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1.
Arch Virol ; 168(11): 266, 2023 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-37798456

RESUMEN

The last record of a rabies case caused by the dog-specific rabies virus (RABV) lineage in dogs or cats in São Paulo State was in 1998. From 2002 to 2021, 57 cases of rabies in these animals were reported, and the vast majority (51) were genetically characterized as belonging to the Desmodus rotundus/Artibeus lituratus RABV lineage. However, it is not currently possible to infer which of these bats is the source of infection by genome sequencing of RABV isolates. The aims of this study were (a) to characterize the Desmodus rotundus/Artibeus lituratus lineage to determine the relationships between the RABV lineages and each reservoir, (b) to assess the phylogeny and common ancestors of the RABV lineages found in D. rotundus and A. lituratus, and (c) to further understand the epidemiology and control of rabies. In this study, we genetically analyzed 70 RABV isolates from São Paulo State that were received by the Virology Laboratory of the Pasteur Institute of São Paulo between 2006 and 2015. Of these isolates, 33 were associated with the hematophagous bat D. rotundus and 37 with the fruit bat A. lituratus. A genomic approach using phylogenetic analysis and nucleotide sequence comparisons demonstrated that these isolates belonged to the same genetic lineage of RABV. We also found that, in São Paulo State, the D. rotundus/A. lituratus lineage could be subdivided into at least four phylogenetic sublineages: two associated with D. rotundus and two with A. lituratus. These results are of importance for the epidemiological surveillance of rabies in São Paulo.


Asunto(s)
Quirópteros , Virus de la Rabia , Rabia , Animales , Perros , Rabia/epidemiología , Rabia/veterinaria , Filogenia , Brasil/epidemiología
2.
Clin Exp Dermatol ; 45(6): 691-698, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32031275

RESUMEN

BACKGROUND: Rising numbers of two-week-wait (2WW) skin cancer referrals have caused increasing pressure on UK dermatology departments. Initiatives to address this include teledermatology. Previous studies have indicated good patient acceptability but most have focused on general dermatology rather than skin cancer referrals, and have taken place in rural settings, where teledermatology may be preferable. AIM: To evaluate patient satisfaction of teledermatology 2WW services in a London-based tertiary National Health Service (NHS) setting. METHODS: A literature search was performed and a patient satisfaction survey was designed to evaluate: (i) ease of completing a questionnaire about the skin lesion; (ii) lifestyle impact; (iii) preferences regarding electronic data collection and communication of results; and (iv) confidence in the service. A five-point Likert scale was used to assess responses. The study took place over a 20-week period. RESULTS: Over half (51%; n = 31 of 60 patients) were female; 78% (47) were aged ≤ 55 years and 65% (39) were Caucasian. Over 80% (49) would recommend the service, and the majority felt confident with the teledermatology model. Overall, patients would be happy to complete electronic questionnaires and receive results electronically, with younger patients being more amenable to this. Patients with better health status, those of younger age and those with less frequent visits to a dermatologist were more accepting of teledermatology. CONCLUSION: To our knowledge, this is the first comprehensive study evaluating patient satisfaction with teledermatology specifically for 2WW referrals in an NHS setting. As skin cancer referrals increase, dermatology departments must adjust. Patient involvement and feedback is paramount in implementing and expanding teledermatology services.


Asunto(s)
Dermatología/métodos , Satisfacción del Paciente , Derivación y Consulta , Neoplasias Cutáneas , Telemedicina , Adulto , Factores de Edad , Actitud Frente a la Salud , Femenino , Humanos , Londres , Masculino , Persona de Mediana Edad , Medicina Estatal , Encuestas y Cuestionarios , Listas de Espera
3.
J Periodontal Res ; 53(5): 743-749, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29851077

RESUMEN

BACKGROUND AND OBJECTIVE: Soluble epoxide hydrolase (sEH) is an enzyme in the arachidonate cascade which converts epoxy fatty acids (EpFAs), such as epoxyeicosatrienoic acids (EETs) produced by cytochrome P450 enzymes, to dihydroxy-eicosatrienoic acids. In the last 20 years with the development of inhibitors to sEH it has been possible to increase the levels of EETs and other EpFAs in in vivo models. Recently, studies have shown that EETs play a key role in blocking inflammation in a bone resorption process, but the mechanism is not clear. In the current study we used the sEH inhibitor (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea [TPPU]) to investigate the immunomodulatory effects in a mouse periodontitis model. MATERIAL AND METHODS: Mice were infected on days 0, 2, and 4 with Aggregatibacter actinomycetemcomitans and divided into groups (n = 6) that were treated orally, daily for 15 days, with 1 mg/kg of TPPU. Then, the mice were killed and their jaws were analyzed for bone resorption using morphometry. Immunoinflammatory markers in the gingival tissue were analyzed by microarray PCR or western blotting. RESULTS: Infected mice treated with TPPU showed lower bone resorption than infected mice without treatment. Interestingly, infected mice showed increased expression of sEH; however, mice treated with TPPU had a reduction in expression of sEH. Besides, several proinflammatory cytokines and molecular markers were downregulated in the gingival tissue in the group treated with 1 mg/kg of TPPU. CONCLUSION: The sEH inhibitor, TPPU, showed immunomodulatory effects, decreasing bone resorption and inflammatory responses in a bone resorption mouse model.


Asunto(s)
Resorción Ósea/inmunología , Resorción Ósea/prevención & control , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/fisiología , Inmunomodulación/efectos de los fármacos , Periodontitis/inmunología , Periodontitis/metabolismo , Compuestos de Fenilurea/farmacología , Piperidinas/farmacología , Administración Oral , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Epóxido Hidrolasas/metabolismo , Encía/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Compuestos de Fenilurea/administración & dosificación , Piperidinas/administración & dosificación
4.
Am J Transplant ; 13(9): 2322-33, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24034707

RESUMEN

Mammalian target of rapamycin kinase inhibitor (mTORi) rapamycin (RAPA) use in transplantation can lead to inflammatory complications in some patients. Our goal was to better understand how mTORi-exposed human monocyte-derived dendritic cells (DC) stimulated with pro-inflammatory cytokines shape T cell allo-immunity. RAPA-conditioned-DC (RAPA-DC) displayed a more immature phenotype than untreated, control (CTRL)-DC. However, subsequent exposure of RAPA-DC to an inflammatory cytokine cocktail (ICC) plus IFN-γ induced a mature Type-1 promoting phenotype, consisting of elevated HLA-DR and co-stimulatory molecules, augmented IL-12p70 and IL-27 production, but decreased IL-10 secretion compared to CTRL-DC. Co-culture of mature (m)RAPA-DC with allogeneic peripheral blood mononuclear cells resulted in significantly increased Type-1 (IFN-γ) responses by T cells. Moreover, NK cells acted as innate modulators that conveyed activating cell-to-cell contact signals in addition to helper (IFN-γ) and/or regulatory (IL-10) soluble cytokines. We conclude that production of IL12-p70, IL-27 and low IL-10 by RAPA-DC allowed us to elucidate how these cytokines as well as NK-DC interaction shapes T cell allo-immunity. Thus, lack of inhibitory NK cell function during allo-specific T cell activation by human ICC + IFN-γ-stimulated RAPA-DC may represent an unwanted effector mechanism that may underlie RAPA-induced inflammatory events in transplant patients undergoing microbial infection or allograft rejection.


Asunto(s)
Células Dendríticas/inmunología , Interleucina-12/metabolismo , Interleucina-27/metabolismo , Células Asesinas Naturales/inmunología , Sirolimus/farmacología , Linfocitos T/inmunología , Diferenciación Celular , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Humanos , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Leucocitos Mononucleares/fisiología
5.
Mol Biol Rep ; 40(9): 5351-8, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23657602

RESUMEN

We performed a meta-analysis of the transcription profiles of type 1, type 2 and gestational diabetes to evaluate similarities and dissimilarities among these diabetes types. cRNA samples obtained from peripheral blood lymphomononuclear cells (PBMC) of 56 diabetes mellitus patients (type 1 = 19; type 2 = 20; gestational = 17) were hybridized to the same whole human genome oligomicroarray platform, encompassing 44,000 transcripts. The GeneSpring software was used to perform analysis and hierarchical clustering, and the DAVID database was used for gene ontology. The gene expression profiles showed more similarity between gestational and type 1 diabetes rather than between type 2 and gestational diabetes, a finding that was not influenced by patient gender and age. The meta-analysis of the three types of diabetes disclosed 3,747 differentially and significantly expressed genes. A total of 486 genes were characteristic of gestational diabetes, 202 genes of type 1, and 651 genes of type 2 diabetes. 19 known genes were shared by type 1, type 2 and gestational diabetes, highlighting EGF, FAM46C, HBEGF, ID1, SH3BGRL2, VEPH1, and TMEM158 genes. The meta-analysis of PBMC transcription profiles characterized each type of diabetes revealing that gestational and type 1 diabetes were transcriptionally related.


Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Leucocitos Mononucleares/metabolismo , Adulto , Anciano , Análisis por Conglomerados , Diabetes Gestacional/clasificación , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Embarazo , ARN Complementario/genética
6.
Genet Mol Res ; 12(3): 2248-59, 2013 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-23884768

RESUMEN

Brazil is the world leader in papaya production. However, only a small number of cultivars are registered for commercial planting, mainly owing to delays in obtaining cultivars and the high costs of the field phase of breeding programs. These costs can be reduced when molecular tools are combined with conventional breeding methods. In the present study, we conducted a molecular analysis of a self-fertilized population of a first backcrossing generation of BC1S1 papaya plants via microsatellite markers both to monitor the level of homozygosity and the gene/allele transfer that confers the Golden trait (fruit color) and to assess the parental genomic proportion in the genotypes studied. Based on the analysis of 20 polymorphic microsatellite loci, 19 genotypes with the Golden trait belonging to BC1S1 were evaluated in addition to the parental genotypes. Genetic distance was estimated through weighted index. The genotypes were then grouped using the hierarchical nearest neighbor method, and the analysis of principal coordinates was used to measure the proportion of parental genomes in the segregating genotypes. The mean value of the inbreeding coefficient was 0.36. The analysis of the principal coordinates revealed that on average, 64% of the recurrent parent genome was present in the population. Together, the analyses allowed the selection of 3 individuals for the next backcross cycle (33BC1S1-18, 34BC1S1-16, and 37BC1S1-10). These individuals had a higher proportion of the recurrent parent and were grouped close to the recurrent parent in the cluster analysis.


Asunto(s)
Carica/genética , Repeticiones de Microsatélite , Autofecundación , Marcadores Genéticos , Genoma de Planta , Genotipo , Técnicas de Genotipaje/métodos , Homocigoto
7.
AJNR Am J Neuroradiol ; 44(7): 828-832, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37321855

RESUMEN

BACKGROUND AND PURPOSE: Retinoblastoma is the most common primary intraocular tumor in childhood. Intra-arterial chemotherapy is becoming the standard of care for both first-line and rescue therapy, thus improving survival rates and decreasing the adverse effects of retinoblastoma treatment. Cardiorespiratory adverse events during general anesthesia for intra-arterial chemotherapy, including decreased lung compliance and bradycardia, have been described, but data regarding associated factors are still lacking. We aimed to assess the characteristics of patients and procedures associated with cardiorespiratory events during intra-arterial chemotherapy. MATERIALS AND METHODS: We performed a prospective monocenter observational study in children diagnosed with retinoblastoma undergoing intra-arterial chemotherapy under general anesthesia. The occurrence of cardiorespiratory events was registered. We also assessed clinical and procedural characteristics potentially associated with these events. RESULTS: A cardiorespiratory event was observed in 22 (12.5%) procedures, predominantly a decrease in tidal volume observed in 16 (9%) procedures. The median age was lower in the procedures with a cardiorespiratory event (20.43 [SD, 11.76] months versus 30.11 [SD, 24.17] months) (P < .05). Other variables such as bilateral disease or a previous intra-arterial chemotherapy treatment were not associated with the occurrence of a cardiorespiratory event. CONCLUSIONS: In children undergoing intra-arterial chemotherapy for retinoblastoma treatment, cardiorespiratory events were observed in 12.5% of procedures. Lower age was associated with this complication. Although predominantly mild, these events should have prompt diagnosis and treatment to prevent further deterioration and worse outcomes.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias de la Retina , Retinoblastoma , Niño , Humanos , Lactante , Retinoblastoma/tratamiento farmacológico , Neoplasias de la Retina/tratamiento farmacológico , Estudios Prospectivos , Infusiones Intraarteriales , Estudios Retrospectivos , Resultado del Tratamiento
8.
J Virol Methods ; 300: 114426, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34902461

RESUMEN

The laboratory diagnosis of rabies is of fundamental importance to the evaluation of suspected cases of rabies virus (RABV) infection. Confirmation of direct fluorescent antibody test (DFAT) results via viral isolation (VI) is recommended, and the mouse inoculation test (MIT) is being replaced by the rabies tissue culture infection (RTCIT) test for ethical reasons. We evaluated 6.514 results from central nervous system (CNS) samples of different animals analyzed at the Pasteur Institute between 2008 and 2016 using the DFAT, RTCIT and MIT techniques and evaluated their concordance, sensitivity, specificity, and accuracy indices. The DFAT technique presented the best sensitivity (93.58 %), specificity (95.90 %), and accuracy (95.67 %) results. The RTCIT values of sensitivity, specificity and accuracy (70.42 %, 86.16 % and 84.62 % respectively) were lower than those of DFAT. The concordance between RTCIT and DFAT was moderate, with a kappa quotient k = 0.341. The MIT values of sensitivity, specificity, and accuracy were 89.58 %, 100 % and 98.97 % respectively. The concordance between MIT and DFAT was substantial, with a k value of 0.720. DFAT, considered the "gold standard", was effective in all animals except horses. Our analyses evidenced that DFAT presents satisfactory results, although RTCIT did not appear favorable as a confirmatory technique.


Asunto(s)
Virus de la Rabia , Rabia , Animales , Técnica del Anticuerpo Fluorescente Directa/métodos , Caballos , Pruebas Inmunológicas , Ratones , Rabia/diagnóstico , Rabia/veterinaria , Sensibilidad y Especificidad
9.
Cancer Genet ; 258-259: 85-92, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34666222

RESUMEN

Osteosarcoma (OS) is a malignant bone tumor, with a peak of incidence in the second decade of life and possibly associated with the presence of germline mutations. Besides, clinicians have pointed to a second, rarer group of patients that develops OS before 10 years old. Here we access, through next-generation sequencing (NGS) strategy, the genetic alterations present in OS and blood samples from patients diagnosed before and during the second decade of life. A custom NGS panel, designed for the main alterations described in childhood and adolescence neoplasms, named Oncomine Childhood Cancer Research Assay (OCCRA©), was used. Of all 84 OS samples investigated, 42 (50%) presented some somatic variant, with TP53, MYC, CDK4, RB1 and PDGFRA genes harboring the most observed genetic variants. MYC CNVs were more frequent in tumors from patients diagnosed before 10 years old (X21= 5.18, p = 0.023). Additionally, patients diagnosed during the second decade of life presented a higher percentage of somatic and germline variants. Germline variants in TP53 and RB1 were found in 5 of the 11 (45.5%) patients analyzed. Clinical variables and tumor histopathological characteristics were also collected and correlated with our molecular findings.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/patología , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Osteosarcoma/patología , Adolescente , Neoplasias Óseas/genética , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Osteosarcoma/genética , Pronóstico
10.
Am J Transplant ; 10(4): 773-783, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20420638

RESUMEN

As the target CD52 molecule is expressed on erythrocytes of most nonhuman primate strains, using alemtuzumab in these species would cause massive hemolysis. Six cynomolgus monkeys of Indonesian origin, screened by agglutination assay for absence of CD52 on erythrocytes, were administered alemtuzumab in a cumulative dose to a maximum of 60 mg/kg. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg alemtuzumab and was more profound than in monkeys treated with antithymocyte globulin (n = 5), as quantified by flow cytometry. Repopulation was suppressed by weekly injections of 10 mg/kg. Without MMF, repopulation of CD20(+)B cells and CD8(+)T cells was complete within 2 and 3 months, respectively, and repopulation of CD4(+)T cells was 67% after 1 year. MMF significantly delayed CD4(+)T-cell repopulation. Among repopulating CD4(+) and CD8(+) T cells, a phenotypic shift was observed from CD45RA(hi)CD62L(hi) naïve cells toward CD45RA(lo)CD62L(lo) effector memory cells. In lymph nodes, the depletion of naïve cells was more profound than of memory cells, which may have initiated a proliferation of memory cells. This model offers opportunities to investigate lymphocyte depletion/repopulation phenomena, as well as the efficacy of alemtuzumab in preclinical transplantation models.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , División Celular/efectos de los fármacos , Depleción Linfocítica , Linfocitos/citología , Alemtuzumab , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/farmacología , Antígenos CD/inmunología , Citometría de Flujo , Inmunofenotipificación , Linfocitos/inmunología , Macaca fascicularis
11.
Am J Transplant ; 9(9): 2057-66, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19624567

RESUMEN

T-cell alloimmunity plays a dominant role in allograft rejection. The precise contribution of naïve and memory T cells to this response however remains unclear. To address this question, we established an ex vivo flow-cytometric assay that simultaneously measures proliferation, precursor frequency and effector molecule (IFNgamma, granzyme B/perforin) production of alloreactive T cells. By applying this assay to peripheral blood mononuclear cells from healthy volunteers, we demonstrate that the CD4+ and CD8+ populations mount similar proliferative responses and contain comparable frequencies of alloreactive precursors. Effector molecule expression, however, was significantly higher among CD8+ T cells. Analysis of sorted naïve and memory T cells showed that alloreactive precursors were equally present in both populations. The CD8+ effector and terminally differentiated effector memory subsets contained the highest proportion of granzyme B/perforin after allostimulation, suggesting that these cells present a significant threat to transplanted organs. Finally, we demonstrate that virus-specific lymphocytes contribute significantly to the alloresponse in certain responder-stimulator HLA combinations, underscoring the importance of T-cell cross-reactivity in alloimmunity. These results provide a quantitative assessment of the roles of naïve and memory T-cell subsets in the normal human alloimmune response and establish a platform for measuring T-cell alloreactivity pre- and posttransplantation.


Asunto(s)
Linfocitos T/citología , Adulto , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Femenino , Citometría de Flujo/métodos , Granzimas/farmacología , Antígenos HLA/química , Humanos , Memoria Inmunológica/inmunología , Interferón gamma/metabolismo , Masculino , Perforina/metabolismo , Subgrupos de Linfocitos T/inmunología
12.
Plant Biol (Stuttg) ; 21(6): 1110-1118, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31173441

RESUMEN

Seedling establishment is a critical step in environment colonisation by higher plants that frequently occurs under adverse conditions. Thus, we carried out an integrated analysis of seedling growth, water status, ion accumulation, reserve mobilisation, metabolite partitioning and hydrolase activity during seedling establishment of the native Caatinga species Piptadenia moniliformis (Benth.) Luckow & R.W. Jobson under salinity. Two-day-old seedlings were cultivated in vitro for 4 days in water agar (control) or supplemented with 50 or 100 mm NaCl. Biochemical determinations were performed according to standard spectrophotometric protocols. We found that 100 mm NaCl stimulated starch degradation, amylase activity and soluble sugar accumulation, but limited storage protein hydrolysis in the cotyledons of P. moniliformis seedlings. Although Na+ accumulation in the seedling affected K+ partitioning between different organs, it was not possible to associate the salt-induced changes in reserve mobilisation with Na+ toxicity, or water status, in the cotyledons. Remarkably, we found that starch content increased in the roots of P. moniliformis seedlings under 100 mm NaCl, probably in response to the toxic effects of Na+ . The mobilisation of carbon and nitrogen reserves is independently regulated in P. moniliformis seedlings under salt stress. The salt-induced delay in seedling establishment and the resulting changes in the source-sink relationship may lead to storage protein retention in the cotyledons. Possibly, the intensification of starch mobilisation in the cotyledons supported starch accumulation in the root as a potential mechanism to mitigate Na+ toxicity.


Asunto(s)
Carbono/metabolismo , Moniliformis/metabolismo , Nitrógeno/metabolismo , Plantones/metabolismo , Animales , Cotiledón/efectos de los fármacos , Cotiledón/metabolismo , Moniliformis/efectos de los fármacos , Salinidad , Plantones/efectos de los fármacos , Sodio/metabolismo , Cloruro de Sodio/farmacología
13.
Neurosci Lett ; 446(2-3): 112-6, 2008 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-18835326

RESUMEN

The involvement of dopamine (DA) mechanisms in the nucleus accumbens (NAC) in fear conditioning has been proposed by many studies that have challenged the view that the NAC is solely involved in the modulation of appetitive processes. However, the role of the core and shell subregions of the NAC in aversive conditioning remains unclear. The present study examined DA release in these NAC subregions using microdialysis during the expression of fear memory. Guide cannulae were implanted in rats in the NAC core and shell. Five days later, the animals received 10 footshocks (0.6 mA, 1 s duration) in a distinctive cage A (same context). On the next day, dialysis probes were inserted through the guide cannulae into the NAC core and shell subregions, and the animals were behaviorally tested for fear behavior either in the same context (cage A) or in a novel context (cage B). Dialysates were collected every 5 min for 90 min and analyzed by high-performance liquid chromatography. The rats exhibited a significant fear response in cage A but not in cage B. Moreover, increased DA levels in both NAC subregions were observed 5-25 min after the beginning of the test when the animals were tested in the same context compared with accumbal DA levels from rats tested in the different context. These findings suggest that DA mechanisms in both the NAC core and shell may play an important role in the expression of contextual fear memory.


Asunto(s)
Reacción de Prevención/fisiología , Dopamina/metabolismo , Miedo/fisiología , Núcleo Accumbens/metabolismo , Animales , Condicionamiento Psicológico/fisiología , Estimulación Eléctrica , Líquido Extracelular/metabolismo , Masculino , Microdiálisis , Vías Nerviosas/fisiología , Ratas , Ratas Wistar , Transmisión Sináptica/fisiología
15.
Neuroscience ; 146(4): 1743-57, 2007 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-17467183

RESUMEN

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy"), is a widely abused, psychoactive recreational drug that is known to induce neurotoxic effects. Human and rat hepatic metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, which are both catechols that can undergo oxidation to the corresponding ortho-quinones. Ortho-quinones may be conjugated with glutathione (GSH) to form glutathionyl adducts, which can be transported into the brain and metabolized to the correspondent N-acetylcysteine (NAC) adducts. In this study we evaluated the neurotoxicity of nine MDMA metabolites, obtained by synthesis: N-Me-alpha-MeDA, alpha-MeDA and their correspondent GSH and NAC adducts. The studies were conducted in rat cortical neuronal cultures, for a 6 h of exposure period, under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings show that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols. On the other hand, N-Me-alpha-MeDA and alpha-MeDA are more neurotoxic than MDMA. GSH and NAC conjugates of N-Me-alpha-MeDA and alpha-MeDA induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones. Finally, thioether MDMA metabolites induced neuronal death and oxidative stress was prevented by NAC, an antioxidant and GSH precursor. This study provides new insights into the neurotoxicity mechanisms of thioether MDMA metabolites and highlights their importance in "ecstasy" neurotoxicity.


Asunto(s)
Alucinógenos/metabolismo , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/metabolismo , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neuronas/efectos de los fármacos , 3,4-Metilenodioxianfetamina/administración & dosificación , Acetilcisteína/farmacología , Adenosina Trifosfato/metabolismo , Animales , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Desoxiepinefrina/administración & dosificación , Desoxiepinefrina/análogos & derivados , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Embrión de Mamíferos , Depuradores de Radicales Libres/farmacología , Glutatión/metabolismo , Alucinógenos/química , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , N-Metil-3,4-metilenodioxianfetamina/química , Ratas , Ratas Wistar , Temperatura , Factores de Tiempo
16.
J Chromatogr B Analyt Technol Biomed Life Sci ; 853(1-2): 127-32, 2007 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-17442639

RESUMEN

Here we present a sensitive and specific liquid chromatography-tandem mass spectrometric method for the quantification of dimenhydrinate (I) in human plasma. Sample preparation is conducted using citalopram (II) addition as an internal standard (IS), liquid-liquid extraction with basified plasma using a mixture hexane/acetate (1:1, v/v) as the extracting solvent, and the final extract reconstituted in the mobile phase. I and II (IS) were injected in a C8 column with the mobile phase composed of methanol:isopropanol:water:formic acid (78.00:19.92:2.00:0.08, v/v/v/v) and monitored using a positive electrospray source with tandem mass spectrometry analyses. The selected reaction monitoring (SRM) was set using precursor ion and product ion combinations of m/z 256.0>167.0 and m/z 325.0>109.0 for I and II, respectively. The limit of quantification (LOQ) was 0.4 ng/mL, the dynamic range being 0.4-200 ng/mL. Validation results on linearity, specificity, accuracy, precision and stability, as well as on application to the analysis of plasma samples taken up to 24 h after oral administration of 100 mg of dimenhydrinate in healthy volunteers demonstrated its applicability to bioavailability studies.


Asunto(s)
Cromatografía Liquida/métodos , Dimenhidrinato/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Disponibilidad Biológica , Dimenhidrinato/química , Dimenhidrinato/farmacocinética , Antagonistas de los Receptores Histamínicos H1/sangre , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Humanos , Estructura Molecular , Reproducibilidad de los Resultados
17.
Cochrane Database Syst Rev ; (4): CD005514, 2007 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-17943862

RESUMEN

BACKGROUND: Sleep bruxism is an oral activity characterised by teeth grinding or clenching during sleep. Several treatments for sleep bruxism have been proposed such as pharmacological, psychological, and dental. OBJECTIVES: To evaluate the effectiveness of occlusal splints for the treatment of sleep bruxism with alternative interventions, placebo or no treatment. SEARCH STRATEGY: We searched the Cochrane Oral Health Group's Trials Register (to May 2007); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1); MEDLINE (1966 to May 2007); EMBASE (1980 to May 2007); LILACS (1982 to May 2007); Biblioteca Brasileira de Odontologia (1982 to May 2007); Dissertation, Theses and Abstracts (1981 to May 2007); and handsearched abstracts of particular importance to this review. Additional reports were identified from the reference lists of retrieved reports and from article reviews about treating sleep bruxism. There were no language restrictions. SELECTION CRITERIA: We selected randomised or quasi-randomised controlled trials (RCTs), in which splint therapy was compared concurrently to no treatment, other occlusal appliances, or any other intervention in participants with sleep bruxism. DATA COLLECTION AND ANALYSIS: Data extraction was carried out independently and in duplicate. Validity assessment of the included trials was carried out at the same time as data extraction. Discrepancies were discussed and a third review author consulted. The author of the primary study was contacted when necessary. MAIN RESULTS: Thirty-two potentially relevant RCTs were identified. Twenty-four trials were excluded. Five RCTs were included. Occlusal splint was compared to: palatal splint, mandibular advancement device, transcutaneous electric nerve stimulation, and no treatment. There was just one common outcome (arousal index) which was combined in a meta-analysis. No statistically significant differences between the occlusal splint and control groups were found in the meta-analyses. AUTHORS' CONCLUSIONS: There is not sufficient evidence to state that the occlusal splint is effective for treating sleep bruxism. Indication of its use is questionable with regard to sleep outcomes, but it may be that there is some benefit with regard to tooth wear. This systematic review suggests the need for further investigation in more controlled RCTs that pay attention to method of allocation, outcome assessment, large sample size, and sufficient duration of follow up. The study design must be parallel, in order to eliminate the bias provided by studies of cross-over type. A standardisation of the outcomes of the treatment of sleep bruxism should be established in the RCTs.


Asunto(s)
Ferulas Oclusales , Bruxismo del Sueño/terapia , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
18.
Pharmacol Biochem Behav ; 152: 30-35, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27461546

RESUMEN

BACKGROUND: Testosterone protects male rats from Temporomandibular Joint (TMJ) pain. This study investigated whether this protective effect is mediated by an organizational action of testosterone during nervous system development, by central estrogen and androgen receptors and by the 5α-reduced metabolite of testosterone, dihydrotestosterone. METHODS: A pharmacological approach was used to assess the ability of the androgen receptor antagonist flutamide, the estrogen receptor antagonist ICI 182 780 and the 5-α reductase inhibitor dutasteride to block the protective effect of testosterone, evaluated through the behavioral response induced by a TMJ injection of 0.5% formalin. Flutamide and ICI 182 780 were injected into the medullary subarachnoid space, and dutasteride and testosterone were systemically administered. RESULTS: The TMJ injection of 0.5% formalin induced a significant nociceptive behavioral response in gonadectomized male and naïve female, but not in sham gonadectomized male rats, confirming that endogenous testosterone prevents TMJ nociception in males. Testosterone administration prevented formalin-induced TMJ nociception in males gonadectomized either in the neonatal (at the day of birth) or adult period and in naïve female rats, suggesting that the protective effect of testosterone on TMJ nociception does not depend on its organizational actions during critical periods of development. The administration of flutamide and dutasteride but not of ICI 182 780 blocked the protective effect of testosterone. CONCLUSIONS: We conclude that the protective effect of testosterone on TMJ nociception depends on activational actions of dihydrotestosterone on androgen receptors rather than on organizational androgenic actions during central nervous system development or estrogenic actions.


Asunto(s)
Inhibidores de 5-alfa-Reductasa/farmacología , Antagonistas de Andrógenos/farmacología , Dimensión del Dolor/efectos de los fármacos , Dolor/prevención & control , Receptores Androgénicos/metabolismo , Articulación Temporomandibular/efectos de los fármacos , Testosterona/farmacología , Animales , Dutasterida/farmacología , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas del Receptor de Estrógeno/farmacología , Femenino , Flutamida/farmacología , Formaldehído , Fulvestrant , Masculino , Ratas , Articulación Temporomandibular/fisiopatología , Testosterona/antagonistas & inhibidores
19.
Zoonoses Public Health ; 64(6): 423-430, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-27863049

RESUMEN

In Brazil, rabies control in dogs and cats was pioneered by the state of São Paulo with the adoption of the Pan American Health Organization recommendations for prophylaxis and control, which led to a reduction in rabies cases from 1994 onwards. As a result of these measures, the rabies virus (RABV) genetic lineage associated with dogs has not been found in the state since 1998, and all the cases in domestic animals reported since then have been caused by bat-associated lineages of RABV. In the light of this, this study sought to investigate rabies cases in dogs and cats in the state of São Paulo between 2005 and 2014 and identify the associated transmission cycles by characterizing the RABV lineages responsible for these cases. Nine samples from dogs (n = 5) and from cats (n = 4) were collected between 2005 and 2014. The tenth animal, a rabid cat, was analysed by a different laboratory. The N gene nucleotide sequences obtained were analysed with the neighbor-joining algorithm and Kimura 2-parameter model using the MEGA 6 program. Phylogenetic analysis revealed that the genetic lineages identified in all the samples were those circulating in Brazilian bats. The findings of this study demonstrate that bats play an important role in the transmission of rabies to domestic animals in São Paulo state and that emphasis should be placed on the implementation of public policies to support surveillance of chiropterans for rabies.


Asunto(s)
Enfermedades de los Gatos/virología , Quirópteros/virología , Enfermedades de los Perros/virología , Rabia/veterinaria , Animales , Brasil/epidemiología , Enfermedades de los Gatos/epidemiología , Enfermedades de los Gatos/etiología , Gatos , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/etiología , Perros , Filogenia , Rabia/epidemiología , Rabia/transmisión , Rabia/virología , Virus de la Rabia/genética , Virus de la Rabia/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Factores de Tiempo
20.
Plant Biol (Stuttg) ; 19(3): 335-344, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28039918

RESUMEN

Reserve mobilisation, metabolite partitioning and reserve-degrading enzyme activity were studied in sunflower seedlings cultivated in vitro under a 12-h photoperiod or in the dark to investigate the involvement of source-sink relation and carbon starvation in the regulation of reserve mobilisation under continuous darkness. Reserves, metabolites and enzyme activity were determined with standard spectrophotometric methods. At the first 24 h of treatment (acclimation phase), darkness did not affect growth, but restricted carbon and nitrogen use, as indicated by sugar and amino acid accumulation in the different seedling parts. After 5 days of treatment (survival phase), extended darkness limited growth and retarded storage lipid mobilisation due to carbon starvation, as evidenced by the depletion of carbohydrates in cotyledons and hypocotyl, as well as the consumption of amino acids in hypocotyls and roots. Alterations in the source-sink relationship might have been a response to prolonged darkness, instead of a mechanism used to regulate reserve mobilisation, as these alterations cannot be associated with negative feedback mediated by metabolite accumulation. Storage lipid degradation depends, at least in part, on mechanisms that co-ordinately regulate the activities of lipases and isocitrate lyase. Taking these results together, it is possible that reserve mobilisation in sunflower seedlings cultivated in the dark might be regulated by mechanisms that perceive the absence of light and predict carbon starvation, adjusting reserve use according to future energy demands to allow, at least in the short term, seedling survival.


Asunto(s)
Enzimas/metabolismo , Helianthus/fisiología , Plantones/crecimiento & desarrollo , Plantones/metabolismo , Carbono/metabolismo , Carotenoides/metabolismo , Clorofila/metabolismo , Cotiledón/crecimiento & desarrollo , Oscuridad , Metabolismo de los Lípidos , Fotoperiodo , Proteínas de Plantas/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Plantones/fisiología
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