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PURPOSE: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. METHODS: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. RESULTS: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. CONCLUSION: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.
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Variación Genética , Genoma Humano , Pruebas Genéticas , Genoma Humano/genética , Genómica , Humanos , Análisis de Secuencia de ADN , VirulenciaRESUMEN
BACKGROUND AND OBJECTIVES: The impact of medications for opioid use disorder (MOUD) on against medical advice (AMA) discharges among people who inject drugs (PWID) hospitalized for endocarditis is unknown. METHODS: A retrospective review of all PWID hospitalized for endocarditis at our institution between 2016 and 2018 (n = 84). RESULTS: PWID engaged with MOUD at admission, compared with those who were not, were less likely to be discharged AMA but this did not reach statistical significance in adjusted analysis (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.033-1.41; P = .11). Among out-of-treatment individuals, newly initiating MOUD did not lead to significantly fewer AMA discharges (OR, 0.98; 95% CI, 0.26-3.7; P = .98). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: PWID hospitalized for endocarditis are at high risk for discharge AMA but more research is needed to understand the impact of MOUD. (Am J Addict 2020;29:155-159).
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Endocarditis/terapia , Tratamiento de Sustitución de Opiáceos/psicología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Cooperación del Paciente/psicología , Alta del Paciente/estadística & datos numéricos , Negativa del Paciente al Tratamiento/psicología , Adulto , Analgésicos Opioides/uso terapéutico , Buprenorfina/uso terapéutico , Endocarditis/etiología , Femenino , Humanos , Inyecciones , Masculino , Metadona/uso terapéutico , Persona de Mediana Edad , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Oportunidad Relativa , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/psicología , Cooperación del Paciente/estadística & datos numéricos , Estudios Retrospectivos , Negativa del Paciente al Tratamiento/estadística & datos numéricosRESUMEN
ClinVar provides open access to variant classifications shared from many clinical laboratories. Although most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences (MSDs). Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with MSDs between the laboratories (650 variants). Next, MSDs were filtered for variants with ≥3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications, which will improve the care of patients with, or at risk for, genetic disorders.
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Bases de Datos Genéticas , Pruebas Genéticas/métodos , Variación Genética/genética , Genoma Humano/genética , HumanosRESUMEN
Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.
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Variaciones en el Número de Copia de ADN/genética , Genoma Humano/genética , Curaduría de Datos , Bases de Datos Genéticas , Variación Genética/genética , HumanosRESUMEN
PURPOSE: To report atypical presentation of neuronal ceroid lipofuscinoses type 8 (CLN8) to the eye clinic and review clinical features of CLN8. OBSERVATIONS: Detailed eye exam by slit lamp exam, indirect ophthalmoscopy, fundus photography, optical coherence tomography, visual fields and electroretinogram (ERG). Molecular genetic testing using Next Generation Sequencing panel (NGS) and array Comparative Genomic Hybridization (aCGH).The siblings in this study presented to the eye clinic with retinitis pigmentosa and cystoid macular edema, and a history of seizures but no severe neurocognitive deficits or regression. Genetic testing identified a c.200C > T (p.A67V) variant in the CLN8 gene and a deletion encompassing the entire gene. Electron microscopy of lymphocytes revealed fingerprint inclusions in both siblings. CONCLUSIONS: and Importance: Pathogenic variants in CLN8 account for the retinitis pigmentosa and seizures in our patients however, currently, they do not have regression or neurocognitive decline. The presentation of NCL can be very diverse and it is important for ophthalmologists to consider this in the differential diagnosis of retinal disorders with seizures or other neurological features. Molecular genetic testing of multiple genes causing isolated and syndromic eye disorders using NGS panels and aCGH along with additional complementary testing may often be required to arrive at a definitive diagnosis.
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In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 µg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.
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Dopamina/metabolismo , Compuestos Organotiofosforados/toxicidad , Serotonina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/farmacología , Colinesterasas/sangre , Masculino , Ratones Endogámicos BALB C , Compuestos Organotiofosforados/administración & dosificación , Soman/toxicidadRESUMEN
BACKGROUND: Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. METHODS: To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. RESULTS: Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/-) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. CONCLUSIONS: Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/- mice mirror some, but not all, of the perturbed molecular pathways in the brain.
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BACKGROUND: No adequate statistical model has been established to estimate future glomerular filtration rate (GFR) in children after kidney transplantation (KTX). Equations based on simple linear regression analysis as used in adults are not established in children. METHODS: An optimal prognostic model of GFR was generated for 63 children at 3-7 years after KTX. The main regression model for prediction of the log-transformed GFR (logGFR) included the mean monthly change of GFR in the period 3-24 months after KTX (∆GFR), the baseline GFR at 3 months (bGFR), and an intercept. Additionally, we investigated if the inclusion of cofactors leads to more precise predictions. The model was validated by leave-one-out cross-validation for years 3-7 after KTX. Prognostic quality was determined with the mean squared error (MSE) and mean absolute error (MAE). Results were compared with the simple linear regression model used in adults. RESULTS: The following statistical model was calculated for every prognosis year (i = 3, , 7):[Formula: see text] [Formula: see text] Comparison of the new statistical model and the simple linear model for adults led to relevantly lower MSEs and MAEs for the new model (year 7: New model: MSE 0.1, MAE 0.3/adult model: MSE 1069, MAE 18). The benefit of inclusion of cofactors was not relevant. CONCLUSIONS: This statistical model is able to predict long-term graft function in children with very high precision.
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Tasa de Filtración Glomerular , Supervivencia de Injerto , Trasplante de Riñón , Riñón/fisiopatología , Riñón/cirugía , Modelos Estadísticos , Adulto , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Trasplante de Riñón/efectos adversos , Modelos Lineales , Masculino , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked disorder resulting from an impairment of the transcellular transportation of thyroid hormones. Within the central nervous system thyroid hormone transport is normally mediated by MCT8. Patients are described as affected by a static or slowly progressive clinical picture which consists of variable degrees of mental retardation, hypotonia, spasticity, ataxia and involuntary movements, occasionally paroxysmal. The authors describe the clinical and neuroradiological picture of 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxysmal extrapyramidal symptoms. In one subject a novel mutation is described.
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Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/genética , Encéfalo/patología , Cromosomas Humanos X/genética , Análisis Mutacional de ADN , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Transportadores de Ácidos Monocarboxílicos/deficiencia , Transportadores de Ácidos Monocarboxílicos/genética , Fibras Nerviosas Mielínicas/patología , Aberraciones Cromosómicas Sexuales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Preescolar , Colina/metabolismo , Codón sin Sentido/genética , Estudios de Seguimiento , Humanos , Lactante , Inositol/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Mutación Missense/genética , Examen Neurológico , Simportadores , Pruebas de Función de la TiroidesRESUMEN
Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62-0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65-0.82), but not for female samples (AUC 0.51, 95% CI 0.36-0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58-0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.
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Trastornos Generalizados del Desarrollo Infantil/genética , Transcriptoma , Niño , Trastornos Generalizados del Desarrollo Infantil/sangre , Estudios de Cohortes , Perfilación de la Expresión Génica , Humanos , Masculino , Modelos Genéticos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
In order to better understand the effects of repeated low-dose exposure to organophosphorus (OPs) on physiological and behavioural functions, we analysed the levels of endogenous monoamines (serotonin and dopamine) in different brain areas after repeated exposure of mice to sublethal dose of soman. Animals were injected once a day for 3 days with 0.12 LD50 of soman (47 microg/kg, i.p.). They did not show either severe signs of cholinergic toxicity or pathological changes in brain tissue. 24 h after the last injection of soman, inhibition of cholinesterase was similar in plasma and brain (32% and 37% of inhibition respectively). Afterwards, recovery of cholinesterase activity was faster in the plasma than in the brain. Dopamine levels were not significantly modified. On the other hand, we observed a significant modification of the serotoninergic system. An increase of the 5-HIAA/5-HT ratio was maintained for 2 and 4 weeks after exposure in the hippocampus and the striatum respectively. This study provides the first evidence of a modification of the 5-HT turnover in the hippocampus and the striatum after repeated low-dose intoxication with a nerve agent. Further experiments are necessary to evaluate the relationship between these modifications and the unexpected neuropsychological disorders usually reported after chronic exposure of organophosphorus.
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Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Soman/toxicidad , Animales , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos BALB C , Soman/administración & dosificaciónRESUMEN
The present study examined, in mice, whether regional patterns of brain monoamines concentrations (DA, 5-HT and their metabolites) and expression of c-Fos protein, that may represent a prolonged functional change in neurons, could be changed after a combined exposure to stress and the peripheral cholinesterase reversible inhibitor pyridostigmine (PYR). Animals were subjected every day to a random combination of mild unescapable electric footshocks and immobilization over a 12-day period, resulting in a significant increase of glucocorticoids levels and an activation of c-fos in hippocampus, thalamus and piriform cortex. This stress protocol induced a significant increase of 5-HT levels in striatum, hippocampus and ponto mesencephalic area (PMA) but failed to induce any DA activation. When PYR (0.2 mg/kg s.c. inducing 19-35% inhibition of the plasmatic ChE activity) was administered twice a day during the last 5 days of the stress session, 5-HIAA levels and expression of c-fos oncogene were significantly increased in the most of the brain areas studied. DA levels were also enhanced in striatum/hippocampus as a result of a possible activation of mesolimbic and nigrostriatal dopamine systems. Taken together, these results suggest that a combined exposure to certain stress conditions and PYR leads, in mice, to functional changes in neurons and may affect centrally controlled functions. The mechanisms underlying these modifications and their behavioral implications remain to be further investigated.
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Monoaminas Biogénicas/metabolismo , Química Encefálica/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Genes fos/genética , Estrés Psicológico/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Colinesterasas/sangre , Dopamina/metabolismo , Electrochoque , Glucocorticoides/farmacología , Hidrocortisona/sangre , Ácido Hidroxiindolacético/metabolismo , Inmovilización , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Bromuro de Piridostigmina/farmacología , Serotonina/metabolismoRESUMEN
Type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse can be delayed by administration of insulin or specific insulin peptides. To better understand how insulin treatment delays diabetes development, NOD mice treated with an insulin peptide (B9-23) were compared with age-matched NOD and NOD congenic mice for gene expression changes in spleen using cDNA microarray. Fifty genes were identified that were significantly altered by B9-23 treatment. Thirty-three of these genes are downregulated by the treatment while they are upregulated during the natural disease progression in NOD from immature (3-4 weeks) to mature (10 weeks) stages. Taken together, our data suggest that the B9-23 treatment, like the protective genes in NOD congenic strains, reduces pro-inflammatory activation of lymphocytes that normally occurs in NOD mice. Furthermore, our studies discovered two genes (Irf4 and Tra1) with increased expression in B9-23-treated mice that promote the Th2 response, providing a molecular basis for the B9-23-protective therapy.
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Diabetes Mellitus Tipo 1/genética , Inmunización , Insulina/inmunología , Insulina/metabolismo , Fragmentos de Péptidos/inmunología , Animales , Regulación hacia Abajo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ratones , Ratones Congénicos , Ratones Endogámicos NOD , Análisis de Secuencia por Matrices de Oligonucleótidos , Fragmentos de Péptidos/metabolismo , Bazo/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
This investigation compared the efficacy of diazepam and the water-soluble prodiazepam-avizafone-in sarin poisoning therapy. Guinea pigs, pretreated with pyridostigmine 0.1 mg/kg, were intoxicated with 4LD(50) of sarin (s.c. route) and 1 min after intoxication treated by intramuscular injection of atropine (3 or 33.8 mg/kg), pralidoxime (32 mg/kg) and either diazepam (2 mg/kg) or avizafone (3.5 mg/kg). EEG and pneumo-physiological parameters were simultaneously recorded. When atropine was administered at a dose of 3 mg/kg, seizures were observed in 87.5% of the cases; if an anticonvulsant was added (diazepam (2 mg/kg) or avizafone (3.5 mg/kg)), seizure was prevented but respiratory disorders were observed. At 33.8 mg/kg, atropine markedly increased the seizure threshold and prevented early respiratory distress induced by sarin. When diazepam was administered together with atropine, seizures were not observed but 62.5% of the animals displayed respiratory difficulties. These symptoms were not observed when using avizafone. The pharmacokinetic data showed marked variation of the plasma levels of atropine and diazepam in different antidote combination groups, where groups receiving diazepam exhibited the lowest concentration of atropine in plasma. Taken together, the results indicate that avizafone is suitable in therapy against sarin when an anticonvulsant is judged necessary.
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Anticonvulsivantes/farmacología , Atropina/farmacología , Inhibidores de la Colinesterasa/envenenamiento , Diazepam/farmacología , Dipéptidos/farmacología , Antagonistas Muscarínicos/farmacología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Sarín/envenenamiento , Animales , Anticonvulsivantes/farmacocinética , Atropina/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/patología , Sustancias para la Guerra Química/toxicidad , Diazepam/farmacocinética , Dipéptidos/farmacocinética , Interacciones Farmacológicas , Electroencefalografía , Cobayas , Histocitoquímica , Antagonistas Muscarínicos/farmacocinética , Enfermedades del Sistema Nervioso/inducido químicamente , Compuestos de Pralidoxima/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Bromuro de Piridostigmina/farmacología , Insuficiencia Respiratoria/tratamiento farmacológico , Sarín/antagonistas & inhibidores , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
Interferon alfa (IFN-alpha)-based treatment is the only therapeutic option for chronic hepatitis C viral infection. However, the molecular mechanisms of IFN-alpha antiviral activity are not completely understood. The recent development of an HCV replicon cell culture system provides a feasible experimental model to investigate the molecular details of IFN-induced direct antiviral activity in hepatocytes. In this report, we show that IFN-alpha can effectively inhibit HCV subgenomic RNA replication and suppress viral nonstructural protein synthesis. Using cDNA microarray analysis, we also show that the replicon cells have different gene expression profile compared with the parental hepatoma cells (Huh7). IFN-alpha can induce a number of responsive genes in the replicon cells. One of the genes, 6-16 (G1P3), can enhance IFN-alpha antiviral efficacy. In addition, we demonstrate that IFN-alpha can significantly activate STAT3 in hepatoma cells, suggesting that this pathway plays a role in IFN-alpha signaling. In conclusion, our results indicate that IFN-alpha antiviral activity is associated with activation of STAT3-signaling pathway and intracellular gene activation. Our results also suggest that IFN-alpha-induced target genes may play an important role in IFN-alpha anti-HCV activity.
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Antivirales/farmacología , Hepacivirus/crecimiento & desarrollo , Hepatitis C Crónica/tratamiento farmacológico , Hepatocitos/fisiología , Interferón-alfa/farmacología , Carcinoma Hepatocelular , Proteínas de Unión al ADN/metabolismo , Expresión Génica/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/fisiopatología , Hepatocitos/citología , Hepatocitos/virología , Humanos , Neoplasias Hepáticas , ARN Viral/genética , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Transducción de Señal/efectos de los fármacos , Transactivadores/metabolismo , Células Tumorales Cultivadas , Proteínas Virales/genética , Replicación Viral/efectos de los fármacosRESUMEN
The Morris water-maze has been designed to test spatial orientation ability, learning and memory processes. In order to improve the analyse of the organization of the trajectory of rats, during the training phase, a computer program was elaborated. The study of the effect of a benzodiazepine, diazepam, was chosen to illustrate and validate this methodological approach. Results showed that rats pre-treated with diazepam (2 mg/kg) presented an impairment of spatial learning associated with the occurrence of a stereotyped circular swimming behaviour.