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1.
Nature ; 632(8025): 513-516, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38914113

RESUMO

The Cosmic Gems arc is among the brightest and highly magnified galaxies observed at redshift z ≈ 10.2 (ref. 1). However, it is an intrinsically ultraviolet faint galaxy, in the range of those now thought to drive the reionization of the Universe2-4. Hitherto the smallest features resolved in a galaxy at a comparable redshift are between a few hundreds and a few tens of parsecs (pc)5,6. Here we report JWST observations of the Cosmic Gems. The light of the galaxy is resolved into five star clusters located in a region smaller than 70 pc. They exhibit minimal dust attenuation and low metallicity, ages younger than 50 Myr and intrinsic masses of about 106M⊙. Their lensing-corrected sizes are approximately 1 pc, resulting in stellar surface densities near 105M⊙ pc-2, three orders of magnitude higher than typical young star clusters in the local Universe7. Despite the uncertainties inherent to the lensing model, they are consistent with being gravitationally bound stellar systems, that is, proto-globular clusters. We conclude that star cluster formation and feedback likely contributed to shaping the properties of galaxies during the epoch of reionization.

2.
N Engl J Med ; 390(10): 900-910, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38446676

RESUMO

BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).


Assuntos
Doenças das Artérias Carótidas , Microplásticos , Placa Aterosclerótica , Humanos , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/etiologia , Estenose das Carótidas/patologia , Microplásticos/efeitos adversos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Placa Aterosclerótica/química , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/mortalidade , Placa Aterosclerótica/patologia , Plásticos/efeitos adversos , Estudos Prospectivos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Fatores de Risco de Doenças Cardíacas , Endarterectomia das Carótidas , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/cirurgia , Seguimentos
3.
Molecules ; 29(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38398567

RESUMO

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on a series of dichloromethane and methanolic extracts prepared from six Asteraceae species, including Acmella bellidioides, Campuloclinium macrocephalum, Grindelia pulchella, Grindelia chiloensis, Helenium radiatum, and Viguiera tuberosa, along with pure phytochemicals isolated from Asteraceae: mikanolide (1), eupatoriopicrin (2), eupahakonenin B (3), minimolide (4), estafietin (5), 2-oxo-8-deoxyligustrin (6), santhemoidin C (7), euparin (8), jaceidin (9), nepetin (10), jaceosidin (11), eryodictiol (12), eupatorin (13), and 5-demethylsinensetin (14). Results showed that the dichloromethane extracts of C. macrocephalum and H. radiatum and the methanolic extracts prepared from C. macrocephalum and G. pulchella were highly active and selective against DENV-2, affording EC50 values of 0.11, 0.15, 1.80, and 3.85 µg/mL, respectively, and SIs of 171.0, 18.8, >17.36, and 64.9, respectively. From the pool of phytochemicals tested, compounds 6, 7, and 8 stand out as the most active (EC50 = 3.7, 3.1, and 6.8 µM, respectively; SI = 5.9, 6.7, and >73.4, respectively). These results demonstrate that Asteraceae species and their chemical constituents represent valuable sources of new antiviral molecules.


Assuntos
Asteraceae , Sesquiterpenos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Asteraceae/química , Cloreto de Metileno , Compostos Fitoquímicos/farmacologia , Antivirais/farmacologia , Sesquiterpenos/química
4.
Org Biomol Chem ; 21(7): 1411-1421, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36722938

RESUMO

Advancing with our project about the development of new antiparasitic agents, we have enzymatically synthesized a series of amides derived from amlodipine, a calcium channel blocker used as an antihypertensive drug. Through lipase-catalyzed acylation with different carboxylic acids, nineteen amlodipine derivatives were obtained, eighteen of which were new compounds. To optimize the reaction conditions, the influence of several reaction parameters was analyzed, finding different requisites for aliphatic carboxylic acids and phenylacetic acids. All synthesized compounds were evaluated as antiproliferative agents against Trypanosoma cruzi, the etiological agent of American trypanosomiasis (Chagas' disease). Some of them showed significant activity against the amastigote form of T. cruzi, the clinically relevant form of the parasite. Among synthesized compounds, the derivatives of myristic and linolenic acids showed higher efficacy and lower cytotoxicity. These results added to the advantages shown by the enzymatic methodology, such as mild reaction conditions and low environmental impact, making this approach a valuable way to synthesize these amlodipine derivatives with an application as promising antiparasitic agents.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Humanos , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Antiparasitários/uso terapêutico , Acilação , Ácidos Carboxílicos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Doença de Chagas/tratamento farmacológico
5.
Molecules ; 27(10)2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35630539

RESUMO

Cancer is one of the most important causes of death worldwide. Solid tumors represent the vast majority of cancers (>90%), and the chemotherapeutic agents used for their treatment are still characterized by variable efficacy and toxicity. Sesquiterpenes are a group of natural compounds that have shown a wide range of biological activities, including cytotoxic and antiparasitic activity, among others. The antiproliferative activity of natural sesquiterpenes, tessaric acid, ilicic acid, and ilicic alcohol and their semisynthetic derivatives against HeLa, T-47D, WiDr, A549, HBL-100, and SW1573 cell lines were evaluated. The effect of the compounds on Trypanosoma cruzi epimastigotes was also assessed. The selectivity index was calculated using murine splenocytes. Derivatives 13 and 15 were the most antiproliferative compounds, with GI50 values ranging between 5.3 (±0.32) and 14 (±0.90) µM, in all cell lines tested. The presence of 1,2,3-triazole groups in derivatives 15−19 led to improvements in activity compared to those corresponding to the starting natural product (3), with GI50 values ranging between 12 (±1.5) and 17 (±1.1) µM and 16 being the most active compound. In relation to the anti-T. cruzi activity, derivatives 7 and 16 obtained from tessaric acid and ilicic acid were among the most active and selective compounds with IC50 values of 9.3 and 8.8 µM (SI = 8.0 and 9.4), respectively.


Assuntos
Antineoplásicos , Sesquiterpenos , Trypanosoma cruzi , Animais , Antineoplásicos/farmacologia , Células HeLa , Humanos , Camundongos , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade
6.
Molecules ; 25(9)2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32344932

RESUMO

The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide have been isolated from Argentinean Astearaceae species and have been found to be active against Trypanosoma cruzi epimastigotes. The aim of this work was to evaluate the activity of these compounds by analyzing their effect against the stages of the parasites that are infective for the human. Even more interesting, we aimed to determine the effect of the most active and selective compound on an in vivo model of T. cruzi infection. Eupatoriopicrin was the most active against amastigotes and tripomastigotes (IC50 = 2.3 µg/mL, and 7.2 µg/mL, respectively) and displayed a high selectivity index. This compound was selected to study on an in vivo model of T. cruzi infection. The administration of 1 mg/kg/day of eupatoriopicrin for five consecutive days to infected mice produced a significant reduction in the parasitaemia levels in comparison with non-treated animals (area under parasitaemia curves 4.48 vs. 30.47, respectively). Skeletal muscular tissues from eupatopicrin-treated mice displayed only focal and interstitial lymphocyte inflammatory infiltrates and small areas of necrotic; by contrast, skeletal tissues from T. cruzi infected mice treated with the vehicle showed severe lymphocyte inflammatory infiltrates with necrosis of the adjacent myocytes. The results indicate that eupatoriopicrin could be considered a promising candidate for the development of new therapeutic agents for Chagas disease.


Assuntos
Asteraceae/química , Lactonas/farmacologia , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Tripanossomicidas/farmacologia , Animais , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Humanos , Lactonas/química , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sensibilidade e Especificidade , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação , Trypanosoma cruzi/efeitos dos fármacos
7.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925657

RESUMO

Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (1), isolated from Stevia alpina (Asteraceae): 11ßH,13-dihydroestafietin (2), epoxyestafietin (3a and 3b), 11ßH,13-methoxyestafietin, (4) and 11ßH,13-cianoestafietin. The antiprotozoal activity against Trypanosoma cruzi and Leishmania braziliensis of these compounds was evaluated. Epoxyestafietin was the most active compound against T. cruzi trypomastigotes and amastigotes (IC50 values of 18.7 and 2.0 µg/mL, respectively). Estafietin (1) and 11ßH,13-dihydroestafietin (2) were the most active and selective compounds on L. braziliensis promastigotes (IC50 values of 1.0 and 1.3 µg/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis.


Assuntos
Leishmania braziliensis/efeitos dos fármacos , Sesquiterpenos de Guaiano/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiparasitários/química , Antiparasitários/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Chlorocebus aethiops , Espectroscopia de Prótons por Ressonância Magnética , Sesquiterpenos de Guaiano/química , Trypanosoma cruzi/crescimento & desenvolvimento , Células Vero
8.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897836

RESUMO

Cancer is one of the most important causes of death worldwide. Solid tumors represent the great majority of cancers (>90%) and the chemotherapeutic agents used for their treatment are still characterized by variable efficacy and toxicity. Sesquiterpene lactones are a group of naturally occurring compounds that have displayed a diverse range of biological activities including cytotoxic activity. A series of oxygenated and oxy-nitrogenated derivatives (4⁻15) from the sesquiterpene lactones cumanin (1), helenalin (2), and hymenin (3) were synthesized. The silylated derivatives of helenalin, compounds 13 and 14, were found to be the most active against tumor cell lines, with GI50 values ranging from 0.15 to 0.59 µM. The ditriazolyl cumanin derivative (11) proved to be more active and selective than cumanin in the tested breast, cervix, lung, and colon tumor cell lines. This compound was the least toxic against splenocytes (CC50 = 524.1 µM) and exhibited the greatest selectivity on tumor cell lines. This compound showed a GI50 of 2.3 µM and a SI of 227.9 on WiDr human colon tumor cell lines. Thus, compound 11 can be considered for further studies and is a candidate for the development of new antitumor agents.


Assuntos
Lactonas/química , Sesquiterpenos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Humanos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Sesquiterpenos de Guaiano
9.
AIDS Behav ; 22(6): 1713-1724, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28501964

RESUMO

Safer conception interventions reduce HIV incidence while supporting the reproductive goals of people living with or affected by HIV. We developed a consensus statement to address demand, summarize science, identify information gaps, outline research and policy priorities, and advocate for safer conception services. This statement emerged from a process incorporating consultation from meetings, literature, and key stakeholders. Three co-authors developed an outline which was discussed and modified with co-authors, working group members, and additional clinical, policy, and community experts in safer conception, HIV, and fertility. Co-authors and working group members developed and approved the final manuscript. Consensus across themes of demand, safer conception strategies, and implementation were identified. There is demand for safer conception services. Access is limited by stigma towards PLWH having children and limits to provider knowledge. Efficacy, effectiveness, safety, and acceptability data support a range of safer conception strategies including ART, PrEP, limiting condomless sex to peak fertility, home insemination, male circumcision, STI treatment, couples-based HIV testing, semen processing, and fertility care. Lack of guidelines and training limit implementation. Key outstanding questions within each theme are identified. Consumer demand, scientific data, and global goals to reduce HIV incidence support safer conception service implementation. We recommend that providers offer services to HIV-affected men and women, and program administrators integrate safer conception care into HIV and reproductive health programs. Answers to outstanding questions will refine services but should not hinder steps to empower people to adopt safer conception strategies to meet reproductive goals.


Assuntos
Antirretrovirais/uso terapêutico , Circuncisão Masculina , Fertilização , Infecções por HIV/prevenção & controle , Acessibilidade aos Serviços de Saúde , Profilaxia Pré-Exposição , Comportamento Reprodutivo , Adulto , Criança , Características da Família , Feminino , Fertilidade , Infecções por HIV/tratamento farmacológico , Heterossexualidade , Humanos , Inseminação Artificial , Masculino , Cuidado Pré-Concepcional , Gravidez , Saúde Reprodutiva , Serviços de Saúde Reprodutiva , Sexo Seguro , Parceiros Sexuais , Estigma Social
10.
BMC Psychiatry ; 17(1): 28, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28100197

RESUMO

BACKGROUND: Time and resource efficient mental disorder screening mechanisms are not available to identify the growing number of refugees and other forcibly displaced persons in priority need for mental health care. The aim of this study was to identify efficient screening instruments and mechanisms for the detection of moderate and severe mental disorders in a refugee setting. METHODS: Lay interviewers applied a screening algorithm to detect individuals with severe distress or mental disorders in randomly selected households in a Palestinian refugee camp in Beirut, Lebanon. The method included household informant and individual level interviews using a Vignettes of Local Terms and Concepts for mental disorders (VOLTAC), individual and household informant portions of the field-test version of the WHO-UNHCR Assessment Schedule of Serious Symptoms in Humanitarian Settings (WASSS) and the WHO Self Reporting Questionnaire (SRQ-20). A subset of participants were then reappraised utilizing the Mini International Neuropsychiatric Interview (MINI), WHO Disability Assessment Schedule II, and the Global Assessment of Functioning. The study constitutes a secondary analysis of interview data from 283 randomly selected households (n = 748 adult residents) who participated in a mental health disorders prevalence study in 2010. RESULTS: The 5-item household informant portion of WASSS was the most efficient instrument among those tested. It detected adults with severe mental disorders with 95% sensitivity and 71% specificity (Area Under Curve (AUC) = 0.85) and adults with moderate or severe mental disorder with 85.1% sensitivity and 74.8% specificity (AUC = 0.82). The complete screening algorithm demonstrated 100% sensitivity and 58% specificity. CONCLUSIONS: Our results suggest that a two phase, screen-confirm approach is likely a useful strategy to detect incapacitating mental disorders in humanitarian contexts where mental health specialists are scarce, and that in the context of a multi-step screen confirm mechanism, the household informant portion of field-test version of the WASSS may be an efficient screening tool to identify adults in greatest need for mental health care in humanitarian settings.


Assuntos
Árabes/psicologia , Programas de Rastreamento/métodos , Transtornos Mentais/diagnóstico , Avaliação das Necessidades/estatística & dados numéricos , Refugiados/psicologia , Adulto , Área Sob a Curva , Estudos Transversais , Características da Família , Feminino , Humanos , Líbano/epidemiologia , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Inquéritos e Questionários , Adulto Jovem
13.
Mol Psychiatry ; 20(11): 1339-49, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25687775

RESUMO

Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/genética , Transtornos da Memória/patologia , Receptores A2 de Adenosina/metabolismo , Transdução de Sinais/genética , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Membrana Celular/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Células HEK293 , Hipocampo/efeitos dos fármacos , Humanos , Técnicas In Vitro , Luz , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Fenetilaminas/farmacologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Receptores A2 de Adenosina/genética , Transdução de Sinais/efeitos dos fármacos , Sinaptossomos/metabolismo , Transfecção
14.
J Infect Dis ; 211(5): 698-707, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25160983

RESUMO

We have reported that attenuated Salmonella (S) carrying plasmids encoding the cysteine protease cruzipain (Cz) protects against Trypanosoma cruzi infection. Here, we determined whether immunoprotection could be improved by the oral coadministration of 3 Salmonella carrying the plasmids that encode the antigens Cz, Tc52, and Tc24. SCz+STc52+STc24-immunized mice presented an increased antibody response against each antigen compared with those in the single antigen-immunized groups, as well as higher trypomastigotes antibody-mediated lyses and cell invasion inhibition compared with controls. SCz+STc52+STc24-immunized and -challenged mice rendered lower parasitemia. Weight loss after infection was detected in all mice except those in the SCz+STc52+STc24 group. Moreover, cardiomyopathy-associated enzyme activity was significantly lower in SCz+STc24+STc52-immunized mice compared with controls. Few or no abnormalities were found in muscle tissues of SCz+STc24+STc52-immunized mice, whereas controls presented with inflammatory foci, necrosis, and amastigote nests. We conclude that a multicomponent approach that targets several invasion and metabolic mechanisms improves protection compared with single-component vaccines.


Assuntos
Doença de Chagas/prevenção & controle , Portadores de Fármacos , Vacinas Protozoárias/imunologia , Salmonella/genética , Trypanosoma cruzi/imunologia , Vacinas de DNA/imunologia , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Peso Corporal , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C3H , Miocárdio/patologia , Parasitemia/prevenção & controle , Vacinas Protozoárias/administração & dosagem , Vacinas Protozoárias/genética , Resultado do Tratamento , Trypanosoma cruzi/genética , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética
15.
Infect Immun ; 82(10): 4265-75, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25069980

RESUMO

In this work we immunized mice with DNA encoding full-length Tc52 or its amino- or carboxy-terminal (N- and C-term, respectively) domain carried by attenuated Salmonella as a DNA delivery system. As expected, Salmonella-mediated DNA delivery resulted in low antibody titers and a predominantly Th1 response, as shown by the ratio of IgG2a/IgG1-specific antibodies. Despite modest expression of Tc52 in trypomastigotes, the antibodies elicited by vaccination were able to mediate lysis of the trypomastigotes in the presence of complement and inhibit their invasion of mammal cells in vitro. The strongest functional activity was observed with sera from mice immunized with Salmonella carrying the N-term domain (SN-term), followed by Tc52 (STc52), and the C-term domain (SC-term). All immunized groups developed strong cellular responses, with predominant activation of Th1 cells. However, mice immunized with SN-term showed higher levels of interleukin-10 (IL-10), counterbalancing the inflammatory reaction, and also strong activation of Tc52-specific gamma interferon-positive (IFN-γ(+)) CD8(+) T cells. In agreement with this, although all prototypes conferred protection against infection, immunization with SN-term promoted greater protection than that with SC-term for all parameters tested and slightly better protection than that with STc52, especially in the acute stage of infection. We conclude that the N-terminal domain of Tc52 is the section of the protein that confers maximal protection against infection and propose it as a promising candidate for vaccine development.


Assuntos
Doença de Chagas/prevenção & controle , Portadores de Fármacos , Vetores Genéticos , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/imunologia , Salmonella typhimurium/genética , Animais , Anticorpos Antiprotozoários/sangue , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C3H , Dados de Sequência Molecular , Proteínas de Protozoários/genética , Vacinas Protozoárias/administração & dosagem , Vacinas Protozoárias/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Análise de Sequência de DNA , Análise de Sobrevida , Células Th1/imunologia , Resultado do Tratamento
16.
Br J Psychiatry ; 204(3): 208-13, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24029537

RESUMO

BACKGROUND: Studies have shown high levels of distress and mental disorder among people living in refugee camps, yet none has confirmed diagnosis through clinical reappraisal. AIMS: To estimate the prevalence of mental disorders, related disability and treatment gap in adult refugees living in the Burj el-Barajneh camp. METHOD: Randomly selected participants were screened by household representative (n = 748) and individual (n = 315) interviews; clinical reappraisal was performed on a subset (n = 194) of 326 selected participants. Weighted prevalence estimates and 95% confidence intervals were calculated. RESULTS: The prevalence of current mental disorders was 19.4% (95% CI 12.6-26.2); depression was the most common diagnosis (8.3%, 95% CI 4.4-12.2) and multiple diagnoses were common (42%) among the 88 persons with mental disorder. Lifetime prevalence of psychosis was 3.3% (95% CI 1.0-5.5). Mental disorders were associated with moderate to severe dysfunction (odds ratio = 8.8, 95% CI 4.5-17.4). The treatment gap was 96% (95% CI 92-100). CONCLUSIONS: A range of mental disorders and associated disability are common in this long-term refugee setting. Combined with an important treatment gap, findings support the current consensus-based policy to prioritise availability of mental health treatment in refugee camps, especially for the most severe and disabling conditions.


Assuntos
Avaliação da Deficiência , Transtornos Mentais/epidemiologia , Refugiados/psicologia , Adulto , Estudos Transversais , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Líbano/epidemiologia , Masculino , Prevalência , Adulto Jovem
17.
ACS Med Chem Lett ; 15(6): 873-878, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38894931

RESUMO

Austroeupatol, the principal diterpene isolated from the invasive shrub Austroeupatorium inulifolium, holds promise for structural diversification and biological assessment of its derivatives due to its abundant availability and high yield isolation. We propose an efficient enzymatic synthesis of a series of austroeupatol esters derived from aliphatic and heterocyclic carboxylic acids. Systematic optimization of reaction parameters, including enzyme type and quantity, acylating agent amount, solvent, and temperature, was conducted. Thermomyces lanuginosus lipase in cyclohexane at 55 °C, yielded esters with favorable conversion rates. Through enzymatic catalysis, mono- and diacylated derivatives were obtained, with a diacylation-monoacylation ratio influenced by temperature and acylating agent amount. The antiprotozoal activity of austroeupatol and all synthesized derivatives was evaluated, observing that acylation improved it. The 19-valeroyl, 19-indolylpropyl, and 19-octyl derivatives were the most potent compounds against Trypanosoma cruzi and Leishmania infantum, highlighting this approach as a valuable method for synthesizing austroeupatol derivatives as potential antiparasitic agents.

18.
Cureus ; 16(7): e65678, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39077673

RESUMO

Introduction Our study aimed to compare meditation and compassion-based group therapy with the standard of care in patients with eating disorders, drug addiction, alcohol addiction, and depression, concerning acceptance, mindfulness awareness, self-compassion, and psychological distress. Methods A controlled designed study was performed, comparing meditation and compassion-focused group therapy added to the standard of care with the standard of care alone, on patients with eating disorders, drug addiction, alcohol addiction, and mood disorders. Four validated questionnaires were administered: the Acceptance and Action Questionnaire-II (AAQ-II), which assesses the ability to be fully in touch with the present moment; the Mindful Attention Awareness Scale (MAAS), which assesses the ability to experience consciously what is happening in the present moment; the Self-Compassion Scale (SCS), which assesses self-compassion characteristics, including loving-kindness; and the Symptom Checklist-90 (SCL-90), which measures psychological distress (anxiety, depression, psychotic behavior, etc.). Results There was a total of 75 subjects, out of which 48 represented the experimental group, and 27 represented the control group. The overall mean age of the subjects was 44.8 ± 13.2 years. There were statistically significant increases in the experimental group (baseline vs. end of study) for the AAQ-II, MAAS, and SCS scores, and a statistically significant decrease in the SCL-90 score. In the control group, there was a statistically significant decrease in the SCL-90 score, but no significant differences for other measurements. The comparisons between the two groups at the end of the study were as follows: AAQ-II: 0.7 (-5.74 to 7.15), p = 0.827; MAAS: 4.78 (-3.19 to 12.75), p = 0.233; SCS: 5.89 (-3.18 to 14.96), p = 0.199; SCL-90: -0.26 (-0.62 to 0.1), p = 0.157. Conclusion Within the experimental group, all scales improved statistically significantly. There were no statistically significant differences at the end of the study concerning the four scales between the groups. The comparison between groups was limited by data availability.

19.
Confl Health ; 18(1): 61, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39415274

RESUMO

BACKGROUND: Conflict-related sexual violence (CRSV) is a significant health and human rights issue in humanitarian contexts, but there is a need of further research on differences between sexes in terms of severity of symptoms and improvement. Consequently, we explored the differences in severity and outcomes among male and female survivors of CRSV who received mental health and psychosocial support (MHPSS) in an armed conflict setting. METHODS: We retrospectively analysed medical records from 3442 CRSV survivors in a MHPSS programme in Borno State, Nigeria, between 2018 and 2019. Patient characteristics, severity (measured with Clinical Global Impression of Severity Scale [CGI-S scale]), and improvement (measured with Clinical Global Impression of improvement [CGI-I] scale) were assessed by an attending counsellor. We assessed predictors for severity and improvement using a multivariable logistic regression analysis and time to improvement by sex using Kaplan Meier (K-M) curves and Cox regression. RESULTS: We included 3442 patients who had at least one CRSV event in this study (2955 [85.9%] female, 486 [14.1%] male, one unknown). The most prevalent categories of symptoms were depression (49.9%; n = 1716), post-traumatic (25.6%; n = 879), and anxiety (20.3%; n = 697) symptoms. Most patients had mild (59.0%; n = 1869/3170) or moderate (36.4%; n = 1153/3170) symptoms at baseline, with 4.7% having severe symptoms (n = 148/3170). The logistic regression analysis (n = 1106), showed male patients had a 59% higher odds of severe symptoms at baseline than female patients (aOR 1.59; 95% CI 1.04-2.45). Among males, those older than 55 years had three times higher odds of presenting severe symptoms than younger patients (aOR 3.65; 95% CI 1.43-9.34). Women aged 36-55 years were more likely to present improvement than younger female patients (aOR 1.32; 95% CI 1.11-1.58). For both sexes, prompt attention after a CRSV event (≤ 3 days) positively predicted improvement (aOR 13.9; 95% CI 1.48-130 males, aOR 2.11; 95% CI 1.22-3.64 females) compared to late attention. Time to improvement did not differ between sexes, with an average of at least three consultations needed to achieve improvement. CONCLUSIONS: Our study suggests that psychological attention of survivors within the first 72 h should be a priority. MHPSS programmes addressing CRSV should be inclusive to all patients, and gender-neutral approaches to ensure access, safety, confidentiality, and non-discrimination for all survivors should be developed.

20.
J Neurointerv Surg ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38960699

RESUMO

We present the first reported case that describes the complete resolution of a meningioma following endovascular embolization. A man in his 70s who presented with gait abnormalities and recurrent falls was diagnosed with normal pressure hydrocephalus (NPH) and found to have a small incidental meningioma. Due to ventriculoperitoneal (VP) shunt placement for cerebrospinal fluid diversion, the patient developed a bilateral subdural hematoma (SDH) requiring evacuation and drain placement. The patient also underwent bilateral middle meningeal artery (MMA) embolization. During the embolization, the known right frontal meningioma was embolized as it was supplied by the right MMA. The patient remained neurologically stable after this procedure. His follow-up magnetic resonance imaging (MRI) 1 year and 2 years after the procedure demonstrated complete resolution of the meningioma.

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