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IntroductionThere is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.MethodsTen single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.ResultsBased on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).DiscussionOur study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.

This systematic review examined, through the UTAUT2 model, the factors influencing the acceptance of artificial intelligence (AI) applications in university contexts. A total of 50 scientific texts published between 2018 and 2023 were analyzed and selected after a rigorous search of specialized databases. These findings confirm the versatility of UTAUT2 in elucidating technological adoption processes in higher education. Performance expectancy and hedonic motivation emerged as significant predictors of intentions and effective use among students, faculty, and administrative staff. Among students, perceived ease of use and social influence were also relevant. The analysis revealed differences in adoption patterns between STEM and non-STEM disciplines and between public and private institutions. Despite widespread positive perceptions of AI's potential, barriers such as distrust and lack of knowledge persist. The research also identified moderating and mediating factors, such as prior technology experience and technological self-efficacy. These results have important implications for the implementation of AI in higher education, suggesting the need for differentiated approaches according to the characteristics of each group and institutional context. It is recommended to develop strategies that address the identified barriers and leverage facilitators, with an emphasis on training, ethical design, and contextual adaptation of AI applications. Future research should explore the longitudinal evolution of these factors and examine AI adoption in non-STEM disciplines in greater depth., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Enhanced vascular permeability at the site of injury is a prominent feature in acute inflammatory pain models, commonly assessed through the Evans Blue test. However, this invasive test requires euthanasia, thereby precluding further investigations on the same animal. Due to these limitations, the integration of non-invasive tools such as IRT has been sought. Here, we aimed to evaluate the use of thermography in a common orofacial pain model that employs formalin as a chemical irritant to induce local orofacial inflammation. Male Hannover rats (290-300 g, N = 43) were used. In the first approach, radiometric images were taken before and after formalin administration, assessing temperature changes and extravasated Evans Blue. The second approach included capturing pre- and post-formalin test radiometric images, followed by cytokine measurements in excised vibrissae tissue. Rats were anesthetized for vibrissae tissue collection, allowing correlations between thermographic patterns, nocifensive behavior duration, and cytokine levels in this area. Our findings revealed a positive correlation between local temperature, measured via thermography, and vascular permeability in the contralateral (r 2  = 0.3483) and ipsilateral (r 2  = 0.4502) side, measured using spectrophotometry. The obtained data supports the notion that thermography-based temperature assessment can effectively evaluate vascular permeability in the orofacial region., Competing Interests: Declaration of competing interest There was no conflict of interest or disagreement between the authors., (Copyright © 2023. Published by Elsevier Ltd.)

Orofacial pain has significant psychological and physiological effects. Citral (3,7-dimethyl-2,6-octadienal) is the main component of Cymbopogon citratus (DC) Stapf, an herb with analgesic properties. Although citral has been considered a potent analgesic, its putative effects on orofacial pain are still unknown., Objective: The objective of this study is to test the hypothesis that citral modulates orofacial pain using two experimental models: formalin-induced hyperalgesia in the vibrissae area and during persistent temporomandibular hypernociception using Complete Freund's Adjuvant - CFA test., Methods: For the formalin test, citral (100 and 300 mg/kg, oral gavage) or its vehicle (Tween 80, 1 %) were given 1 h before the formalin injection subcutaneously (sc) into the vibrissae area. For the CFA model, we analyzed the prophylactic (100 mg/kg of citral by oral gavage, 1 h before CFA injection) and the chronic therapeutic (citral treatment 1-hour post-CFA injection and daily post-CFA injection) effect of citral or its vehicle in animals treated with CFA for 8 days., Results: Citral caused a decrease in formalin-induced local inflammation and the time spent performing nociceptive behavior in a dose-dependent fashion. Similarly, prophylactic and therapeutic citral treatment decreased the CFA-induced persistent mechanical hypernociception in the temporomandibular area., Conclusion: Our data strengthen the notion that citral plays a powerful antinociceptive role by decreasing orofacial hypernociception in formalin and CFA models., Competing Interests: Declaration of Competing Interest The authors have not disclosed any conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Report survival rates, neonatal mortality and morbidity and long-term outcomes of monochorionic (MC) twin pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) or TTTS plus selective fetal growth restriction (sFGR) treated by endoscopic laser surgery., Methods: Retrospective cohort study including 149 MC twin pregnancies complicated by TTTS or TTTS plus sFGR.Medical records were reviewed for survival rates, neonatal mortality, neonatal morbidity and long-term outcomes at 2 and 6 years of age., Results: Survival of both babies was higher in the TTTS group than in the TTTS plus sFGR group (72.9%vs.54.8%); survival of at least one baby was similar in the two groups (90.7% and 88.1%). The incidence of severe neurological disability was not significantly different between TTTS and TTTS plus fetal growth restriction group at both stages, 1.9% versus 2.3% (p-value = 1) and 3.4%vs6.1% (p-value = 0.31). Multivariable analysis demonstrated that intact neurological outcome at 2 years of age was related with gestational age (GA) at birth and z score birthweight (Z BW), and at 6 years of age with GA at birth, Z BW and TTTS stage4. sFGR or abnormal brain findings at neonatal ultrasound were not related with impaired neurological outcome at two or 6 years of age., Conclusions: In pregnancies with TTTS and TTTS plus sFGR survival of at least one baby and long-term neurological outcome are comparable between both groups., (© 2022 John Wiley & Sons Ltd.)

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

1-(1-Naphthyl)piperazine (1-NPZ) has shown promising effects by inhibiting UV radiation-induced immunosuppression. Ultradeformable vesicles are recent advantageous systems capable of improving the (trans)dermal drug delivery. The aim of this study was to investigate 1-NPZ-loaded transethosomes (NPZ-TE) and 1-NPZ-loaded vesicles containing dimethyl sulfoxide (NPZ-DM) as novel delivery nanosystems, and to uncover their chemopreventive effect against UV-induced acute inflammation. Their physicochemical properties were evaluated as follows: vesicles size and zeta potential by dynamic and electrophoretic light scattering, respectively; vesicle deformability by pressure driven transport; rheological behavior by measuring viscosity and I-NPZ entrapment yield by HPLC. In vitro topical delivery studies were performed in order to evaluate the permeation profile of both formulations, whereas in vivo studies sought to assess the photoprotective effect of the selected formulation on irradiated hairless mice by measuring myeloperoxidase activity and the secretion of proinflammatory cytokines. Either NPZ-TE or NPZ-DM exhibited positive results in terms of physicochemical properties. In vitro data revealed an improved permeation of 1-NPZ across pig ear skin, especially by NPZ-DM. In vivo studies demonstrated that NPZ-DM exposure was capable of preventing UVB-induced inflammation and blocking mediators of inflammation in mouse skin. The successful results here obtained encourage us to continue these studies for the management of inflammatory skin conditions that may lead to the development of skin cancers., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Lipoic acid (LA) is an endogenous organosulfur compound with potent antioxidant property. LA is often used as a drug for the treatment of skin disorders. For the accomplishment of topical applications of LA appropriate drug quantification methods are essential. Thus far, no HPLC methods have been reported for the measurement of LA extracted from skin. In this article we report on the development and validation of three sensitive and specific HPLC methods for LA and dihydrolipoic acid (DHLA) using ultraviolet (UV), electrochemical (EC) or evaporative light scattering (ELS) detection. These methods demonstrate different linearity ranges. The chromatographic separations were performed by RP-HPLC (250 × 4 mm, 5 μm) with isocratic elution using an acidic mobile phase for the three detection techniques. The lower limits of detection and quantification were 0.04 and 0.08 ng LA, respectively, for HPLC coupled to ELS, an innovative detector for LA with high sensitivity. The extraction of LA from skin samples showed recoveries greater than 71%. The recovered LA concentrations from stratum corneum and epidermis+dermis layers were: 5.41 ± 0.56 and 4.92 ± 0.33 μg/mL, respectively for HPLC/UV and 6.52 ± 0.49 and 5.01 ± 0.41 μg/mL, respectively, for HPLC/EC for the added LA concentration (6.67 μg/mL), and 8.88 ± 0.46 and 8.95 ± 0.08 μg/mL, respectively, for HPLC/ELS for the added LA concentration (10 μg/mL). These three optimized HPLC methods allowed for a simple, rapid and reliable determination of LA in human skin. They should be useful for the development of drug delivery systems for topical applications of LA., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The study of a drug's dermal penetration profile provides important pharmaceutical data for the rational development of topical and transdermal delivery systems because the skin is a broadly used delivery route for local and systemic drugs and a potential route for gene therapy and vaccines. Monitoring drug penetration across the skin and quantifying its levels in different skin layers have been constant challenges due to the detection limitations of the available techniques, as well as the inherent interference in this tissue. This review explores and discusses several bionalytical methods that are indispensable tools to study drugs across the skin. In addressing the main topic, we structure the review highlighting the skin as an important route of drug administration and its structure, skin membrane models most used and its properties, in vitro and in vivo assays most used in the study of drug delivery to the skin, the techniques for processing the skin for subsequent analysis by bioanalytical methods that have a theoretical and practical approach showing its applicability, limitations and also including examples of its use. This review has a comprehensive approach in order to help researchers design their experiments and update the applicability and advances in this area of expertise.

Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug permeation studies showed that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution.

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls., Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci., Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Benznidazole (BNZ) is the primary chemotherapeutic agent for treating Chagas' disease; however, its poor water solubility and irregular oral absorption lead to the treatment failure in the chronic phase. The aim of this work was to investigate the utility of the polymer hydroxypropyl methylcellulose (HPMC) in controlling the release of BNZ from solid inclusion complexes with cyclodextrin to overcome the problem of its bioavailability. Preliminary studies of solubility were conducted in solution using selected β-cyclodextrin derivatives according to an experimental mixture design. The best cyclodextrin composition was used to produce solid-state systems by kneading in the presence or absence of HPMC. The formulations were characterized by different physico-chemical techniques, including the dissolution rate. Hydroxypropyl-β-cyclodextrin (HPβCD) produced the greatest improvement in drug solubility and was selected for the development of solid systems. Assays confirmed the production of true inclusion complexes between BNZ and HPβCD. The dissolution rate of the BNZ-HPβCD system was markedly increased, while the presence of HPMC retarded drug release. An optimal formulation obtained by the combination of kneading systems developed in appropriate ratios could be a promising drug delivery system with a prolonged therapeutic effect coupled with more balanced bioavailability. The produced systems present interesting perspectives for Chagas' therapy.

Solanum lycocarpum (Solanaceae) is native to the Brazilian Cerrado. Fruits of this species contain the glycoalkaloids solasonine (SN) and solamargine (SM), which display antiparasitic and anticancer properties. A method has been developed for the extraction and HPLC-UV analysis of the SN and SM in different parts of S. lycocarpum, mainly comprising ripe and unripe fruits, leaf, and stem. This analytical method was validated and gave good detection response with linearity over a dynamic range of 0.77-1000.00 μg mL(-1) and recovery in the range of 80.92-91.71%, allowing a reliable quantitation of the target compounds. Unripe fruits displayed higher concentrations of glycoalkaloids (1.04% ± 0.01 of SN and 0.69% ± 0.00 of SM) than the ripe fruits (0.83% ± 0.02 of SN and 0.60% ± 0.01 of SM). Quantitation of glycoalkaloids in the alkaloidic extract gave 45.09% ± 1.14 of SN and 44.37% ± 0.60 of SM, respectively.

A simple, rapid and sensitive analytical procedure for the measurement of celecoxib (CXB) levels in skin samples after in vitro penetration studies was developed and validated. In vitro permeability studies in porcine skin were performed for quantification of CXB at different layers of skin, the stratum corneum (SC) and epidermis plus dermis (EP + D) as well as in the acceptor solution (AS) to assess CXB permeation through skin. CXB was quantified by HPLC using a C18 column and UV detection at 251 nm. The mobile phase was methanol-water 72:28 (v/v) and the flow-rate was 0.8 mL/min. The CXB retention time was 5 min. The assay was linear for CBX in the concentration range of 0.1-3.0 μg/mL in the AS (drug permeated through skin) and 5.0-50.0 μg/mL for drug retained in SC and [EP + D] in vitro. The linear correlation coefficients for the different calibration curves were equal or greater than 0.99. Intra- and inter-assay variabilities were below 8.0%. Extraction of CXB from skin samples showed recoveries higher than 95.0% after 15 min of ultrasonic sound and centrifugation at 2500 rpm for 3 min. The method was considered appropriate for the assay of CXB in skin samples, after in vitro cutaneous penetration studies., (Copyright © 2011 John Wiley & Sons, Ltd.)

The aim of the present investigation was to determine the interaction between the antiepileptic drugs (AEDs) phenytoin, carbamazepine, and phenobarbital and the enantioselective metabolism of albendazole. Thirty-two adults with a diagnosis of the active form of intraparenchymatous neurocysticercosis and treated with albendazole at the dose of 7.5 mg/kg every 12 hours for 8 days were studied. The patients were divided into four groups based on the combined use of AEDs or not: control group (n = 9), phenytoin group (n = 9 patients treated with 3-4 mg/kg/d sodium phenytoin), carbamazepine group (n = 9 patients treated with 10-20 mg/kg/d carbamazepine), and phenobarbital group (n = 5 patients treated with 1.5-4.5 mg/kg/d phenobarbital). Serial blood collections were carried out on day 8 of albendazole treatment during the last 12-hour dose interval. Plasma concentrations of the (+)- and (-)-albendazole sulfoxide (ASOX) and albendazole sulfone (ASON) metabolites were determined by high-performance liquid chromatography using a chiral phase column and fluorescence detection. The pharmacokinetic parameters were analyzed by analysis of variance followed by the Tukey-Kramer test. The results are reported as means. The following differences (P < 0.05) were observed between the control and the phenytoin, carbamazepine, and phenobarbital groups, respectively: (+)-ASOX area under the concentration-time curve for 0 to 12 hours after treatment (AUC(0-12)) 6.1, 2.1, 3.1, 2.4 microg/h/mL; (+)-ASOX maximum plasma concentration (C(max)) 0.8, 0.3, 0.4, 0.3 microg/mL; (+)-ASOX half-life (t1/2) 8.0, 3.8, 4.1, 4.9 h; (-)-ASOX AUC(0-12) 1.8, 0.4, 0.6, 0.5 microg/h/mL; (-)-ASOX C(max) 0.2, 0.06, 0.1, 0.1 microg/mL; (-)-ASOX (t(1/2)) 4.3, 1.9, 2.2, 2.1 h; ASON AUC(0-12) 0.5, 0.2 microg/h/mL; ASON C(max) 0.8, 0.3, 0.4, 0.3 microg/mL; ASON (t(1/2)) 8.0, 3.8, 4.1 h. The results show that phenytoin, carbamazepine, and phenobarbital induce to approximately the same extent the oxidative metabolism of albendazole in a nonenantioselective manner. Notably, a significant reduction in the plasma concentration of the active ASOX metabolite was observed in patients with neurocysticercosis treated with these AEDs.

The purpose of this work is to present the research program of a Clinical Center, the AIGLE Foundation in Buenos Aires, Argentina. It describes the potentialities and advantages of research in this context. It also describes the institute, the types of patients treated and its professional staff. The program covers four areas: determining the demand for psychotherapeutic care in the population at large, studying the conditions making participation in community mental health possible, analyzing and follow-up on the outcomes and studying the personal styles of the therapists. Finally, this work discusses the usefulness and applicability of these results for clinical practice.

At the present time there is no medicament completely harmless to the embryo or fetus. Passage through the placenta probably occurs by simple diffusion. Substances with a molecular weight under 600, low protein binding, a low degree of ionization and good solubility in lipids cross the placenta most easily. The harmful effects of the different groups of medicaments are describedand the substances classified into those not particularly toxic, those which can only be used in certain conditions and those only to be used in exceptional cases. The treatment of the most common infections in pregnancy is dealth with in detail. Infections of the maternal urinary tract and amnionitis raise most problems. For the treatment of amnionitis, direct instillation of the medicament into the amniotic sac is recommended.