Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy.

Neuromuscul Disord. 2017 Jun 27;:

Authors: Tsabari R, Daum H, Kerem E, Fellig Y, Dor T

Abstract
A 7-week-old infant presented with persistent noisy breathing and aspirations during swallowing. Neurological examination and brain MRI were normal. His 12-year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage. The older brother developed subsequently ophthalmoplegia and nystagmus along with mild weakness of the neck flexors and proximal muscles. Exome analysis revealed homozygosity for a novel truncating mutation p.G800fs27* in the Myosin Heavy Chain 2 (MYH2) gene in both brothers, while parents and an unaffected sibling were heterozygous. A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers. The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers. The findings expand the phenotypic spectrum of MYH2 deficiency. MYH2 mutations should be included in the differential diagnosis of infants presenting with recurrent aspirations.

PMID: 28729039 [PubMed - as supplied by publisher]

Don't Push Your Luck! Educational Family Board (Not Bored) Game for School-Age Children Living with Chronic Conditions.

J Pediatr Nurs. 2017 Jul - Aug;35:57-64

Authors: Kennedy A, Semple L, Alderson K, Bouskill V, Karasevich J, Riske B, van Gunst S

Abstract
PURPOSE: Children who are living with chronic conditions may be supported in self-care through enjoyable active learning and family social processes. This research focused on development and evaluation of "Don't Push Your Luck!", an educational board game designed to inspire family discussion about chronic conditions, and help affected children learn about self-care choices and consequences.
DESIGN AND METHODS: Mixed-method research was conducted with families from one outpatient Cystic Fibrosis Clinic and four Hemophilia Treatment Centres in Canada and United States (N=72). In phase I, board game prototype and questionnaires were refined with affected boys, siblings, and parents living with hemophilia (n=11), compared with families living with cystic fibrosis (n=11). In phase II, final board game was evaluated with families living with hemophilia (n=50). Data collection included pre-post-game questionnaires on decision-making and Haemo-QoL Index©, and post-game enjoyment. Analysis included descriptive statistics, inferential statistics (non-parametric), and qualitative themes.
RESULTS: Findings revealed this game was an enjoyable and effective resource to engage families in self-care discussions. Key themes included communication, being involved, knowing, decisions and consequences, and being connected. Qualitative and quantitative findings aligned. Statistical significance suggests the game enhanced family engagement to support decision-making skills, as parents identified that the game helped them talk about important topics, and children gained insight regarding family supports and self-care responsibility.
CONCLUSIONS: This board game was an effective, developmentally appropriate family resource to facilitate engagement and conversation about everyday life experiences in preparation for self-care.
PRACTICE IMPLICATIONS: There is promising potential to extend this educational family board game intervention with a greater range of school-age children and families living with chronic conditions.

PMID: 28728770 [PubMed - in process]

Disclosures of Cystic Fibrosis-Related Information to Romantic Partners.

Qual Health Res. 2017 Aug;27(10):1575-1585

Authors: Broekema K, Weber KM

Abstract
In this article, we offer insights into how individuals with cystic fibrosis (CF) share information about their disease with a romantic partner. Using communication privacy management as a sensitizing theoretical construct, four themes emerged following 13 qualitative interviews with persons with CF. Themes about sharing CF-related information with a romantic partner include weighing the risks and benefits of sharing information, the role of health-related triggered rules, the motivations for disclosures, and the reactions from outsiders. Implications of the research suggest a need for more nuanced understandings of how privacy rules are communicated in relationships, how the mismanagement of co-owned information influences future disclosures, how the public-private nature of rare genetic illnesses is managed, and how people with genetic illnesses make disclosure decisions.

PMID: 28728531 [PubMed - in process]

Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene.

Genes Chromosomes Cancer. 2017 Jan;56(1):51-58

Authors: Nacci L, Valli R, Maria Pinto R, Zecca M, Cipolli M, Morini J, Cesaro S, Boveri E, Rosti V, Corti P, Ambroni M, Pasquali F, Danesino C, Maserati E, Minelli A

Abstract
Shwachman-Diamond syndrome (SDS) (OMIM 260400) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal, and hematological abnormalities and bone marrow (BM) dysfunction. Mutations in the SBDS gene cause SDS. Clonal chromosome anomalies are often present in BM, i(7)(q10) and del(20q) being the most frequent ones. We collected 6 SDS cases with del(20q): a cluster of imprinted genes, including L3MBTL1 and SGK2 is present in the deleted region. Only the paternal allele is expressed for these genes. Based on these data, we made the hypothesis that the loss of this region, in relation to parental origin of deletion, may be of relevance for the hematological phenotype. By comparing hematological data of our 6 cases with a group of 20 SDS patients without evidence of del(20q) in BM, we observed a significant difference for Hb levels (P < 0.012), and a difference slightly above the significance level for RBC counts (P < 0.053): in both cases the values were higher in patients with del(20q). We also report preliminary evidence for an increased number of BFU-E colonies in cases with paternal deletion, data on the presence of the deletion in colonies and in mature circulating lymphocytes. © 2016 Wiley Periodicals, Inc.

PMID: 27553422 [PubMed - indexed for MEDLINE]

A primer on exocrine pancreatic insufficiency, fat malabsorption, and fatty acid abnormalities.

Am J Manag Care. 2017 Jul;23(12 Suppl):S203-S209

Authors: Alkaade S, Vareedayah AA

Abstract
Exocrine pancreatic insufficiency (EPI) is characterized by a deficiency of exocrine pancreatic enzymes, resulting in deficits in digestion of all macronutrients, with deficiencies in digestion of fats being the most clinically relevant. The leading cause of EPI is chronic pancreatitis. However, many other causes and conditions may be implicated, including cystic fibrosis, pancreatic duct obstruction, gastric and pancreatic surgery, diabetes mellitus and other conditions. Physical and biochemical causes of EPI include decreased production and secretion of lipase, increased lipase destruction, pancreatic duct obstruction, decreased lipase stimulation and degradation, as well as gastrointestinal motility disorders. EPI is largely diagnosed clinically, and is often identified by symptoms such as steatorrhea, weight loss, abdominal discomfort, and abdominal bloating. Lifestyle modifications (eg, smoking cessation, limiting or avoiding alcoholic drinks, and reducing dietary fat intake) and exogenous pancreatic enzyme supplements are commonly used to help restore normal digestion and absorption of dietary nutrients in patients with EPI.

PMID: 28727474 [PubMed - in process]

Telephone monitoring and home visits significantly improved the quality of life, treatment adherence and lung function in children with cystic fibrosis.

Acta Paediatr. 2017 Jul 20;:

Authors: Chrysochoou EA, Hatziagorou E, Kirvassilis F, Tsanakas J

Abstract
Cystic Fibrosis (CF) is a chronic and systemic disease with a progressive course. As survival rates continue to improve, there is a growing demand for new therapeutic options that improve treatment adherence, disease management and quality of life (QoL) (1). The aim of this study was to evaluate the safety and effectiveness of a home care programme for children with CF and to assess the value of regular telephone contact with the CF team based at Hippokration Hospital, Thessaloniki, Greece. This article is protected by copyright. All rights reserved.

PMID: 28727186 [PubMed - as supplied by publisher]

Respiratory Tract Infections and the Role of Biologically Active Polysaccharides in Their Management and Prevention.

Nutrients. 2017 Jul 20;9(7):

Authors: Jesenak M, Urbancikova I, Banovcin P

Abstract
Respiratory tract infections (RTIs) are the most common form of infections in every age category. Recurrent respiratory tract infections (RRTIs), a specific form of RTIs, represent a typical and common problem associated with early childhood, causing high indirect and direct costs on the healthcare system. They are usually the consequence of immature immunity in children and high exposure to various respiratory pathogens. Their rational management should aim at excluding other severe chronic diseases associated with increased morbidity (e.g., primary immunodeficiency syndromes, cystic fibrosis, and ciliary dyskinesia) and at supporting maturity of the mucosal immune system. However, RRTIs can also be observed in adults (e.g., during exhausting and stressful periods, chronic inflammatory diseases, secondary immunodeficiencies, or in elite athletes) and require greater attention. Biologically active polysaccharides (e.g., β-glucans) are one of the most studied natural immunomodulators with a pluripotent mode of action and biological activity. According to many studies, they possess immunomodulatory, anti-inflammatory, and anti-infectious activities and therefore could be suggested as an effective part of treating and preventing RTIs. Based on published studies, the application of β-glucans was proven as a possible therapeutic and preventive approach in managing and preventing recurrent respiratory tract infections in children (especially β-glucans from Pleurotus ostreatus), adults (mostly the studies with yeast-derived β-glucans), and in elite athletes (studies with β-glucans from Pleurotus ostreatus or yeast).

PMID: 28726737 [PubMed - in process]

Reconstituting Mouse Lungs with Conditionally Reprogrammed Human Bronchial Epithelial Cells.

Tissue Eng Part A. 2017 Jul 20;:

Authors: LaRanger R, Peters-Hall JR, Coquelin M, Alabi BR, Chen C, Wright WE, Shay J

Abstract
We developed methods for conditionally reprogramming (CR) primary human bronchial epithelial cells (HBECs) to extend their functional life span and permit their differentiation into both upper and lower airway lung epithelium. We also developed a bioreactor to support vascular perfusion and rhythmic breathing of decellularized mouse lungs reconstituted with CR HBECs isolated from patients with and without cystic fibrosis (CF). While conditionally reprogrammed cells only differentiate into an upper airway epithelium after 35 days at the air liquid interface, in reconstituted lungs these cells differentiate into upper airway bronchial epithelium and lower airway alveolar structures after 12 days. Rapid scale-up and the ability to obtain clonal derivatives of primary patient-derived HBECs without the need for genetic manipulation may permit rapid reconstitution of the lung epithelium; facilitating the study of lung disease in tissue engineered models.

PMID: 28726588 [PubMed - as supplied by publisher]

A PRECLINICAL STUDY IN RHESUS MACAQUES FOR CYSTIC FIBROSIS TO ASSESS GENE TRANSFER AND TRANSDUCTION BY AAV1 AND AAV5 WITH A DUAL-LUCIFERASE REPORTER SYSTEM.

Hum Gene Ther Clin Dev. 2017 Jul 20;:

Authors: Guggino W, Benson J, Seagrave J, Yan Z, Engelhardt JF, Gao G, Conlon TJ, Cebotaru L

Abstract
Cystic fibrosis (CF) is an autosomal recessive disease that is potentially treatable by gene therapy. Since the identification of the gene encoding CFTR, a number of preclinical and clinical trials have been conducted using the first generation of adeno-associated virus, AAV2. All these studies showed that AAV gene therapy for CF is safe, but clinical benefit was not clearly demonstrated. Thus, a new generation of AAV Vectors based on other serotypes is needed to move the field forward. Here we have tested two AAV serotypes (AAV1 and AAV5), using a dual-luciferase reporter system with firefly and Renilla luciferase genes packaged into AAV1 or AAV5, respectively. Two male and two female Rhesus macaques were each instilled in their lungs with both serotypes using a Penn-Century microsprayer. Both AAV1 and AAV5 vector genomes were detected in all the lung samples when measured at the time of necropsy, 45 days after instillation. However, the vector genome number for AAV1 was at least 10-fold higher than for AAV5. Likewise, luciferase activity was also detected in the same samples at 45 days. AAV1-derived activity was not statistically greater than that derived from AAV5. These data suggest that gene transfer is greater for AAV1 than for AAV5 in macaque lungs. Serum neutralizing antibodies were increased dramatically against both serotypes but were less abundant with AAV1 than with AAV5. No adverse events were noted, again indicating that AAV gene therapy is safe. Our results suggest that with more lung-tropic serotypes such as AAV1, new clinical studies of gene therapy using AAV are warranted.

PMID: 28726496 [PubMed - as supplied by publisher]

Survival of Patients with Cystic Fibrosis Depending on Mutation Type and Nutritional Status.

Adv Exp Med Biol. 2017 Jul 19;:

Authors: Szwed A, John A, Goździk-Spychalska J, Czaiński W, Czerniak W, Ratajczak J, Batura-Gabryel H

Abstract
The purpose of the study was to evaluate the influence of nutrition and of the severity of mutation type on survival rate in cystic fibrosis (CF) patients. Data were longitudinally collected from 60 hospitalized adult CF patients, aged 18-50. The variables consisted of body mass index (BMI) ratio, Cole's BMI cut-off points, severity of mutation type, and survival rate of CF patients. We found that the mean BMI was strongly associated with the severity of mutation type and was significantly lower in patients with severe mutations of grade I and II. The mutation type significantly affected the patients' survival rate; survival was greater in patients with mild and undefined mutation types. The BMI and Cole's cut-off points also had a significant influence on survival rate. CF patients, who suffered from malnutrition and emaciation, had a shorter survival rate than those with proper nutritional status. In conclusion, the study findings confirmed a significant effect of nutritional status and of mutation type on survival rate of CF patients.

PMID: 28721579 [PubMed - as supplied by publisher]

Reaction-diffusion theory explains hypoxia and heterogeneous growth within microbial biofilms associated with chronic infections.

NPJ Biofilms Microbiomes. 2016;2:16012

Authors: Stewart PS, Zhang T, Xu R, Pitts B, Walters MC, Roe F, Kikhney J, Moter A

Abstract
Reaction-diffusion models were applied to gain insight into the aspects of biofilm infection and persistence by comparing mathematical simulations with the experimental data from varied bacterial biofilms. These comparisons, including three in vitro systems and two clinical investigations of specimens examined ex vivo, underscored the central importance of concentration gradients of metabolic substrates and the resulting physiological heterogeneity of the microorganisms. Relatively simple one-dimensional and two-dimensional (2D) models captured the: (1) experimentally determined distribution of specific growth rates measured in Pseudomonas aeruginosa cells within sputum from cystic fibrosis patients; (2) pattern of relative growth rate within aggregates of streptococcal biofilm harboured in an endocarditis vegetation; (3) incomplete penetration of oxygen into a Pseudomonas aeruginosa biofilm under conditions of exposure to ambient air and also pure oxygen; (4) localisation of anabolic activity around the periphery of P. aeruginosa cell clusters formed in a flow cell and attribution of this pattern to iron limitation; (5) very low specific growth rates, as small as 0.025 h(-1), in the interior of cell clusters within a Klebsiella pneumoniae biofilm in a complex 2D domain of variable cell density.

PMID: 28721248 [PubMed]

Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection.

MBio. 2017 Jul 18;8(4):

Authors: Orazi G, O'Toole GA

Abstract
The airways of cystic fibrosis (CF) patients have thick mucus, which fosters chronic, polymicrobial infections. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients. In this study, we tested whether P. aeruginosa influences the susceptibility of S. aureus to frontline antibiotics used to treat CF lung infections. Using our in vitro coculture model, we observed that addition of P. aeruginosa supernatants to S. aureus biofilms grown either on epithelial cells or on plastic significantly decreased the susceptibility of S. aureus to vancomycin. Mutant analyses showed that 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), a component of the P. aeruginosa Pseudomonas quinolone signal (PQS) system, protects S. aureus from the antimicrobial activity of vancomycin. Similarly, the siderophores pyoverdine and pyochelin also contribute to the ability of P. aeruginosa to protect S. aureus from vancomycin, as did growth under anoxia. Under our experimental conditions, HQNO, P. aeruginosa supernatant, and growth under anoxia decreased S. aureus growth, likely explaining why this cell wall-targeting antibiotic is less effective. P. aeruginosa supernatant did not confer additional protection to slow-growing S. aureus small colony variants. Importantly, P. aeruginosa supernatant protects S. aureus from other inhibitors of cell wall synthesis as well as protein synthesis-targeting antibiotics in an HQNO- and siderophore-dependent manner. We propose a model whereby P. aeruginosa causes S. aureus to shift to fermentative growth when these organisms are grown in coculture, leading to reduction in S. aureus growth and decreased susceptibility to antibiotics targeting cell wall and protein synthesis.IMPORTANCE Cystic fibrosis (CF) lung infections are chronic and difficult to eradicate. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients and are associated with poor patient outcomes. Both organisms adopt a biofilm mode of growth, which contributes to high tolerance to antibiotic treatment and the recalcitrant nature of these infections. Here, we show that P. aeruginosa exoproducts decrease the sensitivity of S. aureus biofilm and planktonic populations to vancomycin, a frontline antibiotic used to treat methicillin-resistant S. aureus in CF patients. P. aeruginosa also protects S. aureus from other cell wall-active antibiotics as well as various classes of protein synthesis inhibitors. Thus, interspecies interactions can have dramatic and unexpected consequences on antibiotic sensitivity. This study underscores the potential impact of interspecies interactions on antibiotic efficacy in the context of complex, polymicrobial infections.

PMID: 28720732 [PubMed - in process]

The potential of phage therapy in cystic fibrosis: Essential human-bacterial-phage interactions and delivery considerations for use in Pseudomonas aeruginosa-infected airways.

J Cyst Fibros. 2017 Jul 15;:

Authors: Trend S, Fonceca AM, Ditcham WG, Kicic A, Cf A

Abstract
As antimicrobial-resistant microbes become increasingly common and a significant global issue, novel approaches to treating these infections particularly in those at high risk are required. This is evident in people with cystic fibrosis (CF), who suffer from chronic airway infection caused by antibiotic resistant bacteria, typically Pseudomonas aeruginosa. One option is bacteriophage (phage) therapy, which utilises the natural predation of phage viruses upon their host bacteria. This review summarises the essential and unique aspects of the phage-microbe-human lung interactions in CF that must be addressed to successfully develop and deliver phage to CF airways. The current evidence regarding phage biology, phage-bacterial interactions, potential airway immune responses to phages, previous use of phages in humans and method of phage delivery to the lung are also summarised.

PMID: 28720345 [PubMed - as supplied by publisher]

Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells.

Cell Stem Cell. 2016 Aug 04;19(2):217-31

Authors: Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J

Abstract
Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD signaling inhibition in a feeder-free culture system, we have been able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium physiologically responsive to clinically relevant drugs, such as CFTR modulators. This approach is effective for the clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers and therefore may be broadly applicable for modeling of epithelia.

PMID: 27320041 [PubMed - indexed for MEDLINE]

Variants in the IL-8 gene and the response to inhaled bronchodilators in cystic fibrosis.

J Pediatr (Rio J). 2017 Jul 15;:

Authors: Furlan LL, Ribeiro JD, Bertuzzo CS, Salomão Junior JB, Souza DRS, Marson FAL

Abstract
OBJECTIVE: IL-8 (interleukin 8) protein promotes inflammatory responses, even in airways. The presence of IL-8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators (BD). Thus, this study analyzed the IL-8 variants (rs4073, rs2227306, and rs2227307) and their association with the response to BD in cystic fibrosis (CF) patients.
METHODS: Analysis of IL-8 gene variants was performed by RFLP-PCR. The association between spirometry markers and the response to BD was evaluated by Mann-Whitney and Kruskal-Wallis tests. The analysis included all CF patients, and subsequently patients with two mutations in the CFTR gene belonging to classes I to III.
RESULTS: This study included 186 CF patients. There was no association of the rs2227307 variant with the response to BD. The rs2227306 variant was associated with FEF50% in the dominant group and in the group with two identified mutations in the CFTR gene. The rs4073 variant was associated with spirometry markers in four genetic models: co-dominant (FEF25-75% and FEF75%) dominant (FEV1, FEF50%, FEF75%, and FEF25-75%), recessive (FEF75% and FEF25-75%), and over-dominant (FEV1/FVC).
CONCLUSIONS: This study highlighted the importance of the rs4073 variant of the IL-8 gene, regarding response to BD, and of the assessment of mutations in the CFTR gene.

PMID: 28719800 [PubMed - as supplied by publisher]

A systematic review of the prevalence and impact of urinary incontinence in cystic fibrosis.

Respirology. 2017 Jul 18;:

Authors: Frayman KB, Kazmerski TM, Sawyer SM

Abstract
This systematic review synthesizes published articles investigating the prevalence, severity and impact of urinary incontinence (UI), a condition associated with cystic fibrosis (CF). References were identified through searching Medline, Embase and PubMed using the medical subject headings 'cystic fibrosis' AND 'urinary incontinence'. Articles were included if UI prevalence was investigated as an outcome. Twelve studies met selection criteria. The prevalence of UI ranged from 5% to 76%. Age and gender contributed to this variability. When assessed, UI commonly limited airway clearance, exercise and/or spirometry, and had a variable impact on patients' lives. Worry and embarrassment were features for many; others were less affected. In CF, UI is common and can interfere with respiratory care and social well-being. The prevalence, characteristics and impact are poorly understood, which is made worse by inconsistent definitions across studies. Future research is needed to improve approaches to prevention, identification, management and education.

PMID: 28718995 [PubMed - as supplied by publisher]

Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone.

Sci Rep. 2017 Jul 17;7(1):5555

Authors: López-Causapé C, Sommer LM, Cabot G, Rubio R, Ocampo-Sosa AA, Johansen HK, Figuerola J, Cantón R, Kidd TJ, Molin S, Oliver A

Abstract
Emergence of epidemic clones and antibiotic resistance development compromises the management of Pseudomonas aeruginosa cystic fibrosis (CF) chronic respiratory infections. Whole genome sequencing (WGS) was used to decipher the phylogeny, interpatient dissemination, WGS mutator genotypes (mutome) and resistome of a widespread clone (CC274), in isolates from two highly-distant countries, Australia and Spain, covering an 18-year period. The coexistence of two divergent CC274 clonal lineages was revealed, but without evident geographical barrier; phylogenetic reconstructions and mutational resistome demonstrated the interpatient transmission of mutators. The extraordinary capacity of P. aeruginosa to develop resistance was evidenced by the emergence of mutations in >100 genes related to antibiotic resistance during the evolution of CC274, catalyzed by mutator phenotypes. While the presence of classical mutational resistance mechanisms was confirmed and correlated with resistance phenotypes, results also showed a major role of unexpected mutations. Among them, PBP3 mutations, shaping up β-lactam resistance, were noteworthy. A high selective pressure for mexZ mutations was evidenced, but we showed for the first time that high-level aminoglycoside resistance in CF is likely driven by mutations in fusA1/fusA2, coding for elongation factor G. Altogether, our results provide valuable information for understanding the evolution of the mutational resistome of CF P. aeruginosa.

PMID: 28717172 [PubMed - in process]

Lower exhaled nitric oxide in infants with Cystic Fibrosis compared to healthy controls.

J Cyst Fibros. 2017 Jul 14;:

Authors: Korten I, Liechti M, Singer F, Hafen G, Rochat I, Anagnostopoulou P, Müller-Suter D, Usemann J, Moeller A, Frey U, Latzin P, Casaulta C, SCILD and BILD study group

Abstract
Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.

PMID: 28716479 [PubMed - as supplied by publisher]

Multidrug-resistant Pseudomonas aeruginosa lower respiratory tract infections in the intensive care unit: Prevalence and risk factors.

Diagn Microbiol Infect Dis. 2017 Jun 19;:

Authors: Trinh TD, Zasowski EJ, Claeys KC, Lagnf AM, Kidambi S, Davis SL, Rybak MJ

Abstract
Intensive care unit (ICU) admission is a risk for multidrug-resistant (MDR) Pseudomonas aeruginosa, but factors specific to critically ill pneumonia patients are not fully characterized. Objective was to determine risk factors associated with MDR P. aeruginosa pneumonia among ICU patients. This was a retrospective case-control study of P. aeruginosa pneumonia in the ICU; cystic fibrosis and colonizers were excluded. Risk factors included comorbid conditions and prior healthcare exposure (anti-pseudomonal antibiotics, hospitalizations, nursing home, P. aeruginosa colonization/infection, mechanical ventilation). Of 200 patients, 47 (23.5%) had MDR P. aeruginosa pneumonia. Independent predictors for MDR were ≥24h antibiotics in the preceding 90days (carbapenems, fluoroquinolones, and piperacillin-tazobactam) (odds ratio, 3.6 [95% CI, 1.6-8.1]) and nursing home residence (2.3 [1.1-4.9]). MDR P. aeruginosa remains prevalent among ICU patients with pneumonia. Given poor outcomes with delayed therapy, patients should be thoroughly assessed for prior anti-pseudomonal antibiotic exposure and nursing home residency.

PMID: 28716451 [PubMed - as supplied by publisher]

The RhlR quorum-sensing receptor controls Pseudomonas aeruginosa pathogenesis and biofilm development independently of its canonical homoserine lactone autoinducer.

PLoS Pathog. 2017 Jul 17;13(7):e1006504

Authors: Mukherjee S, Moustafa D, Smith CD, Goldberg JB, Bassler BL

Abstract
Quorum sensing (QS) is a bacterial cell-to-cell communication process that relies on the production, release, and response to extracellular signaling molecules called autoinducers. QS controls virulence and biofilm formation in the human pathogen Pseudomonas aeruginosa. P. aeruginosa possesses two canonical LuxI/R-type QS systems, LasI/R and RhlI/R, which produce and detect 3OC12-homoserine lactone and C4-homoserine lactone, respectively. Here, we use biofilm analyses, reporter assays, RNA-seq studies, and animal infection assays to show that RhlR directs both RhlI-dependent and RhlI-independent regulons. In the absence of RhlI, RhlR controls the expression of genes required for biofilm formation as well as genes encoding virulence factors. Consistent with these findings, ΔrhlR and ΔrhlI mutants have radically different biofilm phenotypes and the ΔrhlI mutant displays full virulence in animals whereas the ΔrhlR mutant is attenuated. The ΔrhlI mutant cell-free culture fluids contain an activity that stimulates RhlR-dependent gene expression. We propose a model in which RhlR responds to an alternative ligand, in addition to its canonical C4-homoserine lactone autoinducer. This alternate ligand promotes a RhlR-dependent transcriptional program in the absence of RhlI.

PMID: 28715477 [PubMed - as supplied by publisher]