Interdisciplinary research on autism: Behavioral measures in the development of a mouse model of autism / Medidas comportamentales para un modelo de autismo en ratones

A great deal of biomedical research has provided experimental evidence of the function of specific neuropeptides in the development of autistic symptomatology. Interdisciplinary research in this area would provide a more comprehensive understanding of autism by integrating the findings and contributions from both behavior analysis and biology. In this preliminary interdisciplinary study, pregnant mice were injected with lipopolysaccharide - LPS (experimental group) on the 17th day of gestation and their litters were compared to the litters of mice that were not injected. Measures of social interaction were taken in two periods, namely when the pups were juveniles and when they were young adults, using an ABAB design consisting on the presence/absence of the mother in the chamber. The social interaction of each pup was assessed by observing the number of approaches it made towards its mother. Average velocity, calculated as distance traveled over time, for each mouse during the session was also collected. It was concluded that further refinement of the measure of social interaction was needed, and that a measure of behavioral development may prove useful in the construction of a mouse model of autism.

Un gran número de investigación biomédica ha reportado evidencia empírica respecto a la función de neuropéptidos específicos en el desarrollo de la sintomatología del autismo. Se sugiere que con el fin de obtener una mayor comprensión del autismo es necesario establecer un campo de investigación interdisciplinario en el cual es integren contribuciones tanto del Análisis Comportamental como de la Biología. En este estudio interdisciplinario preliminar, ratonas gestantes fueron inyectadas con lipopolisacárido - LPS (grupo experimental) en el 17avo día de gestación. Las camadas de estas ratonas fueron comparadas con camadas control que no fueron inyectadas. Las mediciones de interacción social se realizaron en dos periodos, juvenil y adulto joven, utilizando un diseño ABAB que consistió en la presencia o ausencia de la madre en la cámara experimental. La interacción social de cada cría se evaluó observando el número de acercamientos hacia la madre. El promedio de velocidad, entendida como distancia recorrida sobre tiempo, de cada ratón también fue calculado para cada sesión. Se concluye que es necesario un mayor refinamiento de la medida de interacción social utilizada, y que la introducción de una medida de desarrollo comportamental sería útil en la construcción de un modelo animal de autismo.

[Tetrahydrobiopterin therapy for hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. When and how?]. / Tratamiento de la hiperfenilalaninemia por déficit de fenilalanina hidroxilasa con tetrahidrobiopterina. Cuándo y cómo?

INTRODUCTION: Some patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency respond with a variable decrease in plasma phenylalanine levels after oral tetrahydrobiopterin (BH4) administration and are then able to tolerate higher dietary phenylalanine intake or even to discontinue a phenylalanine-restricted diet. BH4-sensitive patients are usually identified by means of a BH4 loading test, but consensus on the methodology of this test and the interpretation of its results is lacking. Consequently, a simple tool to identify which patients are likely candidates for this treatment and how they will progress in the long-term is required. MATERIAL AND METHODS: A combined oral BH4 loading test with phenylalanine (100 mg/kg) and BH4 (20 mg/kg) was performed in 20 patients with hyperphenylalaninemia under dietary phenylalanine restriction. RESULTS: Independently of the genotype, the result was positive in all the 9 patients whose maximum phenylalanine level at diagnosis was below 815 nmol/ml. Currently, they are under treatment with tetrahydrobiopterin doses of 7-15 mg/kg/day. All these patients have been able to increase their oral phenylalanine intake. Six are currently following a normal diet and the remaining three are close to reaching this goal. None of the patients with a maximum phenylalanine level at diagnosis higher than 938 nmol/ml responded to the BH4 loading test. CONCLUSIONS: The maximum phenylalanine level at diagnosis seems to be a simple and reliable method to predict response to BH4 treatment. A high percentage of BH4-sensitive patients are able to discontinue a phenylalanine-restricted diet after long-term tetrahydrobiopterin treatment.

Comparative study of the efficacy of an induction dose of interferon-alpha2b with ribavirin compared with standard combined treatment in naive patients with chronic hepatitis C.

The efficacy and secondary effects of an induction dose of interferon-alpha2b (IFN-alpha2b) with ribavirin compared with standard combined treatment in naive patients with chronic hepatitis C infection were compared. A prospective study was undertaken between March 1998 and November 2001 in which 84 Spanish hospitals took part. Six hundred and fourteen naive patients (age range 18-65 years) diagnosed with chronic hepatitis C virus (HCV) infection and without cirrhosis or co-infection by other viruses, were included. Patients were divided into two groups. Group A (n = 304) received induction treatment with a daily dose of 5 MU of IFN-alpha2b for 4 weeks, followed by 5 MU three times a week with ribavirin (1000-1200 mg/day, according to weight) until completing 1 year of treatment. Group B (n = 310) received the standard dose of IFN-alpha2b of 3 MU three times per week for 48 weeks together with ribavirin (1000-1200 mg/day, according to weight). Both groups were completely comparable according to age, gender, body weight, transaminase levels, genotype, viral load and hepatic inflammatory activity (Knodell Index). No control group was included for ethical reasons. Pegylated interferon was not available at the time of the study. Serum baseline samples were collected for the determination of genotype. Samples were also collected at baseline, weeks 4, 12, 24, 48 and 72, in order to detect and quantify HCV-RNA. The efficacy of treatment was evaluated by means of sustained viral response (SVR) characterized by persistent negativity of HCV-RNA at the end of the follow-up period. At week 4, the response to treatment was greater in group A (49.6%) compared with group B (34.5%) (P = 0.0002), and was maintained until week 12 (64.1% compared with 55.8% respectively) (P = 0.03). These differences disappeared at week 24, when group A (69%) was compared with group B (65%) (NS). At week 48, the response rate for group A was 50.6% compared with group B 47.4% (NS), and at week 72, the SVR in group A was 46% compared with 40.3% for group B (NS). The global SVR was 43.1%. On analysing the response to treatment according to genotype and viral load, we found that the induction treatment was slightly superior in patients with genotype 1 and an elevated viral load (>2 x 10(6) copies/ml). They achieved a SVR in group A of 39.1% compared with 25.5% in group B (P < 0.05). However, this slight improvement obtained in group A, was achieved at the expense of a greater percentage of dropouts compared with group B (6.4% vs 2.2%, P < 0.01); a greater rate of side effects (58.5 vs 36.7%, P < 0.05) and also a greater percentage of neutropenia (3.1% vs 0.9%, P < 0.05). The induction treatment presented a better initial response, but this was not maintained at the end of treatment, and did not improve the results obtained with the standard treatment. Although the patients with genotype 1 and elevated viral load had a better response with the induction treatment, this was accompanied by a greater percentage of dropouts and secondary effects. It would be interesting to repeat this type of study in the future, using pegylated interferon.