Niederwanger C, Ohuchi H

Abstract
In patients having undergone the Fontan operation, besides the well discussed changes in the cardiac, pulmonary and gastrointestinal system, alterations of further organ systems including the hematologic, immunologic, endocrinological and metabolic are reported. As a medical adjunct to Fontan surgery, the systematic study of the central role of the liver as a metabolizing and synthesizing organ should allow for a better understanding of the pathomechanism underlying the typical problems in Fontan patients, and in this context the profiling of endocrinological and metabolic patterns might offer a tool for the optimization of Fontan follow-up, targeted monitoring and specific adjunct treatment.

PMID: 30747084 [PubMed - as supplied by publisher]

Role of Viscoelasticity in Bacterial Killing by Antimicrobials in Differently Grown P. aeruginosa Biofilms.

Antimicrob Agents Chemother. 2019 Feb 11;:

Authors: Rozenbaum RT, van der Mei HC, Woudstra W, de Jong ED, Busscher HJ, Sharma PK

Abstract
Pseudomonas aeruginosa colonizes the sputum of most adult cystic fibrosis patients, forming hard to eradicate biofilms, in which bacteria are protected in their self-produced EPS-matrix. EPS provides biofilms with viscoelastic properties, causing time-dependent relaxation after stress-induced deformation, according to multiple characteristic time-constants. These time-constants reflect different biofilm (matrix) components. Since viscoelasticity of biofilms has been related with antimicrobial penetration, but not yet with bacterial killing, this study aims to relate killing of P. aeruginosa in its biofilm-mode of growth by three antimicrobials with biofilm viscoelasticity. P. aeruginosa biofilms were grown for 18 h in a constant depth film fermenter, either with mucin-containing artificial sputum medium (ASM+), artificial sputum medium without mucin (ASM-), or Luria-Bertani broth (LB). This yielded 100 μm thick biofilms, that differed in their amounts of matrix eDNA and polysaccharides. Low-load-compression-testing followed by three-element Maxwell analyses, showed that the fastest relaxation component, associated with unbound water, was most important in LB-grown biofilms. Slower components due to water with dissolved polysaccharides, insoluble polysaccharides and eDNA, were most important in relaxation of ASM+-grown biofilms. ASM--grown biofilms showed intermediate stress relaxation. P. aeruginosa in LB-grown biofilms were killed most by exposure to tobramycin, colistin or an antimicrobial peptide, while ASM+ provided the most protective matrix with less water and most insoluble polysaccharides and eDNA. Concluding, stress relaxation of P. aeruginosa biofilms grown in different media revealed differences in matrix composition that, within the constraints of the antimicrobials and growth media applied, correlated with the matrix protection offered against different antimicrobials.

PMID: 30745390 [PubMed - as supplied by publisher]

Characterization of hypermutator Pseudomonas aeruginosa isolates from patients with cystic fibrosis in Australia.

Antimicrob Agents Chemother. 2019 Feb 11;:

Authors: Rees VE, Deveson Lucas DS, López-Causapé C, Huang Y, Kotsimbos T, Bulitta JB, Rees MC, Barugahare A, Peleg AY, Nation RL, Oliver A, Boyce JD, Landersdorfer CB

Abstract
Hypermutable Pseudomonas aeruginosa isolates (hypermutators) have been identified in patients with cystic fibrosis (CF). Hypermutators display a greatly increased mutation rate, an enhanced ability to become resistant to antibiotics during treatment and are associated with reduced lung function in patients. Their prevalence has been established amongst patients with CF, but has not been determined for patients with CF in Australia. This study aimed to determine the prevalence of hypermutable P. aeruginosa isolates from adult patients with CF from a healthcare institution in Australia, and to characterize the genetic diversity and antibiotic susceptibility of these isolates. A total of 59 P. aeruginosa clinical isolates from patients with CF were characterized. For all isolates, rifampicin mutation frequencies and susceptibility to a range of antibiotics were determined. Of the 59 isolates, 13 (22%) were hypermutable. Whole genome sequences were determined for all hypermutable isolates. Core genome polymorphisms were used to assess genetic relatedness of the isolates, both to each other and to a sample of previously characterized P. aeruginosa strains. Phylogenetic analyses showed that the hypermutators were from divergent lineages and hypermutator phenotype was mostly the result of mutations in mutL, or less commonly mutS Hypermutable isolates also contained a range of mutations likely associated with adaptation of P. aeruginosa to the CF lung environment. Multidrug-resistance was greater for hypermutable than non-hypermutable isolates (38% vs 22%). This study revealed that hypermutable P. aeruginosa are common among isolates from patients with CF in Australia and are implicated in the emergence of antibiotic resistance.

PMID: 30745381 [PubMed - as supplied by publisher]

How reliable is your HbA1c test? Revisiting the use of HbA1c in cystic fibrosis-related diabetes (CFRD) screening.

J Cyst Fibros. 2019 Feb 08;:

Authors: Lam GY, Sissons S, Smith MP, Brown NE, Leung WM, Estey MP

PMID: 30745235 [PubMed - as supplied by publisher]

Fungal epidemiology in cystic fibrosis patients with a special focus on Scedosporium species complex.

Microb Pathog. 2019 Feb 08;:

Authors: Hedayati MT, Tavakoli M, Maleki M, Heidari S, Mortezaee V, Gheisari M, Hassanzad M, Mirenayat MS, Mahdaviani SA, Pourabdollah M, Velayati AA, Vakili M, Abastabar M, Haghani I, Jafarzadeh J, Hedayati N, Seyedmousavi S, Alastruey-Izquierdo A

Abstract
In this present study, for the first time, we evaluated the cystic fibrosis (CF) patients for the Scedosporium species and their antifungal susceptibility against eight antifungal agents. During one-year period, 90 Sputum samples were collected from Iranian CF patients. All samples were evaluated by direct microscopic examination, culture onto four different media including Malt extract agar, Inhibitory mold agar, Brain Heart Infusion and Scedo-Select III. The mold isolated fungi were identified by PCR-Sequencing of ITS and β-tubulin genes. In-vitro antifungal susceptibility was performed according to the Clinical & Laboratory Standards Institute (CLSI) M38-A2 guidelines. Out of 90 CF patients, 47 (52.2%) were male. The age of the patients ranged from 1 to 34 years (median of 15.84 ± 7.41 years). Overall, 3 (3.3%) cases were positive for Scedosporium spp. of which two isolates were characterized as Scedosporium boydii and one isolate as S. ellipsoideum. Among Aspergillus genus, A. flavus (29.4%) was the most prevalent species followed by A. tubingensis (24.7%), A. niger (17.0%) and A. fumigatus (14.5%). The minimum effective concentration ranges of micafungin, anidulafungin, and caspofungin were 0.008-0.031 μg/mL, 0.0625-0.25 μg/mL, and 0.0625-0.25 μg/mL, respectively. All isolates of Scedosporium species showed high minimum inhibitory concentration to the triazoles tested, except voriconazole. Our results showed that A. flavus and Scedosporium species are the most prevalent molds isolated from CF patient populations in Iran. Our findings have also showed that Scedo-Select III can be used as a reliable culture media for isolation of Scedosporium spp. in clinical samples.

PMID: 30742949 [PubMed - as supplied by publisher]

A Flow Cytometric Method for Isolating Cystic Fibrosis Airway Macrophages from Expectorated Sputum.

Am J Respir Cell Mol Biol. 2019 Feb 11;:

Authors: Hisert KB, Liles WC, Manicone AM

Abstract
Research to understand the contribution of macrophages to non-resolving airway inflammation in cystic fibrosis (CF) and other chronic suppurative airways diseases has been hindered by a lack of methods for isolating and studying theses cells. With the development of technologies that can characterize small numbers of cells or individual cells, there is an even greater need for methodologies to isolate rare cells in heterogeneous specimens. Here, we describe a method that overcomes the technical obstacles imposed by sputum debris and apoptotic cells, and allows isolation of pure populations of macrophages from CF sputum. In addition to enhancing our ability to study human CF airway macrophages, this protocol can be adapted to study cells in sputum from other chronic suppurative lung diseases (e.g., COPD), and used for isolation of individual cells for single cell analyses.

PMID: 30742539 [PubMed - as supplied by publisher]

Pendrin Mediates Bicarbonate Secretion and Enhances CFTR Function in Airway Surface Epithelia.

Am J Respir Cell Mol Biol. 2019 Feb 11;:

Authors: Kim D, Huang J, Billet A, Abu-Arish A, Goepp J, Matthes E, Tewfik MA, Frenkiel S, Hanrahan JW

Abstract
Bicarbonate facilitates mucin unpacking and bacterial killing however its transport mechanisms in the airways are not well understood. cAMP stimulates anion efflux through the CFTR (ABCC7) anion channel and this is defective in CF. The anion exchanger pendrin (SLC26A4) also mediates HCO3- efflux and is upregulated by proinflammatory cytokines. Here we examined pendrin and CFTR expression and their contributions to HCO3- secretion by human nasal and bronchial epithelia. In native tissue, both proteins were most abundant at the apical pole of ciliated surface cells with little expression in submucosal glands. In well-differentiated primary nasal and bronchial cell cultures, IL-4 dramatically increased pendrin mRNA levels and apical immunostaining. Exposure to low-Cl- apical solution caused intracellular alkalinization (ΔpHi) that was enhanced 4-fold by IL-4 pretreatment. ΔpHi was unaffected by DIDS or CFTRinh-172 but was reduced by adenoviral shRNA targeting pendrin. Forskolin increased ΔpHi and this stimulation was prevented by CFTRinh-172 implicating CFTR, yet forskolin only increased ΔpHi after pendrin expression had been induced by IL-4. The dependence of ΔpHi on pendrin suggests there is minimal electrical coupling between Cl- and HCO3- fluxes and that CFTR activation increases anion exchange-mediated HCO3- influx. Conversely, inducing pendrin expression increased forskolin-stimulated, CFTRinh-172-sensitive current by ~2-fold in epithelial and non-epithelial cells. We conclude that pendrin mediates most HCO3- secretion across airway surface epithelium during inflammation and enhances electrogenic Cl- secretion via CFTR as described for other SLC26A transporters.

PMID: 30742493 [PubMed - as supplied by publisher]

Metabolic Adaptation Supports Persistent Methicillin-Resistant Staphylococcus aureus Pulmonary Infection.

Am J Respir Cell Mol Biol. 2019 Feb 11;:

Authors: Gabryszewski SJ, Wong Fok Lung T, Annavajhala MK, Tomlinson KL, Riquelme SA, Khan IN, Noguera LP, Wickersham M, Zhao A, Mulenos AM, Peaper D, Koff JL, Uhlemann AC, Prince A

Abstract
RATIONALE: Methicillin-resistant Staphylococcus aureus (MRSA) is a versatile human pathogen associated with diverse types of infections, ranging from benign colonization to sepsis. We postulated that MRSA must undergo specific genotypic and phenotypic changes to cause chronic pulmonary disease.
OBJECTIVES: We investigated how MRSA adapts to the human airway to establish chronic infection, as occurs during cystic fibrosis (CF).
METHODS: MRSA isolates from patients with cystic fibrosis collected over a four-year period were analyzed by whole-genome sequencing, transcriptional analysis, and metabolic studies.
MEASUREMENTS AND MAIN RESULTS: Persistent MRSA infection was associated with staphylococcal metabolic adaptation, not changes in immunogenicity. Adaptation was characterized by selective use of the TCA cycle and generation of biofilm, a means of limiting oxidant stress. Increased transcription of specific metabolic genes was conserved in all host-adapted strains, most notably a 10,000-fold increase in fumC that catalyzes the interconversion of fumarate and malate. Elevated fumarate levels promoted in vitro biofilm production in clinical isolates. Host-adapted strains preferred to assimilate glucose polymers and pyruvate, which can be metabolized to generate N-acetylglucosamine polymers that comprise biofilm.
CONCLUSIONS: MRSA undergoes substantial metabolic adaptation to the human airway to cause chronic pulmonary infection, and selected metabolites may be useful therapeutically to inhibit infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/.

PMID: 30742488 [PubMed - as supplied by publisher]

Standard and Specialized Infant Formulas in Europe: Making, Marketing, and Health Outcomes.

Nutr Clin Pract. 2019 Feb 11;:

Authors: Dipasquale V, Serra G, Corsello G, Romano C

Abstract
Infant formulas are the only suitable substitute for human milk. The most common infant formulas are standard formulas based on cow's milk. In addition, there are formulas for infants showing signs and symptoms of intolerance and for clinical conditions such as allergy, prematurity, and gastrointestinal diseases. A comprehensive review of the literature was made to review the composition of standard and specialized infant formulas and analyze indications for use, real or presumed nutrition differences and properties, and impact on infant growth. A brief consideration on costs is outlined for each formula. Over the past few years, industrial production and advertising of infant formulas have increased. Human milk still remains the most complete source of nutrition for infants and should be continued according to the current recommendations. Few differences exist between infant formulas, both for the nutrition action and the macronutrient/micronutrient composition. Specialized infant formulas have limited indications for use and high costs. The role of the pediatrician is crucial in the management of infant nutrition, promotion of breastfeeding, and prescribing of specialized formulas only in specific clinical conditions.

PMID: 30742336 [PubMed - as supplied by publisher]

Thirty Years of Lactobacillus rhamnosus GG: A Review.

J Clin Gastroenterol. 2019 Mar;53 Suppl 1:S1-S41

Authors: Capurso L

Abstract
Lactobacillus rhamnosus GG (LGG) was the first strain belonging to the genus Lactobacillus to be patented in 1989 thanks to its ability to survive and to proliferate at gastric acid pH and in medium containing bile, and to adhere to enterocytes. Furthermore LGG is able to produces both a biofilm that can mechanically protect the mucosa, and different soluble factors beneficial to the gut by enhancing intestinal crypt survival, diminishing apoptosis of the intestinal epithelium, and preserving cytoskeletal integrity. Moreover LGG thanks to its lectin-like protein 1 and 2 inhibits some pathogens such as Salmonella species. Finally LGG is able to promote type 1 immune-responsiveness by reducing the expression of several activation and inflammation markers on monocytes and by increasing the production of interleukin-10, interleukin-12 and tumor necrosis factor-α in macrophages. A large number of research data on Lactobacillus GG is the basis for the use of this probiotic for human health. In this review we have considered predominantly randomized controlled trials, meta-analysis, Cochrane Review, guide lines of Scientific Societies and anyway studies whose results were evaluated by means of relative risk, odds ratio, weighted mean difference 95% confidence interval. The effectiveness of LGG in gastrointestinal infections and diarrhea, antibiotic and Clostridium difficile associated diarrhea, irritable bowel syndrome, inflammatory bowel disease, respiratory tract infections, allergy, cardiovascular diseases, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cystic fibrosis, cancer, elderly end sport were analyzed.

PMID: 30741841 [PubMed - in process]

Cystic fibrosis related diabetes is not independently associated with increased Stenotrophomonas maltophilia infection: Longitudinal data from the UK CF Registry.

J Cyst Fibros. 2018 Oct 25;:

Authors: Frost F, Nazareth D, Shaw M, Walshaw MJ

Abstract
INTRODUCTION: Stenotrophomonas maltophilia is common in the sputum of people with cystic fibrosis related diabetes (CFRD), raising the question as to whether this is a risk factor for its acquisition. We investigated this at a population level.
METHODS: We analysed national Cystic Fibrosis Registry data 2011-2015 for 8047 people with CF > age 6 years, looking at demographics, diagnosis of CFRD, lung function and sputum microbiology; using descriptive and multivariate strategies to establish independent predictors for S. maltophilia culture and associated outcomes.
RESULTS: S. maltophilia was present in 1148 (14.1%). Although univariate analysis confirmed it was more prevalent in those with CFRD, when adjusted for other clinical parameters there was no longer a relationship. Markers of more severe lung disease were independent risk-factors for S. maltophilia.
CONCLUSION: Although S. maltophilia is more common in people with CFRD, it is not an independent risk-factor for S. maltophilia acquisition.

PMID: 30741162 [PubMed - as supplied by publisher]

Kilquist Syndrome: A Novel Syndromic Hearing Loss Disorder Caused by Homozygous Deletion of SLC12A2.

Hum Mutat. 2019 Feb 10;:

Authors: Macnamara EF, Koehler AE, D'Souza P, Estwick T, Lee P, Vezina G, Members of the Undiagnosed Diseases Network, Fauni H, Braddock SR, Torti E, Holt JM, Sharma P, Malicdan MCV, Tifft CJ

Abstract
Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22kb homozygous deletion in SLC12A2, which encodes for a sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared to control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with described phenotype of the Slc12a2 knockout mouse model, our results suggest that absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues. This article is protected by copyright. All rights reserved.

PMID: 30740830 [PubMed - as supplied by publisher]

High-flow oxygen therapy for the management of patients with acute exacerbation of cystic fibrosis.

Ann Transl Med. 2018 Dec;6(Suppl 2):S113

Authors: Thille AW, Joly F, Marjanovic N, Frat JP

PMID: 30740434 [PubMed]

SERPINA1 Z allele is associated with cystic fibrosis liver disease.

Genet Med. 2019 Feb 11;:

Authors: Boëlle PY, Debray D, Guillot L, Corvol H, French CF Modifier Gene Study Investigators

Abstract
PURPOSE: The SERPINA1 Z allele is associated with cystic fibrosis (CF)-related liver disease (CFLD), a common manifestation in patients with CF. We estimated CFLD incidence based on the SERPINA1 genotype in 3328 CF patients with CFLD-phenotype information.
METHODS: The associations of SERPINA1 Z (rs28929474) and S (rs17580) alleles with age at CFLD onset and the development of CFLD-related complications (severe liver disease with cirrhosis, portal hypertension, esophageal varices) were analyzed.
RESULTS: Overall, 3% of patients carried the SERPINA1 Z allele and 13% carried the S allele. The cumulative incidence of CFLD increased more rapidly in patients carrying the Z allele (hazard ratio [HR] = 1.6; 95% confidence interval [CI] = 1.1-2.4, P = 0.019), reaching 47% by age 25 compared with 30% in noncarriers. Increased risk was similar for patients with severe CFLD (HR = 1.5, 95% CI = 0.7-3.2, P = 0.31) but failed to reach significance due to a limited sample size of Z-allele carriers. No significant effect was found for the S allele.
CONCLUSION: CF patients carrying the SERPINA1 Z allele had an increased risk of developing CFLD and related complications compared with noncarriers. Routine SERPINA1 Z genotyping upon CF diagnosis is warranted for identifying patients worthy of closer liver disease monitoring.

PMID: 30739910 [PubMed - as supplied by publisher]