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- Gunst, Jesper D., et al.
(author)
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Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial
- 2021
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In: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 35
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Journal article (peer-reviewed)abstract
- Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001,200-42.Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05).Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality.
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| 3. |
- Bicsak, T A, et al.
(author)
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Tissue-type plasminogen activator in rat oocytes : expression during the periovulatory period, after fertilization, and during follicular atresia.
- 1989
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In: Endocrinology. - 0013-7227 .- 1945-7170. ; 124:1, s. 187-94
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Journal article (peer-reviewed)abstract
- The regulation of tissue-type plasminogen activator (tPA) in rat oocytes during the periovulatory period, in early embryos, and in oocytes during induced follicular atresia was studied using a quantitative chromogenic substrate assay. Oocytes and early embryos were collected from three ovulation models: 1) intact immature female rats treated with PMSG, followed by hCG 48 h later; 2) hypophysectomized immature rats treated with PMSG, followed by a GnRH agonist (GnRHa) 56 h later; and 3) adult cyclic rats on the mornings of proestrus and estrus and up to 5 days after fertilization. In addition, follicular atresia was induced by either withdrawal of diethylstilbestrol (DES) for 2 days or injection of GnRHa for 2 days in hypophysectomized DES-implanted immature rats. Treatment with PMSG alone did not increase oocyte tPA content (5-20 microIU/oocyte) in either immature rat model, but treatment with either hCG or GnRHa induced meiotic maturation and ovulation and increased tPA activity to 80 and 140 microIU/oocyte 24 h after hCG and GnRHa treatment, respectively. Northern blot analysis of total RNA extracted from oocytes of PMSG-treated rats indicated the presence of a specific tPA message at 22S. tPA levels were low in preovulatory oocytes obtained on proestrus morning and increased in ovulated oocytes on estrus morning. After fertilization, tPA levels remained high in the embryos on days 1-4 of pregnancy, but dropped dramatically on day 5. Furthermore, oocytes from atretic follicles of hypophysectomized DES-implanted rats after either DES withdrawal or GnRHa treatment contained elevated levels of tPA, coincident with germinal vesicle breakdown (GVBD). Immunohistochemical staining revealed tPA antigen only in those oocytes that had undergone apparent meiotic maturation, as confirmed by GVBD. Thus, oocytes contain tPA mRNA and synthesize the active protease under a variety of stimuli which result in GVBD. The observed periovulatory increase in oocyte tPA activity, its maintenance until day 5 of pregnancy, and expression of tPA in nonovulatory oocytes of atretic follicles suggest diverse functions for the oocyte and embryo tPA.
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| 7. |
- Frezza, S., et al.
(author)
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Modeling global competencies for computing education
- 2018
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In: ITiCSE 2018 Proceedings of the 23rd Annual ACM Conference on Innovation and Technology in Computer Science Education. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450357074 ; , s. 348-349
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Conference paper (peer-reviewed)abstract
- This working group contributes to formulating a framework for modeling competencies in the current and future disciplines that comprise computing education. We draw upon the innovative approach taken in the curricular document for information technology (IT2017), curricular competency frameworks, other related documents such as the software engineering competency model (SWECOM), the Skills Framework for the Information Age (SFIA), current research in competency models, and elicitation workshop results from other computing conferences. The outcomes contribute to the Computing Curricula 2020 (CC2020) project, and include the formulation and review of sets of disciplinary-relevant competencies for use in computing education. This work directly informs the CC2020 project sponsored by the Association for Computing Machinery (ACM) and the IEEE Computer Society.
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| 8. |
- Frezza, S., et al.
(author)
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Modelling competencies for computing education beyond 2020 : A research based approach to defining competencies in the computing disciplines
- 2018
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In: Annual Conference on Innovation and Technology in Computer Science Education, ITiCSE. - New York, NY, USA : Association for Computing Machinery. - 9781450362238 ; , s. 148-174, s. 148-174
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Conference paper (peer-reviewed)abstract
- How might the content and outcomes of tertiary education programmes be described and analysed in order to understand how they are structured and function? To address this question we develop a framework for modelling graduate competencies linked to tertiary degree programmes in the computing disciplines. While the focus of our work is computing the framework is applicable to education more broadly. The work presented here draws upon the pioneering curricular document for information technology (IT2017), curricular competency frameworks, other related documents such as the software engineering competency model (SWECOM), the Skills Framework for the Information Age (SFIA), current research in competency models, and elicitation workshop results from recent computing conferences. The aim is to inform the ongoing Computing Curricula (CC2020) project, an endeavour supported by the Association for Computing Machinery (ACM) and the IEEE Computer Society. We develop the Competency Learning Framework (CoLeaF), providing an internationally relevant tool for describing competencies. We argue that this competency based approach is well suited for constructing learning environments and assists degree programme architects in dealing with the challenge of developing, describing and including competencies relevant to computer and IT professionals. In this paper we demonstrate how the CoLeaF competency framework can be applied in practice, and though a series of case studies demonstrate its effectiveness and analytical power as a tool for describing and comparing degree programmes in the international higher education landscape.
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| 9. |
- Hosokawa, K, et al.
(author)
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Dominant expression and distribution of oestrogen receptor beta over oestrogen receptor alpha in the human corpus luteum
- 2001
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In: Molecular human reproduction. - : Oxford University Press (OUP). - 1360-9947 .- 1460-2407. ; 7:2, s. 137-145
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Journal article (peer-reviewed)abstract
- To investigate the potential importance of oestrogen as a local regulator of human corpus luteum function, the mRNA expression pattern and cellular localization of oestrogen receptors (ERs), ER-alpha and ER-beta, were studied in corpora lutea grouped according to age, where days 2-5 post-LH rise were designated as the early luteal phase, days 6-10 as mid-luteal and days 11-14 as the late luteal phase respectively. Northern blot analysis using an ER-beta probe in samples from whole ovarian tissue and isolated corpora lutea, revealed a major band at 7.5 kb and several minor bands between 4-10 kb, while no signals for ER-alpha mRNA were obtained. However, using a semi-quantitative reverse transcription-polymerase chain reaction followed by Southern blotting, ER-beta mRNA levels were found to be 63% lower (P: < 0.05, n = 39) in the mid-luteal phase compared with the early luteal phase, while ER-alpha mRNA expression showed no statistical differences between the different age groups. Using in-situ hybridization, ER-beta mRNA expression was localized to the steroidogenic luteal cells as well as perivascular cells and fibroblasts in the corpus luteum. Immunohistochemistry confirmed the localization of ER-beta protein, but no clear staining of luteal cells was found using antibodies against ER-alpha. Collectively, the findings of low to moderate expression of ER-beta mRNA and protein in the steroidogenic cells, and also in vascular endothelial cells of the corpus luteum, as opposed to diminutive amounts of ER-alpha mRNA, suggest that oestrogen activity is primarily transduced via ER-beta in the human corpus luteum.
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| 10. |
- Hsueh, A J, et al.
(author)
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Gonadotropin-releasing hormone induces ovulation in hypophysectomized rats : studies on ovarian tissue-type plasminogen activator activity, messenger ribonucleic acid content, and cellular localization.
- 1988
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In: Endocrinology. - 0013-7227 .- 1945-7170. ; 122:4, s. 1486-95
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Journal article (peer-reviewed)abstract
- GnRH and its agonists are known to induce ovulation in hypophysectomized rats by acting directly at the ovary. Because tissue-type plasminogen activator (tPA) has been implicated in the gonadotropin induction of ovulation, we examined the effect of an ovulatory dose of GnRH on ovarian tPA activity, mRNA content, and cellular localization. Hypophysectomized immature rats were injected sc with 20 IU PMSG and a single dose of a GnRH agonist (GnRHa; des-Gly10,DLeu6(N alpha Me)Leu7,Pro9NHEt-GnRH) 58 h later. At different times after treatment, ovaries were prepared for morphological analysis. Using a fibrin overlay method, tPA activities were measured in ovarian homogenates and cumulus-oocyte complexes, whereas granulosa cells were cultured for 24 h to estimate tPA secretion. Total ovarian RNA was prepared for hybridization analysis of tPA message levels, and tPA localization was studied by immunohistochemistry of ovarian sections. GnRHa induced ovulation in PMSG-primed hypophysectomized rats 14-16 h after injection in a dose-dependent manner, and the GnRHa action was blocked by concomitant treatment with a GnRH antagonist. GnRHa stimulated the induction of tPA, but not urokinase-type PA, activity in ovarian homogenates and granulosa cell-conditioned medium in a time-dependent manner, reaching a maximum before ovulation. tPA activity in cumulus-oocyte complexes was also increased before ovulation, but this increase was sustained. Hybridization analysis of steady state tPA mRNA levels was performed using a rat cRNA probe. Northern blot analysis of total ovarian RNA demonstrated that GnRHa stimulated tPA mRNA levels 12 h after treatment, with a subsequent decrease 24 h after treatment. Immunohistochemistry indicated substantial increases in tPA staining in granulosa cells and oocytes of preovulatory follicles before ovulation. Thus, GnRHa acts through specific receptors to increase ovarian tPA enzyme activity, mRNA content, as well as immunostaining in granulosa cells and oocytes. Like gonadotropins, GnRH may induce ovulation by directly stimulating tPA levels in the ovary.
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