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  • 1
    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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  • 2
    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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  • 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
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    Investigation of the Formation of Coherent Ash Residues during Fluidized Bed Gasification of Wheat Straw Lignin
    MDPI AG ; 2020
    In:  Energies Vol. 13, No. 15 ( 2020-08-01), p. 3935-
    Details
    In: Energies, MDPI AG, Vol. 13, No. 15 ( 2020-08-01), p. 3935-
    Abstract: Thermal conversion of ash-rich fuels in fluidized bed systems is often associated with extensive operation problems caused by the high amount of reactive inorganics. This paper investigates the behavior of wheat straw lignin—a potential renewable fuel for dual fluidized bed gasification. The formation of coherent ash residues and its impact on the operation performance has been investigated and was supported by thermochemical equilibrium calculations in FactSage 7.3. The formation of those ash residues, and their subsequent accumulation on the surface of the fluidized bed, causes temperature and pressure fluctuations, which negatively influence the steady-state operation of the fluidized bed process. This paper presents a detailed characterization of the coherent ash residues, which consists mostly of silica and partially molten alkali silicates. Furthermore, the paper gives insights into the formation of these ash residues, dependent on the fuel pretreatment (pelletizing) of the wheat straw lignin, which increases their stability compared to the utilization of non-pelletized fuel.
    Type of Medium: Online Resource
    ISSN: 1996-1073
    URL: Article
    DOI: 10.3390/en13153935
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2437446-5
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  • 5
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    Online Resource
    Caregivers’ View of Socio-Medical Care in the Terminal Phase of Amyotrophic Lateral Sclerosis—How Can We Improve Holistic Care in ALS?
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 1 ( 2022-01-04), p. 254-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 1 ( 2022-01-04), p. 254-
    Abstract: Multidimensional socio-medical care with an early integration of palliative principles is strongly recommended in amyotrophic lateral sclerosis (ALS), but provided inconsistently. We conducted telephone interviews with 49 former caregivers of deceased ALS patients to examine their experience of care in the terminal phase including caregiver burden. Patients who received specialized palliative care (45% of patients) were more likely to die at home (p = 0.004) and without burdening symptoms (p = 0.021). The majority of caregivers (86%) reported deficits in socio-medical care. Most frequently mentioned were problems receiving medical aids (45%) and a lack of caregiver support (35%). A higher level of deficits experienced by caregivers was associated with negative health outcomes on the side of the caregivers (reported by 57% of them; p = 0.002) and stronger caregiver burden (p = 0.004). To provide good quality of dying to patients and reduce the burden on caregivers, multidimensional—including palliative—care in ALS urgently needs to be strengthened in the healthcare structures.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11010254
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 6
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    Conversion to Everolimus was Beneficial and Safe for Fast and Slow Tacrolimus Metabolizers after Renal Transplantation
    MDPI AG ; 2020
    In:  Journal of Clinical Medicine Vol. 9, No. 2 ( 2020-01-23), p. 328-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 9, No. 2 ( 2020-01-23), p. 328-
    Abstract: Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio 〈 1.05 ng/mL/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio 〈 1.05 ng/mL/mg vs. 17 patients with a C/D ratio ≥1.05 ng/mL/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5–21.9) months and slow metabolizers 3.3 (1.8–23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73 m2 (p = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm9020328
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662592-1
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  • 7
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    Friction Behavior of Pre-Damaged Wet-Running Multi-Plate Clutches in an Endurance Test
    MDPI AG ; 2020
    In:  Lubricants Vol. 8, No. 7 ( 2020-06-30), p. 68-
    Details
    In: Lubricants, MDPI AG, Vol. 8, No. 7 ( 2020-06-30), p. 68-
    Abstract: Wet-running multi-plate clutches should be prevented from failing due to the often safety-relevant functions they fulfill in the drive train. In addition to long-term damage, spontaneous damage is of particular relevance for failures. This paper focuses on the influence of spontaneous damage on frictional behavior in the later life cycle. The aim of the experimental investigations is to initially cause spontaneous damage in wet-running multi-plate clutches with sintered friction linings. For this purpose, three clutches are first pre-damaged in stage tests with different intensities, so that the first spontaneous damage (local discoloration, sinter transfer) occurs. In the second step, an endurance test is carried out with the pre-damaged clutch packs and a non-pre-damaged reference clutch. The friction behavior of the clutches during the endurance test is compared and evaluated. It shows that local discoloration and sinter transfer are no longer visible after the endurance tests. At the beginning of the endurance test, the values of coefficient of friction are higher over the entire speed range of the heavily pre-damaged clutches than with the slightly pre-damaged clutch and the non-pre-damaged reference clutch. At the end of the endurance test, it can be observed that the greater the pre-damage to the clutches is, the greater the coefficient of friction increases with decreasing sliding speed.
    Type of Medium: Online Resource
    ISSN: 2075-4442
    URL: Article
    DOI: 10.3390/lubricants8070068
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2704327-7
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  • 8
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    Online Resource
    The Influence of Parathyroidectomy on Osteoporotic Fractures in Kidney Transplant Recipients: Results from a Retrospective Single-Center Trial
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 3 ( 2022-01-27), p. 654-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 3 ( 2022-01-27), p. 654-
    Abstract: Kidney transplant (KTx) recipients are a high-risk population for osteoporotic fractures. We herein aim to identify the role of pre-transplant parathyroidectomy (PTX) and other modifiable factors associated with osteoporotic fractures in KTx recipients. We conducted a retrospective study involving 711 adult patients (4608 patient-years) who were transplanted at our center between January 2007 and June 2015. Clinical data were extracted from patients’ electronic medical records. Different laboratory and clinical parameters for mineral bone disease (MBD) and osteoporosis, including medication, were evaluated. We chose fracture events unrelated to malignancies or adequate trauma as the primary endpoint. Osteoporotic fractures occurred in 47 (6.6%) patients (median 36.7 months, IQR 45.9) after KTx (fracture incidence of 10 per 1000 person-years). Prior to KTx, subtotal PTX was performed in 116 patients (16.3%, median time 4.2 years before KTx, IQR 5.0). Of the patients with fracture (n = 47), only one (2.2%) patient had previously undergone PTX. After adjusting for the known fracture risk factors MBD and osteoporosis, PTX remained a protective factor against fractures (HR 0.134, CI 0.018–0.991, p = 0.049). We observed a reduced risk for pathological fractures in KTx patients who underwent PTX, independent from elevated parathyroid hormone at the time of KTx or afterwards.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11030654
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 9
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    Online Resource
    Speech and Nonspeech Parameters in the Clinical Assessment of Dysarthria: A Dimensional Analysis
    MDPI AG ; 2023
    In:  Brain Sciences Vol. 13, No. 1 ( 2023-01-07), p. 113-
    Details
    In: Brain Sciences, MDPI AG, Vol. 13, No. 1 ( 2023-01-07), p. 113-
    Abstract: Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral–facial movements and maximum phonation times were compared with auditory–perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain–general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD.
    Type of Medium: Online Resource
    ISSN: 2076-3425
    URL: Article
    DOI: 10.3390/brainsci13010113
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2651993-8
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  • 10
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    Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 15 ( 2020-07-29), p. 5395-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 15 ( 2020-07-29), p. 5395-
    Abstract: An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p 〈 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21155395
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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