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1.
Infectio ; 23(supl.1): 73-91, dic. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | ID: biblio-984511

RESUMO

Resumen: Los pacientes con infección por VIH tienen una mayor incidencia de eventos cardiovasculares en comparación con la población general; los factores que contribuyen al incremento del riesgo de eventos cardiovasculares son la prevalencia de factores de riesgo cardiovascular tradicionales (FRCV), la infección por VIH que condiciona tanto un proceso de inflamación crónica como alteración de la función endotelial y la exposición a los antirretrovirales. Los factores que deben ser objeto de intervención son los FRCV tradicionales, en especial la alta tasa de fumadores entre este grupo de pacientes, la tamización y tratamiento de HTA, el síndrome metabólico y el acceso temprano a la terapia antirretroviral con medicamentos con mayor perfil de seguridad . Esta guía pretende proveer información y recomendaciones en el ámbito nacional acerca de la relación entre la infección por VIH/SIDA (Síndrome de Inmunodeficiencia Adquirida), uso de antirretrovirales y riesgo cardiovascular.


Abstract: Patients with VIH infection have greater risk for cardiovascular diseases compared to general population. Risk factors that increase the frequency of cardiovascular events are: presence of cardiovascular traditional risk factors, chronic inflammation by HIV that impairs endothelial function and the exposure to antiretrovirals. The factors that should be the target for intervention are the traditional know cardiovascular factors such, especially high rate of smokers, screening and treatment for hypertension, metabolic syndrome and early access to HAART. The present guidelines provides information about the use of antiretrovirals in patients with HIV and its relation with cardiovascular risk.

2.
Infectio ; 23(supl.1): 106-128, dic. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | ID: biblio-984514

RESUMO

Resumen Los inhibidores de transferencia de la cadena de integrasa (INSTI) son medicamentos cuyo mecanismo de acción consiste en bloquear el proceso de integración del ADN proviral al ADN del hospedero mediante la unión al sitio catalítico de la integrasa viral y de esta manera evitar su replicación. Actualmente se cuenta con la aprobación INSTI de primera y segunda generación, presentan similitud en su mecanismo de acción, cambios en su estructura que modifican su barrera genética, pero mantienen su perfil de seguridad y efectividad. Desde su aprobación en el año 2007, se han llevado a cabo múltiples estudios clínicos cuyos resultados han permitido avanzar en el conocimiento de su efectividad en diferentes escenarios clínicos; (pacientes naive, experimentados, esquemas de simplificación y profilaxis, así, como en el conocimiento de su perfil de mutaciones de resistencia). En el presente artículo se hizo una revisión de los miembros de esta familia de antirretrovirales (ARV).


Abstract: Integrase strand transfer inhibitors (INSTI) are drugs whose mechanism of action consists of blocking the integration process of the proviral DNA to the host DNA by binding to the catalytic site of the viral integration and thus preventing its replication. Currently it has the approval of INSTI of first generation, two of second generation and in process of approval of a third of second generation. The two generations has similitude in its mechanisms of action, changes in its structures that modify its genetic barrier, but keeping his security and effectiveness profile. Since the approval of INSTI´s in 2007 to date, multiple clinical studies have been carried out, whose results have allowed us to advance in the knowledge of their effectiveness in different clinical scenarios; (naive patients, experienced patients, simplification and prophylaxis schemes, as well as in the knowledge of their profile of resistance mutations). In the present article, we made a review of the members of this family of antiretrovirals (ARV).

3.
Infectio ; 23(4): 347-351, Dec. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | ID: biblio-1019864

RESUMO

Resumen Objetivo: Describir las características clínicas, demográficas, frecuencia, tipo de aislamientos microbiológicos y resistencia a los antimicrobianos de pacientes con neoplasias hematológicas que presentaron como complicación neutropenia febril en el Hospital Universitario de San Ignacio Métodos: Estudio descriptivo observacional, se tomaron datos de historias clínicas de los pacientes adultos hospitalizados en la Unidad de Hematología y Trasplante de Médula Ósea, que cumplieron criterios de neutropenia febril entre enero de 2013 y diciembre de 2014 Resultados: se recolectaron 345 episodios de neutropenia febril, correspondientes a 193 pacientes. Se documentó foco infeccioso en el 68,1% de los episodios, con aislamiento microbiológico en el 62.9% de los episodios, con predominio de bacilos gram negativos, en 63,7% de los casos, seguido por los cocos gram positivos en 27,9% y hongos en 4,9%. En cuanto a los mecanismos de resistencia, en los aislamientos Escherichia coli y Klebsiella peumoniae se encontró producción de Beta Lactamasas de Espectro Extendido (BLEEs) en 17,5 y 13,8%; Carbapenemasas tipo KPC en 1,25 y 2,8% respectivamente. En cuanto a Staphylococcus aureus, se encontró resistencia a meticilina en 6,8% de los aislamientos. Mortalidad asociada a infección en 16,5% de los casos. Conclusión: En pacientes con Neoplasias Hematológicas con neutropenia febril post quimioterapia en el Hospital Universitario de San Ignacio encontramos alta probabilidad de documentación de foco infeccioso, con predominio de microorganismos gram negativos, especialmente enterobacterias; con comportamiento similar en pacientes post trasplante de precursores hematopoyéticos.


Abstract Objective: To describe the demographic and clinical characteristics, as well as frequency and type of bacterial isolate and resistance patterns in patients with hematological neoplasms complicated by febrile neutropenia at San Ignacio University Hospital Methods: This is a retrospective observational study. Data were collected from medical records of adult patients admitted in the Hemato-oncology and Bone Marrow Transplant Unit. Inclusion criteria was presence of febrile neutropenia in the setting of a hematological neoplasm from January 2013 to December 2014. Results: 345 episodes of febrile neutropenia from 193 patients were studied. An infectious focus was identified in 68.1% of episodes, and a bacterial isolate was obtained in 62.9% of episodes. The predominant microorganisms were gram-negative rods, gram-positive cocci, and fungi with a frequency of 63.7%, 27.9%, and 4.9% respectively. In term of resistance patterns, Escherichia coli and Klebsiella peumoniae isolates had a frequency of ESBL susceptibility pattern of 17.5% and 13.8% respectively; and a frequency of KPC susceptibility pattern of 1.25% and 2.8% respectively. The frequency of methicillin resistant Staphylococcus aureus was 6.8%. Death associated to infection ocurred in 16.5% of episodes. Conclusions: In patients with hematological neoplasms complicated by febrile neutropenia at San Ignacio University Hospital, we found a high rate of documentation of infectious focus, with a predominance of gram-negative rods, specially Enterobacteriacea; with a similar pattern in receptors of hematopoietic stem cell transplantation.

4.
Braz J Infect Dis ; 23(5): 352-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31545952

RESUMO

Exposure to Pneumocystis jirovecii (P. jirovecii) can lead to a wide variety of presenting features ranging from colonization in immunocompetent patients with lung disease, to invasive infections in immunocompromised hosts. Colonization by this fungus in patients with chronic obstructive pulmonary disease (COPD) could be associated with higher rates of exacerbations and impaired lung function in these patients. Our objective was to determine whether colonization by P. jirovecii in patients with COPD is associated with increased exacerbations and deterioration of lung function. This was a prospective cohort study on patients with COPD. All participants meeting selection criteria underwent clinical and microbiological assessments and were then classified as colonized vs. non-colonized patients. Chi-squared tests were performed and multivariate logistic models were fitted in order to obtain risk ratios (RR) with 95% confidence intervals (CI). We documented a frequency of colonization by P. jirovecii of 32.3%. Most patients were categorized as having GOLD B and D COPD. The history of significant exacerbations in the last year, health status impairment (COPD Assesment Tool ≥10), airflow limitation (percent of post-bronchodilator FEV1), and BODEx score (≥5) were similar between groups. After a 52-week follow-up period, the rate of adjusted significant exacerbations did not differ between groups. However, a decrease in FEVI was found in both groups.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31300301

RESUMO

BACKGROUND/PURPOSE: The aim of this study was to characterize the Staphylococcus aureus strains isolated from periodontal lesions of patients, to determine the expression of genes involved in cell adhesion upon their infection of human epithelial cells using an in vitro model, its biofilm formation, and its resistance to antibiotics. METHODS: S. aureus was analysed by PCR, Kirby-Bauer, and pulsed-field gel electrophoresis (PFGE), measuring gene expression by real-time PCR after infection of human cells in vitro. RESULTS: S. aureus was identified in 18.6% (50/268) of the samples. All strains (n = 50) possessed the virulence genes spa (Staphylococcal protein A), coa (coagulase), and icaAB (intercellular adhesin); 96% (n = 48) possessed clfB (clumping factor B), and 88% (n = 44) possessed ebps (elastin-binding protein) and sdrD (serine aspartate repeat protein D). All strains were resistant to methicillin, ampicillin, dicloxacillin, cefotaxime, and penicillin, and were multidrug resistant to 6-12 antibiotics. PFGE analysis showed 37 different pulsed-field types and most strains (60.4%) had a unique pulsed-field type. Twenty-four distinct combinations of virulence genes and antibiotic-resistant phenotypes were identified. CONCLUSION: Although S. aureus has been considered a transient member of the oral microbiota, our results indicate a high-level expression of virulence genes and multidrug resistance in the strains isolated from periodontal lesions. These strains might complicate the successful treatment of the disease.

6.
Antioxid Redox Signal ; 31(7): 503-520, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31088288

RESUMO

Aims: Histidine triad nucleotide-binding protein 1 (HINT1) exhibits proapoptotic and tumor-suppressive activity. HINT1 binds to transcription factors such as teneurin1 and to the regulator of G protein signaling 17 (RGS) (Z2) protein, which incorporates the small ubiquitin-like modifier (SUMO), and is implicated in several types of cancer. HINT1 interacts with proteins such as PKCγ and Raf-1 through zinc ions provided by the cysteine-rich domain of RGSZ2 and the coupled neural nitric oxide synthase (nNOS). Recently, a series of HINT1 mutants have been reported to cause human autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM). However, the specific alteration in the function of HINT1 induced by these mutants remains to be elucidated. Because sumoylation modifies protein association and transcriptional regulation, we investigated whether HINT1 exhibits zinc- and redox-regulated sumoylase activity, which may be altered in those mutants. Results: HINT1 exhibits cysteine protease activity to remove SUMO from a variety of signaling proteins. HINT1 sumoylase activity is blocked by zinc, and it is released by nitric oxide or calcium-activated calmodulin (CaM). HINT1 contains a SUMO-interacting motif (110-116 HIHLHVL) and the catalytic triad Cys84-Asp87-His114 in the C-terminal region. Thus, zinc probably provided by the RGSZ2-nNOS complex may bind to Cys84 to block HINT1 isopeptidase activity. Innovation: To date, HINT1 is the only sumoylase that is regulated by two alternate pathways, redox- and calcium-activated CaM. Conclusion: The 15 human HINT1 mutants reported to cause ARAN-NM exhibited altered sumoylase activity, which may contribute to the onset of this human motor disease.

7.
BMC Microbiol ; 19(1): 106, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122184

RESUMO

BACKGROUND: The introduction of MALDI-TOF MS in the clinical microbiology laboratory has modified the approaches for the identification of fungi. Thanks to this tool, it is possible to identify cryptic species, which possess critical susceptibility patterns. Clinical strains were identified using the MicroScan and MALDI-TOF MS systems. Discrepant results from both methods were investigated using ITS rDNA barcoding. Finally, these isolates were also tested for in vitro susceptibility. RESULTS: The percentage of agreement between both methods to 498 yeast isolates was of 93.6% (32 discrepant isolates). The concordance of ITS sequencing with MALDI-TOF MS was higher (99%) than that of MicroScan (94%). Several of these discordant yeasts displayed high MICs for antifungal agents. CONCLUSIONS: Our study highlights the need of the MS and molecular approaches such as MALDI-TOF MS and ITS rDNA barcoding for the correct identification of emerging or cryptic yeast species; besides, some of these could be multidrug resistant. This work was the first experience in the implementation of the MALDI-TOF MS technology in Colombia. We found the first uncommon yeasts including Candida auris and we could identify Trichosporon faecalis. Our work highlights a clear necessity of an accurate yeast identification as a much more pertinent technique than the susceptibility profiles, because the most unusual yeasts exhibit resistance profiles to the few available antifungals.

8.
Cell Rep ; 27(9): 2558-2566.e4, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141682

RESUMO

RIF1 is a multifunctional protein implicated in controlling DNA replication and repair. Here, we show that human RIF1 protects nascent DNA from over-degradation at stalled replication forks. The major nuclease resecting nascent DNA in the absence of RIF1 is DNA2, operating with WRN as an accessory helicase. We show that RIF1 acts with protein phosphatase 1 to prevent over-degradation and that RIF1 limits phosphorylation of WRN at sites implicated in resection control. Protection by RIF1 against inappropriate degradation prevents accumulation of DNA breakage. Our observations uncover a crucial function of human RIF1 in preventing genome instability by protecting forks from unscheduled DNA2-WRN-mediated degradation.

9.
Infectio ; 23(1): 22-26, Jan.-Mar. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | ID: biblio-975558

RESUMO

Resumen Introducción: La histoplasmosis diseminada es una forma de presentación común en pacientes inmunosuprimidos. La introducción de nuevos métodos diagnós ticos y la mejoría de la sobrevida de los pacientes con VIH pueden hacer cambiar las características clínicas de los pacientes con esta enfermedad. El objetivo de este estudio es describir las características demográficas, clínicas y métodos diagnósticos para esta enfermedad utilizados en una institución de cuarto nivel de complejidad en Colombia durante los últimos cinco años. Métodos: Se realizó un estudio observacional tipo serie de casos, incluyendo pacientes con diagnóstico de histoplasmosis manejados en el Hospital Universitario San Ignacio en Bogotá (Colombia) entre enero de 2012 y diciembre de 2016. Los casos fueron identificados utilizando una herramienta automatizada a partir de las historias clínicas electrónicas (DISEARCH). Resultados: 34 pacientes fueron incluidos, 73,5% con VIH. La enfermedad fue más sintomática en los pacientes con VIH. Los síntomas más frecuentes fueron fiebre y tos (80%), seguidas por diarrea (47%) y manifestaciones cutáneas (35%). El estudio histopatológico fue el método de confirmación más frecuente. El antígeno urinario, fue positivo en el 92.8% de los pacientes a quienes se les realizó la prueba. Las enfermedades autoinmunes fueron la principal causa asociada en pacientes VIH negativos. Conclusiones: Las características clínicas de los pacientes con histoplasmosis son similares a las descritas en estudios previos en colombia, llamando la atención la alta prevalencia de diarrea y manifestaciones cutáneas. El antígeno urinario para histoplasma y las biopsias cutáneas son excelentes métodos diagnósticos, menos invasivos y con resultados rápidamente disponibles.


Abstract Introduction: Disseminated histoplasmosis is a common presentation in immunosuppressed patients. The introduction of new diagnostic methods and the impro vement of the survival of patients with HIV could have changed the clinical characteristics of patients with this disease. The objective of this study is to describe the demographic characteristics, clinical and methods for diagnosis of this disease in a high conplexity institution in Colombia during the last five years. Methods: A serie of cases was conducted, including patients diagnosed with histoplasmosis managed at the San Ignacio University Hospital in Bogotá (Colombia) between January 2012 and December 2016. The cases were selected using an automatic tool for searching in health electronic records (DISEARCH). Results: 34 patients were included, 73.5% with HIV. The disease was more symptomatic in patients with HIV. The most frequent symptoms were fever and cough (80%), followed by diarrhea (47%) and skin manifestations (35%). The histopathological study was the most frequent confirmation method. The urinary antigen was positive in 92.8% of the patients, in whom the test was performed. Autoimmune diseases were the main cause associated in HIV negative patients. Conclusions: The clinical characteristics of patients with histoplasmosis are similar to those described in previous studies in Colombia. It was remarkably the high prevalence of diarrhea and cutaneous manifestations. The urinary antigen for histoplasma and skin biopsies are excellent diagnostic methods, less invasive and with rapidly available results.

10.
Trends Psychol ; 26(4): 2119-2132, out.-dez. 2018. tab
Artigo em Espanhol | LILACS-Express | ID: biblio-986183

RESUMO

Resumen Siguiendo el modelo transdiagnóstico, se diseñó un protocolo de evaluación para estrés, ansiedad y depresión. Se realizaron dos estudios. El primero fue de tipo instrumental en el cual se estableció la validez de contenido del protocolo a través del juicio de armonía interjueces, con nueve expertos en evaluación transdiagnóstica, quienes evaluaron los aspectos generales, las variables transdiagnósticas incluidas, las problemáticas clínicas e instrumentos propuestos, mediante la técnica Angoff Modificada. Los coeficientes rwg oscilaron entre .33 y .97 valores que indicaron acuerdo entre jueces. Los indicadores de severidad e indulgencia permiten inferir que la evaluación de los expertos fue favorable. En el segundo estudio se compararon las puntuaciones medias obtenidas en la aplicación del protocolo a 15 víctimas del conflicto armado y 73 personas sintomáticas. No se encontraron diferencias estadísticamente significativas entre las medias de las variables transdiagnósticas entre los dos grupos los valores p oscilaron entre .09 y .95, resultados que permiten inferir que la sensitividad ansiosa, intolerancia a la incertidumbre y afecto positivo-negativo, como variables transdiagnósticas pueden ser identificadas mediante el protocolo, independientemente del tipo de diagnóstico o condición de víctima.


Resumo O objetivo deste estudo foi descrever as propriedades de um protocolo para a avaliação do estresse, a ansiedade e a depressão, elaborado segundo o modelo transdiagnóstico. Realizaram-se dois estudos. No primeiro (do tipo instrumental) foram procuradas evidências de validade de conteúdo por meio da estimação da concordância entre juízes. Nove especialistas na área de avaliação transdiagnóstica analisaram as características gerais, as problemáticas clínicas, os instrumentos propostos e as variáveis transdiagnósticas contidas no protocolo, por meio da técnica Angoff modificada. Os coeficientes rwg mostraram uma boa concordância entre os juízes. A análise dos índices de severidade e indulgencia indica que a avaliação dos especialistas foi favorável. No segundo estudo, o protocolo foi aplicado a 15 vítimas do conflito armado e 73 pessoas sintomáticas, e suas pontuações foram comparadas. Não houve diferenças estatisticamente significativas entre os dois grupos quanto às variáveis transdiagnósticas, esses resultados permitem inferir que o protocolo pode ser utilizado para identificar a sensitividade ansiosa, a intolerância à incerteza e o afeto positivo-negativo, como variáveis transdiagnósticas, independentemente do tipo de diagnóstico ou a condição da vítima.


Abstract Two studies were undertaken following the transdiagnostic model, an evaluation protocol for stress, anxiety, and depression was designed. The first one was instrumental, in which the validity of the content of the protocol was established through interjudged harmony judgment, with nine experts in transdiagnostic evaluation, who evaluated the general aspects, the transdiagnostic variables included, the clinical problems, and the instruments proposed, using the modified Angoff technique. The rwg coefficients fluctuated between .33 and .97 showing inter-judge agreement. The indicators of severity and indulgence allowed us to infer that the evaluation of the experts was favorable. In the second study, the average scores obtained in the application of the protocol were compared to 15 victims of the armed conflict and 73 symptomatic people. There were no statistically significant differences between the means of the transdiagnostic variables between the two groups, p-values fluctuated between .09 and .95, this results allow us to infer that anxiety sensitivity, intolerance to uncertainty and positive-negative affect as transdiagnostic variables can be identified by means of the protocol regardless of the type of diagnosis or condition of victim.

11.
Mol Brain ; 11(1): 51, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30223868

RESUMO

Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer. CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke. In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion. These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.

12.
Int J Neuropsychopharmacol ; 21(10): 938-948, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860313

RESUMO

Background: Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3ß that accompanies this disease. Methods: In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the "manic" Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors. Results: The activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3ß inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the "bipolar" HINT1-/- mice during pro-depressive episodes. Conclusions: σ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.

13.
Oncotarget ; 9(34): 23373-23389, 2018 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29805740

RESUMO

Fenfluramine exhibits antiepileptic properties and thus diminishes epileptiform discharges in experimental animal models of Dravet syndrome. Fenfluramine is metabolized into norfenfluramine in vivo, which shows greater affinity and agonist activity at serotonin 5HT2 receptors (5HT2R) than fenfluramine. In this study, we found that fenfluramine and norfenfluramine disrupted the regulatory association of the sigma 1 receptor (σ1R) with NR1 subunits of glutamate N-methyl-D-aspartate receptors (NMDAR), an effect that was also produced by σ1R antagonists such as S1RA and prevented by σ1R agonists such as PPCC. The antagonists removed σ1R bound to NMDAR NR1 subunits enabling calcium-regulated calmodulin (CaM) to bind to those subunits. As a result, CaM may inhibit calcium permeation through NMDARs. The serotoninergic activity of fenfluramine at 5HT2AR, and likely also at 5HT2CR, collaborated with its activity at σ1Rs to prevent the convulsive syndrome promoted by NMDAR overactivation. Notably, fenfluramine enhanced the inhibitory coupling of G protein-coupled receptors such as 5HT1AR and cannabinoid type 1 receptor with NMDARs, thus allowing the more effective restrain of NMDAR activity. Thus, fenfluramine circumvents the negative side effects of direct NMDAR antagonists and may improve the quality of life of subjects affected by such proconvulsant dysfunctions.

14.
Int J Infect Dis ; 69: 63-67, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29421668

RESUMO

BACKGROUND: Candida auris is a recently reported Candida species that is phenotypically similar to Candida haemulonii and related to hospital outbreaks. This organism can be misidentified as Candida haemulonii, Candida famata, Candida catenulata, or Rhodotorula glutinis by phenotypic approaches. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and DNA sequence analysis using internal transcribed spacer rDNA bar-coding provide an accurate identification. CASE REPORTS: Three cases of C. auris infection in patients with risk factors for fungal infection (one admitted to the intensive care unit, one with lymphoma, and one with HIV; all three with previous antibiotic use) are reported; these infections were not epidemiologically related. Yeast isolates were recovered from blood, ocular secretion, and bronchoalveolar lavage and were misidentified as C. catenulata and Candida albicans by the phenotypic MicroScan method. The isolates were confirmed to be C. auris by means of MALDI-TOF MS and DNA sequence analysis. Antifungal susceptibility testing was performed on these C. auris isolates, which exhibited high minimum inhibitory concentrations to triazoles and amphotericin B. One patient survived and the other two died. Only one of these deaths was related to fungemia. CONCLUSIONS: C. auris is an emerging and opportunistic multidrug-resistant human pathogen. It is necessary to strengthen measures to achieve an accurate and quick identification and also to avoid its dissemination. This will require improvements in health and infection control measures, as well as the promotion of antifungal stewardship in healthcare facilities.


Assuntos
Candida/genética , Candida/isolamento & purificação , Candidíase/epidemiologia , Surtos de Doenças , Idoso , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Colômbia/epidemiologia , Farmacorresistência Fúngica Múltipla/genética , Feminino , Humanos , Controle de Infecções , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA , Triazóis/farmacologia
15.
Mol Neurobiol ; 55(6): 4940-4951, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28779350

RESUMO

The glutamate N-methyl-D-aspartate receptor (NMDAR) plays an essential role in the excitotoxic neural damage that follows ischaemic stroke. Because the sigma-1 receptor (σ1R) can regulate NMDAR transmission, exogenous and putative endogenous regulators of σ1R have been investigated using animal models of ischaemic stroke. As both agonists and antagonists provide some neural protection, the selective involvement of σ1Rs in these effects has been questioned. The availability of S1RA (E-52862/MR309), a highly selective σ1R antagonist, prompted us to explore its therapeutic potential in an animal model of focal cerebral ischaemia. Mice were subjected to right middle cerebral artery occlusion (MCAO), and post-ischaemic infarct volume and neurological deficits were determined across a range of intervals after the stroke-inducing surgery. Intracerebroventricular or intravenous treatment with S1RA significantly reduced the cerebral infarct size and neurological deficits caused by permanent MCAO (pMCAO). Compared with the control/sham-operated mice, the neuroprotective effects of S1RA were observed when delivered up to 5 h prior to surgery and 3 h after ischaemic onset. Interestingly, neither mice with the genetic deletion of σ1R nor wild-type mice that were pre-treated with the σ1R agonist PRE084 showed beneficial effects after S1RA administration with regard to stroke infarction. S1RA-treated mice showed faster behavioural recovery from stroke; this finding complements the significant decreases in matrix metalloproteinase-9 (MMP-9) expression and reactive astrogliosis surrounding the infarcted cortex. Our data indicate that S1RA, via σ1R, holds promising potential for clinical application as a therapeutic agent for ischaemic stroke.

16.
EMBO Rep ; 18(3): 403-419, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28077461

RESUMO

The human RIF1 protein controls DNA replication, but the molecular mechanism is largely unknown. Here, we demonstrate that human RIF1 negatively regulates DNA replication by forming a complex with protein phosphatase 1 (PP1) that limits phosphorylation-mediated activation of the MCM replicative helicase. We identify specific residues on four MCM helicase subunits that show hyperphosphorylation upon RIF1 depletion, with the regulatory N-terminal domain of MCM4 being particularly strongly affected. In addition to this role in limiting origin activation, we discover an unexpected new role for human RIF1-PP1 in mediating efficient origin licensing. Specifically, during the G1 phase of the cell cycle, RIF1-PP1 protects the origin-binding ORC1 protein from untimely phosphorylation and consequent degradation by the proteasome. Depletion of RIF1 or inhibition of PP1 destabilizes ORC1, thereby reducing origin licensing. Consistent with reduced origin licensing, RIF1-depleted cells exhibit increased spacing between active origins. Human RIF1 therefore acts as a PP1-targeting subunit that regulates DNA replication positively by stimulating the origin licensing step, and then negatively by counteracting replication origin activation.


Assuntos
Replicação do DNA , Proteína Fosfatase 1/metabolismo , Origem de Replicação , Proteínas de Ligação a Telômeros/metabolismo , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Cromatina/genética , Cromatina/metabolismo , Humanos , Proteínas de Manutenção de Minicromossomo/metabolismo , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Fosfatase 1/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Proteínas de Ligação a Telômeros/química
17.
Univ. psychol ; 15(4): 1-13, oct.-dic. 2016. tab
Artigo em Espanhol | LILACS-Express | ID: biblio-963202

RESUMO

Se estimaron las propiedades psicométricas de la Environmental Reward Observation Scale (EROS) en población colombiana, con dos muestras: población comunitaria y clínica. Para la primera, se evaluaron 507 personas en 22 departamentos del país, con edades entre 18 y 72 años, 60.5 % mujeres y el restante hombres; la segunda muestra estuvo compuesta por 68 personas, con edades comprendidas entre 18 y 72 años, atendidas en el momento de la evaluación por profesionales en salud mental. Se realizó la aplicación de los instrumentos (Enviromental Reward Observation Scale y Escala Autoaplicada de Depresión de Zung), a través de redes sociales y correos electrónicos, con el fin de tener una muestra más amplia y una mayor variabilidad de la misma. Se encontraron niveles apropiados de consistencia interna (alfa de 0.87) e importantes evidencias de validez de constructo (agrupación en un factor que explica el 46.82 % de la varianza total) y discriminante ( r = -0.67).


In the present study the psychometric properties of the Environmental Reward Observation Scale (EROS) in Colombian population were estimated with two different samples: population and clinic. For the first sample 517 people were evaluated in 22 departments of the country aged 18 to 72, 60.5% are women and the remaining men, the second sample was composed of 68 people aged between 18 and 72 years who They are served at present by mental health professionals. Based on the above, the application of the instruments (Environmental Observation Reward Scale Y Auto Scale Applied Zung Depression) was made through social networks and emails in order to have a larger sample and greater variability the same in relation to the general population. Appropriate levels of internal consistency (alpha of 0.87) and significant evidence of construct validity (grouping by a factor that explains the 46.815% of the total variance) and discriminant ( r = -0.67).

18.
Antioxid Redox Signal ; 22(10): 799-818, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25557043

RESUMO

AIMS: The in vivo pharmacology of the sigma 1 receptor (σ1R) is certainly complex; however, σ1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the σ1R is involved in the negative control that glutamate N-methyl-d-aspartate acid receptors (NMDARs) exert on opioid antinociception. RESULTS: The MOR C terminus carries the histidine triad nucleotide-binding protein 1 (HINT1) coupled to the regulator of G-protein signaling RGSZ2-neural nitric oxide synthase assembly. Activated MORs stimulate the production of nitric oxide (NO), and the redox zinc switch RGSZ2 converts this signal into free zinc ions that are required to recruit the redox sensor PKCγ to HINT1 proteins. Then, PKCγ impairs HINT1-RGSZ2 association and enables σ1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of σ1Rs prevents HINT1-PKCγ interaction, and MOR-NMDAR cross-regulation fails. The σ1R antagonists transitorily remove the binding of σ1Rs to NR1 subunits, facilitate the entrance of negative regulators of NMDARs, likely Ca(2+)-CaM, and prevent NR1 interaction with HINT1, thereby impairing the negative feedback of glutamate on opioid analgesia. INNOVATION: A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the σ1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit. CONCLUSION: The σ1R antagonists enhance opioid analgesia in naïve mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, σ1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs.


Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores sigma/metabolismo , Analgésicos Opioides/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Camundongos , Camundongos Knockout , Morfina/farmacologia , Óxido Nítrico/metabolismo , Oxirredução , Proteína Quinase C/metabolismo , Proteínas RGS/metabolismo , Receptores sigma/antagonistas & inibidores , Zinco/metabolismo
19.
Neuropharmacology ; 89: 412-23, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25445489

RESUMO

In the nervous system, the glutamate N-methyl-D-aspartate receptor (NMDAR) restricts the activity of the mu-opioid receptor (MOR). Both receptors are present in midbrain periaqueductal grey (PAG) neurons, an area that plays a central role in the supraspinal antinociceptive effects of opioids. The cross-talk that occurs between these receptors is sustained by the MOR-associated histidine triad nucleotide binding protein 1 (HINT1), which displays nucleoside phosphoramidase and acyl-AMP hydrolase activity. Here we report that the inhibitor of HINT1 enzymatic activity guanosine-5'-tryptamine carbamate (TpGc) significantly enhanced morphine antinociception while preventing the development of tolerance. At the molecular level, TpGc reduced the capacity of MORs to recruit NMDAR activity to negatively regulate opioid signaling. In mice suffering from chronic constriction injury concurrent with increased NMDAR activity, a single intracerebroventricular administration of TpGc attenuated NMDAR function and alleviated mechanical allodynia for several days. These data suggest a potential therapeutic role for HINT1 inhibitors in the clinical management of acute and neuropathic pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Hiperalgesia/tratamento farmacológico , Morfina/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Tolerância a Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Hiperalgesia/etiologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/complicações , Receptores de N-Metil-D-Aspartato/genética , Natação/psicologia
20.
Methods Mol Biol ; 1230: 233-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25293330

RESUMO

After iron, zinc is the second most abundant transition metal in living organisms and it is known to be a contributory factor in a series of neurological disorders. In biological systems zinc exists as either bound Zn(2+), representing the majority of the total zinc in tissues, or free (chelatable) Zn(2+). Several fluorescents dyes have been developed to detect free zinc when it is released from zinc-binding proteins, which occurs via redox mechanisms in response to the stimulation of a number of neurotransmitter receptors, including the µ opioid receptor. Here we describe a detailed protocol to detect drug stimulated intracellular zinc release in rodent brain slices using time-lapse microscopy and fluorescence imaging.


Assuntos
Microscopia de Fluorescência/métodos , Receptores Opioides mu/metabolismo , Imagem com Lapso de Tempo/métodos , Zinco/isolamento & purificação , Analgésicos Opioides/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Receptores Opioides mu/agonistas , Zinco/metabolismo
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