Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
1.
Elife ; 92020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33141022

RESUMO

Human cells lacking RIF1 are highly sensitive to replication inhibitors, but the reasons for this sensitivity have been enigmatic. Here, we show that RIF1 must be present both during replication stress and in the ensuing recovery period to promote cell survival. Of two isoforms produced by alternative splicing, we find that RIF1-Long alone can protect cells against replication inhibition, but RIF1-Short is incapable of mediating protection. Consistent with this isoform-specific role, RIF1-Long is required to promote the formation of the 53BP1 nuclear bodies that protect unrepaired damage sites in the G1 phase following replication stress. Overall, our observations show that RIF1 is needed at several cell cycle stages after replication insult, with the RIF1-Long isoform playing a specific role during the ensuing G1 phase in damage site protection.

2.
Rev Chilena Infectol ; 37(3): 265-275, 2020 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-32853319

RESUMO

SARS-CoV-2 is the pathogen responsible for COVID-19, an infectious disease that can evolve from a mild viral illness to multiple organ failure and death. This disease is characterized by a high transmissibility rate, which has lead to its spread throughout the world. There are no clear prognostic markers to guide the severity of the condition; however, some clinical elements could be considered possible predictors of severity. Knowing its viral structure and pathogenesis has allowed to recognize specific molecular pathways candidates as therapeutic targets for various drugs, which are still under investigation and will set the guidelines for future protocols.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Infecções por Coronavirus/diagnóstico , Humanos , Pneumonia Viral/diagnóstico
3.
Microb Pathog ; 148: 104436, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32781099

RESUMO

Candida albicans is an opportunistic fungus frequently associated with periodontal diseases. The objective of this study was to determine the expression patterns of virulence genes associated with those of azole resistance among the strains of C. albicans isolated from patients with periodontal disease. We isolated 80 strains of C. albicans from patients with periodontal disease enrolled from two dental clinics and their antifungal susceptibilities were evaluated using the disc diffusion method. C. albicans and its virulence genes were identified using PCR. The expressions of the virulence genes of C. albicans were analyzed using real-time PCR post in vitro infection of the cell line A549. The phenotype for resistance against azoles such as ketoconazole and fluconazole was observed in all analyzed strains (n = 80), which coincided with the high frequency of occurrence of the genes CDR1 and MDR1 associated with resistance. The frequencies of detection and expression of the genes HWP1 (47/15), ALS1 (80/66), ALS3 (70/30), LIP1 (78/44), LIP4 (77/65), LIP5 (79/58), LIP6 (79/58), PLB1 (79/65), and PLB2 (80/66) were found to be higher in the strains of C. albicans isolated from patients with moderate periodontitis and different expression patterns associated with those for azole resistance were identified. It could be elucidated that the high expression of virulence markers associated with azole resistance in C. albicans might be contributing to the chronicity of periodontal infections.

4.
Rev. chil. infectol ; 37(3): 265-275, jun. 2020. tab
Artigo em Espanhol | LILACS | ID: biblio-1126119

RESUMO

Resumen El SARS-CoV-2 es el agente patógeno responsable del COVID-19, enfermedad infecciosa que puede evolucionar desde un cuadro viral leve hasta la falla multiorgánica y muerte. Esta enfermedad se caracteriza por tener una tasa de transmisibilidad elevada, lo que ha permitido su diseminación por el mundo. No existen marcadores pronósticos claros que guíen la gravedad del cuadro; no obstante, hay elementos clínicos que podrían considerarse posibles predictores de gravedad. Conocer su estructura viral y patogenia ha posibilitado objetivar los pasos moleculares específicos que pueden ser blancos terapéuticos de variados fármacos, los cuales se mantienen en investigación y marcarán las directrices de futuros protocolos.


Abstract SARS-CoV-2 is the pathogen responsible for COVID-19, an infectious disease that can evolve from a mild viral illness to multiple organ failure and death. This disease is characterized by a high transmissibility rate, which has lead to its spread throughout the world. There are no clear prognostic markers to guide the severity of the condition; however, some clinical elements could be considered possible predictors of severity. Knowing its viral structure and pathogenesis has allowed to recognize specific molecular pathways candidates as therapeutic targets for various drugs, which are still under investigation and will set the guidelines for future protocols.


Assuntos
Humanos , Pneumonia Viral/diagnóstico , Infecções por Coronavirus/diagnóstico , Pandemias , Betacoronavirus
5.
Infectio ; 24(1): 9-14, ene.-mar. 2020. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1090537

RESUMO

Abstract Objective: To evaluate the cost-effectiveness of ceftolozane/tazobactam + metronidazole (C/T+M) and ceftolozane/tazobactam (C/T) compared with 8 alternatives used in the treatment of complicated intraabdominal infection (cIAI) and complicated urinary tract infection (cUTI) respectively. Methods: A Monte Carlo simulation decision model was used for the estimation and comparison of treatment-related costs, and quality adjusted life years for patients with cIAI treated with C/T+M in comparison with cefepime + metronidazole, ciprofloxacin + metronidazole, doripenem, levofloxacin + metronidazole, meropenem, piperacillin/tazobactam, ceftazidime + metronidazole or imipenem/cilastatin and patients with cUTI treated with C/T in comparison with cefepime, ciprofloxacin, doripenem, levofloxacin, meropenem, piperacillin/tazobactam, ceftazidime or imipenem/cilastatin. Local costs were estimated using base cases identified by experts and consulting local databases. Sensitivity values of the PACTS (Program to Assess Ceftolozane/Tazobactam Susceptibility) study in Latin America were used in the model. Results: C/T+M and C/T obtained incremental cost-effectiveness ratios (ICER) that were below the Colombian cost-effectiveness threshold (3 GDP per capita) in most comparisons, and were dominated by meropenem, considering only gram-negative microorganisms. Sensitivity assessments were also carried out, in which only the population with P. aeruginosa infections was considered, showing positive results for C/T+M and C/T (cost-effective or dominant with regards to all comparators). Conclusions: C/T+M and C/T could be cost-effective alternatives in the treatment of CIAI and CUTI in Colombia, when there is an adequate and rational use of antibiotics. The results of the sensitivity analyses showed dominance and cost-effectiveness with regards to every comparator in patients infected with P. aeruginosa


Resumen Objetivo: Evaluar la costo-efectividad de ceftolozano/tazobactam + metronidazol (C/T + M) y ceftolozano/tazobactam (C/T) en comparación con 8 alternativas utilizadas en el tratamiento de las infecciones intraabdominales complicadas (IAAc) e infecciones del tracto urinario complicadas (ITUc) respectivamente. Métodos: Se usó un modelo de decisión de simulación de Monte Carlo para la estimación y comparación de los costos relacionados con el tratamiento y los años de vida ajustados por calidad para pacientes con IAAc tratados con C/T + M, en comparación con cefepima + metronidazol, ciprofloxacina + metronidazol, doripenem , levofloxacina + metronidazol, meropenem, piperacilina / tazobactam, ceftazidima + metronidazol o imipenem/cilastatina, y pacientes con ITUc tratados con C/T en comparación con cefepime, ciprofloxacina, doripenem, levofloxacina, meropenem, piperacilina / tazobactam, ceftazidima o imipenem/cilastatina . Los costos locales se estimaron por medio de casos base identificados por expertos y consultando bases de datos locales. Se utilizaron los valores de sensibilidad bacteriana del estudio PACTS (Programa para evaluar la susceptibilidad al ceftolozano/tazobactam) en América Latina para poblar el modelo. Resultados: C/T + M y C/T obtuvieron razones de costo-efectividad incrementales (RCEI) que estaban por debajo del umbral de costo-efectividad colombiano (3 PIB per cápita) en la mayoría de las comparaciones, y fueron dominados por meropenem, considerando solo microorganismos gran-negativos También se llevaron a cabo análisis de sensibilidad, en los que solo se consideró la población con infecciones por P. aeruginosa, mostrando resultados positivos para C/T + M y C/T (costo efectivo o dominante con respecto a todos los comparadores). Conclusiones: C/T + M y C/T podrían ser alternativas costo efectivas en el tratamiento de IAAc e ITUc en Colombia, cuando existe un uso adecuado y racional de antibióticos. Los resultados de los análisis de sensibilidad mostraron dominio y costo-efectividad en relación con todos los comparadores en pacientes infectados con P. aeruginosa.

6.
Infectio ; 23(supl.1): 73-91, dic. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | 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.

7.
Infectio ; 23(supl.1): 106-128, dic. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | 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).

8.
Infectio ; 23(4): 347-351, Dec. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | 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.

9.
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.


Assuntos
Pulmão/fisiopatologia , Infecções por Pneumocystis/microbiologia , Pneumocystis carinii/genética , Doença Pulmonar Obstrutiva Crônica/microbiologia , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Infecções por Pneumocystis/fisiopatologia , Pneumocystis carinii/isolamento & purificação , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
10.
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.

11.
Front Pharmacol ; 10: 634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249525

RESUMO

The sigma 1 receptor (σ1R) and the mu-opioid receptor (MOR) regulate the transient receptor potential (TRP) V1 calcium channel. A series of proteins are involved in the cross-regulation between MORs and calcium channels like the glutamate N-methyl-D-aspartate receptor (NMDAR), including the histidine triad nucleotide-binding protein 1 (HINT1), calmodulin (CaM), and the σ1R. Thus, we assessed whether similar mechanisms also apply to the neural TRP ankyrin member 1 (TRPA1), TRP vanilloid member 1 (TRPV1), and TRP melastatin member 8 (TRPM8). Our results indicate that σ1R and CaM bound directly to cytosolic regions of these TRPs, and this binding increased in the presence of calcium. By contrast, the association of HINT1 with these TRPs was moderately dependent on calcium. The σ1R always competed with CaM for binding to the TRPs, except for its binding to the TRPA1 C-terminal where σ1R binding cooperated with that of CaM. However, σ1R dampened HINT1 binding to the TRPA1 N-terminal. When the effect of σ1R ligands was addressed, the σ1R agonists PRE084 and pregnenolone sulfate enhanced the association of the σ1R with the TRPM8 N-terminal and TRPV1 C-terminal in the presence of physiological calcium, as seen for the σ1R-NMDAR interactions. However, these agonists dampened σ1R binding to the TRPA1 and TRPV1 N-terminal domains, and also to the TRPA1 C-terminal, as seen for σ1R-binding immunoglobulin protein (BiP) interactions in the endoplasmic reticulum (ER). By contrast, the σ1R antagonists progesterone and S1RA reduced the association of σ1R with TRPA1 and TRPV1 C-terminal regions, as seen for the σ1R-NMDAR interactions. Conversely, they enhanced the σ1R interaction with the TRPA1 N-terminal, as seen for σ1R-BiP interactions, whereas they barely affected the association of σ1R with the TRPV1 N-terminal. Thus, depending on the calcium channel and the cytosolic region examined, the σ1R agonists pregnenolone sulfate and PRE084 opposed or collaborated with the σ1R antagonists progesterone and S1RA to disrupt or promote such interactions. Through the use of cloned cytosolic regions of selected TRP calcium channels, we were able to demonstrate that σ1R ligands exhibit biased activity to regulate particular σ1R interactions with other proteins. Since σ1Rs are implicated in essential physiological processes, exploiting such ligand biases may represent a means to develop more selective and efficacious pharmacological interventions.

12.
BMC Microbiol ; 19(1): 106, 2019 05 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.


Assuntos
DNA Ribossômico/genética , Farmacorresistência Fúngica Múltipla , Micoses/microbiologia , Leveduras/isolamento & purificação , Antifúngicos/farmacologia , Colômbia , DNA Fúngico/genética , Humanos , Testes de Sensibilidade Microbiana , Filogenia , Análise de Sequência de DNA , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Atenção Terciária à Saúde , Leveduras/classificação , Leveduras/efeitos dos fármacos , Leveduras/genética
13.
Cell Rep ; 27(9): 2558-2566.e4, 2019 05 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.


Assuntos
Replicação do DNA , DNA/metabolismo , Instabilidade Genômica , Receptores de Neuropeptídeo Y/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Helicase da Síndrome de Werner/metabolismo , DNA/química , DNA/genética , Células HEK293 , Humanos , Fosforilação , Receptores de Neuropeptídeo Y/genética , Proteínas de Ligação a Telômeros/genética , Helicase da Síndrome de Werner/genética
14.
Antioxid Redox Signal ; 31(7): 503-520, 2019 09 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.


Assuntos
Axônios/metabolismo , Calmodulina/metabolismo , Cisteína/metabolismo , Suscetibilidade a Doenças , Proteínas do Tecido Nervoso/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Zinco/metabolismo , Sequência de Aminoácidos , Animais , Domínio Catalítico , Humanos , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Modelos Moleculares , Mutação , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade
15.
Infectio ; 23(1): 22-26, Jan.-Mar. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | 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.

16.
Trends Psychol ; 26(4): 2119-2132, out.-dez. 2018. tab
Artigo em Espanhol | LILACS-Express | LILACS | 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.

17.
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.


Assuntos
Canabidiol/farmacologia , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Receptores sigma/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Animais , Anticonvulsivantes/farmacologia , Canabidiol/administração & dosagem , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos Knockout , N-Metilaspartato , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
18.
Int J Neuropsychopharmacol ; 21(10): 938-948, 2018 10 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.


Assuntos
Antimaníacos/farmacologia , Camundongos Knockout/psicologia , Proteínas do Tecido Nervoso/genética , Receptores sigma/antagonistas & inibidores , Animais , Animais não Endogâmicos/psicologia , Ciclopropanos/farmacologia , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Camundongos , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores sigma/agonistas
19.
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.

20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA