Quantitative Magnetic Resonance Imaging of Human Brain Development: Ages 4-18

Brain magnetic resonance images (MRI) of 104 healthy childrenand adolescents, aged 4–18, showed significant effectsof age and gender on brain morphometry. Males had larger cerebral(9%) and cerebellar (8%) volumes (P < 0.0001 and P = 0.008.respectively), which remained significant even after correctionfor height and weight After adjusting for cerebral size, theputamen and globus pallidus remained larger in males, whilerelative caudate size was larger in females. Neither cerebralnor cerebellar volume changed significantly across this agerange. Lateral ventricular volume increased significantly inmales (trend for females), with males showing an increase inslope after age 11. In males only, caudate and putamen decreasedwith age (P = 0.007 and 0.05, respectively). The left lateralventricles and putamen were significantly greater than the rightP = 0.01 and 0.0001, respectively). In contrast, the cerebralhemispheres and caudate showed a highly consistent right greater-than-leftasymmetry (P < 0.0001 for both). All volumes demonstrateda high degree of variability. These findings highlight gender-specificmaturational changes of the developing brain and the need forlarge gender-matched samples in pediatric neuropsychiatric studies.     

PULMONARY RESECTION FOR METASTATIC BREAST CANCER

Background : A patient with a solitary pulmonary metastasis who had breast cancer in the past may benefit from pulmonary resection. Methods : Between 1984 and 1996, 17 patients underwent metastatectomy for metastatic breast cancer. There were 15 females and two males whose average age was 59 (range: 40–74 years). The median tumour-free interval after the primary breast-cancer operation was 5.1 years (range: 8 months-18.2 years). Sixteen patients had complete resections, which included six lobectomies and 10 lesser resections. Results : The postoperative mortality was nil and the morbidity rate was 6%. Follow-up was complete in all patients. Recurrent disease developed in four patients and two patients died of their disease. The 5-year survival was 62%. Conclusion : An aggressive surgical approach is warranted in patients with isolated resectable pulmonary metastases from breast cancer.     

Expression of a 1,25-dihydroxyvitamin D3 membrane-associated rapid-response steroid binding protein during human tooth and bone development and biomineralization.

The calciotropic hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has been established to control skeletal tissue formation and biomineralization via the regulation of gene expression. This action involves the well-characterized nuclear 1,25(OH)2D3 receptor. However, it has been recognized that several cellular responses to 1,25(OH)2D3 may not to be related to the exclusive nuclear receptor. Indeed, this secosteroid is able to generate rapid responses that have been proposed to be mediated by interactions of the ligand, which is a putative cell membrane-associated rapid-response steroid (MARRS) binding protein for 1,25(OH)2D3 [1,25D3-MARRS]. The nongenomic pathway of 1,25(OH)2D3 was studied here in detail by immunolocalization of the 1,25D3-MARRS during the specific context of human prenatal development. Western blotting with proteins extracted from 4 week- to 27-week-old embryos was performed, evidencing a 65-kDa molecular species recognized by antibody Ab 099 generated against synthetic peptides corresponding to the N terminus of the 1,25D3-MARRS from chick intestinal basolateral membranes. Based on this biochemical conservation of protein in the human species, the temporospatial expression patterns were established in the craniofacial skeleton at the same ages. Comparative analysis was performed in teeth and bones from early morphogenesis to terminal cell differentiation and extracellular biomineralization. The data show the potential implication of 1,25D3-MARRS in the heterogeneous cell population including ameloblasts, odontoblasts, osteoblasts, and osteoclasts. The epithelial-mesenchymal cascade related to odontogenesis was coincident with a sequence of up- and down-regulation of immunoreactive 1,25D3-MARRS. Biomineralization was associated with a striking up-regulation in the adjoining secretory cells in all tissues. Finally, osteoclasts appeared also to express the 1,25D3-MARRS during these early phases of bone modeling. Previously obtained data of the nuclear vitamin D receptor (VDR) expression and this study on 1,25D3-MARRS suggest the existence of cross-talk between the genomic and nongenomic pathways during human development.     

Adeno-associated virus vector-mediated systemic delivery of IFN-beta combined with low-dose cyclophosphamide affects tumor regression in murine neuroblastoma models.

PURPOSE: Type I IFNs (IFN-alpha/beta) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models. EXPERIMENTAL DESIGN: Continuous liver-generated expression of human IFN-beta (hINF-beta) was achieved through a gene therapy-mediated approach using adeno-associated virus vectors encoding hIFN-beta (AAV hINF-beta). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy. RESULTS: The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-beta. Continued growth of established retroperitoneal tumors, treated with AAV hINF-beta as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-beta. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-beta was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease. CONCLUSIONS: AAV-mediated delivery of hIFN-beta when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-beta was able to effect complete tumor regression.