Venous thromboembolism in children with cystic fibrosis: Retrospective incidence and intrapopulation risk factors.

Thromb Res. 2017 Sep 05;158:161-166

Authors: Knight-Perry J, Branchford BR, Thornhill D, Martiniano SL, Sagel SD, Wang M

Abstract
INTRODUCTION: Pediatric venous thromboembolism (VTE) is a rare but serious medical condition. Cystic fibrosis (CF) is a risk for recurrent pediatric VTE and has potential thrombophilic tendency. However, much remains unknown, including incidence and intrapopulation risk factors.
METHODS: A retrospective cohort of pediatric CF patients followed at Children's Hospital Colorado from January 1st 2003 through May 20th 2016 was examined. Cases were identified by informatics and validated manually. Data on CF severity, co-morbidities and treatment, central venous catheter (CVC) use, and thrombophilia were obtained from an institutional CF database and chart review.
RESULTS: Nineteen VTE occurred in 458 participants followed for 3595 person-years, yielding an incidence rate of 53 VTE per 10,000 children with CF. VTE cases had additional co-morbidities including CF-related diabetes (p=0.002) and sinus disease (p=0.04), more total admissions (p<0.001), admit days (p<0.001), positive respiratory cultures (p<0.001), pseudomonas infections (p<0.001), steroid courses (p=0.001), and total CVC days (PICC p=0.03, port p=0.007). On univariate analysis, older age (RR 1.162, p=0.007), sinus disease (RR 2.62, p=0.05), longer hospital stay (RR 1.03, p<0.001), higher ESR (RR 1.02, p=0.03) and CRP (RR 1.07, p=0.007), and an absence of systemic steroids (RR 0.19, p=0.004) increased the risk of VTE.
CONCLUSIONS: In this cohort, children with CF had a higher incidence of VTE when compared to the previously reported incidence in the overall pediatric population at Children's Hospital Colorado. Overall, those with VTE had a greater disease burden and older age, sinus disease, longer hospitalization and increased inflammation were VTE risk factors.

PMID: 28934665 [PubMed - as supplied by publisher]

Restriction-modification mediated barriers to exogenous DNA uptake and incorporation employed by Prevotella intermedia.

PLoS One. 2017;12(9):e0185234

Authors: Johnston CD, Skeete CA, Fomenkov A, Roberts RJ, Rittling SR

Abstract
Prevotella intermedia, a major periodontal pathogen, is increasingly implicated in human respiratory tract and cystic fibrosis lung infections. Nevertheless, the specific mechanisms employed by this pathogen remain only partially characterized and poorly understood, largely due to its total lack of genetic accessibility. Here, using Single Molecule, Real-Time (SMRT) genome and methylome sequencing, bisulfite sequencing, in addition to cloning and restriction analysis, we define the specific genetic barriers to exogenous DNA present in two of the most widespread laboratory strains, P. intermedia ATCC 25611 and P. intermedia Strain 17. We identified and characterized multiple restriction-modification (R-M) systems, some of which are considerably divergent between the two strains. We propose that these R-M systems are the root cause of the P. intermedia transformation barrier. Additionally, we note the presence of conserved Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) systems in both strains, which could provide a further barrier to exogenous DNA uptake and incorporation. This work will provide a valuable resource during the development of a genetic system for P. intermedia, which will be required for fundamental investigation of this organism's physiology, metabolism, and pathogenesis in human disease.

PMID: 28934361 [PubMed - in process]

Variability in objective and subjective measures affects baseline values in studies of patients with COPD.

PLoS One. 2017;12(9):e0184606

Authors: Anderson WH, Ha JW, Couper DJ, O'Neal WK, Barr RG, Bleecker ER, Carretta EE, Cooper CB, Doerschuk CM, Drummond MB, Han MK, Hansel NN, Kim V, Kleerup EC, Martinez FJ, Rennard SI, Tashkin D, Woodruff PG, Paine R, Curtis JL, Kanner RE, SPIROMICS Research Group

Abstract
RATIONALE: Understanding the reliability and repeatability of clinical measurements used in the diagnosis, treatment and monitoring of disease progression is of critical importance across all disciplines of clinical practice and in clinical trials to assess therapeutic efficacy and safety.
OBJECTIVES: Our goal is to understand normal variability for assessing true changes in health status and to more accurately utilize this data to differentiate disease characteristics and outcomes.
METHODS: Our study is the first study designed entirely to establish the repeatability of a large number of instruments utilized for the clinical assessment of COPD in the same subjects over the same period. We utilized SPIROMICS participants (n = 98) that returned to their clinical center within 6 weeks of their baseline visit to repeat complete baseline assessments. Demographics, spirometry, questionnaires, complete blood cell counts (CBC), medical history, and emphysema status by computerized tomography (CT) imaging were obtained.
RESULTS: Pulmonary function tests (PFTs) were highly repeatable (ICC's >0.9) but the 6 minute walk (6MW) was less so (ICC = 0.79). Among questionnaires, the Saint George's Respiratory Questionnaire (SGRQ) was most repeatable. Self-reported clinical features, such as exacerbation history, and features of chronic bronchitis, often produced kappa values <0.6. Reported age at starting smoking and average number of cigarettes smoked were modestly repeatable (kappa = 0.76 and 0.79). Complete blood counts (CBC) variables produced intraclass correlation coefficients (ICC) values between 0.6 and 0.8.
CONCLUSIONS: PFTs were highly repeatable, while subjective measures and subject recall were more variable. Analyses using features with poor repeatability could lead to misclassification and outcome errors. Hence, care should be taken when interpreting change in clinical features based on measures with low repeatability. Efforts to improve repeatability of key clinical features such as exacerbation history and chronic bronchitis are warranted.

PMID: 28934249 [PubMed - in process]

Acute exacerbations of COPD: risk factors for failure and relapse.

Int J Chron Obstruct Pulmon Dis. 2017;12:2687-2693

Authors: Mantero M, Rogliani P, Di Pasquale M, Polverino E, Crisafulli E, Guerrero M, Gramegna A, Cazzola M, Blasi F

Abstract
Acute exacerbations are a leading cause of worsening COPD in terms of lung function decline, quality of life, and survival. They also have a relevant economic burden on the health care system. Determining the risk factors for acute exacerbation and early relapse could be a crucial element for a better management of COPD patients. This review analyzes the current knowledge and underlines the main risk factors for recurrent acute exacerbations. Comprehensive evaluation of COPD patients during stable phase and exacerbation could contribute to prevent treatment failure and relapses.

PMID: 28932112 [PubMed - in process]

Question 8: How should distal intestinal obstruction syndrome [DIOS] be managed?

Paediatr Respir Rev. 2017 Jan;21:68-71

Authors: Groves T, Kench A, Dutt S, Gaskin K, Fitzgerald DA

PMID: 27425011 [PubMed - indexed for MEDLINE]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2017/09/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Treatments for priapism in boys and men with sickle cell disease.

Cochrane Database Syst Rev. 2017 Sep 19;9:CD004198

Authors: Chinegwundoh FI, Smith S, Anie KA

Abstract
BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals.
OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 15 September 2017.Date of most recent search of trial registries and of Embase: 12 December 2016.
SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism.
DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials.
MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence but all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome. No significant effect of any of the treatments was seen compared to placebo. Immediate side effects were not found to be significantly different from placebo in the two trials where this information was reported. We considered the quality of evidence to be low to very low as all of the trials were at risk of bias and all had low participant numbers.
AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

PMID: 28926088 [PubMed - as supplied by publisher]

Generation of a gene-corrected isogenic control iPSC line from cystic fibrosis patient-specific iPSCs homozygous for p.Phe508del mutation mediated by TALENs and ssODN.

Stem Cell Res. 2017 Aug;23:95-97

Authors: Merkert S, Bednarski C, Göhring G, Cathomen T, Martin U

Abstract
Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which affects multiple organs. Human induced pluripotent stem cells (iPSCs) derived from CF patients and the generation of isogeneic gene-corrected control cell lines enable disease modelling, drug discovery or toxicological studies and therefore the development of CF patient-specific therapies. We have previously generated a hiPSC line from a CF patient homozygous for the p.Phe508del mutation. Here we used TALENs and single-stranded oligonucleotides to correct the mutated triplet in our CF-iPSC line.

PMID: 28925369 [PubMed - in process]

Interplay among resistance profiles, high-risk clones and virulence in the Caenorhabditis elegans Pseudomonas aeruginosa infection model.

Antimicrob Agents Chemother. 2017 Sep 18;:

Authors: Sánchez-Diener I, Zamorano L, López-Causapé C, Cabot G, Mulet X, Peña C, Del Campo R, Cantón R, Doménech-Sánchez A, Martínez-Martínez L, Arcos SC, Navas A, Oliver A

Abstract
The increasing prevalence of nosocomial infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa is frequently linked to widespread international strains designated as high-risk clones. In this work we attempted to decipher the interplay between resistance profiles, high-risk clones and virulence, testing a large (n=140) collection of well characterized P. aeruginosa isolates from different sources (bloodstream infections, nosocomial outbreaks, cystic fibrosis and environment) in a Caenorhabditis elegans infection model. Consistently with previous data, we documented a clear inverse correlation between antimicrobial resistance and virulence in the C. elegans model. Indeed, lowest virulence was linked to XDR profiles, which were typically linked to defined high-risk clones. However, virulence varied broadly depending on the involved high-risk clone; it was high for ST111 and ST235 but very low for ST175. The highest virulence of ST235 could be attributed to its ExoU+ Type III secretion system (TTSS) genotype, found to be linked with higher virulence in our C. elegans model. Other markers, such as motility or pigment production were not essential for virulence in the C. elegans model, but seemed to be related with the higher values of the statistical normalized data. Opposite to ST235, the ST175 high-risk clone, widespread in Spain and France, seems to be associated with a particularly low virulence in the C. elegans model. Moreover, the previously described G154R AmpR mutation, prevalent in ST175, was found to contribute to the reduced virulence, although it was not the only factor involved. Altogether, our results provide a major step forward for understanding the interplay between P. aeruginosa resistance profiles, high-risk clones and virulence.

PMID: 28923877 [PubMed - as supplied by publisher]

An Anti-Persister Strategy for the Treatment of Chronic Pseudomonas aeruginosa Infections.

Antimicrob Agents Chemother. 2017 Sep 18;:

Authors: Koeva M, Gutu AD, Hebert W, Wager JD, Yonker LM, O'Toole GA, Ausubel FM, Moskowitz SM, Joseph-McCarthy D

Abstract
Bacterial persisters are a quasi-dormant sub-population of cells that are tolerant to antibiotic treatment. The combination of the aminoglycoside tobramycin with fumarate as an antibacterial potentiator utilizes an anti-persister strategy that is aimed at reducing recurrent Pseudomonas aeruginosa infections by enhancing the killing of P. aeruginosa persisters. Stationary phase cultures of P. aeruginosa were used to generate persister cells. A range of tobramycin concentrations was tested with a range of metabolite concentrations to determine the potentiation effect of the metabolite under a variety of conditions, including a range of pH values and in the presence of azithromycin or cystic fibrosis (CF) patient sputum. In addition, 96-well dish biofilm and colony biofilm assays were performed, and the cytotoxicity of the tobramycin-fumarate combination was determined utilizing an LDH assay. Enhanced killing of up to 6 orders of magnitude of P. aeruginosa persisters over a range of CF isolates including mucoid and non-mucoid strains was observed for the tobramycin-fumarate combination compared to tobramycin alone. Furthermore, significant fumarate-mediated potentiation was seen in the presence of azithromycin or CF patient sputum. Fumarate also reduced the cytotoxicity of tobramycin treated P. aeruginosa to human epithelial airway cells. Finally, in mucoid and non-mucoid CF isolates, complete eradication of P. aeruginosa biofilm was observed in the colony biofilm assay due to fumarate potentiation. These data suggest that a combination of tobramycin with fumarate as an antibacterial potentiator may be an attractive therapeutic for eliminating recurrent P. aeruginosa infections in CF patients through the eradication of bacterial persisters.

PMID: 28923873 [PubMed - as supplied by publisher]

Blood flow regulation and oxidative stress during submaximal cycling exercise in patients with cystic fibrosis.

J Cyst Fibros. 2017 Sep 08;:

Authors: Tucker MA, Berry B, Seigler N, Davison GW, Quindry JC, Eidson D, McKie KT, Harris RA

Abstract
BACKGROUND: The impact of blood flow regulation and oxidative stress during exercise in cystic fibrosis (CF) has yet to be investigated.
METHODS: A maximal graded exercise test was conducted to determine exercise capacity (VO2 peak) and peak workload in 14 pediatric patients with mild CF (age 14±3y, FEV1 93±16 % predicted) and 14 demographically-matched controls. On a separate visit, participants performed submaximal cycling up to 60% of peak workload where brachial artery blood velocity was determined using Doppler ultrasound. Retrograde and antegrade components were further analyzed as indices of blood flow regulation.
RESULTS: The cumulative AUC for retrograde velocity was lower in patients versus controls (1770±554 vs. 3440±522cm, P=0.038). In addition, an exaggerated oxidative stress response during exercise occurred in patients only (P=0.004).
CONCLUSION: These data suggest that patients with mild CF exhibit impaired blood flow regulation and an exaggerated oxidative stress response to submaximal exercise.

PMID: 28923457 [PubMed - as supplied by publisher]

Outbreak of Burkholderia cepacia bacteraemia in a tertiary care centre due to contaminated ultrasound probe gel.

J Hosp Infect. 2017 Sep 15;:

Authors: Abdelfattah R, Aljumaah S, Alqahtani A, Althawadi S, Barron I, Almofada S

Abstract
BACKGROUND: Burkholderia cepacia is a significant opportunistic organism in hospitalized and immunocompromised patients, particularly in cystic fibrosis [1] AIMS: We describe the epidemiological investigation of an outbreak of B. cepacia bacteraemia.
METHODS: The study examined 14 patients during their admission to three ICUs (Intensive Care Units) in a tertiary care hospital between January-June 2016. The outbreak involved 9 (57%) female and 6 (43%) male patients. All patients were adults of ages ranging from 19-85 years with a median age of 52 years. Patients' medical charts, laboratory cultures, exposures, and central line insertion procedures were reviewed.
FINDINGS: B. cepacia was isolated from the blood cultures of 14 patients resulting from contamination of the gel applied to the ultrasound probe used to guide the insertion of a central venous catheter. Molecular pathogen typing using pulsed field gel electrophoresis showed 95% similarity between the B. cepacia isolates from the blood of these patients and those isolated from the ultrasound gel.
CONCLUSIONS: Ongoing surveillance and prompt investigation of unusual disease outbreaks are vital for identifying sources of contamination of B. cepacia and protecting at-risk patients. Sound epidemiological methods are very important for identifying the source of any hospital infection outbreak.

PMID: 28923373 [PubMed - as supplied by publisher]

Characterization of environmental Pseudomonas aeruginosa using multilocus sequence typing scheme.

J Med Microbiol. 2017 Sep 19;:

Authors: Radó J, Kaszab E, Petrovics T, Pászti J, Kriszt B, Szoboszlay S

Abstract
PURPOSE: The objectives of this study were to examine environmental (hydrocarbon degrading) Pseudomonas aeruginosa isolates with Multilocus Sequence Typing (MLST) and to determine their relevant features, such as serotype, virulence genes, biofilm forming ability and hydrocarbon degrading capacity.
METHODOLOGY: The diversity of environmental isolates was assessed with an MLST scheme. Investigation of virulence determinants included serotyping, hemolytic activity test and the detection of virulence genes exoS, exoY, exoT, exoU, exoA. Biofilm forming ability was examined in a modified microtiter assay, hydrocarbon degrading capacity was determined with gravimetric methods.
RESULTS: The majority of environmental isolates shared the same MLST profiles with isolates of cystic fibrosis (CF). Virulence patterns and serotypes were slightly connected to the phylogenetic localization, but further clinically important features such as antibiotic resistance were not. At least one of the examined environmental isolates was multidrug-resistant, virulent and had biofilm forming ability such as nosocomial P. aeruginosa and retained its hydrocarbon degradation ability.
CONCLUSION: The current theses that distinguish isolates originating from different sources are questionable; environmental P. aeruginosa can be a potential risk to public health and cannot be excluded as an external (non-nosocomial) source of infections, especially in patients with CF. Further studies such as pulsed-field gel electrophoresis (PFGE) and the determination of other clinically important virulence factors are needed to confirm these findings.

PMID: 28923132 [PubMed - as supplied by publisher]

Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice.

Respir Res. 2017 Sep 18;18(1):173

Authors: Raju SV, Rasmussen L, Sloane PA, Tang LP, Libby EF, Rowe SM

Abstract
BACKGROUND: Dysfunction in cystic fibrosis transmembrane conductance regulator (CFTR) can be elicited by cigarette smoke and is observed in patients with chronic bronchitis. We have previously demonstrated in human airway epithelial cell monolayers that roflumilast, a clinically approved phosphodiesterase 4 inhibitor that reduces the risk of exacerbations in chronic obstructive pulmonary disease patients with chronic bronchitis and a history of exacerbations, activates CFTR-dependent chloride secretion via a cAMP-mediated pathway, partially restores the detrimental effects of cigarette smoke on CFTR-mediated ion transport, and increases CFTR-dependent gastrointestinal fluid secretion in isolated murine intestine segments. Based on these findings, we hypothesized that roflumilast could improve CFTR-mediated chloride transport and induce secretory diarrhea in mice exhibiting cigarette smoke-induced CFTR dysfunction.
METHODS: A/J mice expressing wild type CFTR (+/+) were exposed to cigarette smoke or air with or without roflumilast and the effect of treatment on CFTR-dependent chloride transport was quantified using nasal potential difference (NPD) measurements in vivo and short-circuit current (Isc) analysis of trachea ex vivo. Stool specimen were collected and the wet/dry ratio measured to assess the effect of roflumilast on secretory diarrhea.
RESULTS: Acute roflumilast treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice (smoke, -2.0 ± 0.4 mV, 131.3 ± 29.3 μA/cm(2), P < 0.01 and air, 3.9 ± 0.8 mV, 147.7 ± 38.0 μA/cm(2), P < 0.01 vs. vehicle -0.3 ± 0.7 mV, 10.4 ± 7.0 μA/cm(2)). Oral administration of roflumilast over five weeks completely reversed the deleterious effects of cigarette smoke on CFTR function in smoke-exposed animals, in which CFTR-dependent chloride transport was 64% that of air controls (roflumilast, -15.22 ± 2.7 mV vs. air, -14.45 ± 1.4 mV, P < 0.05). Smoke exposure increased the wet/dry ratio of stool specimen to a level beyond which roflumilast had little additional effect.
CONCLUSIONS: Roflumilast effectively rescues CFTR-mediated chloride transport in vivo, further implicating CFTR activation as a mechanism through which roflumilast benefits patients with bronchitis.

PMID: 28923049 [PubMed - in process]

Meta-analyses and the evidence base for microbial outcomes in the treatment of pulmonary Mycobacterium avium-intracellulare complex disease.

J Antimicrob Chemother. 2017 Sep 01;72(suppl_2):i3-i19

Authors: Pasipanodya JG, Ogbonna D, Deshpande D, Srivastava S, Gumbo T

Abstract
Objectives: To perform a systematic review and meta-analysis of the level of funding support and the sputum culture conversion rates in pulmonary Mycobacterium avium-intracellulare complex (P-MAC) disease in adult patients without cystic fibrosis or HIV infection, treated with recommended antibiotic regimens.
Methods: We performed a literature search to identify clinical trials, prospective studies and registries that reported outcomes in P-MAC patients. Studies that reported P-MAC diagnosis and treatments based on established guidelines met the inclusion criteria and were examined for bias and quality. We modified existing quality scales and came up with a 10 star quality score. Outcomes meta-analysed were sputum conversion incidence ratios (IR) and their 95% CI, weighted for study quality.
Results: Twenty-one studies that examined 28 regimens, including 2534 patients in intent-to-treat analyses and 1968 in per-protocol analyses, were identified. The study quality mean ± SD scores were 5.4 ± 2.2 out of 10 stars. Only two (9.5%) studies received public funding. There was significant heterogeneity of microbial effect among treatment regimens (I2 > 40%; P > 0.001). The pooled IR for sustained sputum conversion was 0.54 (95% CI 0.45-0.63) for macrolide-containing regimens versus 0.38 (0.25-0.52) with macrolide-free regimens. Prolonging therapy duration beyond 12 months was associated with an average decline in sputum conversion to 22% (95% CI 1%-44%).
Conclusions: Researchers working on P-MAC therapy have received very little public funding support. As a result, the evidence base for treatment guidelines is based on studies of relatively small numbers of patients in low-quality studies. Nevertheless, these studies showed poor sputum conversion rates in patients receiving recommended treatment regimens.

PMID: 28922813 [PubMed - in process]

Susceptibility genes for nontuberculous mycobacterial disease.

Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(1):60-67

Authors: Namkoong H, Hasegawa N, Betsuyaku T

Abstract
  The number of patients with nontuberculous mycobacterial (NTM) disease is reportedly increasing both in Japan and worldwide. NTM diseases are classified into disseminated and pulmonary diseases based on their clinical characteristics. These two types of NTM diseases are thought to be controlled by different mechanisms. Disseminated NTM disease is caused by a defect in signal transduction of Th1 cellular immune responses, including the IFN-γ/IL-12 axis. The precise molecular mechanisms of disseminated NTM disease are understood in detail. Pulmonary NTM disease progression is associated with both bacterial factors as well as host factors. Furthermore, it is suggested that some susceptibility genes for NTM diseases may also exist. A previous study on the susceptibility genes for pulmonary NTM disease was performed using Single Nucleotide Polymorphism (SNP) analysis and microsatellite marker analysis. However, a number of challenges remain in terms of the reproducibility. The emergence of next generation sequencing enables genome-wide analysis, and further studies on the susceptibility genes for pulmonary NTM disease are expected in the future.

PMID: 28539556 [PubMed - indexed for MEDLINE]

Current status of domino heart transplantation.

J Card Surg. 2017 Mar;32(3):229-232

Authors: Shudo Y, Ma M, Boyd JH, Woo YJ

Abstract
Domino heart transplant, wherein the explanted heart from the recipient of an en-bloc heart-lung is utilized for a second recipient, represents a unique surgical strategy for patients with end-stage heart failure. With a better understanding of the potential advantages and disadvantages of this procedure, its selective use in the current era can improve and maximize organ allocation in the United States. In this report, we reviewed the current status of domino heart transplantation.

PMID: 28219115 [PubMed - indexed for MEDLINE]

Pharmacological Chaperones: Design and Development of New Therapeutic Strategies for the Treatment of Conformational Diseases.

ACS Chem Biol. 2016 06 17;11(6):1471-89

Authors: Convertino M, Das J, Dokholyan NV

Abstract
Errors in protein folding may result in premature clearance of structurally aberrant proteins, or in the accumulation of toxic misfolded species or protein aggregates. These pathological events lead to a large range of conditions known as conformational diseases. Several research groups have presented possible therapeutic solutions for their treatment by developing novel compounds, known as pharmacological chaperones. These cell-permeable molecules selectively provide a molecular scaffold around which misfolded proteins can recover their native folding and, thus, their biological activities. Here, we review therapeutic strategies, clinical potentials, and cost-benefit impacts of several classes of pharmacological chaperones for the treatment of a series of conformational diseases.

PMID: 27097127 [PubMed - indexed for MEDLINE]

MexXY efflux pump overexpression and aminoglycoside resistance in cystic fibrosis isolates of <i>Pseudomonas aeruginosa </i>from chronic infections.

Can J Microbiol. 2017 Sep 18;:

Authors: Singh M, Yau Y, Wang S, Waters V, Kumar A

Abstract
In this study, we analyzed 15 multidrug resistant cystic fibrosis isolates of Pseudomonas aeruginosa from chronic lung infections for expression of four different multidrug efflux systems, MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY, using quantitative reverse transcriptase-PCR. Overexpression of MexXY pump was observed in all of the isolates tested. Analysis of regulatory genes that control the expression of these four efflux pumps revealed a number of previously uncharacterized mutations. Our work shows that MexXY pump overexpression is common in cystic fibrosis isolates and could be contributing to their reduced aminoglycoside susceptibility. Further, we also identified novel mutations in the regulatory genes of four above-mentioned RND pumps that may be involved in the overexpression of these pumps.

PMID: 28922614 [PubMed - as supplied by publisher]

Elevated IgG4 serum levels in patients with cystic fibrosis.

PLoS One. 2017;12(9):e0181888

Authors: Clerc A, Reynaud Q, Durupt S, Chapuis-Cellier C, Nové-Josserand R, Durieu I, Lega JC

Abstract
OBJECTIVE: Serum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients.
METHODS: In a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL.
RESULTS: One hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations.
CONCLUSION: An elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

PMID: 28922375 [PubMed - in process]