Case report: Cholecystoduodenostomy for cholestatic liver disease in a premature infant with cystic fibrosis and short gut syndrome.

BMC Pediatr. 2019 Mar 11;19(1):78

Authors: Fawcett LK, Widger J, Henry GM, Ooi CY

Abstract
BACKGROUND: Cholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation.
CASE PRESENTATION: A premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an "obstructive/cholestatic" picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry.
CONCLUSIONS: This is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.

PMID: 30857526 [PubMed - in process]

Cystic fibrosis-related diabetes before lung transplantation is associated with lower survival but does not affect long-term renal function.

Pediatr Pulmonol. 2019 Mar 10;:

Authors: Mainbourg S, Philit F, Touzet S, Nove-Josserand R, Durupt S, Sénéchal A, Occelli P, Poupon-Bourdy S, Maury JM, Tronc F, Mornex JF, Durieu I, Reynaud Q

Abstract
OBJECTIVE: To describe the prevalence of cystic fibrosis-related diabetes (CFRD) before and after lung transplantation (LT); to analyse the survival and renal function after LT according to the CFRD status before LT.
METHODS: Sixty cystic fibrosis (CF) patients transplanted at the Lyon University Hospital between 2004 and 2014 were included. Genotype, pancreatic status, age at LT, survival were recorded. Glucose tolerance status, daily insulin dose requirement, glomerular filtration rate (GFR), and daily glucocorticoid (GC) dose were recorded before LT and until December 2016.
RESULTS: The median follow-up was 5.6 (3.8-8.2) years, and nine patients died. Survival was poorest for patients with CFRD before LT compared with those without CFRD (P = 0.03) but was not correlated with the GFR before LT, with sex, age at LT, or CF genotype. The prevalence of CFRD was 68% at 2 years and 54% at 5 years. For persistent insulin-treated CFRD, the insulin requirement decreased (-2.1 IU/d/y; P < 0.01) and was correlated with the daily GC dose (+0.4 IU/d for one additional milligram, P = 0.012). Seven (11%) patients who had insulin-treated CFRD before LT became nondiabetic after LT, with a median time of 2 (1-4) years. After LT, the GFR decreased (-5.3 ml/min/1.73 m 2 /y; P < 0.001) and was not correlated with the CFRD status before LT.
CONCLUSIONS: CFRD before LT is associated with poor survival after LT, which should lead to better management of diabetes. Some patients with pre-LT CFRD became nondiabetic after LT. CFRD is not associated with renal insufficiency after LT.

PMID: 30854801 [PubMed - as supplied by publisher]

Effects of a primary palliative care intervention on quality of life and mental health in cystic fibrosis.

Pediatr Pulmonol. 2019 Mar 10;:

Authors: Friedman D, Linnemann RW, Altstein LL, Georgiopoulos AM, Islam S, Bach KT, St John A, Fracchia MS, Neuringer I, Lapey A, Sicilian L, Moskowitz SM, Yonker LM

Abstract
BACKGROUND: Despite the significant impact of chronic symptoms on quality of life with cystic fibrosis (CF), the role of palliative care in management of this disease is not well defined. The coping, goal assessment, and relief from evolving CF symptoms (CF-CARES) model is a primary palliative care intervention designed to provide chronic symptom management at all stages of the disease. The goal of this pilot study was to estimate the effectiveness of the CF-CARES intervention on improving chronic symptoms and quality of life for people living with CF.
METHODS: A structured assessment was used to guide referral to supportive services intended to address burdensome symptoms. Follow-up assessments were performed approximately 3 and 6 months later. Longitudinal regression analyses of changes in symptoms and quality of life were performed for all participants regardless of utilization of supportive services. Subgroup analyses were performed for subjects participating in mental health and alternative health services.
RESULTS: Forty-one subjects completed assessment and referral processes. The mean number of CF-associated symptoms decreased over time, as did respiratory symptom-related distress and depressive symptoms. Subjects utilizing alternative health services reported less psychological distress at follow-up. Among subjects with severe disease, mental health, and quality of life improved, especially for those using mental health services.
CONCLUSIONS: The CF-CARES model resulted in significant mental health and quality-of-life benefits, suggesting the value of integrating symptom management interventions into routine CF care. Moreover, mental health services can play a key role in CF-specific primary palliative care, especially for those with advanced disease.

PMID: 30854795 [PubMed - as supplied by publisher]

Extracorporeal membrane oxygenation after lung transplantation: risk factors and outcomes analysis.

Ann Cardiothorac Surg. 2019 Jan;8(1):54-61

Authors: Boffini M, Simonato E, Ricci D, Scalini F, Marro M, Pidello S, Attisani M, Solidoro P, Lausi PO, Fanelli V, Barbero C, Brazzi L, Rinaldi M

Abstract
Background: Lung transplantation is the treatment of choice for end-stage pulmonary disease in selected patients. However, severe primary graft dysfunction is a significant complication of transplant and requires the implantation of an extracorporeal support. The aim of the study is to evaluate the impact of extracorporeal membrane oxygenation (ECMO) after transplant in our center.
Methods: From January 2008 till June 2018, 195 consecutive unselected patients receiving a lung transplant were considered. Mean age was 49±15 years. Main indications for transplant were idiopathic pulmonary fibrosis in 72 patients, chronic obstructive pulmonary disease in 60 patients, and cystic fibrosis in 40 patients. Prior to transplant, 18 patients were on mechanical ventilation and 14 were on ECMO.
Results: Twenty-five patients required venous-venous ECMO after transplant. Vascular disease as cause of transplant [relative risk (RR) 7.8, 95% CI: 1.5-41, P=0.02], donor age (RR 1.6, 95% CI: 1.03-2.3, P=0.03) and need for cardiopulmonary by-pass during transplant (RR 3.1, 95% CI: 1.02-9, P=0.04) were associated with ECMO implantation. Patients requiring post-transplant ECMO received more transfusions (P<0.01), had a longer mechanical ventilation (P<0.01) and ICU stay (P<0.01) and had a higher hospital mortality (P<0.01). Post-transplant ECMO significantly influenced one- and five-year survival [hazard ratio (HR) 5.5, 95% CI: 3-10, P<0.001 and HR 3.5, 95% CI: 2-6, P<0.001, respectively]. However, conditional survival after t months is similar for patients with or without post-transplant ECMO.
Conclusions: In our experience, although ECMO is a reliable and effective strategy to support pulmonary function, severe graft dysfunction after lung transplantation still has a significant impact on early and late results.

PMID: 30854312 [PubMed]

Inhaled bacteriophage-loaded polymeric microparticles ameliorate acute lung infections.

Nat Biomed Eng. 2018 Nov;2(11):841-849

Authors: Agarwal R, Johnson CT, Imhoff BR, Donlan RM, McCarty NA, García AJ

PMID: 30854250 [PubMed]

Improving Clinical Outcomes and Quality of Life with Massage Therapy in Youth and Young Adults with Cystic Fibrosis: a Pilot Study.

Int J Ther Massage Bodywork. 2019 Mar;12(1):4-15

Authors: Zink KK, Chini B, Cowens J, Kremer L, Lin L

Abstract
Background: Cystic Fibrosis (CF) is an autosomal recessive disorder of exocrine glands characterized by abnormal production of thick mucus, primarily in bronchi of the lungs. Individuals experience recurrent respiratory infections, increased work of breathing, cough and musculoskeletal changes with pain. Previous research found that massage therapy (MT) decreased pain, muscle tightness, and anxiety in individuals with CF, but did not use valid/reliable measurements of quality of life (QOL).
Purpose: To evaluate the effects of MT on QOL and clinical outcomes in individuals 8 to 21 years old with CF.
Setting: A 622-bed nonprofit pediatric hospital in Ohio in the United States.
Participants: Convenience sample of 24 patients with CF; 12 randomly assigned to treatment and control groups, respectively.
Research Design and Intervention: Prospective two-group controlled pre/post pilot study using deep tissue myofascial trigger point massage over 10 to 12 weeks.
Measurements: Pediatric Quality of Life Inventory (Peds QL 4.0); Cystic Fibrosis Questionnaire-Revised (CFQ-R); numeric rating scales (NRS) for pain, muscle tightness, ease of breathing, relaxation; pulmonary function (PFT); single breath count; thoracic excursion (TE).
Results: All participants were Caucasian; mean age 15.7 (SD = 3.5) years; 16 (66.6%) female. No significant differences were found in terms of age, gender, baseline pain between MT and control groups. At the final visit, compared to the control group, the children in MT group showed statistically significantly reduced muscle tightness (p = .048) with a large effect size (ω2 =0.163) and marginally statistically significantly higher levels of relaxation (p = .052), less pain (p = .076), and improved upper TE (p = .078) and lower TE (p = .056) scores with large and moderate effect sizes (ω2 = 0.156, ω2 = 0.095, ω2 = 0.083, and ω2 = 0.073). No statistically significant differences in children's and caregivers' QOL scores between the two groups were found.
Conclusions: Massage therapy was found to significantly reduce muscle tightness, marginally significantly help pain, relaxation, and thoracic excursion in participants with CF.

PMID: 30854150 [PubMed]

Investigating transmission of Mycobacterium abscessus amongst children in an Australian cystic fibrosis centre.

J Cyst Fibros. 2019 Mar 07;:

Authors: Yan J, Kevat A, Martinez E, Teese N, Johnson K, Ranganathan S, Harrison J, Massie J, Daley A

Abstract
BACKGROUND: Mycobacterium abscessus is an emerging pathogen in cystic fibrosis (CF) lung disease. Hospital transmission of M. abscessus has been described. This paper details the investigation into possible cross-transmission of M. abscessus locally at our paediatric hospital CF centre, and the subsequent infection control response.
METHODS: Whole genome sequencing (WGS) of M. abscessus respiratory isolates with epidemiological linkage analysis using hospital electronic medical records.
RESULTS: 6.7% (22/328) of CF patients had M. abscessus isolated from respiratory specimens. WGS revealed a cluster of three patients with genomically related isolates that differed by <7 single nucleotide polymorphisms (SNPs), suggesting a shared recent ancestor and probable cross-transmission. Epidemiological investigation revealed multiple potential crossovers between patients with genomically similar M. abscessus isolates.
CONCLUSIONS: Cross-infection of NTM occurs in CF hospital patients. Hospital infection control practices should be upgraded to reflect this. Consensus is needed between centres.

PMID: 30853372 [PubMed - as supplied by publisher]

A clean sweep: mucin bundles clear the airway.

Eur Respir J. 2018 08;52(2):

Authors: Birket S

PMID: 30166495 [PubMed - indexed for MEDLINE]

Parents' experience with positive newborn screening results for cystic fibrosis.

Eur J Pediatr. 2019 Mar 09;:

Authors: Brockow I, Nennstiel U

Abstract
In Germany, screening for cystic fibrosis (CF) is part of the newborn screening since September 2016. The risk of psychological harm due to false-positive screening results is a longstanding concern. We investigated the parents' perception of the CF screening process in Bavaria and the communication after positive screening results with a questionnaire. Until August 2018, 192 children went through a final diagnostic testing after a positive CF screening result, and 105 (54.7%) families completed the questionnaire. Of these, only 30 parents obtained information about the newborn screening by a physician, despite this being mandatory in Germany. Parents being informed by a CF specialist (28.6%) about the positive screening result were more satisfied with the given information (80.0 versus 50% informed by the maternity ward), and the delay until the final diagnostic testing was shorter. More than 3 days between the information about the screening result and the diagnostic testing was too long for 77.7% of the families.Conclusion: Performing final diagnostic testing with only short delays and receiving satisfactory information is important. Therefore, parents should be informed directly by a CF center about positive screening results and only when sweat testing is possible within the next days. What is Known: • The risk of psychological harm due to false-positive screening results is a longstanding concern. • Satisfactory information about the positive CF screening result seem to reduce the parental stress. What is New: • Parents being informed directly by a CF specialist were more satisfied with the given information and the delay until the final diagnostic testing was shorter. • Our data support the concept that parents should better be informed directly by a CF specialist about positive screening results and only when sweat testing is possible within the next days to reduce parental stress.

PMID: 30852643 [PubMed - as supplied by publisher]

Efficient Gene Editing at Major CFTR Mutation Loci.

Mol Ther Nucleic Acids. 2019 Feb 16;16:73-81

Authors: Ruan J, Hirai H, Yang D, Ma L, Hou X, Jiang H, Wei H, Rajagopalan C, Mou H, Wang G, Zhang J, Li K, Chen YE, Sun F, Xu J

Abstract
Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Nuclease-mediated precise gene editing (PGE) represents a promising therapy for CF, for which an efficient strategy that is free of viral vector, drug selection, and reporter enrichment (VDR free) is desirable. Here we compared different transfection methods (lipofectamine versus electroporation) and formats (plasmid DNA versus ribonucleoprotein) in delivering the CRISPR/Cas9 elements along with single-stranded oligodeoxynucleotides (ssODNs) to clinically relevant cells targeting major CFTR mutation loci. We demonstrate that, among different combinations, electroporation of CRISPR/Cas9 and guide RNA (gRNA) ribonucleoprotein (Cas9 RNP) is the most effective one. By using this VDR-free method, 4.8% to 27.2% efficiencies were achieved in creating dF508, G542X, and G551D mutations in a wild-type induced pluripotent stem cell (iPSC) line. When it is applied to a patient-derived iPSC line carrying the dF508 mutation, a greater than 20% precise correction rate was achieved. As expected, genetic correction leads to the restoration of CFTR function in iPSC-derived proximal lung organoids, as well as in a patient-derived adenocarcinoma cell line CFPAC-1. The present work demonstrates the feasibility of gene editing-based therapeutics toward monogenic diseases such as CF.

PMID: 30852378 [PubMed - as supplied by publisher]

Two CFTR mutations within codon 970 differently impact on the chloride channel functionality.

Hum Mutat. 2019 Mar 09;:

Authors: Amato F, Scudieri P, Musante I, Tomati V, Caci E, Comegna M, Maietta S, Manzoni F, di Lullo AM, De Wachter E, Vanderhelst E, Terlizzi V, Braggion C, Castaldo G, Galietta LJV

Abstract
Pharmacological rescue of mutant CFTR in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By cDNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of mRNA from patients cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level in order to determine if the pharmacotherapy of CFTR basic defect is appropriate. This article is protected by copyright. All rights reserved.

PMID: 30851139 [PubMed - as supplied by publisher]

Evolution of the Pseudomonas aeruginosa quorum-sensing hierarchy.

Proc Natl Acad Sci U S A. 2019 Mar 08;:

Authors: Kostylev M, Kim DY, Smalley NE, Salukhe I, Greenberg EP, Dandekar AA

Abstract
The bacterial pathogen Pseudomonas aeruginosa activates expression of many virulence genes in a cell density-dependent manner by using an intricate quorum-sensing (QS) network. QS in P. aeruginosa involves two acyl-homoserine-lactone circuits, LasI-LasR and RhlI-RhlR. LasI-LasR is required to activate many genes including those coding for RhlI-RhlR. P. aeruginosa causes chronic infections in the lungs of people with cystic fibrosis (CF). In these infections, LasR mutants are common, but rhlR-rhlI expression has escaped LasR regulation in many CF isolates. To better understand the evolutionary trajectory of P. aeruginosa QS in chronic infections, we grew LasR mutants of the well-studied P. aeruginosa strain, PAO1, in conditions that recapitulate an environment where QS signal synthesis by other bacteria might still occur. When QS is required for growth, addition of the RhlI product butyryl-homoserine lactone (C4-HSL), or bacteria that produce C4-HSL, to LasR mutants results in the rapid emergence of a population with a LasR-independent RhlI-RhlR QS system. These evolved populations exhibit subsequent growth without added C4-HSL. The variants that emerge have mutations in mexT, which codes for a transcription factor that controls expression of multiple genes. LasR-MexT mutants have a competitive advantage over both the parent LasR mutant and a LasR-MexT-RhlR mutant. Our findings suggest a plausible evolutionary trajectory for QS in P. aeruginosa CF infections where LasR mutants arise during infection, but because these mutants are surrounded by C4-HSL-producing P. aeruginosa, variants rewired to have a LasR-independent RhlIR system quickly emerge.

PMID: 30850547 [PubMed - as supplied by publisher]

NHS and Vertex remain deadlocked over price of cystic fibrosis drug.

BMJ. 2019 Mar 08;364:l1094

Authors: Wise J

PMID: 30850360 [PubMed - in process]

Diagnosis of chronic anaemia in gastrointestinal disorders: A guideline by the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO) and the Italian Society of Paediatric Gastroenterology Hepatology and Nutrition (SIGENP).

Dig Liver Dis. 2019 Feb 11;:

Authors: Elli L, Norsa L, Zullo A, Carroccio A, Girelli C, Oliva S, Romano C, Leandro G, Bellini M, Marmo R, Soncini M, Monica F, De Francesco V, Paulon E, Cappellini MD, Motta I, Ferretti F, Orlando S, Mansueto P, Buscarini E, Manfredi G, Agostoni C, Tomba C, Cannizzaro R

Abstract
Anaemia is a common pathologic condition, present in almost 5% of the adult population. Iron deficiency is the most common cause; other mechanisms can be involved, making anaemia a multi-factorial disorder in most cases. Anaemia being a frequent manifestation in the diseases of the gastrointestinal tract, patients are often referred to gastroenterologists. Furthermore, upper and lower endoscopy and enteroscopy are pivotal to the diagnostic roadmap of anaemia. In spite of its relevance in the daily clinical practice, there is a limited number of gastroenterological guidelines dedicated to the diagnosis of anaemia. For this reason, the Italian Association of Hospital Gastroenterologists and Endoscopists and the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition commissioned a panel of experts to prepare a specific guideline on anaemia and its diagnostic roadmap in the gastroenterological scenario. The panel also discussed about the potential involvement of gastroenterologists and endoscopists in the management of patients with anaemia, with particular attention to the correct use of investigations. The panel paid particular attention to practical issues with the aim to support gastroenterologists in their clinical practice when dealing with patients with anaemia.

PMID: 30850345 [PubMed - as supplied by publisher]

Ciprofloxacin Dry Powder for Inhalation: Inspiratory Flow in Patients with Non-cystic Fibrosis Bronchiectasis.

J Aerosol Med Pulm Drug Deliv. 2019 Mar 08;:

Authors: Stass H, Nagelschmitz J, Kappeler D, Sommerer K, Patzlaff A, Weimann B

Abstract
BACKGROUND: As non-cystic fibrosis bronchiectasis (NCFB) progresses, patients suffer irreversible lung damage and deterioration in lung function. This study explored whether inhalational parameters (peak inspiratory flow [PIF, primary endpoint], inspiratory volume and time [secondary endpoints]) represent barriers to complete dosing in patients with poor lung function who are using Ciprofloxacin dry powder for inhalation (DPI) (a drug-device combination of the T-326 inhaler device and a Ciprofloxacin dry powder formulation).
METHODS: This open-label, multicenter study generated inspiratory flow rate data from patients with NCFB using the breath-actuated T-326 dry powder inhaler. These rates were compared against reference values to identify whether patients with all degrees of lung function impairment could generate sufficient flow rates to facilitate adequate drug delivery. Patients attended screening and a second visit 1 - 14 days later. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, and inspiratory capacity were measured via spirometry at both visits. Forty-two patients were screened for inclusion; 33 met eligibility criteria and were stratified into one of three groups based on their FEV1% predicted value (group 1: 25% ≤ FEV1% predicted <45%; group 2: 45% ≤ FEV1% predicted <70%; group 3: FEV1% predicted ≥70%).
RESULTS: No significant between-group differences occurred in PIF (mean flow rates 68.21, 66.01, and 65.18 L/min in groups 1, 2, and 3, respectively). Individual minimum PIFs of 46.0-49.0 L/min were observed across groups. These results all exceeded the reference value (minimum PIF 45 L/min for Ciprofloxacin DPI) indicating that regardless of the level of airflow obstruction, patients were capable of achieving sufficient PIFs to aerosolize and inhale Ciprofloxacin dry powder with the T-326 inhaler.
CONCLUSIONS: Our data indicate that T-326 is suitable for use in the drug-device combination Ciprofloxacin DPI to provide targeted pulmonary delivery in patients with NCFB, including those with significantly impaired lung function.

PMID: 30848695 [PubMed - as supplied by publisher]

Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection.

Am J Respir Cell Mol Biol. 2019 Mar 08;:

Authors: Zhang X, Pan A, Jia S, Ideozu JE, Woods K, Murkowski K, Hessner MJ, Simpson PM, Levy H

Abstract
RATIONALE: Cystic fibrosis (CF) is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment.
OBJECTIVES: To characterize the peripheral immune signatures in CF and its association with clinical phenotypes.
METHODS: Healthy peripheral blood mononuclear cells (PBMCs) were cultured with plasma from CF probands (CF) or healthy controls (HC) followed by nCounter gene and microRNA (miRNA) profiling. A discovery cohort of 12 CF and 12 HC and a validation cohort of 103 CF and 31 HC (our previous microarray data, GSE71799) were analyzed to characterize the composition of cultured immune cells and establish a miRNA‒mRNA network. Cell compositions and miRNA profiles were associated with clinical characteristics of the cohorts.
MEASUREMENTS AND MAIN RESULTS: Significantly differentially expressed genes and abundance of myeloid cells were downregulated in PMBCs after culture with CF plasma (p < 0.05). Top-ranked miRNAs that increased in response to CF plasma (adjusted p < 0.05) included miR-155 and miR-146a, which target many immune-related genes such as IL-8. Pseudomonas aeruginosa infection was negatively associated with abundance of monocytes and the presence of those regulatory miRNAs.
CONCLUSIONS: Extrinsic signals in plasma from CF patients led to monocyte inactivation and miRNA upregulation in PBMC. An improved understanding of the immune effects of extrinsic factors in CF holds great promise for integrating immunomodulatory cell therapies into current treatment strategies in CF.

PMID: 30848661 [PubMed - as supplied by publisher]

SMAD Signaling Restricts Mucous Cell Differentiation In Human Airway Epithelium.

Am J Respir Cell Mol Biol. 2019 Mar 08;:

Authors: Feldman MB, Wood M, Lapey A, Mou H

Abstract
Mucin-secreting goblet cell metaplasia and hyperplasia (GCMH) is a common pathological phenotype in many human respiratory diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, primary ciliary dyskinesia, and infections. A better understanding of how goblet cell quantities or proportions in the airway epithelium are regulated may provide novel therapeutic targets to mitigate GCMH in these devastating diseases. We identify canonical SMAD signaling as the principle pathway restricting goblet cell differentiation in human airway epithelium. Differentiated goblet cells express low levels of phosphorylated SMAD. Accordingly, inhibition of SMAD signaling markedly amplifies GCMH induced by mucous mediators. In contrast, SMAD signaling activation impedes goblet cell generation and accelerates the resolution of preexisting GCMH. SMAD signaling inhibition can override the suppressive effects imposed by a GABAergic receptor inhibitor, suggesting the GABAergic pathway likely operates through inhibition of SMAD signaling in regulating mucous differentiation. Collectively, our data demonstrate that SMAD signaling plays a determining role in mucous cell differentiation and thus raises the possibility that dysregulation of this pathway contributes to respiratory pathophysiology during airway inflammation and pulmonary diseases. Additionally, our study also highlights the potential for SMAD modulation as a therapeutic target in mitigating GCMH.

PMID: 30848657 [PubMed - as supplied by publisher]

Mapping and correcting hyperpolarized magnetization decay with radial keyhole imaging.

Magn Reson Med. 2019 Mar 07;:

Authors: Niedbalski PJ, Willmering MM, Robertson SH, Freeman MS, Loew W, Giaquinto RO, Ireland C, Pratt RG, Dumoulin CL, Woods JC, Cleveland ZI

Abstract
PURPOSE: Hyperpolarized (HP) media enable biomedical imaging applications that cannot be achieved with conventional MRI contrast agents. Unfortunately, quantifying HP images is challenging, because relaxation and radio-frequency pulsing generate spatially varying signal decay during acquisition. We demonstrate that, by combining center-out k-space sampling with postacquisition keyhole reconstruction, voxel-by-voxel maps of regional HP magnetization decay can be generated with no additional data collection.
THEORY AND METHODS: Digital phantom, HP 129 Xe phantom, and in vivo 129 Xe human (N = 4 healthy; N = 2 with cystic fibrosis) imaging was performed using radial sampling. Datasets were reconstructed using a postacquisition keyhole approach in which 2 temporally resolved images were created and used to generate maps of regional magnetization decay following a simple analytical model.
RESULTS: Mean, keyhole-derived decay terms showed excellent agreement with the decay used in simulations (R2 = 0.996) and with global attenuation terms in HP 129 Xe phantom imaging (R2 > 0.97). Mean regional decay from in vivo imaging agreed well with global decay values and displayed spatial heterogeneity that matched expected variations in flip angle and oxygen partial pressure. Moreover, these maps could be used to correct variable signal decay across the image volume.
CONCLUSIONS: We have demonstrated that center-out trajectories combined with keyhole reconstruction can be used to map regional HP signal decay and to quantitatively correct images. This approach may be used to improve the accuracy of quantitative measures obtained from hyperpolarized media. Although validated with gaseous HP 129 Xe in this work, this technique can be generalized to any hyperpolarized agent.

PMID: 30847967 [PubMed - as supplied by publisher]

Maternal and Perinatal Outcomes in Pregnant Women with Cystic Fibrosis.

Rev Bras Ginecol Obstet. 2019 Mar 07;:

Authors: Osmundo Junior GS, Athanazio RA, Rached SZ, Francisco RPV

Abstract
OBJECTIVES:  To assess the perinatal and maternal outcomes of pregnant women with cystic fibrosis (CF) and severe lung impairment.
METHODS:  This was a series of cases aiming to review the maternal and fetal outcomes in cases of singleton pregnant women with a diagnosis of CF. We have included all of the cases of singleton pregnancy in patients with CF who were followed-up at the obstetrics department of the Medical School of the Universidade de São Paulo, between 2003 and 2016. The exclusion criteria were the unattainability of the medical records of the patient, and delivery at other institutions. A forced expiratory volume in 1 second < 50% was considered as severe lung impairment. We have also analyzed data regarding maternal hospitalization and respiratory exacerbations (REs).
RESULTS:  Pregnant women with CF and severe lung impairment did not present an association with spontaneous prematurity, fetal growth restriction or fetal demise. All of the cases involved multiple RE episodes requiring antibiotic therapy. The median (range) of events per patient was of 4 (2-4) events.
CONCLUSION:  Cystic fibrosis patients with severe lung impairment may achieve successful term pregnancies. However, pregnancies of women with CF are frequently complicated by REs, and this population may require hospital admission during the course of the pregnancy. Cystic fibrosis patients should be followed by a specialized team with experience in treating respiratory diseases.

PMID: 30847877 [PubMed - as supplied by publisher]

New Advances for Newborn Screening of Inborn Errors of Metabolism by Capillary Electrophoresis-Mass Spectrometry (CE-MS).

Methods Mol Biol. 2019;1972:139-163

Authors: Shanmuganathan M, Britz-McKibbin P

Abstract
Expanded newborn screening of inborn errors of metabolism (IEM) based on tandem mass spectrometry (MS/MS) technology is one of the most successful preventative healthcare initiatives for presymptomatic diagnosis and treatment of rare yet treatable genetic diseases in the population. However, confirmatory testing of presumptive screen-positive cases is required using high efficiency separations for improved specificity in order to improve the positive predictive value (PPV) for certain classes of IEMs. Here, we describe recent advances using capillary electrophoresis-mass spectrometry (CE-MS) for reliable second-tier screening or confirmatory testing based on targeted analysis of amino acids, acylcarnitines, nucleosides, and other classes of polar metabolites associated with IEMs. Additionally, nontargeted metabolite profiling enables the identification of unknown biomarkers of clinical significance for other genetic diseases that are currently screened by bioassays and/or mutation panels, such as cystic fibrosis (CF). Noteworthy, CE-MS allows for resolution of isobaric/isomeric interferences without complicated sample handling that is ideal when analyzing volume-restricted biospecimens from neonates/infants, including dried blood spots and sweat specimens. New developments to improve concentration sensitivity, as well as enhance sample throughput and quality control for unambiguous confirmatory testing of IEMs will also be discussed when using multiplexed separations based on multisegment injection-CE-MS.

PMID: 30847789 [PubMed - in process]