The AMPA receptor potentiator LY404187 increases cerebral glucose utilization and c-fos expression in the rat.

AMPA receptor potentiators enhance AMPA receptor-mediated glutamatergic neurotransmission and may have therapeutic potential as cognitive enhancers or antidepressants. The anatomical basis for the action of AMPA receptor potentiators is unknown. The aim of this study was to determine the effects of the biarylpropylsulfonamide AMPA receptor potentiator, LY404187 (0.05 to 5 mg/kg subcutaneously), upon cerebral glucose utilization and c-fos expression using 14C-2-deoxglucose autoradiography and c-fos immunocytochemistry. LY404187 (0.5 mg/kg) produced significant elevations in glucose utilization in 28 of the 52 anatomical regions analyzed, which included rostral neocortical areas and the hippocampus, as well the dorsal raphe nucleus, lateral habenula, and locus coeruleus. No significant decreases in glucose utilization were observed in any region after LY404187 administration. The increases in glucose utilization with LY404187 (0.5 mg/kg) were blocked by pretreatment with the AMPA receptor antagonist LY293558 (25 mg/kg), indicating that LY404187 acts through AMPA receptor-mediated mechanisms. LY404187 (0.5 mg/kg) also produced increases in c-fos immunoreactivity in the cortex, locus coeruleus, and the dorsal raphe nucleus. These studies demonstrate neuronal activation in key brain areas that are associated with memory processes and thus provide an anatomical basis for the cognitive enhancing effects of AMPA receptor potentiators.     

Cellular and Molecular Foundation for Fracture Healing in Children

Abstract Dealing with pediatric fracture patients requires a funded knowledge of complications and remodeling capability of the youth skeleton to find the accurate therapy decision and to avoid unnecessary invasive procedures. Due to the different mechanical environment, fractures in children occur at specific fracture-vulnerable areas. One of those is the growth plate, which on one hand gives rise to the unique ability of correcting angular deformities by specifically increasing the growth rate in definite regions, and on the other hand leads to complications like growth arrest or angular deformity. The pediatric diaphysis presents the exclusive greenstick fracture, only seen in the growing skeleton, which occurs because of the different composition of the pediatric bone. To understand these very specific features of the youth skeleton, the molecular and cellular basis should be taken into consideration. Therefore, this review will present the common characteristics of skeletal development and fracture healing. An insight into the mechanotransduction as part of the remodeling and self-correcting ability of pediatric bone is given to span the bridge between clinical treatment options and scientific background.     

Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget's disease of bone.

Paget's disease is a focal condition of bone. To study changes in cells within pagetic lesions, we cultured osteoblasts and stromal cells from 22 patients and compared gene expression in these cells to cells from healthy bone. We identified several differentially regulated genes, and we suggest that these changes could lead to the formation of the lesions. INTRODUCTION: Paget's disease is a focal condition of bone of unknown cause. Although it is regarded as primarily an osteoclast disorder, the tight coupling of the activity of osteoclasts and osteoblasts suggests that the osteoblast could play a key role in its pathogenesis. The aim of the study was to identify possible changes in pagetic osteoblasts and stromal cells that might contribute to the development of pagetic lesions. MATERIALS AND METHODS: Candidate genes were identified based on known bone cell regulators, supplemented with microarray analysis. Gene expression was determined by real-time PCR in primary cultures of osteoblasts and bone marrow stromal cells from pagetic patients and control subjects. Concentrations of secreted proteins were determined by ELISA. RESULTS: Dickkopf1 mRNA and protein levels were increased in both pagetic osteoblast and stromal cell cultures, and interleukin (IL)-1 and IL-6 were overexpressed in pagetic osteoblasts. These changes parallel recent findings in myeloma bone disease, which shares some clinical similarities with Paget's disease. Alkaline phosphatase was overexpressed, and bone sialoprotein and osteocalcin were underexpressed in pagetic osteoblasts, consistent with their circulating levels in pagetic patients. It is hypothesized that overexpression of Dickkopf1, IL-1, and IL-6 would result in stimulation of osteoclast proliferation and inhibition of osteoblast growth, leading to the development of the characteristic lytic bone lesions. By stimulating osteoblast differentiation, Dickkopf1 and IL-6 may also promote mineralization, leading to the conversion of lytic lesions to sclerotic. CONCLUSIONS: These findings suggest that dysregulated gene expression in pagetic osteoblasts could cause the changes in bone cell number and function characteristic of Paget's disease.     

ON BEING THERE, ON STRUGGLING TO BE THERE AND ON BEING ORDINARY

ABSTRACT It is my view that healing takes place in a situation of intimacy around a vulnerable and damaged area and that, in order to have access to that area, the therapist must conduct himself as an ordinary and decent human being. He must have the capacity to 'be there'. This paper discusses what it means to 'be there' and examines why it is of such central importance in bringing about change. Included in this is the struggle to 'be there', that is, the intimate struggle between the therapist and patient, as well as the separate and private struggle that both therapist and patient have intrapersonally. A clinical example is given in illustration.