Ceftaroline pharmacokinetics and pharmacodynamics in patients with cystic fibrosis.

J Cyst Fibros. 2017 Nov 02;:

Authors: Barsky EE, Pereira LM, Sullivan KJ, Wong A, McAdam AJ, Sawicki GS, Priebe GP, Goobie SM

Abstract
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a prevalent pathogen in patients with cystic fibrosis (CF) associated with increased morbidity. Ceftaroline fosamil is an intravenous (IV) cephalosporin with activity against MRSA. There are minimal data regarding dosing in the CF population. The objective of this study was to determine the pharmacokinetic and pharmacodynamic profile of IV ceftaroline in patients with CF.
METHODS: We conducted a single-center prospective study of children and young adults with CF receiving ceftaroline (15mg/kg IV up to 600mg every 8h) as part of treatment for a CF pulmonary exacerbation between June 2016 and April 2017. Seven patients were enrolled for a total of 10 treatment courses. For each treatment course, up to 8 plasma samples were assayed for ceftaroline using ultra-high performance liquid chromatography with mass spectrometry. Maximum plasma concentration, systemic clearance, and elimination half-life were calculated. The area under the curve (AUC) above the minimum inhibitory concentration (MIC) and the percent time above the MIC (%fT>MIC) were determined for each subject using MICs of 0.5, 1, and 2μg/mL and the measured MIC if available.
RESULTS: The mean (SD) age for the 7 patients was 20.3 (8.0) years. Mean (SD) maximum plasma concentration of ceftaroline was 22.7 (9.6) μg/mL, systemic clearance 7.9 (3.3) L/h, and half-life 1.1 (0.4) hours. Using a MIC of 1 μg/mL, accepted as the MIC 90 of MRSA isolates, AUC above MIC mean (SD) was 53.6 (19.5) μg·h/mL, mean (SD) %fT>MIC was 75.7 (10.4), and all subjects had >60%fT>MIC.
CONCLUSIONS: In this cohort of CF patients, mean ceftaroline half-life was 1.1h, which is notably lower than the general population. The dosing regimen studied, which exceeds the recommended dosing in the non-CF population, was adequate to achieve >60% time above the MIC in all patients.

PMID: 29103924 [PubMed - as supplied by publisher]

Effects of Ivacaftor in Three Pediatric Siblings With Cystic Fibrosis Carrying the Mutations G551D And F508del.

Arch Bronconeumol. 2017 Nov 02;:

Authors: Mainz JG, Arnold C, Hentschel J, Tabori H

PMID: 29103672 [PubMed - as supplied by publisher]

Intestinal Na+, K+, 2Cl- cotransporter 2 plays a crucial role in hyperosmotic transitions of a euryhaline teleost.

Physiol Rep. 2016 Nov;4(22):

Authors: Esbaugh AJ, Cutler B

Abstract
Euryhaline fishes, such as the red drum (Sciaenops ocellatus), must quickly transition between hyperosmotic and hypoosmotic physiological strategies. When freshwater individuals transition to seawater they are exposed to increased diffusive water loss and ion gain. To maintain osmoregulatory balance these animals must drink and absorb seawater through the intestine, followed by ion excretion at the gills. The ability of fishes to transition between strategies can limit the magnitude of osmotic shock that can be tolerated. Here, we demonstrate that red drum can tolerate direct transfer from freshwater to full-strength seawater with marginal impacts on osmotic balance, as indicated by plasma and muscle ion concentration, as well as muscle water. Seawater transition is concurrent with a significant increase in intestinal fluid volume. Typical patterns of osmoregulatory plasticity were observed in the gill with increased expression of nkcc1 and cftr Expression changes in the anterior intestine were observed after 24 h for nkcc2 with smaller and later responses observed for slc26a3, slc26a6, and nbc Immunofluorescence staining demonstrated similar patterns of NKCC localization in freshwater and seawater intestines; however, reduced basolateral staining of V-type ATPase was observed in seawater. Electrophysiological preparations demonstrated that seawater fish had increased absorptive current in the anterior intestine, which was significantly reduced in the presence of 10 μmol/L bumetanide. Overall, these results suggest that nkcc2 plays a crucial role during hyperosmotic transitions, and may be a more important complement to the well-known bicarbonate secretion pathway than generally considered.

PMID: 27881573 [PubMed - indexed for MEDLINE]

Cystic Fibrosis: Diagnosis and management

Book. 2017 10

Authors: National Guideline Alliance (UK)

Abstract
Cystic fibrosis is a multi-system genetic disorder affecting the lungs, pancreas, liver and intestine. It can have a significant impact on life expectancy and quality of life. The current median age of those who have died is 28 years and the median predicted survival is 45.1 years. Diagnosis is primarily made during newborn screening. The median age at diagnosis is 2 months and 1 in every 2500 babies born in the UK has cystic fibrosis. Approximately 60% of people on the UK CF registry are aged over 16 years. Many different mutations are responsible for cystic fibrosis. The UK CF registry shows that 90.8% of people with cystic fibrosis have one known genotype. However 8.9% of people have at least one unknown genotype. Lung function is often reduced in cystic fibrosis. The typical measure of lung function is forced expiratory volume in 1 second (FEV1). FEV1 is a key predictor of life expectancy in people with cystic fibrosis, and optimising lung function is a major goal of care. Lung infections are a cause of significant morbidity in cystic fibrosis. Chronic infection (for example with Staphlococcus aureus and Pseudomonas aeruginosa) may need long-term use of antibiotics. There is variation across the country in the multidisciplinary team structures used, the arrangements services make for providing care and in the resources available to support services. Particular problems may arise with smaller shared-care clinic arrangements. In some centres, both inpatient and outpatient facilities are limited. For example, there may be problems in arranging admission to single rooms with en-suite facilities. If adequate protocols are not in place, then there is a risk of cross-infection. By making robust recommendations based on the available evidence and best practice in cystic fibrosis care, this guideline will help improve care for this highly complex condition.

PMID: 29106796

Cost Effectiveness of Screening Individuals with Cystic Fibrosis for Colorectal Cancer.

Gastroenterology. 2017 Nov 01;:

Authors: Gini A, Zauber AG, Cenin DR, Omidvari AH, Hempstead SE, Fink AK, Lowenfels AB, Lansdorp-Vogelaar I

Abstract
BACKGROUND & AIMS: Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared to the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis.
METHODS: We adjusted the existing MISCAN-Colon microsimulation model to reflect increased CRC risk and lower life-expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess if optimal screening strategies would change.
RESULTS: Colonoscopy every 5 years, starting at an age of 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in population is not clear.
CONCLUSIONS: Using a MISCAN-Colon microsimulation model, we found screening of patients with cystic fibrosis for CRC to be cost effective. Due to the higher risk in these patients for CRC, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT screening) may be limited by restricted evidence available for patients with cystic fibrosis.

PMID: 29102616 [PubMed - as supplied by publisher]

Ion channels as targets to treat cystic fibrosis lung disease.

J Cyst Fibros. 2017 Oct 25;:

Authors: Martin SL, Saint-Criq V, Hwang TC, Csanády L

Abstract
Lung health relies on effective mucociliary clearance and innate immune defence mechanisms. In cystic fibrosis (CF), an imbalance in ion transport due to an absence of chloride ion secretion, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and a concomitant sodium hyperabsorption, caused by dyregulation of the epithelial sodium channel (ENaC), results in mucus stasis which predisposes the lungs to cycles of chronic infection and inflammation leading to lung function decline. An increased understanding of CFTR structure and function has provided opportunity for the development of a number of novel modulators targeting mutant CFTR however, it is important to also consider other ion channels and transporters present in the airways as putative targets for drug development. In this review, we discuss recent advances in CFTR biology which will contribute to further drug discovery in the field. We also examine developments to inhibit the epithelial sodium channel (ENaC) and potentially activate alternative chloride channels and transporters as a multi-tracked strategy to hydrate CF airways and restore normal mucociliary clearance mechanisms in a manner independent of CFTR mutation.

PMID: 29102290 [PubMed - as supplied by publisher]

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

Thorax. 2017 Nov 03;:

Authors: Dicker AJ, Crichton ML, Cassidy AJ, Brady G, Hapca A, Tavendale R, Einarsson GG, Furrie E, Elborn JS, Schembri S, Marshall SE, Palmer CNA, Chalmers JD

Abstract
BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.
METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD.
FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency.
INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

PMID: 29101284 [PubMed - as supplied by publisher]

Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation.

J Cyst Fibros. 2017 Oct 31;:

Authors: Wagener JS, Millar SJ, Mayer-Hamblett N, Sawicki GS, McKone EF, Goss CH, Konstan MW, Morgan WJ, Pasta DJ, Moss RB

Abstract
BACKGROUND: Patients with cystic fibrosis (CF) experience variable lung disease phenotypes. The R117H mutation is often associated with preserved lung function. Our objective was to compare the rate of lung function decline in patients with the R117H mutation and patients homozygous for the F508del mutation.
METHODS: Rate of decline in percentage-of-predicted FEV1 (ppFEV1) was analyzed using the 2006-2010 US CF Foundation Patient Registry.
RESULTS: 4-year rate of decline was slower in 156 R117H patients compared with 6251 F508del patients (-0.61 vs -2.03 ppFEV1/year, P<0.001). Rates of decline in children were slower in R117H vs F508del patients (6-12-year-olds: +0.73 vs -1.91 ppFEV1/year, P<0.001 and 13-17-year-olds: -1.55 vs -2.66 ppFEV1/year, P=0.046), whereas rates in adults were not significantly different (18-24-year-olds: -1.52 vs -2.12, P=0.26 and ≥25-year-olds: -1.17 vs -1.40, P=0.33).
CONCLUSIONS: These findings are consistent with a delayed onset, but ultimately similar progression, of lung disease in R117H compared with homozygous F508del patients.

PMID: 29100868 [PubMed - as supplied by publisher]

"NETtling" the host: Breaking of tolerance in chronic inflammation and chronic infection.

J Autoimmun. 2017 Oct 31;:

Authors: Skopelja-Gardner S, Jones JD, Rigby WFC

Abstract
How and why we break tolerance to self-proteins still remains a largely unanswered question. Neutrophils have been identified as a rich source of autoantigens in a wide array of autoimmune diseases that arise as a consequence of different environmental and genetic factors, e.g. rheumatoid arthritis (RA), lupus, vasculitis, cystic fibrosis (CF) etc. Specifically, neutrophil extracellular trap (NET) formation has been identified as a link between innate and adaptive immune responses in autoimmunity. Autoantigens including neutrophil granular proteins (targeted by anti-neutrophil cytoplasmic antibodies, ANCA) as well as post-translationally modified proteins, i.e. citrullinated and carbamylated proteins targeted by anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein antibodies (ACarPA), respectively, localize to the NETs. Moreover, NETs provide stimuli to dendritic cells that potentiate adaptive autoimmune responses. However, while NETs promote inflammation and appear to induce humoral autoreactivity across autoimmune diseases, the antigen specificity of autoantibodies found in these disorders is striking. These unique autoantigen signatures suggest that not all NETs are created equal and that the environment in which NETs arise shapes their disease-specific character. In this review article, we discuss the effects of different stimuli on the mechanism of NET formation as well as how they contribute to antigen specificity in the breaking of immune tolerance. Specifically, we compare and contrast the autoreactive nature of NETs in two settings of chronic airway inflammation: one triggered by smoking, a recognized environmental NET stimulus in RA patients, and one mediated by Pseudomonas aeruginosa, the most prevalent lung pathogen in CF patients. Finally, we draw attention to novel findings that, together with the specific environmental/chemical stimuli, should be taken into account when investigating how and why antigen specificity arises in the context of NET formation.

PMID: 29100671 [PubMed - as supplied by publisher]

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Electrochemical immunosensors for the detection of survival motor neuron (SMN) protein using different carbon nanomaterials-modified electrodes.

Biosens Bioelectron. 2017 Oct 10;101:282-289

Authors: Eissa S, Alshehri N, Rahman AMA, Dasouki M, Salah KMA, Zourob M

Abstract
Spinal muscular atrophy is an untreatable potentially fatal hereditary disorder caused by loss-of-function mutations in the survival motor neuron (SMN) 1 gene which encodes the SMN protein. Currently, definitive diagnosis relies on the demonstration of biallelic pathogenic variants in SMN1 gene. Therefore, there is an urgent unmet need to accurately quantify SMN protein levels for screening and therapeutic monitoring of symptomatic newborn and SMA patients, respectively. Here, we developed a voltammetric immunosensor for the sensitive detection of SMN protein based on covalently functionalized carbon nanofiber-modified screen printed electrodes. A comparative study of six different carbon nanomaterial-modified electrodes (carbon, graphene (G), graphene oxide (GO), single wall carbon nanotube (SWCNT), multi-wall carbon nanotube (MWCNT), and carbon nanofiber (CNF)) was performed. 4-carboxyphenyl layers were covalently grafted on the six electrodes by electroreduction of diazonium salt. Then, the terminal carboxylic moieties on the electrodes surfaces were utilized to immobilize the SMN antibody via EDC/NHS chemistry and to fabricate the immunosensors. The electrochemical characterization and analytical performance of the six immunosensors suggest that carbon nanofiber is a better electrode material for the SMN immunosensor. The voltammetric SMN carbon nanofiber-based immunosensor showed high sensitivity (detection limit of 0.75pg/ml) and selectivity against other proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and dystrophin (DMD). We suggest that this novel biosensor is superior to other developed assays for SMN detection in terms of lower cost, higher sensitivity, simplicity and capability of high throughput screening.

PMID: 29096367 [PubMed - as supplied by publisher]

The implications of CFTR structural studies for cystic fibrosis drug development.

Curr Opin Pharmacol. 2017 Oct 30;34:112-118

Authors: Callebaut I, Hoffmann B, Mornon JP

Abstract
Development of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators, targeting the root cause of cystic fibrosis (CF), represents a challenge in the era of personalized medicine, as CFTR mutations lead to a variety of phenotypes, which likely require different, specific treatments. CF drug development is also complicated by the need to preserve the right balance between stability and flexibility, required for optimal function of the CFTR protein. In this review, we highlight how structural data can be exploited in this context to understand the molecular mechanisms of disease-associated mutations, to characterize the mechanisms of action of known modulators and to rationalize the search for novel, specific compounds.

PMID: 29096277 [PubMed - as supplied by publisher]

Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases.

Am J Respir Cell Mol Biol. 2017 Nov 02;:

Authors: Saco TV, Breitzig MT, Lockey RF, Kolliputi N

Abstract
Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are three chronic pulmonary diseases that affect an estimated 420 million individuals across the globe. A key factor contributing to each of these conditions is mucus hypersecretion. While management of these diseases is vastly studied, researchers have only begun to scratch the surface of the mechanisms contributing to mucus hypersecretion. Epigenetic regulation of mucus hypersecretion, other than micro RNA (miRNA) post-translational modification, is even more scarcely researched. Detailed study of epigenetic mechanisms, such as DNA methylation and histone modification, could not only help to better understand these respiratory conditions, but also reveal new treatments for these crippling diseases. Since mucus hypersecretion is such a complex event, there are innumerous genes involved in the process, which is beyond the scope of a single review. Therefore, the purpose of this review is to narrow the focus and summarize specific epigenetic research that has been conducted on a few aspects of mucus hypersecretion in asthma, COPD, CF, and some cancers. Specifically, this article will emphasize the contribution of DNA methylation and histone modification of particular genes involved in mucus hypersecretion in order to identify possible targets for the development of future therapies for these conditions. Elucidating the role of epigenetics in these respiratory diseases may provide a breath of fresh air to millions of affected individuals around the world.

PMID: 29096066 [PubMed - as supplied by publisher]

Burkholderia puraquae sp. nov., a novel species of the Burkholderia cepacia complex isolated from hospital settings and agricultural soils.

Int J Syst Evol Microbiol. 2017 Nov 02;:

Authors: Martina P, Leguizamon M, Prieto CI, Sousa SA, Montanaro P, Draghi WO, Stämmler M, Bettiol M, de Carvalho CCCR, Palau J, Figoli C, Alvarez F, Benetti S, Lejona S, Vescina C, Ferreras J, Lasch P, Lagares A, Zorreguieta A, Leitão JH, Yantorno OM, Bosch A

Abstract
Bacteria from the Burkholderia cepacia complex (Bcc) are capable of causing severe infections in patients with cystic fibrosis (CF). These opportunistic pathogens are also widely distributed in natural and man-made environments. After a 12-year epidemiological surveillance involving Bcc bacteria from respiratory secretions of Argentinean patients with CF and from hospital settings, we found six isolates of the Bcc with a concatenated species-specific allele sequence that differed by more than 3 % from those of the Bcc with validly published names. According to the multilocus sequence analysis (MLSA), these isolates clustered with the agricultural soil strain, Burkholderia sp. PBP 78, which was already deposited in the PubMLST database. The isolates were examined using a polyphasic approach, which included 16S rRNA, recA, Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), DNA base composition, average nucleotide identities (ANIs), fatty acid profiles, and biochemical characterizations. The results of the present study demonstrate that the seven isolates represent a single novel species within the Bcc, for which the name Burkholderia puraquae sp. nov. is proposed. Burkholderia puraquae sp. nov. CAMPA 1040(T) (=LMG 29660(T)=DSM 103137(T)) was designated the type strain of the novel species, which can be differentiated from other species of the Bcc mainly from recA gene sequence analysis, MLSA, ANIb, MALDI-TOF MS analysis, and some biochemical tests, including the ability to grow at 42 °C, aesculin hydrolysis, and lysine decarboxylase and β-galactosidase activities.

PMID: 29095137 [PubMed - as supplied by publisher]

Chronic Rhinosinusitis.

Am Fam Physician. 2017 Oct 15;96(8):500-506

Authors: Sedaghat AR

Abstract
Chronic rhinosinusitis is an inflammatory disease of the paranasal sinuses that occurs in 1% to 5% of the U.S.
POPULATION: It may significantly decrease quality of life. Chronic rhinosinusitis is defined by the presence of at least two out of four cardinal symptoms (i.e., facial pain/pressure, hyposmia/anosmia, nasal drainage, and nasal obstruction) for at least 12 consecutive weeks, in addition to objective evidence. Objective evidence of chronic rhinosinusitis may be obtained on physical examination (anterior rhinoscopy, endoscopy) or radiography, preferably from sinus computed tomography. Treatment is directed at enhancing mucociliary clearance, improving sinus drainage/outflow, eradicating local infection and inflammation, and improving access for topical medications. First-line treatment is nasal saline irrigation and intranasal corticosteroid sprays. There may be a role for antibiotics in patients with evidence of an active, superimposed acute sinus infection. If medical management fails, endoscopic sinus surgery may be effective. Patients not responding to first-line medical therapy should be referred to an otolaryngologist, and selected patients with a history suggestive of other comorbidities (e.g., vasculitides, granulomatous diseases, cystic fibrosis, immunodeficiency) may also benefit from referral to an allergist or pulmonologist.

PMID: 29094889 [PubMed - in process]

Access to Primary Care and Subspecialty Care After Positive Cystic Fibrosis Newborn Screening.

WMJ. 2016 12;115(6):295-9

Authors: Parker-McGill K, Rosenberg M, Farrell P

Abstract
PROBLEM CONSIDERED: Accessibility by telephone to cystic fibrosis (CF) centers for a diagnostic sweat test appointment from a parental perspective—which can be stressful—compared to experience in contacting a general pediatrics practice in the same area.
METHODS: We called each CF center and affiliate twice, plus a sample of multiphysician general pediatrics practices selected from yellowpages.com after being matched by area and ZIP codes to 50 randomly selected CF centers, including Wisconsin’s 2 nationally accredited centers. After alerts to CF centers nationally, we made follow-up calls to randomly selected centers. A call was considered successful if the center or practice provided the time and date of the next available sweat test or well-baby checkup appointment.
RESULTS: In contrast to calls made to general pediatricians’ offices, in which 98% were successful and an appointment was available in an average of 8.6 days, only 31% of CF centers and affiliates could be contacted successfully. Although a sweat test appointment was available in 4.9 days on average, delays as long as 26 days were possible. In subsequent follow-up calls, only 40% were successful.
CONCLUSIONS: Substantial difficulties and inconsistencies were encountered in accessing CF centers, suggesting that parents often may be challenged in their efforts, while they generally have no difficulty contacting and scheduling an appointment with a general pediatrician. This contrasting experience could be stressful to parents when their baby has a positive screening test. The role of primary care physicians in newborn screening communications is increasingly important, while the role of regional centers needs reconsideration.

PMID: 29094862 [PubMed - in process]

Exophiala dermatitidis Revealing Cystic Fibrosis in Adult Patients with Chronic Pulmonary Disease.

Mycopathologia. 2017 Nov 01;:

Authors: Grenouillet F, Cimon B, Pana-Katatali H, Person C, Gainet-Brun M, Malinge MC, Le Govic Y, Richaud-Thiriez B, Bouchara JP

Abstract
Cystic fibrosis (CF) is a genetic inherited disease due to mutations in the gene cystic fibrosis transmembrane conductance regulator (CFTR). Because of the huge diversity of CFTR mutations, the CF phenotypes are highly heterogeneous, varying from typical to mild form of CF, also called atypical CF. These atypical features are more frequently diagnosed at adolescence or adulthood, and among clinical signs and symptoms leading to suspect a mild form of CF, colonization or infection of the respiratory tract due to well-known CF pathogens should be a warning signal. Exophiala dermatitidis is a melanized dimorphic fungus commonly detected in respiratory specimens from CF patients, but only very rarely from respiratory specimens from non-CF patients. We described here two cases of chronic colonization of the airways by E. dermatitidis, with recurrent pneumonia and hemoptysis in one patient, which led clinicians to diagnose mild forms of CF in these elderly patients who were 68- and 87-year-old. These cases of late CF diagnosis suggest that airway colonization or respiratory infections due to E. dermatitidis in patients with bronchiectasis should led to search for a mild form of CF, regardless of the age and associated symptoms. On a broader level, in patients with chronic respiratory disease and recurrent pulmonary infections, an allergic bronchopulmonary mycosis or an airway colonization by CF-related fungi like E. dermatitidis or some Aspergillus, Scedosporium or Rasamsonia species, should be considered as potential markers of atypical CF and should led clinicians to conduct investigations for CF diagnosis.

PMID: 29094263 [PubMed - as supplied by publisher]

Clinical chronic rhinosinusitis outcomes in pediatric patients with cystic fibrosis.

Laryngoscope Investig Otolaryngol. 2017 Oct;2(5):276-280

Authors: Virgin FW

Abstract
Objectives: Chronic rhinosinusitis and nasal polyposis are common conditions in cystic fibrosis (CF). Approximately 2-3% of pediatric CF patients per year have sinus disease requiring surgery. It has been well established that there is a significant negative impact on quality of life associated with chronic rhinosinusitis (CRS) in the non-CF patient population. However, the impact of CRS on the pediatric CF population remains uncertain. The purpose of this article is to review the current state of outcome measures for CRS in pediatric CF patients.
Data Sources: PubMed and EMBASE literature review.
Methods: PubMed and EMBASE electronic databases were searched using Boolean searches that incorporated mesh headings and plain language for quality of life, symptom evaluation, pediatric patients, and sinusitis/rhinosinusitis. Studies were included if the study primarily evaluated a pediatric Cystic Fibrosis-Chronic Rhinosinusitis (CF-CRS) population and the primary outcome measure was quality of life evaluation.
Results: The search yielded 34 unique articles. A total of 7 articles met inclusion criteria.
Conclusions: Despite the high frequency of chronic rhinosinusitis in the pediatric CF patient population, its impact on quality of life is not well understood. Currently there is a lack of a validated disease specific quality of life instruments available to assess the impact of CRS on the pediatric CF patient population.
Level of Evidence: 5.

PMID: 29094071 [PubMed]

Less common etiologies of exocrine pancreatic insufficiency.

World J Gastroenterol. 2017 Oct 21;23(39):7059-7076

Authors: Singh VK, Haupt ME, Geller DE, Hall JA, Quintana Diez PM

Abstract
Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malabsorption, results from primary pancreatic diseases or secondarily impaired exocrine pancreatic function. Besides cystic fibrosis and chronic pancreatitis, the most common etiologies of EPI, other causes of EPI include unresectable pancreatic cancer, metabolic diseases (diabetes); impaired hormonal stimulation of exocrine pancreatic secretion by cholecystokinin (CCK); celiac or inflammatory bowel disease (IBD) due to loss of intestinal brush border proteins; and gastrointestinal surgery (asynchrony between motor and secretory functions, impaired enteropancreatic feedback, and inadequate mixing of pancreatic secretions with food). This paper reviews such conditions that have less straightforward associations with EPI and examines the role of pancreatic enzyme replacement therapy (PERT). Relevant literature was identified by database searches. Most patients with inoperable pancreatic cancer develop EPI (66%-92%). EPI occurs in patients with type 1 (26%-57%) or type 2 diabetes (20%-36%) and is typically mild to moderate; by definition, all patients with type 3c (pancreatogenic) diabetes have EPI. EPI occurs in untreated celiac disease (4%-80%), but typically resolves on a gluten-free diet. EPI manifests in patients with IBD (14%-74%) and up to 100% of gastrointestinal surgery patients (47%-100%; dependent on surgical site). With the paucity of published studies on PERT use for these conditions, recommendations for or against PERT use remain ambiguous. The authors conclude that there is an urgent need to conduct robust clinical studies to understand the validity and nature of associations between EPI and medical conditions beyond those with proven mechanisms, and examine the potential role for PERT.

PMID: 29093615 [PubMed - in process]

Thiol-benzo-triazolo-quinazolinone covalently modifies Alg44 to inhibit c-di-GMP binding and reduces alginate production by Pseudomonas aeruginosa.

ACS Chem Biol. 2017 Nov 01;:

Authors: Zhou E, Seminara AB, Kim SK, Hall CL, Wang Y, Lee VT

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that affects a large proportion of cystic fibrosis (CF) patients. CF patients have dehydrated mucus within the airways that leads to the inability of the mucociliary escalator to expel inhaled microbes. Once inhaled, P. aeruginosa can persist in the lungs of the CF patients for the remainder of their lives. During this chronic infection, a phenomenon called mucoid conversion can occur in which P. aeruginosa can mutate and inactivate their mucA gene. As a consequence, transcription of the alg operon is highly expressed leading to the copious secretion of the alginate exopolysaccharide, which is associated with decreased lung function and increased CF patient morbidity and mortality. Alginate biosynthesis by P. aeruginosa is post-translationally regulated by bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), which binds to the receptor protein Alg44 to activate alginate production. The identification of small molecules that disrupt the binding of c-di-GMP to Alg44 could inhibit the ability of P. aeruginosa to produce alginate. In this work, a class of thiol-benzo-triazolo-quinazolinone compounds that inhibited Alg44 binding to c-di-GMP in vitro was identified after screening chemical libraries consisting of ~50,000 chemical compounds. Thiol-benzo-triazolo-quinazolinones were shown to specifically inhibit Alg44-c-di-GMP interactions by forming a disulfide bond with the cysteine residue in the PilZ domain of Alg44. The more potent thiol-benzo-triazolo-quinazolinone had the ability to reduce P. aeruginosa alginate secretion by up to 30%. These compounds serve as leads in the development of novel inhibitors of alginate production by P. aeruginosa after mucoid conversion.

PMID: 29091392 [PubMed - as supplied by publisher]