Genome-wide survey of Pseudomonas aeruginosa PA14 reveals a role for the glyoxylate pathway and extracellular proteases in the utilization of mucin.

Infect Immun. 2017 May 15;:

Authors: Flynn JM, Phan C, Hunter RC

Abstract
Chronic airway infections by the opportunistic pathogen Pseudomonas aeruginosa are a major cause of mortality in cystic fibrosis (CF) patients. While this bacterium has been extensively studied for its virulence determinants, biofilm growth and immune evasion mechanisms, comparatively little is known about the nutrient sources that sustain its growth in vivo Respiratory mucins represent a potentially abundant bioavailable nutrient source, though we have recently shown that canonical pathogens inefficiently use these host glycoproteins as a growth substrate. Yet, given that P. aeruginosa, particularly in its biofilm mode of growth is thought to grow slowly in vivo, the inefficient use of mucin glycoproteins may have relevance to its persistence within the CF airways. To this end, here we use whole genome fitness analysis, combining transposon mutagenesis with high throughput sequencing (TnSeq), to identify genetic determinants required for P. aeruginosa growth using intact purified mucins as a sole carbon source. Our analysis reveals a biphasic growth phenotype, during which the glyoxylate pathway and amino acid biosynthetic machinery are required for mucin utilization. Secondary analyses confirmed the simultaneous liberation and consumption of acetate during mucin degradation and revealed a central role for the extracellular proteases LasB and AprA. Together, these studies describe a molecular basis for mucin-based nutrient acquisition by P. aeruginosa and reveal a host-pathogen dynamic that may contribute to its persistence within the CF airways.

PMID: 28507068 [PubMed - as supplied by publisher]

Global initiative for meticillin-resistant Staphylococcus aureus pneumonia (GLIMP): an international, observational cohort study.

Lancet Infect Dis. 2016 Dec;16(12):1364-1376

Authors: Aliberti S, Reyes LF, Faverio P, Sotgiu G, Dore S, Rodriguez AH, Soni NJ, Restrepo MI, GLIMP investigators

Abstract
BACKGROUND: Antibiotic resistance is a major global health problem and pathogens such as meticillin-resistant Staphylococcus aureus (MRSA) have become of particular concern in the management of lower respiratory tract infections. However, few data are available on the worldwide prevalence and risk factors for MRSA pneumonia. We aimed to determine the point prevalence of MRSA pneumonia and identify specific MRSA risk factors in community-dwelling patients hospitalised with pneumonia.
METHODS: We did an international, multicentre study of community-dwelling, adult patients admitted to hospital with pneumonia who had microbiological tests taken within 24 h of presentation. We recruited investigators from 222 hospitals in 54 countries to gather point-prevalence data for all patients admitted with these characteristics during 4 days randomly selected during the months of March, April, May, and June in 2015. We assessed prevalence of MRSA pneumonia and associated risk factors through logistic regression analysis.
FINDINGS: 3702 patients hospitalised with pneumonia were enrolled, with 3193 patients receiving microbiological tests within 24 h of admission, forming the patient population. 1173 (37%) had at least one pathogen isolated (culture-positive population). The overall prevalence of confirmed MRSA pneumonia was 3·0% (n=95), with differing prevalence between continents and countries. Three risk factors were independently associated with MRSA pneumonia: previous MRSA infection or colonisation (odds ratio 6·21, 95% CI 3·25-11·85), recurrent skin infections (2·87, 1·10-7·45), and severe pneumonia disease (2·39, 1·55-3·68).
INTERPRETATION: This multicountry study shows low prevalence of MRSA pneumonia and specific MRSA risk factors among community-dwelling patients hospitalised with pneumonia.
FUNDING: None.

PMID: 27593581 [PubMed - indexed for MEDLINE]

Early childhood lung function is a stronger predictor of adolescent lung function in cystic fibrosis than early Pseudomonas aeruginosa infection.

PLoS One. 2017;12(5):e0177215

Authors: Pittman JE, Noah H, Calloway HE, Davis SD, Leigh MW, Drumm M, Sagel SD, Accurso FJ, Knowles MR, Sontag MK

Abstract
OBJECTIVE: Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF.
METHODS: Two populations of subjects with CF were studied: from the Gene Modifier Study (GMS), 346 F508del homozygotes with severe vs. mild adolescent lung disease, and from the Colorado Newborn Screen Study (NBS) 172 subjects diagnosed with CF by newborn screening. Associations of Pseudomonas infection and lung function in early childhood with lung function in adolescence were investigated using multivariate linear regression analyses.
RESULTS: Among GMS subjects, those with severe adolescent lung disease had worse lung function in childhood (FEV1 25 percentage points lower) compared to subjects with mild adolescent lung disease, regardless of early childhood Pseudomonas status. Among NBS subjects, those with lowest adolescent lung function had significantly lower early childhood lung function and faster rate of decline in FEV1 than subjects with highest adolescent lung function; early Pseudomonas infection was not associated with rate of FEV1 decline. The strongest predictor of adolescent lung function was early childhood lung function. Subjects with a higher percentage of cultures positive for Pseudomonas before age 6 or a lower BMI at 2-4 years old also had lower adolescent lung function, though these associations were not as strong as with early childhood lung function.
CONCLUSIONS: In separate analyses of two distinct populations of subjects with CF, we found a strong correlation between lower lung function in early childhood and adolescence, regardless of early childhood Pseudomonas status. Factors in addition to early Pseudomonas infection have a strong impact on lung function in early childhood in CF. Further exploration may identify novel underlying genetic or environmental factors that predispose children with CF to early loss of lung function.

PMID: 28505188 [PubMed - in process]

Early Lung Function Decline in Cystic Fibrosis: Can Registry Data Explain Divergent Phenotypes?

Am J Respir Crit Care Med. 2017 May 15;:

Authors: Kazmerski TM, Sawicki GS

PMID: 28504907 [PubMed - as supplied by publisher]

Scedosporium apiospermum complex in cystic fibrosis; should we treat?

Mycoses. 2017 May 15;:

Authors: Noni M, Katelari A, Kapi A, Stathi A, Dimopoulos G, Doudounakis SE

Abstract
Species of the Scedosporium apiospermum complex are the second most frequent filamentous fungi after Aspergillus fumigatus that can be found in cystic fibrosis (CF). Mixed colonisation by S. apiospermum complex and A. fumigatus is also quite common. In this study we summarise all CF patients who were colonised by S. apiospermum complex during their childhood and we present two CF patients who were treated as fungal bronchitis due to S. apiospermum complex. The medical records of 400 CF patients were reviewed in order to identify those with positive respiratory cultures for S. apiospermum complex. Scedosporium apiospermum complex was isolated in 10 CF patients and six of them had more than two positive sputum cultures during the study period. By the time of first isolation, the median age was 14.5 years, the median BMI was 19.41 kg/m(2) , the median predicted FEV1 % was 78.65% and six patients had a history of A. fumigatus isolation. Two patients presented symptoms of infection while they were colonised by S. apiospermum complex. A rapid remission of their symptoms was observed only when antifungal therapy was administered. Antifungal treatment should be considered in CF patients who present symptoms of infection not responding to antibacterial therapy and S. apiospermum complex is persistently growing in sputum cultures.

PMID: 28504471 [PubMed - as supplied by publisher]

Pancreatic Disorders.

Pediatr Clin North Am. 2017 Jun;64(3):685-706

Authors: Uc A, Fishman DS

Abstract
Once considered uncommon, pancreatic diseases are increasingly recognized in the pediatric age group. Acute pancreatitis, acute recurrent pancreatitis, and chronic pancreatitis occur in children with an incidence approaching that of adults. Risk factors are broad, prompting the need for a completely different diagnostic and therapeutic approach in children. Although cystic fibrosis remains the most common cause of exocrine pancreatic insufficiency, other causes such as chronic pancreatitis may be as common as Shwachman Diamond syndrome. Long-term effects of pancreatic diseases may be staggering, as children suffer from significant disease burden, high economic cost, nutritional deficiencies, pancreatogenic diabetes, and potentially pancreatic cancer.

PMID: 28502446 [PubMed - in process]

Essential Role of CFTR in PKA-Dependent Phosphorylation, Alkalinization, and Hyperpolarization During Human Sperm Capacitation.

J Cell Physiol. 2017 Jun;232(6):1404-1414

Authors: Puga Molina LC, Pinto NA, Torres Rodríguez P, Romarowski A, Vicens Sanchez A, Visconti PE, Darszon A, Treviño CL, Buffone MG

Abstract
Mammalian sperm require to spend a limited period of time in the female reproductive tract to become competent to fertilize in a process called capacitation. It is well established that HCO3(-) is essential for capacitation because it activates the atypical soluble adenylate cyclase ADCY10 leading to cAMP production, and promotes alkalinization of cytoplasm, and membrane hyperpolarization. However, how HCO3(-) is transported into the sperm is not well understood. There is evidence that CFTR activity is involved in the human sperm capacitation but how this channel is integrated in the complex signaling cascades associated with this process remains largely unknown. In the present work, we have analyzed the extent to which CFTR regulates different events in human sperm capacitation. We observed that inhibition of CFTR affects HCO3(-) -entrance dependent events resulting in lower PKA activity. CFTR inhibition also affected cAMP/PKA-downstream events such as the increase in tyrosine phosphorylation, hyperactivated motility, and acrosome reaction. In addition, we demonstrated for the first time, that CFTR and PKA activity are essential for the regulation of intracellular pH, and membrane potential in human sperm. Addition of permeable cAMP partially recovered all the PKA-dependent events altered in the presence of inh-172 which is consistent with a role of CFTR upstream of PKA activation. J. Cell. Physiol. 232: 1404-1414, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 27714810 [PubMed - indexed for MEDLINE]

Actinin-1 binds to the C-terminus of A2B adenosine receptor (A2BAR) and enhances A2BAR cell-surface expression.

Biochem J. 2016 Jul 15;473(14):2179-86

Authors: Sun Y, Hu W, Yu X, Liu Z, Tarran R, Ravid K, Huang P

Abstract
A2BAR (A2B adenosine receptor) has been implicated in several physiological conditions, such as allergic or inflammatory disorders, vasodilation, cell growth and epithelial electrolyte secretion. For mediating the protein-protein interactions of A2BAR, the receptor's C-terminus is recognized to be crucial. In the present study, we unexpectedly found that two point mutations in the A2BAR C-terminus (F297A and R298A) drastically impaired the expression of A2BAR protein by accelerating its degradation. Thus we tested the hypothesis that these two point mutations disrupt A2BAR's interaction with a protein essential for A2BAR stability. Our results show that both mutations disrupted the interaction of A2BAR with actinin-1, an actin-associated protein. Furthermore, actinin-1 binding stabilized the global and cell-surface expression of A2BAR. By contrast, actinin-4, another non-muscle actinin isoform, did not bind to A2BAR. Thus our findings reveal a previously unidentified regulatory mechanism of A2BAR abundance.

PMID: 27208173 [PubMed - indexed for MEDLINE]

Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment.

Dig Dis Sci. 2017 May 13;:

Authors: Lew D, Afghani E, Pandol S

Abstract
This paper reviews the current status of our understanding of the epidemiology, diagnosis, and management of the continuum of pancreatic diseases from acute and recurrent acute pancreatitis to chronic pancreatitis and the diseases that are often linked with pancreatitis including diabetes mellitus and pancreatic cancer. In addition to reviewing the current state of the field, we identify gaps in knowledge that are necessary to address to improve patient outcomes in these conditions.

PMID: 28501969 [PubMed - as supplied by publisher]

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Cochrane Database Syst Rev. 2017 May 13;5:CD012389

Authors: Estcourt LJ, Fortin PM, Hopewell S, Trivella M, Doree C, Abboud MR

Abstract
BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient.
OBJECTIVES: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD.
SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 19 September 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 06 October 2016.
SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.
MAIN RESULTS: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention.Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents).The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence).No deaths were reported in either trial.Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence).Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial)Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence).We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence).The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence).Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence).Neither trial reported on quality of life or cognitive function.
AUTHORS' CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD.Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises).In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions.Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention.All other evidence in this review is of very low-quality.

PMID: 28500860 [PubMed - as supplied by publisher]

Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis.

Int J Pharm. 2017 May 09;:

Authors: Torge A, Wagner S, Chaves PS, Oliveira EG, Guterres SS, Pohlmann AR, Titz A, Schneider M, Beck RCR

Abstract
Treatment of bacterial airway infections is essential for cystic fibrosis therapy. However, effectiveness of antibacterial treatment is limited as bacteria inside the mucus are protected from antibiotics and immune response. To overcome this biological barrier, ciprofloxacin was loaded into lipid-core nanocapsules (LNC) for high mucus permeability, sustained release, and antibacterial activity. Ciprofloxacin-loaded LNC with a mean size of 180nm showed a by 50% increased drug permeation through mucus. In antibacterial growth assays, the drug in the LNC had similar minimum inhibitory concentrations as the free drug in P. aeruginosa and S. aureus. Interestingly, formation of biofilm-like aggregates, which were observed for S. aureus treated with free ciprofloxacin, was avoided by exposure to LNC. With the combined advantages over the non-encapsulated drug, ciprofloxacin-loaded LNC represent a promising drug delivery system with the prospect of an improved antibiotic therapy in cystic fibrosis.

PMID: 28499793 [PubMed - as supplied by publisher]

Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory.

BMC Infect Dis. 2017 May 12;17(1):340

Authors: Bosch L, Bosch B, De Boeck K, Nawrot T, Meyts I, Vanneste D, Le Bourlegat CA, Croda J, da Silva Filho LVRF

Abstract
BACKGROUND: The reason why Cystic Fibrosis (CF) is the most common fatal genetic disease among Caucasians has been incompletely studied. We aimed at deepening the hypothesis that CF carriers have a relative protection against Mycobacterium tuberculosis (Mtb) infection.
METHODS: Applying spatial epidemiology, we studied the link between CF carriership rate and tuberculosis (TB) incidence in Brazil. We corrected for 5 potential environmental and 2 immunological confounders in this relation: monthly income, sanitary provisions, literacy rates, racial composition and population density along with AIDS incidence rates and diabetes mellitus type 2. Smoking data were incomplete and not available for analysis.
RESULTS: A significant, negative correlation between CF carriership rate and TB incidence, independent of any of the seven confounders was found.
CONCLUSION: We provide exploratory support for the hypothesis that carrying a single CFTR mutation arms against Mtb infections.

PMID: 28499359 [PubMed - in process]

The intestinal microbiome and paediatric liver disease.

Lancet Gastroenterol Hepatol. 2017 Jun;2(6):446-455

Authors: Leung DH, Yimlamai D

Abstract
The intestinal microbiome has been the intense focus of recent study, but how the microbiota affects connected organs, such as the liver, has not been fully elucidated. The microbiome regulates intestinal permeability and helps to metabolise the human diet into small molecules, thus directly affecting liver health. Several studies have linked intestinal dysbiosis to the severity and progression of liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, primary sclerosing cholangitis, total parenteral nutrition-associated liver disease, and cystic fibrosis-associated liver disease. However, there is limited information and interpretation with regard to how the microbiome could contribute to liver disease in the paediatric population. Notably, the gut microbiota is distinct at birth and does not establish an adult profile until the third year of life. Clinical research suggests that paediatric liver disease differs in both severity and rate of progression compared with adult forms, suggesting independent mechanisms of pathogenesis. We discuss data linking the intestinal microbiome to liver disease development and therapeutic efforts to modify the microbiome in children.

PMID: 28497760 [PubMed - in process]

[XBP1 and inflammation in cystic fibrosis alveolar macrophages].

Med Sci (Paris). 2017 Apr;33(4):380-382

Authors: Lubamba BA

PMID: 28497731 [PubMed - in process]

Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling.

FASEB J. 2017 May 11;:

Authors: Liu Y, Xu J, Xu L, Wu T, Sun Y, Lee YW, Wang B, Chan HC, Jiang X, Zhang J, Li G

Abstract
Tendons are a mechanosensitive tissue, which enables them to transmit to bone forces that are derived from muscle. Patients with tendon injuries, such as tendinopathy or tendon rupture, were often observed with matrix degeneration, and the healing of tendon injuries remains a challenge as a result of the limited understanding of tendon biology. Our study demonstrates that the stretch-mediated activation channel, cystic fibrosis transmembrane conductance regulator (CFTR), was up-regulated in tendon-derived stem cells (TDSCs) during tenogenic differentiation under mechanical stretching. Tendon tissues in CFTR dysfunctional mice (DF508) exhibited irregular cell arrangement, uneven fibril diameter distribution, weak mechanical properties, and less matrix formation in a tendon defect model. Moreover, both tendon tissues and TDSCs isolated from DF508 mice showed significantly decreased levels of tendon markers, such as scleraxis, tenomodulin, Col1A1 (collagen type I α 1 chain), and decorin Furthermore, by RNA sequencing analysis, we demonstrated that Wnt/β-catenin signaling was abnormally activated in TDSCs from DF508 mice, thereby further activating the pERK1/2 signaling pathway. Of most importance, we found that intervention in pERK1/2 signaling could promote tenogenic differentiation and tendon regeneration both in vitro and in vivo Taken together, our study demonstrates that CFTR plays an important role in tenogenic differentiation and tendon regeneration by inhibiting the β-catinin/pERK1/2 signaling pathway. The therapeutic strategy of intervening in the CFTR/β-catenin/pERK1/2 regulatory axis may be helpful for accelerating tendon injury healing, which has implications for tendon injury management.-Liu, Y., Xu, J., Xu, L., Wu, T., Sun, Y., Lee, Y.-W., Wang, B., Chan, H.-C., Jiang, X., Zhang, J., Li, G. Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling.

PMID: 28495756 [PubMed - as supplied by publisher]

Tropical Australia is a potential reservoir of non-tuberculous mycobacteria in cystic fibrosis.

Eur Respir J. 2017 May;49(5):

Authors: Sherrard LJ, Tay GT, Butler CA, Wood ME, Yerkovich S, Ramsay KA, Reid DW, Moore VL, Kidd TJ, Bell SC

PMID: 28495693 [PubMed - in process]

The RESPIRE trials: Two phase III, randomized, multicentre, placebo-controlled trials of Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) in non-cystic fibrosis bronchiectasis.

Contemp Clin Trials. 2017 May 08;:

Authors: Aksamit T, Bandel TJ, Criollo M, De Soyza A, Stuart Elborn J, Operschall E, Polverino E, Roth K, Winthrop KL, Wilson R

Abstract
The primary goals of long-term disease management in non-cystic fibrosis bronchiectasis (NCFB) are to reduce the number of exacerbations, and improve quality of life. However, currently no therapies are licensed for this. Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) has potential to be the first long-term intermittent therapy approved to reduce exacerbations in NCFB patients. The RESPIRE programme consists of two international phase III prospective, parallel-group, randomized, double-blinded, multicentre, placebo-controlled trials of the same design. Adult patients with idiopathic or post-infectious NCFB, a history of ≥2 exacerbations in the previous 12months, and positive sputum culture for one of seven pre-specified pathogens, undergo stratified randomization 2:1 to receive twice-daily Ciprofloxacin DPI 32.5mg or placebo using a pocket-sized inhaler in one of two regimens: 28-days on/off treatment or 14-days on/off treatment. The treatment period is 48weeks plus an 8-week follow-up after the last dose. The primary efficacy endpoints are time to first exacerbation after treatment initiation and frequency of exacerbations using a stringent definition of exacerbation. Secondary endpoints, including frequency of events using different exacerbation definitions, microbiology, quality of life and lung function will also be evaluated. The RESPIRE trials will determine the efficacy and safety of Ciprofloxacin DPI. The strict entry criteria and stratified randomization, the inclusion of two treatment regimens and a stringent definition of exacerbation should clarify the patient population best positioned to benefit from long-term inhaled antibiotic therapy. Additionally RESPIRE will increase understanding of NCFB treatment and could lead to an important new therapy for sufferers.
TRIAL REGISTRATION: The RESPIRE trials are registered in ClinicalTrials.gov, ID number NCT01764841 (RESPIRE 1; date of registration January 8, 2013) and NCT02106832 (RESPIRE 2; date of registration April 4, 2014).

PMID: 28495619 [PubMed - as supplied by publisher]

Role of iron in the pathogenesis of respiratory disease.

Int J Biochem Cell Biol. 2017 May 07;:

Authors: Ali MK, Kim RY, Karim R, Mayall JR, Martin KL, Shahandeh A, Abbasian F, Starkey MR, Loustaud-Ratti V, Johnstone D, Milward EA, Hansbro PM, Horvat JC

Abstract
Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.

PMID: 28495571 [PubMed - as supplied by publisher]

Outcomes associated with antibiotic regimens for treatment of Mycobacterium abscessus in cystic fibrosis patients.

J Cyst Fibros. 2017 May 08;:

Authors: DaCosta A, Jordan CL, Giddings O, Lin FC, Gilligan P, Esther CR

Abstract
BACKGROUND: Mycobacterium abscessus infection is associated with declining lung function in cystic fibrosis (CF), but there is little evidence on clinical efficacy to guide treatment.
METHODS: Retrospective review of 37 CF patients treated for M. abscessus respiratory infection at a single center from 2006 to 2014. Outcomes included change in FEV1 at 30, 60, 90, 180, and 365days after treatment and clearance of M. abscessus from sputum cultures.
RESULTS: Lung function was significantly improved after 30 and 60days of treatment, but not at later time points. Gains were inversely related to starting lung function. Antibiotic choices did not influence outcomes except for greater clearance with clarithromycin.
CONCLUSIONS: Treatment of M. abscessus resulted in short term improvement in lung function that is inversely related to pre-treatment FEV1.

PMID: 28495380 [PubMed - as supplied by publisher]

Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences.

Microbiome. 2017 May 12;5(1):53

Authors: Cope EK, Goldberg AN, Pletcher SD, Lynch SV

Abstract
BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. The basis of this heterogeneity is poorly understood. We sought to address the hypothesis that a limited number of compositionally distinct pathogenic bacterial microbiota exist in CRS patients and invoke discrete immune responses and clinical phenotypes in CRS patients.
RESULTS: Sinus brushings from patients with CRS (n = 59) and healthy individuals (n = 10) collected during endoscopic sinus surgery were analyzed using 16S rRNA gene sequencing, predicted metagenomics, and RNA profiling of the mucosal immune response. We show that CRS patients cluster into distinct sub-groups (DSI-III), each defined by specific pattern of bacterial co-colonization (permutational multivariate analysis of variance (PERMANOVA); p = 0.001, r (2) = 0.318). Each sub-group was typically dominated by a pathogenic family: Streptococcaceae (DSI), Pseudomonadaceae (DSII), Corynebacteriaceae [DSIII(a)], or Staphylococcaceae [DSIII(b)]. Each pathogenic microbiota was predicted to be functionally distinct (PERMANOVA; p = 0.005, r (2) = 0.217) and encode uniquely enriched gene pathways including ansamycin biosynthesis (DSI), tryptophan metabolism (DSII), two-component response [DSIII(b)], and the PPAR-γ signaling pathway [DSIII(a)]. Each is also associated with significantly distinct host immune responses; DSI, II, and III(b) invoked a variety of pro-inflammatory, TH1 responses, while DSIII(a), which exhibited significantly increased incidence of nasal polyps (Fisher's exact; p = 0.034, relative risk = 2.16), primarily induced IL-5 expression (Kruskal Wallis; q = 0.045).
CONCLUSIONS: A large proportion of CRS patient heterogeneity may be explained by the composition of their sinus bacterial microbiota and related host immune response-features which may inform strategies for tailored therapy in this patient population.

PMID: 28494786 [PubMed - in process]