A comparison between pure active pharmaceutical ingredients and therapeutic deep eutectic solvents: solubility and permeability studies

THEDES, so called therapeutic deep eutectic solvents are here defined as a mixture of two components, which at a particular molar composition become liquid at room temperature and in which one of them is an active pharmaceutical ingredient (API). In this work, THEDES based on menthol complexed with three different APIs, ibuprofen (ibu), BA (BA) and phenylacetic acid (PA), were prepared. The interactions between the components that constitute the THEDES were studied by NMR, confirming that the eutectic system is formed by H-bonds between menthol and the API. The mobility of the THEDES components was studied by PFGSE NMR spectroscopy. It was determined that the self-diffusion of the species followed the same behavior as observed previously for ionic liquids, in which the components migrate via jumping between voids in the suprastructure created by punctual thermal fluctuations. The solubility and permeability of the systems in an isotonic solution was evaluated and a comparison with the pure APIs was established through diffusion and permeability studies carried out in a Franz cell. The solubility of the APIs when in the THEDES system can be improved up to 12 fold, namely for the system containing ibu. Furthermore, for this system the permeability was calculated to be 14 105 cm/s representing a 3 fold increase in comparison with the pure API. With the exception of the systems containing PA an increase in the solubility, coupled with an increase in permeability was observed. In this work, we hence demonstrate the efficiency of THEDES as a new formulation for the enhancement of the bioavailability of APIs by changing the physical state of the molecules from a solid dosage to a liquid system.he European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement nREGPOT-CT2012-316331- POLARIS and from Project ‘‘Novel smart and biomimetic materials for innovative regenerative medicine approaches (Ref.: RL1 - ABMR - NORTE-01-0124-FEDER-000016)” co-financed by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF). Funding was also provided by Fundação para a Ciência e a Tecnologia, through contracts LAQV-REQUIMTE: UID/QUI/50006/2013 and UCIBIOREQUIMTE: UID/Multi/04378/2013. This work was co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01- 0145-FEDER-007728).info:eu-repo/semantics/publishedVersio

Dyspareunia in HIV-positive and HIV-negative middle-aged women: a cross-sectional study

To evaluate whether dyspareunia is associated with HIV status in menopausal women and also to assess which factors are associated with dyspareunia in a group of HIV-positive menopausal women. A cross-sectional study was conducted with 178 HIV-negative and 128 HIV-positive women aged 40-60 years. The Short Personal Experiences Questionnaire (SPEQ) was used to collect data. Sociodemographic, clinical, behavioural and reproductive factors were evaluated, as well as factors related to the HIV infection. Dyspareunia was defined as pain during intercourse. A bivariate analysis and Poisson multiple regression analysis were performed. Overall, 41.4% of the HIV-positive women reported dyspareunia compared with 34.8% of the HIV-negative women (p=0.242). In the HIV-positive women, bivariate analysis revealed an association between dyspareunia and having a steady partner (p=0.047); the woman's partner having undergone HIV testing (p=0.020); vaginal dryness (p<0.001); muscle/joint pain (p=0.021); physical/emotional violence (p=0.049); urinary incontinence (p=0.004); and the use of lamivudine/zidovudine (p=0.048). The Poisson multiple regression analysis found an association between dyspareunia and vaginal dryness (prevalence ratio (PR)=1.96, 95% CI 1.10 to 3.50, p=0.023) and urinary incontinence (PR=1.86, 95% CI 1.06 to 3.27, p=0.031). Dyspareunia was common in this group of HIV-positive women and was associated principally with vaginal dryness and urinary incontinence. The importance of treating dyspareunia within the context of sexual health in this group of women should be emphasised and appropriate management of this issue may reduce the likelihood of lesions on the vaginal wall, which may act as a portal of entry for other infections.To evaluate whether dyspareunia is associated with HIV status in menopausal women and also to assess which factors are associated with dyspareunia in a group of HIV-positive menopausal women. A cross-sectional study was conducted with 178 HIV-negativ416FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2010/06037-

Inter-cultural differences in response to a computer-based anti-bullying intervention

Background and purpose: Many holistic anti-bullying interventions have been attempted, with mixed success, while little work has been done to promote a 'self-help' approach to victimisation. The rise of the ICT curriculum and computer support in schools now allows for approaches that benefit from technology to be implemented. This study evaluates the cross-cultural effects of a computer-based anti-bullying intervention on primary school-aged children's knowledge about bullying and relevant coping strategies. Programme description: FearNot! is an interactive computer-based virtual learning environment designed for use as an anti-bullying intervention. It includes interactive virtual agents who assume the most common participant roles found in episodes of bullying. FearNot! was used by children over three consecutive weeks to allow its effectiveness to be evaluated in a longitudinal in situ programme. Sample: Two comparable samples were drawn from the UK and Germany. In the UK, 651 participants (aged 8-11) were recruited from primary schools in Hertfordshire, Coventry and Warwickshire, whereas the 535 German participants (aged 7-10) were sourced from Grundschulen in the Bayern and Hessen regions. Because of lack of parental consent, late joiners and absences/missing responses, data from 908 participants (UK 493; Germany 415) were analysed. Design and methods: A quasi-experimental, pre/post-tests control group design employed pre-published and bespoke questionnaires to collect data. Descriptive and inferential analyses were conducted. Results: UK students possessed higher coping strategy knowledge scores than German participants, but German children's scores improved over time and as a result of the FearNot! intervention. Conclusions: Overall, while not effective at increasing children's coping strategy knowledge in this study, the FearNot! intervention could prove a useful classroom tool to approach the issue of bullying as part of a wider initiative. Cultural differences at baseline and reactions to the intervention are discussed

The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells

In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34(+) samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34(+) samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients

Safety and outcomes of routine endovascular thrombectomy in large artery occlusion recorded in the SITS Register: An observational study

[Background and objective] We aimed to evaluate the safety and outcomes of thrombectomy in anterior circulation acute ischaemic stroke recorded in the SITS–International Stroke Thrombectomy Register (SITS-ISTR) and compare them with pooled randomized controlled trials (RCTs) and two national registry studies.[Methods] We identified centres recording ≥10 consecutive patients in the SITS-ISTR with at least 70% of available modified Rankin Scale (mRS) at 3 months during 2014–2019. We defined large artery occlusion as intracranial internal carotid artery, first and second segment of middle cerebral artery and first segment of anterior cerebral artery. Outcome measures were functional independence (mRS score 0-2) and death at 3 months and symptomatic intracranial haemorrhage (SICH) per modified SITS-MOST.[Results] Results are presented in the following order: SITS-ISTR, RCTs, MR CLEAN Registry and German Stroke Registry (GSR). Median age was 73, 68, 71 and 75 years; baseline NIHSS score was 16, 17, 16 and 15; prior intravenous thrombolysis was 62%, 83%, 78% and 56%; onset to reperfusion time was 289, 285, 267 and 249 min; successful recanalization (mTICI score 2b or 3) was 86%, 71%, 59% and 83%; functional independence at 3 months was 45.5% (95% CI: 44–47), 46.0% (42–50), 38% (35–41) and 37% (35–41), respectively; death was 19.2% (19–21), 15.3% (12.7–18.4), 29.2% (27–32) and 28.6% (27–31); and SICH was 3.6% (3–4), 4.4% (3.0–6.4), 5.8% (4.7–7.1) and not available.[Conclusion] Thrombectomy in routine clinical use registered in the SITS-ISTR showed safety and outcomes comparable to RCTs, and better functional outcomes and lower mortality than previous national registry studies.SITS (Safe Implementation of Treatment in Stroke) is financed directly and indirectly by grants from Karolinska Institutet, Stockholm County Council, the Swedish Heart-Lung Foundation, the Swedish Order of St. John, Friends of Karolinska Institutet and private donors, as well as from an unrestricted sponsorship from Boehringer Ingelheim. SITS has previously received grants from the European Union Framework 7, the European Union Public Health Authority, Ferrer International and EVER Pharma. SITS is currently conducting studies supported by Boehringer Ingelheim and Biogen, as well as in collaboration with Karolinska Institutet, supported by Stryker, Covidien and Phenox. N Ahmed is supported by grants provided by the Stockholm County Council and the Swedish Heart-Lung Foundation. S Holmin is supported by grants provided by the Söderberg Foundations, the Stockholm County Council, the Erling Persson Foundation, VINNOVA and HMT. Irene Escudero-Martínez has received a grant from ‘Fundación Progreso y Salud, Junta de Andalucía’ (grant EF-0437-2018). RM has been supported by the project no. LQ1605 from the National Program of Sustainability II (MEYS CR). RH has been supported by the grants no. DRO–UHHK 00179906 from the Ministry of Health of the Czech Republic and no. PROGRES Q40 from Charles University, Czech Republic.Peer reviewe

EuroFlow Lymphoid Screening Tube (LST) data base for automated identification of blood lymphocyte subsets

In recent years the volume and complexity of flow cytometry data has increased substantially. This has led to a greater number of identifiable cell populations in a single measurement. Consequently, new gating strategies and new approaches for cell population definition are required. Here we describe how the EuroFlow Lymphoid Screening Tube (LST) reference data base for peripheral blood (PB) samples was designed, constructed and validated for automated gating of the distinct lymphoid (and myeloid) subsets in PB of patients with chronic lymphoproliferative disorders (CLPD). A total of 46 healthy/reactive PB samples which fulfilled predefined technical requirements, were used to construct the LST-PB reference data base. In addition, another set of 92 PB samples (corresponding to 10 healthy subjects, 51 B-cell CLPD and 31 T/NK-cell CLPD patients), were used to validate the automated gating and cell-population labeling tools with the Infinicyt software. An overall high performance of the LST-PB data base was observed with a median percentage of alarmed cellular events of 0.8% in 10 healthy donor samples and of 44.4% in CLPD data files containing 49.8% (range: 1.3–96%) tumor cells. The higher percent of alarmed cellular events in every CLPD sample was due to aberrant phenotypes (75.6% cases) and/or to abnormally increased cell counts (86.6% samples). All 18 (22%) data files that only displayed numerical alterations, corresponded to T/NK-cell CLPD cases which showed a lower incidence of aberrant phenotypes (41%) vs B-cell CLPD cases (100%). Comparison between automated vs expert-bases manual classification of normal (r2 = 0.96) and tumor cell populations (rho = 0.99) showed a high degree of correlation. In summary, our results show that automated gating of cell populations based on the EuroFlow LST-PB data base provides an innovative, reliable and reproducible tool for fast and simplified identification of normal vs pathological B and T/NK lymphocytes in PB of CLPD patients

Abundância e sazonalidade de cigarrinhas (Hemiptera, Cicadellidae, Cicadellinae) em vegetação herbácea de pomar de laranja doce, no município de Montenegro, Estado do Rio Grande do Sul, Brasil.

O presente estudo teve por objetivo conhecer a flutuação populacional e a constância de cicadelíneos presentes na vegetação herbácea de um pomar de laranja doce (Citrus sinensis (L.) Osbeck), variedade Valência, em Montenegro, RS. O levantamento foi realizado com a metodologia da rede-de-varredura, tendo início em fevereiro de 2001 e finalizando-se em janeiro de 2002. Mensalmente foram coletadas dez amostras, sendo cada uma destas composta por 50 golpes de rede em movimento de avanço sobre a vegetação herbácea e cultura intercalar nas entrelinhas do pomar (n = 500 golpes/ocasião de coleta). No total foram coletados 928 cicadelíneos,pertencentes a nove espécies: Bucephalogonia xanthophis (Berg, 1879), Diedrocephala variegata(Fabricius, 1775), Hortensia similis(Walker, 1851), Macugonalia leucomelas (Walker, 1851), Parathona gratiosa (Blanchard, 1840), Plesiommata corniculata Young,1977, Sibovia sagata (Signoret, 1854), Sonesimia grossa (Signoret, 1854) e Tapajosa rubromarginata (Signoret, 1855). O período de maior abundância da comunidade de cicadelíneos foi durante a primavera e o verão. Hortensia similis e M. leucomelas foram as únicas espécies consideradas constantes durante o levantamento. A menor abundância dos cicadelíneos em abril e dezembro provavelmente devese a efeitos causados por fatores abióticos (pluviosidade) e aqueles relativos à estrutura da vegetação (altura das plantas) sobre a comunidade

Production of electrospun fast-dissolving drug delivery systems with therapeutic eutectic systems encapsulated in gelatin

Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/ v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.The research leading to these results has received funding from Fundação para a Ciência e a Tecnologia (FCT) through the projects ENIGMA - PTDC/EQU-EPR/ 121491/2010 and UID/CTM/50025/2013, LAQVREQUIMTE: UID/QUI/50006/2013, UCIBIO-REQUIMTE: UID/Multi/04378/2013 (co-financed by the ERDF under the PT2020 Partnership Agreement [POCI-01-0145-FEDER- 007728]) and by FEDER through the COMPETE 2020 Programme. Marta Martins is grateful for financial support from FCT through the grant BIM/PTDC/EQUEPR/121491/ 2010/ENIGMA. This research has also received funding from the European Union Seventh Framework Programme (FP7/ 2007-2013) under grant agreement number REGPOTCT2012-316331-POLARIS and from the project BNovel smart and biomimetic materials for innovative regenerative medicine approaches^ RL1 - ABMR - NORTE-01-0124- FEDER-000016) co-financed by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF).info:eu-repo/semantics/publishedVersio

The importance of Portuguese Continental Shelf Waters to Balearic Shearwaters revealed by aerial census

The Balearic shearwater Puffinus mauretanicus is one of the most threatened seabirds in the world. To evaluate the abundance and distribution of Balearic Shearwaters in Portuguese Continental Shelf Waters, during the post-breeding period when migrating birds are outside the Mediterranean Sea, we conducted 5 aerial surveys between 2010 and 2014 (21 survey days covering 62,716 km2). Following a line transect method, observers recorded a total of 181 Balearic Shearwaters sightings. Using Distance sampling software, we estimated an overall species abundance (2010–2014) of 10,182, ranging between 2338 in 2010 and 23,221 individuals in 2012. During the 2012 post-breeding period, the Portuguese Continental Shelf Waters were used by up to 96.8% of the latest migratory population assessment. Considering Balearic Shearwater estimates per sampling block, there was a preference for the North and Center sectors of the Portuguese coast (respectively, 7058 and 1366 individuals) where several SPAs were already designated. We computed the annual and overall habitat predictive models for Balearic Shearwaters using a maximum entropy algorithm on MaxEnt software. In all models, the Balearic shearwater distribution was best predicted by mean chlorophyll concentration. Balearic Shearwaters are mostly present in shallow shelf and coastal waters particularly in the widest portions of the continental shelf. These areas are strongly influenced by upwelling, which concurs with the chlorophyll concentration being the most important predicting variable. Portuguese Continental Shelf Waters are one of the most important post-breeding grounds to the Balearic ShearwaterPortuguese Wildlife Society and projects SafeSea EEA-Grants, FAME (Proj. 2009-1/089) and European Commission’s Life Programme (MarPro NAT/PT/00038). This study was also partly supported by the Portuguese Foundation for Science and Technology (FCT) with Grants SFRH/ BD/30240/2006 to M. Ferreira and SFRH/BD/32841/2006 to P. C. Rodrigues. C. Eira is supported by FCT through CESAM UID/AMB/50017/2013 co-funded by FCT/MEC and FEDER, within PT2020 and Compete 2020 and S. Monteiro is financed by a Grant (BPD/0043/AMB/50017) from UID/AMB/50017/2013. This work was also partially supported by the strategic programme UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) funded by FCT and by ERDF (COMPETE2020). The authors thank observers and airplane pilots who contributed to this workinfo:eu-repo/semantics/publishedVersio