Cystic fibrosis and insulin therapy: a reality check.

Diabet Med. 2019 Apr 09;:

Authors: Warren RE

Abstract
Diabetes is a complication of cystic fibrosis, caused by progressive loss of insulin secretion [1]. Insulin therapy seems logical for cystic fibrosis-related diabetes (CFRD) and is established in clinical practice. This article is protected by copyright. All rights reserved.

PMID: 30964946 [PubMed - as supplied by publisher]

CFTR and FOXO1 gene expression are reduced and high mobility group box 1 (HMGB1) is increased in the ovaries and serum of women with polycystic ovarian syndrome.

Gynecol Endocrinol. 2019 Apr 09;:1-5

Authors: Cirillo F, Catellani C, Sartori C, Lazzeroni P, Morini D, Nicoli A, Giorgi-Rossi P, Amarri S, La Sala GB, Street ME

Abstract
We previously described increased HMGB1 and reduced FOXO1 dependent on CFTR loss of function in cystic fibrosis (CF) and we showed in vitro that HMGB1 was lowered by insulin. Reduced CFTR gene expression has been described in granulosa cells (GC) from PCOS-induced rats. We aimed at studying CFTR and FOXO1 gene expression in GC, HMGB1 concentrations in serum and follicular fluids (FF), and insulin and IL-6 in FF in PCOS women. Thirty PCOS and 36 non-PCOS women (CTRL) undergoing in vitro fertilization were enrolled. CFTR and FOXO1 gene expression were downregulated in PCOS (p ≤ .05). HMGB1 was higher in PCOS both in FF (p ≤ .05) and in serum (p < .005) whereas insulin was lower, and IL-6 was unchanged with respect to controls. 17-β estradiol was higher in PCOS than in CTRL (p ≤ .005). HMGB1 correlated negatively with insulin in FF (p ≤ .005). The increase in HMGB1 both in FF and in serum, likely reflects both low grade inflammation and insulin sensitivity. IL-6 was unchanged possibly reflecting functions other than inflammation.

PMID: 30964354 [PubMed - as supplied by publisher]

Detection of pyocyanin using a new biodegradable surface enhanced Raman spectroscopy (SERS) biosensor fabricated using gold coated zein nanostructures further decorated with gold nanoparticles.

J Agric Food Chem. 2019 Apr 09;:

Authors: Jia F, Barber EA, Turasan H, Seo S, Dai R, Liu GL, Li X, Bhunia AK, Kokini JL

Abstract
In this paper, a biodegradable gold coated zein film Surface Enhanced Raman Spectroscopy (SERS) platform, with gold nanoparticles (AuNPs) deposited on the surface to further enhance the Raman signal was used to detect pyocyanin (PYO), the toxin secreted by Pseudomonas aeruginosa. An inverted pyramid structure imprinted on a zein film and gold coated during the transfer process was further improved with the deposition and fixing of gold nanoparticles which resulted in enhancement of the SERS signal by approximately a decade. This new platform served as a lab-on-a-chip sensor to enable the sensitive and rapid detection of PYO in drinking water. The size, distribution and morphology of the zein film nanostructures including the presence and distribution of gold nanoparticles were characterized by scanning electron microscopy (SEM). The new zein-based platform has the advantage of being largely biodegradable compared with commercial silicon or glass based platforms. The limit of detection for PYO using the newly developed zein-based SERS sensor platform was calculated as 25 µM, considerably lower than the concentration of PYO in the blood of people with cystic fibrosis which has been reported to be 70 µM.

PMID: 30964288 [PubMed - as supplied by publisher]

Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus.

Proc Biol Sci. 2019 Feb 13;286(1896):20182886

Authors: Zhang J, Snelders EE, Zwaan BJ, Schoustra SE, Kuijper EJ, Arendrup MC, Melchers WJG, Verweij PE, Debets AJM

Abstract
Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. Aspergillus fumigatus, being a generalist saprotroph, may initially establish lung colonization due to its physiological versatility and subsequently adapt through genetic changes to the human lung environment and antifungal treatments. Human lung-adapted genotypes can arise by spontaneous mutation and/or recombination and subsequent selection of the fittest genotypes. Sexual and asexual spores are considered crucial contributors to the genetic diversity and adaptive potential of aspergilli by recombination and mutation supply, respectively. However, in certain Aspergillus diseases, such as cystic fibrosis and chronic pulmonary aspergillosis, A. fumigatus may not sporulate but persist as a network of fungal mycelium. During azole therapy, such mycelia may develop patient-acquired resistance and become heterokaryotic by mutations in one of the nuclei. We investigated the relevance of heterokaryosis for azole-resistance development in A. fumigatus. We found evidence for heterokaryosis of A. fumigatus in patients with chronic Aspergillus diseases. Mycelium from patient-tissue biopsies segregated different homokaryons, from which heterokaryons could be reconstructed. Whereas all variant homokaryons recovered from the same patient were capable of forming a heterokaryon, those from different patients were heterokaryon-incompatible. We furthermore compared heterokaryons and heterozygous diploids constructed from environmental isolates with different levels of azole resistance. When exposed to azole, the heterokaryons revealed remarkable shifts in their nuclear ratio, and the resistance level of heterokaryons exceeded that of the corresponding heterozygous diploids.

PMID: 30963936 [PubMed - in process]

Mucus and mucins in diseases of the intestinal and respiratory tracts.

J Intern Med. 2019 Apr 08;:

Authors: Hansson GC

Abstract
This review describes the organization and importance of mucus in the intestine and lungs in relation to the diseases cystic fibrosis, ulcerative colitis and COPD. The inner surfaces of the body are protected by mucus built around polymeric glycoproteins called mucins. In the disease Cystic Fibrosis (CF), the small intestinal mucus is in contrast the normal attached to the epithelium, explaining the intestinal problems at this disease. The inner of the two mucus layers of colon is normally impenetrable to bacteria, keeping the commensals away from and protecting the epithelium. This impenetrable property is dependent on the bacterial composition and the host diet, observations that can explain the increased incidence of inflammatory bowel diseases in the western world as bacteria reach the epithelial cells in active ulcerative colitis. The respiratory tract is normally cleared by thick mucus bundles that moved by the cilia sweep the epithelial surface. In CF, the bundles are non-moving already at birth. Cholinergic stimulations stop the bundle movement explaining some of the beneficial effect of anticholinergic treatment in COPD. In this disease as well as in more developed CF, an attached mucus layer is formed. This mucus has features similar to the protective inner colon mucus and is by this able to separate bacteria from the epithelial surface. When formed in healthy individuals this mucus can be coughed up, but in chronically diseased lungs, bacteria colonizing the mucus will remain in the lungs and the resulting inflammation contribute to the destruction of the lungs. This article is protected by copyright. All rights reserved.

PMID: 30963635 [PubMed - as supplied by publisher]

Malnutrition in Children With Chronic Disease.

Nutr Clin Pract. 2019 Apr 08;:

Authors: Larson-Nath C, Goday P

Abstract
Malnutrition occurs when nutrient intake does not meet the needs for normal body functions and as a consequence leads to alterations of growth and development in children. Chronic illness puts children at risk for developing malnutrition. Because of children's rapid periods of growth and development, early diagnosis, prevention, and management of malnutrition are paramount. The reasons for malnutrition in children with chronic disease are multifactorial and are related to the underlying disease and non-illness-associated factors. This review addresses the causes, evaluation, and management of malnutrition in pediatric congenital heart disease, chronic kidney disease, liver disease, and cystic fibrosis.

PMID: 30963628 [PubMed - as supplied by publisher]

Distal intestinal obstructive syndrome (DIOS): a gastrointestinal complication of cystic fibrosis in adults.

Clin J Gastroenterol. 2019 Apr 08;:

Authors: Mavilia M

Abstract
Distal intestinal obstructive syndrome (DIOS) is a gastrointestinal complication of cystic fibrosis caused by increased viscosity of intraluminal contents leading to partial or complete bowel obstruction. DIOS is often misdiagnosed or mistaken for surgical bowel obstruction or appendicitis. This can lead to unnecessary surgical intervention when DIOS should be treated medically with aggressive bowel regimen. The aim of this report is to present a case of a young female with cystic fibrosis presenting with DIOS and discuss the clinical recognition and management of DIOS.

PMID: 30963407 [PubMed - as supplied by publisher]

Polarized AAVR expression determines infectivity by AAV gene therapy vectors.

Gene Ther. 2019 Apr 08;:

Authors: Hamilton BA, Li X, Pezzulo AA, Abou Alaiwa MH, Zabner J

Abstract
Adeno-associated virus (AAV) has been investigated to transfer the cystic fibrosis transmembrane conductance regulator (CFTR) to airways. Inhaled AAV2-CFTR in people with cystic fibrosis (CF) is safe, but inefficient. In vitro, AAV2 transduction of human airway epithelia on the apical (luminal) side is inefficient, but efficient basolaterally. We previously selected AAV2.5T, a novel capsid that apically transduces CF human airway epithelia and efficiently restores CFTR function. We hypothesize the AAV receptor (AAVR) is basolaterally localized, and that AAV2.5T utilizes an alternative apical receptor. We found AAVR in human airway epithelia by western blot and RNA-Seq analyses. Using immunocytochemistry we did not find endogenous AAVR at membranes but overexpression localized AAVR to the basolateral membrane, where it preferentially increased transduction. Anti-AAVR antibodies blocked transduction by AAV2 from the basolateral side but not AAV2.5T from the apical side, suggesting a unique apical receptor. Finally, we found infection by AAV2 but not AAV2.5T was blocked by CRISPR knockout of AAVR in cell lines. Our data suggest the absence of apical AAVR is rate limiting for AAV2, and efficient transduction by AAV2.5T is accomplished using an AAVR independent pathway. Our findings inform the development of gene therapy for CF, and AAV vectors in general.

PMID: 30962536 [PubMed - as supplied by publisher]

Burkholderia cepacia complex contact-dependent growth inhibition systems mediate interbacterial competition.

J Bacteriol. 2019 Apr 08;:

Authors: Myers-Morales T, Oates AE, Byrd MS, Garcia EC

Abstract
Burkholderia species, including opportunistic pathogens in the Burkholderia cepacia complex (Bcc), encode genes to produce contact-dependent growth inhibition (CDI) system proteins. CDI is a phenomenon in which Gram-negative bacteria use the toxic C-terminus of a polymorphic surface-exposed exoprotein, BcpA, to inhibit the growth of susceptible bacteria upon direct cell-cell contact. Production of a small immunity protein, BcpI, prevents autoinhibition. Although CDI systems appear widespread in Gram-negative bacteria, their function has been primarily examined in several model species. Here we demonstrate that genes encoding predicted CDI systems in Bcc species encompass considerable diversity. We also show that Burkholderia multivorans, which causes pulmonary infection in patients with cystic fibrosis, expresses genes that encode two CDI systems, both of which appear distinct from the typical Burkholderia-type CDI system. Each system can mediate intra-strain interbacterial competition and contributes to bacterial adherence. Surprisingly, the immunity-encoding bcpI gene of CDI system-1 could be mutated without obvious deleterious effects. We also show that non-pathogenic B. thailandensis uses CDI to control B. multivorans growth during co-culture, providing one of the first examples of inter-species CDI and suggesting that CDI systems could be manipulated to develop therapeutic strategies targeting Bcc pathogens.IMPORTANCECompetition among bacteria impacts microbial colonization of environmental niches and host organisms, particularly during polymicrobial infections. The Burkholderia cepacia complex is a group of environmental bacteria that can cause life-threatening opportunistic infections in patients with cystic fibrosis or who are immunocompromised. Understanding the mechanisms used by these bacterial pathogens to compete with one another may lead to the development of more effective therapies. Findings presented here demonstrate that a B. cepacia complex species, Burkholderia multivorans, produces functional contact-dependent growth inhibition (CDI) system proteins and that growth of this pathogen can be controlled by CDI system proteins produced by neighboring Burkholderia.

PMID: 30962350 [PubMed - as supplied by publisher]

Implications of fatherhood in cystic fibrosis.

Paediatr Respir Rev. 2019 Mar 16;:

Authors: Bianco B, Horsley A, Brennan A

Abstract
Advances in fertility treatment mean that men with CF are increasingly able to become fathers. Here we report clinical outcomes in 22 men with CF who have become fathers for the first time. Overall mean (SD) FEV1% predicted declined from 60.1(18.0)% to 57.4(20.2)% from baseline to 1 year (p = 0.15). Weight declined from mean (SD) 70.6 kg (10.4) to 68.3 kg (10.2), p = 0.0001. Six men had an FEV1% predicted ≤40% at the time of birth: 50% died or received lung transplantation within the 12-15 month follow up period. Becoming a parent is a major life event, and as with new mothers, fathers with CF may be at risk of significant decline.

PMID: 30962151 [PubMed - as supplied by publisher]

Cystic fibrosis: Diagnosis and management - NICE guideline 78.

Paediatr Respir Rev. 2019 Feb 28;:

Authors: Walshaw MJ

Abstract
NICE produced a guideline for the diagnosis and management of CF (NG78) in October 2017. This paper describes the process of producing the guideline and highlights some of the areas covered by it, including ideas for further research and tools that can be used by purchasers to help improve CF care.

PMID: 30962150 [PubMed - as supplied by publisher]

Health-related quality of life and stress-related post-transplant trajectories of lung transplant recipients: a three-year follow-up of the Swiss Transplant Cohort Study

Swiss Med Wkly. 2019 Feb 11;149(07-08):

Authors: Bleisch B, Schuurmans MM, Klaghofer R, Benden C, Seiler A, Jenewein J

Abstract
Background: Lung transplantation (LTx) provides a viable option for the survival of end-stage lung diseases. Besides survival as a clinical outcome measure, health-related quality of life (HRQoL) and psychological distress have become important outcomes in studies investigating the effectiveness of LTx in the short- and long-term.
Objective: To assess and compare HRQoL trajectories of patients after LTx prior to and over a follow-up period of three years post-transplant, and to identify differences regarding distress, HRQoL and patient-related outcomes.
Methods: In this longitudinal study, 27 lung transplant recipients were prospectively examined for psychological distress (Symptom Checklist short version-9; SCL-K-9), health-related quality of life (EuroQOL five dimensions questionnaire; EQ-5D), depression (HADS-Depression scale), and socio-demographic and medical outcomes at two weeks, three months, six months and three years following LTx. Additionally, potential outcome-related predictors for LTx-outcomes at three years post-transplant were assessed. Data were collected in accordance with guidelines set by the STROBE (strengthening the reporting of observational studies in epidemiology) statement.
Results: Lung transplant recipients showed the most pronounced improvements in HRQoL and reduction in psychological distress between two weeks and three months post-transplant, with relative stable HRQoL and distress trajectories thereafter. The most important predictors of poor somatic health trajectories over time were the pre-transplant disease severity score and the pre-transplant HADS-Depression score. In addition, idiopathic pulmonary fibrosis (IPF) and pre-transplant extracorporeal membrane oxygenation (ECMO)-use predicted poorer survival, while cystic fibrosis was associated with better survival three years post-transplant.
Conclusion: Lung transplantation yields significant survival and HRQoL benefits, with its peak improvement at three months post-transplant. The majority of patients can preserve these health changes in the long-term. Patients with a worse HRQoL and higher psychological distress at six months post-transplant tended to have a poorer survival post-transplant. Other risk factors for poorer survival included IPF, pre-transplant ECMO-use, pre-transplant symptoms of depression, high pre-transplant disease severity and worse somatic disease severity trajectories. The majority of LTx-recipients were unable to work due to illness-related reasons.

PMID: 30961347 [PubMed - in process]

Disseminated Scedosporium apiospermum central nervous system infection after lung transplantation: A case report with successful recovery.

Med Mycol Case Rep. 2019 Jun;24:37-40

Authors: Paajanen J, Halme M, Palomäki M, Anttila VJ

Abstract
Scedosporium species are fungal opportunistic pathogens frequently seen in chronic lung diseases such as in cystic fibrosis (CF). They can cause a wide spectrum of diseases mainly in immunodeficient patients. Invasive, disseminated infections with poor prognosis have been described after lung transplantation. We present a CF-patient with disseminated Scedosporium apiospermum infection after lung transplantation. The patient had skin, surgical wound, spinal cord, and brain involvements. She recovered fully after prolonged course of voriconazole treatment.

PMID: 30956943 [PubMed]

Porphyromonas, a potential predictive biomarker of Pseudomonas aeruginosa pulmonary infection in cystic fibrosis.

BMJ Open Respir Res. 2019;6(1):e000374

Authors: Keravec M, Mounier J, Guilloux CA, Fangous MS, Mondot S, Vallet S, Gouriou S, Le Berre R, Rault G, Férec C, Barbier G, Lepage P, Héry-Arnaud G

Abstract
Introduction: Pseudomonas aeruginosa pulmonary infections are the primary cause of morbi-mortality in patients with cystic fibrosis (CF). In this cohort study, the objective was to identify candidate biomarkers of P. aeruginosa infection within the airway microbiota.
Methods: A 3-year prospective multicentre study (PYOMUCO study) was conducted in Western France and included patients initially P. aeruginosa free for at least 1 year. A 16S-targeted metagenomics approach was applied on iterative sputum samples of a first set of patients (n=33). The composition of airway microbiota was compared according to their P. aeruginosa status at the end of the follow-up (colonised vs non-colonised), and biomarkers associated with P. aeruginosa were screened. In a second step, the distribution of a candidate biomarker according to the two groups of patients was verified by qPCR on a second set of patients (n=52) coming from the same cohort and its load quantified throughout the follow-up.
Results: Porphyromonas (mainly P. catoniae) was found to be an enriched phylotype in patients uninfected by P. aeruginosa (p<0.001). This result was confirmed by quantitative PCR. Conversely, in patients who became P. aeruginosa-positive, P. catoniae significantly decreased before P. aeruginosa acquisition (p=0.014).
Discussion: Further studies on replication cohorts are needed to validate this potential predictive biomarker, which may be relevant for the follow-up in the early years of patients with CF. The identification of infection candidate biomarkers may offer new strategies for CF precision medicine.

PMID: 30956802 [PubMed]

Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis.

Clin Med Insights Circ Respir Pulm Med. 2019;13:1179548419835788

Authors: Bisch AL, Wheatley CM, Baker SE, Peitzman ER, Van Iterson EH, Laguna TA, Morgan WJ, Snyder EM

Abstract
Background: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation.
Methods: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C2H2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del).
Results: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m2 vs healthy = 1.84 ± 0.04 m2, P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m2 vs healthy = 39.9 ± 2.5 mL/beat/m2, P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm-5 vs healthy = 1616 ± 74 dynes*s/cm-5, P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV (P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F(2,14) = 7.982, P < .01) and SV index (F(2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions).
Conclusions: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

PMID: 30956528 [PubMed]

Proline-Glycine-Proline Peptides Are Critical in the Development of Smoke-Induced Emphysema.

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

Authors: Abdul Roda M, Xu X, Abdalla TH, Sadik M, Szul T, Bratcher PE, Viera L, Solomon GM, Wells JM, McNicholas CM, Redegeld FA, Folkerts G, Blalock JE, Gaggar A

Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of worldwide mortality and is characterized by an excessive airway neutrophilic response. The neutrophil chemoattractant proline-glycine-proline (PGP) and its more potent acetylated form (acPGP) have been found to be elevated in COPD patients and act via CXCR2. Here, we investigate the impact of neutralizing PGP peptides in a murine model for emphysema. The PGP neutralizing peptide L-arginine-threonine-arginine (RTR) was used first in a 6-week model of cigarette smoke exposure, where it attenuated lung inflammation. Further a chronic cigarette smoke exposure was conducted with mice starting RTR treatment after 10 weeks of smoke exposure and then continuing the treatment together with the smoke exposure during the last 13 weeks, totaling 23 weeks of smoke exposure. RTR significantly inhibited neutrophil and macrophage influx into the lungs in the 6-week model of exposure. RTR also attenuated the development of emphysema, normalized lung volumes, and reduced right ventricular hypertrophy (RVH) in the chronic exposure model. Murine epithelia expressed CXCR2 and this expression was increased after smoke exposure. In vitro, human bronchial epithelial (HBE) cells also demonstrated robust expression for CXCR2 and stimulation of primary HBE cells with acPGP led to increased release of MMP-9 and IL-8. Overall, these results provide evidence for a critical role of acPGP during emphysema development in cigarette smoke-induced injury and highlight a new epithelial mechanism by which acPGP augments neutrophilic inflammation.

PMID: 30958968 [PubMed - as supplied by publisher]

[CURRENT APPROACHES TO PREVENTION OF BLEEDINGS, ASSOCIATED WITH VITAMIN K DEFICIENCY IN NEWBORNS AND INFANTS].

Georgian Med News. 2019 Feb;(287):45-50

Authors: Kiselova M

Abstract
In the article intended for neonatologists, general practitioners and family doctors, the main causes of hemostatic disorders that lead to the development of hemorrhagic syndrome in newborns and infants are given. The emphasis is on the different forms of neonatal hemorrhagic disease (HD), which is based on the deficiency of vitamin K1, and therefore the bleeding that is observed in children who are breastfed in the first half of life is mostly associated, namely, with vitamin K deficiency. Risk factors of HD depending from the time of the beginning, of the action of one or another factor. The main clinical manifestations of both early and late forms of HD are described, it is shown which of them are mistakenly diagnosed that lead to the appointment of the wrong treatment. The assessment of the need for prevention of late form of bleeding associated with vitamin K deficiency is carried out by determining the concentration in the blood of a functional coagulation marker - PIVKA II. Modern methods of prevention of late bleeding associated with vitamin K1 deficiency, based on nosological units - chronic cholestasis, cystic fibrosis, are presented. The current recommendations on the use of vitamin K1 in newborns and infants of the American Academy of Pediatrics, the scientific community of Canada, Netherlands, Switzerland, Germany, France, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the World Health Organization, which are clearly followed by the effects of local peculiarities are described and interpreted. on approaches to the prevention of bleeding associated with vitamin K1 deficiency, which affects the choice of a single dose, the duration of the prophylactic course and the route of administration of vitamin in K1 (phytomenadion). The role of parents in the prevention of vitamin K deficiency is emphasized.

PMID: 30958287 [PubMed - in process]

SLC9A3 Affects Vas Deferens Development and Associates with Taiwanese Congenital Bilateral Absence of the Vas Deferens.

Biomed Res Int. 2019;2019:3562719

Authors: Wu YN, Chen KC, Wu CC, Lin YH, Chiang HS

Abstract
Background: The pathophysiology of Taiwanese congenital bilateral absence of the vas deferens (CBAVD) is different from that in Caucasians. In particular, major cystic fibrosis transmembrane conductance regulator (CFTR) mutations and cystic fibrosis are absent in the former. Instead, deficiency in solute carrier family 9 sodium/hydrogen exchanger isoform 3 (SLC9A3) may play a role by generating obstructive azoospermia and degraded epithelial structure in the reproductive tract.
Objectives: The objective of the study was to test whether SLC9A3 variants cause Taiwanese CBAVD.
Materials and Methods: Six-month-old Slc9a3 -/-male mice were used to evaluate the effect of long-term SLC9A3 loss on the reproductive system. A case-control cohort of 29 men with CBAVD and 32 fertile men were genotyped for SLC9A3 variants.
Results: SLC9A3 was expressed and localized in the apical border of the epithelium of human vas deferens and glandular epithelium of the seminal vesicle. SLC9A3 deficiency specifically induces atrophy of vas deferens and unfolding of seminal vesicle mucosa in mice. Loss of SLC9A3 increased the incidence of CBAVD in humans from 3.1% to 37.9% (p < 0.001). Up to 75.9% of CBAVD patients carry at least one variant in either SLC9A3 or CFTR.
Discussion: Our findings build upon previous data associated with CBAVD pathogenesis. Here, we now report for the first time an association between CBAVD and loss of SLC9A3 and propose that specific defects in the reproductive duct due to SLC9A3 variants drive CBAVD development.
Conclusion: The data implicate loss of SLC9A3 as a basis of Taiwanese CBAVD and highlight SLC9A3 function in reproduction.

PMID: 30956978 [PubMed - in process]

Cytomegalovirus - an unrecognised potential contributor to cystic fibrosis disease progression?

Eur Respir J. 2019 Apr 07;:

Authors: Parkins MD, Ramos KJ, Goss CH, Somayaji R

Abstract
Cytomegalovirus (CMV) is a common human beta-herpes virus most notable for causing visceral disease in profoundly immune-suppressed populations, and congenital infections. However, an increasing body of work has demonstrated that CMV seropositivity is associated with a number of chronic medical conditions including heart disease and dementia - potentially related to the effects of chronic inflammation. We hypothesided that the outcomes of individuals with cystic fibrosis (CF), a chronic inflammatory disease, could similarly be associated with CMV-status. We performed a single-centre retrospective study of all 71 individuals with CF referred for lung transplantation from our CF centre between 1991-2017 and assessed how CMV serostatus associated with patient pre-transplant outcomes. We observed CMV IgG positivity was associated with disproportionate progression to end-stage lung disease as defined by death/or transplantation in our cohort (27.2 versus 35.1 years, difference 7.95 (95% CI 3.61-12.29 years), p<0.001) which remained significant following adjustment for confounders (difference 6.96 (95% CI 2.51-11.41 years). CMV may represent a potentially important modifier of CF lung disease, warranting further study.

PMID: 30956206 [PubMed - as supplied by publisher]

Newborn screening for cystic fibrosis: Is there benefit for everyone?

Paediatr Respir Rev. 2019 Feb 28;:

Authors: Course CW, Hanks R

Abstract
Newborn screening for cystic fibrosis (CF) has become a widely accepted and endorsed public health strategy in economically developed countries, although there is little consensus on optimal screening methods and gene panels. Increasing understanding of CFTR genetics and consequent unpredictability of phenotypic and clinical outcomes lead to diagnostic uncertainty, and emergence of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CF-SPID). Many of these children are clinically well or have a mild phenotype yet may still experience the psychosocial impact of a CF diagnosis. This questions the role of newborn screening and how best to manage those it identifies with CF-SPID.

PMID: 30956155 [PubMed - as supplied by publisher]