The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease

AbstractChronic lung disease remains the major cause of morbidity and mortality of cystic fibrosis (CF) patients. Cftr mutant mice developed severe intestinal obstruction, but did not exhibit the characteristic CF ion transport defects (i.e. deficient cAMP-dependent Cl− secretion and increased Na+ absorption) in the lower airways, and failed to develop CF-like lung disease. These observations led to the generation of transgenic mice with airway-specific overexpression of the epithelial Na+ channel (ENaC) as an alternative approach to mimic CF ion transport pathophysiology in the lung. Studies of the phenotype of βENaC-transgenic mice demonstrated that increased airway Na+ absorption causes airway surface liquid (ASL) depletion, reduced mucus transport and a spontaneous CF-like lung disease with airway mucus obstruction and chronic airway inflammation. Here, we summarize approaches that can be applied for studies of the complex in vivo pathogenesis and preclinical evaluation of novel therapeutic strategies in this model of CF lung disease

Effects of lumacaftor—ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in F508del homozygous patients with cystic fibrosis aged 2–11 years

Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown.Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2–11 years before and 8–16 weeks after treatment initiation.Results: A total of 13 children with CF homozygous for F508del aged 2–11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L (p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal (p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older.Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2–11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters

Influence of Different Cut-Off Values on the Diagnosis of Mild Cognitive Impairment in Parkinson's Disease

Comparable to Alzheimer’s disease, mild cognitive impairment in Parkinson’s disease (PD-MCI) is associated with an increased risk for dementia. However different definitions of PD-MCI may have varying predictive accuracy for dementia. In a cohort of 101 nondemented Parkinson patients who underwent neuropsychological testing, the frequency of PD-MCI subjects and PDMCI subtypes (i.e., amnestic/nonamnestic) was determined by use of varying healthy population-based cut-off values. We also investigated the association between defined PD-MCI groups and ADL scales. Varying cut-off values for the definition of PD-MCI were found to affect frequency of PD-MCI subjects (9.9%–92.1%) and, maybe more important, lead to a “shift” of proportion of detected PD-MCI subtypes especially within the amnestic single-domain subtype. Models using a strict cut-off value were significantly associated with lower ADL scores. Thus, the use of defined cut-off values for the definition of PD-MCI is highly relevant for comparison purposes. Strict cut-off values may have a higher predictive value for dementia

Guidelines for the Neuropsychological Assessment of Patients with Parkinson's Disease

Background Presence of mild cognitive impairment is currently the best predictor for the development of Parkinson's disease dementia. Diagnostic criteria for both Parkinson's with mild cognitive impairment and Parkinson's disease dementia have been suggested by the Movement Disorder Society. However, not all cognitive tests recommended are available in the German language with proper standard values. Objectives To define evidence-based guidelines for neuropsychological assessment of patients with Parkinson's disease in German. Methods Two systematic literature searches were conducted. First, articles that presented international guidelines (consensus papers or reviews) for the application of standardized neuropsychological assessments for the diagnosis of cognitive impairment in Parkinson's disease were selected. Of those, only neuropsychological assessments in German language with normative values referring either to a German, Austrian, or Swiss population were considered. Second, articles comparing test performances of healthy controls vs. Parkinson's disease and/or different cognitive Parkinson's disease subtypes (e.g. no cognitive impairment, Parkinson's with mild cognitive impairment, Parkinson's disease dementia) were selected. Effect sizes for group differentiation were calculated. Results Out of 127 full-text articles reviewed, 48 tests were identified during the first literature search. In the second search, 1716 articles were reviewed and 23 papers selected. The strongest effect sizes for group discrimination were revealed for tests assessing executive function, attention, and visuo-cognitive abilities. Based on the results of the two literature searches, consensus guidelines were defined by the authors, allowing for Level-II diagnosis for Parkinson's with mild cognitive impairment and Parkinson's disease dementia. Conclusions: The presented guidelines may have the potential to standardize and improve the neuropsychological assessment of Parkinson's disease patients in German speaking countries

Comparison of Oropharyngeal Microbiota from Children with Asthma and Cystic Fibrosis

A genuine microbiota resides in the lungs which emanates from the colonization by the oropharyngeal microbiota. Changes in the oropharyngeal microbiota might be the source of dysbiosis observed in the lower airways in patients suffering from asthma or cystic fibrosis (CF). To examine this hypothesis, we compared the throat microbiota from healthy children (n=62) and that from children with asthma (n=27) and CF (n=57) aged 6 to 12 years using 16S rRNA amplicon sequencing. Our results show high levels of similarities between healthy controls and children with asthma and CF revealing the existence of a core microbiome represented by Prevotella, Streptococcus, Neisseria, Veillonella, and Haemophilus. However, in CF, the global diversity, the bacterial load, and abundances of 53 OTUs were significantly reduced, whereas abundances of 6 OTUs representing opportunistic pathogens such as Pseudomonas, Staphylococcus, and Streptococcus were increased compared to those in healthy controls controls and asthmatics. Our data reveal a core microbiome in the throat of healthy children that persists in asthma and CF indicating shared host regulation favoring growth of commensals. Furthermore, we provide evidence for dysbiosis with a decrease in diversity and biomass associated with the presence of known pathogens consistent with impaired host defense in children with CF

Gonorrhö mit einem high-level-Azithromycin-resistenten Erreger in Deutschland

Das Epidemiologische Bulletin 32/33 2019 berichtet über eine urogenitale Gonorrhö bei einem 42-jährigen Patienten mit einem high-level-Azithromycin-resistenten N. gonorrhoeae-Stamm. Die Erkrankung wurde Ende Juni 2019 in Deutschland diagnostiziert. Eine Reiseanamnese beim Patienten bestand nicht, ebenso keine Vorerkrankungen und keine relevanten vorherigen Antibiotikatherapien. Die Partnerin des Patienten war ebenfalls erkrankt. Bei ihr wurde eine Gonorrhö sowohl endozervikal als auch pharyngeal nachgewiesen.Peer Reviewe

Psychometric properties of the apathy evaluation scale in patients with Parkinson's disease

Parkinson's disease (PD) frequently entails non-motor symptoms, worsening the course of the disease. Apathy is one of the core neuropsychiatric symptoms that has been investigated in recent years; research is however hampered by the limited availability of well-evaluated apathy scales for these patients. We evaluated the psychometric properties of the Apathy Evaluation Scale (AES) in a sample of PD patients. Psychometric properties, convergent and discriminant validity and sensitivity/specificity were evaluated in patients with (n=582) or without dementia/depression (n=339). Internal consistency was high in the entire sample as well as in patients without dementia/depression. Correlations were moderate for convergent validity (UPDRS I item 4: motivation). While apathy could be differentiated from cognitive decline, it was related to depression (Geriatric Depression Scale, GDS-15). The overall classification accuracy based on the UPDRS I item 4 was comparable for AES and GDS scores. The AES exhibits good psychometric properties in PD patients with and without dementia and/or depression. Commonly used screenings on the presence of apathy had low detection rates compared to the AES and reflected both apathetic and depressive symptoms. Psychometric evaluation of available instruments will support further research on the clinical relevance of apathy for disease progression and treatment approaches in PD patients