Hereditary pancreatitis of 3 Chinese children: Case report and literature review.

Medicine (Baltimore). 2016 Sep;95(36):e4604

Authors: Dai LN, Chen YW, Yan WH, Lu LN, Tao YJ, Cai W

Abstract
BACKGROUND: Hereditary pancreatitis (HP) is quite rare and is distinguished by incomplete penetrance presentation as early-onset relapsing pancreatitis, usually beginning in childhood. HP is now known to be commonly relevant to mutations in the PRSS1 (gene-encoding cationic trypsinogen), SPINK1 (serine protease inhibitor, Kazal type 1), CFTR (cystic fibrosis), carboxypeptidase A1 (CPA1), and chymotrypsin C (CTRC) genes as reported in some Caucasian studies. HP has a variable spectrum of severity and may develop complications.
METHODS & RESULTS: We describe the clinical course of 3 preschool children, hospitalized with postprandial abdominal pain, whose laboratory tests showed high serum amylase. Similar episodes of abdominal pain led to readmission, and the patients recovered quickly after using symptomatic therapy. The condition of the first boy, who developed a pancreatic tail pseudocyst and splenic infarction, was especially complicated. The boy underwent 2 endoscopic retrograde cholangiopancreatographies and stenting, along with a surgical procedure that completely relieved his symptoms for 3 months. The 3 patients and their parents were given genetic testing. All of the patients carried 1 or more gene mutations inherited from their mothers, fathers, or both parents; however, none of the parents were affected.
CONCLUSION: For children with repeated pancreatitis, clinicians should consider HP in the differential diagnosis. It is reliable to perform gene sequencing on suspicious patients and their parents. Multidisciplinary and comprehensive treatment should be recommended to manage HP and its complications. Cholangiopancreatography and stenting is a relatively minimally invasive approach when compared with surgery and can be tried as an early intervention. Surgical procedures should be reserved for patients with complications.

PMID: 27603351 [PubMed - as supplied by publisher]

Particle-Tracking Microrheology Using Micro-Optical Coherence Tomography.

Biophys J. 2016 Sep 6;111(5):1053-1063

Authors: Chu KK, Mojahed D, Fernandez CM, Li Y, Liu L, Wilsterman EJ, Diephuis B, Birket SE, Bowers H, Martin Solomon G, Schuster BS, Hanes J, Rowe SM, Tearney GJ

Abstract
Clinical manifestations of cystic fibrosis (CF) result from an increase in the viscosity of the mucus secreted by epithelial cells that line the airways. Particle-tracking microrheology (PTM) is a widely accepted means of determining the viscoelastic properties of CF mucus, providing an improved understanding of this disease as well as an avenue to assess the efficacies of pharmacologic therapies aimed at decreasing mucus viscosity. Among its advantages, PTM allows the measurement of small volumes, which was recently utilized for an in situ study of CF mucus formed by airway cell cultures. Typically, particle tracks are obtained from fluorescence microscopy video images, although this limits one's ability to distinguish particles by depth in a heterogeneous environment. Here, by performing PTM with high-resolution micro-optical coherence tomography (μOCT), we were able to characterize the viscoelastic properties of mucus, which enables simultaneous measurement of rheology with mucociliary transport parameters that we previously determined using μOCT. We obtained an accurate characterization of dextran solutions and observed a statistically significant difference in the viscosities of mucus secreted by normal and CF human airway cell cultures. We further characterized the effects of noise and imaging parameters on the sensitivity of μOCT-PTM by performing theoretical and numerical analyses, which show that our system can accurately quantify viscosities over the range that is characteristic of CF mucus. As a sensitive rheometry technique that requires very small fluid quantities, μOCT-PTM could also be generally applied to interrogate the viscosity of biological media such as blood or the vitreous humor of the eye in situ.

PMID: 27602733 [PubMed - as supplied by publisher]

Metabolomics of pulmonary exacerbations reveals the personalized nature of cystic fibrosis disease.

PeerJ. 2016;4:e2174

Authors: Quinn RA, Lim YW, Mak TD, Whiteson K, Furlan M, Conrad D, Rohwer F, Dorrestein P

Abstract
Background. Cystic fibrosis (CF) is a genetic disease that results in chronic infections of the lungs. CF patients experience intermittent pulmonary exacerbations (CFPE) that are associated with poor clinical outcomes. CFPE involves an increase in disease symptoms requiring more aggressive therapy. Methods. Longitudinal sputum samples were collected from 11 patients (n = 44 samples) to assess the effect of exacerbations on the sputum metabolome using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The data was analyzed with MS/MS molecular networking and multivariate statistics. Results. The individual patient source had a larger influence on the metabolome of sputum than the clinical state (exacerbation, treatment, post-treatment, or stable). Of the 4,369 metabolites detected, 12% were unique to CFPE samples; however, the only known metabolites significantly elevated at exacerbation across the dataset were platelet activating factor (PAF) and a related monacylglycerophosphocholine lipid. Due to the personalized nature of the sputum metabolome, a single patient was followed for 4.2 years (capturing four separate exacerbation events) as a case study for the detection of personalized biomarkers with metabolomics. PAF and related lipids were significantly elevated during CFPEs of this patient and ceramide was elevated during CFPE treatment. Correlating the abundance of bacterial 16S rRNA gene amplicons to metabolomics data from the same samples during a CFPE demonstrated that antibiotics were positively correlated to Stenotrophomonas and Pseudomonas, while ceramides and other lipids were correlated with Streptococcus, Rothia, and anaerobes. Conclusions. This study identified PAF and other inflammatory lipids as potential biomarkers of CFPE, but overall, the metabolome of CF sputum was patient specific, supporting a personalized approach to molecular detection of CFPE onset.

PMID: 27602256 [PubMed]

Are allergic fungal rhinosinusitis and allergic bronchopulmonary aspergillosis lifelong conditions?

Med Mycol. 2016 Sep 6;

Authors: Agarwal R, Bansal S, Chakrabarti A

Abstract
Aspergillus fumigatus can cause several allergic disorders including Aspergillus-sensitized asthma, allergic bronchopulmonary aspergillosis (ABPA), and allergic fungal rhinosinusitis (AFRS). ABPA is an immunological pulmonary disorder caused by allergic reactions mounted against antigens of A. fumigatus colonizing the airways of patients with asthma (and cystic fibrosis). Allergic bronchopulmonary mycosis is an allergic fungal airway disease caused by thermotolerant fungi other than A. fumigatus On the other hand, AFRS is a type of chronic rhinosinusitis that is also a result of hypersensitivity reactions to the presence of fungi that become resident in the sinuses. The pathogenesis of ABPA and AFRS share several common features, and in fact, AFRS can be considered as the upper airway counterpart of ABPA. Despite sharing similar immunopathogenetic features, the simultaneous occurrence of the two disorders is uncommon. Due to the lacuna in understanding of the causative mechanisms, and deficiencies in the diagnosis and treatment, these disorders unfortunately are lifelong illnesses. This review provides an overview of the pathogenesis, diagnosis, and long-term outcomes of both these disorders.

PMID: 27601608 [PubMed - as supplied by publisher]

Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.

J Cyst Fibros. 2016 Sep 3;

Authors: Schwarzenberg SJ, Hempstead SE, McDonald CM, Powers SW, Wooldridge J, Blair S, Freedman S, Harrington E, Murphy PJ, Palmer L, Schrader AE, Shiel K, Sullivan J, Wallentine M, Marshall BC, Leonard AR

Abstract
Nutrition is integral to the care of individuals with cystic fibrosis (CF). Better nutritional status is associated with improved pulmonary function. In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status. Current nutrition guidelines do not include detailed recommendations for enteral tube feeding. The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion. These guidelines address when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding. These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process.

PMID: 27599607 [PubMed - as supplied by publisher]

8 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 2016/09/07

PubMed comprises more than 24 million 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.

Approach to the evaluation of adverse antibiotic reactions in patients with cystic fibrosis.

Ann Allergy Asthma Immunol. 2016 Aug 30;

Authors: Petroni DH, Aitken ML, Ham E, Chung S, Menalia L, Altman MC, Ayars AG

Abstract
BACKGROUND: Adverse drug reactions (ADRs) to antibiotics in patients with cystic fibrosis (CF) are common and often mislabeled as allergies. The labeling of an antibiotic reaction as an allergy can lead to the use of antibiotics that are less efficacious, are more expensive, or have a greater risk of adverse effects.
OBJECTIVE: To establish a safe approach for the evaluation of ADRs to antibiotics in patients with CF to help clarify future use of these medications.
METHODS: Patients with CF whose antibiotic allergies were causing difficulty in their medical management were referred for an allergy evaluation that consisted of a thorough drug allergy history and antibiotic testing if appropriate. If the history was not consistent with a true hypersensitivity reaction (HSR) and test results were negative, the patient underwent a challenge to the offending agent(s) to rule out an HSR. Challenges were only performed if the medication was indicated for future use.
RESULTS: A total of 17 patients (mean age, 32.4 years) underwent a thorough allergy evaluation. A total of 17 antibiotic challenges were performed in 11 patients without a reaction consistent with an HSR or severe delayed reaction. Only 2 medications had a history consist with an HSR, and it was recommended that they undergo a desensitization procedure if the drug was required.
CONCLUSION: If treatment with appropriate antibiotics becomes difficult in patients with CF because of drug allergies, then referral to an allergist can help safely identify treatment options. Our findings suggest that a thorough evaluation by an allergy specialist can lead to more appropriate treatment options in patients with CF.

PMID: 27590641 [PubMed - as supplied by publisher]

HUMAN AIRWAY EPITHELIAL CELLS INVESTIGATED BY ATOMIC FORCE MICROSCOPY: A HINT TO CYSTIC FIBROSIS EPITHELIAL PATHOLOGY.

Exp Cell Res. 2016 Aug 30;

Authors: Lasalvia M, Castellani S, D'Antonio P, Perna G, Carbone A, Colia AL, Maffione AB, Capozzi V, Conese M

Abstract
The pathophysiology of cystic fibrosis (CF) airway disease stems from mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, leading to a chronic respiratory disease. Actin cytoskeleton is disorganised in CF airway epithelial cells, likely contributing to the CF-associated basic defects, i.e.defective chloride secretion and sodium/fluid hypersorption. In this work, we aimed to find whether this alteration could be pointed out by means of Atomic Force Microscopy (AFM) investigation, as roughness and Young's elastic module. Moreover, we also sought to determine whether disorganisation of actin cytoskeleton is linked to hypersoption of apical fluid. Not only CFBE41o- (CFBE) cells, immortalised airway epithelial cells homozygous for the F508del CFTR allele showed a different morphology in comparison with 16HBE14o- (16HBE) epithelial cells, wild-type for CFTR, but also they displayed a lack of stress fibers, suggestive of a disorganised actin cytoskeleton. AFM measurements showed that CFBE cells presented a higher membrane roughness and decreased rigidity as compared with 16HBE cells. CFBE overexpressing wtCFTR became more elongated than the parental CFBE cell line and presented actin stress fibers. CFBE cells absorbed more fluid from the apical compartment. Study of fluid absorption with the F-actin-depolymerising agent Latrunculin B demonstrated that actin cytoskeletal disorganisation increased fluid absorption, an effect observed at higher magnitude in 16HBE than in CFBE cells. For the first time, we demonstrate that actin cytoskeleton disorganisation is reflected by AFM parameters in CF airway epithelial cells. Our data also strongly suggest that the lack of stress fibers is involved in at least one of the early step in CF pathophysiology at the levels of the airways, i.e. fluid hypersorption.

PMID: 27590528 [PubMed - as supplied by publisher]

FGF and EDA pathways control initiation and branching of distinct subsets of developing nasal glands.

Dev Biol. 2016 Aug 30;

Authors: May A, Headon D, Rice D, Noble A, Tucker AS

Abstract
Hypertrophy, hyperplasia and altered mucus secretion from the respiratory submucosal glands (SMG) are characteristics of airway diseases such as cystic fibrosis, asthma and chronic bronchitis. More commonly, hyper-secretion of the nasal SMGs contributes to allergic rhinitis and upper airway infection. Considering the role of these glands in disease states, there is a significant dearth in understanding the molecular signals that regulate SMG development and patterning. Due to the imperative role of FGF signalling during the development of other branched structures, we investigated the role of Fgf10 during initiation and branching morphogenesis of murine nasal SMGs. Fgf10 is expressed in the mesenchyme around developing SMGs while expression of its receptor Fgfr2 is seen within glandular epithelial cells. In the Fgf10 null embryo, Steno's gland and the maxillary sinus gland were completely absent while other neighbouring nasal glands showed normal duct elongation but defective branching. Interestingly, the medial nasal glands were present in Fgf10 homozygotes but missing in Fgfr2b mutants, with expression of Fgf7 specifically expressed around these developing glands, indicating that Fgf7 might compensate for loss of Fgf10 in this group of glands. Intriguingly the lateral nasal glands were only mildly affected by loss of FGF signalling, while these glands were missing in Eda mutant mice, where the Steno's and maxillary sinus gland developed as normal. This analysis reveals that regulation of nasal gland development is complex with different subsets of glands being regulated by different signalling pathways. This analysis helps shed light on the nasal gland defects observed in patients with hypohidrotic ectodermal dysplasia (HED) (defect EDA pathway) and LADD syndrome (defect FGFR2b pathway).

PMID: 27590203 [PubMed - as supplied by publisher]

7 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 2016/09/03

PubMed comprises more than 24 million 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.

11 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 2016/09/02

PubMed comprises more than 24 million 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.

8 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 2016/09/01

PubMed comprises more than 24 million 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.

10 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 2016/08/31

PubMed comprises more than 24 million 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.

Discriminating between typical and atypical cystic fibrosis-related bacterial species by multiplex PNA-FISH.

Biotechnol Bioeng. 2016 Aug 29;

Authors: Lopes SP, Carvalho DT, Pereira MO, Azevedo NF

Abstract
This study aims to report the development of peptide nucleic acid (PNA) probes to specifically detect the cystic fibrosis (CF)-associated traditional and atypical species Pseudomonas aeruginosa and Inquilinus limosus, respectively. PNA probes were designed in silico, developed and tested in smears prepared in phosphate-buffer saline and in artificial sputum medium. A multiplex fluorescent in situ hybridization (FISH) approach using the probes was further validated in artificially contaminated clinical sputum samples and also applied to polymicrobial 24h-old biofilms involving the aforementioned and other CF-related bacteria. Both probes showed high predictive and experimental specificities/sensitivities. The multiplex PNA-FISH, associated with non-specific staining, was successfully adapted in the clinical samples and in biofilms of CF-related bacteria, allowing differentiating the community members and inferring about microbial-microbial interactions within the consortia. This study revealed the great potential of PNA-FISH as a diagnostic tool to discriminate between classical and emerging CF-associated bacteria, being suitable to further describe species-dependent prevention strategies and deliver more effective target control therapeutics. This article is protected by copyright. All rights reserved.

PMID: 27571488 [PubMed - as supplied by publisher]

Immune Modulation of the T Cell Response in Asthma through Wnt10b.

Am J Respir Cell Mol Biol. 2016 Apr;54(4):584-93

Authors: Trischler J, Shiomi T, Turner DL, Sklepkiewicz PL, Goldklang MP, Tanaka KF, Xu M, Farber DL, D'Armiento JM

Abstract
Asthma is a chronic inflammatory disease, which is characterized by activation of CD4(+) T helper 2 cells orchestrating an allergic airway response. Whereas the role of Wnt family members in regulating T cell maintenance and maturation is established, their contribution to T cell activation in allergic asthma is not known. We hypothesized that Wnt10b plays a role in the modulation of the allergic airway response and affects T cell activation and polarization. Using an in vivo house dust mite asthma model, Wnt10b-deficient (Wnt10b(-/-)) mice were allergen-sensitized and inflammation, as well as T cell activation, was studied in vivo and in vitro. Wnt10b(-/-) mice exhibited an augmented inflammatory phenotype with an increase in eosinophils in the bronchoalveolar lavage and IL-4 and IL-13 in the lungs when compared with wild-type mice. In vitro studies confirmed an increased T helper type 2 polarization and increased T cell activation of Wnt10b(-/-) cells. Accordingly, the percentage of naive T cells was elevated by the addition of recombinant Wnt10b protein. Finally, Wnt10b(-/-) mice exhibited an increase in the percentage of effector T cells in the lungs after house dust mite sensitization, which indicated a heightened activation state, measured by an increased percentage of CD69(hi)CD11a(hi) cells. These findings suggest that Wnt10b plays an important role in regulating asthmatic airway inflammation through modification of the T cell response and is a prospective target in the disease process.

PMID: 26436894 [PubMed - indexed for MEDLINE]

IL-13 Augments Compressive Stress-Induced Tissue Factor Expression in Human Airway Epithelial Cells.

Am J Respir Cell Mol Biol. 2016 Apr;54(4):524-31

Authors: Mitchel JA, Antoniak S, Lee JH, Kim SH, McGill M, Kasahara DI, Randell SH, Israel E, Shore SA, Mackman N, Park JA

Abstract
Tissue factor (TF) is best known as a cellular initiator of coagulation, but it is also a multifunctional protein that has been implicated in multiple pathophysiologic conditions, including asthma. In the lung, airway epithelial cells express TF, but it is unknown how TF expression is regulated by asthma-associated mediators. We investigated the role of IL-13, a type 2 cytokine, alone and in combination with compressive stress, which mimics asthmatic bronchoconstriction, on TF expression and release of TF-positive extracellular vesicles from primary normal human bronchial epithelial cells. Well-differentiated normal human bronchial epithelial cells were treated with IL-13 and compressive stress, alone and in combination. TF mRNA, protein and activity were measured in the cells and conditioned media. TF was also measured in the bronchoalveolar lavage (BAL) fluid of allergen-challenged mice and patients with asthma. IL-13 and compressive stress increased TF expression, but only compressive stress induced TF-positive extracellular vesicle release. Pretreatment with IL-13 augmented compressive stress-induced TF expression and release. TF protein and activity in BAL fluid were increased in allergen-sensitized and -challenged mice. TF was elevated in the BAL fluid of patients with mild asthma after an allergen challenge. Our in vitro and in vivo data indicate close cooperation between mechanical and inflammatory stimuli on TF expression and release of TF-positive extracellular vesicles in the lungs, which may contribute to pathophysiology of asthma.

PMID: 26407210 [PubMed - indexed for MEDLINE]

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis.

Cell Death Differ. 2015 Dec;22(12):2087-97

Authors: Fung G, Shi J, Deng H, Hou J, Wang C, Hong A, Zhang J, Jia W, Luo H

Abstract
We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin-protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at amino-acid 327 between glutamine and alanine, resulting in the generation of an N- and C-terminal cleavage fragment of ~35 and ~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection.

PMID: 25976304 [PubMed - indexed for MEDLINE]

50 Years Ago in TheJournal ofPediatrics: Macroscopic Cysts of the Pancreas in a Case of Cystic Fibrosis.

J Pediatr. 2016 Sep;176:134

Authors: Abu-El-Haija M

PMID: 27568252 [PubMed - as supplied by publisher]

50 Years Ago in TheJournal ofPediatrics: Macroscopic Cysts of the Pancreas in a Case of Cystic Fibrosis.

J Pediatr. 2016 Sep;176:133

Authors: Leung DH, Grand RJ

PMID: 27568251 [PubMed - as supplied by publisher]

Nrf2 Modulates Host Defense during Streptococcus pneumoniae Pneumonia in Mice.

J Immunol. 2016 Aug 26;

Authors: Gomez JC, Dang H, Martin JR, Doerschuk CM

Abstract
Nrf2 regulates the transcriptional response to oxidative stress. These studies tested the role of Nrf2 during Streptococcus pneumoniae pneumonia and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils. Nrf2 null and wild type (WT) mice were studied at 6 and 24 h after instillation of S. pneumoniae or PBS. At 6 h, fewer neutrophils were recruited and the number of bacteria remaining in the lungs tended to be less (p = 0.06) in the Nrf2 null compared with WT mice. In uninfected lungs, 53 genes were already differentially expressed in Nrf2 null compared with WT mouse lungs, and gene sets involved in phagocytosis, Fc receptor function, complement, and Ig regulation are enhanced in PBS-treated Nrf2 null gene profiles compared with those of WT mice. These results suggest that initial host defense is enhanced in Nrf2 null mice, resulting in less recruitment of neutrophils. At 24 h, neutrophil recruitment was greater. The percentages of early apoptotic and late apoptotic/necrotic neutrophils were similar. At increasing inoculum numbers, mortality rates strikingly increased from 15 to 31 and 100% in Nrf2 null mice, whereas all WT mice survived, and Nrf2 null mice had a defect in clearance, particularly at the intermediate dose. The mortality was due to enhanced lung injury and greater systemic response. Gene profiling identified differentially regulated genes and pathways in neutrophils and lung tissue, including those involved in redox stress response, metabolism, inflammation, immunoregulatory pathways, and tissue repair, providing insight into the mechanisms for the greater tissue damage and increased neutrophil accumulation.

PMID: 27566827 [PubMed - as supplied by publisher]