Evaluating performance in sweat testing in medical biochemistry laboratories in Croatia.

Biochem Med (Zagreb). 2017 Feb 15;27(1):122-130

Authors: Aralica M, Krleza JL

Abstract
INTRODUCTION: Sweat test has a diagnostic role in evaluation of cystic fibrosis. Its performance includes sweat stimulation, collection and analysis. All listed may be sources of inconsistencies in everyday practice. The aim of this study was an evaluation of external quality assessment (EQA) of sweat chloride measurement including sweat test performance in medical biochemistry laboratories in Croatia.
MATERIALS AND METHODS: EQA for sweat chloride measurement was provided by Croatian Centre for Quality Assessment in Laboratory Medicine (CROQALM) in five consecutive exercises to medical biochemistry laboratories (MBL) that offered sweat testing. A questionnaire regarding all phases of testing was mailed to involved MBL (N = 10). Survey results were compared to current guidelines for sweat test performance.
RESULTS: Reported results of EQA in 2015 exercises showed coefficients of variation (CV) from 28.9%, 29.0% to 35.3%, respectively. An introduction of uniform sweat chloride measurement protocol resulted in CV of 15.5% and 14.7% reported in following two exercises in 2016. All MBL included in this study replied to the questionnaire. Results reported by MBL indicated: lack of patient information policy (7/10), use of unacceptable electrodes (6/9), misuse of minimum of acceptable sweat weight (6/9), lack of internal quality assessment (5/9) and recommended reference ranges (5/9 and 4/9). Agreements to guidelines were found in approach to unsuitable patients (9/10) and sweat collection (8/9).
CONCLUSION: Presented results indicate major weak points of current practice in sweat test performance in Croatian MBL and stress the need for its standardization on a national level.

PMID: 28392735 [PubMed - in process]

An empirical method to cluster objective nebulizer adherence data among adults with cystic fibrosis.

Patient Prefer Adherence. 2017;11:631-642

Authors: Hoo ZH, Campbell MJ, Curley R, Wildman MJ

Abstract
BACKGROUND: The purpose of using preventative inhaled treatments in cystic fibrosis is to improve health outcomes. Therefore, understanding the relationship between adherence to treatment and health outcome is crucial. Temporal variability, as well as absolute magnitude of adherence affects health outcomes, and there is likely to be a threshold effect in the relationship between adherence and outcomes. We therefore propose a pragmatic algorithm-based clustering method of objective nebulizer adherence data to better understand this relationship, and potentially, to guide clinical decisions.
METHODS TO CLUSTER ADHERENCE DATA: This clustering method consists of three related steps. The first step is to split adherence data for the previous 12 months into four 3-monthly sections. The second step is to calculate mean adherence for each section and to score the section based on mean adherence. The third step is to aggregate the individual scores to determine the final cluster ("cluster 1" = very low adherence; "cluster 2" = low adherence; "cluster 3" = moderate adherence; "cluster 4" = high adherence), and taking into account adherence trend as represented by sequential individual scores. The individual scores should be displayed along with the final cluster for clinicians to fully understand the adherence data.
THREE ILLUSTRATIVE CASES: We present three cases to illustrate the use of the proposed clustering method.
CONCLUSION: This pragmatic clustering method can deal with adherence data of variable duration (ie, can be used even if 12 months' worth of data are unavailable) and can cluster adherence data in real time. Empirical support for some of the clustering parameters is not yet available, but the suggested classifications provide a structure to investigate parameters in future prospective datasets in which there are accurate measurements of nebulizer adherence and health outcomes.

PMID: 28392678 [PubMed - in process]

Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase.

Structure. 2017 Mar 31;:

Authors: Hvorecny KL, Bahl CD, Kitamura S, Lee KS, Hammock BD, Morisseau C, Madden DR

Abstract
Pseudomonas aeruginosa secretes an epoxide hydrolase with catalytic activity that triggers degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and perturbs other host defense networks. Targets of this CFTR inhibitory factor (Cif) are largely unknown, but include an epoxy-fatty acid. In this class of signaling molecules, chirality can be an important determinant of physiological output and potency. Here we explore the active-site chemistry of this two-step α/β-hydrolase and its implications for an emerging class of virulence enzymes. In combination with hydrolysis data, crystal structures of 15 trapped hydroxyalkyl-enzyme intermediates reveal the stereochemical basis of Cif's substrate specificity, as well as its regioisomeric and enantiomeric preferences. The structures also reveal distinct sets of conformational changes that enable the active site to expand dramatically in two directions, accommodating a surprising array of potential physiological epoxide targets. These new substrates may contribute to Cif's diverse effects in vivo, and thus to the success of P. aeruginosa and other pathogens during infection.

PMID: 28392259 [PubMed - as supplied by publisher]

Obstetric care in women with genetic disorders.

Best Pract Res Clin Obstet Gynaecol. 2017 Mar 18;:

Authors: Chetty S, Norton ME

Abstract
The management of pregnant women who are themselves affected with genetic diseases is an increasingly relevant and important issue. Improvements in early diagnosis and management of genetic disease, as well as advances in assisted reproductive technology have impacted pregnancy rates in a cohort of women who may not have otherwise been able to conceive. A multidisciplinary approach is key to the management of pregnant women with complex health conditions, including genetic diseases. Pertinent issues should be addressed in the preconception, antepartum, intrapartum and postpartum periods to optimize maternal and fetal health. Additionally, counseling regarding risk of inheritance in offspring and options for prenatal diagnosis should be reviewed if available. This reviews aims to help provide background and insight into the management strategies for various commonly encountered and complex genetic conditions in the setting of pregnancy.

PMID: 28392223 [PubMed - as supplied by publisher]

Modeling cystic fibrosis disease progression in patients with the rare CFTR mutation P67L.

J Cyst Fibros. 2017 Apr 05;:

Authors: MacKenzie IE, Paquette V, Gosse F, George S, Chappe F, Chappe V

Abstract
BACKGROUND: The progression of cystic fibrosis (CF) in patients with the rare mutation P67L was examined to determine if it induced a milder form of CF compared to the common severe ΔF508 mutation.
METHODS: Parameters of lung function, level of bacterial infection, nutritional status and hospitalization were used to represent CF progression. Age at diagnosis and pancreatic status were used to assess CF presentation. Analysis of data from the CF Canada Registry collected over a 15-year period included 266 ΔF508/ΔF508 homozygote patients from CF clinics in Atlantic Canada and 26 compound heterozygote patients with the rare P67L mutation from clinics across Canada.
RESULTS: Late age at diagnosis, high incidence of pancreatic sufficiency, maintained Body Mass Index (BMI) with age, delayed life-threatening bacterial infection, and fewer days in hospital were observed for P67L heterozygote patients included in this study. Although the decline of lung function did not differ from ΔF508 homozygotes, the fact that a greater proportion of P67L heterozygotes live to an older age suggests that lung function is not the primary factor determining CF progression for P67L heterozygote patients.
CONCLUSION: The P67L mutation is associated with a mild disease, even when combined with the severe ΔF508 mutation.

PMID: 28392015 [PubMed - as supplied by publisher]

A treatment evaluator tool to monitor the real-world effectiveness of inhaled aztreonam lysine in cystic fibrosis.

J Cyst Fibros. 2017 Apr 06;:

Authors: Plant BJ, Downey DG, Eustace JA, Gunaratnam C, Haworth CS, Jones AM, McKone EF, Peckham DG, Ketchell RI, Bilton D

Abstract
BACKGROUND: Studies are required that evaluate real-world outcomes of inhaled aztreonam lysine in patients with cystic fibrosis (CF).
METHODS: Our treatment-evaluator tool assessed the effectiveness of inhaled aztreonam in routine practice in 117 CF patients across four time periods (6-12 (P2) and 0-6months (P1) pre-initiation, and 0-6 (T1) and 6-12months (T2) post-initiation). Outcomes were: changes in %-predicted forced expiratory volume in 1s (FEV1), body-mass index (BMI), hospitalisation days and intravenous antibiotic usage.
RESULTS: Median FEV1% predicted for each 6-month period was 38.9%, 34.6%, 37.1% and 36.5%; median change was -2.0% between P2 and P1, increasing to +0.6% (p<0.001) between P1 and T1. Annualised hospital bed-days was reduced (p=0.05) post-initiation, as was intravenous antibiotics days (p=0.001). BMI increased over 6months post-initiation (p≤0.001).
CONCLUSIONS: In patients with CF in routine practice, inhaled aztreonam lysine is associated with improved lung function and weight, and reduced hospitalisation and intravenous antibiotic use.

PMID: 28392014 [PubMed - as supplied by publisher]

Does clinical indication play a role in CT radiation dose in pediatric patients?

Phys Med. 2017 Apr 05;:

Authors: Triantopoulou S, Tsapaki V

Abstract
PURPOSE: The purpose of this study was to identify the main pathologies for which CT is applied on pediatric patients and the related radiation doses as reported in the literature in order to facilitate justification and CT optimization.
METHODS: A critical analysis of a literature review was performed. Different search engines were used such as PubMed, Google Scholar and Science Direct. Various terms and keywords were used to locate pertinent articles such as Pediatric, Computed tomography, Radiation Dose, Organ dose, Effective dose.
RESULTS: The results showed that the main pathologies for which CT is applied are: Crohn's disease, hydrocephalus, cystic fibrosis and pediatric malignancies-mainly lymphoma. The related radiation dose data are extremely scarce and are in the range of 3.48-17.56, 0.2-15.3mSv, 0.14-6.20mSv, and 2.8-518.0mSv, respectively. The radiation doses reported are high especially in pediatric oncology.
CONCLUSIONS: Pediatric patients with malignancies are those exposed to the higher levels of radiation during CT imaging. Literature is lacking reporting of dose in Pediatric CT imaging. More studies need to be realized for the determination of radiation dose in those patients. Special protocols need to be recommended in order to reduce the exposure of children in radiation.

PMID: 28391959 [PubMed - as supplied by publisher]

Classifying oxidative stress by F2-isoprostane levels across human diseases: A meta-analysis.

Redox Biol. 2017 Mar 28;12:582-599

Authors: van 't Erve TJ, Kadiiska MB, London SJ, Mason RP

Abstract
The notion that oxidative stress plays a role in virtually every human disease and environmental exposure has become ingrained in everyday knowledge. However, mounting evidence regarding the lack of specificity of biomarkers traditionally used as indicators of oxidative stress in human disease and exposures now necessitates re-evaluation. To prioritize these re-evaluations, published literature was comprehensively analyzed in a meta-analysis to quantitatively classify the levels of systemic oxidative damage across human disease and in response to environmental exposures. In this meta-analysis, the F2-isoprostane, 8-iso-PGF2α, was specifically chosen as the representative marker of oxidative damage. To combine published values across measurement methods and specimens, the standardized mean differences (Hedges' g) in 8-iso-PGF2α levels between affected and control populations were calculated. The meta-analysis resulted in a classification of oxidative damage levels as measured by 8-iso-PGF2α across 50 human health outcomes and exposures from 242 distinct publications. Relatively small increases in 8-iso-PGF2α levels (g<0.8) were found in the following conditions: hypertension (g=0.4), metabolic syndrome (g=0.5), asthma (g=0.4), and tobacco smoking (g=0.7). In contrast, large increases in 8-iso-PGF2α levels were observed in pathologies of the kidney, e.g., chronic renal insufficiency (g=1.9), obstructive sleep apnoea (g=1.1), and pre-eclampsia (g=1.1), as well as respiratory tract disorders, e.g., cystic fibrosis (g=2.3). In conclusion, we have established a quantitative classification for the level of 8-iso-PGF2α generation in different human pathologies and exposures based on a comprehensive meta-analysis of published data. This analysis provides knowledge on the true involvement of oxidative damage across human health outcomes as well as utilizes past research to prioritize those conditions requiring further scrutiny on the mechanisms of biomarker generation.

PMID: 28391180 [PubMed - as supplied by publisher]

Antenatal prognostic factor of fetal echogenic bowel.

Eur J Obstet Gynecol Reprod Biol. 2017 Mar 03;212:166-170

Authors: Ronin C, Mace P, Stenard F, Loundou A, Capelle M, Mortier I, Pellissier MC, Sigaudy S, Levy A, D'ercole C, Hoffmann P, Merrot T, Lopater J, De Lagausie P, Philip N, Bretelle F

Abstract
OBJECTIVE: The aim of this study was to identify antenatal prognostic factors of neonatal outcomes in cases of fetal echogenic bowel (FEB).
STUDY DESIGN: A retrospective study in three tertiary referral centers including fetal echogenic bowel over a 10-year period (from January 2003 to December 2013). The echogenicity of the fetal bowel was graded from 1 to 3, according to Slotnick's definition. Associated echographic findings such as bowel dilations, gallbladder abnormalities, calcifications, extra-abdominal abnormalities, intrauterine growth restriction (IUGR) and a decrease in amniotic fluid volume, if present were also recorded. This was followed by the FEB's sonographic evolution. The sonographic evolution was considered favorable if it was stable or decreasing and unfavorable if the echogenicity of the bowel increased or if additional sonographic findings appeared. Neonates had a pediatric examination in the delivery room and upon discharge from the maternity hospital. An outcome was considered good in the case of on-term delivery of a newborn with normal clinical examination and meconium elimination.
RESULTS: Complete pregnancy outcome data were available for 409 pregnancies. 338 newborns had uneventful outcomes (82.6%). Antenatal exploration diagnosed 4 cases of aneuploidy (1 case of trisomy 13, 1 case of trisomy 18 and 2 cases of triploidies), 16 cases of congenital infections, 9 cases of cystic fibrosis and 11 cases of bowel abnormalities. After a multivariate analysis, we discovered the sonographic grade of the echogenic bowel was not a prognostic factor of neonatal outcome. The isolated fetal echogenic bowel had a 6.6-fold increase chance of uneventful outcomes (adjusted odd ratio (aOR) 6.6, 95% CI 3-14.4). Notably, favorable sonographic evolution (aOR 8.1, 95% CI 4.1-16) and late gestational age at the time of the diagnosis (aOR 1.17, 95% CI 1.07-1.27) are independent, good prognostic factors of good neonatal outcomes. None of the 180 fetuses with isolated fetal echogenic bowel and favorable sonographic evolution had adverse outcomes. Among these, 4 cases (0.98%) of aneuploïdy, 17 cases (4.2%) of congenital infections and 9 cases (2.2%) of cystic fibroses were also diagnosed. No cases of Down syndrome (DS) were reported.
CONCLUSION: Our study shows that the grade should not be considered a prognostic factor of neonatal outcomes. Our data suggests the need to reevaluate the concept of systematic amniocentesis. Sonographic evolution of fetal bowel is an independent, strong prognostic factor for good neonatal outcomes. It also better defines the FEB prognostic.

PMID: 28391132 [PubMed - as supplied by publisher]

PEGylated composite nanoparticles of PLGA and polyethylenimine for safe and efficient delivery of pDNA to lungs.

Int J Pharm. 2017 Apr 05;:

Authors: Kolte A, Patil S, Lesimple P, Hanrahan JW, Misra A

Abstract
Achieving stable, efficient and non-toxic pulmonary gene delivery is most challenging requirement for successful gene therapy to lung. Composite nanoparticles (NPs) of the poly(lactic-co-glycolic acid) (PLGA) and cationic polymer polyethyleneimine (PEI) is an efficient alternative to viral and liposomal vectors for the pulmonary delivery of pDNA. NPs with different weight ratios (0-12.5%w/w) of PLGA/PEI were prepared and characterized for size, morphology, surface charge, pDNA loading and in vitro release. The in vitro cell uptake and transfection studies in the CFBE41o-cell line revealed that NPs with 10% w/w PEI were more efficient but they exhibited significant cytotoxicity in MTT assays, challenging the safety of this formulation. Surface modifications of these composite NPs through PEGylation reduced toxicity and enhanced cellular uptake and pDNA expression. PEGylation improved diffusion of NPs through the mucus barrier and prevented uptake by pulmonary macrophages. Finally, PEGylated composite NPs were converted to DPI by lyophilization and combined with lactose carrier particles, which resulted in improved aerosolization properties and lung deposition, without affecting pDNA bioactivity. This study demonstrates that a multidisciplinary approach may enable the local delivery of pDNA to lung tissue for effective treatment of deadly lung diseases.

PMID: 28391040 [PubMed - as supplied by publisher]

Recurrence of Protracted Bacterial Bronchitis in Children: What Can We Do?

Chest. 2017 Apr;151(4):940

Authors: Sacco O, Capizzi AF, Silvestri M, Rossi GA

PMID: 28390630 [PubMed - in process]

Enhanced Chemosensory Sensitivity in Idiopathic Rhinitis Patients and its Reversal by Nasal Capsaicin Treatment.

J Allergy Clin Immunol. 2017 Apr 04;:

Authors: Van Gerven L, Alpizar YA, Steelant B, Callebaut I, Kortekaas Krohn I, Wouters M, Vermeulen F, Boeckxstaens G, Talavera K, Hellings PW

Abstract
We show electrophysiological evidence for an increased chemical sensitivity in idiopathic rhinitis patients compared to healthy controls. This abnormality is decreased after capsaicin treatment, along with a reduction of symptoms.

PMID: 28389389 [PubMed - as supplied by publisher]

Vanishing Lung Syndrome in a Cystic Fibrosis Patient.

Arch Bronconeumol. 2017 Apr 04;:

Authors: Fila L, Suchanek V, Marel M

PMID: 28389031 [PubMed - as supplied by publisher]

Protein Requirements of the Critically Ill Pediatric Patient.

Nutr Clin Pract. 2017 Apr;32(1_suppl):128S-141S

Authors: Coss-Bu JA, Hamilton-Reeves J, Patel JJ, Morris CR, Hurt RT

Abstract
This article includes a review of protein needs in children during health and illness, as well as a detailed discussion of protein metabolism, including nitrogen balance during critical illness, and assessment and prescription/delivery of protein to critically ill children. The determination of protein requirements in children has been difficult and challenging. The protein needs in healthy children should be based on the amount needed to ensure adequate growth during infancy and childhood. Compared with adults, children require a continuous supply of nutrients to maintain growth. The protein requirement is expressed in average requirements and dietary reference intake, which represents values that cover the needs of 97.5% of the population. Critically ill children have an increased protein turnover due to an increase in whole-body protein synthesis and breakdown with protein degradation leading to loss of lean body mass (LBM) and development of growth failure, malnutrition, and worse clinical outcomes. The results of protein balance studies in critically ill children indicate higher protein needs, with infants and younger children requiring higher intakes per body weight compared with older children. Monitoring the side effects of increased protein intake should be performed. Recent studies found a survival benefit in critically ill children who received a higher percentage of prescribed energy and protein goal by the enteral route. Future randomized studies should evaluate the effect of protein dosing in different age groups on patient outcomes, including LBM, muscle structure and function, duration of mechanical ventilation, intensive care unit and hospital length of stay, and mortality.

PMID: 28388381 [PubMed - in process]

Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine.

Nutr Clin Pract. 2017 Apr;32(1_suppl):30S-47S

Authors: Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB

Abstract
Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.

PMID: 28388380 [PubMed - in process]

WITHDRAWN: Interventions for fatigue and weight loss in adults with advanced progressive illness.

Cochrane Database Syst Rev. 2017 Apr 07;4:CD008427

Authors: Payne C, Wiffen PJ, Martin S

Abstract
BACKGROUND: Fatigue and unintentional weight loss are two of the commonest symptoms experienced by people with advanced progressive illness. Appropriate interventions may bring considerable improvements in function and quality of life to seriously ill people and their families, reducing physical, psychological and spiritual distress.
OBJECTIVES: To conduct an overview of the evidence available on the efficacy of interventions used in the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness by reviewing the evidence contained within Cochrane reviews.
METHODS: We searched the Cochrane Database of Systematic Reviews (CDSR) for all systematic reviews evaluating any interventions for the management of fatigue and/or unintentional weight loss in adults with advanced progressive illness (The Cochrane Library 2010, Issue 8). We reviewed titles of interest by abstract. Where the relevance of a review remained unclear we reached a consensus regarding the relevance of the participant group and the outcome measures to the overview. Two overview authors extracted the data independently using a data extraction form. We used the measurement tool AMSTAR (Assessment of Multiple SysTemAtic Reviews) to assess the methodological quality of each systematic review.
MAIN RESULTS: We included 27 systematic reviews (302 studies with 31,833 participants) in the overview. None of the included systematic reviews reported quantitative data on the efficacy of interventions to manage fatigue or weight loss specific to people with advanced progressive illness. All of the included reviews apart from one were deemed of high methodological quality. For the remaining review we were unable to ascertain the methodological quality of the research strategy as it was described. None of the systematic reviews adequately described whether conflict of interests were present within the included studies. Management of fatigueAmyotrophic lateral sclerosis/motor neuron disease (ALS/MND) - we identified one systematic review (two studies and 52 participants); the intervention was exercise.Cancer - we identified five systematic reviews (116 studies with 17,342 participants); the pharmacological interventions were eicosapentaenoic acid (EPA) and any drug therapy for the management of cancer-related fatigue and the non pharmacological interventions were exercise, interventions by breast care nurses and psychosocial interventions.Chronic obstructive pulmonary disease (COPD) - we identified three systematic reviews (59 studies and 4048 participants); the interventions were self management education programmes, nutritional support and pulmonary rehabilitation.Cystic fibrosis - we identified one systematic review (nine studies and 833 participants); the intervention was physical training.Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) - we identified two systematic reviews (21 studies and 748 participants); the interventions were progressive resistive exercise and aerobic exercise.Multiple sclerosis (MS) - we identified five systematic reviews (23 studies and 1502 participants); the pharmacological interventions were amantadine and carnitine. The non pharmacological interventions were diet, exercise and occupational therapy.Mixed conditions in advanced stages of illness - we identified one systematic review (five studies and 453 participants); the intervention was medically assisted hydration. Management of weight lossALS/MND - we identified one systematic review but no studies met the inclusion criteria for the systematic review; the intervention was enteral tube feeding.Cancer - we identified three systematic reviews with a fourth systematic review also containing extractable data on cancer (66 studies and 5601 participants); the pharmacological interventions were megestrol acetate and eicosapentaenoic acid (EPA) (this systematic review is also included in the cancer fatigue section above). The non pharmacological interventions were enteral tube feeding and non invasive interventions for patients with lung cancer.COPD - we identified one systematic review (59 studies and 4048 participants); the intervention was nutritional support. This systematic review is also included in the COPD fatigue section.Cystic fibrosis - we identified two systematic reviews (three studies and 131 participants); the interventions were enteral tube feeding and oral calorie supplements.HIV/AIDS - we identified four systematic reviews (42 studies and 2071 participants); the pharmacological intervention was anabolic steroids. The non pharmacological interventions were nutritional interventions, progressive resistive exercise and aerobic exercise. Both of the systematic reviews on exercise interventions were also included in the HIV/AIDS fatigue section.MS - we found no systematic reviews which considered interventions to manage unintentional weight loss for people with a clinical diagnosis of multiple sclerosis at any stage of illness.Mixed conditions in advanced stages of illness - we identified two systematic reviews (32 studies and 4826 participants); the interventions were megestrol acetate and medically assisted nutrition.
AUTHORS' CONCLUSIONS: There is a lack of robust evidence for interventions to manage fatigue and/or unintentional weight loss in the advanced stage of progressive illnesses such as advanced cancer, heart failure, lung failure, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia and AIDS. The evidence contained within this overview provides some insight into interventions which may prove of benefit within this population such as exercise, some pharmacological treatments and support for self management.Researchers could improve the methodological quality of future studies by blinding of outcome assessors. Adopting uniform reporting mechanisms for fatigue and weight loss outcome measures would also allow the opportunity for meta-analysis of small studies.Researchers could also improve the applicability of recommendations for interventions to manage fatigue and unintentional weight loss in advanced progressive illness by including subgroup analysis of this population within systematic reviews of applicable interventions.More research is required to ascertain the best interventions to manage fatigue and/or weight loss in advanced illness. There is a need for standardised reporting of these symptoms and agreement amongst researchers of the minimum duration of studies and minimum percentage change in symptom experience that proves the benefits of an intervention. There are, however, challenges in providing meaningful outcome measurements against a background of deteriorating health through disease progression. Interventions to manage these symptoms must also be mindful of the impact on quality of life and should be focused on patient-orientated rather than purely disease-orientated experiences for patients. Systematic reviews and primary intervention studies should include the impact of the interventions on standardised validated quality of life measures.

PMID: 28387447 [PubMed - as supplied by publisher]

Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis.

Sci Rep. 2017 Apr 06;7(1):700

Authors: Manunta MD, Tagalakis AD, Attwood M, Aldossary AM, Barnes JL, Munye MM, Weng A, McAnulty RJ, Hart SL

Abstract
The inhibition of ENaC may have therapeutic potential in CF airways by reducing sodium hyperabsorption, restoring lung epithelial surface fluid levels, airway hydration and mucociliary function. The challenge has been to deliver siRNA to the lung with sufficient efficacy for a sustained therapeutic effect. We have developed a self-assembling nanocomplex formulation for siRNA delivery to the airways that consists of a liposome (DOTMA/DOPE; L), an epithelial targeting peptide (P) and siRNA (R). LPR formulations were assessed for their ability to silence expression of the transcript of the gene encoding the α-subunit of the sodium channel ENaC in cell lines and primary epithelial cells, in submerged cultures or grown in air-liquid interface conditions. LPRs, containing 50 nM or 100 nM siRNA, showed high levels of silencing, particularly in primary airway epithelial cells. When nebulised these nanocomplexes still retained their biophysical properties and transfection efficiencies. The silencing ability was determined at protein level by confocal microscopy and western blotting. In vivo data demonstrated that these nanoparticles had the ability to silence expression of the α-ENaC subunit gene. In conclusion, these findings show that LPRs can modulate the activity of ENaC and this approach might be promising as co-adjuvant therapy for cystic fibrosis.

PMID: 28386087 [PubMed - in process]

Symptoms mimicking Sjögren syndrome in a heterozygous carrier of CFTR deltaF508 mutation.

Pol Arch Med Wewn. 2016 Nov 28;126(11):895-896

Authors: Domżalska M, Zdrojewski Z, Buda N, Masiak A, Szade J, Romanowicz G

PMID: 27890909 [PubMed - indexed for MEDLINE]

Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction.

PLoS One. 2017;12(4):e0175467

Authors: Darrah R, Bederman I, Vitko M, Valerio DM, Drumm ML, Hodges CA

Abstract
Growth deficits are common in cystic fibrosis (CF), but their cause is complex, with contributions from exocrine pancreatic insufficiency, pulmonary complications, gastrointestinal obstructions, and endocrine abnormalities. The CF mouse model displays similar growth impairment despite exocrine pancreatic function and in the absence of chronic pulmonary infection. The high incidence of intestinal obstruction in the CF mouse has been suggested to significantly contribute to the observed growth deficits. Previous studies by our group have shown that restoration of the cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium prevents intestinal obstruction but does not improve growth. In this study, we further investigate growth deficits in CF and gut-corrected CF mice by assessing insulin-like growth factor 1 (IGF-1). IGF-1 levels were significantly decreased in CF and gut-corrected CF adult mice compared to wildtype littermates and were highly correlated with weight. Interestingly, perinatal IGF-1 levels were not significantly different between CF and wildtype littermates, even though growth deficits in CF mice could be detected late in gestation. Since CFTR has been suggested to play a role in water and nutrient exchange in the placenta through its interaction with aquaporins, we analyzed placental aquaporin expression in late-gestation CF and control littermates. While significant differences were observed in Aquaporin 9 expression in CF placentas in late gestation, there was no evidence of placental fluid exchange differences between CF and control littermates. The results from this study indicate that decreased IGF-1 levels are highly correlated with growth in CF mice, independent of CF intestinal obstruction. However, the perinatal growth deficits that are observed in CF mice are not due to decreased IGF-1 levels or differences in placenta-mediated fluid exchange. Further investigation is necessary to understand the etiology of early growth deficits in CF, as growth has been shown to be a significant factor in disease outcomes.

PMID: 28384265 [PubMed - in process]

Loss of SLC9A3 decrease CFTR protein and causes obstructed azoospermia in mice.

PLoS Genet. 2017 Apr 06;13(4):e1006715

Authors: Wang YY, Lin YH, Wu YN, Chen YL, Lin YC, Cheng CY, Chiang HS

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF) and are associated with congenital bilateral absence of the vas deferens (CBAVD), which is the major cause of infertility in male patients with CF. However, most Taiwanese patients with CBAVD do not carry major CFTR mutations. Some patients have a single copy deletion of the solute carrier family 9 isoform 3 (SLC9A3) gene. SLC9A3 is a Na+/H+ exchanger, and depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules. Furthermore, SLC9A3 interacts with CFTR in the pancreatic duct and functions as a genetic modifier of CF. However, SLC9A3 function and its relation to CFTR expression in the male reproductive tract in vivo remain elusive. In the present study, we found that CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice. Adult Slc9a3-/- mice showed not only significantly decreased epididymis and vas deferens weight but also increased testis weight. Furthermore, Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification in the lumen of the reproductive tract. Ultrastructural analysis of the epithelium in Slc9a3-/-epididymis and vas deferens displayed disorganized and reduced number of stereocilia and numerous secretory apparatuses. Our data revealed that interdependence between SLC9A3 and CFTR is critical for maintaining a precise microenvironment in the epithelial cytoarchitecture of the male reproductive tract. The Slc9a3-deficient mice with impaired male excurrent ducts in this study provide proof for our clinical findings that some Taiwanese of CBAVD carry SLC9A3 deletion but without major CFTR mutations.

PMID: 28384194 [PubMed - as supplied by publisher]