Personalized CFTR Modulator Therapy for G85E and N1303K Homozygous Patients with Cystic Fibrosis.

CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E, but not N1303K. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a G85E homozygous patient and an N1303K homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in G85E/G85E and N1303K/N1303K pHNECs. In the G85E/G85E and the N1303K/N1303K patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare CFTR mutations.

Age-Related Differences in Structure and Function of Nasal Epithelial Cultures From Healthy Children and Elderly People.

The nasal epithelium represents the first line of defense against inhaled pathogens, allergens, and irritants and plays a key role in the pathogenesis of a spectrum of acute and chronic airways diseases. Despite age-dependent clinical phenotypes triggered by these noxious stimuli, little is known about how aging affects the structure and function of the airway epithelium that is crucial for lung homeostasis and host defense. The aim of this study was therefore to determine age-related differences in structural and functional properties of primary nasal epithelial cultures from healthy children and non-smoking elderly people. To achieve this goal, highly differentiated nasal epithelial cultures were established from nasal brushes at air-liquid interface and used to study epithelial cell type composition, mucin (MUC5AC and MUC5B) expression, and ion transport properties. Furthermore, we determined age-dependent molecular signatures using global proteomic analysis. We found lower numeric densities of ciliated cells and higher levels of MUC5AC expression in cultures from children vs. elderly people. Bioelectric studies showed no differences in basal ion transport properties, ENaC-mediated sodium absorption, or CFTR-mediated chloride transport, but detected decreased calcium-activated TMEM16A-mediated chloride secretory responses in cultures from children vs. elderly people. Proteome analysis identified distinct age-dependent molecular signatures associated with ciliation and mucin biosynthesis, as well as other pathways implicated in aging. Our data identified intrinsic, age-related differences in structure and function of the nasal epithelium and provide a basis for further studies on the role of these findings in age-dependent airways disease phenotypes observed with a spectrum of respiratory infections and other noxious stimuli.

Application of 3D-printed colored 3D-models for the fabrication of full ceramic restorations: A technical report.

OBJECTIVE: This paper presents a novel digital workflow that expedites and facilitates the manufacturing of high-end full-ceramic restorations based on "Print and Press"-Technology combined with 3D-printed colored 3D-models. CLINICAL CONSIDERATIONS: Despite ongoing innovations and developments in the digital workflow, the precision, and the final esthetic outcome is still limited compared with conventional press ceramics. The proposed method combines the advantages of digital scan- and design technologies with the proven conventional press-technology to accomplish high-end full-ceramic restorations. The restoration is digitally designed, the data set is 3D-printed in resin that can be burned out, subsequently conventionally embedded and pressed. Final esthetic finishing of the partial restorations is done on a 3D-printed physical colored 3D-model. CONCLUSION: The report describes synergetic effects of digital and analog procedures. 3D-printed colored 3D-models can positively support the manufacturing of full ceramic restorations regarding their optical integration. Therefore, the use of 3D-printed colored 3D-models signifies a new innovative technique with many promising application areas. CLINICAL SIGNIFICANCE: The combination of excellent clinical long-term data for pressed ceramic restorations and proven digital processes, like intraoral scanning, design, and additive manufacturing, in the dental field promise an individual workflow for predictability and excellent esthetics.

Retrospectively analysed tooth loss in periodontally compromised patients: Long-term results 10 years after active periodontal therapy-Patient-related outcomes.

BACKGROUND AND OBJECTIVE: Long-term tooth retention is the ultimate goal of periodontal therapy. Aim of this study was to evaluate tooth loss (TL) during 10 years of supportive periodontal therapy (SPT) in periodontal compromised patients and to identify factors influencing TL on patient level. MATERIAL AND METHODS: Patients were re-examined 120 ± 12 months after active periodontal therapy. TL and risk factors [smoking, initial diagnosis, SPT adherence, interleukin-1 polymorphism, cardiovascular diseases, age at baseline, bleeding on probing (BOP), change of practitioner, insurance status, number of SPT, marital and educational status] influencing TL on patient level were assessed. RESULTS: One-hundred patients (52 female, mean age 65.6 ± 11 years) lost 121 of 2428 teeth (1.21 teeth/patient; 0.12 teeth/patient/y) during 10 years of SPT. Forty-two of these were lost for periodontal reasons (0.42 teeth/patient; 0.04 teeth/patient/y). Significantly more teeth were lost due to other reasons (P < .001). Smoking, baseline severity of periodontitis, non-adherent SPT, positive interleukin-1 polymorphism, marital and educational status, private insurance, older age at baseline and BOP, small number of SPT were identified as patient-related risk factors for TL (P < .05). CONCLUSION: During 120 ± 12 months of SPT, only a small number of teeth was lost in periodontally compromised patients showing the positive effect of a well-established periodontal treatment concept. The remaining risk for TL should be considered using risk-adopted SPT allocation.

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans.

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.

Quality assessment of baby food made of different pre-processed organic raw materials under industrial processing conditions.

The market for processed food is rapidly growing. The industry needs methods for "processing with care" leading to high quality products in order to meet consumers' expectations. Processing influences the quality of the finished product through various factors. In carrot baby food, these are the raw material, the pre-processing and storage treatments as well as the processing conditions. In this study, a quality assessment was performed on baby food made from different pre-processed raw materials. The experiments were carried out under industrial conditions using fresh, frozen and stored organic carrots as raw material. Statistically significant differences were found for sensory attributes among the three autoclaved puree samples (e.g. overall odour F = 90.72, p < 0.001). Samples processed from frozen carrots show increased moisture content and decrease of several chemical constituents. Biocrystallization identified changes between replications of the cooking. Pre-treatment of raw material has a significant influence on the final quality of the baby food.

Organic food quality: a framework for concept, definition and evaluation from the European perspective.

Consumers buy organic food because they believe in the high quality of the product. Furthermore, the EU legal regulatory framework for organic food and farming defines high quality of the products as an important goal of production. A major challenge is the need to define food quality concepts and methods for determination. A background is described which allows embedding of the quality definitions as well as evaluation methods into a conceptual framework connected to the vision and mission of organic agriculture and food production. Organic food quality is defined through specific aspects and criteria. For evaluation each criterion has to be described by indicators. The determination of indicators should be through parameters, where parameters are described by methods. Conversely, the conceptual framework is described according to underlying principles and starting definitions are given, but further work has do be done on the detailed scientific description of the indicators. Furthermore, parameters have to be defined for the evaluation of suitability of these indicators for organic food production.

Feeding trials in organic food quality and health research.

Feeding experiments comparing organically and conventionally produced food are performed to assess the overall impact on the animals' health as a model for the effects experienced by the human consumers. These experiments are based on systems research and characterized by their focus on production methods, whole food testing and procedures in accordance with the terms of organic farming. A short review of such experiments shows that the majority of these tests revealed effects of the organically produced feed on health parameters such as reproductive performance and immune responses. Systems research is not just about simple cause-effect chains, but rather about the pluralism of interactions in biological networks; therefore, the interpretation of the outcome of whole food experiments is difficult. Furthermore, the test diets of organic and conventional origin can be constituted in different ways, compensating for or maintaining existing differences in nutrient and energy contents. The science-based results suggest positive influences from organic feeds, but there is still a need for confirmation in animals and, finally, in humans. For this purpose animal feeding trials with feed from different production systems should be conducted, with the aims to define health indicators and to establish biomarkers as a basis for future dietary intervention studies in humans.

Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome.

Ror2 is a receptor tyrosine kinase mutated in the human syndromes Brachydactyly type B (BDB) and recessive Robinow syndrome (RS). In this study, we used the chick as a model to investigate the role of Ror2 in skeletogenesis and to elucidate the functional consequences of Ror2 mutations. For this purpose, we cloned chicken Ror2 and analyzed its expression pattern at various embryonic stages by in situ hybridization and immunolabeling. We document expression of cRor2 in several organs, including mesonephros, heart, nervous system, intestine and cartilage. The high conservation of expression when compared with the mouse underlines the validity of the chick as a model system. Using replication-competent retroviral vector-mediated overexpression, we analyzed the functional consequences of truncating BDB and RS mutations in the developing chick limb. Overexpression of Ror2 mutants led to a disturbance of growth plate architecture and a severe block of chondrocyte differentiation, demonstrating the functional importance of Ror2 in skeletogenesis.