Cystic fibrosis transmembrane conductance regulator modulates enteric cholinergic activities and is abnormally expressed in the enteric ganglia of patients with slow transit constipation.

J Gastroenterol. 2019 Aug 07;:

Authors: Yeh KM, Johansson O, Le H, Rao K, Markus I, Perera DS, Lubowski DZ, King DW, Zhang L, Chen H, Liu L

Abstract
BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) was recently found in the enteric nervous system, where its role is unclear. We aimed to identify which enteric neuronal structures express CFTR, whether CFTR modulates enteric neurotransmission and if altered CFTR expression is associated with slow transit constipation (STC).
METHODS: Immunofluorescence double labeling was performed to localize CFTR with various neuronal and glial cell markers in the human colon. The immunoreactivity (IR) of CFTR and choline acetyltransferase (ChAT) on myenteric plexus of control and STC colon was quantitatively analyzed. In control colonic muscle strips, electrical field stimulation (EFS) evoked contractile responses and the release of acetylcholine (ACh) was measured in the presence of the CFTR channel inhibitor, CFTR(inh)-172.
RESULTS: CFTR-IR was densely localized to myenteric ganglia, where it was co-localized with neuronal markers HuC/D and β-tubulin, and glial marker S-100 but little with glial fibrillary acidic protein. Vesicular ACh transport was almost exclusively co-localized with CFTR, but neurons expressing nitric oxide synthase were CFTR negative. Significant reductions of CFTR-IR (P < 0.01) and ChAT-IR (P < 0.05) were observed on myenteric ganglia of STC compared to control. Pre-treatment of colonic muscle strips with CFTR(inh)-172 (10 µM) significantly inhibited EFS-evoked contractile responses (P < 0.01) and ACh release (P < 0.05).
CONCLUSIONS: Co-localization of CFTR-IR with cholinergic markers, inhibition of EFS-induced colonic muscle contractility and ACh release by CFTR(inh)-172 suggest that CFTR modulates enteric cholinergic neurotransmission. The downregulation of CFTR and ChAT in myenteric ganglia of STC correlated with the impaired contractile responses to EFS.

PMID: 31392489 [PubMed - as supplied by publisher]

Cystic Fibrosis Gene Mutation Frequency Among a Group of Suspected Children in King Hussein Medical Center.

Med Arch. 2019 Apr;73(2):118-120

Authors: Al-Abadi B, Al-Hiary M, Khasawneh R, Al-Momani A, Bani-Salameh A, Al-Saeidat S, Al-Khlaifat A, Aboalsondos O

Abstract
Introduction: Cystic fibrosis (CF) is a genetic multisystem disorder that affects mostly the lungs, but other organs such as liver, pancreas and intestine also affected. CF is inherited in an autosomal recessive manner and occurs in males and females equally. Cystic fibrosis Transmembrane Conductance Regulator (CFTR) mutations are classified into five classes. Class 1 (non-functional protein), class 2 (near-absence of mature CFTR protein at the apical cell membrane), class 3 (full-length CFTR protein incorporated into the cell membrane), class 4 (reduced conductance CFTR mutation), and class 5 (reduced amount of CFTR protein with normal function). Globally F508 mutation is the most common.
Aim: The aim of this study was to determine the frequency of CFTR gene mutation in Jordanian populations attending a major hospital (KHMC).
Material and Methods: This is a retrospective study was conducted on 777 sera samples for patients clinically suspected to have cystic fibrosis over a six year period 1/1/2013-1/10/2018. The patient's age range between 1year and 33 years, of which 59.2% (460) were male and 40.8% (317) female. Blood samples were analyzed at Princess Iman Centre for Research and Laboratory Sciences at King Hussein Medical Centre. The samples were tested for 34 mutations of CFTR gene using CF Strip Assay VIENNA LAB Diagnostics GmbH, Austria by polymerase chain reaction (PCR).
Results: A total of 777 patients samples were analyzed for cystic gene mutations. Twelve (12) mutations were identified. In 49 patients (6.3%) were heterozygous genotype mutant and 28 (3.6%) were homozygous. The most frequent mutation F508del was found in 32/77 (41.5%). 20 (25.9%) of them were heterozygous genotype mutant and 12 (15.6%) were homozygous genotype mutant. The second frequent mutation was N1303K with frequency rate 15.6% (12/77), 9 (11.7%) of them were heterozygous and 3 (3.9%) were homozygous. Regarding frequency of cystic fibrosis gene mutation depending on sex, 55.8% (43/77) of mutations were found in male, whereas 44.2% (34/77) in female.
Conclusion: Our findings suggest that cystic fibrosis in Jordan is not a rare disease, and found that the most frequent CFTR gene mutation was F508del, which is in keeping with results from other Mediterranean countries.

PMID: 31391700 [PubMed - in process]

Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing.

Nat Commun. 2019 Aug 07;10(1):3556

Authors: Maule G, Casini A, Montagna C, Ramalho AS, De Boeck K, Debyser Z, Carlon MS, Petris G, Cereseto A

Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 3272-26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 3272-26A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases.

PMID: 31391465 [PubMed - in process]

Niclosamide repurposed for the treatment of inflammatory airway disease.

JCI Insight. 2019 Aug 08;4(15):

Authors: Cabrita I, Benedetto R, Schreiber R, Kunzelmann K

Abstract
Inflammatory airway diseases, such as asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD), are characterized by mucus hypersecretion and airway plugging. In both CF and asthma, enhanced expression of the Ca2+-activated Cl- channel TMEM16A is detected in mucus-producing club/goblet cells and airway smooth muscle. TMEM16A contributes to mucus hypersecretion and bronchoconstriction, which are both inhibited by blockers of TMEM16A, such as niflumic acid. Here we demonstrate that the FDA-approved drug niclosamide, a potent inhibitor of TMEM16A identified by high-throughput screening, is an inhibitor of both TMEM16A and TMEM16F. In asthmatic mice, niclosamide reduced mucus production and secretion, as well as bronchoconstriction, and showed additional antiinflammatory effects. Using transgenic asthmatic mice, we found evidence that TMEM16A and TMEM16F are required for normal mucus production/secretion, which may be due to their effects on intracellular Ca2+ signaling. TMEM16A and TMEM16F support exocytic release of mucus and inflammatory mediators, both of which are blocked by niclosamide. Thus, inhibition of mucus and cytokine release, bronchorelaxation, and reported antibacterial effects make niclosamide a potentially suitable drug for the treatment of inflammatory airway diseases, such as CF, asthma, and COPD.

PMID: 31391337 [PubMed - in process]

Intranasal micro-optical coherence tomography imaging for cystic fibrosis studies.

Sci Transl Med. 2019 Aug 07;11(504):

Authors: Leung HM, Birket SE, Hyun C, Ford TN, Cui D, Solomon GM, Shei RJ, Adewale AT, Lenzie AR, Fernandez-Petty CM, Zheng H, Palermo JH, Cho DY, Woodworth BA, Yonker LM, Hurley BP, Rowe SM, Tearney GJ

Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance.

PMID: 31391319 [PubMed - in process]

Nebulized hypertonic saline in noncystic fibrosis bronchiectasis: a comprehensive review.

Ther Adv Respir Dis. 2019 Jan-Dec;13:1753466619866102

Authors: Máiz Carro L, Martínez-García MA

Abstract
Bronchiectasis occurs as a result of a vicious circle consisting of an impaired mucociliary transport system, inflammation, and infection and repair of the airways. Damage to the mucociliary system prevents secretion elimination and facilitates bacterial growth and bronchial inflammation. To facilitate mucociliary clearance, current guidelines recommend the use of hypertonic saline (HS) solutions in patients with bronchiectasis not secondary to cystic fibrosis (CF), although the evidence of efficacy in this pathology is sparse. A high percentage of patients with CF and bronchiectasis tolerate HS solutions, but often patients report cough, dyspnoea, throat irritation, or salty taste after inhalation. These adverse effects negatively impact adherence to treatment, which sometimes must be discontinued. Some studies have shown that the addition of hyaluronic acid increases the tolerability of HS solutions, both in patients with CF and in bronchiectasis of other etiologies. We aimed to review the benefits and safety of HS solutions in patients with bronchiectasis. The reviews of this paper are available via the supplemental material section.

PMID: 31390940 [PubMed - in process]

Protein and lipid interactions - Modulating CFTR trafficking and rescue.

J Cyst Fibros. 2018 03;17(2S):S9-S13

Authors: Farinha CM, Miller E, McCarty N

Abstract
Different levels of CFTR regulation in the cell contribute to a stringent control of chloride secretion in epithelia. Tuning of chloride transport is achieved by modulating CFTR biogenesis, exit from the endoplasmic reticulum, trafficking, membrane stability and channel activity. In this short review, we summarize recent findings identifying interactions with other proteins - directly or through membrane lipids - and briefly discuss how these observations can provide clues to the design of better therapeutic approaches.

PMID: 28887112 [PubMed - indexed for MEDLINE]

Alginate/Chitosan Particle-Based Drug Delivery Systems for Pulmonary Applications.

Pharmaceutics. 2019 Aug 02;11(8):

Authors: Hill M, Twigg M, Sheridan EA, Hardy JG, Elborn JS, Taggart CC, Scott CJ, Migaud ME

Abstract
Cystic fibrosis (CF) is a complex, potentially life-threatening disease that is most effectively treated through the administration of antibiotics (e.g., colistimethate sodium). Chronic infection with Pseudomonas aeruginosa is one of the most significant events in the pathogenesis of cystic fibrosis, and tobramycin is the treatment of choice for those patients with chronic P. aeruginosa infection who are deteriorating despite regular administration of colistimethate sodium. Effective treatment can be challenging due to the accumulation of thickened mucus in the pulmonary environment, and here we describe the results of our investigation into the development of alginate/chitosan particles prepared via precipitation for such environments. Tobramycin loading and release from the alginate/chitosan particles was investigated, with evidence of both uptake and release of sufficient tobramycin to inhibit P. aeruginosa in vitro. Functionalisation of the alginate/chitosan particles with secretory leukocyte protease inhibitor (SLPI) was shown to help inhibit the inflammatory response associated with lung infections (via inhibition of neutrophil elastase activity) and enhance their interaction with cystic fibrosis mucus (assayed via reduction of the depth of particle penetration into the mucus) in vitro, which have prospects to enhance their efficacy in vivo.

PMID: 31382357 [PubMed]

Prevalence and risk factors for Enterobacteriaceae in patients hospitalized with community-acquired pneumonia.

Respirology. 2019 Aug 05;:

Authors: Villafuerte D, Aliberti S, Soni NJ, Faverio P, Marcos PJ, Wunderink RG, Rodriguez A, Sibila O, Sanz F, Martin-Loeches I, Menzella F, Reyes LF, Jankovic M, Spielmanns M, Restrepo MI, GLIMP Investigators

Abstract
BACKGROUND AND OBJECTIVE: Enterobacteriaceae (EB) spp. family is known to include potentially multidrug-resistant (MDR) microorganisms, and remains as an important cause of community-acquired pneumonia (CAP) associated with high mortality. The aim of this study was to determine the prevalence and specific risk factors associated with EB and MDR-EB in a cohort of hospitalized adults with CAP.
METHODS: We performed a multinational, point-prevalence study of adult patients hospitalized with CAP. MDR-EB was defined when ≥3 antimicrobial classes were identified as non-susceptible. Risk factors assessment was also performed for patients with EB and MDR-EB infection.
RESULTS: Of the 3193 patients enrolled with CAP, 197 (6%) had a positive culture with EB. Fifty-one percent (n = 100) of EB were resistant to at least one antibiotic and 19% (n = 38) had MDR-EB. The most commonly EB identified were Klebsiella pneumoniae (n = 111, 56%) and Escherichia coli (n = 56, 28%). The risk factors that were independently associated with EB CAP were male gender, severe CAP, underweight (body mass index (BMI) < 18.5) and prior extended-spectrum beta-lactamase (ESBL) infection. Additionally, prior ESBL infection, being underweight, cardiovascular diseases and hospitalization in the last 12 months were independently associated with MDR-EB CAP.
CONCLUSION: This study of adults hospitalized with CAP found a prevalence of EB of 6% and MDR-EB of 1.2%, respectively. The presence of specific risk factors, such as prior ESBL infection and being underweight, should raise the clinical suspicion for EB and MDR-EB in patients hospitalized with CAP.

PMID: 31385399 [PubMed - as supplied by publisher]

Review of the British Thoracic Society Winter Meeting 2018, 5-7 December 2018, London, UK.

Thorax. 2019 Aug 05;:

Authors: Goodwin AT, Singanayagam A, Jenkins G

Abstract
INTRODUCTION: The Winter Meeting of the British Thoracic Society (BTS) is a platform for the latest clinical and scientific research in respiratory medicine. This review summarises some key symposia and presentations from the BTS Winter Meeting 2018.
METHODS: Key symposia and research presentations from the BTS Winter Meeting 2018 were attended and reviewed by the authors.
RESULTS: The seminal messages from the latest clinical and scientific research covering a range of respiratory diseases, including asthma, interstitial lung disease, infection, cystic fibrosis, pulmonary vascular disease, pleural disease and occupational lung disease were summarised in this review.
DISCUSSION: The BTS Winter Meeting 2018 brought the very best of respiratory research to an audience of scientists, physicians, nurses and allied health professionals. The Winter Meeting continues to be a highlight of the UK respiratory research calendar, and we look forward to the next meeting in December 2019.

PMID: 31383777 [PubMed - as supplied by publisher]

Potentiation of aminoglycoside lethality by C4-dicarboxylates requires RpoN in antibiotic tolerant Pseudomonas aeruginosa.

Antimicrob Agents Chemother. 2019 Aug 05;:

Authors: Hall CW, Farkas E, Zhang L, Mah TF

Abstract
Antibiotic tolerance contributes to the inability of standard antimicrobial therapies to clear the chronic Pseudomonas aeruginosa lung infections that often afflict patients with cystic fibrosis (CF). Metabolic potentiation of bactericidal antibiotics with carbon sources has emerged as a promising strategy to re-sensitise tolerant bacteria to antibiotic killing. Fumarate (FUM), a C4-dicarboxylate, has been recently shown to re-sensitise tolerant P. aeruginosa to killing by tobramycin (TOB), an aminoglycoside antibiotic, when used in combination (TOB+FUM). Fumarate and other C4-dicarboxylates are taken up intracellularly by transporters regulated by the alternative sigma factor, RpoN. Once in the cell, FUM is metabolised, leading to enhanced electron transport chain activity, regeneration of the proton motive force, and increased TOB uptake. In this work, we demonstrate that a ΔrpoN mutant displays impaired FUM uptake and, consequently, non-susceptibility to TOB+FUM treatment. RpoN was also found to be essential for susceptibility to other aminoglycoside and C4-dicarboxylate combinations. Importantly, RpoN loss-of-function mutations have been documented to evolve in the CF lung, and these loss-of-function alleles can also result in TOB+FUM non-susceptibility. In a mixed genotype population of wildtype and ΔrpoN cells, TOB+FUM specifically killed cells with RpoN function and spared the cells that lacked RpoN function. Unlike C4-dicarboylates, both D-glucose and L-arginine were able to potentiate TOB killing of ΔrpoN stationary phase cells. Our findings raise the question of whether TOB+FUM will be a suitable treatment option in the future for CF patients infected with P. aeruginosa isolates that lack RpoN function.

PMID: 31383655 [PubMed - as supplied by publisher]

Targeted Activation of Cystic Fibrosis Transmembrane Conductance Regulator.

Mol Ther. 2019 Jul 15;:

Authors: Villamizar O, Waters SA, Scott T, Saayman S, Grepo N, Urak R, Davis A, Jaffe A, Morris KV

Abstract
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The majority of CFTR mutations result in impaired chloride channel function as only a fraction of the mutated CFTR reaches the plasma membrane. The development of a therapeutic approach that facilitates increased cell-surface expression of CFTR could prove clinically relevant. Here, we evaluate and contrast two molecular approaches to activate CFTR expression. We find that an RNA-guided nuclease null Cas9 (dCas9) fused with a tripartite activator, VP64-p65-Rta can activate endogenous CFTR in cultured human nasal epithelial cells from CF patients. We also find that targeting BGas, a long non-coding RNA involved in transcriptionally modulating CFTR expression with a gapmer, induced both strong knockdown of BGas and concordant activation of CFTR. Notably, the gapmer can be delivered to target cells when generated as electrostatic particles with recombinant HIV-Tat cell penetrating peptide (CPP), when packaged into exosomes, or when loaded into lipid nanoparticles (LNPs). Treatment of patient-derived human nasal epithelial cells containing F508del with gapmer-CPP, gapmer-exosomes, or LNPs resulted in increased expression and function of CFTR. Collectively, these observations suggest that CRISPR/dCas-VPR (CRISPR) and BGas-gapmer approaches can target and specifically activate CFTR.

PMID: 31383454 [PubMed - as supplied by publisher]

Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility.

Elife. 2018 02 02;7:

Authors: Zhang DL, Sun YJ, Ma ML, Wang YJ, Lin H, Li RR, Liang ZL, Gao Y, Yang Z, He DF, Lin A, Mo H, Lu YJ, Li MJ, Kong W, Chung KY, Yi F, Li JY, Qin YY, Li J, Thomsen ARB, Kahsai AW, Chen ZJ, Xu ZG, Liu M, Li D, Yu X, Sun JP

Abstract
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.

PMID: 29393851 [PubMed - in process]

The outcomes of 80 lung transplants in a single center from Saudi Arabia.

Ann Saudi Med. 2019 Jul-Aug;39(4):221-228

Authors: Akram S, Nizami IY, Hussein M, Saleh W, Ismail MS, AlKattan K, Rajput MSA

Abstract
BACKGROUND: Lung transplantation has become a standard of care for a select group of patients with advanced lung diseases. Lung transplantation has undergone rapid growth in the last few years in Saudi Arabia.
OBJECTIVE: Describe five years of experience with lung transplantation.
DESIGN: Retrospective, descriptive.
SETTINGS: Major tertiary care hospital.
PATIENTS: All patients who underwent lung transplant surgery between 2010 to 2015.
MAIN OUTCOME MEASURES: Indications for lung transplant demographics, body mass index, blood group, type of transplant surgery, morbidity rate using the Clavien-Dindo classification, rate of early- and late-onset bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans-free survival, 30- and 90-day mortality rate, and survival (30 days, 90 days, 1-year, 3-years and 5-years) for lung transplant recipients. The duration of mechanical ventilation, colonization by bacteria and need for lung volume reduction surgery for lung donors.
SAMPLE SIZE: 80, 45% women and 55% men.
RESULTS: The most common indication for lung transplant in Saudi Arabia is pulmonary fibrosis (45%), followed by non-cystic fibrosis bronchiectasis (25%) and cystic fibrosis-related bronchiectasis (20%). Only 45% of our lung transplant recipients had a normal BMI (18-28 kg/m2). The most frequent blood group was A (40%), followed by blood group O (32.5%). Most (85%) lung transplants were bilateral while 15% were single lung transplants. Postoperative complications developed in 64 patients, 34 (42.5%) had minor grade 1 complications, while 13 (16.5%) had severe complications leading to death (grade V). Early onset BOS developed in 6 (7.5%) patients while 16 (20%) had late onset BOS. The BOS-free survival rate was 72.5%. The mean duration of mechanical ventilation in lung donors was 9 days and most were infected by bacteria. The majority of recipients required lung volume reduction. The 30-day mortality rate was 12.5% and the 90-day mortality rate was 17.5%. Survival rates at our center were 87.5% at 30 days, 82.5% at 90 days, 81.2% at 1 year, 67.9% at 2 years and 62.1% at 5 years.
CONCLUSIONS: Lung transplantation has become an invaluable approach for the treatment of end-stage respiratory disease. Our 5-year experience has shown exciting promises for lung transplantation in Saudi Arabia.
LIMITATIONS: Retrospective design, single center experience.
CONFLICT OF INTEREST: None.

PMID: 31381371 [PubMed - in process]

Regulation of Pseudomonas aeruginosa-Mediated Neutrophil Extracellular Traps.

Front Immunol. 2019;10:1670

Authors: Skopelja-Gardner S, Theprungsirikul J, Lewis KA, Hammond JH, Carlson KM, Hazlett HF, Nymon A, Nguyen D, Berwin BL, Hogan DA, Rigby WFC

Abstract
Pseudomonas aeruginosa is the most prevalent opportunistic pathogen in the airways of cystic fibrosis (CF) patients. The pulmonary disorder is characterized by recurrent microbial infections and an exaggerated host inflammatory immune response led primarily by influx of neutrophils. Under these conditions, chronic colonization with P. aeruginosa is associated with diminished pulmonary function and increased morbidity and mortality. P. aeruginosa has a wide array of genetic mechanisms that facilitate its persistent colonization of the airway despite extensive innate host immune responses. Loss of function mutations in the quorum sensing regulatory gene lasR have been shown to confer survival advantage and a more pathogenic character to P. aeruginosa in CF patients. However, the strategies used by LasR-deficient P. aeruginosa to modulate neutrophil-mediated bactericidal functions are unknown. We sought to understand the role of LasR in P. aeruginosa-mediated neutrophil extracellular trap (NET) formation, an important anti-microbial mechanism deployed by neutrophils, the first-line responder in the infected airway. We observe mechanistic and phenotypic differences between NETs triggered by LasR-sufficient and LasR-deficient P. aeruginosa strains. We uncover that LasR-deficient P. aeruginosa strains fail to induce robust NET formation in both human and murine neutrophils, independently of bacterial motility or LPS expression. LasR does not mediate NET release via downstream quorum sensing signaling pathways but rather via transcriptional regulation of virulence factors, including, but not restricted to, LasB elastase and LasA protease. Finally, our studies uncover the differential requirements for NADPH oxidase in NET formation triggered by different P. aeruginosa strains.

PMID: 31379861 [PubMed - in process]

The German National Registry of Primary Immunodeficiencies (2012-2017).

Front Immunol. 2019;10:1272

Authors: El-Helou SM, Biegner AK, Bode S, Ehl SR, Heeg M, Maccari ME, Ritterbusch H, Speckmann C, Rusch S, Scheible R, Warnatz K, Atschekzei F, Beider R, Ernst D, Gerschmann S, Jablonka A, Mielke G, Schmidt RE, Schürmann G, Sogkas G, Baumann UH, Klemann C, Viemann D, von Bernuth H, Krüger R, Hanitsch LG, Scheibenbogen CM, Wittke K, Albert MH, Eichinger A, Hauck F, Klein C, Rack-Hoch A, Sollinger FM, Avila A, Borte M, Borte S, Fasshauer M, Hauenherm A, Kellner N, Müller AH, Ülzen A, Bader P, Bakhtiar S, Lee JY, Heß U, Schubert R, Wölke S, Zielen S, Ghosh S, Laws HJ, Neubert J, Oommen PT, Hönig M, Schulz A, Steinmann S, Schwarz K, Dückers G, Lamers B, Langemeyer V, Niehues T, Shai S, Graf D, Müglich C, Schmalzing MT, Schwaneck EC, Tony HP, Dirks J, Haase G, Liese JG, Morbach H, Foell D, Hellige A, Wittkowski H, Masjosthusmann K, Mohr M, Geberzahn L, Hedrich CM, Müller C, Rösen-Wolff A, Roesler J, Zimmermann A, Behrends U, Rieber N, Schauer U, Handgretinger R, Holzer U, Henes J, Kanz L, Boesecke C, Rockstroh JK, Schwarze-Zander C, Wasmuth JC, Dilloo D, Hülsmann B, Schönberger S, Schreiber S, Zeuner R, Ankermann T, von Bismarck P, Huppertz HI, Kaiser-Labusch P, Greil J, Jakoby D, Kulozik AE, Metzler M, Naumann-Bartsch N, Sobik B, Graf N, Heine S, Kobbe R, Lehmberg K, Müller I, Herrmann F, Horneff G, Klein A, Peitz J, Schmidt N, Bielack S, Groß-Wieltsch U, Classen CF, Klasen J, Deutz P, Kamitz D, Lassay L, Tenbrock K, Wagner N, Bernbeck B, Brummel B, Lara-Villacanas E, Münstermann E, Schneider DT, Tietsch N, Westkemper M, Weiß M, Kramm C, Kühnle I, Kullmann S, Girschick H, Specker C, Vinnemeier-Laubenthal E, Haenicke H, Schulz C, Schweigerer L, Müller TG, Stiefel M, Belohradsky BH, Soetedjo V, Kindle G, Grimbacher B

Abstract
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

PMID: 31379802 [PubMed - in process]

Clinical evaluation of the dental hard tissues in an adult population with cystic fibrosis.

Pol Arch Intern Med. 2019 Jul 31;:

Authors: Pawlaczyk-Kamieńska T, Borysewicz-Lewicka M, Śniatała R, Batura-Gabryel H

PMID: 31379359 [PubMed - as supplied by publisher]

Scedosporium apiospermum.

Trends Microbiol. 2019 Aug 02;:

Authors: Bouchara JP, Papon N

PMID: 31378439 [PubMed - as supplied by publisher]

Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation.

J Thorac Cardiovasc Surg. 2017 04;153(4):e67-e69

Authors: Cypel M, Waddell T, Singer LG, Del Sorbo L, Fan E, Binnie M, Ferguson ND, Keshavjee S

PMID: 28017368 [PubMed - indexed for MEDLINE]

Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience.

Inflamm Bowel Dis. 2019 Aug 03;:

Authors: Lega S, Pin A, Arrigo S, Cifaldi C, Girardelli M, Bianco AM, Malamisura M, Angelino G, Faraci S, Rea F, Romeo EF, Aloi M, Romano C, Barabino A, Martelossi S, Tommasini A, Di Matteo G, Cancrini C, De Angelis P, Finocchi A, Bramuzzo M

Abstract
BACKGROUND AND AIMS: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis.
METHODS: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected.
RESULTS: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT.
CONCLUSION: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

PMID: 31375816 [PubMed - as supplied by publisher]