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  • 1
    Online Resource
    Online Resource
    Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 4 ( 2020-04-23), p. 1035-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 4 ( 2020-04-23), p. 1035-
    Abstract: Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12041035
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa
    MDPI AG ; 2021
    In:  Pharmaceutics Vol. 13, No. 11 ( 2021-11-10), p. 1904-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 13, No. 11 ( 2021-11-10), p. 1904-
    Abstract: Intranasal drug delivery is a promising approach for the delivery of drugs to the CNS, but too heterogenous, unprecise delivery methods without standardization decrease the quality of many studies in rodents. Thus, the lack of a precise and region-specific application technique for mice is a major drawback. In this study, a previously developed catheter-based refined technique was validated against the conventional pipette-based method and used to specifically reach the olfactory or the respiratory nasal regions. This study successfully demonstrated region-specific administration at the olfactory mucosa resulting in over 20% of the administered fluorescein dose in the olfactory bulbs, and no peripheral bioactivity of insulin detemir and Fc-dependent uptake of two murine IgG1 (11C7 and P3X) along the olfactory pathway to cortex and hippocampus. An scFv of 11C7 showed hardly any uptake to the CNS. Elimination was dependent on the presence of the IgG’s antigen. In summary, it was successfully demonstrated that region-specific intranasal administration via the olfactory region resulted in improved brain targeting and reduced peripheral targeting in mice. The data are discussed with regard to their clinical potential.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics13111904
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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  • 3
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    Online Resource
    Osteo-Proliferative Lesions of the Phalanges on Radiography: Associations with Sex, Age, and Osteoarthritis
    MDPI AG ; 2022
    In:  Diagnostics Vol. 12, No. 3 ( 2022-03-02), p. 618-
    Details
    In: Diagnostics, MDPI AG, Vol. 12, No. 3 ( 2022-03-02), p. 618-
    Abstract: Objectives: The effects of aging such as osteophyte formation, acral shape changes, cortical tunneling, and bone porosity as well as enthesophytes can be studied in the X-rays of hands. However, during the interpretation of radiographs of the hands, misinterpretation and false-positive findings for psoriatic arthritis often occur because periosteal proliferations of the phalanges are overinterpreted and too little is known about enthesophytes of the phalanges in this area. Method: It included a total of 1153 patients (577 men, 576 women) who presented themselves to the emergency department and received a radiography of their right hand to exclude fractures. The Osseographic Scoring System was used in a modified form to record osteophytes and enthesophytes. A linear regression model for periosteal lesions was computed with age, sex, osteophytes, and global diagnosis as covariables. The inter-reader agreement was assessed using ICC (two-way mixed model) on the sum scores of osteophytes and periosteal lesions. Results: Overall, men exhibited more periosteal lesions, demonstrated by a higher mean sum score of 4.14 vs. 3.21 in women (p = 0.008). In both sexes, the second and third proximal phalanx were most frequently affected by periosteal lesions, but the frequencies were significantly higher in men. The female sex was negatively associated with an extent of periosteal lesions with a standardized beta of −0.082 (p = 0.003), while age and osteophytes were positively associated with betas of 0.347 (p 〈 0.001) and 0.156 (p 〈 0.001), respectively. The distribution of osteophytes per location did not differ between men and women (p 〉 0.05). The inter-reader agreement was excellent for periosteal lesions with ICC of 0.982 (95%CI 0.973–0.989, p 〈 0.001). Conclusions: Special care should be taken not to confuse normal periosteal changes in aging with periosteal apposition in psoriatic arthritis.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics12030618
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662336-5
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  • 4
    Online Resource
    Online Resource
    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
    SSG: 15,3
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  • 5
    Online Resource
    Online Resource
    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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  • 6
    Online Resource
    Online Resource
    Motor-Independent Cognitive Testing in Motor Degenerative Diseases
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 3 ( 2022-02-03), p. 814-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 3 ( 2022-02-03), p. 814-
    Abstract: Cognitive function is tested through speech- or writing-based neuropsychological instruments. The application and validity of those tests is impeded for patients with diseases that affect speech and hand motor skills. We therefore developed a “motor-free” gaze-controlled version of the Trail Making Test (TMT), including a calibration task to assess gaze accuracy, for completion by means of an eye-tracking computer system (ETCS). This electronic TMT version (eTMT) was evaluated for two paradigmatic “motor-neurodegenerative” diseases, Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). We screened 146 subjects, of whom 44 were excluded, e.g., because of vision deficits. Patients were dichotomized into subgroups with less (ALS−, PD−) or severe motor affection (ALS+, PD+). All 66 patients and all 36 healthy controls (HC) completed the eTMT. Patients with sufficient hand motor control (ALS−, PD−, PD+) and all HC additionally completed the original paper–pencil-based version of the TMT. Sufficient and comparable gaze fixation accuracy across all groups and the correlations of the eTMT results with the TMT results supported the reliability and validity of the eTMT. PD+ patients made significantly more errors than HC in the eTMT-B. We hereby proved the good applicability of a motor-free cognitive test. Error rates could be a particularly sensitive marker of executive dysfunction.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11030814
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 7
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    Online Resource
    Imaging of Joints and Bones in Autoinflammation
    MDPI AG ; 2020
    In:  Journal of Clinical Medicine Vol. 9, No. 12 ( 2020-12-17), p. 4074-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 9, No. 12 ( 2020-12-17), p. 4074-
    Abstract: Autoinflammatory disorders are commonly characterized by seemingly unprovoked systemic inflammation mainly driven by cells and cytokines of the innate immune system. In many disorders on this spectrum, joint and bone involvement may be observed and imaging of these manifestations can provide essential diagnostic information. This review aimed to provide a comprehensive overview of the imaging characteristics for major diseases and disease groups on the autoinflammatory spectrum, including familial Mediterranean fever (FMF), Behçet disease (BD), crystal deposition diseases (including gout), adult-onset Still’s disease (AoSD), and syndromatic synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO)/chronic recurrent multifocal osteomyelitis (CRMO). Herein, we discuss common and distinguishing imaging characteristics, phenotypical overlaps with related diseases, and promising fields of future research.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm9124074
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662592-1
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  • 8
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    Online Resource
    The Tacrolimus Metabolism Rate and Dyslipidemia after Kidney Transplantation
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 14 ( 2021-07-11), p. 3066-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 14 ( 2021-07-11), p. 3066-
    Abstract: Fast tacrolimus (Tac) metabolism is associated with reduced survival rates after renal transplantation (RTx), mainly due to cardiovascular events. Because dyslipidemia is a leading cause of cardiovascular death, we hypothesized that most RTx patients do not achieve recommended target low-density lipoprotein cholesterol (LDL-C) levels (European cardiology society guidelines) and that fast Tac metabolizers have higher dyslipidemia rates. This study included RTx recipients who received initial immunosuppression with immediate-release tacrolimus (IR-Tac), mycophenolate, and prednisolone. Patients were grouped according to their Tac concentration-to-dose ratio (C/D ratio) 3 months after RTx. Dyslipidemia parameters were analyzed at RTx, 3 months, and 12 months after RTx. Statin use and renal function were documented in a 12-month follow-up, and death was documented in a 60-month follow-up. Ninety-six RTx recipients were divided into two groups: 31 fast Tac metabolizers (C/D ratio 〈 1.05 ng/mL·1/mg) and 65 slow metabolizers (C/D ratio ≥ 1.05 ng/mL·1/mg). There were no differences in triglyceride or cholesterol levels between groups at RTx, 3, and 12 months after RTx. A total of 93.5% of fast and 95.4% of slow metabolizers did not achieve target LDL-C levels (p = 0.657). Fast metabolizers developed lower renal function compared to slow metabolizers 12 months after RTx (p = 0.009). Fast metabolizers showed a 60 month survival rate of 96.8% compared to 94.7% in the slow metabolizer group (p = 0.811). As most RTx recipients do not reach recommended target LDL-C levels, individualized nutritional counseling and lipid-lowering therapy must be intensified. Fast Tac metabolism is associated with lower renal function after RTx, but does not play a significant role in dyslipidemia.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10143066
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 9
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    Online Resource
    Identification and Validation of Linear Friction Models Using ANOVA and Stepwise Regression
    MDPI AG ; 2022
    In:  Lubricants Vol. 10, No. 11 ( 2022-10-29), p. 286-
    Details
    In: Lubricants, MDPI AG, Vol. 10, No. 11 ( 2022-10-29), p. 286-
    Abstract: For wet disk clutches, the energy input is strongly influenced by its friction behavior. However, the friction behavior cannot be simulated and therefore is mostly derived from experimental data for specific clutch systems. This paper presents a new approach for the identification and validation of linear friction models using analysis of variance (ANOVA) and stepwise regression. Therefore, we use experimental data of three different friction systems with paper- and carbon-based friction lining. The designed experiments support an efficient parameter-based analysis of the friction behavior. The obtained models can be used as an input for thermal simulations, for example, but can also support a better understanding of the main influencing factors and are applicable to various friction systems. For validation, the obtained models are applied to measured data. A good correspondence between the simulated and measured friction behavior can be shown for speeds in the investigated operating range. The presented procedure can be easily adapted, for different factors and operation modes, as well as other applications.
    Type of Medium: Online Resource
    ISSN: 2075-4442
    URL: Article
    DOI: 10.3390/lubricants10110286
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2704327-7
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  • 10
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    Online Resource
    Analysis of the Thermo-Mechanical Behavior of a Multi-Plate Clutch during Transient Operating Conditions Using the FE Method
    MDPI AG ; 2022
    In:  Lubricants Vol. 10, No. 5 ( 2022-04-21), p. 76-
    Details
    In: Lubricants, MDPI AG, Vol. 10, No. 5 ( 2022-04-21), p. 76-
    Abstract: Failures of multi-plate clutches must be reliably excluded due to safety-critical functionalities in the drive train. The main reason for failures of multi-plate clutches due to long-term and spontaneous damage is thermal damage. In this paper, a parameterizable two-dimensional finite element model is developed and validated for damage prevention and for analyzing the thermo-mechanical behavior of a clutch in transient operation. Both numerical verification and validation with experimental results are very good despite the simplifications in the model. Subsequently, the temperature and pressure distribution of the individual friction areas is determined. The results show that the maximum temperatures tend to occur at the outer diameter of the friction area. The pressure distribution is very homogeneous. In a parameter study, the influence of Young’s modulus of the friction lining, the thermal conductivity of the friction lining, and the steel plate thickness on the temperature and pressure behavior in the clutch is investigated. Although the Young’s modulus of the friction lining influences the pressure distribution in the friction contact, the temperature behavior is only slightly changed by the variation of the elastic modulus due to the load case. The thermal conductivity of the lining and steel plate thickness have a strong influence on the temperature level in the clutch. However, the distribution of pressures is still very homogeneous compared to the reference model.
    Type of Medium: Online Resource
    ISSN: 2075-4442
    URL: Article
    DOI: 10.3390/lubricants10050076
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2704327-7
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