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1.
BJOG ; 131(3): 334-342, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37555464

RESUMO

OBJECTIVE: To assess whether aspirin treatment can be discontinued in pregnancies with normal uterine artery pulsatility index (≤90th percentile) at 24-28 weeks. DESIGN: Post-hoc analysis of a clinical trial. SETTING: Nine maternity hospitals in Spain. POPULATION OR SAMPLE: Pregnant individuals at high risk of pre-eclampsia at 11-13 weeks and normal uterine artery Doppler at 24-28 weeks. METHODS: All participants received treatment with daily aspirin at a dose of 150 mg. Participants were randomly assigned, in a 1:1 ratio, either to continue aspirin treatment until 36 weeks (control group) or to discontinue aspirin treatment (intervention group), between September 2019 and September 2021. In this secondary analysis, women with a UtAPI >90th percentile at 24-28 weeks were excluded. The non-inferiority margin was set at a difference of 1.9% for the incidence of preterm pre-eclampsia. MAIN OUTCOME MEASURES: Incidence of preterm pre-eclampsia. RESULTS: Of the 1611 eligible women, 139 were excluded for UtAPI >90th percentile or if UtAPI was not available. Finally, 804 were included in this post-hoc analysis. Preterm pre-eclampsia occurred in three of 409 (0.7%) women in the aspirin discontinuation group and five of 395 (1.3%) women in the continuation group (-0.53; 95% CI -1.91 to 0.85), indicating non-inferiority of aspirin discontinuation. CONCLUSIONS: Discontinuing aspirin treatment at 24-28 weeks in women with a UtAPI ≤90th percentile was non-inferior to continuing aspirin treatment until 36 weeks for preventing preterm pre-eclampsia.


Assuntos
Aspirina , Pré-Eclâmpsia , Feminino , Humanos , Recém-Nascido , Gravidez , Aspirina/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/tratamento farmacológico , Ultrassonografia Doppler , Artéria Uterina/diagnóstico por imagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
2.
Acta Obstet Gynecol Scand ; 103(11): 2273-2280, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39171611

RESUMO

INTRODUCTION: This study aims to evaluate the safety of discontinuing aspirin treatment at 24-28 weeks in women at high risk after first-trimester combined screening for preeclampsia (PE) and normal placental growth factor (PlGF) levels at 24-28 weeks of gestation. MATERIAL AND METHODS: This is a post hoc analysis of the StopPRE trial, conducted at nine Spanish maternity hospitals from September 2019 to September 2021. In the StopPRE trial, all high-risk single pregnancies identified during first-trimester screening for PE were treated with 150 mg of daily aspirin. Out of 1604 eligible women with a soluble fms-like tyrosine kinase-1 to PlGF ratio (sFlt-1/PlGF) ≤38 at 24-28 weeks, 968 were randomly assigned in a 1:1 ratio to either continue aspirin until 36 weeks (control group) or discontinue it (intervention group). In this secondary analysis, only women with PlGF ≥100 pg/mL at 24-28 weeks were included. As in the StopPRE trial, the non-inferiority margin was set at a 1.9% difference in preterm PE incidence between the groups. RESULTS: Among the 13 983 screened pregnant women, 1984 (14.2%) were deemed high-risk for preterm PE, of which 397 (20.0%) were ineligible, 636 declined participation, and 32 were excluded. Ultimately, 919 women with PlGF >100 pg/mL were randomized and included in this analysis. Preterm PE occurred in 0.9% of the intervention group (4 out of 465) and 1.5% of the control group (7 out of 454), indicating non-inferiority of aspirin discontinuation. There were no significant differences between the groups in adverse pregnancy outcomes before 37 weeks, at <34 weeks, or ≥37 weeks. Minor antepartum hemorrhage incidence was significantly lower in the intervention group (absolute difference, -5.96; 95% CI, -10.10 to -1.82). CONCLUSIONS: Discontinuation of aspirin treatment at 24-28 weeks in women with PlGF levels ≥100 pg/mL was non-inferior to continuing until 36 weeks for preventing preterm PE. However, these findings should be interpreted with caution, as they originate from a subanalysis of the StopPRE trial.


Assuntos
Aspirina , Fator de Crescimento Placentário , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Fator de Crescimento Placentário/sangue , Aspirina/uso terapêutico , Aspirina/administração & dosagem , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/epidemiologia , Adulto , Gravidez de Alto Risco , Suspensão de Tratamento , Primeiro Trimestre da Gravidez , Biomarcadores/sangue , Espanha/epidemiologia
3.
JAMA ; 329(7): 542-550, 2023 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-36809321

RESUMO

Importance: Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy. Objective: To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia. Design, Setting, and Participants: Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants. Interventions: Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group). Main Outcomes and Measures: Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%. Results: Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority. Conclusions and Relevance: Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio. Trial Registration: ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.


Assuntos
Aspirina , Pré-Eclâmpsia , Nascimento Prematuro , Suspensão de Tratamento , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Biomarcadores/sangue , Hemorragia/sangue , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Período Periparto , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/prevenção & controle , Complicações na Gravidez/sangue , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/prevenção & controle , Primeiro Trimestre da Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/prevenção & controle , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
4.
J Cancer Educ ; 38(5): 1683-1689, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37368119

RESUMO

We designed and tested the feasibility of the Smoking Cessation Training Program for Oncology Practice (STOP), a hybrid (face-to-face plus web-based) educational intervention to enhance Spanish-speaking cancer care professionals' (CCPs') ability to provide brief smoking prevention and cessation counseling to cancer patients and survivors. Changes in the CCPs' competencies (knowledge, attitude, self-efficacy, and practices toward smoking and smoking cessation services) were assessed post-training. Sixty CCPs from one major cancer center in Colombia (n = 30) and Peru (n = 30) were invited to participate in a 4-module hybrid training program on smoking prevention and cessation. Demographic and pre- and post-test evaluation data were collected. The training's acceptability was measured after each module. Bivariate analysis was conducted using Wilcoxon signed-rank test to compare the CCPs' competencies before and after the delivery of the STOP Program. Effect sizes were computed over time to assess the sustainability of the acquired competencies. Twenty-nine CCPs in Colombia and 24 CCPs in Peru completed the STOP Program (96.6% and 80.0% retention rates, respectively). In both countries, 98.2% of the CCPs reported that the overall structure and organization of the program provided an excellent learning experience. The pre-post-test evaluations indicated that the CCPs significantly improved their knowledge, attitude, self-efficacy, and practices toward smoking, smoking prevention, and cessation services. We found that the CCPs' self-efficacy and practices increased over time (1-, 3-, and 6-month assessments after completing the 4 educational modules). The STOP Program was effective and well-received, demonstrating remarkable changes in CCPs' competencies in providing smoking prevention and cessation services to cancer patients.


Assuntos
Neoplasias , Abandono do Hábito de Fumar , Humanos , Prevenção do Hábito de Fumar , Colômbia , Peru , Fumar , Neoplasias/prevenção & controle
5.
Am J Transplant ; 21(11): 3618-3628, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33891793

RESUMO

Normothermic regional perfusion (NRP) allows the in situ perfusion of organs with oxygenated blood in donation after the circulatory determination of death (DCDD). We aimed at evaluating the impact of NRP on the short-term outcomes of kidney transplants in controlled DCDD (cDCDD). This is a multicenter, nationwide, retrospective study comparing cDCDD kidneys obtained with NRP versus the standard rapid recovery (RR) technique. During 2012-2018, 2302 cDCDD adult kidney transplants were performed in Spain using NRP (n = 865) or RR (n = 1437). The study groups differed in donor and recipient age, warm, and cold ischemic time and use of ex situ machine perfusion. Transplants in the NRP group were more frequently performed in high-volume centers (≥90 transplants/year). Through matching by propensity score, two cohorts with a total of 770 patients were obtained. After the matching, no statistically significant differences were observed between the groups in terms of primary nonfunction (p = .261) and mortality at 1 year (p =  .111). However, the RR of kidneys was associated with a significantly increased odds of delayed graft function (OR 1.97 [95% CI 1.43-2.72]; p < .001) and 1-year graft loss (OR 1.77 [95% CI 1.01-3.17]; p = .034). In conclusion, compared with RR, NRP appears to improve the short-term outcomes of cDCDD kidney transplants.


Assuntos
Transplante de Rim , Obtenção de Tecidos e Órgãos , Adulto , Morte , Sobrevivência de Enxerto , Humanos , Preservação de Órgãos , Perfusão , Estudos Retrospectivos , Doadores de Tecidos
6.
J Neurovirol ; 27(3): 397-402, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33830465

RESUMO

The frequency of central nervous system infections due to herpesvirus have been studied in various populations; however, studies in Mexican mestizo patients are scant. This paper documents the frequency of herpesvirus encephalitis in Mexican mestizo patients from the National Institute of Neurology and Neurosurgery (NINN) of Mexico. To study the frequency of herpetic viral encephalitis at the NINN in the period from 2004 to 2009. We reviewed clinical records from patients with clinically suspected encephalitis; polymerase chain reaction assays were done for detection of herpesviruses in cerebrospinal fluid (CSF) samples. The total number of patients studied was 502; in 59 (12%), the diagnosis of herpetic encephalitis was confirmed by PCR-based testing of CSF. Of them, 21 (36%) were positive for herpes simplex virus type 1, 15 (25%) for Epstein-Barr virus, 10 (17%) for varicella zoster virus, 8 (14%) for cytomegalovirus, 3 (5%) for human herpesvirus 6, and 2 (3%) for herpes simplex virus 2. Our results show a varied frequency of viral encephalitis in mestizo patients due to herpesviruses in a tertiary neurological center and point out the importance of modern molecular technology to reach the etiological diagnosis in cases of encephalitis.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Encefalite por Varicela Zoster/diagnóstico , Encefalite Viral/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Herpes Genital/diagnóstico , Herpes Simples/diagnóstico , Infecções por Roseolovirus/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Citomegalovirus/genética , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etnologia , Infecções por Citomegalovirus/virologia , Encefalite por Varicela Zoster/epidemiologia , Encefalite por Varicela Zoster/etnologia , Encefalite por Varicela Zoster/virologia , Encefalite Viral/epidemiologia , Encefalite Viral/etnologia , Encefalite Viral/virologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/etnologia , Infecções por Vírus Epstein-Barr/virologia , Etnicidade , Feminino , Herpes Genital/epidemiologia , Herpes Genital/etnologia , Herpes Genital/virologia , Herpes Simples/epidemiologia , Herpes Simples/etnologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/patogenicidade , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/patogenicidade , Humanos , Incidência , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Estudos Retrospectivos , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/etnologia , Infecções por Roseolovirus/virologia
7.
Fetal Diagn Ther ; 48(10): 746-756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34775388

RESUMO

OBJECTIVE: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and "solo" clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. METHODOLOGY: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. RESULTS: During the study period (2015-2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. CONCLUSIONS: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.


Assuntos
Exoma , Ultrassonografia Pré-Natal , Feminino , Feto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Gravidez , Primeiro Trimestre da Gravidez
8.
J Neurophysiol ; 123(3): 1216-1235, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31967931

RESUMO

The amygdala contributes toward emotional processes such as fear, anxiety, and social cognition. Furthermore, evidence suggests that increased excitability of basolateral amygdala (BLA) principal neurons underlie certain neuropsychiatric disorders. Gain-of-function mutations in neuronal L-type calcium channels (LTCCs) are linked to neurodevelopmental diseases, including autism spectrum disorders (ASDs). While LTCCs are expressed throughout the BLA, direct evidence for increased LTCC activity affecting BLA excitability and potentially contributing to disease pathophysiology is lacking. In this study, we utilized a pharmacological approach to examine the contributions of LTCCs to BLA principal cell excitability and synaptic activity at immature (postnatal day 7, P7) and juvenile (P21) developmental stages. Acute upregulation of LTCC activity in brain slices by application of the agonist (S)-Bay K 8644 resulted in increased intrinsic excitability properties including firing frequency response, plateau potential, and spike-frequency adaptation selectively in P7 neurons. Contrastingly, for P21 neurons, the main effect of (S)-Bay K 8644 was to enhance burst firing. (S)-Bay K 8644 increased spontaneous inhibitory synaptic currents at both P7 and P21 but did not affect evoked synaptic currents at either stage. (S)-Bay K 8644 did not alter P7 spontaneous excitatory synaptic currents, although it increased current amplitude in P21 neurons. Overall, the results provide support for the notion that alteration of LTCC activity at specific periods of early brain development may lead to functional alterations to neuronal network activity and subsequently contribute to underlying mechanisms of amygdala-related neurological disorders.NEW & NOTEWORTHY The role of L-type calcium channels (LTCCs) in regulating neuronal electrophysiological properties during development remains unclear. We show that in basolateral amygdala principal neurons, an increase of LTCC activity alters both neuronal excitability and synaptic activity. The results also provide evidence for the distinct contributions of LTCCs at different stages of neurodevelopment and shed insight into our understanding of LTCC dysfunction in amygdala-related neurological disorders.


Assuntos
Potenciais de Ação/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Canais de Cálcio Tipo L/fisiologia , Neurônios/fisiologia , Potenciais Sinápticos/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/crescimento & desenvolvimento , Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Estimulação Elétrica , Masculino , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Potenciais Sinápticos/efeitos dos fármacos
9.
Proc Natl Acad Sci U S A ; 114(9): 2401-2406, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28223480

RESUMO

Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wild-type (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the CaV2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of CaV2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.


Assuntos
Analgésicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/genética , Ataxia Cerebelar/tratamento farmacológico , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Enxaqueca com Aura/tratamento farmacológico , Pregabalina/farmacologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Canais de Cálcio Tipo N/metabolismo , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/patologia , Imagem de Difusão por Ressonância Magnética , Modelos Animais de Doenças , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/patologia , Enxaqueca com Aura/diagnóstico por imagem , Enxaqueca com Aura/metabolismo , Enxaqueca com Aura/patologia , Mutação , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Transmissão Sináptica
10.
Mol Pain ; 14: 1744806918765806, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29580153

RESUMO

Background Following peripheral nerve chronic constriction injury, the accumulation of the α2δ-1 auxiliary subunit of voltage-gated Ca2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ-1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+ influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. Results Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+ channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ-1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ-1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/ß4/α2δ-1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/ß4/α2δ-3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. Conclusion We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ-1 may contribute to its anti-allodynic action.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Subunidades Proteicas/metabolismo , Substância Gelatinosa/metabolismo , Transmissão Sináptica , Aminas/farmacologia , Animais , Bovinos , Constrição Patológica , Ácidos Cicloexanocarboxílicos/farmacologia , Di-Hidropiridinas/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Gabapentina , Células HEK293 , Humanos , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Masculino , Nitrendipino/farmacologia , Células PC12 , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Xenopus , Ácido gama-Aminobutírico/farmacologia
11.
Addict Sci Clin Pract ; 19(1): 36, 2024 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715116

RESUMO

BACKGROUND: Digital technologies have positively impacted the availability and usability of clinical algorithms through the advancement in mobile health. Therefore, this study aimed to determine if a web-based algorithm designed to support the decision-making process of cancer care providers (CCPs) differentially impacted their self-reported self-efficacy and practices for providing smoking prevention and cessation services in Peru and Colombia. METHODS: A simple decision-making tree algorithm was built in REDCap using information from an extensive review of the currently available smoking prevention and cessation resources. We employed a pre-post study design with a mixed-methods approach among 53 CCPs in Peru and Colombia for pilot-testing the web-based algorithm during a 3-month period. Wilcoxon signed-rank test was used to compare the CCPs' self-efficacy and practices before and after using the web-based algorithm. The usability of the web-based algorithm was quantitatively measured with the system usability scale (SUS), as well as qualitatively through the analysis of four focus groups conducted among the participating CCPs. RESULTS: The pre-post assessments indicated that the CCPs significantly improved their self-efficacy and practices toward smoking prevention and cessation services after using the web-based algorithm. The overall average SUS score obtained among study participants was 82.9 (± 9.33) [Peru 81.5; Colombia 84.1]. After completing the qualitative analysis of the focus groups transcripts, four themes emerged: limited resources currently available for smoking prevention and cessation in oncology settings, merits of the web-based algorithm, challenges with the web-based algorithm, and suggestions for improving this web-based decision-making tool. CONCLUSION: The web-based algorithm showed high usability and was well-received by the CCPs in Colombia and Peru, promoting a preliminary improvement in their smoking prevention and cessation self-efficacy and practices.


Assuntos
Algoritmos , Autoeficácia , Abandono do Hábito de Fumar , Humanos , Abandono do Hábito de Fumar/métodos , Colômbia , Masculino , Feminino , Peru , Adulto , Pessoa de Meia-Idade , Prevenção do Hábito de Fumar/métodos , Internet , Pessoal de Saúde , Neoplasias/prevenção & controle
12.
Br J Pharmacol ; 181(18): 3503-3526, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38779706

RESUMO

BACKGROUND AND PURPOSE: Excitotoxicity due to mitochondrial calcium (Ca2+) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the mitochondrial calcium uniporter (MCU) has been proposed as a therapeutic avenue to prevent calcium overloading. Ru265 (ClRu(NH3)4(µ-N)Ru(NH3)4Cl]Cl3) is a cell-permeable inhibitor of the mitochondrial calcium uniporter (MCU) with nanomolar affinity. Ru265 reduces sensorimotor deficits and neuronal death in models of ischemic stroke. However, the therapeutic use of Ru265 is limited by the induction of seizure-like behaviours. EXPERIMENTAL APPROACH: We examined the effect of Ru265 on synaptic and neuronal function in acute brain slices and hippocampal neuron cultures derived from mice, in control and where MCU expression was genetically abrogated. KEY RESULTS: Ru265 decreased evoked responses from calyx terminals and induced spontaneous action potential firing of both the terminal and postsynaptic principal cell. Recordings of presynaptic Ca2+ currents suggested that Ru265 blocks the P/Q type channel, confirmed by the inhibition of currents in cells exogenously expressing the P/Q type channel. Measurements of presynaptic K+ currents further revealed that Ru265 blocked a KCNQ current, leading to increased membrane excitability, underlying spontaneous spiking. Ca2+ imaging of hippocampal neurons showed that Ru265 increased synchronized, high-amplitude events, recapitulating seizure-like activity seen in vivo. Importantly, MCU ablation did not suppress Ru265-induced increases in neuronal activity and seizures. CONCLUSIONS AND IMPLICATIONS: Our findings provide a mechanistic explanation for the pro-convulsant effects of Ru265 and suggest counter screening assays based on the measurement of P/Q and KCNQ channel currents to identify safe MCU inhibitors.


Assuntos
Canais de Cálcio , Neurônios , Compostos de Rutênio , Transmissão Sináptica , Animais , Canais de Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos de Rutênio/farmacologia , Camundongos , Transmissão Sináptica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Células Cultivadas , Cálcio/metabolismo
13.
ACS Catal ; 14(15): 11522-11531, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39114085

RESUMO

The influence of surface morphology and the oxidation state on the electrocatalytic activity of nanostructured electrodes is well recognized, yet disentangling their individual roles in specific reactions remains challenging. Here, we investigated the electrooxidation of sulfite ions in an alkaline environment using cyclic voltammetry on copper oxide nanostructured electrodes with different oxidation states and morphologies but with similar active areas. To this aim, we synthesized nanostructured Cu films made of nanoparticles or nanorods on top of glassy carbon electrodes. Our findings showed an enhanced sensitivity and a lower detection threshold when utilizing Cu(I) over Cu(II). Density functional theory-based thermochemical analysis revealed the underlying oxidation mechanism, indicating that while the energy gain associated with the process is comparable for both oxide surfaces, the desorption energy barrier for the resulting sulfate molecules is three times higher on Cu(II). This becomes the limiting step of the reaction kinetics and diminishes the overall electrooxidation efficiency. Our proposed mechanism relies on the tautomerization of hydroxyl groups confined on the surface of Cu-based electrodes. This mechanism might be applicable to electrochemical reactions involving other sulfur compounds that hold technological significance.

14.
Proc Natl Acad Sci U S A ; 107(43): 18694-9, 2010 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-20937883

RESUMO

The dynamics, computational power, and strength of neural circuits are essential for encoding and processing information in the CNS and rely on short and long forms of synaptic plasticity. In a model system, residual calcium (Ca(2+)) in presynaptic terminals can act through neuronal Ca(2+) sensor proteins to cause Ca(2+)-dependent facilitation (CDF) of P/Q-type channels and induce short-term synaptic facilitation. However, whether this is a general mechanism of plasticity at intact central synapses and whether mutations associated with human disease affect this process have not been described to our knowledge. In this report, we find that, in both exogenous and native preparations, gain-of-function missense mutations underlying Familial Hemiplegic Migraine type 1 (FHM-1) occlude CDF of P/Q-type Ca(2+) channels. In FHM-1 mutant mice, the alteration of P/Q-type channel CDF correlates with reduced short-term synaptic facilitation at cerebellar parallel fiber-to-Purkinje cell synapses. Two-photon imaging suggests that P/Q-type channels at parallel fiber terminals in FHM-1 mice are in a basally facilitated state. Overall, the results provide evidence that FHM-1 mutations directly affect both P/Q-type channel CDF and synaptic plasticity and that together likely contribute toward the pathophysiology underlying FHM-1. The findings also suggest that P/Q-type channel CDF is an important mechanism required for normal synaptic plasticity at a fast synapse in the mammalian CNS.


Assuntos
Canais de Cálcio Tipo N/genética , Canais de Cálcio Tipo N/fisiologia , Sinalização do Cálcio/fisiologia , Enxaqueca com Aura/genética , Enxaqueca com Aura/fisiopatologia , Plasticidade Neuronal/fisiologia , Animais , Canais de Cálcio/genética , Canais de Cálcio/fisiologia , Sinalização do Cálcio/genética , Linhagem Celular , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Mutantes , Modelos Neurológicos , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Mutação de Sentido Incorreto , Células de Purkinje/fisiologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
15.
Mol Neurobiol ; 60(12): 6774-6788, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37480498

RESUMO

Parkinson's disease (PD) is the second most frequent neurodegenerative disease associated with motor dysfunction secondary to the loss of dopaminergic neurons in the nigrostriatal axis. Actual therapy consists mainly of levodopa; however, its long-term use promotes secondary effects. Consequently, finding new therapeutic alternatives, such as neuroprotective molecules, is necessary. Among these alternatives is silybin (Sb), the major bioactive flavonolignan in silymarin. Both exert neuroprotective effects, preserving dopamine levels and dopaminergic neurons when administered in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model, being probably Sb the potential therapeutic molecule behind this effect. To elucidate the role of Sb in the PD model, we determined the dose-dependent conservation of striatal dopamine content following Sb oral administration. Then, we evaluated motor deficit tests using the best dopamine conservative dose of Sb and determined a cytokine-dependent inflammatory profile status, malondialdehyde as an oxidative stress product, and neurotrophic factors content in the MPTP-induced mouse PD model. Our results show that oral Sb at 100 mg/kg dose conserved about 60% dopamine levels. Also, Sb improved motor deficits, preserved neurotrophic factors content and mitochondrial function, reduced lipid peroxidation, diminished proinflammatory cytokines to basal levels, enhanced fractalkine production in the striatum and substantia nigra, and increased IL-10 and IL-4 levels in the substantia nigra in the MPTP mice. Thus, oral Sb may be a potential pharmacological PD treatment alternative.


Assuntos
Intoxicação por MPTP , Doenças Neurodegenerativas , Animais , Camundongos , Citocinas , Silibina/farmacologia , Silibina/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo , Dopamina , Administração Oral , Modelos Animais de Doenças
16.
Clin Transl Oncol ; 25(10): 3021-3031, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37036596

RESUMO

PURPOSE: Both venous and arterial thrombotic events (VTE/AT) can be associated with immune checkpoint inhibitors (ICI). However, there is a paucity of information apropos patients in routine clinical practice. METHODS/PATIENTS: Retrospective, multicenter study promoted by the Thrombosis and Cancer Section of the Spanish Society of Medical Oncology (SEOM). Individuals with kidney or bladder cancer who initiated ICI between 01/01/2015 and 12/31/2020 were recruited. Minimum follow-up was 6 months (except in cases of demise). The primary objective was to calculate the incidence of ICI-associated VTE/AT and secondary objectives included to analyze their impact on survival and identify variables predictive of VTE/AT. RESULTS: 210 patients with kidney cancer were enrolled. The incidence of VTE/AT during follow-up (median 13 months) was 5.7%. Median overall survival (OS) was relatively lower among subjects with VTE/AT (16 months, 95% CI 0.01-34.2 vs. 27 months, 95% CI 22.6-31.4; p = 0.43). Multivariate analysis failed to reveal predictive variables for developing VTE/ AT. 197 patients with bladder were enrolled. There was a 9.1% incidence rate of VTE/AT during follow-up (median 8 months). Median OS was somewhat higher in patients with VTE/AT (28 months, 95% CI 18.4-37.6 vs 25 months, 95% CI 20.7-29.3; p = 0.821). Serum albumin levels < 3.5 g/dl were predictive of VTE/ AT (p < 0.05). CONCLUSIONS: There appears to be no association between developing VTE/AT and ICI use in patients with renal or bladder cancer. Serum albumin levels are a predictive factor in individuals with bladder cancer.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Trombose , Neoplasias da Bexiga Urinária , Tromboembolia Venosa , Humanos , Inibidores de Checkpoint Imunológico , Tromboembolia Venosa/etiologia , Estudos Retrospectivos , Bexiga Urinária , Oncologia , Neoplasias Renais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Albumina Sérica , Fatores de Risco
17.
eNeuro ; 9(1)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35064022

RESUMO

Postnatal CNS development is fine-tuned to drive the functional needs of succeeding life stages; accordingly, the emergence of sensory and motor functions, behavioral patterns and cognitive abilities relies on a complex interplay of signaling pathways. Strictly regulated Ca2+ signaling mediated by L-type channels (LTCCs) is crucial in neural circuit development and aberrant increases in neuronal LTCC activity are linked to neurodevelopmental and psychiatric disorders. In the amygdala, a brain region that integrates signals associated with aversive and rewarding stimuli, LTCCs contribute to NMDA-independent long-term potentiation (LTP) and are required for the consolidation and extinction of fear memory. In vitro studies have elucidated distinct electrophysiological and synaptic properties characterizing the transition from immature to functionally mature basolateral subdivision of the amygdala (BLA) principal neurons. Further, acute increase of LTCC activity selectively regulates excitability and spontaneous synaptic activity in immature BLA neurons, suggesting an age-dependent regulation of BLA circuitry by LTCCs. This study aimed to elucidate whether early life alterations in LTCC activity subsequently affect synaptic strength and amygdala-dependent behaviors in early adulthood. In vivo intra-amygdala injection of an LTCC agonist at a critical period of postnatal neurodevelopment in male rat pups was used to examine synaptic plasticity of BLA excitatory inputs, expression of immediate early genes (IEGs) and glutamate receptors, as well as anxiety and social affiliation behaviors at a juvenile age. Results indicate that enhanced LTCC activity in immature BLA principal neurons trigger persistent changes in the developmental trajectory to modify membrane properties and synaptic LTP at later stages, concomitant with alterations in amygdala-related behavioral patterns.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Adulto , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Medo/fisiologia , Humanos , Potenciação de Longa Duração , Masculino , Plasticidade Neuronal/fisiologia , Ratos
18.
JMIR Res Protoc ; 11(10): e37452, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36222789

RESUMO

BACKGROUND: Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. OBJECTIVE: The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. METHODS: This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. RESULTS: Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. CONCLUSIONS: The angiogenic factor-based protocol may reduce the number of pregnancies classified as having fetal growth restriction without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. TRIAL REGISTRATION: ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37452.

19.
Sci Rep ; 11(1): 15180, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312446

RESUMO

Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking Kv1.1 subunits (Kcna1-/-) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in Kcna1-/- mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. Yet, the functional alterations leading to amygdala hyperexcitability have not been identified. In this study, we used Kcna1-/- mice to examine the contributions of Kv1.1 subunits to excitability in neuronal subtypes from basolateral (BLA) and central lateral (CeL) amygdala known to exhibit distinct firing patterns. We also analyzed synaptic transmission properties in an amygdala local circuit predicted to be involved in epilepsy-related comorbidities. Our data implicate Kv1.1 subunits in controlling spontaneous excitatory synaptic activity in BLA pyramidal neurons. In the CeL, Kv1.1 loss enhances intrinsic excitability and impairs inhibitory synaptic transmission, notably resulting in dysfunction of feed-forward inhibition, a critical mechanism for controlling spike timing. Overall, we find inhibitory control of CeL interneurons is reduced in Kcna1-/- mice suggesting that basal inhibitory network functioning is less able to prevent recurrent hyperexcitation related to seizures.


Assuntos
Tonsila do Cerebelo/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Canal de Potássio Kv1.1/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Núcleo Central da Amígdala/metabolismo , Modelos Animais de Doenças , Retroalimentação Fisiológica , Feminino , Canal de Potássio Kv1.1/deficiência , Canal de Potássio Kv1.1/genética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Inibição Neural/fisiologia , Células Piramidais/metabolismo , Convulsões/metabolismo , Transmissão Sináptica/fisiologia
20.
Biochem Pharmacol ; 191: 114478, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33609561

RESUMO

Mind wandering (MW), or having thoughts unrelated to the task at hand, is a very pervasive phenomenon. Although research on MW has exponentially grown during the last decade and a half, the mechanisms behind this omnipresent phenomenon remain largely unknown. In this review, we will discuss some factors that have been shown to contribute to the occurrence of MW: the quality of sleep, the time of day when the task is performed, the chronotype of the individual and the duration of the task. The intriguing commonality between these specific factors is that they all suggest a relation between MW and sleep pressure. In line with recent work relating MW to local sleep-like activity, we here will argue that one of the mechanisms underlying the pervasiveness of MW might be the local build-up of homeostatic sleep pressure that inevitably occurs during task performance in the brain areas related to the task. Mind wandering could then occur not only to serve a biological purpose, e.g. brain protection, but also a functional one, e.g. off-line learning, that can be beneficial for behavioral performance.


Assuntos
Pesquisa Biomédica/tendências , Encéfalo/fisiologia , Ritmo Circadiano/fisiologia , Fantasia , Sono/fisiologia , Humanos , Desempenho Psicomotor/fisiologia
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