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This work investigated interactions ascribed to the administration of phytomedicines containing Valeriana officinalis and Piper methysticum with conventional drugs. The phytomedicines were characterized by HPLC and administered per os to male Wistar rats, either concomitantly or not with the CYP3A substrate midazolam. To distinguish between the presystemic or systemic effect, midazolam was given orally and intravenously. The effects on the P-gp substrate fexofenadine uptake by Caco-2 cells were examined. The valerenic acid content was 1.6 ± 0.1 mg per tablet, whereas kavain was 13.7 ± 0.3 mg/capsule. Valerian and kava-kava extracts increased the maximum plasma concentration (Cmax) of midazolam 2- and 4-fold compared to the control, respectively. The area under the plasma concentrations versus time curve (AUC(0-∞)) was enhanced from 994.3 ± 152.3 ng.h/mL (control) to 3041 ± 398 ng.h/mL (valerian) and 4139 ± 373 ng.h/mL (kava-kava). The half-life of midazolam was not affected. These changes were attributed to the inhibition of midazolam metabolism by the enteric CYP3A since the i.âv. pharmacokinetic of midazolam remained unchanged. The kava-kava extract augmented the uptake of fexofenadine by 3.5-fold compared to the control. Although Valeriana increased the uptake of fexofenadine, it was not statistically significant to that of the control (12.5 ± 3.7 ng/mg protein vs. 5.4 ± 0.3 ng/mg protein, respectively). Therefore, phytomedicines containing V. officinalis or P. methysticum inhibited the intestinal metabolism of midazolam in rats. Conversely, the P-gp-mediated transport of fexofenadine was preferably affected by kava-kava.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Citocromo P-450 CYP3A , Kava , Midazolam , Extractos Vegetales , Ratas Wistar , Terfenadina , Valeriana , Animales , Valeriana/química , Midazolam/farmacocinética , Midazolam/farmacología , Masculino , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Terfenadina/análogos & derivados , Terfenadina/farmacocinética , Humanos , Células CACO-2 , Ratas , Kava/química , Interacciones de Hierba-Droga , Piper/química , Indenos , Pironas , SesquiterpenosRESUMEN
Antiviral therapy is constantly challenged by the emergence of resistant pathogens. At the same time, experimental approaches to understand and predict resistance are limited by long periods required for evolutionary processes. Here, we present a herpes simplex virus 1 mutant with impaired proofreading capacity and consequently elevated mutation rates. Comparing this hypermutator to parental wild type virus, we study the evolution of antiviral drug resistance in vitro. We model resistance development and elucidate underlying genetic changes against three antiviral substances. Our analyzes reveal no principle difference in the evolutionary behavior of both viruses, adaptive processes are overall similar, however significantly accelerated for the hypermutator. We conclude that hypermutator viruses are useful for modeling adaptation to antiviral therapy. They offer the benefit of expedited adaptation without introducing apparent bias and can therefore serve as an accelerator to predict natural evolution.
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Antivirales , Farmacorresistencia Viral , Evolución Molecular , Herpesvirus Humano 1 , Farmacorresistencia Viral/genética , Antivirales/farmacología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/efectos de los fármacos , Mutación , Tasa de Mutación , Evolución Biológica , HumanosRESUMEN
BACKGROUND: Low medication literacy is prevalent among older adults and is associated with adverse drug events. The Medication Literacy Test for Older Adults (TELUMI) was developed and content validated in a previously published study. AIM: To evaluate the psychometric properties and provide norms for TELUMI scores. METHOD: This was a cross-sectional methodological study with older adults selected from the community and from two outpatient services. Descriptive item-analysis, exploratory factor analysis (EFA), item response theory (IRT), reliability, and validity analysis with schooling and health literacy were performed to test the psychometric properties of the TELUMI. The classification of the TELUMI scores was performed using percentile norms. RESULTS: A total of 344 participants, with a mean age of 68.7 years (standard deviation = 6.7), were included; most were female (66.6%), black/brown (61.8%), had low schooling level (60.2%) and low income (55.2%). The EFA pointed to the one-dimensional structure of TELUMI. A three-parameter logistic model was adopted for IRT. All items had an adequate difficulty index. One item had discrimination < 0.65, and three items had an unacceptable guessing index (< 0.35) and were excluded. The 29-item version of TELUMI had excellent internal consistency (KR20 = 0.89). There was a positive and strong association between TELUMI scores and health literacy and education level. The scores were classified as inadequate medication literacy (≤ 10.0 points), medium medication literacy (11-20 points), and adequate medication literacy (≥ 21 points). CONCLUSION: The results suggest that the 29-item version of TELUMI is psychometrically adequate for measuring medication literacy in older adults.
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This study aimed to analyze the toxic effects of Roundup Transorb® on the endangered Neotropical annual killifish Austrolebias charrua through the assessment of molecular and biochemical biomarkers. The fish were collected in temporary ponds and exposed to environmentally realistic concentrations of the herbicide (5 mg.L-1 for 96 h). The production of ROS, lipid peroxidation, DNA damage, and membrane fluidity were evaluated in the blood cells by flow cytometry. The mRNA expression of the antioxidant-related genes sod2, cat, gstα, atp1a1, gclc, and ucp1 across the brain, liver, and gills was quantified. The acute exposure of annual killifish to Roundup significantly increased ROS production, lipid peroxidation, and DNA damage in their erythrocytes. Likewise, Roundup Transorb® decreased membrane fluidity in the blood cells of the exposed fish. Gene expression analysis revealed that Roundup exposure alters the relative expression of genes associated with oxidative stress and antioxidant defense. Our results give rise to new insights into adaptive mechanisms of A. charrua in response to Roundup. Since Brazilian annual killifishes strongly risk extinction, this study paves the way for developing novel biotechnologies applied to environmental monitoring and aquatic toxicology assessment.
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Glifosato , Herbicidas , Animales , Antioxidantes/metabolismo , Glicina/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Herbicidas/toxicidad , Peces/metabolismo , Fundulus heteroclitus , Biomarcadores/metabolismoRESUMEN
Objetivos: identificar e descrever as notícias sobre erros de medicação ocorridos no Brasil e divulgados na mídia digital brasileira. Metodológia: pesquisa de caráter exploratório, com dados coletados em notícias de mídias digitais do Brasil entre 2015 e 2019. A busca das notícias sobre erros de medicação foi realizada no Google®. Os casos divulgados na mídia foram descritos conforme o tipo e a classificação do erro, medicamento e profissional envolvido na ocorrência do erro, características do paciente que sofreu o erro e local onde o erro ocorreu. Resultados: dos 20 erros noticiados identificados na busca, foram encontrados 11 casos de erros com morte (55,0%), seis casos de erros com dano (30,0%) e três casos de erros sem danos (15,0%). Dos 23 pacientes envolvidos nos erros, 14 pertenciam a grupos de extremos etários, sendo nove pacientes pediátricos (39,1%) e cinco pacientes geriátricos (21,8%). Quanto ao tipo de erro, quatro casos noticiados envolvendo erros de prescrição (20,0%), cinco reportando erros de dispensação (25,0%), 10 erros de administração (50,0%), e um envolvendo erro de dispensação e administração concomitantemente (5,0%). Dentre os 11 casos de erros com morte do paciente, oito traziam a informação sobre qual medicamento estava envolvido no erro, sendo seis deles considerados medicamentos potencialmente perigosos (MPP). Conclusão: os resultados do presente estudo apontam para a necessidade de implementação de melhorias nos estabelecimentos de saúde em geral farmácias, drogarias, hospitais, centros de saúde no que tange a prevenção de erros de medicação. Para isso, devem ser priorizadas iniciativas envolvendo os sistemas de medicação com elevada efetividade, sobretudo em contextos de situações de alto risco como uso de MPP e cuidado a pacientes em extremos etários
Aims: to identify and describe the news about medication errors that occurred in Brazil and were published in the Brazilian digital media. Methods: exploratory research, with data collected in news from digital media in Brazil, between 2015 and 2019. The search for news about medication errors was carried out on Google®. The cases published in the media were described according to the type and classification of the error, medication and professional involved in the occurrence of the error, characteristics of the patient who suffered the error and place where the error occurred. Results: of the 20 reported errors identified in the search, 11 cases of errors with death (55.0%), six cases of errors with harm (30.0%) and three cases of errors without harm (15.0%) were found. Of the 23 patients involved in the errors, 14 belonged to extreme age groups, nine pediatric patients (39.1%) and five geriatric patients (21.8%). As for the type of error, four reported cases involving prescription errors (20.0%), five reporting dispensing errors (25.0%), 10, administration errors (50.0%) and one involving concurrent dispensing and administration error (5.0%). Among the 11 cases of errors resulting in patient death, eight contained information about which medication was involved in the error, six of which were considered high alert medications. Conclusions: the results of this study point to the need to implement improvements in health institutions in general - pharmacies, drugstores, hospitals, health centers - with regard to the prevention of medication errors. For this, initiatives involving medication systems with high effectiveness should be prioritized, especially in contexts of high-risk situations such as the use of high alert medications and care for patients at extremes of age
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Humanos , NoticiasRESUMEN
Avaliar os resultados clínicos de serviços de gerenciamento da terapia medicamentosa (GTM) oferecidos a pessoas vivendo com HIV (PVHIV) em uma unidade de dispensação de medicamentos brasileira. O estudo foi dividido em uma etapa transversal (etapa I), que avaliou o fator associado à identificação de dois ou mais problemas relacionados ao uso de medicamentos (PRM) na avaliação inicial; e uma etapa quasi- experimental (etapa II), realizada com um único grupo de pacientes para avaliar desfechos clínicosForam acompanhadas 52 PVHIV. A média de idade foi de 60±11,3 anos (min. = 29; máx. =78). A presença de dislipidemia (OR=5,38; IC 95%=1,61-17,97; p=0,006) e o uso de sete ou mais medicamentos (OR=4,28; IC 95%=1,32-13,88; p=0,015) foram fatores associados a identificação de dois ou mais PRM. Foi demonstrada uma diferença significativa entre os valores iniciais e finais de pressão arterial sistólica, carga viral do HIV, contagem de células T CD4+ e triglicerídeos (p<0,05). O serviço de GTM favoreceu os desfechos clínicos positivos.
To assess the clinical outcomes of comprehensive medication management (CMM) services offered to people living with HIV (PLHIV) at a Brazilian Antiretroviral Medication Dispensing Unit. The study was divided into a cross-sectional stage (stage I), to evaluate associated factor with the identification of two or more drug therapy problems (DTP) in the initial assessment; and a quasi-experimental stage (stage II), conducted with a single group of PLHIV to evaluate clinical outcomes. A total of 52 PLHIV, with 60±11.3 years of age were followed up. In stage I, the presence of dyslipidemia (OR=5.38; 95%CI=1.61-17.97) and the use of seven or more medications (OR=4.28; 95% CI=1.32-13.88) were factors associated with the identification of DTP. In stage II, a significant difference was demonstrated between the initial and final values of systolic blood pressure, triglycerides, HIV viral load and CD4+T-cells count (p<0,05). The CMM service favored positive clinical outcomes.
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A falta de uso de um medicamento necessário envolve riscos consideráveis para o idoso. Por meio da prestação de serviços de gerenciamento da terapia medicamentosa (GTM), os farmacêuticos podem contribuir na identificação de condições de saúde não tratadas que precisam de tratamento farmacológico. O objetivo deste estudo é descrever potenciais omissões de prescrição identificadas por farmacêuticos que cuidam de idosos na atenção primária brasileira e se elas estão incluídas na ferramenta START - Screening Tool to Alert to Right Treatment. Os dados foram coletados dos prontuários de 585 idosos acompanhados em serviços de GTM na atenção básica em Minas Gerais, Brasil, de 2014 a 2017. Os farmacêuticos identificaram a necessidade de adicionar pelo menos um medicamento para 28,4% dos pacientes idosos, totalizando 233 medicamentos relacionados a 31 diferentes problemas de saúde não tratados. Um terço (n = 79) dos medicamentos sugeridos pelos farmacêuticos correspondeu a algum critério proposto pela ferramenta START. Estes resultados enfatizam a importância do atendimento holístico ao paciente nos serviços de GTM.
The lack of use of a necessary medication involves considerable risks to the older person. Through the provision of comprehensive medication management (CMM) services, pharmacists may identify untreated health conditions that need pharmacological treatment. The purpose of this study is to describe potential prescribing omissions identified by pharmacists taking care of older adults in Brazilian primary care and whether they are included in the Screening Tool to Alert to Right Treatment (START). Data were collected directly from the records of 585 older adults followed up in CMM services in primary care in Minas Gerais, Brazil, from 2014-2017. Pharmacists identified the need to add at least one medication for 28.4 % of the older patients, totaling 233 drugs related to 31 different untreated health problems. One third (n=79) of the drugs suggested corresponded to some criterion proposed by START. These results emphasize the importance of holistic patient care in CMM services.
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Melanoma is a skin cancer with a high mortality rate due to its invasive characteristics. Currently, immunotherapy and targeted therapy increase patient survival but are ineffective in the advanced stages of the tumor. Quercetin (Que) is a natural compound that has demonstrated chemopreventive effects against different types of tumors. This review provides evidence for the therapeutic potential of Que in melanoma and identifies its main targets. The Scopus, Web of Science, and PubMed databases were searched, and studies that used free or encapsulated Que in melanoma models were included, excluding associations, analogs, and extracts. As a result, 73 articles were retrieved and their data extracted. Que has multiple cellular targets in melanoma models, and the main regulated pathways are cell death, redox metabolism, metastasis, and melanization. Que was also able to regulate important targets of signaling pathways, such as PKC, RIG-I, STAT, and P53. In murine models, treatment with Que reduced tumor growth and weight, and decreased metastatic nodules and angiogenic vasculature. Several studies have incorporated Que into carriers, demonstrating improved efficacy and delivery to tumors. Thus, Que is a promising therapeutic agent for the treatment of melanoma; however, further studies are needed to evaluate its effectiveness in clinical trials.
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Melanoma , Neoplasias Cutáneas , Humanos , Animales , Ratones , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Quercetina/farmacología , Quercetina/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Melanoma Cutáneo MalignoRESUMEN
Live attenuated vaccines (LAVs) administered via the mucosal route may offer better control of the COVID-19 pandemic than non-replicating vaccines injected intramuscularly. Conceptionally, LAVs have several advantages, including presentation of the entire antigenic repertoire of the virus, and the induction of strong mucosal immunity. Thus, immunity induced by LAV could offer superior protection against future surges of COVID-19 cases caused by emerging SARS-CoV-2 variants. However, LAVs carry the risk of unintentional transmission. To address this issue, we investigated whether transmission of a SARS-CoV-2 LAV candidate can be blocked by removing the furin cleavage site (FCS) from the spike protein. The level of protection and immunity induced by the attenuated virus with the intact FCS was virtually identical to the one induced by the attenuated virus lacking the FCS. Most importantly, removal of the FCS completely abolished horizontal transmission of vaccine virus between cohoused hamsters. Furthermore, the vaccine was safe in immunosuppressed animals and showed no tendency to recombine in vitro or in vivo with a SARS-CoV-2 field strain. These results indicate that removal of the FCS from SARS-CoV-2 LAV is a promising strategy to increase vaccine safety and prevent vaccine transmission without compromising vaccine efficacy.
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Vacunas contra la COVID-19 , COVID-19 , Animales , Cricetinae , Humanos , COVID-19/prevención & control , Pandemias , SARS-CoV-2 , Vacunas Atenuadas , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
Background: Peripheral nerve disease may lead to physical disability because of decreased muscle strength and/or loss of sensitivity in the dermatomes of affected peripheral nerves. Both human immunodeficiency virus (HIV)- and leprosy-affected patients can develop neurological damage; therefore, the coinfection of these diseases presents new challenges to the health care of these patients. Aims and Objective: This study aimed to investigate the motor alterations of patients coinfected with HIV and leprosy and their relationship with clinical and anthropometric characteristics, compared with individuals with isolated diseases. Materials and Methods: In this cross-sectional study, 90 individuals were divided equally into three groups: HIV/acquired immunodeficiency syndrome (AIDS) group, leprosy group and HIV/leprosy group. All individuals underwent an evaluation of muscle strength and upper limb endurance adjusted for the Brazilian standards, a palm print pressure test using a digital dynamometer and anthropometric measurements (weight, height and skin folds). Results: The HIV/leprosy group had the highest mean body mass index, followed by the leprosy group and the HIV/AIDS group. Skinfolds were similar between the groups. Multiple linear regression, adjusted for sex and age, revealed the coinfection of HIV and leprosy as possible contributor to a worse prognosis of muscle function, highlighting the bilateral reduction in the levels of palm print compression strengths compared with isolated diseases (HIV and leprosy). High CD4 count and shorter antiretroviral therapy duration were associated with worse indices of muscle strength, such as gripping and resistance, in coinfected patients. Conclusion: Patients coinfected with HIV and leprosy exhibited greater motor damage than those with isolated diseases. Thus, motor damage may be related to the sum of the neurological manifestations of the two morbidities.
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Cladophialophora exuberans is a filamentous fungus related to black yeasts in the order Chaetothyriales. These melanized fungi are known for their 'dual ecology', often occurring in toxic environments and also being frequently involved in human infection. Particularly Cladophialophora exuberans, C. immunda, C. psammophila, and Exophiala mesophila have been described with a pronounced ability to degrade aromatic compounds and xenobiotic volatiles, such as benzene, toluene, ethyl-benzene, and xylene, and are candidates for bioremediation applications. The objective of the present study is the sequencing, assembly, and description of the whole genome of C. exuberans focusing on genes and pathways related to carbon and toxin management, assessing the tolerance and bioremediation of lead and copper, and verifying the presence of genes for metal homeostasis. Genomic evaluations were carried out through a comparison with sibling species including clinical and environmental strains. Tolerance of metals was evaluated via a microdilution method establishing minimum inhibitory (MIC) and fungicidal concentrations (MFC), and agar diffusion assays. Heavy metal bioremediation was evaluated via graphite furnace atomic absorption spectroscopy (GFAAS). The final assembly of C. exuberans comprised 661 contigs, with genome size of 38.10 Mb, coverage of 89.9X and a GC content of 50.8%. In addition, inhibition of growth was shown at concentrations of 1250 ppm for copper and at 625 ppm for lead, using the MIC method. In the agar tests, the strain grew at 2500 ppm of copper and lead. In GFAAS tests, uptake capacities were observed of 89.2% and 95.7% for copper and lead, respectively, after 21 experimental days. This study enabled the annotation of genes involved in heavy metal homeostasis and also contributed to a better understanding of the mechanisms used in tolerance of and adaptation to extreme conditions.
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Ascomicetos , Metales Pesados , Humanos , Biodegradación Ambiental , Benceno/metabolismo , Cobre/metabolismo , Agar/metabolismo , Ascomicetos/genética , Ascomicetos/metabolismo , Hidrocarburos/metabolismo , Metales Pesados/metabolismo , EcosistemaRESUMEN
This study aimed at evaluating the coefficients of total tract apparent digestibility (CTTAD) of nutrients, metabolisable energy (ME), diet palatability, faecal fermentative products and microbiota of dogs fed yeasts from different fermentation media and its fractions. Four diets were evaluated: control, without yeast (CO); diet with 10 g/kg brewer's yeast (BY); diet with 10 g/kg brewer's yeast + corn yeast (BCY); and diet with 10 g/kg BCY + cell wall fractions (BCYF). Twelve adult dogs were distributed in a randomized block design (periods). Each of the four diets was fed to a group of three dogs per period of 20 days, totalling two periods and six repetitions per treatment. Sixteen adult dogs were used for the palatability test, which compared the CO diet versus each one of the yeast diets. Data with normal distribution were subjected to analysis of variance (p < 0.05). Means were compared by orthogonal contrasts (p < 0.05): (A) CO diet versus BY, BCY and BCYF diets; (B) BY diet versus BCY and BCYF diets; (C) BCY diet versus BCYF diet. There was no difference in the CTTAD and ME of the diets (p > 0.05). Yeast diets reduced faecal odour and indole peak area (p < 0.05). Faecal short-chain fatty acids concentration was greater in dogs fed yeast diets compared to those fed the CO (p < 0.05). Yeast diets showed a higher intake ratio compared to the CO (p < 0.05). The BCY and BCYF diets resulted in a greater abundance of Bacteroides, Faecalibacterium, Coprococcus, and Phascolarctobacterium in relation to the CO (p < 0.05). Our results suggest that dietary yeast supplementation results in beneficial changes in intestinal functionality indicators, mainly with the combination of yeasts from brewers and corn fermentation media. In addition, yeast supplementation improves diet palatability without compromising nutrient digestibility.
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Microbiota , Saccharomyces cerevisiae , Animales , Perros , Alimentación Animal/análisis , Dieta/veterinaria , Suplementos Dietéticos/análisis , Digestión , Heces/microbiología , FermentaciónRESUMEN
OBJECTIVES: Medication literacy comprises the skills needed to access, understand, and act on medication information. Low medication literacy is frequent among older adults, making them more susceptible to negative health outcomes. The aim of this study was to develop and evaluate the content validity of an instrument to measure medication literacy in this population. METHOD: Multistage methodological study. Items were generated according to a conceptual model and a literature review. The instrument was submitted to a panel of experts to assess item's relevance, clarity, and theoretical classification. Subsequently, the instrument was applied to the target population to assess its comprehensibility. RESULTS: Content Validity Index results indicated excellent agreement among experts on the instrument's relevance (0.98) and clarity (0.91). Overall agreement between experts regarding the theoretical subdimensions was moderate [Fleiss' kappa=0.57 (p = 0.00)]. Items were reported to be fully understood by most representatives of the target population. The final version of the instrument had 33 items divided into eight scenarios of medication use. CONCLUSION: The instrument seems to have adequate content validity and good suitability for the target population. Therefore, it can help health professionals to identify older adults with low medication literacy, aiming to improve their medication use skills.
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Alfabetización en Salud , Humanos , Anciano , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , PsicometríaRESUMEN
BACKGROUND: Dietary sodium is a well-known risk factor for cardiovascular and renal disease; however, direct evidence of the longitudinal changes that occur with aging, and the influence of dietary sodium on the age-associated alterations are scarce. METHODS: C57BL/6 mice were maintained for 13 months on a low (LS, 0.02 % Na+), normal (NS, 0.3 % Na+) or high (HS, 1.6 % Na+) salt diet. We assessed 1) the longitudinal trajectories for two markers of cardiovascular and renal dysfunction (blood pressure (BP) and albuminuria), as well as hormonal changes, and 2) end-of-study cardiac and renal parameters. RESULTS: The effect of aging on BP and kidney damage did not reach significance levels in the LS group; however, relative to baseline, there were significant increases in these parameters for animals maintained on NS and HS diets, starting as early as month 7 and month 5, respectively. Furthermore, changes in albuminuria preceded the changes in BP relative to baseline, irrespective of the diet. Circulating aldosterone and plasma renin activity displayed the expected decreasing trends with age and dietary sodium loading. As compared to LS - higher dietary sodium consumption associated with increasing trends in left ventricular mass and volume indices, consistent with an eccentric dilated phenotype. Functional and molecular markers of kidney dysfunction displayed similar trends with increasing long-term sodium levels: higher renovascular resistance, increased glomerular volumes, as well as higher levels of renal angiotensin II type 1 and mineralocorticoid receptors, and lower renal Klotho levels. CONCLUSION: Our study provides a timeline for the development of cardiorenal dysfunction with aging, and documents that increasing dietary salt accelerates the age-induced phenotypes. In addition, we propose albuminuria as a prognostic biomarker for the future development of hypertension. Last, we identified functional and molecular markers of renal dysfunction that associate with long-term dietary salt loading.
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Hipertensión , Enfermedades Renales , Sodio en la Dieta , Animales , Ratones , Albuminuria , Presión Sanguínea , Riñón , Ratones Endogámicos C57BL , Cloruro de Sodio DietéticoRESUMEN
Rhabdomyolysis is characterized by muscle damage and leads to acute kidney injury (AKI). Clinical and experimental studies suggest that glycogen synthase kinase 3ß (GSK3ß) inhibition protects against AKI basically through its critical role in tubular epithelial cell apoptosis, inflammation and fibrosis. Treatment with a single dose of lithium, an inhibitor of GSK3ß, accelerated recovery of renal function in cisplatin and ischemic/reperfusion-induced AKI models. We aimed to evaluate the efficacy of a single dose of lithium in the treatment of rhabdomyolysis-induced AKI. Male Wistar rats were allocated to four groups: Sham, received saline 0.9% intraperitoneally (IP); lithium (Li), received a single IP injection of lithium chloride (LiCl) 80 mg/kg body weight (BW); glycerol (Gly), received a single dose of glycerol 50% 5 mL/kg BW intramuscular (IM); glycerol plus lithium (Gly+Li), received a single dose of glycerol 50% IM plus LiCl IP injected 2 hours after glycerol administration. After 24 hours, we performed inulin clearance experiments and collected blood / kidney / muscle samples. Gly rats exhibited renal function impairment accompanied by kidney injury, inflammation and alterations in signaling pathways for apoptosis and redox state balance. Gly+Li rats showed a remarkable improvement in renal function as well as kidney injury score, diminished CPK levels and an overstated decrease of renal and muscle GSK3ß protein expression. Furthermore, administration of lithium lowered the amount of macrophage infiltrate, reduced NFκB and caspase renal protein expression and increased the antioxidant component MnSOD. Lithium treatment attenuated renal dysfunction in rhabdomyolysis-associated AKI by improving inulin clearance and reducing CPK levels, inflammation, apoptosis and oxidative stress. These therapeutic effects were due to the inhibition of GSK3ß and possibly associated with a decrease in muscle injury.
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Lesión Renal Aguda , Rabdomiólisis , Ratas , Masculino , Animales , Litio/uso terapéutico , Litio/farmacología , Ratas Wistar , Glucógeno Sintasa Quinasa 3 beta , Glicerol/farmacología , Inulina/farmacología , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/tratamiento farmacológico , Rabdomiólisis/complicaciones , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/inducido químicamente , Riñón/metabolismo , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , ApoptosisRESUMEN
Seoul orthohantavirus (SEOV) is a rat-associated zoonotic pathogen with an almost worldwide distribution. In 2019, the first autochthonous human case of SEOV-induced hemorrhagic fever with renal syndrome was reported in Germany, and a pet rat was identified as the source of the zoonotic infection. To further investigate the SEOV reservoir, additional rats from the patient and another owner, all of which were purchased from the same vendor, were tested. SEOV RNA and anti-SEOV antibodies were found in both of the patient's rats and in two of the three rats belonging to the other owner. The complete coding sequences of the small (S), medium (M), and large (L) segments obtained from one rat per owner exhibited a high sequence similarity to SEOV strains of breeder rat or human origin from the Netherlands, France, the USA, and Great Britain. Serological screening of 490 rats from breeding facilities and 563 wild rats from Germany (2007-2020) as well as 594 wild rats from the Netherlands (2013-2021) revealed 1 and 6 seropositive individuals, respectively. However, SEOV RNA was not detected in any of these animals. Increased surveillance of pet, breeder, and wild rats is needed to identify the origin of the SEOV strain in Europe and to develop measures to prevent transmission to the human population.
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Virus Seoul , Zoonosis , Humanos , Animales , Ratas , Europa (Continente) , Cruzamiento , Exones , Francia , ARN , Virus Seoul/genéticaRESUMEN
Herpes simplex virus 1 (HSV-1) encodes a family B DNA polymerase (Pol) capable of exonucleolytic proofreading whose functions have been extensively studied in the past. Early studies on the in vitro activity of purified Pol protein found that the enzymatic functions of the holoenzyme are largely separate. Consequently, exonuclease activity can be reduced or abolished by certain point mutations within catalytically important regions, with no or only minor effects on polymerase activity. Despite unimpaired polymerase activity, the recovery of HSV-1 mutants with a catalytically inactive exonuclease has been so far unsuccessful. Hence, mutations such as D368A, which abolish exonuclease activity, are believed to be lethal. Here, we show that HSV-1 can be recovered in the absence of Pol intrinsic exonuclease activity and demonstrate that a lack of proofreading causes the rapid accumulation of likely detrimental mutations. Although mutations that abolish exonuclease activity do not appear to be lethal, the lack of proofreading yields viruses with a suicidal phenotype that cease to replicate within few passages following reconstitution. Hence, we conclude that high replication fidelity conferred by proofreading is essential to maintain HSV-1 genome integrity and that a lack of exonuclease activity produces an initially viable but rapidly suicidal phenotype. However, stably replicating viruses with reduced exonuclease activity and therefore elevated mutation rates can be generated by mutating a catalytically less important site located within a conserved exonuclease domain. IMPORTANCE Recovery of fully exonuclease-deficient herpes simplex virus 1 (HSV-1) DNA polymerase mutants has been so far unsuccessful. However, exonuclease activity is not known to be directly essential for virus replication, and the lethal phenotype of certain HSV-1 polymerase mutants is thus attributed to factors other than exonuclease activity. Here, we showed that the recovery of a variety of exonuclease-deficient HSV-1 polymerase mutants is possible and that these mutants are initially replication competent. We, however, observed a progressive loss of mutant viability upon cell culture passaging, which coincided with the rapid accumulation of mutations in exonuclease-deficient viruses. We thus concluded that a lack of DNA proofreading in exonuclease-deficient viruses causes an initially viable but rapidly suicidal hypermutator phenotype and, consequently, the extinction of mutant viruses within few generations following recovery. This would make the absence of exonuclease activity the primary reason for the long-reported difficulties in culturing exonuclease-deficient HSV-1 mutants.
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Herpesvirus Humano 1 , Replicación del ADN/genética , Exonucleasas/genética , Exonucleasas/metabolismo , Herpesvirus Humano 1/enzimología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Mutación , FenotipoRESUMEN
OBJECTIVE: To investigate the use of sedatives by older adults attending a private outpatient geriatric clinic in Belo Horizonte (MG), Brazil, and its association with falls and hip fractures. METHODS: Using a longitudinal design, the prevalence of benzodiazepine and nonbenzodiazepine ("z-drugs") intake by older adults was described and their association with the incidence of falls and fractures (30 days after the initial visit) was evaluated through logistic regression. RESULTS: A total of 7821 older adults were included in the study, most of them women (72.50%), with a mean age of 77.5 years and a mean Clinical-Functional Vulnerability Index (IVCF-20) score of 16.5. The overall prevalence of sedative use (any sedative) was 6.19%, with 4.48% benzodiazepines and 1.98% z-drugs. The most widely used sedatives were clonazepam (29.04%), zolpidem (28.65%), and alprazolam (23.44%). Falls were reported for 182 patients (2.33%), with a higher incidence among users of any sedatives (4.34; p = 0.002; OR = 1.94, adjusted for sex, age, and IVCF-20) and benzodiazepines (5.14%; p < 0.001; OR = 2.28) than among non-users (2.19%). Hip fractures occurred in 33 patients (0.42%), and again were more frequent among users of sedatives (1.03%; p = 0.032; OR = 2.57) and benzodiazepines (1.43%; p = 0.003; OR = 3.45) than among non-users (0.38%). CONCLUSIONS: The use of sedatives, especially benzodiazepines, is associated with an increased incidence of falls and hip fractures in older adults
OBJETIVO: Investigar a utilização de sedativos entre idosos atendidos em ambulatório privado de geriatria em Belo Horizonte (MG), bem como sua associação com quedas e fraturas de fêmur. METODOLOGIA: Trata-se de estudo longitudinal, no qual foi descrita a prevalência de uso de benzodiazepínicos e drogas Z entre idosos (60 anos ou mais) e avaliada sua associação com a incidência de queda e fratura (30 dias após consulta inicial) por meio de regressão logística. RESULTADOS: Foram incluídos no estudo 7821 idosos, com maioria feminina (72,50%), idade média de 77,5 anos e Índice de Vulnerabilidade Clínico Funcional (IVCF-20) médio de 16,5 pontos. A prevalência de uso de sedativos em geral foi de 6,19%, sendo 4,48% de benzodiazepínicos e 1,98% de drogas Z. Os medicamentos sedativos mais utilizados foram clonazepam (29,04%), zolpidem (28,65%) e alprazolam (23,44%). Relatou-se queda para 182 idosos (2,33%), com incidência maior entre usuários de sedativos (4,34; p = 0,002; OR = 1,94 ajustada por sexo, idade e IVCF-20) e de benzodiazepínicos (5,14%; p < 0,001; OR = 2,28) do que entre não usuários (2,19%). Identificou-se fratura de fêmur em 33 idosos (0,42%), sendo mais frequente entre usuários de sedativos (1,03%; p = 0,032; OR = 2,57) e de benzodiazepínicos (1,43%; p = 0,003; OR = 3,45) do que entre não usuários (0,38%). CONCLUSÃO: Concluiu-se que a incidência de quedas e fraturas de fêmur em idosos possui associação com o uso de medicamentos sedativos, em especial os benzodiazepínicos
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Benzodiazepinas/administración & dosificación , Accidentes por Caídas , Fracturas del Fémur/tratamiento farmacológico , Servicios de Salud para Ancianos , Hipnóticos y Sedantes/administración & dosificación , Estudios LongitudinalesRESUMEN
Resumo A divisão sexual do trabalho ocasiona iniquidade entre gêneros, bem como situações de violência direcionadas às mulheres no ambiente laboral. Na área farmacêutica, a maioria feminina e a inserção em múltiplos cenários, que envolvem contato com público e parcerias profissionais diferenciadas, potencializam a exposição à violência. Assim, o objetivo deste estudo foi analisar situações de violência vivenciadas por farmacêuticas no ambiente laboral. Para tal, utilizou-se método qualitativo, com análise de conteúdo, realizada no software NVivo®, de uma survey on line, respondida por farmacêuticas (n=381) registradas no Conselho Regional de Farmácia de Minas Gerais, Brasil. Como resultado, identificou-se quatro categorias: 'Convivendo com o desrespeito, ameaças e vulnerabilidade', 'O sexismo e o machismo estrutural que cala, diminui e atordoa', 'A discriminação contra a mulher como obstáculo à equidade' e 'Assédio sexual e objetificação da mulher'. Emergiram diversas expressões de violências no ambiente laboral provenientes de múltiplos agressores. Farmacêuticas reconheceram prejuízo profissional e pouco reconhecimento pela capacidade técnica. Conclui-se que os relatos expuseram a falta de proteção da integridade farmacêutica no ambiente de trabalho. Espera-se que esses resultados tragam à luz a desigualdade de gênero no trabalho farmacêutico, com destaque para situações de violência, ampliando a discussão e proporcionando evolução dessa profissão majoritariamente feminina.
Abstract The sexual division of labor causes inequality between genders, as well as situations of violence directed to women in the workplace. In the pharmaceutical area, the majority of women and insertion in multiple scenarios, involving contact with public and differentiated professional partnerships, enhance exposure to violence. Thus, the objective of this study was to analyze situations of violence experienced by pharmacists in the workplace. For this, a qualitative method was used, with content analysis, performed in the NVivo® software, of an online survey, answered by pharmacists (n=381) registered in the Regional Pharmacy Council of Minas Gerais, Brazil. As a result, four categories were identified: 'Living with disrespect, threats and vulnerability,' 'Sexism and structural chauvinism that shuts down, diminishes and torments,' 'Discrimination against women as an obstacle to equity' and 'Sexual harassment and objectification of women.' Several expressions of violence in the labor environment emerged from multiple aggressors. Pharmacists recognized professional impairment and little recognition for technical capacity. We concluded that the reports exposed the lack of protection of pharmaceutical integrity in the workplace. It is expected that these results bring to light the gender inequality in pharmaceutical work, with emphasis on situations of violence, expanding the discussion and providing evolution of this mostly female profession.
Resumen La división sexual del trabajo ocasiona iniquidad entre los géneros, así como situaciones de violencia dirigidas a las mujeres en el entorno laboral. En el ámbito farmacéutico, la mayoría de las mujeres y la inserción en múltiples escenarios, que implican contacto con el público y asociaciones profesionales diferenciadas, potencian la exposición a la violencia. Por lo tanto, el objetivo de este estudio fue analizar las situaciones de violencia experimentadas por las farmacéuticas en el entorno laboral. Para esto, se utilizó un método cualitativo, con análisis de contenido, realizado en el software NVivo®, de una encuesta en línea, respondida por farmacéuticas (n=381) registradas en el Consejo Regional de Farmacia de Minas Gerais, Brasil. A consecuencia, se identificaron cuatro categorías: 'Conviviendo con falta de respeto, amenazas y vulnerabilidad', 'el sexismo y el machismo estructural que cala, disminuye y atormentó', 'la discriminación contra la mujer como obstáculo a la equidad' y 'el acoso sexual y la objeción de la mujer'. Han surgido varias expresiones de violencia en el entorno laboral procedentes de múltiples agresores. Los productos farmacéuticos han reconocido el daño profesional y el escaso reconocimiento de la capacidad técnica. Se concluye que los informes haciendo hincapié de manifiesto la falta de protección de la integridad farmacéutica en el entorno laboral. Se espera que estos resultados traigan a la luz la desigualdad de género en el trabajo farmacéutico, haciendo hincapié en las situaciones de violencia, ampliando el debate y dando lugar a la evolución de esa profesión principalmente femenina.