RESUMEN
BACKGROUND: Type 1 diabetes (T1D) is a complex disease with a higher incidence in Europeans than other populations. The Colombians Living in Medellin (CLM) is admixed with ancestry contributions from Europeans, Native Americans (NAT) and Africans (AFR). AIM: Our aim was to analyze the genetic admixture component at candidate T1D loci in Colombian individuals with the disease. METHODS: Seventy-four ancestry informative markers (AIMs), which tagged 41 T1D candidate loci/genes, were tested by studying a cohort of 200 Northwest Colombia diseased individuals. T1D status was classified by testing for glutamic acid decarboxylase (GAD-65 kDa) and protein tyrosine-like antigen-2 auto-antibodies in serum samples. Candidate loci/genes included HLA, INS, PTPN22, CTLA4, IL2RA, SUMO4, CLEC16A, IFIH1, EFR3B, IL7R, NRP1 and RNASEH1, amongst others. The 1,000 genome database was used to analyze data from 94 individuals corresponding to the reference CLM. As the data did not comply with a normal distribution, medians were compared between groups using the Mann-Whitney U-test. RESULTS: Both T1D patients and individuals from CLM displayed mainly European ancestry (61.58 vs 62.06) followed by Native American (27.34 vs 27.46) and to a lesser extent the AFR ancestry (10.28 vs 10.65) components. However, compared to CLM, ancestry of T1D patients displayed a decrease of NAT ancestry at gene EFR3B (24.30 vs 37.10) and an increase at genes IFIH1 (32.07 vs 14.99) and IL7R (52.18 vs 39.18). Also, for gene NRP1 (36.67 vs 0.003), we observed a non-AFR contribution (attributed to NAT). Autoimmune patients (positive for any of two auto-antibodies) displayed lower NAT ancestry than idiopathic patients at the MHC region (20.36 vs 31.88). Also, late onset patients presented with greater AFR ancestry than early onset patients at gene IL7R (19.96 vs 6.17). An association analysis showed that, even after adjusting for admixture, an association exists for at least seven such AIMs, with the strongest findings on chromosomes 5 and 10 (gene IL7R, P = 5.56 × 10-6 and gene NRP1, P = 8.70 × 10-19, respectively). CONCLUSION: Although Colombian T1D patients have globally presented with higher European admixture, specific T1D loci have displayed varying levels of Native American and AFR ancestries in diseased individuals.
RESUMEN
Docosahexaeonic acid (DHA) is the final compound in the omega-3 polyunsaturated fatty acids (PUFA) synthetic pathway and the most abundant PUFA found in the brain. DHA plays an essential role in the development of the brain, and the intakes in pregnancy and early life affect growth and cognitive performance later in childhood. Recently, it has been proposed that dietary intake of DHA could be a non-pharmacological interventional strategy for the treatment of seizures in humans. However, to date, the experimental approaches to study the antiepileptic effect of DHA have been exclusively restricted to rodent models during short-to-medium periods of treatment. The purpose of the present study was to test the chronic anticonvulsivant effects of DHA supplementation in zebrafish from the pre-spawning stage to aging, taking advantage of our recently described kainate-induced seizure model using this animal. To that end, two groups of adult female zebrafish were fed with standard or 200mg/kg DHA-enriched diets during 1 month previous to the spawning, and offspring subdivided in two categories, and subsequently fed with standard or DHA diets, generating 4 groups of animals that were aged until 20 months. Afterward, KA was intraperitoneally administered and epileptic score determined. All the DHA-enriched groups presented antiepileptic effects compared to the control group, showing that DHA presents an anticonvulsant potential. Among the studied groups, zebrafish fed with DHA from the pre-spawning stage to aging presented the best antiepileptic profile. These results show a neuroprotective benefit in zebrafish fed with DHA-enriched diet before birth and during the whole life.
Asunto(s)
Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Kaínico/toxicidad , Convulsiones/prevención & control , Animales , Ácidos Docosahexaenoicos/fisiología , Embrión no Mamífero , Femenino , Ácido Kaínico/antagonistas & inhibidores , Masculino , Convulsiones/inducido químicamente , Convulsiones/embriología , Pez CebraRESUMEN
Glutamate is the major excitatory neurotransmitter of the central nervous system in vertebrates. Excitotoxicity, caused by over-stimulation of the glutamate receptors, is a major cause of neuron death in several brain diseases, including epilepsy. We describe here how behavioural seizures can be triggered in adult zebrafish by the administration of kainate and are very similar to those observed in rodent models. Kainate induced a dose-dependent sequence of behavioural changes culminating in clonus-like convulsions. Behavioural seizures were suppressed by DNQX (6,7-dinitroquinoxaline-2,3-dione) dose-dependently, whilst MK-801 (a non-competitive NMDA receptor antagonist) had a lesser effect. Kainate triggers seizures in adult zebrafish, and thus this species can be considered as a new model for studying seizures and subsequent excitotoxic brain injury.
Asunto(s)
Modelos Animales de Enfermedad , Ácido Kaínico/farmacología , Convulsiones/inducido químicamente , Pez Cebra/fisiología , Animales , Maleato de Dizocilpina/uso terapéutico , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ácido Glutámico/metabolismo , Quinoxalinas/uso terapéutico , Ratas , Receptores de Glutamato/metabolismo , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatologíaRESUMEN
N-Heterocyclic carbene (NHC) ligands have attracted great interest over the last decade for their use in the design of homogenous catalysts. NHC-based metal complexes have interesting potential biomedical applications, such as in antimicrobial and cancer therapy, which are beginning to be explored more fully. We have studied here the oxidant activities of a series of Ru(II) complexes in vitro and zebrafish (Danio rerio) have been used as a model in vivo to investigate and characterize the toxicity of some of these compounds. Dual behavior was observed for the NHC-based complexes as they behaved as antioxidants at low concentrations but showed pro-oxidant capacity at higher concentrations. Zebrafish embryos were exposed to Ru(II) complexes under several different conditions (0 or 24 h postfertilization, with or without the chorion) and various parameters, such as viability, edema, heart rate, blood coagulation, pigmentation, scoliosis, malformation, and hatching, were tested. In general, zebrafish embryos were not harmed by exposure to Ru(II) complexes whatever the experimental conditions. Several toxicity profiles were observed depending upon the chemical structure of the compound in question. Their characteristics as pro-oxidant and/or antioxidant agents together with their biosafety may point to their having biomedical applications as antitumoral or neuroprotective drugs.
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Compuestos Heterocíclicos/toxicidad , Metano/análogos & derivados , Oxidantes/toxicidad , Compuestos de Rutenio/toxicidad , Pez Cebra/embriología , Animales , Corazón/efectos de los fármacos , Corazón/embriología , Compuestos Heterocíclicos/química , Larva/efectos de los fármacos , Metano/química , Metano/toxicidad , Estructura Molecular , Oxidantes/química , Compuestos de Rutenio/química , Relación Estructura-ActividadRESUMEN
The zebrafish (Danio rerio) is rapidly gaining ground as a disease model. However, until now, the use of this species with human pathogens has been restricted to just three bacteria; no studies involving viruses that infect humans are recorded. In this study, the zebrafish was used as a model of herpes simplex virus type 1 (HSV-1) infection of the nervous system. Fish infected using viral culture supernatants showed detectable HSV-1 DNA concentrations 1-4 days after inoculation, indicating that this virus can experimentally infect and persist in this host. The kinetics of infection was dose dependent, especially in the head. Histological immunodetection of HSV-1 glycoproteins confirmed the presence of HSV-1 in the organs studied; infection led to histopathological changes. Moreover, the suppression of the immune system by cyclophosphamide and the antiviral effect of acyclovir were demonstrated. The infection of the encephalon was studied in detail, and the time course of viral colonization recorded. Immunofluorescence studies provided immunoreactive evidence of viral antigens in the encephalon and spinal cord. Viruses cleared from infected brains showed the ability to infect human neuroblastoma cells. This study is the first to demonstrate HSV-1 infection in the zebrafish and manifests the potential use of this species in herpesvirus studies.
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Modelos Animales de Enfermedad , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Pez Cebra , Aciclovir/uso terapéutico , Animales , Antivirales/uso terapéutico , Ciclofosfamida/efectos adversos , Femenino , Herpes Simple/patología , Inmunosupresores/efectos adversos , Masculino , Factores de TiempoRESUMEN
Disseminated herpes simplex virus type 1 (HSV-1) infection during pregnancy is poorly described even though it is associated with high maternal and fetal morbidity and neonatal mortality in humans. In a previous paper using mice as a model, the authors demonstrated that HSV-1 is transmitted hematogenously from mother to offspring, the virus colonizing the central nervous system and provoking high mortality. In the present study, viral DNA levels in latently infected mothers were investigated during pregnancy and after delivery in mice. Samples from different organs were obtained before gestation (latency), three times during pregnancy (17, 4.5, and 1 day before delivery), and four times after delivery (1 day, 1 week, 1 and 2 months). A dramatic decrease in viral DNA concentration was observed during pregnancy, especially in the nervous system, with postnatal recovery to latent levels. All the brain regions studied showed similar trends. The viral copy numbers detected in mothers at delivery +1 day were independent of viral inoculum size. The spread of the virus to the above organs was examined immunohistochemically and, in general, more intense viral staining was observed after delivery in each. Because immunoglobulin levels can be modified by infections during pregnancy, the authors examined the levels of specific HSV-1 antibodies. Variation in HSV-1 DNA concentration was found to be associated with changes in the full spectrum of immunoglobulins (but especially immunoglobulin M [IgM]) over pregnancy, whereas at delivery -1 day a significant inverse relationship between immunoglobulins and HSV-1 DNA was observed. IgGs provided protection during the postnatal phase.
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Anticuerpos Antivirales/sangre , Encefalitis por Herpes Simple/inmunología , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Complicaciones Infecciosas del Embarazo/virología , Animales , Animales Recién Nacidos , ADN Viral/metabolismo , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Femenino , Herpes Simple/patología , Herpesvirus Humano 1/genética , Inmunoglobulina A/metabolismo , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , Ratones , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/patologíaRESUMEN
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that causes severe disease and death in newborn humans but, to date, it remains unclear how neonatal infection occurs. We show here that the vertical transmission of HSV-1 in mice is mainly hematogenous and involves the colonization of the neonate central nervous system (CNS). HSV-1 DNA was mainly detected in the blood and CNS of the offspring born to latently infected mothers; no significant differences were seen between the viral DNA concentrations in the blood of these mothers and their female progeny (either neonate or adult). The administration of acyclovir during gestation reduced or eliminated both the maternal and the neonatal viral DNA in the blood. Embryo transfer was performed to ensure (as far as possible) that only vertical hematogenous infection took place. Immunohistochemical analysis detected viral proteins in the encephalon of the offspring. Immunofluorescence studies provided immunoreactive evidence of HSV-1 proteins in the neurons of the hippocampus and showed that these viruses can molecularly reactivate after hyperthermia. Neonatal HSV-1 infection therefore appears to be mainly caused by hematogenous vertical transmission, and the viruses that colonize the offspring CNS are capable of molecular reactivation after a period of latency.
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ADN Viral/sangre , Herpes Simple/transmisión , Herpesvirus Humano 1/fisiología , Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo/virología , Latencia del Virus , Animales , Animales Recién Nacidos , Células Cultivadas , Líquido Cefalorraquídeo/virología , Femenino , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/aislamiento & purificación , Hipocampo/citología , Hipocampo/virología , Humanos , Ratones , Ratones Endogámicos C57BL , Embarazo , Activación ViralRESUMEN
Herpes simplex virus type 1 (HSV-1) causes disease in humans and animals. Infection usually occurs via the neural route and possibly occurs via the hematogenous route. The latter, however, is the main route by which immunosuppressed individuals and neonates are infected. Gender-dependent differences in the incidence and severity of some viral infections have been reported. To detect differences between the sexes with respect to HSV-1 colonization and disease, the characteristics of both acute and latent infections in hematogenously infected male and female mice were compared. In acute infection, the female mice had a poorer outcome: HSV-1 colonization was more effective, especially in the gonads and brain. In the encephalon, the midbrain had the highest viral load. In latent infection, brain viral loads were not significantly different with respect to sex. Significant differences were seen, however, in the blood and trigeminal ganglia: HSV-1 seroprevalence was observed in females, with no virus detected in males. In brain dissections, only the cerebral cortex of the females had viral loads statistically higher than those observed in the males. The spread of the virus to several organs of interest during acute infection was examined immunohistochemically. Female mice showed greater viral immunostaining, especially in the adrenal cortex, gonads, and midbrain. In male mice, HSV-1 was detected predominantly in the adrenal cortex. It was also found that apolipoprotein E promotes virus colonization of the ovaries, the APOE gene dose being directly related to viral invasiveness.
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Apolipoproteínas E/metabolismo , Herpes Simple/fisiopatología , Herpesvirus Humano 1/patogenicidad , Ovario/virología , Caracteres Sexuales , Enfermedad Aguda , Glándulas Suprarrenales/virología , Animales , Apolipoproteínas E/genética , Encéfalo/virología , Femenino , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Médula Espinal/virología , Carga Viral , Latencia del VirusRESUMEN
BACKGROUND: So far there have been no reports on the expression pattern of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) in human breast cells and its relationship to the estrogen receptors, ER-alpha and ER-beta, and the androgen receptor (AR). METHODS: In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas. RESULTS: In BBD and breast carcinomas, DAX-1 was present in both the nuclei and the cytoplasm of epithelial cells, although in infiltrative carcinomas the percentage of nuclear immunoreaction was higher than in CIS. An important relation was observed between DAX-1 and AR expression and between this orphan receptor and nodal status. CONCLUSION: DAX-1 might modify the AR and ER-beta intracellular location, and because a direct positive relation between the expression of these three receptors was found it could be assumed that the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies.
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Enfermedades de la Mama/metabolismo , Neoplasias de la Mama/química , Proteínas de Unión al ADN/análisis , Proteínas de Neoplasias/análisis , Receptores Androgénicos/análisis , Receptores de Estrógenos/análisis , Receptores de Ácido Retinoico/análisis , Proteínas Represoras/análisis , Adulto , Anciano , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/química , Carcinoma Lobular/química , Carcinoma Lobular/patología , Núcleo Celular/química , Citoplasma/química , Receptor Nuclear Huérfano DAX-1 , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Células Epiteliales/química , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Fibroadenoma/química , Fibroadenoma/patología , Humanos , Metástasis Linfática , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Neoplasias Hormono-Dependientes/química , Neoplasias Hormono-Dependientes/patología , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/fisiología , Proteínas Represoras/genética , Proteínas Represoras/fisiologíaRESUMEN
The aim of this study was to evaluate the presence and distribution of retinoid X receptors (RXRs) alpha, beta, and gamma in normal, hyperplastic (nodular, basal cell, and atrophic hyperplasia), and carcinomatous human prostates in order to elucidate the relationship among these receptors and the onset and development of prostatic adenocarcinoma. RXRalpha and RXRgamma were immunodetected in all samples of normal, nodular, and basal cell hyperplasia, as well as carcinomatous prostates. In atrophic glands, the expression of both receptors was found in 22.5% of samples. Positive immunostaining for RXRbeta was observed in 53.3% of normal prostates, 100% of samples showed basal cell hyperplasia, and were negative in nodular and atrophic hyperplasia. In prostatic adenocarcinoma, only 3 of 25 samples (the 3 diagnosed as well-differentiated) were positive for RXRbeta. Results suggest that diminished RXRbeta expression might be related to prostate cancer progression and because the responsiveness to retinoic acid treatments depends on the expression of different receptors, it is important to study their expression before therapy.
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Próstata/metabolismo , Receptores de Ácido Retinoico/metabolismo , Factores de Transcripción/metabolismo , Adenocarcinoma/metabolismo , Anciano , Anciano de 80 o más Años , Western Blotting , Estudios de Casos y Controles , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Hiperplasia Prostática/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores X Retinoide , Distribución TisularRESUMEN
p53, p21, and Rb are proteins with an important role in cell-cycle control. The expression and distribution of these gene products and the apoptotic rate were studied in the marbled-newt testis along the annual cycle to know the role of these factors in the control of spermatogenesis and glandular tissue formation. The study was carried out using Western blot analysis and immunohistochemistry. The results differed from those, previously reported in mammals showing constant spermatogenesis. Greater expression of p53 and p21 was found in the quiescence period and was detected in PCGs (primordial germ cells), spermatogonia, follicular, interstitial cells, and glandular tissue. Greater expression of Rb and phosph-Rb was present in the proliferation period, in PCGs, and spermatogonia. Apoptosis was only detected in secondary spermatogonia (quiescence and spermiogenesis periods) and primary spermatocytes (proliferation and spermiogenesis periods). In the quiescence period, the increase in p53 expression activates p21 expression, which inhibits Rb phosphorylation and arrests the cell cycle in G1. In the proliferation period and, in a lesser degree, in the spermiogenesis period, the expressions of p53 and p21 decrease and phosph-Rb increases, enhancing cell proliferation. These gene products do not seem to be related to apoptosis.
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Ciclinas/fisiología , Proteína de Retinoblastoma/fisiología , Salamandridae/fisiología , Testículo/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Apoptosis/fisiología , Western Blotting , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Etiquetado Corte-Fin in Situ , Masculino , Fosforilación , Factores de TiempoRESUMEN
La relación entre hipotiroidismo juvenil, quistes ováricos y signos de pubertad precoz es reconocida en la literatura desde hace más de tres décadas (4-6). Se presenta el caso de una niña con masa abdominal quística e hipotiroidismo no tratado durante varios años, asociados a talla baja e inicios de ciclos menstruales; se destaca la ausencia de caracteres sexuales secundarios, la presencia de masa ovárica unilateral y la resolución completa de los signos clínicos con la terapéutica de reemplazo...