Bio-availability of three formulations of glibenclamide

Eighteen healthy men participated in a double-blind, randomised, crossover study to compare the bio-availability of three 5 mg formulations of glibenclamide. The products compared were Daonil (Hoechst), Glycomin (Lennon) and Melix (Lagamed). Volunteers received a continuous intravenous infusion of glucose at a rate of 0,25 g/kg/h for 10 hours. Two hours after commencement of this infusion medication was given orally with 200 ml of a 10% (m/v) glucose solution. The subjects also drank 200 ml of the glucose solution hourly for 5 hours after medication. Blood samples were taken up to 22 hours after medication for radio-immunoassay of glibenclamide as well as for measurement of glucose concentrations. The following kinetic variables were calculated; maximum concentration, time to maximum concentration, terminal halflife, areas under the serum concentration-time curves, relative total clearance, total mean time and relative volume of distribution. Daonil and Glycomin were bio-equivalent, but important differences were demonstrated between these two formulations and Melix. This study method necessitates close surveillance of volunteers in order to detect and treat hypoglycaemia.S Afr Med J 1989; 76: 146-14

Effects of tutor-related behaviours on the process of problem-based learning

Tutors in a Problem-Based Learning (PBL) curriculum are thought to play active roles in guiding students to develop frameworks for use in the construction of knowledge. This implies that both subject-matter expertise and the ability of tutors to facilitate the learning process must be important in helping students learn. This study examines the behavioural effects of tutors in terms of subject-matter expertise, social congruence and cognitive congruence on students’ learning process and on their final achievement. The extent of students’ learning at each PBL phase was estimated by tracking the number of relevant concepts recalled at the end of each learning phase, while student achievement was based on students’ ability to describe and elaborate upon the relationship between relevant concepts learned. By using Analysis of Covariance, social congruence of the tutor was found to have a significant influence on learning in each PBL phase while all of the tutor-related behaviours had a significant impact on student achievement. The results suggest that the ability of tutors to communicate informally with students and hence create a less threatening learning environment that promotes a free flow exchange of ideas, has a greater impact on learning at each of the PBL phases as compared to tutors’ subject-matter expertise and their ability to explain concepts in a way that is easily understood by students. The data presented indicates that these tutor-related behaviours are determinants of learning in a PBL curriculum, with social congruence having a greater influence on learning in the different PBL phases

Size Matters: Microservices Research and Applications

In this chapter we offer an overview of microservices providing the introductory information that a reader should know before continuing reading this book. We introduce the idea of microservices and we discuss some of the current research challenges and real-life software applications where the microservice paradigm play a key role. We have identified a set of areas where both researcher and developer can propose new ideas and technical solutions.Comment: arXiv admin note: text overlap with arXiv:1706.0735

Neural correlates of heterotopic facilitation induced after high frequency electrical stimulation of nociceptive pathways

<p>Abstract</p> <p>Background</p> <p>High frequency electrical stimulation (HFS) of primary nociceptive afferents in humans induce a heightened sensitivity in the surrounding non-stimulated skin area. Several studies suggest that this heterotopic effect is the result of central (spinal) plasticity. The aim of this study is to investigate HFS-induced central plasticity of sensory processing at the level of the brain using the electroencephalogram (EEG). To this end we measured evoked potentials in response to noxious electrical pinprick-like stimuli applied in the heterotopic skin area before, directly after and 30 minutes after HFS.</p> <p>Results</p> <p>We observed potential cortical electrophysiological correlates of heterotopic facilitation. Two different cortical correlates were found; the first one was a lateralized effect, i.e. a larger N100 amplitude on the conditioned arm than the control arm 30 minutes after end of HFS. This was comparable with the observed lateralized effect of visual analogue scale (VAS) scores as response to the mechanical punctate stimuli. The second correlate seems to be a more general (non-lateralized) effect, because the result affects both arms. On average for both arms the P200 amplitude increased significantly 30 minutes after end of HFS with respect to baseline.</p> <p>Conclusions</p> <p>We suggest that for studying heterotopic nociceptive facilitation the evoked brain response is suitable and relevant for investigating plasticity at the level of the brain and is perhaps a more sensitive and reliable marker than the perceived pain intensity (e.g. VAS).</p

Unwinding of a cholesteric liquid crystal and bidirectional surface anchoring

We examine the influence of bidirectional anchoring on the unwinding of a planar cholesteric liquid crystal induced by the application of a magnetic field. We consider a liquid crystal layer confined between two plates with the helical axis perpendicular to the substrates. We fixed the director twist on one boundary and allow for bidirectional anchoring on the other by introducing a high-order surface potential. By minimizing the total free energy for the system, we investigate the untwisting of the cholesteric helix as the liquid crystal attempts to align with the magnetic field. The transitions between metastable states occur as a series of pitchjumps as the helix expels quarter or half-turn twists, depending on the relative sizes of the strength of the surface potential and the bidirectional anchoring. We show that secondary easy axis directions can play a significant role in the unwinding of the cholesteric in its transition towards a nematic, especially when the surface anchoring strength is large

Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3

Background: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. Results: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p <= 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. Conclusions: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

High Log-Scale Expansion of Functional Human Natural Killer Cells from Umbilical Cord Blood CD34-Positive Cells for Adoptive Cancer Immunotherapy

Immunotherapy based on natural killer (NK) cell infusions is a potential adjuvant treatment for many cancers. Such therapeutic application in humans requires large numbers of functional NK cells that have been selected and expanded using clinical grade protocols. We established an extremely efficient cytokine-based culture system for ex vivo expansion of NK cells from hematopoietic stem and progenitor cells from umbilical cord blood (UCB). Systematic refinement of this two-step system using a novel clinical grade medium resulted in a therapeutically applicable cell culture protocol. CD56+CD3− NK cell products could be routinely generated from freshly selected CD34+ UCB cells with a mean expansion of >15,000 fold and a nearly 100% purity. Moreover, our protocol has the capacity to produce more than 3-log NK cell expansion from frozen CD34+ UCB cells. These ex vivo-generated cell products contain NK cell subsets differentially expressing NKG2A and killer immunoglobulin-like receptors. Furthermore, UCB-derived CD56+ NK cells generated by our protocol uniformly express high levels of activating NKG2D and natural cytotoxicity receptors. Functional analysis showed that these ex vivo-generated NK cells efficiently target myeloid leukemia and melanoma tumor cell lines, and mediate cytolysis of primary leukemia cells at low NK-target ratios. Our culture system exemplifies a major breakthrough in producing pure NK cell products from limited numbers of CD34+ cells for cancer immunotherapy

Potentially inappropriate medication in older participants of the Berlin Aging Study II (BASE-II) - Sex differences and associations with morbidity and medication use

INTRODUCTION: Multimorbidity in advanced age and the need for drug treatment may lead to polypharmacy, while pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug events (ADEs). OBJECTIVE: The aim of this study was to determine the proportion of subjects using potentially inappropriate medication (PIM) in a cohort of older and predominantly healthy adults in relation to polypharmacy and morbidity. METHODS: Cross-sectional data were available from 1,382 study participants (median age 69 years, IQR 67-71, 51.3% females) of the Berlin Aging Study II (BASE-II). PIM was classified according to the EU(7)-PIM and German PRISCUS (representing a subset of the former) list. Polypharmacy was defined as the concomitant use of at least five drugs. A morbidity index (MI) largely based on the Charlson Index was applied to evaluate the morbidity burden. RESULTS: Overall, 24.1% of the participants were affected by polypharmacy. On average, men used 2 (IQR 1-4) and women 3 drugs (IQR 1-5). According to PRISCUS and EU(7)-PIM, 5.9% and 22.6% of participants received at least one PIM, while use was significantly more prevalent in females (25.5%) compared to males (19.6%) considering EU(7)-PIM (p = 0.01). In addition, morbidity in males receiving PIM according to EU(7)-PIM was higher (median MI 1, IQR 1-3) compared to males without PIM use (median MI 1, IQR 0-2, p<0.001). CONCLUSION: PIM use occurred more frequently in women than in men, while it was associated with higher morbidity in males. As expected, EU(7)-PIM identifies more subjects as PIM users than the PRISCUS list but further studies are needed to investigate the differential impact of both lists on ADEs and outcome. KEY POINTS: We found PIM use to be associated with a higher number of regular medications and with increased morbidity. Additionally, we detected a higher prevalence of PIM use in females compared to males, suggesting that women and people needing intensive drug treatment are patient groups, who are particularly affected by PIM use