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Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28â days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50â mg/kg) or fluoxetine (FLU, 10â mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1ß) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1ß levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.
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Antidepresivos , Astrocitos , Depresión , Modelos Animales de Enfermedad , Hipocampo , Microglía , Enfermedades Neuroinflamatorias , Estrés Psicológico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fluoxetina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Fármacos Neuroprotectores/farmacología , Conducta Animal/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismoRESUMEN
Neonatal immune activation (NIA) through exposure to lipopolysaccharide (LPS) induces adult behavioral changes in rodents that resemble symptoms of developmental disorders, such as autism spectrum disorder. The neonatal timing of LPS exposure appears to play a crucial role in determining the nature and extent of long-term changes. This study aims to explore whether a 3-day LPS-NIA triggers sex- and age-related changes in gut function, potentially linking LPS-NIA to gastrointestinal dysfunction. Male and female Swiss mice received intraperitoneal injections of LPS or saline on postnatal days (PN) 3, 5, and 7. At PN35 (juvenile) and PN70 (adult), gut inflammation and oxidative stress were evaluated in addition to assessments of working memory, depressive-like symptoms, sociability, and repetitive behavior. Gut examination showed elevated C-X-C motif chemokine receptor 3 (CXCR3) in LPS-NIA mice, while MyD88 and Zonulin expressions were significantly higher only in adult LPS-NIA females. Interleukin (IL)-23 expression increased in juvenile and adult male and juvenile female LPS-NIA mice. Oxidative changes included decreased duodenal reduced glutathione (GSH) in juvenile females and ileal GSH in adult females exposed to LPS-NIA. Regarding behavioral alterations, adult LPS-NIA females exhibited depressive-like behavior. Working memory deficits were observed across all LPS-NIA groups. Only juvenile LPS-NIA females increased grooming, while rearing was higher in adult LPS-NIA mice of both sexes. The findings imply that LPS-NIA impacts intestinal barrier function and causes gut inflammatory alterations that are sex- and age-specific. These findings pave the way for exploring potential mechanisms that could contribute to LPS-induced gastrointestinal disturbances among individuals with ASD.
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OBJECTIVES: This systematic review sought to provide evidence for the effectiveness of common pharmacological interventions used for treating attention deficit hyperactivity disorder (ADHD) symptoms in the autism spectrum disorder (ASD) population, considering studies attempting to find safe and effective drugs. METHODS: We searched for randomized controlled trials describing the effectiveness and/or safety profile of pharmacological interventions for treating ASD and ADHD or ASD with ADHD symptoms using three bibliographic databases: PubMed, Cochrane Library, and Embase. We have chosen ADHD symptoms measured by any clinical scale as the primary outcome. As additional outcomes, we have used other symptoms of aberrant behavior measured by the aberrant behavior checklist, satisfaction with treatment, and peer satisfaction. RESULTS: Twenty-two publications met the inclusion criteria for the systematic review and eight for the meta-analysis. In our investigation, we found a few articles using clonidine, modafinil, and bupropion as interventions when compared to methylphenidate (MPH). Our meta-analysis showed that MPH had positive changes compared to placebo in symptoms such as hyperactivity, irritability, or inattention. However, no effect was found in stereotyped symptoms, and our data's quantitative analysis revealed a large effect of MPH-induced adverse effects on the dropout rate. On the other hand, atomoxetine initiation had positive effects when compared to placebo on symptoms of hyperactivity and inattention. We have found no effect of atomoxetine on stereotypes or irritability. Furthermore, atomoxetine did not influence side effects that caused dropouts from studies. CONCLUSION: Our results indicated that atomoxetine has a modest effect on hyperactivity and inattention symptoms, with a relatively benign profile of side effects. MPH appears to be effective in handling hyperactivity, inattention, and irritability symptoms. However, our results on atomoxetine revealed increased dropouts due to adverse effects when compared to MPH or placebo. Evidence for other substances such as guanfacine, clonidine, bupropion, or modafinil is either preliminary or nonexistent.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Humanos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Clonidina/uso terapéutico , Metilfenidato/uso terapéutico , Resultado del TratamientoRESUMEN
Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.
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Modelos Animales de Enfermedad , Ambiente , Hipocampo , Esquizofrenia , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Animales , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/genética , Ratones , Masculino , Proteína Doblecortina , Regiones Promotoras Genéticas , Metilación de ADN , Poli I-C , Neurogénesis/fisiología , Filtrado Sensorial/fisiologíaRESUMEN
As the prevalence of drug-resistant Candida isolates continues to rise, the imperative for identifying novel compounds to enhance the arsenal of antifungal drugs becomes increasingly critical. Consequently, exploring new treatment strategies, including synthesizing molecular hybrids and applying combination therapy, is essential. For this reason, this study evaluated the efficacy of ten molecular hybrids of aza-bicyclic 2-isoxazoline-acylhydrazone belonging to two series 90 and 91 as possible anti-Candida agents. In addition, we also investigated the interaction between the hybrids and fluconazole, a commonly used antifungal drug. We evaluated the antifungal effect of aza-bicyclic 2-isoxazoline-acylhydrazone hybrid compounds against six Candida spp. strains that target planktonic cells. However, none of these new molecules were inhibitory active at the tested concentrations (2 to 1,024 µg/mL). Moreover, we analyzed the interaction between the ten new hybrid molecules and fluconazole using the checkerboard assay, employing two different methodologies for reading the plate. For this, one isolate fluconazole-resistant was selected. We observed that only one combination, 6-(4-tert-butylbenzoil)-4,5,6,6a-tetrahydro-3a-H-pirrole[3,2-d]isoxazole-3-carboxylic(furan-2-metilidene)-hydrazide (91e) and fluconazole, exhibited a synergistic interaction (FICI range 0.0781 to 0.4739). The combination successfully inhibited the growth of C. albicans CA2 fluconazole-resistant, and no interaction was observed in an isolate susceptible to fluconazole. Additionally, these results emphasize the continued need for research into new compounds and the importance of using combined approaches to increase their activity.
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Antifúngicos , Candida albicans , Farmacorresistencia Fúngica , Sinergismo Farmacológico , Fluconazol , Hidrazonas , Isoxazoles , Pruebas de Sensibilidad Microbiana , Antifúngicos/farmacología , Antifúngicos/química , Fluconazol/farmacología , Candida albicans/efectos de los fármacos , Hidrazonas/farmacología , Hidrazonas/química , Isoxazoles/farmacología , Isoxazoles/química , HumanosRESUMEN
Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1ß and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.
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Ansiedad , Conducta Animal , Celecoxib , Inhibidores de la Ciclooxigenasa 2 , Depresión , Lipopolisacáridos , Estrés Oxidativo , Animales , Masculino , Ratones , Lipopolisacáridos/farmacología , Estrés Oxidativo/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Depresión/tratamiento farmacológico , Depresión/inducido químicamente , Depresión/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Celecoxib/farmacología , Celecoxib/administración & dosificación , Etoricoxib/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/metabolismoRESUMEN
Species from Candida parapsilosis complex are frequently found in neonatal candidemia. The antifungal agents to treat this infection are limited and the occurrence of low in vitro susceptibility to echinocandins such as micafungin has been observed. In this context, the chaperone Hsp90 could be a target to reduce resistance. Thus, the objective of this research was to identify isolates from the C. parapsilosis complex and verify the action of Hsp90 inhibitors associated with micafungin. The fungal identification was based on genetic sequencing and mass spectrometry. Minimal inhibitory concentrations were determined by broth microdilution method according to Clinical Laboratory and Standards Institute. The evaluation of the interaction between micafungin with Hsp90 inhibitors was realized using the checkerboard methodology. According to the polyphasic taxonomy, C. parapsilosis sensu stricto was the most frequently identified, followed by C. orthopsilosis and C. metapsilosis, and one isolate of Lodderomyces elongisporus was identified by genetic sequencing. The Hsp90 inhibitor geladanamycin associated with micafungin showed a synergic effect in 31.25% of the isolates, a better result was observed with radicicol, which shows synergic effect in 56.25% tested yeasts. The results obtained demonstrate that blocking Hsp90 could be effective to reduce antifungal resistance to echinocandins.
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Antifúngicos , Candida parapsilosis , Candidemia , Proteínas HSP90 de Choque Térmico , Micafungina , Humanos , Recién Nacido , Antifúngicos/farmacología , Benzoquinonas/farmacología , Candida parapsilosis/efectos de los fármacos , Candida parapsilosis/aislamiento & purificación , Candida parapsilosis/genética , Candidemia/microbiología , Farmacorresistencia Fúngica , Sinergismo Farmacológico , Equinocandinas/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/genética , Lactamas Macrocíclicas/farmacología , Lipopéptidos/farmacología , Micafungina/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Balanoposthitis can affect men in immunocompromised situations, such as HIV infection and diabetes. The main associated microorganism is Candida albicans, which can cause local lesions, such as the development of skin cracks associated with itching. As an alternative to conventional treatment, there is a growing interest in the photodynamic inactivation (PDI). It has been shown that the association of photosensitizers with metallic nanoparticles may improve the effectiveness of PDI via plasmonic effect. We have recently shown that the association of methylene blue (MB), a very known photosensitizer, with silver prismatic nanoplatelets (AgNPrs) improved PDI of a resistant strain of Staphylococcus aureus. To further investigate the experimental conditions involved in PDI improvement, in the present study, we studied the effect of MB concentration associated with AgNPrs exploring spectral analysis, zeta potential measurements, and biological assays, testing the conjugated system against C. albicans isolated from a resistant strain of balanoposthitis. The AgNPrs were synthesized through silver anisotropic seed growth induced by the anionic stabilizing agent poly(sodium 4-styrenesulfonate) and showed a plasmon band fully overlapping the MB absorption band. MB and AgNPrs were conjugated through electrostatic association and three different MB concentrations were tested in the nanosystems. Inactivation using red LED light (660 nm) showed a dose dependency in respect to the MB concentration in the conjugates. Using the highest MB concentration (100 µmolâ L-1) with AgNPr, it was possible to completely inactivate the microorganisms upon a 2 min irradiation exposure. Analyzing optical changes in the conjugates we suggest that these results indicate that AgNPrs are enhancers of MB photodynamic action probably by a combined mechanism of plasmonic effect and reduction of MB dimerization. Therefore, MBAgNPrs can be considered a suitable choice to be applied in PDI of resistant microorganisms.
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Candida albicans , Azul de Metileno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Plata , Candida albicans/efectos de los fármacos , Azul de Metileno/farmacología , Fármacos Fotosensibilizantes/farmacología , Fotoquimioterapia/métodos , Plata/farmacología , Nanopartículas del Metal/uso terapéutico , Nanopartículas del Metal/química , Balanitis/tratamiento farmacológico , Balanitis/microbiología , HumanosRESUMEN
Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8-14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY's ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug's antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent.
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Antioxidantes , Doxiciclina , Hipocampo , Manía , Neuronas , Animales , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Antioxidantes/farmacología , Manía/inducido químicamente , Manía/tratamiento farmacológico , Doxiciclina/farmacología , Conducta Animal/efectos de los fármacos , Células Cultivadas , Anfetamina/farmacología , Anfetamina/toxicidad , Modelos Animales de Enfermedad , Estimulantes del Sistema Nervioso Central/toxicidad , Monoaminas Biogénicas/metabolismo , Dextroanfetamina/farmacología , Dextroanfetamina/toxicidad , Antimaníacos/farmacología , Fármacos Neuroprotectores/farmacologíaRESUMEN
Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients' adherence.
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BACKGROUND: Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS: We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION: The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.
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Enfermedad de Alzheimer , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiología , Peptidil-Dipeptidasa A/metabolismo , Peptidil-Dipeptidasa A/uso terapéutico , Riñón/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Sistema Nervioso Central/metabolismoRESUMEN
O objetivo do estudo foi descrever e analisar a percepção dos usuários e profissionais de uma equipe de Saúde da Família em relação à oferta de grupos como estratégia para promover a Saúde Mental na Atenção Primária à Saúde (APS). Trata-se de uma pesquisa descritiva, exploratória e qualitativa realizada em uma Unidade Básica de Saúde (UBS) de Santa Maria, RS. Utilizou-se a análise de conteúdo e cinco categorias emergiram: 1) APS centrada no sujeito e na sua comunidade; 2) Acolhimento e construção de vínculo; 3) Efetivação da promoção de Saúde Mental em dispositivos comunitários e territoriais; 4) Cuidado em Saúde Mental: construindo caminhos e 5) Trabalho em rede: uma expectativa. Os grupos despontaram como potenciais promotores de Saúde Mental na APS. Por enfatizar o componente socioafetivo e a longitudinalidade do cuidado, eles favorecem o bem-estar físico e mental dos usuários, fortalecendo sua autonomia e independência.
The aim of this study was to analyze and describe the perceptions of patients and family health team staff regarding the role of health groups as a strategy for promoting mental health in primary health care (PHC). We conducted an exploratory descriptive study in a primary care center in Santa Maria, Rio Grande do Sul. The data were analyzed using content analysis, resulting in the emergence of five categories: 1) Patient and community-centered PHC; 2) Welcoming and building bonds; 3) The effective implementation of mental health promotion in community and territorial services; 4) Mental health care: building pathways; and 5) Working in networks: an expectation. Groups emerged as potential promotors of mental health in PHC. By emphasizing the socio-affective component and longitudinality of care, groups promote patient physical and mental well-being, strengthening autonomy and independence.
El objetivo del estudio fue describir y analizar la percepción de los usuarios y profesionales de un equipo de salud de la familia, en relación a la oferta de grupos como estrategia para promover la salud mental en la Atención Primaria de la Salud (APS). Se trata de una investigación descriptiva, exploratoria y cualitativa realizada en una Unidad Básica de Salud (UBS) de Santa Maria, Estado de Rio Grande do Sul. Se utilizó el análisis de contenido y surgieron cinco categorías: 1) APS centrada en el sujeto y en su comunidad; 2) Acogida y construcción de vínculo; 3) Efectuación de la promoción de salud mental en dispositivos comunitarios y territoriales; 4) Cuidado en salud mental: construcción de caminos y 5) Trabajo en red: una expectativa. Los grupos surgieron como potenciales promotores de salud mental en la APS. Por enfatizar el componente socioafectivo y la longitudinalidad del cuidado, ellos favorecen el bienestar físico y mental de los usuarios, fortaleciendo su autonomía e independencia.
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BACKGROUND: The prevalence and pathophysiological mechanisms of cognitive deficits (CD) Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA) are very heterogeneous and poorly understood. We characterized CD in patients with SLE compared with RA patients and healthy controls. We compared the neuropsychological profile of SLE and RA with patients' oxidative/inflammatory biomarkers for CD. METHODS: We performed a cross-sectional study, including 50 SLE patients, 29 RA patients, and 32 healthy controls. SLEDAI and DAS28 assessed disease activity. SF-36 questionnaire and a battery of cognitive tests were applied to all participants. Blood samples were collected to determine IL-6, S100ß, myeloperoxidase (MPO), malondialdehyde and reduced glutathione (GSH) alterations. RESULTS: In the SLE group, higher GSH was associated with the absence of CD (With CD = 69 ± 49, Without CD = 112 ± 81, p = 0.030), while higher IL-6 was associated with the presence of CD in the RA group (With CD = 603 ± 173, Without CD = 431 ± 162, p = 0.032). Regarding specific cognitive domains, in SLE higher MPO was associated with poor performance in reasoning and abstraction (p = 0.039), higher IL-6 was associated with poor performance in inhibitory control and attention (p = 0.031), and higher GSH was associated with better performance in memory(p = 0.021). Higher SLEDAI was associated with poor performance in semantic fluency(p = 0.031), inhibitory control, and attention in the SLE group(p = 0.037). In the RA group, higher DAS-28 was associated with poor performance in executive functions(p = 0.016) and phonemic fluency (p = 0.003). CONCLUSION: SLE patients' disease activity, inflammatory state, and oxidative stress were associated with CD. In RA patients, CD was associated with disease activity and inflammatory state. These results encourage further studies with larger samples aiming to confirm oxidative stress parameters as biomarkers of CD in SLE patients.
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Artritis Reumatoide , Disfunción Cognitiva , Lupus Eritematoso Sistémico , Humanos , Estudios Transversales , Interleucina-6 , Artritis Reumatoide/complicaciones , Lupus Eritematoso Sistémico/complicaciones , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Biomarcadores , Estrés OxidativoRESUMEN
Premature hospitalized neonates have a greater risk for candidemia, however, fungemia due to rare opportunistic yeasts have been recently reported and is associated with high mortality rates. We herein report the first case in Latin America of Lodderomyces elongisporus fungemia in a premature neonate with a fatal outcome.
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Candidemia , Fungemia , Enfermedades del Recién Nacido , Saccharomycetales , Recién Nacido , Humanos , Fungemia/diagnóstico , Fungemia/tratamiento farmacológico , América Latina , Saccharomycetales/genética , Candidemia/tratamiento farmacológico , Levaduras , Antifúngicos/farmacología , Antifúngicos/uso terapéuticoRESUMEN
BACKGROUND: We explored the relationship between symptoms, cognitive performance, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) (three markers of inflammation), and antipsychotic dose (in chlorpromazine units) in male and female patients with schizophrenia. METHODS: We conducted a cross-sectional analysis in patients with schizophrenia of the complete blood count and the results of neuropsychological testing, using the Welch t-test to compare groups and the Pearson test for correlations. RESULTS: We found that the NLR and the PLR are higher among women with schizophrenia when compared with men. In women, the NLR and the PLR correlate positively with antipsychotic drug dose and inversely with a working memory test (Direct Digit Span). Higher doses of antipsychotics are associated with worse working and semantic memory and mental flexibility in the women in our sample. CONCLUSION: Higher doses of antipsychotics were associated with worse working and semantic memory and mental flexibility in women with schizophrenia. No such correlations were present in men, suggesting that, in female patients, cognitive performance deteriorates as the antipsychotic dose is increased, a finding that could be mediated by inflammatory mechanisms, given the demonstrated relationship to biomarkers of inflammation - e.g., the NLR and the PLR. TRIAL REGISTRATION: NCT03788759 (ClinicalTrials.gov).
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Antipsicóticos , Esquizofrenia , Femenino , Humanos , Masculino , Antipsicóticos/uso terapéutico , Cognición , Estudios Transversales , Inflamación , Linfocitos , Neutrófilos , Esquizofrenia/tratamiento farmacológicoRESUMEN
Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = +1.049; CI +0.62 - +1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g= -0.27; CI -1.76 - +1.22, p = 0.71), M1 macrophage (Hedges's g= -0.32; CI -1.78 - +1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI -0.93 - +1.814, p = 0.07) profiles. Comparing clozapine-treated patients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 - 1.15, p<0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS activation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the importance of this drug for treating resistant schizophrenia.
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Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Clozapina/efectos adversos , Esquizofrenia/tratamiento farmacológico , Interleucina-6 , Antipsicóticos/efectos adversos , Estrés OxidativoRESUMEN
BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can infect common mice inducing significant pathological lung lesions and inflammatory responses. This substantially mimics coronavirus disease 19 (COVID-19) infection and pathogenesis in humans. OBJECTIVES: To characterise the effects of recombinant SARS-CoV-2 S1 receptor-binding domain (RBD) peptide in murine macrophage and microglial cells' immune activation compared with classical PAMPs in vitro. METHODS: Murine RAW 264.7 macrophages and BV2 microglial cells were exposed to increasing concentrations of the RBD peptide (0.01, 0.05, and 0.1 µg/mL), Lipopolysaccharide (LPS) and Poly(I:C) and evaluated after two and 24 h for significant markers of macrophage activation. We determined the effects of RBD peptide on cell viability, cleaved caspase 3 expressions, and nuclear morphometry analysis. FINDINGS: In RAW cells, RBD peptide was cytotoxic, but not for BV2 cells. RAW cells presented increased arginase activity and IL-10 production; however, BV2 cells expressed iNOS and IL-6 after RBD peptide exposure. In addition, RAW cells increased cleaved-caspase-3, apoptosis, and mitotic catastrophe after RBD peptide stimulation but not BV2 cells. CONCLUSION: RBD peptide exposure has different effects depending on the cell line, exposure time, and concentration. This study brings new evidence about the immunogenic profile of RBD in macrophage and microglial cells, advancing the understanding of SARS-Cov2 immuno- and neuropathology.
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COVID-19 , Humanos , Animales , Ratones , SARS-CoV-2 , ARN Viral , Microglía/metabolismo , Anticuerpos Antivirales , Proteínas Recombinantes , Macrófagos/metabolismoRESUMEN
Candidemia is responsible for substantial morbidity and mortality in neonatal intensive care units and represents a challenge due to the complexity of hospitalized neonates, the deficiency in approved and precise diagnostic techniques, and the increasing number of species resistant to antifungal agents. Thus, the objective of this study was to detect candidemia among neonates evaluating the risk factors, epidemiology, and antifungal susceptibility. Blood samples were obtained from neonates with suspected septicemia, and the mycological diagnosis was based on yeast growth in culture. The fungal taxonomy was based on classic identification, automated system, and proteomic, when necessary molecular tools were used. The in vitro susceptibility tests were performed according to the broth microdilution method from Clinical and Laboratory Standards Institute. Statistical analysis was performed using the R software version R-4.2.2. The prevalence of neonatal candidemia was 10.97%. The major risk factors involved were previous use of parenteral nutrition, exposure to broad-spectrum antibiotics, prematurity, and prior use central venous catheter, but only this last was statistically associated with mortality risk. Species from Candida parapsilosis complex and C. albicans were the most frequent. All isolates were susceptible to amphotericin B, except C. haemulonii that also exhibited elevated MICs to fluconazole. C. parapsilosis complex and C. glabrata exhibit the highest MICs to echinocandins. Considering these data, we emphasize that an effective management strategy to reduce the impact of neonatal candidemia should involve the knowledge of risk factors, rapid and precise mycological diagnostic, and tests of antifungal susceptibility to help in the selection of an appropriate treatment.
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Candidemia , Recién Nacido , Humanos , Candidemia/microbiología , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida , Brasil/epidemiología , Unidades de Cuidado Intensivo Neonatal , Proteómica , Fluconazol , Farmacorresistencia Fúngica , Factores de Riesgo , Candida glabrata , Candida albicans , Candida parapsilosis , Pruebas de Sensibilidad MicrobianaRESUMEN
Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, associated with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins; TSPO and aromatase; and estrogen receptors ERα, ERß, and GPER. We also collected peripheral blood mononuclear cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.