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1.
Artigo em Inglês | MEDLINE | ID: mdl-38244610

RESUMO

OBJECTIVE: To determine the prevalence and predictive factors of visual manifestations in a large registry of patients with GCA. METHODS: ARTESER is a large Spanish multicentre registry supported by the Spanish Society of Rheumatology. It includes patients with GCA from across the entire country diagnosed between June 2013 and March 2019. The variables collected at diagnosis were demographics, clinical manifestations (including all visual manifestations), laboratory, temporal artery biopsy, and imaging findings (ultrasound, FDG-PET/CT, MRI angiography, CT angiography). Patients with and without visual involvement were compared in a bivariate analysis. Multivariate logistic regression was performed to determine potential predictive factors of visual manifestations. RESULTS: The study population comprised 1636 GCA patients, of whom 599 (36.6%) presented visual manifestations. Anterior ischemic optic neuropathy was the most frequent (n = 274 of 599; 45.7%) ocular complication. The independent predictors that increased the risk (OR; 95% confidence interval) of visual involvement were older age (1.027; 1.009-1.045) and jaw claudication (1.724; 1.325-2.243). The variables associated with a reduced risk were polymyalgia rheumatica (0.541; 0.414-0.708), fever (0.373; 0.264-0.527), longer symptom duration (0.946; 0.909-0.985), and higher erythrocyte sedimentation rate (ESR) (0.992; 0.988-0.997), common features of patients with large vessel-GCA. CONCLUSION: One-third of GCA patients present visual manifestations at diagnosis. Older age and jaw claudication are independent predictors of visual manifestations, whereas polymyalgia rheumatica, fever, longer symptom duration, and high ESR reduce the risk of visual involvement.

2.
Graefes Arch Clin Exp Ophthalmol ; 262(5): 1443-1453, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38197992

RESUMO

PURPOSE: The main purpose of this study was to perform an immunohistochemical, functional, and anatomical evaluation of patients with idiopathic epiretinal membrane (ERM). METHODS: Twenty-four specimens of idiopathic ERM from 24 consecutive patients who underwent 23 G pars plana vitrectomy for ERM and internal limiting membrane (ILM) peeling at the San Juan University Hospital in Alicante (Spain) in 2019 were analyzed. All patients underwent a complete ophthalmological examination including measurement of best corrected visual acuity (BCVA) and macular analysis by spectral-domain optical coherence tomography (SD-OCT) at the time of diagnosis and 3 months after surgery. Specific glial fibrillar acid protein antibodies (GFAP) and S100 calcium-binding protein ß (S100ß) immunostaining markers were used to identify the macroglial component of the ERM, Müller cells, and astrocytes. Ionized calcium-binding adapter molecule 1 protein (Iba1) antibodies were used as specific markers for inflammatory cells, such as microglia and macrophages. RESULTS: Mean preoperative BCVA measured with Snellen chart was 0.3 and 0.6 preoperatively and at 3 months after surgery, respectively. SD-OCT identified 15 patients (62.5%) with a disruption of the outer retinal hyperreflective bands. The immunohistochemical study showed the presence of Müller cells in almost all cases (91.6%), as well of abundant microglia and macrophages. Microglia and macrophages were more frequently present in earlier stages of ERM. Microglia were present in ERM independently of the outer retinal hyperreflective bands integrity as measured by SD-OCT. A greater presence of macrophages was found in those ERMs with no outer retinal hyperreflective band disruption. CONCLUSIONS: Müller cells seem to be the most frequent cell group in ERMs, with also presence of microglia cells and macrophages. Astrocytes were more frequently found in early stages of ERMs. Microglia and macrophages were most frequent in ERMs with early stage (1, 2, or 3) than in advanced stages (4).


Assuntos
Membrana Epirretiniana , Humanos , Membrana Epirretiniana/diagnóstico , Membrana Epirretiniana/cirurgia , Retina , Vitrectomia/métodos , Membrana Basal/cirurgia , Tomografia de Coerência Óptica/métodos , Estudos Retrospectivos
3.
J Clin Child Adolesc Psychol ; 53(1): 98-113, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-36689641

RESUMO

OBJECTIVE: As a result of the COVID-19 pandemic, Latinx youth report high rates of negative mental health outcomes such as anxiety and depression. Similarly, research with lesbian, gay, bisexual, transgender, and queer (LGBTQ) youth have documented increased negative mental health outcomes such as depression and anxiety as a result of the COVID-19 pandemic. However, the current literature has yet to systematically uncover the intersectional experiences of Latinx LGBTQ youth during this time. METHOD: We conducted a systematic review to uncover the experiences of Latinx LGBTQ youth during the pandemic. Our systematic review resulted in 14 empirical studies that explored the challenges, stressors, and impact of the COVID-19 pandemic on Latinx LGBTQ youth. RESULTS: Findings revealed that most studies include cisgender, gender binary, heterosexual, Latinx youth. Findings across studies include: (a) impact from school closures, (b) pandemic stressors, (c) impact from online media, (d) family and Latinx cultural values as a source of support and stress, and (e) the implementation and evaluation of interventions during the COVID-19 pandemic. DISCUSSION: We provide recommendations for clinicians working with Latinx LGBTQ youth including expanding their knowledge about the impact of the COVID-19 pandemic on these communities, considering the experiences of Latinx LGBTQ youth as multifaceted, and considering the role of heterogeneity in the mental health of Latinx LGBTQ Youth.


Assuntos
COVID-19 , Minorias Sexuais e de Gênero , Adolescente , Humanos , Hispânico ou Latino , Pandemias , Bem-Estar Psicológico
4.
Clin Exp Rheumatol ; 41(4): 829-836, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36377586

RESUMO

OBJECTIVES: Tocilizumab (TCZ) is the only biologic therapy approved for giant cell arteritis (GCA). There is general agreement on the initial/maintenance dose, duration of TCZ therapy is not well established. In GiACTA trial, after one year on TCZ, most patients had GCA relapse after withdrawal. The aim of this study is to assess the effectiveness and safety of TCZ therapy optimisation in a large unselected series of patients with GCA in a clinical practice scenario. METHODS: We carried out a multicentre study on 471 GCA patients treated with TCZ. Once prolonged remission was achieved (n=231) and based on a decision between patient and physician, TCZ was optimised (n=125). We compared optimised (TCZOPT) and not optimised (TCZNON-OPT) groups. Prolonged remission defined as normalisation of clinical and laboratory data for 6 months. Optimisation was carried out by decreasing TCZ dose and/or increasing dosing interval. RESULTS: We evaluated 231 GCA patients on TCZ in prolonged remission. At TCZ onset, no differences in demographic, clinical, or laboratory data were observed. First TCZ optimisation was performed after a median follow-up of 12[6-17] months. Intravenous TCZ was optimised from 8 to 4mg/kg/4weeks in 44% patients, while subcutaneous TCZ was optimised from 162mg/w to 162mg/every-other-week in 65% cases. At the end of follow-up, prolonged remission (78.2% vs. 84.2%; p=0.29) and relapses (5.6% vs. 10.4%, p=0.177) were similar in TCZOPT vs. TCZNON-OPT. Severe infections were more frequent in TCZNON-OPT (12.9% vs. 6.6%; p=0.009). CONCLUSIONS: TCZ optimisation may be done once complete remission is achieved by reducing dose or increasing dosing interval. This seems to be effective, safe and cost-effective therapeutic scheme.


Assuntos
Arterite de Células Gigantes , Humanos , Arterite de Células Gigantes/tratamento farmacológico , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/efeitos adversos , Glucocorticoides/uso terapêutico , Recidiva
5.
Proc Natl Acad Sci U S A ; 116(19): 9318-9323, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30962368

RESUMO

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.


Assuntos
Antiprotozoários/administração & dosagem , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/diagnóstico por imagem , Inibidores de Proteassoma/administração & dosagem , Proteínas de Protozoários/antagonistas & inibidores , Animais , Antiprotozoários/química , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Leishmania donovani/química , Leishmania donovani/enzimologia , Leishmania infantum/química , Leishmania infantum/enzimologia , Leishmaniose Visceral/parasitologia , Masculino , Camundongos , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo
6.
Clin Exp Rheumatol ; 39 Suppl 132(5): 37-42, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886457

RESUMO

OBJECTIVES: Anti-IL6R tocilizumab (TCZ) therapy has proved to be useful in the treatment of refractory ocular and/or neurological involvement of Behçet's disease (BD). However, TCZ efficacy in other BD manifestations remains unclear. In this study we aimed to assess the efficacy of TCZ in the different clinical phenotypes of BD. METHODS: This is a multicentre study of BD patients treated with TCZ, due to refractivity to standard systemic treatment. RESULTS: We studied 16 patients (10 men/6 women); mean age 36.5±18.2 years. The main clinical manifestations at TCZ onset were ocular, oral and/or genital ulcers, arthritis, folliculitis and/or neurological involvement. Before TCZ, they had received several conventional and/or biological immunosuppressants, such as methotrexate, cyclosporine, adalimumab or infliximab. TCZ was used in monotherapy or combined with conventional immunosuppressive drugs. The main indications for TCZ prescription were refractory uveitis (n=14) and refractory neurobehçet (n=2). After a median [IQR] follow-up of 20 [9-45] months using TCZ, neurological and ocular domains improved in most cases with complete remission in most patients with uveitis. Articular and peripheral venous manifestations also experienced a favourable evolution. However, oral/genital ulcers, skin lesions and intestinal manifestations followed a torpid course. CONCLUSIONS: TCZ is effective in BD with major clinical involvement. However, it does not seem to be effective in oral/genital ulcers or skin lesions.


Assuntos
Síndrome de Behçet , Uveíte , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Uveíte/etiologia , Adulto Jovem
7.
Ann Vasc Surg ; 70: 341-348, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32599110

RESUMO

BACKGROUND: Bypass surgery remains the gold standard for long and complex arterial occlusions in the lower limb. The vein is regarded superior to prosthetic conduits in peripheral arterial bypass surgery. However, this option is often limited because of previous bypass, stripping, or poor quality of the ipsilateral and/or contralateral great saphenous vein (GSV). Under these circumstances, the arm vein (AV) and small saphenous vein (SSV) are the only alternative autologous vein grafts. METHODS: We analyzed all consecutive patients treated at an academic tertiary referral center between January 1998 and July 2018 using either the AV or SSV as the main peripheral bypass graft. Study end points were primary patency, secondary patency, limb salvage, and survival. RESULTS: In total, 416 bypass procedures using exclusively AV (n = 327) or SSV (n = 89) were performed. There was a predominance of male gender. The majority of risk factors were evenly distributed between groups. The mean follow-up period was 2.3 years (0.9 to 13.3 years). Five-year primary and secondary patency rates were 39% (95% CI: 31-47%) and 67% (59-75%) for AV and 53% (41-66%) and 76% (67-86%) for SSV, respectively (P = 0.2 and 0.25). The five-year limb salvage and survival rates were 71% (68-81%) and 84% (77-90%) for AV and 78% (67-88%) and 90% (82-98%) for SSV, respectively (P = 0.52 and 0.11). CONCLUSIONS: Both AV and SSV are equally effective alternatives for peripheral bypass if no GSV is available. Although there was a trend toward better results with the SSV, there was no significant difference between the 2 options.


Assuntos
Braço/irrigação sanguínea , Doença Arterial Periférica/cirurgia , Veia Safena/transplante , Enxerto Vascular , Adulto , Idoso , Idoso de 80 Anos ou mais , Amputação Cirúrgica , Feminino , Humanos , Salvamento de Membro , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Enxerto Vascular/efeitos adversos , Enxerto Vascular/mortalidade , Grau de Desobstrução Vascular
8.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924714

RESUMO

Oxidative stress has been postulated as an underlying pathophysiologic mechanism of diabetic retinopathy (DR), the main cause of avoidable blindness in working-aged people. This review addressed the current daily clinical practice of DR and the role of antioxidants in this practice. A systematic review of the studies on antioxidant supplementation in DR patients was presented. Fifteen studies accomplished the inclusion criteria. The analysis of these studies concluded that antioxidant supplementation has a IIB level of recommendation in adult Type 1 and Type 2 diabetes mellitus subjects without retinopathy or mild-to-moderate nonproliferative DR without diabetic macular oedema as a complementary therapy together with standard medical care.


Assuntos
Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Suplementos Nutricionais , Administração Oral , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/fisiopatologia , Humanos , Fatores de Risco
9.
J Enzyme Inhib Med Chem ; 35(1): 199-210, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752556

RESUMO

Previous reports have validated the glycogen synthase kinase-3 (GSK-3) as a druggable target against the human protozoan parasite Leishmania. This prompted us to search for new leishmanicidal scaffolds as inhibitors of this enzyme from our in-house library of human GSK-3ß inhibitors, as well as from the Leishbox collection of leishmanicidal compounds developed by GlaxoSmithKline. As a result, new leishmanicidal inhibitors acting on Leishmania GSK-3 at micromolar concentrations were found. These inhibitors belong to six different chemical classes (thiadiazolidindione, halomethylketone, maleimide, benzoimidazole, N-phenylpyrimidine-2-amine and oxadiazole). In addition, the binding mode of the most active compounds into Leishmania GSK-3 was approached using computational tools. On the whole, we have uncovered new chemical scaffolds with an appealing prospective in the development and use of Leishmania GSK-3 inhibitors against this infectious protozoan.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Leishmania/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Leishmania/citologia , Leishmania/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
10.
Am J Obstet Gynecol ; 221(4): 320.e1-320.e23, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31121144

RESUMO

BACKGROUND: Although uterine leiomyomas and leiomyosarcomas are considered biologically unrelated tumors, they share morphologic and histologic characteristics that complicate their differential diagnosis. The long-term therapeutic option for leiomyoma is laparoscopic myomectomy with morcellation, particularly for patients who wish to preserve their fertility. However, because of the potential dissemination of undiagnosed or hidden leiomyosarcoma from morcellation, there is a need to develop a preoperative assessment of malignancy risk. OBJECTIVE: Through an integrated comparative genomic and transcriptomic analysis, we aim to identify differential genetic targets in leiomyomas vs leiomyosarcomas using next-generation sequencing as the first step toward preoperative differential diagnosis. STUDY DESIGN: Targeted sequencing of DNA and RNA coding regions for solid tumor-associated genes was performed on formalin-fixed paraffin-embedded samples from 13 leiomyomas and 13 leiomyosarcoma cases. DNA sequencing was used to identify copy number variations, single-nucleotide variants, and small insertions/deletions. RNA sequencing was used to identify gene fusions, splice variants, and/or differential gene expression profiles. RESULTS: In leiomyosarcomas, tumor mutation burden was higher in terms of copy number variations, single nucleotide variants, small insertions/deletions, and gene fusions compared with leiomyomas. For copy number variations, 20 genes were affected by deletions in leiomyosarcomas, compared with 6 observed losses in leiomyomas. Gains (duplications) were identified in 19 genes in leiomyosarcomas, but only 3 genes in leiomyomas. The most common mutations (single-nucleotide variants and insertions/deletions) for leiomyosarcomas were identified in 105 genes of all analyzed leiomyosarcomas; 82 genes were affected in leiomyomas. Of note, 1 tumor previously diagnosed as leiomyosarcoma was established as inflammatory myofibroblastic tumor along this study with a novel ALK-TNS1 fusion. Finally, a differential transcriptomic profile was observed for 11 of 55 genes analyzed in leiomyosarcomas; 8.5% of initially diagnosed leiomyosarcomas showed high-confidence, novel gene fusions that were associated with these tumors. CONCLUSION: Through integrated comparative genomic and transcriptomic analyses, we identified novel differential genetic targets that potentially differentiate leiomyosarcomas and leiomyomas. This provides a new insight into the differential diagnosis of these myometrial tumors.


Assuntos
Leiomioma/diagnóstico , Leiomiossarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Idoso , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Feminino , Deleção de Genes , Duplicação Gênica , Perfilação da Expressão Gênica , Fusão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leiomioma/genética , Leiomiossarcoma/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Análise de Sequência de RNA , Neoplasias Uterinas/genética
11.
Ann Vasc Surg ; 57: 272.e1-272.e4, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30684616

RESUMO

Management of recurrent thoracoabdominal aneurysmal disease of the aorta is challenging. We report three patients with previous endovascular or open aortic repair requiring redo repair by treatment by stent-graft implantation of the thoracoabdominal aorta and visceral debranching using an antegrade inflow from the ascending aorta. All three interventions were successful, with two patients alive 5 and 2 years, respectively, after this operation, while the third patient died 2 days after the procedure due to cardiac failure. No paraplegia was observed. As complications from complex open and endovascular procedures are increasing, vascular surgeons should get familiar with alternative management options.


Assuntos
Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/métodos , Procedimentos Endovasculares/métodos , Idoso , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aortografia/métodos , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Angiografia por Tomografia Computadorizada , Progressão da Doença , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Humanos , Masculino , Pessoa de Meia-Idade , Reoperação , Fatores de Tempo , Resultado do Tratamento
12.
Ann Vasc Surg ; 60: 264-269, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31075469

RESUMO

BACKGROUND: Bypass in the upper extremity is a rare procedure mainly performed for chronic ischemia, trauma, or hemodialysis access complications. Feasibility and success of use of the arm vein and small saphenous vein (SSV) for autologous vein bypass have been reported in peripheral artery bypass procedures. There are very few reports on the use of alternative veins in upper extremity bypass. We report our experience with arm vein and SSV as a graft source in upper extremity arterial disease. METHODS: Retrospective analysis of a consecutively collected case series in an academic tertiary referral center from January 2010 to February 2018. Study end points were primary patency, secondary patency, limb salvage, and survival. RESULTS: In total, 47 patients were treated with upper extremity bypass either using the SSV (n = 17) or arm veins (n = 30). Indications were either acute (n = 12) or chronic ischemia (n = 35) caused by acute (n = 8) and chronic (n = 9) trauma, sequela of iatrogenic interventions (n = 4), peripheral artery disease (n = 14), thrombangiitis obliterans (n = 3), and dialysis-access-related complications (n = 9). An arm vein was used in 30 and the SSV in 17 patients. Primary patency after 12 months was 87% with the SSV and 75% with an arm vein (P = 0.8) and 63% and 75% after 36 months (P = 0.9). Secondary patency were 100% with an arm vein and 100% with the SSV after 36 months (P = 0.4). One patient had to undergo major amputation and 2 minor amputations. CONCLUSIONS: Arm vein revascularization using the primarily arm vein or SSV as a bypass conduit can be performed with reasonable mortality and morbidity rates and provide good results comparable with the greater saphenous vein.


Assuntos
Isquemia/cirurgia , Veia Safena/transplante , Extremidade Superior/irrigação sanguínea , Enxerto Vascular/métodos , Adulto , Idoso , Feminino , Oclusão de Enxerto Vascular/etiologia , Oclusão de Enxerto Vascular/fisiopatologia , Oclusão de Enxerto Vascular/terapia , Humanos , Isquemia/diagnóstico por imagem , Isquemia/mortalidade , Isquemia/fisiopatologia , Salvamento de Membro , Masculino , Pessoa de Meia-Idade , Retratamento , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Enxerto Vascular/efeitos adversos , Enxerto Vascular/mortalidade , Grau de Desobstrução Vascular
13.
Artigo em Inglês | MEDLINE | ID: mdl-29463533

RESUMO

With the World Health Organization reporting over 30,000 deaths and 200,000 to 400,000 new cases annually, visceral leishmaniasis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet need to improve treatment. Miltefosine remains one of the main treatments for leishmaniasis, yet its mode of action (MoA) is still unknown. Understanding the MoA of this drug and parasite response to treatment could help pave the way for new and more successful treatments for leishmaniasis. A novel method has been devised to study the metabolome and lipidome of Leishmania donovani axenic amastigotes treated with miltefosine. Miltefosine caused a dramatic decrease in many membrane phospholipids (PLs), in addition to amino acid pools, while sphingolipids (SLs) and sterols increased. Leishmania major promastigotes devoid of SL biosynthesis through loss of the serine palmitoyl transferase gene (ΔLCB2) were 3-fold less sensitive to miltefosine than wild-type (WT) parasites. Changes in the metabolome and lipidome of miltefosine-treated L. major mirrored those of L. donovani A lack of SLs in the ΔLCB2 mutant was matched by substantial alterations in sterol content. Together, these data indicate that SLs and ergosterol are important for miltefosine sensitivity and, perhaps, MoA.


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/metabolismo , Leishmania major/metabolismo , Fosforilcolina/análogos & derivados , Serina C-Palmitoiltransferase/genética , Esfingolipídeos/metabolismo , Esteróis/metabolismo , Ergosterol/metabolismo , Humanos , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Lipídeos de Membrana/metabolismo , Metaboloma/efeitos dos fármacos , Metaboloma/genética , Fosfolipídeos/metabolismo , Fosforilcolina/farmacologia
14.
Antimicrob Agents Chemother ; 60(6): 3524-32, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27021313

RESUMO

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis, a disease potentially fatal if not treated. Current available treatments have major limitations, and new and safer drugs are urgently needed. In recent years, advances in high-throughput screening technologies have enabled the screening of millions of compounds to identify new antileishmanial agents. However, most of the compounds identified in vitro did not translate their activities when tested in in vivo models, highlighting the need to develop more predictive in vitro assays. In the present work, we describe the development of a robust replicative, high-content, in vitro intracellular L. donovani assay. Horse serum was included in the assay media to replace standard fetal bovine serum, to completely eliminate the extracellular parasites derived from the infection process. A novel phenotypic in vitro infection model has been developed, complemented with the identification of the proliferation of intracellular amastigotes measured by EdU incorporation. In vitro and in vivo results for miltefosine, amphotericin B, and the selected compound 1 have been included to validate the assay.


Assuntos
Anfotericina B/farmacologia , Antiprotozoários/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Leishmania donovani/crescimento & desenvolvimento , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Leishmania donovani/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Parasitária , Fosforilcolina/farmacologia
15.
Bioorg Med Chem ; 24(8): 1608-18, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26964673

RESUMO

Chagas disease is a tropical disease caused by the parasite Trypanosoma cruzi, which is endemic in Central and South America. Few treatments are available with effectiveness limited to the early (acute) stage of disease, significant toxicity and widespread drug resistance. In this work we report the outcome of a HTS-ready assay chemical library screen to identify novel, nontoxic, small-molecule inhibitors of T. cruzi. We have selected 50 compounds that possess hydrazone as a common group. The compounds were screened using recombinant T. cruzi (Tulahuen strain) expressing beta-galactosidase. A 3D quantitative structure-activity relationship (QSAR) analysis was performed using descriptors calculated from comparative molecular field analysis (CoMFA). Our findings show that of the fifty selected hydrazones, compounds LpQM-19, 28 and 31 displayed the highest activity against T. cruzi, leading to a selectivity index (SI) of 20-fold. The 3D-QSAR analysis indicates that a particular electrostatic arrangement, where electron-deficient atoms are aligned along the molecule main axis positively correlates with compound biological activity. These results provide new candidate molecules for the development of treatments against Chagas disease.


Assuntos
Hidrazonas/farmacologia , Relação Quantitativa Estrutura-Atividade , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Células NIH 3T3 , Testes de Sensibilidade Parasitária , Tripanossomicidas/síntese química , Tripanossomicidas/química
17.
Clin Exp Rheumatol ; 32(3 Suppl 82): S30-3, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24709033

RESUMO

OBJECTIVES: The Xq28 region, containing IRAK and MECP2, represent a common susceptibility locus for a high number of autoimmune diseases. Our aim in the present study was to evaluate the influence of the IRAK1 and MECP2 autoimmunity-associated genetic variants in the giant cell arteritis (GCA) susceptibility and its clinical subphenotypes. METHODS: We analysed a total of 627 female biopsy-proven GCA patients and 1,520 female healthy controls of Spanish Caucasian origin. Two polymorphisms, rs1059702 and rs17345, located at IRAK1 and MECP2, respectively, were genotyped using TaqMan® allelic discrimination assays. RESULTS: No association with any of the analysed polymorphisms was evident when genotype and allele frequencies were compared between GCA patients and controls (rs1059702: allelic p-value=0.699, OR=0.96, CI 95% 0.80-1.17; rs17435: allelic p-value=0.994, OR=1.00, CI 95% 0.84-1.19). Likewise, the subphenotype analysis yield similar negative results. CONCLUSIONS: We have assessed for the first time the possible role of IRAK1 and MECP2 autoimmune disease-associated polymorphisms in GCA. Our data suggest that IRAK1 rs1059702 and MECP2 rs17435 genetic variants do not play a significant role in GCA susceptibility or severity.


Assuntos
Artérias/patologia , Autoimunidade/genética , Arterite de Células Gigantes , Quinases Associadas a Receptores de Interleucina-1/genética , Proteína 2 de Ligação a Metil-CpG/genética , Idoso , Biópsia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Arterite de Células Gigantes/epidemiologia , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Humanos , Polimorfismo de Nucleotídeo Único , Espanha/epidemiologia , População Branca/genética
18.
J Fam Psychol ; 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38900543

RESUMO

Parental support is crucial in the well-being of transgender and gender diverse (TGD) youth. Research shows that parents of TGD youth often experience stigma and negative mental health outcomes as a result of being exposed to cissexist settings as they advocate and seek services for their child. Yet, there is a lack of research on the experiences of parents of TGD youth in the United States. This study explores the reported hopes of 990 parents (Mage = 48.6 years; SD = 6.7; 88.1% White; 67.3% heterosexual; 89.4% cisgender women) of TGD youth for their children (youth ages 3-18 years) in the United States. Radical hope framework is applied to unpack narratives of hopes by parents of TGD youth as a critical component of resistance and motivation toward healing from oppression. For this study, the following open-ended question was analyzed using thematic analysis: What is your greatest hope for your child? Four main themes and 11 subthemes of parental hopes emerged: (1) living authentically (freely expressing themselves, developing self-love, living a happy and normal life), (2) interpersonal connections (finding community, building social networks and friendships, developing romantic relationships, building their own family, and loved by others), (3) meeting life milestones (career and employment, achieving goals and dreams, and becoming an advocate), and (4) acceptance by society. We provide clinical recommendations grounded on the tenets of radical hope such as collective ways in which parents of TGD youth can engage in both resisting systemic oppression and building strong loving relationships with their child. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

19.
Eur J Intern Med ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38908981

RESUMO

OBJECTIVE: Aortitis in Giant Cell Arteritis (GCA-aortitis) is a frequent complication that may lead to aneurysms. Tocilizumab (TCZ) was approved in GCA, but the efficacy in GCA-aortitis and aneurysms has not been analyzed to date. Our aim was to assess the effectiveness and safety of TCZ in a wide series of GCA-aortitis and aneurysms. METHODS: Multicentre observational study with GCA-aortitis treated with TCZ. GCA was diagnosed by: a) ACR criteria, b) temporal artery biopsy, and/or c) imaging techniques. Aortitis was diagnosed mainly by PET/CT. Main outcomes were EULAR and imaging remission. Others were clinical remission, analytical normalization, corticosteroid-sparing effect, and the prevention and improvement of aneurysms. RESULTS: 196 patients with GCA-aortitis treated with TCZ. After 6 months, 72.2% reached EULAR remission but only 12% an imaging remission; increasing up-to 81.4% and 31.8%, respectively, at 24 months. A rapid clinical remission, ESR and CRP normalization was observed in 47.4%, 84.3% and 55.6%, at 1 month, increasing to 89.6%, 85.3% and 80.3% at 24 months, respectively. Aneurysms were present in 10 (5%) patients. Five of them required early surgery, while 3 others enlarged. No patient on TCZ therapy developed aneurysms during follow-up. CONCLUSION: In patients with GCA-aortitis treated with TCZ, a rapid and maintained clinical and analytical improvement was observed. However, there was an uncoupling between clinical and EULAR remission with imaging remission.

20.
Materials (Basel) ; 17(1)2023 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-38203955

RESUMO

The structural systems of residential buildings in many developed countries have widely utilized reinforced concrete as the most common solution in construction systems since the early 20th century. The durability of reinforced concrete columns and beams is compromised, in most cases, by pathologies caused by the corrosion of their reinforcements. This study analyses the corrosion processes induced by carbonation in 25 buildings with reinforced concrete structures. The models estimate the service life of reinforced concrete elements by differentiating between the initiation period and the propagation period of damage, considering two possible stages: the time of corrosion propagation until the cracking of the concrete cover, and the time of propagation until a loss of section is considered unacceptable for structural safety. However, the mathematical expressions that model the propagation periods consider the same corrosion rate in both cases. This research has found that the average corrosion rate in elements with an unacceptable loss of reinforcement section was in the order of 8 times higher than the corrosion rate in cracked columns and beams without a loss of reinforcement. This opens up a path to improve the definition of the different stages experienced by a reinforced concrete element suffering corrosion of its reinforcements due to carbonation, because once the concrete has cracked, the corrosion rate increases significantly.

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