207 research outputs found
A jigsaw puzzle framework for homogenization of high porosity foams
An approach to homogenization of high porosity metallic foams is explored.
The emphasis is on the \Alporas{} foam and its representation by means of
two-dimensional wire-frame models. The guaranteed upper and lower bounds on the
effective properties are derived by the first-order homogenization with the
uniform and minimal kinematic boundary conditions at heart. This is combined
with the method of Wang tilings to generate sufficiently large material samples
along with their finite element discretization. The obtained results are
compared to experimental and numerical data available in literature and the
suitability of the two-dimensional setting itself is discussed.Comment: 11 pages, 7 figures, 3 table
New methods for quantification of amoxicillin and clindamycin in human plasma using HPLC with UV detection
OBJECTIVES: We aimed to develop simple and rapid HPLC methods for determination of amoxicillin and clindamycin in human plasma. METHODS: Plasma samples were pretreated by direct deproteinization with acetonitrile and the analytical separation took place on a reverse phase Poroshell 120 EC-C18 column (2.7ā
Ī¼m, 2.1āĆā100ā
mm) with a gradient of acetonitrile. UV detection at 229ā
nm for amoxicillin and 204ā
nm for clindamycin was used for determination of the antibiotics in plasma. RESULTS: The calibration curves were linear over the concentration ranges of 1ā100ā
mg/L for amoxicillin and 1ā15ā
mg/L for clindamycin with a correlation coefficient of ā„0.98. Intra-assay precisions were all ā¤15% and the accuracies were within Ā±15%. The limit of quantification (LOQ) was found to be 0.5ā
mg/L for amoxicillin and 1ā
mg/L for clindamycin with inter-assay imprecision coefficient of variances (CVs) of 18.7% and 15.6%, respectively. The present HPLC methods were successfully applied on spike-in samples and on plasma samples collected 4ā6 and 3.5ā5.5ā
h after oral antibiotic administration of 500ā
mg of amoxicillin and 600ā
mg of clindamycin, respectively. CONCLUSIONS: We have developed HPLC methods with UV detection for quantification of amoxicillin and clindamycin in human plasma. The methods are fast, simple and suitable for use in routine settings and clinical studies
Future subnational population change in Germany: The role of internal and international migration
Population change in Germany at the sub-national level is particularly driven by changes in net international migration and overall internal migration patterns, namely between urbanization, suburbanization and counter-urbanization. Official population projections at the county level only consist of one scenario, thereby omitting uncertainty that arises from changing patterns in the assumed components of demographic change. We use a cohort-component model that incorporates the spatial distribution of a net number of international migrants and internal migration matrices to provide population projections for 401 counties in Germany until 2070, encompassing a range of nine international and internal migration scenarios. Our results highlight the variability in possible population change in terms of population structure, size, and spatial distribution. According to our scenarios, the total projected population of Germany is expected to range between 74.25 to 86.84 million people. There are considerable differences in expected population change both spatially (e.g. between urban and rural areas) and concerning county population age structure, depending on the assumed absolute level of net international migration as well as the direction of internal migratory patterns. Our results highlight the large role internal and international migration patterns will play in future population development in Germany at the county level. We also discuss what our results and the uncertainty of future population change at the regional level mean for local policy making and planning
Quantitative Histomorphometry of the Healthy Peritoneum
The peritoneum plays an essential role in preventing abdominal frictions and
adhesions and can be utilized as a dialysis membrane. Its physiological
ultrastructure, however, has not yet been studied systematically. 106
standardized peritoneal and 69 omental specimens were obtained from 107
patients (0.1ā60 years) undergoing surgery for disease not affecting the
peritoneum for automated quantitative histomorphometry and
immunohistochemistry. The mesothelial cell layer morphology and protein
expression pattern is similar across all age groups. Infants below one year
have a thinner submesothelium; inflammation, profibrotic activity and
mesothelial cell translocation is largely absent in all age groups. Peritoneal
blood capillaries, lymphatics and nerve fibers locate in three distinct
submesothelial layers. Blood vessel density and endothelial surface area
follow a U-shaped curve with highest values in infants below one year and
lowest values in children aged 7ā12 years. Lymphatic vessel density is much
lower, and again highest in infants. Omental blood capillary density
correlates with parietal peritoneal findings, whereas only few lymphatic
vessels are present. The healthy peritoneum exhibits major thus far unknown
particularities, pertaining to functionally relevant structures, and subject
to substantial changes with age. The reference ranges established here provide
a framework for future histomorphometric analyses and peritoneal transport
modeling approaches
Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency
Background: While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear localization of the previously reported LSC marker p63. The recent identification of the ATP-binding cassette transporter ABCB5 as a plasma membrane-spanning marker of LSCs that are capable of restoring the cornea and the development of an antibody directed against an extracellular loop of the ABCB5 molecule stimulated us to develop a novel treatment strategy based on the utilization of in vitro expanded allogeneic ABCB5+ LSCs derived from human cadaveric limbal tissue. Methods: We developed and validated a Good Manufacturing Practice- and European Pharmacopeia-conform production and quality-control process, by which ABCB5+ LSCs are derived from human corneal rims, expanded ex vivo, isolated as homogenous cell population, and manufactured as an advanced-therapy medicinal product (ATMP). This product was tested in a preclinical study program investigating the cellsā engraftment potential, biodistribution behavior, and safety. Results: ABCB5+ LSCs were reliably expanded and manufactured as an ATMP that contains comparably high percentages of cells expressing transcription factors critical for LSC stemness maintenance (p63) and corneal epithelial differentiation (PAX6). Preclinical studies confirmed local engraftment potential of the cells and gave no signals of toxicity and tumorgenicity. These findings were sufficient for the product to be approved by the German Paul Ehrlich Institute and the U.S. Food & Drug Administration to be tested in an international multicenter phase I/IIa clinical trial (NCT03549299) to evaluate the safety and therapeutic efficacy in patients with LSCD. Conclusion: Building upon these data in conjunction with the previously shown cornea-restoring capacity of human ABCB5+ LSCs in animal models of LSCD, we provide an advanced allogeneic LSC-based treatment strategy that shows promise for replenishment of the patientās LSC pool, recreation of a functional barrier against invading conjunctival cells and restoration of a transparent, avascular cornea
Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis.
Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells
A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity
The use of chemically synthesized short interfering RNAs (siRNAs) is currently the method of choice to manipulate gene expression in mammalian cell culture, yet improvements of siRNA design is expectably required for successful application in vivo. Several studies have aimed at improving siRNA performance through the introduction of chemical modifications but a direct comparison of these results is difficult. We have directly compared the effect of 21 types of chemical modifications on siRNA activity and toxicity in a total of 2160 siRNA duplexes. We demonstrate that siRNA activity is primarily enhanced by favouring the incorporation of the intended antisense strand during RNA-induced silencing complex (RISC) loading by modulation of siRNA thermodynamic asymmetry and engineering of siRNA 3ā²-overhangs. Collectively, our results provide unique insights into the tolerance for chemical modifications and provide a simple guide to successful chemical modification of siRNAs with improved activity, stability and low toxicity
Pharyngeal electrical stimulation for neurogenic dysphagia following stroke, traumatic brain injury or other causes: Main results from the PHADER cohort study
BackgroundNeurogenic dysphagia is common and has no definitive treatment. We assessed whether pharyngeal electrical stimulation (PES) is associated with reduced dysphagia.MethodsThe PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) was a prospective single-arm observational cohort study. Participants were recruited with neurogenic dysphagia (comprising five groups ā stroke not needing ventilation; stroke needing ventilation; ventilation acquired; traumatic brain injury; other neurological causes). PES was administered once daily for three days. The primary outcome was the validated dysphagia severity rating scale (DSRS, score best-worst 0ā12) at 3 months.FindingsOf 255 enrolled patients from 14 centres in Austria, Germany and UK, 10 failed screening. At baseline, mean (standard deviation) or median [interquartile range]: age 68 (14) years, male 71%, DSRS 11Ā·4 (1Ā·7), time from onset to treatment 32 [44] days; age, time and DSRS differed between diagnostic groups. Insertion of PES catheters was successfully inserted in 239/245 (98%) participants, and was typically easy taking 11Ā·8 min. 9 participants withdrew before the end of treatment. DSRS improved significantly in all dysphagia groups, difference in means (95% confidence intervals, CI) from 0 to 3 months: stroke (n = 79) ā6Ā·7 (ā7Ā·8, ā5Ā·5), ventilated stroke (n = 98) ā6Ā·5 (ā7Ā·6, ā5Ā·5); ventilation acquired (n = 35) ā6Ā·6 (ā8Ā·4, ā4Ā·8); traumatic brain injury (n = 24) -4Ā·5 (ā6Ā·6, ā2Ā·4). The results for DSRS were mirrored for instrumentally assessed penetration aspiration scale scores. DSRS improved in both supratentorial and infratentorial stroke, with no difference between them (p = 0Ā·32). In previously ventilated participants with tracheotomy, DSRS improved more in participants who could be decannulated (n = 66) ā7Ā·5 (ā8Ā·6, ā6Ā·5) versus not decannulated (n = 33) ā2Ā·1 (ā3Ā·2, ā1Ā·0) (
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