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  • 11
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    Online Resource
    Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 3 ( 2020-01-31), p. 956-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 3 ( 2020-01-31), p. 956-
    Abstract: Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the α-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ≥3% of wild type enzyme activity and a relative increase in enzyme activity of ≥1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own α-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21030956
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 12
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    Birth Order, Caesarean Section, or Daycare Attendance in Relation to Child- and Adult-Onset Type 1 Diabetes: Results from the German National Cohort
    MDPI AG ; 2022
    In:  International Journal of Environmental Research and Public Health Vol. 19, No. 17 ( 2022-08-31), p. 10880-
    Details
    In: International Journal of Environmental Research and Public Health, MDPI AG, Vol. 19, No. 17 ( 2022-08-31), p. 10880-
    Abstract: (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.
    Type of Medium: Online Resource
    ISSN: 1660-4601
    URL: Article
    DOI: 10.3390/ijerph191710880
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2175195-X
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  • 13
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    Influence of PEGDA Molecular Weight and Concentration on the In Vitro Release of the Model Protein BSA–FITC from Photo Crosslinked Systems
    MDPI AG ; 2023
    In:  Pharmaceutics Vol. 15, No. 4 ( 2023-03-23), p. 1039-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 15, No. 4 ( 2023-03-23), p. 1039-
    Abstract: Novel 3D printing techniques enable the development of medical devices with drug delivery systems that are tailored to the patient in terms of scaffold shape and the desired pharmaceutically active substance release. Gentle curing methods such as photopolymerization are also relevant for the incorporation of potent and sensitive drugs including proteins. However, retaining the pharmaceutical functions of proteins remains challenging due to the possible crosslinking between the functional groups of proteins, and the used photopolymers such as acrylates. In this work, the in vitro release of the model protein drug, albumin–fluorescein isothiocyanate conjugate (BSA–FITC) from differently composed, photopolymerized poly(ethylene) glycol diacrylate (PEGDA), an often employed, nontoxic, easily curable resin, was investigated. Different PEGDA concentrations in water (20, 30, and 40 wt %) and their different molecular masses (4000, 10,000, and 20,000 g/mol) were used to prepare a protein carrier with photopolymerization and molding. The viscosity measurements of photomonomer solutions revealed exponentially increasing values with increasing PEGDA concentration and molecular mass. Polymerized samples showed increasing medium uptake with an increasing molecular mass and decreasing uptake with increasing PEGDA content. Therefore, the modification of the inner network resulted in the most swollen samples (20 wt %) also releasing the highest amount of incorporated BSA–FITC for all PEGDA molecular masses.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics15041039
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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  • 14
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    Divergent Patterns and Trends in Breast Cancer Incidence, Mortality and Survival Among Older Women in Germany and the United States
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 9 ( 2020-08-26), p. 2419-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 9 ( 2020-08-26), p. 2419-
    Abstract: Background: Breast cancer treatment has changed tremendously over the last decades. In addition, the use of mammography screening for early detection has increased strongly. To evaluate the impact of these developments, long-term trends in incidence, mortality, stage distribution and survival were investigated for Germany and the United States (US). Methods: Using population-based cancer registry data, long-term incidence and mortality trends (1975–2015), shifts in stage distributions (1998–2015), and trends in five-year relative survival (1979–2015) were estimated. Additionally, trends in five-year relative survival after standardization for stage were explored (2004–2015). Results: Age-standardized breast cancer incidence rates were much higher in the US than in Germany in all periods, whereas age-standardized mortality began to lower in the US from the 1990s on. The largest and increasing differences were observed for patients aged 70+ years with a 19% lower incidence but 45% higher mortality in Germany in 2015. For this age group, large differences in stage distributions were observed, with 29% (Germany) compared to 15% (US) stage III and IV patients. Age-standardized five-year relative survival increased strongly between 1979–1983 and 2013–2015 in Germany (+17% units) and the US (+19% units) but was 9% units lower in German patients aged 70+ years in 2013–2015. This difference was entirely explained by differences in stage distributions. Conclusions: Overall, our results are in line with a later uptake and less extensive utilization of mammography screening in Germany. Further studies and efforts are highly needed to further explore and overcome the increased breast cancer mortality among elderly women in Germany.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12092419
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 15
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    The Combined Use of Automated Milking System and Sensor Data to Improve Detection of Mild Lameness in Dairy Cattle
    MDPI AG ; 2023
    In:  Animals Vol. 13, No. 7 ( 2023-03-28), p. 1180-
    Details
    In: Animals, MDPI AG, Vol. 13, No. 7 ( 2023-03-28), p. 1180-
    Abstract: This study aimed to develop a tool to detect mildly lame cows by combining already existing data from sensors, AMSs, and routinely recorded animal and farm data. For this purpose, ten dairy farms were visited every 30–42 days from January 2020 to May 2021. Locomotion scores (LCS, from one for nonlame to five for severely lame) and body condition scores (BCS) were assessed at each visit, resulting in a total of 594 recorded animals. A questionnaire about farm management and husbandry was completed for the inclusion of potential risk factors. A lameness incidence risk (LCS ≥ 2) was calculated and varied widely between farms with a range from 27.07 to 65.52%. Moreover, the impact of lameness on the derived sensor parameters was inspected and showed no significant impact of lameness on total rumination time. Behavioral patterns for eating, low activity, and medium activity differed significantly in lame cows compared to nonlame cows. Finally, random forest models for lameness detection were fit by including different combinations of influencing variables. The results of these models were compared according to accuracy, sensitivity, and specificity. The best performing model achieved an accuracy of 0.75 with a sensitivity of 0.72 and specificity of 0.78. These approaches with routinely available data and sensor data can deliver promising results for early lameness detection in dairy cattle. While experimental automated lameness detection systems have achieved improved predictive results, the benefit of this presented approach is that it uses results from existing, routinely recorded, and therefore widely available data.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani13071180
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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  • 16
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    Resolved Simulation of the Clarification and Dewatering in Decanter Centrifuges
    MDPI AG ; 2023
    In:  Processes Vol. 12, No. 1 ( 2023-12-19), p. 9-
    Details
    In: Processes, MDPI AG, Vol. 12, No. 1 ( 2023-12-19), p. 9-
    Abstract: Solid–liquid separation is a fundamental operation in process engineering and thus an important part of many process chains in the preparation of slurries in the chemical industry and other parts of the industrial environment. For the separation of micron-sized particles which, due to their size, do not settle or settle very slowly in the earth’s gravity field, centrifuges are often used. The preferred choice are often decanter centrifuges because they work continuously and stabilize the process against product fluctuations due to their adjustment possibilities. The design of the apparatus is complex: The main components of the apparatus are the cylindrical-conical bowl, which rotates at a high speed, and a screw located inside the bowl, which rotates in the same direction at a low differential speed to transport the separated solids out of the apparatus. Geometrical properties of the apparatus, as well as the adjustable operating parameters, such as rotational speed or differential speed, have a significant influence on the separation. In practice, analytical models and the experience of the manufacturers form the basis for the design. Characteristics of the disperse phase, interactions with the liquid, as well as the influence of the flow on the separation, are not taken into account. As a consequence, the transfer to industrial scale always requires a large number of pilot-scale experiments, which are time-consuming and expensive. Due to the increasing computational power, computational fluid dynamics (CFD) provides one possibility to minimize the experimental effort in centrifuge design. In this work, the open-source software OpenFOAM is used to simulate the multi-phase flow in a laboratory decanter centrifuge. For validation, experiments were carried out on a laboratory scale and the main operating parameters, such as speed, differential speed, and volume flow rate, were varied. The simulation results show a good agreement with the experimental data. Furthermore, the numerical investigations show the influence of the flow on the separation of the particles. To evaluate the transportability of a material, the transport efficiency was introduced as a dimensionless parameter. In addition, the simulation allows the consideration of the individual velocity components, making it possible to generate an impression of the complex three-dimensional flow in the apparatus for the first time.
    Type of Medium: Online Resource
    ISSN: 2227-9717
    URL: Article
    DOI: 10.3390/pr12010009
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2720994-5
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  • 17
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    A Resolved Simulation Approach to Investigate the Separation Behavior in Solid Bowl Centrifuges Using Material Functions
    MDPI AG ; 2022
    In:  Separations Vol. 9, No. 9 ( 2022-09-06), p. 248-
    Details
    In: Separations, MDPI AG, Vol. 9, No. 9 ( 2022-09-06), p. 248-
    Abstract: The separation of finely dispersed particles from liquids is a basic operation in mechanical process engineering. On an industrial scale, continuously operating decanter centrifuges are often used, whose separation principle is based on the density difference between the solid and the liquid phase due to high g-forces acting on both phases. The design of centrifuges is based on the experience on the individual manufacturer or simplified black box models, which only consider a stationary state. Neither the physical behavior of the separation process nor the sediment formation and its transport is considered. In this work, a computationally-efficient approach is proposed to simulate the separation process in decanter centrifuges. Thereby, the open-source computation software OpenFOAM was used to simulate the multiphase flow within the centrifuge. Sedimentation, consolidation of the sediment, and its transport are described by material functions which are derived from experiments. The interactions between the particles and the fluid are considered by locally defined viscosity functions. This work shows that the simulation method is suitable for describing the solid-liquid separation in a simplified test geometry of a decanter centrifuge. In addition, the influence of the rheological behavior on the flow in the test geometry can be observed for the first time.
    Type of Medium: Online Resource
    ISSN: 2297-8739
    URL: Article
    DOI: 10.3390/separations9090248
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2869930-0
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  • 18
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    Association of Serum GFAP with Functional and Neurocognitive Outcome in Sporadic Small Vessel Disease
    MDPI AG ; 2022
    In:  Biomedicines Vol. 10, No. 8 ( 2022-08-02), p. 1869-
    Details
    In: Biomedicines, MDPI AG, Vol. 10, No. 8 ( 2022-08-02), p. 1869-
    Abstract: Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines10081869
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720867-9
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  • 19
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    Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa
    MDPI AG ; 2020
    In:  Pharmaceutics Vol. 12, No. 11 ( 2020-10-23), p. 1014-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 12, No. 11 ( 2020-10-23), p. 1014-
    Abstract: Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG antibodies through the nasal mucosa. IgGs were used in their wild type and deglycosylated form to investigate the impact of glycosylation. Further, the expression of FcRn and Fc-gamma receptor (FCGR) and their interaction with IgG were analyzed. Comparable permeation rates for human and porcine IgG were observed in OEPC, which display the highest expression of FcRn. Only traces of porcine IgGs could be recovered at the basolateral compartment in ex vivo olfactory tissue, while human IgGs reached far higher levels. Deglycosylated human IgG showed significantly higher permeation in comparison to the wild type in RPMI 2650 and OEPC, but insignificantly elevated in the ex vivo model. An immunoprecipitation with porcine primary cells and tissue identified FCGR2 as a potential interaction partner in the nasal mucosa. Glycosylation sensitive receptors appear to be involved in the uptake, transport, but also degradation of therapeutic IgGs in the airway epithelial layer.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics12111014
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527217-2
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  • 20
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    Biological Diabrotica Management and Monitoring of Metarhizium Diversity in Austrian Maize Fields Following Mass Application of the Entomopathogen Metarhizium brunneum
    MDPI AG ; 2021
    In:  Applied Sciences Vol. 11, No. 20 ( 2021-10-12), p. 9445-
    Details
    In: Applied Sciences, MDPI AG, Vol. 11, No. 20 ( 2021-10-12), p. 9445-
    Abstract: Inundative mass application of Metarhizium brunneum BIPESCO 5 (Hypocreales, Clavicipitaceae) is used for the biological control of Diabrotica v. virgifera (Coleoptera, Chrysomelidae). Long-term field trials were performed in three Austrian maize fields—with different cultivation techniques and infestation rates—in order to evaluate the efficacy of the treatment to control the pest larvae. In addition, the indigenous Metarhizium spp. population structure was assessed to compare the different field sites with BIPESCO 5 mass application. Annual application of the product Granmet-PTM (Metarhizium colonized barley kernels) significantly increased the density of Metarhizium spp. in the treated soil above the upper natural background level of 1000 colony forming units per gram dry weight soil. Although a decrease in the pest population over time was not achieved in heavily infested areas, less damage occurred in treated field sites in comparison to control sites. The Metarhizium population structure was significantly different between the treated field sites. Results showed that inundative mass application should be repeated regularly to achieve good persistence of the biological control agent, and indicated that despite intensive applications, indigenous populations of Metarhizium spp. can coexist in these habitats. To date, crop rotation remains the method of choice for pest reduction in Europe, however continuous and preventive application of M. brunneum may also present an alternative for the successful biological control of Diabrotica.
    Type of Medium: Online Resource
    ISSN: 2076-3417
    URL: Article
    DOI: 10.3390/app11209445
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2704225-X
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