Synthesis, Bioavailability, and Cytotoxicity Studies

Funding Information: This work was supported by Portuguese funds from FCT/MCTES through the Associate Laboratory for Green Chemistry—LAQV (UIDB/50006/2020 and UIDP/50006/2020) and the project numbers PTDC/QUI-QOR/32406/2017 and PTDC/EAM-AMB/2023/2021. Ana R. Jesus and Ana Rita C. Duarte acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme, under grant agreement No ERC-2016-CoG 725034. Publisher Copyright: © 2023 by the authors.Thyroid diseases affect a considerable portion of the population, with hypothyroidism being one of the most commonly reported thyroid diseases. Levothyroxine (T4) is clinically used to treat hypothyroidism and suppress thyroid stimulating hormone secretion in other thyroid diseases. In this work, an attempt to improve T4 solubility is made through the synthesis of ionic liquids (ILs) based on this drug. In this context, [Na][T4] was combined with choline [Ch]+ and 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMiM]+ cations in order to prepare the desired T4-ILs. All compounds were characterized by NMR, ATR-FTIR, elemental analysis, and DSC, aiming to check their chemical structure, purities, and thermal properties. The serum, water, and PBS solubilities of the T4-ILs were compared to [Na][T4], as well as the permeability assays. It is important to note an improved adsorption capacity, in which no significant cytotoxicity was observed against L929 cells. [C2OHMiM][T4] seems to be a good alternative to the commercial levothyroxine sodium salt with promising bioavailability.publishersversionpublishe

Development and Characterization of Nanoemulsions for Ophthalmic Applications: Role of Cationic Surfactants

The eye is a very complex organ comprising several physiological and physical barriers that compromise drug absorption into deeper layers. Nanoemulsions are promising delivery systems to be used in ocular drug delivery due to their innumerous advantages, such as high retention time onto the site of application and the modified release profile of loaded drugs, thereby contributing to increasing the bioavailability of drugs for the treatment of eye diseases, in particular those affecting the posterior segment. In this review, we address the main factors that govern the development of a suitable nanoemulsion formulation for eye administration to increase the patient's compliance to the treatment. Appropriate lipid composition and type of surfactants (with a special emphasis on cationic compounds) are discussed, together with manufacturing techniques and characterization methods that are instrumental for the development of appropriate ophthalmic nanoemulsions. Keywords: nanoemulsions, ocular barriers, ocular delivery, cationic surfactant

Swept-source OCTA quantification of capillary closure predicts ETDRS severity staging of NPDR

To test whether a single or composite set of parameters evaluated with optical coherence tomography angiography (OCTA), representing retinal capillary closure, can predict non-proliferative diabetic retinopathy (NPDR) staging according to the gold standard ETDRS grading scheme. 105 patients with diabetes, either without retinopathy or with different degrees of retinopathy (NPDR up to ETDRS grade 53), were prospectively evaluated using swept-source OCTA (SS-OCTA, PlexElite, Carl Zeiss Meditec) with 15×9 mm and 3×3 mm angiography protocols. Seven-field photographs of the fundus were obtained for ETDRS staging. Eyes from age-matched healthy subjects were also imaged as control. In eyes of patients with type 2 diabetes without retinopathy or ETDRS levels 20 and 35, retinal capillary closure was in the macular area, with predominant alterations in the parafoveal retinal circulation (inner ring). Retinal capillary closure in ETDRS stages 43-53 becomes predominant in the retinal midperiphery with vessel density average values of 25.2±7.9 (p=0.001) in ETDRS 43 and 23.5±3.4 (p=0.001) in ETDRS 47-53, when evaluating extended areas of 15×9 protocol. Combination of acquisition protocols 3×3 mm and 15×9 mm, using SS-OCTA, allows discrimination between eyes with mild NPDR (ETDRS 10, 20, 35) and eyes with moderate-to-severe NPDR (ETDRS grades 43-53). Retinal capillary closure, quantified by SS-OCTA, can identify NPDR severity progression. It is located mainly in the perifoveal retinal capillary circulation in the initial stages of NPDR, whereas the retinal midperiphery is predominantly affected in moderate-to-severe NPDR.info:eu-repo/semantics/publishedVersio

Choroidal Indices as Predictors of Visual Outcomes to anti-VEGF Treatment in DME patients, using Swept Source OCT

[Purpose : To evaluate the associations between anti-VEGF therapy and central choroidal thickness (CCT), choroidal vascular density (CVD) and choroidal vascular volume (CVV), in patients with Diabetic Macular Edema (DME) using Swept Source OCT (SS-OCT), and to correlate these findings with treatment visual outcomes.]info:eu-repo/semantics/publishedVersio

Prognostic indicators for poor outcomes in low back pain patients consulted in primary care

SAICT-POL/23439/2016| LISBOA-01-0145-FEDER-023439). This Grant covers all the planned activities for this study including, the design of the study, data collection, data analysis and interpretation and the writing of this manuscript.The funder did not play any role in the study design, data collection and analysis, decision to publish, or preparation of this manuscriptBackground Non-specific low back pain (NSLBP) is the most prevalent musculoskeletal condition in western countries and is associated with persistent disability and high consumption of health care resources. NSLBP patients first seek primary health care services but the outcomes are often uncertain. This study aimed to examine the clinical course of the outcomes and to identify prognostic indicators for poor outcomes in NSLBP patients who consulted primary care. Methods A prospective cohort study of 115 patients seeking treatment for NSLBP in primary care was conducted. Participants were consecutively recruited by their General Practitioners (GPs) and then assessed at baseline and 2 and 6 months later. Baseline assessment included socio-demographic and clinical data, psychosocial factors, pain, disability, and health related quality of life (HRQoL). Pain, disability, HRQoL and global perception of change were also assessed at 2 and 6-months’ follow-up. In addition, information regarding the GP’ practice was collected. Poor outcomes were determined according to the cut-off point used to define a persistent disabling condition and the minimal important change established for disability, pain and for global perception of change. The relationship between variables on baseline and poor outcomes was modulated through binary logistic regression analysis. The significance of associations was evaluated at ≤ 0.05 p-value with 95% confidence intervals (CI) and adjusted odds ratios (AOR). Results 110 (94.8%) and 104 (89.7%) participants completed the follow-up assessment at 2 and 6 months, respectively. The mean age (±SD) was 48.06 ± 11.41, with 53.9%, (N = 62) reporting an acute presentation of NSLBP. Six months after GP consultation, 53.8% (N = 56) of the participants reported a persistent disabling condition. An “LBP episode of less than 12 weeks” [AOR: 0.26; 95% CI (0.10, 0.65); AOR: 0.34; 95% CI (0.14, 0.81); AOR: 0.21; 95% CI (0.09, 0.53)],”maladaptive psychosocial factors” [AOR: 2.06; 95% CI (1.40, 3.04); AOR: 1.82; 95% CI (1.27, 2.59); AOR: 1.72; 95% CI (1.20, 2.47)] were significantly associated with poor outcomes on disability, pain and global perception of change, respectively. Besides these factors, being employed reduces the chances of poor outcomes on disability [AOR 0.31; 95% CI (0.11, 0.92)]. Conclusions A large proportion of LBP patients seeking primary health care reported poor outcomes 6 months after GP consultation. Patients who report chronic LBP, maladaptive psychosocial factors and are unemployed have a significant increase in the risk of poor outcome. These findings suggest the need of implementing effective models of care able to provide early screening and appropriate treatment to those at greatest risk of a poor outcome.publishersversionpublishe

Massive hypereosinophilia and vasculitis associated with major expansion of interleukin-5-producing CD8+ T cells in HIV-1 infection

© 2014 Wolters Kluwer Health | Lippincott Williams & WilkinsThis work was supported by ‘Fundação para a Ciência e a Tecnologia’ (FCT) and by ‘Programa Operacional Ciência e Inovação 2010’ [POCI2010][PIC/IC/82712/2007 to AES], as well as by Fundação Calouste Gulbenkian to AES. RBF and RT received scholarships from FCT

Synthesis, Solubility, Permeability, and In Vitro Activity against Mycobacterium tuberculosis

Funding Information: This work was supported by FCT-MCTES (PTDC/QUI-QOR/32406/2017, PEst-C/LA0006/2013, RECI/BBBBQB/0230/2012) and by the Associate Laboratory for Green Chemistry-LAQV (FCT-MCTES UIDB/50006/2020 and UIDP/50006/2020). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project N° 022161 (co-financed by FEDER through COMPETE 2020, POCI, PORL, and FCT through PIDDAC). Publisher Copyright: © 2022 by the authors.The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).publishersversionpublishe

New physical and biological evidence of lateral transport affecting dinoflagellate cyst distribution in the benthic nepheloid layer along a land-sea transect off Figueira da Foz (Atlantic Iberian margin)

30 pages, 12 figures, 3 tables.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)[Introduction] The production of resting cysts is a key dispersal and survival strategy of many dinoflagellate species. However, little is known about the role of suspended cysts in the benthic nepheloid layer (BNL) in the initiation and decline of planktonic populations. [Method] In September 2019, sampling of the dinoflagellate cyst community at different water depths in the water column and in the bottom sediments, and studies of spatio-temporal changes in physical properties (temperature, salinity, density and suspended sediment concentration), were carried out along a land-sea transect off Figueira da Foz (NW Portugal) to investigate the dinoflagellate cyst distribution and the factors (physical and biological) affecting it. A clustering analysis was used to compare the BNL and sediment cyst records with the cyst rain recorded by a sediment trap at a fixed station. Furthermore, Lagrangian particle experiments enabled simulating cyst trajectories in the BNL 5 and 10 days before sampling and assessing cross-shore, vertical and alongshore transport within the studied region. [Results] A well-developed BNL was present during the survey, which covered a change from active (14th of September) to relaxed (19th of September) upwelling conditions. Organic-walled dinoflagellate cysts were dominant in all samples, although calcareous dinoflagellate cysts consistently occurred (at low abundances). High proportions of full cysts were observed in the BNL, of which a significant portion was viable as shown by excystment experiments. Moreover, BNL cyst records collected on the 19th of September along the land-sea transect were similar to the sediment trap cyst record but greatly differed from sediment cyst records. The heterotrophic small spiny brown cysts (SBC) and cysts of the autotrophic yessotoxin-producer Protoceratium reticulatum notably increased during the survey, in the BNL and in the water column above. [Discussion] The comparison of the BNL, surface sediment and sediment trap cyst records supported that the main origin of cysts in the BNL was the recent production in the water column. The spatial coincidences in the distribution of cysts and vegetative cells of Protoceratium reticulatum also supported that full cysts in the water column were being produced in surface waters. New data evidenced the presence of a significant reservoir of viable cysts in the BNL that have the potential to seed new planktonic blooms. Furthermore, back-track particle modelling evidenced that alongshore advection was the main physical mechanism controlling cyst dynamics in the BNL during most part of the survey period, being particularly intense in coastal stations (<100 m depth). Consequently, the sediment cyst signal is a mixture of locally and regionally produced cysts. We provide multi-disciplinary data evidencing that cysts recently formed in the photic zone can be laterally advected within the studied region through the BNL, contributing to a better understanding of the role of the BNL in cyst dynamics and tracing the seed sources of the new bloomsThis work is a contribution to HABWAVE project LISBOA-01-0145-FEDER-031265, co-funded by EU ERDF funds, within the PT2020 Partnership Agreement and Compete 2020, and national funds through Fundação para a Ciência e Tecnologia, I.P.(FCT, I.P.) also to AQUIMAR project MAR2020; MAR-02.01.01-FEAMP-017. This study had the support of FCT through the strategic projects UIDB/04292/2020 and UIDP/04292/2020 awarded to MARE and through project LA/P/0069/2020 granted to the Associate Laboratory ARNET, the strategic project UIDB/04326/2020 awarded to CCMAR. Thanks are also due for the financial support to CESAM by FCT/MCTES (UIDP/50017/2020+UIDB/50017/2020+LA/P/0094/2020), Partnership Agreement and Compete 2020. IG-M was supported by a postdoctoral fellowship from Xunta de Galicia, Spain (ref. ED481B-2019-074, 2019). JM gratefully acknowledges the Fundação para a Ciência e Tecnologia and its support via strategic funding UIDB/04423/2020 and UIDP/04423/2020, and project MIWAVES (PTDC/2022.01215.PTDC)Peer reviewe

Transition of plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein pumilio

Many eukaryotic developmental and cell fate decisions that are effected post-transcriptionally involve RNA binding proteins as regulators of translation of key mRNAs. In malaria parasites (Plasmodium spp.), the development of round, non-motile and replicating exo-erythrocytic liver stage forms from slender, motile and cell-cycle arrested sporozoites is believed to depend on environmental changes experienced during the transmission of the parasite from the mosquito vector to the vertebrate host. Here we identify a Plasmodium member of the RNA binding protein family PUF as a key regulator of this transformation. In the absence of Pumilio-2 (Puf2) sporozoites initiate EEF development inside mosquito salivary glands independently of the normal transmission-associated environmental cues. Puf2- sporozoites exhibit genome-wide transcriptional changes that result in loss of gliding motility, cell traversal ability and reduction in infectivity, and, moreover, trigger metamorphosis typical of early Plasmodium intra-hepatic development. These data demonstrate that Puf2 is a key player in regulating sporozoite developmental control, and imply that transformation of salivary gland-resident sporozoites into liver stage-like parasites is regulated by a post-transcriptional mechanism