IRE1α kinase-mediated unconventional protein secretion rescues misfolded CFTR and pendrin.

Sci Adv. 2020 Feb;6(8):eaax9914

Authors: Park H, Shin DH, Sim JR, Aum S, Lee MG

Abstract
The most prevalent pathogenic mutations in the CFTR (ΔF508) and SLC26A4/pendrin (p.H723R), which cause cystic fibrosis and congenital hearing loss, respectively, evoke protein misfolding and subsequent defects in their cell surface trafficking. Here, we report that activation of the IRE1α kinase pathway can rescue the cell surface expression of ΔF508-CFTR and p.H723R-pendrin through a Golgi-independent unconventional protein secretion (UPS) route. In mammalian cells, inhibition of IRE1α kinase, but not inhibition of IRE1α endonuclease and the downstream effector XBP1, inhibited CFTR UPS. Treatment with the IRE1α kinase activator, (E)-2-(2-chlorostyryl)-3,5,6-trimethyl-pyrazine (CSTMP), rescued cell surface expression and functional activity of ΔF508-CFTR and p.H723R-pendrin. Treatment with a nontoxic dose of CSTMP to ΔF508-CFTR mice restored CFTR surface expression and CFTR-mediated anion transport in the mouse colon. These findings suggest that UPS activation via IRE1α kinase is a strategy to treat diseases caused by defective cell surface trafficking of membrane proteins, including ΔF508-CFTR and p.H723R-pendrin.

PMID: 32128399 [PubMed - in process]

Two Unanticipated Pregnancies While on Cystic Fibrosis Gene-Specific Drug Therapy.

J Patient Exp. 2020 Feb;7(1):4-7

Authors: Ladores S, Bray LA, Brown J

Abstract
Women with cystic fibrosis (CF) desire to become pregnant and accomplish the same life goals as women without CF. The underlying pathology of CF and medications used to treat this genetically transmitted disease can affect women's reproductive potential. An interview with Ana (pseudonym), who became pregnant twice while taking the medication lumacaftor/ivacaftor (LUMA/IVA), was analyzed using thematic analysis. She described her experiences related to "Fertility and Pregnancy Surrounding LUMA/IVA," the major theme that emerged from her narrative. While there are anecdotal reports of infants conceived by women on LUMA/IVA and other CF precision medications, pregnancy rates and outcomes are not systematically tracked. Education about risks and benefits of these medications should be provided as part of comprehensive clinical care.

PMID: 32128363 [PubMed]

Collaborative Cross Mice Yield Genetic Modifiers for Pseudomonas aeruginosa Infection in Human Lung Disease.

mBio. 2020 Mar 03;11(2):

Authors: Lorè NI, Sipione B, He G, Strug LJ, Atamni HJ, Dorman A, Mott R, Iraqi FA, Bragonzi A

Abstract
Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression.IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.

PMID: 32127447 [PubMed - in process]

Transcutaneous electrical nerve stimulation (TENS) for pain management in sickle cell disease.

Cochrane Database Syst Rev. 2020 Mar 03;3:CD012762

Authors: Pal S, Dixit R, Moe S, Godinho MA, Abas AB, Ballas SK, Ram S, Yousuf UAM

Abstract
BACKGROUND: Sickle cell disease (SCD), one of the most common inherited disorders, is associated with vaso-occlusive pain episodes and haemolysis leading to recurrent morbidity, hospital admissions and work or school absenteeism. The crises are conventionally treated with opioids, non-opioids and other adjuvants with the risk of developing complications, addictions and drug-seeking behaviour. Different non-pharmacological treatments, such as transcutaneous electrical nerve stimulation (TENS) have been used for managing pain in other painful conditions. Hence, the efficacy of TENS for managing pain in SCD needs to be reviewed.
OBJECTIVES: To assess the benefits and harms of TENS for managing pain in people with SCD who experience pain crises or chronic pain (or both).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of the last search: 26 Febraury 2020.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs, where TENS was evaluated for managing pain in people with SCD.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of the trials identified by the literature searches according to the inclusion criteria. Two review authors then independently extracted data, assessed for risk of bias using the Cochrane standard tool and rated the quality of evidence using the GRADE guidelines.
MAIN RESULTS: One double-blind cross-over RCT with 22 participants with SCD (aged 12 to 27 years) was eligible for inclusion. Following stratification into four pain crises severity grades, participants were then randomised to receive TENS or placebo (sham TENS). The trial was concluded after 60 treatment episodes (30 treatment episodes of each treatment group). There is a lack of clarity regarding the trial design and the analysis of the cross-over data. If a participant was allocated to TENS treatment for an episode of pain and subsequently returned with a further episode of a similar degree of pain, they would then receive the sham TENS treatment (cross-over design). For those experiencing a pain episode of a different severity, it is not clear whether they were re-randomised or given the alternate treatment. Reporting and analysis was based on the total number pain events and not on the number of participants. It is unclear how many participants were crossed over from the TENS group to the sham TENS group and vice versa. The trial had a high risk of bias regarding random sequence generation and allocation concealment; an unclear risk regarding the blinding of participants and personnel; and a low risk regarding the blinding of the outcome assessors and selective outcome reporting. The trial was small and of very low quality; furthermore, given the issue with trial design we were unable to quantitatively analyse the data. Therefore, we present only a narrative summary and caution is advised in interpreting the results. In relation to our pre-defined primary outcomes, the included trial did not report pain relief at two to four weeks post intervention. The trial authors reported that no difference was found in the changes in pain ratings (recorded at one hour and four hours post intervention) between the TENS and the placebo groups. In relation to our secondary outcomes, the analgesic usage during the trial also did not show any difference between groups. Given the quality of the evidence, we are uncertain whether TENS improves overall satisfaction as compared to sham TENS. The ability to cope with activities of daily living was not evaluated. Regarding adverse events, although one case of itching was reported in the TENS group, the site and nature of itching was not clearly stated; hence it cannot be clearly attributed to TENS. Also, two participants receiving 'sham' TENS reported a worsening of pain with the intervention.
AUTHORS' CONCLUSIONS: Since we have only included one small and very low-quality trial, with a high risk of bias across several domains, we are unable to conclude whether TENS is harmful or beneficial for managing pain in people with SCD. There is a need for a well-designed, adequately-powered, RCT to evaluate the role of TENS in managing pain in people with SCD.

PMID: 32124977 [PubMed - in process]

Physiological mechanisms determining eccrine sweat composition.

Eur J Appl Physiol. 2020 Mar 02;:

Authors: Baker LB, Wolfe AS

Abstract
PURPOSE: The purpose of this paper is to review the physiological mechanisms determining eccrine sweat composition to assess the utility of sweat as a proxy for blood or as a potential biomarker of human health or nutritional/physiological status.
METHODS: This narrative review includes the major sweat electrolytes (sodium, chloride, and potassium), other micronutrients (e.g., calcium, magnesium, iron, copper, zinc, vitamins), metabolites (e.g., glucose, lactate, ammonia, urea, bicarbonate, amino acids, ethanol), and other compounds (e.g., cytokines and cortisol).
RESULTS: Ion membrane transport mechanisms for sodium and chloride are well established, but the mechanisms of secretion and/or reabsorption for most other sweat solutes are still equivocal. Correlations between sweat and blood have not been established for most constituents, with perhaps the exception of ethanol. With respect to sweat diagnostics, it is well accepted that elevated sweat sodium and chloride is a useful screening tool for cystic fibrosis. However, sweat electrolyte concentrations are not predictive of hydration status or sweating rate. Sweat metabolite concentrations are not a reliable biomarker for exercise intensity or other physiological stressors. To date, glucose, cytokine, and cortisol research is too limited to suggest that sweat is a useful surrogate for blood.
CONCLUSION: Final sweat composition is not only influenced by extracellular solute concentrations, but also mechanisms of secretion and/or reabsorption, sweat flow rate, byproducts of sweat gland metabolism, skin surface contamination, and sebum secretions, among other factors related to methodology. Future research that accounts for these confounding factors is needed to address the existing gaps in the literature.

PMID: 32124007 [PubMed - as supplied by publisher]

Changes in the R-region interactions depend on phosphorylation and contribute to PKA and PKC regulation of the cystic fibrosis transmembrane conductance regulator chloride channel.

FASEB Bioadv. 2020 Jan;2(1):33-48

Authors: Poroca DR, Amer N, Li A, Hanrahan JW, Chappe VM

Abstract
The CFTR chloride channel is regulated by phosphorylation at PKA and PKC consensus sites within its regulatory region (R-region) through a mechanism, which is still not completely understood. We used a split-CFTR construct expressing the N-term-TMD1-NBD1 (Front Half; FH), TMD2-NBD2-C-Term (Back Half; BH), and the R-region as separate polypeptides (Split-R) in BHK cells, to investigate in situ how different phosphorylation conditions affect the R-region interactions with other parts of the protein. In proximity ligation assays, we studied the formation of complexes between the R-region and each half of the Split-CFTR. We found that at basal conditions, the density of complexes formed between the R-region and both halves of the split channel were equal. PKC stimulation alone had no effect, whereas PKA stimulation induced the formation of more complexes between the R-region and both halves compared to basal conditions. Moreover, PKC + PKA stimulation further enhanced the formation of FH-R complexes by 40% from PKA level. In cells expressing the Split-R with the two inhibitory PKC sites on the R-region inactivated (SR-S641A/T682A), density of FH-R complexes was much higher than in Split-R WT expressing cells after PKC or PKC + PKA stimulation. No differences were observed for BH-R complexes measured at all phosphorylation conditions. Since full-length CFTR channels display large functional responses to PKC + PKA in WT and S641A/T682A mutant, we conclude that FH-R interactions are important for CFTR function. Inactivation of consensus PKC site serine 686 (S686A) significantly reduced the basal BH-R interaction and prevented the PKC enhancing effect on CFTR function and FH-R interaction. The phospho-mimetic mutation (S686D) restored basal BH-R interaction and the PKC enhancing effect on CFTR function with enhanced FH-R interaction. As the channel function is mainly stimulated by PKA phosphorylation of the R-region, and this response is known to be enhanced by PKC phosphorylation, our data support a model in which the regulation of CFTR activation results from increased interactions of the R-region with the N-term-TMD1-NBD1. Also, serine S686 was found to be critical for the PKC enhancing effect which requires a permissive BH-R interaction at basal level and increased FH-R interaction after PKC + PKA phosphorylation.

PMID: 32123855 [PubMed]

Activity of lumacaftor is not conserved in zebrafish Cftr bearing the major cystic fibrosis-causing mutation.

FASEB Bioadv. 2019 Oct;1(10):661-670

Authors: Laselva O, Erwood S, Du K, Ivakine Z, Bear CE

Abstract
F508del-cystic fibrosis transmembrane conductance regulator (CFTR) is the major mutant responsible for cystic fibrosis (CF). ORKAMBI®, approved for patients bearing this mutant, contains lumacaftor (VX-809) that partially corrects F508del-CFTR's processing defect and ivacaftor (VX-770) that potentiates its defective channel activity. Unfortunately, the clinical efficacy of ORKAMBI® is modest, highlighting the need to understand how the small molecules work so that superior compounds can be developed. Because, human CFTR (hCFTR) and zebrafish Cftr (zCftr) are structurally conserved as determined in recent cryo-EM structural models, we hypothesized that the consequences of the major mutation and small molecule modulators would be similar for the two species of protein. As expected, like the F508del mutation in hCFTR, the homologous mutation in zCftr (F507del) is misprocessed, yet not as severely as the human mutant and this defect was restored by low-temperature (27°C) culture conditions. After rescue to the cell surface, F507del-zCftr exhibited regulated channel activity that was potentiated by ivacaftor. Surprisingly, lumacaftor failed to rescue misprocessing of the F507del-zCftr at either 37 or 27°C suggesting that future comparative studies with F508del-hCFTR would provide insight into its structure: function relationships. Interestingly, the robust rescue of F508del-zCftr at 27°C and availability of methods for in vivo screening in zebrafish present the opportunity to define the cellular pathways underlying rescue.

PMID: 32123813 [PubMed]

Finding the relevance of antimicrobial stewardship for cystic fibrosis.

J Cyst Fibros. 2020 Feb 29;:

Authors: Cogen JD, Kahl BC, Maples H, McColley SA, Roberts JA, Winthrop KL, Morris AM, Holmes A, Flume PA, VanDevanter DR, Waters V, Muhlebach MS, Elborn JS, Saiman L, Bell SC, Antimicrobial Resistance International Working Group in Cystic Fibrosis

Abstract
Antimicrobials have undoubtedly improved the lives of people with CF, but important antimicrobial-related toxicities and the emergence of antimicrobial-resistant bacteria associated with their use must be considered. Antimicrobial stewardship (AMS) is advocated across the spectrum of healthcare to promote the appropriate use of antimicrobials to preserve their current effectiveness and to optimise treatment, and it is clear that AMS strategies are applicable to and can benefit both non-CF and CF populations. This perspective explores the definition and components of an AMS program, the current evidence for AMS, and the reasons why AMS is a challenging concept in the provision of CF care. We also discuss the elements of CF care which align with AMS programs and principles and propose research priorities for AMS in CF.

PMID: 32122785 [PubMed - as supplied by publisher]

19 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 2020/03/03

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

19 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 2020/03/03

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

DNA Methylation Changes in Cystic Fibrosis: Cause or Consequence?

Clin Genet. 2020 Feb 29;:

Authors: Scott M, De Sario A

Abstract
Twin and sibling studies have shown that lung disease severity is variable among cystic fibrosis (CF) patients and affected to the same extent by genetic and non-heritable factors. Genetic factors have been thoroughly assessed, whereas the molecular mechanisms whereby non-heritable factors contribute to the phenotypic variability of CF patients are still unknown. Epigenetic modifications may represent the missing link between non-heritable factors and phenotypic variation in cystic fibrosis. Herein, we review recent studies showing that DNA methylation is altered in cystic fibrosis and we address three possible factors responsible for these variations: (i) overproduction of reactive oxygen species, (ii) depletion of DNA methylation cofactors and (iii) susceptibility to acute and chronic bacterial infections. Also, we hypothesize that the unique DNA methylation profile of each patient can modulate the phenotype and discuss the interest of implementing integrated genomic, epigenomic and transcriptomic studies to further understand the clinical diversity of CF patients (Graphical Abstract). This article is protected by copyright. All rights reserved.

PMID: 32112395 [PubMed - as supplied by publisher]

Host responses to mucosal biofilms in the lung and gut.

Mucosal Immunol. 2020 Feb 28;:

Authors: Domingue JC, Drewes JL, Merlo CA, Housseau F, Sears CL

Abstract
The impact of the human microbiome on health and disease is of utmost importance and has been studied intensively in recent years. Microbes promote immune system development and are essential to the production and absorption of nutrients for the host but are also implicated in disease pathogenesis. Particularly, bacterial biofilms have long been recognized as contributors to chronic infections and diseases in humans. However, our understanding of how the host responds to the presence of biofilms, specifically the immune response to biofilms, and how this contributes to disease pathogenesis is limited. This review aims to highlight what is known about biofilm formation and in vivo models available for the biofilm study. We critique the contribution of biofilms to human diseases, focusing on the lung diseases, cystic fibrosis and chronic obstructive pulmonary disease, and the gut diseases, inflammatory bowel disease and colorectal cancer.

PMID: 32112046 [PubMed - as supplied by publisher]

A mouse model of pulmonary Mycobacteroides abscessus infection.

Sci Rep. 2020 Feb 28;10(1):3690

Authors: Maggioncalda EC, Story-Roller E, Mylius J, Illei P, Basaraba RJ, Lamichhane G

Abstract
There is no preclinical mouse model to investigate pulmonary Mycobacteroides abscessus (formerly Mycobacterium abscessus) infection in an immunocompetent mouse strain, especially in the context of antibiotic testing and regimen development. We developed a mouse model of pulmonary M. abscessus infection using the aerosolized route of infection that leads to an increase in bacterial burden post- implantation and develops pathology as a result. In this mouse model, treatment with corticosteroid allows for initial proliferation and sustained M. abscessus pulmonary infection and permits evaluation of efficacies of antibiotics. Administration of corticosteroids that permitted higher levels of bacterial burden in the lungs were more likely to have pathology. Treatment of mice with antibiotics administered intranasally or subcutaneously significantly reduced lung M. abscessus burden. In addition to the reference strain, independent clinical isolates of M. abscessus also readily establish infection and proliferate in the lungs of mice in this model.

PMID: 32111900 [PubMed - as supplied by publisher]

Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis.

J Cyst Fibros. 2020 Feb 25;:

Authors: Prentice BJ, Ooi CY, Verge CF, Hameed S, Widger J

Abstract
It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test. Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.

PMID: 32111453 [PubMed - as supplied by publisher]

Impact of gastrointestinal physiology on drug absorption in special populations - An UNGAP review.

Eur J Pharm Sci. 2020 Feb 25;:105280

Authors: Stillhart C, Vučićević K, Augustijns P, Basit AW, Batchelor H, Flanagan TR, Gesquiere I, Greupink R, Keszthelyi D, Koskinen M, Madla CM, Matthys C, Miljuš G, Mooij MG, Parrott N, Ungell AL, de Wildt SN, Orlu M, Klein S, Müllertz A

Abstract
The release and absorption profile of an oral medication is influenced by the physicochemical properties of the drug and its formulation, as well as by the anatomy and physiology of the gastrointestinal (GI) tract. During drug development the bioavailability of a new drug is typically assessed in early clinical studies in a healthy adult population. However, many disease conditions are associated with an alteration of the anatomy and/or physiology of the GI tract. The same holds true for some subpopulations, such as paediatric or elderly patients, or populations with different ethnicity. The variation in GI tract conditions compared to healthy adults can directly affect the kinetics of drug absorption, and thus, safety and efficacy of an oral medication. This review provides an overview of GI tract properties in special populations compared to healthy adults and discusses how drug absorption is affected by these conditions. Particular focus is directed towards non-disease dependent conditions (age, sex, ethnicity, genetic factors, obesity, pregnancy), GI diseases (ulcerative colitis and Crohn's disease, celiac disease, cancer in the GI tract, Roux-en-Y gastric bypass, lactose intolerance, Helicobacter pylori infection, and infectious diseases of the GI tract), as well as systemic diseases that change the GI tract conditions (cystic fibrosis, diabetes, Parkinson's disease, HIV enteropathy, and critical illness). The current knowledge about GI conditions in special populations and their impact on drug absorption is still limited. Further research is required to improve confidence in pharmacokinetic predictions and dosing recommendations in the targeted patient population, and thus to ensure safe and effective drug therapies.

PMID: 32109493 [PubMed - as supplied by publisher]

Contraceptive use among women with cystic fibrosis: A pilot study linking reproductive health questions to the Cystic Fibrosis Foundation National Patient Registry.

Contraception. 2020 Feb 25;:

Authors: Godfrey EM, Mody S, Schwartz MR, Heltshe SL, Taylor-Cousar JL, Jain R, Sufian S, Josephy T, Aitken ML

Abstract
OBJECTIVES: To examine contraceptive use, pregnancy intention and the association of hormonal contraceptive type with adverse health outcomes among women with cystic fibrosis (CF).
STUDY DESIGN: We recruited 150 women with CF, ages 18-49 from three adult CF programs to complete an online survey regarding their pregnancy and contraceptive use history. Survey findings were merged with retrospective clinical information from the CF Foundation Patient Registry (CFFPR). We used descriptive analyses to report contraceptive method and pregnancy frequencies, and logistic regression to examine the association between contraceptive method type and adverse health outcomes.
RESULTS: Combined hormonal contraceptives were the most commonly used methods (42%), followed by condoms (34%), and long-acting reversible contraceptives methods (27%). Thirty-three percent (n=50) reported ever being pregnant, half of whom reported having at least one unplanned pregnancy. We found no significant association for mucoid Pseudomonas aeruginosa infection among progestin-only (aOR 1.53, 95% CI .07-32.2) and estrogen-containing hormonal contraceptive users (aOR 3.9, 95 % CI .20-76.5). Risk of osteoporosis was elevated among women with CF who used depot-medroxyprogesterone acetate compared to non-users (OR 5.36, 95% CI 1.00-29.12).
CONCLUSIONS: Both contraceptive use and unplanned pregnancy among women with CF are common. Associations between hormonal contraceptive use and adverse pulmonary or bone outcomes among women with CF are inconclusive due to the study's small sample size. Larger studies are warranted.
IMPLICATIONS: Women with CF should be informed about the risks and benefits of contraceptives in the context of their disease. CFFPR data capturing contraceptive method use may be the most efficient way to elucidate the association of hormonal contraceptives on disease in women with CF.

PMID: 32109430 [PubMed - as supplied by publisher]

Coping with Cystic Fibrosis in the Republic of Macedonia-Parent Perspective.

Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2019 Dec 01;40(3):69-75

Authors: Zorcec T, Pop-Jordanova N, Fustik S, Jakovska T, Spirevska L

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a progressive, life-threatening, genetic disease which mainly damages the lungs and the digestive system. It's a complex medical condition, with several individual forms and variation in the symptoms severity. Few factors such as age of establishing the diagnosis, the number and the type of infections and their management, best treatment options, comorbid conditions etc. can influence the patient's overall health, disease progression and quality of life. Many CF patients will reach adulthood, so coping with the chronic disease is very important for the overall health and everyday living.
AIM OF THE STUDY: To screen the quality of life in CF patients in the Republic of Macedonia, from the parent perspective.
SUBJECTS AND METHODS: In the study we have included 55 parents of CF patients. We have created a questionnaire, specially designed for this survey, with questions related to their everyday coping with CF and quality of life.
RESULTS: The majority of the parents refer to the overall typical social and emotional life of their children, addressing some difficulties concerning the financial aspect of the disease and still significantly having fear from the stigma in the society.
CONCLUSION: CF patients and their families in the Republic of Macedonia must overcome many obstacles on daily basis. Despite that, they can still have full and meaningful lives.

PMID: 32109219 [PubMed - as supplied by publisher]

Deviations of body functions and structure, activity limitations, and participation restrictions of the International Classification of Functioning, Disability, and Health model in children with cystic fibrosis and non-cystic fibrosis bronchiectasis.

Pediatr Pulmonol. 2020 Feb 28;:

Authors: Ozipek M, Arikan H, Calik-Kutukcu E, Kerem-Gunel M, Saglam M, Inal-Ince D, Vardar-Yagli N, Livanelioglu A, Bozdemir-Ozel C, Cakmak A, Sonbahar-Ulu H, Emiralioglu N, Ozcelik U

Abstract
BACKGROUND: To the best of our knowledge, there is no study in the literature investigating the extrapulmonary outcomes of children with non-cystic fibrosis (CF) bronchiectasis and CF under the framework of the International Classification of Functioning, Disability, and Health (ICF) model. The purpose of the present study is to evaluate the children with CF and non-CF bronchiectasis using the ICF model.
MATERIALS AND METHODS: Children with CF, non-CF bronchiectasis, and healthy counterparts were evaluated (20 participants in each group) according to the ICF items in domain b (body functions), domain s (body structures), and domain d (activities and participation). The pulmonary functions, respiratory and peripheral muscle strength tests, and posture analysis were carried out for domain b. For domain d, however, the Glittre-activities of daily living test and Pediatric Outcome Data Collection were used.
RESULTS: Muscle strength of shoulder abductors and hip extensors in children with CF was significantly lower than healthy children and adolescents (P < .05). The severity of lateral and posterior postural abnormalities in children with CF and non-CF bronchiectasis was higher than those of healthy children (P < .05). Among the patient groups, global function, sports/physical function, expectations, transfers/basic mobility, and pain/comfort were the most affected participation dimensions (P < .05).
CONCLUSIONS: This study highlights the need for comprehensive up-to-date evaluation methods according to the ICF model for understanding rehabilitation requirements in CF and non-CF bronchiectasis in different age groups.

PMID: 32109001 [PubMed - as supplied by publisher]

Successful treatment of allergic bronchopulmonary aspergillosis with posaconazole in a child with cystic fibrosis: Case report and review of the literature.

Lung India. 2020 Mar-Apr;37(2):161-163

Authors: Yakut N, Kadayifci EK, Eralp EE, Gokdemir Y

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) is recognized as a rare, progressive, allergic disorder in patients with cystic fibrosis (CF) and asthma. Treatment of ABPA mainly includes systemic corticosteroids (CSs) and antifungal agents. Here, we report posaconazole treatment in a 9-year-old male child with ABPA and also review the literature on antifungal management of ABPA. The child with CF was admitted to the emergency room with complaints of fever, productive cough, and acute dyspnea. Auscultation of the lungs revealed obvious bilateral fine crackles and bilateral rhonchus. He was started with intravenous meropenem and amikacin for acute exacerbation. The patient was diagnosed with ABPA because of his failure to respond to antibiotherapy, elevated serum immunoglobulin (Ig) E, specific IgE, to Aspergillus fumigatus levels and sputum growth of A. fumigatus. He was successfully treated with posaconazole with marked clinical and laboratory improvement and no adverse effects. CSs and antifungal agents are the mainstay of therapy in patients with ABPA based on observational studies in children. Posaconazole is a useful treatment option for patients with ABPA.

PMID: 32108603 [PubMed - as supplied by publisher]

Lipid-Modified Aminoglycosides for mRNA Delivery to the Liver.

Adv Healthc Mater. 2020 Feb 28;:e1901487

Authors: Yu X, Liu S, Cheng Q, Wei T, Lee S, Zhang D, Siegwart DJ

Abstract
Cationic lipid nanoparticles (LNPs) are widely used as carriers for delivery of nucleic acids. Most synthetic routes toward cationic lipids have derived from simple amine cores. Greater chemical diversity can be obtained through starting with natural products containing basic nitrogen atoms, which offers routes to more complex molecules. Natural building blocks are not extensively explored, such as aminoglycosides, which are both structurally and functionally interesting for developing new carriers for nucleic acid delivery. Herein, cationic lipid-modified aminoglycosides (CLAs) are explored as a family of vehicles for messenger RNA (mRNA) delivery. CLAs are synthesized from natural existing aminoglycosides coupling with alkyl epoxides and acrylates. The top hit (GT-EP10) is able to deliver Luc mRNA to C57BL/6 mice at a dose of 0.05 mg kg-1 to achieve a 107 average luminescence intensity in the liver. The Lox-Stop-Lox tdTomato mouse model is used to further demonstrate that this efficient mRNA delivery system can be potentially used for gene editing. Successful delivery of human erythropoietin mRNA shows that CLA-based LNPs have promising opportunities for delivery of therapeutic nucleic acids in the future.

PMID: 32108440 [PubMed - as supplied by publisher]