Guilty as CHARGED: p53's expanding role in disease.

Unrestrained p53 activity during development, as occurs upon loss of the p53 negative regulators Mdm2 or Mdmx, causes early embryonic lethality. Surprisingly, co-expression of wild-type p53 and a transcriptionally-dead variant of p53, with mutations in both transactivation domains (p53(L25Q,W26S,F53Q,F54S)), also causes lethality, but later in gestation and in association with a host of very specific phenotypes reminiscent of a syndrome known as CHARGE. Molecular analyses revealed that wild-type p53 is inappropriately activated in p53(5,26,53,54/)(+) embryos, triggering cell-cycle arrest or apoptosis during development to cause CHARGE phenotypes. In addition, CHARGE syndrome is typically caused by mutations in the CHD7 chromatin remodeler, and we have shown that activated p53 contributes to phenotypes caused by CHD7-deficiency. Together, these studies provide new insight into CHARGE syndrome and expand our understanding of the role of p53 in diseases other than cancer.

Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects.

Although isolated reports of hard-tissue reconstruction in the cranio-maxillofacial skeleton exist, multipatient case series are lacking. This study aimed to review the experience with 13 consecutive cases of cranio-maxillofacial hard-tissue defects at four anatomically different sites, namely frontal sinus (3 cases), cranial bone (5 cases), mandible (3 cases), and nasal septum (2 cases). Autologous adipose tissue was harvested from the anterior abdominal wall, and adipose-derived stem cells were cultured, expanded, and then seeded onto resorbable scaffold materials for subsequent reimplantation into hard-tissue defects. The defects were reconstructed with either bioactive glass or ß-tricalcium phosphate scaffolds seeded with adipose-derived stem cells (ASCs), and in some cases with the addition of recombinant human bone morphogenetic protein-2. Production and use of ASCs were done according to good manufacturing practice guidelines. Follow-up time ranged from 12 to 52 months. Successful integration of the construct to the surrounding skeleton was noted in 10 of the 13 cases. Two cranial defect cases in which nonrigid resorbable containment meshes were used sustained bone resorption to the point that they required the procedure to be redone. One septal perforation case failed outright at 1 year because of the postsurgical resumption of the patient's uncontrolled nasal picking habit.

Glial choristoma in the oral and maxillofacial region: a clinicopathologic study of 6 cases.

CONTEXT: Glial choristoma is an uncommon developmental abnormality typically presenting at birth or in early childhood. The nasal region is most frequently affected. Palate, tongue, cheek, scalp, and orbit can also be affected but these occurrences are relatively rare. OBJECTIVE: To report 6 cases of glial choristoma arising in the oral and maxillofacial region and to document the clinical and pathologic features of these lesions. DESIGN: Histologic and immunocytochemical examinations were performed on 6 cases of glial choristoma. Biologic behavior, prognosis, and pathogenesis were discussed together with a review of the literature. RESULT: The patients included 5 boys and 1 girl. They all presented with the lesions at birth or soon after birth. Four lesions occurred on the dorsal side of the tongue, near the foramen caecum. One lesion was present in the infratemporal fossa and parapharyngeal space, and the other one was in the submandibular region. All patients received surgical excision, and follow-up data revealed no recurrence for a period of 10 months to 5 years after surgery. Histologically, the lesions showed mature glial cells intermixed with connective tissue. The glial tissue was strongly positive for glial fibrillary acidic protein and S100 but negative for neurofilament. CONCLUSION: Glial choristoma should be classified as a developmental malformation that occurs in many sites of the head and neck. In oral cavity, the tongue is the most frequently affected site. Although these lesions are rare, they should be included in the differential diagnosis of congenital masses in the oral and maxillofacial region.

Immunohistochemical identification of TGF-beta1 at the maxillaries in growing Sprague-Dawley rats and after muscle section.

Growth factors are currently being extensively studied in the literature to ascertain their role during maxillofacial development. Taking into account that few investigations refer to the functions of growth in the maxillaries, our aim was to identify the TGF-beta1 immunohistochemical expression pattern in the maxillaries of growing rats. A secondary aim was to identify this pattern after orofacial function inhibition by muscle section. In the palate and the mandibular symphysis and body, we found that bone was formed through an endomembranous pathway with intense TGF-beta1 staining inside chondroid cells during the maximum development stages. At the midpalatal suture and the mandibular symphysis and condyle, endochondral ossification was detected with an intense expression of TGF-beta1 inside the chondrocytes when major growth occurred. After the muscle had been sectioned, at the mandible the maturation process was accelerated, this change being transitory until muscular function was recovered. However, at the palate, the intervention caused a greater disturbance of the growing pattern, which did not recover normality.

High-dose retinoic acid modulates rat calvarial osteoblast biology.

Retinoic acid has been shown to adversely affect craniofacial development. Cleft palate and craniosynostosis are two examples of craniofacial defects associated with prenatal exposure to this agent. Although the effects of retinoic acid on cephalic neural crest-derived tissues have previously been studied, the specific effects of retinoic acid on the cellular biology of osteoblasts remain unclear. The purpose of this study was to analyze in detail the effects of pharmacologic doses of retinoic acid on the differentiation and proliferation of osteoblasts derived from an intramembranous source. Primary rat calvarial osteoblasts were established in culture and treated with 1 or 10 microM all-trans-retinoic acid. Retinoic acid treatment markedly increased expression of osteopontin up to 48 h after stimulation. Consistent with this early stage of differentiation, both mRNA and protein analysis of FGF receptor isoforms demonstrated a switch in predominance from fibroblast growth factor receptor 2 (fgfr2) to fgfr1. Analysis of PCNA protein confirmed inhibition of proliferation by retinoic acid. To determine whether these alterations in osteoblast biology would lead to increased differentiation, we examined short term [alkaline phosphatase (AP) activity] and long term (von Kossa staining) surrogates of bone formation in vitro. These assays confirmed that retinoic acid increased osteogenesis, with a 4-fold increase in bone nodule formation in cells treated with 10 microM retinoic acid after 28 days. Overall, our results demonstrated that pharmacologic doses of all-trans-retinoic acid decreased osteoblast proliferation and increased differentiation, suggesting that retinoic acid may effect craniofacial development by pathologically enhancing osteogenesis.