Structures and Evaluation of Biologically Active Constituents of "Cussonia Zimmermannii" Harms

For the present thesis 22 samples of seven African medicinal plants, the extracts of which had previously proved to possess an in vitro activity against T. b. rhodesiense and/or P. falciparum and 13 samples of six randomly selected plant species based on availability were collected in Tanzania. Of these 35 samples, 140 crude extracts were produced with four solvents of different polarity, and the extracts were tested for in vitro antitrypanosomal and antiplasmodial activity and for cytotoxicity. In addition the extracts were tested for the affinity to the GABAA receptor performed by radioligand binding experiments. Based on the considerable antitrypanosomal and antiplasmodial activity and the affinity to the GABAA receptor, two extracts were selected for bioassay-guided fractionation : the petroleum ether extract of the stembark of Commiphora fulvotomentosa Engl. because of its promising IC50 value of 2.1 mg/ml against T. b. rhodesiense and the high selectivity index of 21.4, and the petroleum ether extract of the rootbark of Cussonia zimmermannii Harms because of its IC50 value of 4.8 mg/ml against T. b. rhodesiense, its IC50 value of 3.3 mg/ml against P. falciparum, and the potent modulatory effect at the GABAA receptor of 151 %. After three fractionation steps the fractions of the petroleum ether extract of the stembark of Commiphora fulvotomentosa Engl. did not show any inhibitory activity against T. b. rhodesiense and were therefore not investigated further. Bioassay-guided fractionation of the petroleum ether extract of the rootbark of Cussonia zimmermannii Harms lead to the isolation of four polyacetylenes. By the application of MS, HR-MS, UV/VIS and IR methods and NMR experiments (1H-NMR, 13C-NMR, DEPT135, 1H-1H COSY, HMQC and HMBC) the structures of the four novel diynes were established : 8-Hydroxyheptadeca-4,6-diyn-3-yl acetate (MS-1 (25)), 8-Hydroxyheptadeca-1-ene-4,6-diyn-3-yl acetate (MS-2 (26)), 16-Acetoxy-11- hydroxyoctadeca-17-ene-12,14-diynyl acetate (MS-4 (27)), and 11,16-Diacetoxyoctadeca- 17-ene-12,14-diynyl acetate (MS-5 (28)). Additionally, stigmasterol (42) was isolated and identified by comparison of its spectroscopic data with those of an authentic sample. For the determination of the absolute configuration of MS-4 (27) at C(11) the Mosher method was used. The negative d values for the neighbouring protons suggested the S-configuration. But this result could not be confirmed by the 13C-NMR data since both positive and negative d values were obtained for the neighbouring carbons. Due to the fact, that the results for the protons and the carbons were not consistent the S-configuration for C(11) of MS-4 (27) could not be assigned with certainty. The isolated compounds MS-1 (25), MS-2 (26), and MS-4 (27) were tested for in vitro inhibitory activity against additional parasites like T. cruzi and L. donovani (axenic and in infected macrophages). 42 was not tested because it was a well known phytosterol which is ubiquitous in plants. Neither was MS-5 (28) tested, since the isolated amount was not sufficient. It was found that MS-1 (25) showed in all antiparasitic in vitro assays no higher inhibitory activity than the crude extract. MS-2 (26) showed promising activities in the T. cruzi and L. donovani (axenic and in infected macrophages) assay with IC50 values of 0.2, 0.039, and 0.098 mg/ml, respectively. The respective IC50 values of the standard drugs were 0.62, 0.18, and 0.29. The cytotoxicity was relatively high; therefore the selectivity with SI values of 18.0 and 36.7, respectively (T. cruzi, L. donovani in inf. mac.), was in a moderate range. MS-4 (27) showed also interesting activities in the T. cruzi and L. donovani (axenic) assays with IC50 values of 0.15 and 0.054 mg/ml. The SI value of 145.3 (T. cruzi) was high. Compared with the standard drugs the activities of MS-2 (26) and MS-4 (27) against T. b. rhodesiense and P. falciparum were in a moderate range. MS-1 (25), MS-2 (26), and MS-4 (27) were also tested in the GABAA receptor binding assay. Here MS-4 (27) showed the highest relative specific binding of 158 % at a concentration of 20 mg/ml, followed by MS-2 (26) with 152 % and MS-1 (25) with 138 %. In order to investigate whether the modulatory effect at the GABAA receptor leads to a chanel opening, the isolated compounds were investigated electrophysiologically. It was found that MS-1 (25), MS-2 (26), and MS-4 (27) act as potent positive allosteric modulators at GABAA receptors with a half maximal stimulation at a concentration of 0.6-3.5 mM and a maximal stimulation of 110-450 %. The compounds also showed unique subunit selectivity profiles, the stimulation was independend from the presence of the g subunit and resistant to the benzodiazepine antagonist Ro15-1788. These in vitro data suggested that MS-1 (25), MS-2 (26), and MS-4 (27) may be used to treat diseases of the central nervous system, specifically they may be used to treat states of anxiety, as sedatives/hypnotics, as muscle relaxants and as anticonvulsives (e.g. in epilepsy), and in the treatment of drug addiction. Therefore it was decided to patent the compounds for these indications [174]. All data are on the in vitro level. For a pharmaceutical application in vivo data are needed. Therefore MS-1 (25), MS-2 (26), and MS-4 (27) need to be synthesized in order to get more material for subsequent in vivo experiments

High-level synthesis under I/O Timing and Memory constraints

The design of complex Systems-on-Chips implies to take into account communication and memory access constraints for the integration of dedicated hardware accelerator. In this paper, we present a methodology and a tool that allow the High-Level Synthesis of DSP algorithm, under both I/O timing and memory constraints. Based on formal models and a generic architecture, this tool helps the designer to find a reasonable trade-off between both the required I/O timing behavior and the internal memory access parallelism of the circuit. The interest of our approach is demonstrated on the case study of a FFT algorithm

Synthesis of functionalized indolines and dihydrobenzofurans by iron and copper catalyzed aryl C-N and C-O bond formation

A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to indolines, dihydrobenzofurans and six-membered analogues. The general applicability and functional group tolerance of this method was exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process

SAHRA - an integrated software tool for STPA

SAHRA (STPA based Hazard and Risk Analysis) as a software tool for STAMP/STPA improves the analysis workflow by not only supporting the complete STPA process but by also offering a unique way to capture Step 1 and 2 using the visual style of mind maps. SAHRA is seamlessly integrated into the widely used UML solution Sparx Systems Enterprise Architect (EA). This integration enables synergies between design of a system and its safety analysis and thus allows to use STPA in the paradigm of safety-guided design

Quality and variation of care for chronic kidney disease in Swiss general practice: A retrospective database study

Background Chronic kidney disease (CKD) is a common condition in general practice. Data about quality and physician-level variation of CKD care provided by general practitioners is scarce. In this study, we evaluated determinants and variation of achievement of 14 quality indicators for CKD care using electronic medical records data from Swiss general practice during 2013–2019. Methods We defined two patient cohorts from 483 general practitioners, one to address renal function assessment in patients with predisposing conditions (n = 47,201, median age 68 years, 48.7% female) and one to address care of patients with laboratory-confirmed CKD (n = 14,654, median age 80 years, 57.5% female). We investigated quality indicator achievement with mixed-effect logistic regression and expressed physician-level variation as intraclass correlation coefficients (ICCs) and range odds ratios (rORs). Results We observed the highest quality indicator achievement rate for withholding non-steroidal anti-inflammatory drug prescription in patients with CKD staged G2–3b within 12 months of follow-up (82.6%), the lowest for albuminuria assessment within 18 months of follow-up (18.1%). Highest physician-level variation was found for renal function assessment during 18 months of follow-up in patients with predisposing conditions (diabetes: ICC 0.31, rOR 26.5; cardiovascular disease: ICC 0.28, rOR 17.4; hypertension: ICC 0.24, rOR 17.2). Conclusion This study suggests potentially unwarranted variation in general practice concerning RF assessment in patients affected by conditions predisposing for CKD. We further identified potential gaps in quality of CKD monitoring as well as lower quality of CKD care for female patients and patients not affected by comorbidities

A two-microphone noise reduction system for cochlear implant users with nearby microphones. Part II: Performance Evaluation

Users of cochlear implants (auditory aids, which stimulate the auditory nerve electrically at the inner ear) often suffer from poor speech understanding in noise. We evaluate a small (intermicrophone distance 7 mm) and computationally inexpensive adaptive noise reduction system suitable for behind-the-ear cochlear implant speech processors. The system is evaluated in simulated and real, anechoic and reverberant environments. Results from simulations show improvements of 3.4 to 9.3 dB in signal to noise ratio for rooms with realistic reverberation and more than 18 dB under anechoic conditions. Speech understanding in noise is measured in 6 adult cochlear implant users in a reverberant room, showing average improvements of 7.9–9.6 dB, when compared to a single omnidirectional microphone or 1.3–5.6 dB, when compared to a simple directional two-microphone device. Subjective evaluation in a cafeteria at lunchtime shows a preference of the cochlear implant users for the evaluated device in terms of speech understanding and sound quality

Advanced Technologies and the Future of Medicine and Surgery

Technology has become a major driver of the future direction of healthcare and surgery. Likewise, the speed of change has accelerated beyond comprehension, with a number of revolutions occurring during a surgeon's career. Being an agent of change or rapidly adapting to change has become the hallmark of the gifted surgeon. The fundamental challenges to a future surgeon are addressed from a technological viewpoint, with emphasis on the impact upon healthcare