Magnitude and duration of hyperactivity following neonatal 6-hydroxydopamine is related to the extent of brain dopamine depletion

This experiment examined the relationship between the extent of brain dopamine (DA) neuron destruction in the neonatal rat and locomotor hyperactivity during subsequent development. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular injections of 6-hydroxydopamine (6-OHDA) following desmethylimipramine (DMI) pretreatment of both days 3 and 6 of life. Groups of rats received total doses of 50, 70, 100 or 200 microgram of 6HDA or the vehicle solution. Each group of rats given 6-OHDA displayed 3- to 5-fold increases in locomotor activity relative to vehicle control rats on days 16 and 18 of life. Rats given 50 or 70 microgram of 6-OHDA displayed hyperactivity that diminished during days 18-32 of life, approaching the level of activity seen in vehicle-treated rats. It contrast, rats given 100 or 200 microgram of 6-OHDA displayed consistently high levels of locomotion during days 18-32 of life. When tested as adults (days 55-66 of life) only those rats given 200 micrograms of 6-OHDA as neonates continued to display locomotor hyperactivity. The extent of 6-OHDA-induced depletion of DA was proportional to the magnitude of locomotor hyperactivity seen during neonatal life. Brain DA was depleted to the greatest extent in rats which displayed permanent hyperactivity. Regardless of the extent of depletion of brain DA, adult rats given intraventricular injections of 125, 200 or 275 micrograms of 6-OHDA at 48 days of age (following pargyline and DMI pretreatment) displayed no significant change in locomotor activity. These results indicate that the magnitude and duration of locomotor hyperactivity seen following neonatal 6-OHDA injections are correlated with the extent of loss of central DA neurons and suggest that brain DA projections exert important influences on the ontogeny of normal locomotion.     

Aging‐ and vascular‐related pathologies

Our aging population is set to grow considerably in the coming decades. In fact, the number of individuals older than 65 years will double by 2050. This projected increase in people living with extended life expectancy represents an inevitable upsurge in the presentation of age‐related pathologies. However, our current understanding of the impact of aging on a number of biological processes is unfortunately inadequate. Cardiovascular, cerebrovascular, and neurodegenerative diseases are particularly prevalent in the elderly population. Intriguingly, these pathologies are all associated with vascular dysfunction, suggesting that the process of aging can induce structural and functional impairments in vascular networks. Together with elevated cell senescence, pre‐existing comorbidities, and the emerging concept of age‐associated inflammatory imbalance, impaired vascular functions can significantly increase one's risk in acquiring age‐related diseases. In this short review, we highlight some current clinical and experimental evidence of how biological aging contributes to three vascular‐associated pathologies: atherosclerosis, stroke, and Alzheimer's disease.     

Functional and morphometric brain dissociation between dyslexia and reading ability

In functional neuroimaging studies, individuals with dyslexia frequently exhibit both hypoactivation, often in the left parietotemporal cortex, and hyperactivation, often in the left inferior frontal cortex, but there has been no evidence to suggest how to interpret the differential relations of hypoactivation and hyperactivation to dyslexia. To address this question, we measured brain activation by functional MRI during visual word rhyme judgment compared with visual cross-hair fixation rest, and we measured gray matter morphology by voxel-based morphometry in dyslexic adolescents in comparison with (i) an age-matched group, and (ii) a reading-matched group younger than the dyslexic group but equal to the dyslexic group in reading performance. Relative to the age-matched group (n = 19; mean 14.4 years), the dyslexic group (n = 19; mean 14.4 years) exhibited hypoactivation in left parietal and bilateral fusiform cortices and hyperactivation in left inferior and middle frontal gyri, caudate, and thalamus. Relative to the reading-matched group (n = 12; mean 9.8 years), the dyslexic group (n = 12; mean 14.5 years) also exhibited hypoactivation in left parietal and fusiform regions but equal activation in all four areas that had exhibited hyperactivation relative to age-matched controls as well. In regions that exhibited atypical activation in the dyslexic group, only the left parietal region exhibited reduced gray matter volume relative to both control groups. Thus, areas of hyperactivation in dyslexia reflected processes related to the level of current reading ability independent of dyslexia. In contrast, areas of hypoactivation in dyslexia reflected functional atypicalities related to dyslexia itself, independent of current reading ability, and related to atypical brain morphology in dyslexia.     

Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.     

Intraoperative electron beam treatment for pediatric malignancies: The Ohio State University experience

PURPOSE: To report the result of intraoperative electron beam radiation therapy (IOERT) in patients with extensive pediatric tumors. METHOD: From October 1989 through June 2000, 13 children were treated with chemotherapy, maximal surgery, and 10-15 Gy IOERT at a total of 18 sites. IOERT was used for palliative purposes in 5 children with metastatic disease and in 3 others who were previously treated with external beam radiation (EBRT). The remaining five patients received definitive IOERT. Postoperative EBRT of 35.4-45 Gy was given in 5 patients. RESULTS: After a median follow-up of 42 months (range = 18-63 months), 4 patients were alive and without evidence of disease. Overall and 3 year actuarial survival rates were 31% (4/13) and 26%, respectively. Local control was achieved at 13/18 sites (72%). Poor prognostic factors included metastatic disease, recurrent disease, and the absence of adjuvant EBRT. Two children with Wilms tumors had 100% local control, disease-free survival, and overall survival without the addition of EBRT. CONCLUSION: A boost dose of IOERT allows for reduction in the dose of EBRT, thereby limiting growth-related morbidity without compromising local control or disease-free survival. Except for Wilms tumors, which achieved 100% local control and disease-free survival, adjuvant EBRT is necessary for successful local control and survival in children with soft tissue sarcomas. Based on this study and others, intraoperative irradiation should be considered for inclusion in prospective, multi-institutional trials designed to treat localized malignancies in young children.     

Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies

Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.