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1.
J Surg Case Rep ; 2024(10): rjae585, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39364426

RESUMO

Steal syndrome is characterized by the disruption of blood flow from specific vascular territories due to perfusion via collateral vessels bypassing an obstructed artery segment. In the neurovascular setting, this can lead to entities such as subclavian steal syndrome or the less prevalent double steal phenomenon, primarily associated with atherosclerosis. We present a case of an early 80s patient with cerebrovascular insufficiency who exhibited neurological deficits during mastication. The angiographic evaluation showed occlusion at the origins of the left common carotid and of the brachiocephalic trunk. This configuration caused the left vertebral artery to be the only vessel filling anterograde. The flow in the right vertebral artery is retrograde, filling the subclavian and the right common carotid artery. Endovascular revascularization of the brachiocephalic trunk was successfully performed using a Gore Viabahn VBX Balloon Expandable Stent (W.L. Gore & Associates, Flagstaff, AZ, USA), leading to symptom resolution.

2.
J Neurointerv Surg ; 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39357888

RESUMO

BACKGROUND: The pipeline embolization device (PED) has been increasingly used to treat brain aneurysms; however, concerns have been raised about braid stability with newer drawn filled tubing technology devices. OBJECTIVE: To evaluate braid stability of PED early generations using data from the PREMIER trial. METHODS: All consecutive intracranial aneurysms treated with PED (Classic and Flex) within the PREMIER trial were reviewed for braid stability (fish mouthing, foreshortening, braid bump, braid collapsing). Immediate postprocedure cone-beam CT and angiography were compared with 1- and 2- years' follow-up. Analyses included safety, measured with the modified Rankin Scale (mRS) score, including +1 mRS point and a good clinical outcome (mRS score 0-2), vessel stenosis ≥50%, effectiveness measured with Raymond-Roy Scale, and re-treatment rates. RESULTS: 133/141 aneurysms had a complete dataset. 8/133 (6%) aneurysms showed braid deformations. Inter-reader agreement was excellent (κ=0.83). Braid deformations were statistically significantly associated with in-stent vessel stenosis >50% (P=0.029), without impact on effectiveness or safety. Fish mouthing was found in 1/133 (0.75%) at 1 year, causing >50% vessel stenosis. Foreshortening occurred in 6/133 (4.5%), and braid bump in 1/133 (0.75%) associated with severe in-stent stenosis. Four other cases (3.0%) of asymptomatic in-stent stenosis due to neointimal hyperplasia were seen without braid changes. No new braid stability deformations were found at the 2-year follow-up. CONCLUSION: Our study demonstrates excellent braid stability among patients treated with the PED Classic and Flex in the PREMIER trial. Within the uncommon braid changes observed, none affected the PED safety or efficacy. TRIAL REGISTRATION NUMBER: NCT02186561.

4.
Clin Neurol Neurosurg ; 244: 108396, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38981168

RESUMO

BACKGROUND: Some centers utilize ventriculopleural shunt (VPLS) for treating hydrocephalus when conventional approaches are not feasible. Nonetheless, the literature regarding this approach is scarce. PURPOSE: Evaluate the outcomes of VPLS through a single-arm meta-analysis. METHODS: Following PRISMA guidelines, the authors systematically searched for articles utilizing the VPLS in a cohort with more than four patients. Outcomes included: mortality, pleural effusion, number of patients who underwent revisions, obstructions, shunt migration, emphysema, and subdural hematoma. RESULTS: A total of 404 articles were reviewed, resulting in the inclusion of 13 retrospective studies encompassing 543 patients, with the majority being children (62.6 %). The median average follow-up period was 35.4 months (10-64.1). After analysis, results yielded a revision rate of 54 % (95 % CI: 44 %-64 %; I2=73 %). The most common complication observed was pleural effusion, with a post-analysis incidence of 16 % (95 % CI: 11 %-21 %; I2=63 %), followed by infections at 7 % (95 % CI: 4 %-10 %; I2=33 %). Shunt obstruction occurred in 13 % (95 % CI: 4 %-21 %; I2=84 %) of cases after analysis, while migrations, overdrainage, subdural hematoma, and cutaneous emphysema had minimal occurrence rates (0 %, 95 % CI: 0 %-1 %; I2=0 %). Notably, there were no reported cases of shunt-related mortality. CONCLUSION: VPLS can be considered when there are no other suitable options for placing the distal catheter. However, the notable rates of shunt revisions, pleural effusion, infections, and the inherent heterogeneity of outcomes currently limit the widespread adoption of VPLS. In this scenario, other alternatives should be given priority.


Assuntos
Derivações do Líquido Cefalorraquidiano , Hidrocefalia , Cavidade Pleural , Humanos , Derivações do Líquido Cefalorraquidiano/métodos , Derivações do Líquido Cefalorraquidiano/efeitos adversos , Hidrocefalia/cirurgia , Derrame Pleural/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Reoperação/estatística & dados numéricos , Resultado do Tratamento , Cavidade Pleural/cirurgia
5.
World Neurosurg ; 188: e59-e63, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38735565

RESUMO

OBJECTIVE: To evaluate variability in aneurysm detection and the potential of artificial intelligence (AI) software as a screening tool by comparing conventional computed tomography angiography (CTA) images (standard care) with AI software. METHODS: Neuroradiologists reviewed 770 CTA images and reported the presence or absence of saccular aneurysms. Subsequently, the images were analyzed by AI software. If the software suspected an aneurysm, it flagged the corresponding image. In cases where there was a mismatch between the radiologist's report and the AI findings, an expert neurosurgeon evaluated CTA images providing a definitive conclusion on the presence or absence of an aneurysm. RESULTS: AI software flagged 33 cases as potential aneurysms; 16 cases were positively identified as aneurysms by radiologists, and 17 were dismissed. A total of 737 cases were considered negative by AI software, while in the same group, radiologists identified aneurysms in 28 CTA images. Compared with the radiologist's report, AI performance had a sensitivity of 36%, specificity of 97.6%, and negative predictive value of 96.2%. There were 45 mismatch cases between AI and radiologists. AI flagged 17 images as showing an aneurysm that was unreported by radiologists; the expert neurosurgeon confirmed that 7 of the 17 images showed an aneurysm. In 28 images considered negative by AI, radiologists indicated aneurysms; 17 of those confirmed by the neurosurgeon. CONCLUSIONS: AI has the potential to increase the diagnosis of unruptured intracranial aneurysms. However, it must be used as an adjacent tool within the standard of care due to limited applicability in real-world settings.


Assuntos
Inteligência Artificial , Angiografia por Tomografia Computadorizada , Aneurisma Intracraniano , Software , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Feminino , Masculino , Angiografia por Tomografia Computadorizada/métodos , Pessoa de Meia-Idade , Idoso , Adulto , Angiografia Cerebral/métodos , Sensibilidade e Especificidade , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia
6.
Environ Monit Assess ; 196(6): 499, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38696108

RESUMO

Due to the anthropogenic pressures of expansion areas for livestock and agricultural production in the Brazilian Cerrado, it is of paramount importance to understand the dynamics of land use/land cover (LULC) changes in this region. Thus, we investigated LULC changes in two sub-basins of the Tocantins-Araguaia River basin from 1997 to 2015 and consequently projected future changes for the timespan between 2030 and 2050. The Formoso sub-basin experienced significant expansion of agricultural and pasture areas, whereas the Sono sub-basin limited farmland expansion (more stable native vegetation) due to substantial protected areas, trends that were also observed for future projections (2030 and 2050). Pastureland in the Formoso sub-basin increased by 5.8%, while the Sono sub-basin saw significant gains in cultivated land, according to change detection analyses during the 1997-2015 period. High stability probabilities of no change (> 70%) for grassland areas in the Sono River sub-basin and pasturelands in the Formoso River sub-basin were computed. The CA-Markov model demonstrated a high consistency level with actual LULC classes for both sub-basins, as indicated by an overall Kappa coefficient above 0.8. Future projections for 2030 and 2050 show a substantial expansion of agriculture and pasture in both sub-basins, driven by specific factors such as soil organic carbon stocks, distance from rural settlements, and proximity to rivers. Short- and mid-term simulations indicate substantial expansion of agriculture and pasture in both basins, with potential adverse impacts on water erosion. Consequently, developing policies for soil management and sustainable land use planning is essential for agroecosystem sustainability, promoting a balanced approach to economic development while addressing climate change and anthropogenic challenges.


Assuntos
Agricultura , Conservação dos Recursos Naturais , Monitoramento Ambiental , Rios , Rios/química , Monitoramento Ambiental/métodos , Brasil
7.
Artigo em Inglês | MEDLINE | ID: mdl-38781482

RESUMO

Aneurysm treatment presents various therapeutic options. Flow diverters (FD) stents are a revolutionizing endovascular technique for previously untreatable aneurysms.1 FD stents have documented success rates up to 95% and complication rates as low as 2.3%.2 This modality has proven its effectiveness and safety, but it is critical to consider potential complications. Complications include vascular-related problems such as perforation, occlusion, cerebral hyperperfusion, stent thrombosis, restenosis, and embolic events.3 To date, there is no standardized definition for braid collapse and fish-mouthing; however, braid collapse has been reported to occur at a rate of 1% and the latter at a rate of 3%.4 This technical video presents a case of a 51-year-old woman initially treated with a Surpass Evolve flow diverter (Stryker) for a right ophthalmic aneurysm. Secondary to device malapposition and collapse, she developed recurrent ischemic progressive neurologic impairment symptoms. The braid collapse was treated using a Pipeline Embolization device 3.25 × 20 mm (Medtronic) because this device exhibited a larger partial compressive force when compared with the 64-wire device.5 The procedure was uneventful and significantly improved the patient's neurologic symptoms. This technical video illustrates rescue stenting as a salvage intervention for FD collapse cases. The patient gave informed consent for surgery. Institutional review board approval was deemed unnecessary.

8.
Hum Vaccin Immunother ; 20(1): 2304393, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38497413

RESUMO

Current influenza vaccines could be augmented by including recombinant neuraminidase (rNA) protein antigen to broaden protective immunity and improve efficacy. Toward this goal, we investigated formulation conditions to optimize rNA physicochemical stability. When rNA in sodium phosphate saline buffer (NaPBS) was frozen and thawed (F/T), the tetrameric structure transitioned from a "closed" to an "open" conformation, negatively impacting functional activity. Hydrogen deuterium exchange experiments identified differences in anchorage binding sites at the base of the open tetramer, offering a structural mechanistic explanation for the change in conformation and decreased functional activity. Change to the open configuration was triggered by the combined stresses of acidic pH and F/T. The desired closed conformation was preserved in a potassium phosphate buffer (KP), minimizing pH drop upon freezing and including 10% sucrose to control F/T stress. Stability was further evaluated in thermal stress studies where changes in conformation were readily detected by ELISA and size exclusion chromatography (SEC). Both tests were suitable indicators of stability and antigenicity and considered potential critical quality attributes (pCQAs). To understand longer-term stability, the pCQA profiles from thermally stressed rNA at 6 months were modeled to predict stability of at least 24-months at 5°C storage. In summary, a desired rNA closed tetramer was maintained by formulation selection and monitoring of pCQAs to produce a stable rNA vaccine candidate. The study highlights the importance of understanding and controlling vaccine protein structural and functional integrity.


Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Influenza Humana/prevenção & controle , Neuraminidase/genética , Vacinas Sintéticas/genética , RNA
9.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338774

RESUMO

Although calcineurin inhibitors are very effective as immunosuppressants in organ transplantation, complete graft acceptance remains as a challenge. Transfer of genes with immunosuppressant functions could contribute to improving the clinical evolution of transplantation. In this sense, hydrodynamic injection has proven very efficacious for liver gene transfer. In the present work, the hIL-10 gene was hydrofected 'ex vivo' to pig livers during the bench surgery stage, to circumvent the cardiovascular limitations of the procedure, in a model of porcine orthotopic transplantation with a 10-day follow-up. We used IL-10 because human and porcine proteins can be differentially quantified and for its immunomodulatory pleiotropic functions. Safety (biochemical parameters and histology), expression efficacy (RNA transcription and blood protein expression), and acute inflammatory response (cytokines panel) of the procedure were evaluated. The procedure proved safe as no change in biochemical parameters was observed in treated animals, and human IL-10 was efficaciously expressed, with stationary plasma protein levels over 20 pg/mL during the follow-up. Most studied cytokines showed increments (interferon-α, IFN-α; interleukin-1ß, IL-1ß; tumor necrosis factor α, TNFα; interleukin-6, IL-6; interleukin-8, IL-8; interleukin-4, IL-4; and transforming growth factor-ß, TGF-ß) in treated animals, without deleterious effects on tissue. Collectively, the results support the potential clinical interest in this gene therapy model that would require further longer-term dose-response studies to be confirmed.


Assuntos
Hidrodinâmica , Interleucina-10 , Humanos , Animais , Suínos , Interleucina-10/genética , Interleucina-10/metabolismo , Fígado/metabolismo , Citocinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-38329349

RESUMO

Severe symptomatic carotid artery stenosis poses a significant risk for recurrent strokes. Best treatment options depend on multiple factors, including patient medical conditions and lesion characteristics.1 Despite treatment options such as carotid endarterectomy, conventional carotid angioplasty/stent, and transcervical carotid revascularization, certain patients are not ideal candidates for any of these modalities. Novel technical advances such as intravascular lithotripsy (Shockwave Medical Inc.) have emerged as a potential treatment modality to treat patients with severely calcified plaques, a well-described limitation for carotid stent expansion and apposition.2-4 The safety and efficacy of intravascular lithotripsy have been demonstrated through select case series and coronary artery disease I-II-III studies, culminating in its Food and Drug Administration approval for the management of novo, calcified, stenotic coronary arteries before stent placement.2,5 This technical video presents an illustrative case of a patient with symptomatic severely calcified carotid plaque with previous neck radiation precluding endarterectomy, treated with off-label use of balloon lithotripsy plus stent.6 The patient consented to the procedure.

11.
Pharmacol Res ; 200: 107061, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199278

RESUMO

The development of Pharmacogenetics and Pharmacogenomics in Western Europe is highly relevant in the worldwide scenario. Despite the usually low institutional support, many research groups, composed of basic and clinical researchers, have been actively working for decades in this field. Their contributions made an international impact and paved the way for further studies and pharmacogenomics implementation in clinical practice. In this manuscript, that makes part of the Special Issue entitled Spanish Pharmacology, we present an analysis of the state of the art of Pharmacogenetics and Pharmacogenomics research in Europe, we compare it with the developments in Spain, and we summarize the most salient contributions since 1988 to the present, as well as recent developments in the clinical application of pharmacogenomics knowledge. Finally, we present some considerations on how we could improve translation to clinical practice in this specific scenario.


Assuntos
Farmacogenética , Medicina de Precisão , Europa (Continente)
14.
Rev Sci Instrum ; 94(3): 033903, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37012774

RESUMO

Here, we present an integrated ultra-high-vacuum (UHV) apparatus for the growth of complex materials and heterostructures. The specific growth technique is the Pulsed Laser Deposition (PLD) by means of a dual-laser source based on an excimer KrF ultraviolet and solid-state Nd:YAG infra-red lasers. By taking advantage of the two laser sources-both lasers can be independently used within the deposition chambers-a large number of different materials-ranging from oxides to metals, to selenides, and others-can be successfully grown in the form of thin films and heterostructures. All of the samples can be in situ transferred between the deposition chambers and the analysis chambers by using vessels and holders' manipulators. The apparatus also offers the possibility to transfer samples to remote instrumentation under UHV conditions by means of commercially available UHV-suitcases. The dual-PLD operates for in-house research as well as user facility in combination with the Advanced Photo-electric Effect beamline at the Elettra synchrotron radiation facility in Trieste and allows synchrotron-based photo-emission as well as x-ray absorption experiments on pristine films and heterostructures.

15.
Cancers (Basel) ; 15(5)2023 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-36900216

RESUMO

BACKGROUND: Pharmacogenetics is a personalized medicine tool that aims to optimize treatments by adapting them to each individual's genetics, maximizing their efficacy while minimizing their toxicity. Infants with cancer are especially vulnerable, and their co-morbidities have vital repercussions. The study of their pharmacogenetics is new in this clinical field. METHODS: A unicentric, ambispective study of a cohort of infants receiving chemotherapy (from January 2007 to August 2019). The genotypes of 64 patients under 18 months of age were correlated with severe drug toxicities and survival. A pharmacogenetics panel was configured based on PharmGKB, drug labels, and international experts' consortiums. RESULTS: Associations between SNPs and hematological toxicity were found. Most meaningful were: MTHFR rs1801131 GT increasing the anemia risk (OR 1.73); rs1517114 GC, XPC rs2228001 GT, increasing neutropenia risk (OR 1.50 and 4.63); ABCB1 rs1045642 AG, TNFRSF11B rs2073618 GG, CYP2B6 rs4802101 TC and SOD2 rs4880 GG increasing thrombocytopenia risk (OR 1.70, 1.77, 1.70, 1.73, respectively). Regarding survival, MTHFR rs1801133 GG, TNFRSF11B rs2073618 GG, XPC rs2228001 GT, CYP3A4 rs2740574 CT, CDA rs3215400 del.del, and SLC01B1 rs4149015 GA were associated with lower overall survival probabilities (HR 3.12, 1.84, 1.68, 2.92, 1.90, and 3.96, respectively). Lastly, for event-free survival, SLC19A1 rs1051266 TT and CDA rs3215400 del.del increased the relapse probability (HR 1.61 and 2.19, respectively). CONCLUSIONS: This pharmacogenetic study is a pioneer in dealing with infants under 18 months of age. Further studies are needed to confirm the utility of the findings in this work to be used as predictive genetic biomarkers of toxicity and therapeutic efficacy in the infant population. If confirmed, their use in therapeutic decisions could improve the quality of life and prognosis of these patients.

16.
Artigo em Inglês | LILACS | ID: biblio-1526194

RESUMO

Introduction: promoting scientifi c research is one of the main functions of universities. Medical schools should not be an exception; deans should also have appropriate research experience that allows them to have a different perspective on the importance of research in undergraduate medicine. Aim: to determine the medical school dean's scientific production of the main universities by continent. Methods: an observational, analytical, and transversal study. We identify the medical school dean's scientific production of the 20 universities with the best position from South America, Central America, North America, Europe, Asia, Africa, and Oceania, according to the Ranking Webometrics 2022, in the Scopus database. Results: 140 directors or deans of medicine were evaluated, of which 136 (97.1%) had published an article at least once in their life, 128 (91.4%) in the last fi ve years, 103 (73.6%) in the previous year, and 93 (66.4%) in the current year. The total number of published articles was 24.5 (Me=98), receiving a total of 1,251,766 citations (range 0 to 101,868), an Hindex 24 (range 0 to 140), and in collaboration with 154,711 coauthors. Conclusions: the medical school dean's scientific production from the main universities by continent was high, with notable differences between those who came from universities in Asia, North America, and Europe compared to Oceania, Africa, South America, and Central America


Introdução: promover a pesquisa científica é uma das principais funções das universidades. As escolas médicas não devem ser uma exceção. Os reitores também devem ter uma experiência de pesquisa adequada que lhes permita ter uma perspectiva diferente sobre a importância da pesquisa na graduação em medicina. Objetivo: determinar a produção científica dos reitores de medicina das principais universidades por continente. Métodos: estudo observacional, analítico e transversal. Identificamos a produção científica dos pró-reitores de medicina das 20 universidades com melhor posição da América do Sul, América Central, América do Norte, Europa, Ásia, África e Oceania, segundo o Ranking Webometrics 2022, na base Scopus. Resultados: foram avaliados 140 diretores ou reitores de medicina, dos quais 136 (97.1%) publicaram artigo pelo menos uma vez na vida, 128 (91.4%) nos últimos cinco anos, 103 (73.5%) no ano anterior, e 93 (66.4%) no ano corrente. O número total de artigos publicados foi de 24.5 (Me=98), recebendo um total de 1,251,766 citações (intervalo de 0 a 101.868), índice H = 24 (intervalo de 0 a 140) e em colaboração com 154,711 coautores. Conclusões: a produção científica dos reitores de medicina das principais universidades por continente foi alta, com diferenças notáveis entre aqueles que vieram de universidades da Ásia, América do Norte e Europa em comparação com Oceania, África, América do Sul e América Central


Assuntos
Universidades , Pesquisa Biomédica , Atividades Científicas e Tecnológicas , Diretores Médicos
17.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1431292

RESUMO

Introducción: El Perú posee un gran número revistas de áreas biomédicas, pero solo algunas han logrado visibilizar e indizar sus publicaciones en diferentes medios de indización de alcance global. Objetivo: Analizar las características de publicación de la Revista del Cuerpo Médico Hospital Nacional Almanzor Aguinaga Asenjo (Chiclayo) a partir de indicadores bibliométricos. Material y métodos: Estudio descriptivo que analiza 587 registros bibliográficos de los artículos publicados en la revista durante 2011-2020, a partir de indicadores de impacto científico y análisis de términos. Resultados: La mayor producción de artículos corresponde a originales (60%; X̅=66). Los artículos publicados sobre medicina general obtuvieron más impacto en años anteriores. Los temas más frecuentes fueron estudios sobre pacientes de hospitales de Chiclayo, Lambayeque con casos de covid-19. Conclusiones: La Revista del Cuerpo Médico HNAAA se perfila como una publicación seriada de importancia para visibilizar la producción nacional y local por la cobertura temática en especialidades médicas de relevancia regional que publica.


Background: There are several journals about biomedical areas in Peru, however only a few have managed to make their publications avisible and indexed in different global indexing media. Objective: To analyze the main publication characteristics from Revista del Cuerpo Médico Hospital Nacional Almanzor Aguinaga Asenjo (Chiclayo) based on bibliometric methods. Material and methods: Descriptive study that analyzes 587 articles published by the journal from 2011 to 2020, based on bibliometric methods and indicators: citations, scientific impact and co-word analysis. Results: Original articles were the highest types of document published (60%; X̅=66). Published research articles on general medicine received more impact in previous years than the recents. Most frequent topic analyzed were studies about patients from hospitals in Chiclayo city (Lambayeque) with covid-19 clinical cases. Conclusion: Revista del Cuerpo Médico HNAAA is emerging as an important serial publication to make local, national, and international production visible due to thematic coverage in relevant medical specialties.

18.
Faraday Discuss ; 236(0): 429-441, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35506865

RESUMO

The technological interest in MoTe2 as a phase engineered material is related to the possibility of triggering the 2H-1T' phase transition by optical excitation, potentially allowing for an accurate patterning of metallic areas into a semiconducting canvas via laser irradiation. In this paper, we investigate the photo-induced modifications of a bulk 2H-MoTe2 crystal by means of time-resolved X-ray photoemission spectroscopy. We observe that in the microsecond timescale, the core levels shift to higher kinetic energies due to surface photovoltage fields, while in the sub-nanosecond range, the photoemission peaks shift in the opposite direction. With the support of DFT calculations, we ascribe the latter effect to the deformation of the lattice in the out-of-plane direction, which is along the pathway for the 2H-1T' phase transition. Our data indicate an intermediate lattice excitation state with a measured lifetime in the order of 600 ps, in which the displacement of Mo and Te atoms causes the Te 4d electrons to shift towards higher binding energies.

19.
Int J Mol Sci ; 23(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35628649

RESUMO

Therapeutic oligonucleotides have achieved great clinical interest since their approval as drug agents by regulatory agencies but their access and distribution in blood cells are not completely known. We evaluated by flow cytometry the ability of short fluorescent scramble oligonucleotides (ON*) to access human peripheral blood mononuclear cells (PBMC) after incubating with ON* during 1 h and 7 days of culture follow-up 'in vitro'. Blood samples were treated with chemically modified oligonucleotides (phosphorothioate backbone and 2' O-Me ends) to resist nuclease digestion under culture conditions. The ON* internalization was determined after discarding the membrane-associated fluorescence by trypan blue quenching. Whereas the oligonucleotide accessed neutrophils and monocytes rapidly, achieving their maximum in 1 h and 24 h, respectively, lymphocytes required 7 days to achieve the maximum (80% of cells) transfection. The ON*ability to access lymphocyte types (T, B, and NK) and T cell subtypes (CD4+, CD8+, and CD4-CD8-) were similar, with T cells being more accessible. Regulatory CD4+ and CD8+ T cells were classified in low and high Foxp3 expressers, whose expression proved not to alter the ON* internalization during the first hour, achieving 53% of CD4+Foxp3+ and 40% of CD8+Foxp3+ cells. Our results contribute to understanding and improving the management of therapeutic ONs.


Assuntos
Leucócitos Mononucleares , Oligonucleotídeos , Linfócitos T CD8-Positivos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo
20.
Pharmaceutics ; 14(2)2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-35214086

RESUMO

Some gene polymorphisms have been previously associated individually with tacrolimus efficacy and toxicity, but no long-term study to determine the role of pharmacogene variants in the clinical evolution of liver-transplanted patients has been addressed so far. In the present work, we analyzed the relation between highly-evidenced genetic polymorphisms located in relevant pharmacogenes and the risk of suffering premature death and other comorbidities such as cancer, diabetes mellitus, arterial hypertension, graft rejection, infections and nephrotoxicities in a cohort of 87 patients (8 were excluded due to early loss of follow-up) transplanted at Hospital La Fe in Valencia (Spain) during a 12-year follow-up. Employing a logistic regression model with false discovery rate penalization and Kaplan-Meier analyses, we observed significant association between survival rates and metabolizer genes. In this sense, our results show an association between MTHFR gene variants in donor rs1801133 (HR: 7.90; p-value: 0.032) and recipient rs1801131 (HR: 7.34; p-value: 0.036) and the group of patients who died during the follow-up period, supporting the interest of confirming these results with larger patient cohorts. In addition, donor polymorphisms in UGT1A9 metabolizer gene rs6714486 (OR: 0.13; p-value: 0.032) were associated with a lower risk of suffering from de novo cancer. Genetic variants in CYP2B6 metabolizer gene rs2279343 demonstrated an association with a risk of infection. Other variants in different locations of SLCO1A2, ABCC2 and ABCB1 transporter genes were associated with a lower risk of suffering from type 2 diabetes mellitus, chronic and acute nephrotoxicities and arterial hypertension. Results suggest that pharmacogenetics-derived information may be an important support for personalized drug prescription, clinical follow-up and the evolution of liver-transplanted patients.

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