Formulation And Comparison Of Spray Dried Non-Porous And Large Porous Particles Containing Meloxicam For Pulmonary Drug Delivery.

Int J Pharm. 2019 Jan 21;:

Authors: Chvatal A, Ambrus R, Party P, Katona G, Jójárt-Laczkovich O, Szabó-Révész P, Fattal E, Tsapis N

Abstract
Meloxicam is an anti-inflammatory drug that could be interesting to deliver locally to the lungs to treat inflammation occurring in cystic fibrosis or chronic obstructive pulmonary disease (COPD). Spray drying conditions were optimized to prepare inhalable dry powders, from meloxicam aqueous solution with pH adjustment. A comparison study between non-porous and large porous particles (LPPs) was carried out to demonstrate the relevance of the aimed large size (>5 µm) and low density (<0.2 mg/cm3) formulations. With the appropriate amount of porogen agent, ammonium bicarbonate, LPPs exhibited the same aerodynamic diameter and a higher deposited fraction than smaller but dense particles. The aerodynamic evaluation of LPPs showed that the fine particle fraction (FPF) reached up to 65.8%, while the emitted fraction (EF) reached 85.4%, both higher than for the non-porous particles. Stability tests demonstrated that, after 10 weeks of storage, no significant difference could be detected in the aerodynamic behaviour of the formulations. To the best of our knowledge this is the first time large porous particles, with enhanced aerodynamic properties, from an aqueous solution of meloxicam are reported.

PMID: 30677482 [PubMed - as supplied by publisher]

Inhalation treatment of cystic fibrosis with lumacaftor and ivacaftor co-delivered by nanostructured lipid carriers.

J Control Release. 2019 Jan 21;:

Authors: Garbuzenko OB, Kbah N, Kuzmov A, Pogrebnyak N, Pozharov V, Minko T

Abstract
Cystic fibrosis (CF), a most deadly genetic disorder, is caused by mutations of CF transmembrane receptor (CFTR) - a chloride channel present at the surface of epithelial cells. In general, two steps have to be involved in treatment of the disease: correction of cellular defects and potentiation to further increase channel opening. Consequently, a combinatorial simultaneous treatment with two drugs with different mechanisms of action, lumacaftor and ivacaftor, has been recently proposed. While lumacaftor is used to correct p.Phe508del mutation (the loss of phenylalanine at position 508) and increase the amount of cell surface-localized CFTR protein, ivacaftor serves as a CFTR potentiator that increases the open probability of CFTR channels. Since the main organ that is affected by cystic fibrosis is the lung, the delivery of drugs directly to the lungs by inhalation has a potential to enhance the efficacy of the treatment of CF and limit adverse side effects upon healthy tissues and organs. Based on our extensive experience in inhalation delivering of drugs by different nanocarriers, we selected nanostructured lipid carriers (NLC) for the delivery both drugs directly to the lungs by inhalation and tested NLC loaded with drugs in vitro (normal and CF human bronchial epithelial cells) and in vivo (homozygote/homozygote bi-transgenic mice with CF). The results show that the designed NLCs demonstrated a high drug loading efficiency and were internalized in the cytoplasm of CF cells. It was found that NLC-loaded drugs were able to restore the expression and function of CFTR protein. As a result, the combination of lumacaftor and ivacaftor delivered by lipid nanoparticles directly into the lungs was highly effective in treating lung manifestations of cystic fibrosis.

PMID: 30677435 [PubMed - as supplied by publisher]

Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews.

Cochrane Database Syst Rev. 2019 Jan 24;1:CD011231

Authors: Wilson LM, Morrison L, Robinson KA

Abstract
BACKGROUND: Cystic fibrosis is a life-limiting genetic condition in which thick mucus builds up in the lungs, leading to infections, inflammation, and eventually, deterioration in lung function. To clear their lungs of mucus, people with cystic fibrosis perform airway clearance techniques daily. There are various airway clearance techniques, which differ in terms of the need for assistance or equipment, and cost.
OBJECTIVES: To summarise the evidence from Cochrane Reviews on the effectiveness and safety of various airway clearance techniques in people with cystic fibrosis.
METHODS: For this overview, we included Cochrane Reviews of randomised or quasi-randomised controlled trials (including cross-over trials) that evaluated an airway clearance technique (conventional chest physiotherapy, positive expiratory pressure (PEP) therapy, high-pressure PEP therapy, active cycle of breathing techniques, autogenic drainage, airway oscillating devices, external high frequency chest compression devices and exercise) in people with cystic fibrosis.We searched the Cochrane Database of Systematic Reviews on 29 November 2018.Two review authors independently evaluated reviews for eligibility. One review author extracted data from included reviews and a second author checked the data for accuracy. Two review authors independently graded the quality of reviews using the ROBIS tool. We used the GRADE approach for assessing the overall strength of the evidence for each primary outcome (forced expiratory volume in one second (FEV1), individual preference and quality of life).
MAIN RESULTS: We included six Cochrane Reviews, one of which compared any type of chest physiotherapy with no chest physiotherapy or coughing alone and the remaining five reviews included head-to-head comparisons of different airway clearance techniques. All the reviews were considered to have a low risk of bias. However, the individual trials included in the reviews often did not report sufficient information to adequately assess risk of bias. Many trials did not sufficiently report on outcome measures and had a high risk of reporting bias.We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV1, except for reporting no difference between PEP therapy and oscillating devices after six months of treatment, mean difference -1.43% predicted (95% confidence interval -5.72 to 2.87); the quality of the body of evidence was graded as moderate. The quality of the body of evidence comparing different airway clearance techniques for other outcomes was either low or very low.
AUTHORS' CONCLUSIONS: There is little evidence to support the use of one airway clearance technique over another. People with cystic fibrosis should choose the airway clearance technique that best meets their needs, after considering comfort, convenience, flexibility, practicality, cost, or some other factor. More long-term, high-quality randomised controlled trials comparing airway clearance techniques among people with cystic fibrosis are needed.

PMID: 30676656 [PubMed - as supplied by publisher]

Sleep hygiene in patients with chronic respiratory disease.

Nursing. 2019 Feb;49(2):64-69

Authors: Dobson L, Stutzman SE, Hicks AD, Olson DM

Abstract
PURPOSE: This study assessed the effectiveness of patient-directed interventions for improving sleep quality in patients with cystic fibrosis and pulmonary hypertension.
METHODS: A nonrandomized, prospective pilot study was used to monitor the effectiveness of patient-initiated sleep preferences in 15 hospitalized patients.
RESULTS: During their stay, 53.3% of patients reported better sleep associated with the intervention, supporting the need for and efficacy of patient-driven sleep interventions.
CONCLUSION: Patients unanimously recognized the need for sleep interventions and were open to seeking a good sleep hygiene regimen to improve their sleep quality while in the hospital.

PMID: 30676563 [PubMed - in process]

Pandoraea fibrosis sp. nov., a novel Pandoraea species isolated from clinical respiratory samples.

Int J Syst Evol Microbiol. 2019 Jan 24;:

Authors: See-Too WS, Ambrose M, Malley R, Ee R, Mulcahy E, Manche E, Lazenby J, McEwan B, Pagnon J, Chen JW, Chan KG, Turnbull L, Whitchurch CB, Roddam LF

Abstract
Pandoraea species have been isolated from diverse environmental samples and are emerging important respiratory pathogens, particularly in people with cystic fibrosis (CF). In the present study, two bacterial isolates initially recovered from consecutive sputum samples collected from a CF patient and identified as Pandoraea pnomenusa underwent a polyphasic taxonomic analysis. The isolates were found to be Gram-negative, facultative anaerobic motile bacilli and subsequently designated as strains 6399T (=LMG29626T=DSM103228T) and 7641 (=LMG29627=DSM103229), respectively. Phylogenetic analysis based on 16S rRNA and gyrB gene sequences revealed that 6399T and 7641 formed a distinct phylogenetic lineage within the genus Pandoraea. Genome sequence comparison analysis indicated that strains 6399T and 7641 are clonal and share 100 % similarity, however, similarity to other type strains (ANIb 73.2-88.8 %, ANIm 83.5-89.9 % and OrthoANI 83.2-89.3 %) indicates that 6399T and 7641 do not belong to any of the reported type species. The major cellular fatty acids of 6399T were C16 : 0 (32.1 %) C17 : 0cyclo (18.7 %) and C18 : 1ω7c (14.5 %), while Q-8 was the only respiratory quinone detected. The major polar lipids identified were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The genomic DNA G+C content of 6399T was 62.9 (mol%). Strain 6399T can be differentiated from other members of Pandoraea by the absence of C19 : 0ω8c cyclo and by the presence of C17 : 0ω8c cyclo. Together our data show that the bacterial strains 6399T and 7641 represent a novel species of the genus Pandoraea, for which the name Pandoraea fibrosis sp. nov. is proposed (type strain 6399T).

PMID: 30676309 [PubMed - as supplied by publisher]

Delivery of nucleic acids to ex vivo porcine airways using electrospray.

Exp Lung Res. 2019 Jan 24;:1-12

Authors: Riddell P, Gilbert JL, Molloy EL, Finnegan S, Egan JJ, O'Dea S

Abstract
AIM OF THE STUDY: Nucleic acid-based therapies have the potential to provide clinically meaningful benefit across a wide spectrum of lung disease. However, in vivo delivery remains a challenge. Here we examined the feasibility of using electrospray to deliver nucleic acids to both porcine tracheal tissue sections and whole lung ex vivo.
MATERIALS AND METHODS: The effect of electrospray solution, emitter gauge, flow rate and voltage on plasmid DNA integrity was examined by analyzing supercoiled:open circle structure ratio by gel electrophoresis. Optimal parameters were used to deliver luciferase DNA and mRNA and siRNA-FITC to tracheal tissue sections. Luciferase mRNA was delivered to whole porcine lungs ex vivo using a catheter and bronchoscope system. Luciferase activity and fluorescence were analyzed by luminometry and microscopy respectively.
RESULTS: The incidence of DNA plasmid nicking was greatest in a low salt solution without ethanol compared with 1% and 20% ethanol with salt. From a range of emitters tested, a 32 gauge emitter produced the best supercoiled:open circle structure ratio, likely because less voltage was required to produce a stable electrospray with this emitter. Lower flow rates also showed a trend towards reduced DNA nicking. GFP DNA electrosprayed at 5 kV and 6 kV resulted in lower levels of GFP expression in A549 lung cells following lipofection compared with 3 kV and 4 kV. Optimised parameters of 20% ethanol solution, 32 gauge emitter, low flow rates and voltages of 3-5 kV, nucleic acid molecules were successful for delivery of luciferase DNA and mRNA as well as siRNA-FITC to porcine tracheal tissue sections and for delivery of luciferase mRNA to whole porcine lungs via bronchoscope.
CONCLUSIONS: We report ex vivo delivery of nucleic acids to porcine lung tissue via electrospray and bronchoscopic electrospray delivery of nucleic acid to an ex vivo porcine lung model.

PMID: 30675820 [PubMed - as supplied by publisher]

Microbiome networks and change-point analysis reveal key community changes associated with cystic fibrosis pulmonary exacerbations.

NPJ Biofilms Microbiomes. 2019;5:4

Authors: Layeghifard M, Li H, Wang PW, Donaldson SL, Coburn B, Clark ST, Caballero JD, Zhang Y, Tullis DE, Yau YCW, Waters V, Hwang DM, Guttman DS

Abstract
Over 90% of cystic fibrosis (CF) patients die due to chronic lung infections leading to respiratory failure. The decline in CF lung function is greatly accelerated by intermittent and progressively severe acute pulmonary exacerbations (PEs). Despite their clinical impact, surprisingly few microbiological signals associated with PEs have been identified. Here we introduce an unsupervised, systems-oriented approach to identify key members of the microbiota. We used two CF sputum microbiome data sets that were longitudinally collected through periods spanning baseline health and PEs. Key taxa were defined based on three strategies: overall relative abundance, prevalence, and co-occurrence network interconnectedness. We measured the association between changes in the abundance of the key taxa and changes in patient clinical status over time via change-point detection, and found that taxa with the highest level of network interconnectedness tracked changes in patient health significantly better than taxa with the highest abundance or prevalence. We also cross-sectionally stratified all samples into the clinical states and identified key taxa associated with each state. We found that network interconnectedness most strongly delineated the taxa among clinical states, and that anaerobic bacteria were over-represented during PEs. Many of these anaerobes are oropharyngeal bacteria that have been previously isolated from the respiratory tract, and/or have been studied for their role in CF. The observed shift in community structure, and the association of anaerobic taxa and PEs lends further support to the growing consensus that anoxic conditions and the subsequent growth of anaerobic microbes are important predictors of PEs.

PMID: 30675371 [PubMed - in process]

Letter to editor.

Patient Educ Couns. 2018 11;101(11):2039-2040

Authors: Nave E, Bignamini E

PMID: 30087022 [PubMed - indexed for MEDLINE]

The correlation between age and sweat chloride levels in sweat tests.

Rev Port Pneumol (2006). 2017 Jul - Aug;23(4):227-230

Authors: Faria AG, Marson FAL, Ribeiro AF, Ribeiro JD

PMID: 28038996 [PubMed - indexed for MEDLINE]

Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol-Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties.

AAPS PharmSciTech. 2019 Jan 23;20(2):85

Authors: Liu C, Lin L, Huang Z, Wu Q, Jiang J, Lv L, Yu X, Quan G, Li G, Wu C

Abstract
Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03 μm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.

PMID: 30673901 [PubMed - in process]

A safety lancet for neonatal blood spot tests: a design that facilitates pain-free, atraumatic samples.

Br J Nurs. 2019 Jan 24;28(2):S24-S28

Authors: Goodwin S, Supachana N

Abstract
Safety lancets are used to collect capillary blood samples to test if neonates have rare but serious congenital conditions, such as sickle cell disease, cystic fibrosis, congenital hypothyroidism and inherited metabolic diseases. Blood samples are taken from the heel, but the procedure can cause the neonate pain or discomfort, as well as a risk of local trauma to the nerves and blood vessels, bleeding, infection and scarring. This article explores the need for blood sampling in neonates, discusses the procedure and outlines the types of lancets available. It describes the Neoheel Safety Lancet (Smiths Medical), whose features are designed to avoid pain and trauma during the procedure. Three case studies are included to describe its use in clinical practice.

PMID: 30673311 [PubMed - in process]

Arthropathy and Cutaneous Eruption in a Patient With Cystic Fibrosis.

JAMA Dermatol. 2019 Jan 23;:

Authors: Luu LA, Guffey DJ, Zlotoff BJ

PMID: 30673074 [PubMed - as supplied by publisher]

Nocturnal oximetry in children with obstructive lung disease or sleep-disordered breathing.

Pediatr Pulmonol. 2019 Jan 22;:

Authors: Katsouli G, Polytarchou A, Tsaoussoglou M, Loukou I, Chrousos G, Kaditis AG

Abstract
OBJECTIVES: Although progress has been made in the standardized interpretation of nocturnal oximetry in children with obstructive sleep-disordered breathing (SDB), no evidence exists on oximetry abnormalities in other respiratory disorders. We aimed to compare obstructive lung disease (OLD) and SDB regarding nocturnal oximetry parameters.
METHODS: We analyzed oximetry recordings from children with (i) OLD (obliterative bronchiolitis; cystic fibrosis); (ii) snoring and adenotonsillar hypertrophy (SDB); and (iii) no respiratory disorder (controls). The three groups were compared regarding: (i) oxygen desaturation of hemoglobin index (SpO2 drops ≥3%/h-ODI3) and (ii) basal SpO2 (average SpO2 between SpO2 drops). The associations of oximetry parameters (natural logarithm) with study group were tested using linear regression including age as covariate.
RESULTS: Data of 16 subjects with OLD (median age: 7.3 years; Q25, Q75: 5.4, 12), 22 children with SDB (6.3 years; 4, 9) and 22 controls (6.8 years; 5.6, 10.3) were analyzed. Children with OLD or SDB had significantly lower basal SpO2 than controls (91.9% [90.8, 93.4] vs 96.3% [96, 97.4] vs 97.6% [97.1, 97.9]; P < 0.01). No subjects in the SDB or control groups had basal SpO2  < 95%. Children with SDB had significantly higher ODI3 than children with OLD or controls [8.4 episodes/h (6.2, 16.6) vs 4.4 episodes/h (3.6, 6.6) vs 2 episodes/h (1.3, 2.7); P < 0.01]. OLD had the greatest negative effect on basal SpO2 (R2  = 0.62; P < 0.001) and SDB the greatest positive effect on ODI3 (R2  = 0.34; P < 0.001).
CONCLUSION: OLD is associated mostly with reduced basal SpO2 , whereas SDB is characterized by elevated ODI3.

PMID: 30672145 [PubMed - as supplied by publisher]

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study.

Pediatr Pulmonol. 2019 Jan 22;:

Authors: Goetz D, Kopp BT, Salvator A, Moore-Clingenpeel M, McCoy K, Leung DH, Kloster M, Ramsey BR, Heltshe SH, Borowitz D

Abstract
IMPORTANCE: Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence.
OBJECTIVE: To report observations about pulmonary correlates of growth and other clinical features in infants with CF.
METHODS: We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life.
RESULTS: Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal = 0; maximum score = 100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR = 5.47; 95%CI = 1.36, 21.92; P = 0.02) or PPI plus histamine-2 (H2) blocker (OR = 8.2; 95%CI = 2.41, 27.93; P = 0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade.
CONCLUSIONS: Cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants.
TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).

PMID: 30672141 [PubMed - as supplied by publisher]

Reframing health and illness: a collaborative autoethnography on the experience of health and illness transformations in the life course.

Sociol Health Illn. 2019 Jan 22;:

Authors: Nowakowski ACH, Sumerau JE

Abstract
In this collaborative autoethnography, we examine the processes whereby people may reframe their interpretations and understandings of health and illness as a result of new diagnostic information. In so doing, we utilise the first author's experience receiving a conclusive diagnosis of cystic fibrosis after years of misdiagnosis to outline some ways changes in diagnosis facilitate shifts in illness management, the nature of health and illness and the experience of the self in relation to health and medicine. Furthermore, we discuss the ways this case reveals the importance of examining and comparing the social construction and transformation of health and illness within and between different individual and collective lived experiences over time. In closing, we draw out theoretical and empirical implications for understanding transformations in the nature of health and illness over the life course as well as future directions for research investigating shifts in illness management and understanding over time (A virtual abstract of this paper is available to view at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA).

PMID: 30671982 [PubMed - as supplied by publisher]

Establishment of a ΔF508-CF promyelocytic cell line for cystic fibrosis research and drug screening.

J Cyst Fibros. 2019 Jan;18(1):44-53

Authors: Jennings S, Ng HP, Wang G

Abstract
Cystic fibrosis (CF), one of the most common genetic disorders, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In spite of significant improvement in patient life expectancy, the disease remains lethal and incurable. Clinically, CF lung disease claims the most morbidity and mortality, characterized by chronic bacterial infection, persistent neutrophilic inflammation, and purulent small airway obstruction. Although all these manifestations are highly associated with neutrophils, the actual role of this phagocyte in the disease pathogenesis has not been fully appreciated. One of the major obstacles impeding such progress is the lack of CF neutrophil cell lines. Taking advantage of the new CRISPR/Cas9 gene-editing technology, we have generated a homozygous ΔF508-CF promyelocytic cell line from HL-60 cells, from which unlimited CF neutrophil cells can be differentiated. The derived cells showed defective CFTR presentation, deficient phagosomal hypochlorous acid (HOCl) production, and compromised microbial killing. Such a phenotype recapitulates that of primary neutrophils from CF patients. Thus, the established human CF promyelocytic cell line should be a useful tool for future CF basic research and drug screening.

PMID: 30670178 [PubMed - in process]

Histone Acetylation Promotes Neutrophil Extracellular Trap Formation.

Biomolecules. 2019 Jan 18;9(1):

Authors: Hamam HJ, Khan MA, Palaniyar N

Abstract
Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation. However, the importance of other forms of histone modifications in NETosis has not been established. We considered that acetylation of histones would also facilitate NETosis. To test this hypothesis, we induced NOX-dependent NETosis in human neutrophils with phorbol myristate acetate or lipopolysaccharide (from Escherichia coli 0128), and NOX-independent NETosis with calcium ionophores A23187 or ionomycin (from Streptomyces conglobatus) in the presence or absence of two pan histone deacetylase inhibitors (HDACis), belinostat and panobinostat (within their half maximal inhibitory concentration (IC50) range). The presence of these inhibitors increased histone acetylation (e.g., AcH4) in neutrophils. Histone acetylation was sufficient to cause a significant increase (~20%) in NETosis in resting neutrophils above baseline values. When acetylation was promoted during NOX-dependent or -independent NETosis, the degree of NETosis additively increased (~15⁻30%). Reactive oxygen species (ROS) production is essential for baseline NETosis (mediated either by NOX or mitochondria); however, HDACis did not promote ROS production. The chromatin decondensation step requires promoter melting and transcriptional firing in both types of NETosis; consistent with this point, suppression of transcription prevented the NETosis induced by the acetylation of histones. Collectively, this study establishes that histone acetylation (e.g., AcH4) promotes NETosis at baseline, and when induced by both NOX-dependent or -independent pathway agonists, in human neutrophils. Therefore, we propose that acetylation of histone is a key component of NETosis.

PMID: 30669408 [PubMed - in process]

Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees.

Mol Genet Genomic Med. 2018 11;6(6):1097-1103

Authors: Yang B, Wang X, Zhang W, Li H, Wang B

Abstract
BACKGROUND: Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility. Mutations of CFTR caused the majority of CBAVD cases, and ADGRG2 was recently identified as a new pathogenic gene. Yet, most of the genetic evidence came from sporadic cases, and only one mutation in CFTR can be found in patients.
METHODS: In present study, we collected two CBAVD pedigrees, each having two affected male siblings. We performed whole exome sequencing on all patients and validated all potential variants by Sanger sequencing.
RESULTS: We excluded ADGRG2 variants but identified compound heterozygous variants of CFTR in both families (NM_000492.3:c.1210-33_1210-6GT[13]T[5] and c.4056G>C;p.Gln1352Cys in pedigree 1, c.592G>C;p.Ala198Pro and c.3717G>A;p.Arg1239= in pedigree 2), which were subsequently validated by direct sequencing. c.1210-33_1210-6GT[13]T[5] (also known as IVS8-T5-TG13) was a known disease-causing variant causing the skipping of exon 9 of CFTR and inherited from the proband's mother. p.Gln1352Cys and Ala198Pro were rare or novel in public databases and predicted to be deleterious. The p.Arg1239= was a synonymous variant but located at the end of an exon, which was predicted to alter the splicing pattern.
CONCLUSION: Our study, in which compound heterozygous variants were identified in two pedigrees, provides more familial evidence that only recessive variants (homozygous or compound heterozygous) in CFTR cause CBAVD. Furthermore, whole exome sequencing may be utilized as a useful tool for mutation screening of genes causing CBAVD.

PMID: 30450785 [PubMed - indexed for MEDLINE]

Efficacy and effectiveness of Ceftaroline Fosamil in patients with pneumonia: a systematic review and meta-analysis.

Respir Res. 2018 Oct 23;19(1):205

Authors: Sotgiu G, Aliberti S, Gramegna A, Mantero M, Di Pasquale M, Trogu F, Saderi L, Blasi F

Abstract
BACKGROUND: Pneumonia is a relevant clinical and public health issue worldwide frequently associated with infections caused by Multi-Drug Resistant (MDR) pathogens. Ceftaroline fosamil is a promising new antibiotics with broad-spectrum bacterial activity. The aim of this systematic review and meta-analysis is to assess the efficacy and the effectiveness of ceftaroline fosamil in community-acquired (CAP), hospital-acquired (HAP), healthcare-associated (HCAP) and ventilator-associated (VAP) pneumonia.
METHODS: A systematic review and meta-analysis was carried out retrieving both experimental and observational studies.
RESULTS: A total of 2364 records was found and 14 manuscripts were finally considered eligible. The pooled efficacy/effectiveness was 81.2% (I2: 1.2%) in all types of pneumonia. The pooled relative risk of clinical cure was 1.1 (I2: 0.0%). The success rate was higher than 70% for infections caused by S. pneumoniae and S. aureus, including MDR pathogens.
CONCLUSIONS: Ceftaroline fosamil showed a high efficacy/effectiveness in patients with any type of pneumonia with a good safety profile.

PMID: 30352588 [PubMed - indexed for MEDLINE]

Dietary Factors Modulate Colonic Tumorigenesis Through the Interaction of Gut Microbiota and Host Chloride Channels.

Mol Nutr Food Res. 2018 03;62(5):

Authors: Zhang Y, Kang C, Wang XL, Zhou M, Chen MT, Zhu XH, Liu K, Wang B, Zhang QY, Zhu JD, Mi MT

Abstract
SCOPE: In recent decades, the association among diet, gut microbiota, and the risk of colorectal cancer (CRC) has been established. Gut microbiota and associated metabolites, such as bile acids and butyrate, are now known to play a key role in CRC development. The aim of this study is to identify that the progression to CRC is influenced by cholic acid, sodium butyrate, a high-fat diet, or different dose of dihydromyricetin (DMY) interacted with gut microbiota.
METHODS AND RESULTS: An AOM/DSS (azoxymethan/dextran sodium sulfate) model is established to study the gut microbiota compsition before and after tumor formation during colitis-induced tumorigenesis. All above dietary factors profoundly influence the composition of gut microbiota and host colonic tumorigenesis. In addition, mice with DMY-modified initial microbiota display different degrees of chemically induced tumorigenesis. Mechanism analysis reveals that gut microbiota-associated chloride channels participated in colon tumorigenesis.
CONCLUSION: Gut microbiota changes occur in the hyperproliferative stage before tumor formation. Gut microbiota and host chloride channels, both of which are regulated by dietary factors, are associated with CRC development.

PMID: 29331105 [PubMed - indexed for MEDLINE]