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school:SOM

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Analysis of TGF-beta production by fusing and nonfusing mouse cranial sutures in vitro

Sagiroglu JS; Mehrara BJ; Chau D; Saadeh PB; Gittes GK; Longaker MT
The role of transforming growth factor beta (TGF-beta) in the regulation of cranial suture fusion has been studied by various qualitative techniques such as in situ hybridization and immunohistochemistry. Although the relative expression of TGF-beta isoforms has been assessed in these studies, increased expression of TGF-beta has not been demonstrated in a quantitative fashion. Therefore, the purpose of this study was to quantify TGF-beta production by fusing (posterofrontal [PF]) and nonfusing (sagittal) mouse sutures using two different quantitative TGF-beta assays. The PF and sagittal sutures of 25-day-old mice were harvested and cultured separately in vitro. Culture media conditioned for 48 hours were collected after 3, 6, 9, 12, 15, 18, 21, 24, 27, and 30 days of culture, and total TGF-beta production was assessed using a TGF-beta bioassay. For a quantitative TGF-beta1 immunoassay, media conditioned for 48 hours were collected after 3, 5, 7, 9, 14, 22, and 28 days of culture. The TGF-beta bioassay revealed large amounts of total TGF-beta activity in both PF and sagittal sutures during the first week of culture, with decreasing amounts thereafter. Absolute TGF-beta activity in conditioned media collected from PF sutures at several early time points was higher than those obtained from sagittal sutures; however, these differences were not statistically significant. The results of the TGF-beta1 immunoassay (enzyme-linked immunosorbent assay) were similar to the bioassay in that the highest TGF-beta1 levels were noted during the first week of culture period and decreased thereafter. Analysis of variance of these samples, however, revealed significantly more TGF-beta1 protein in samples collected from the PF suture compared with the sagittal suture on days 3 and 5 of culture (p < 0.05). TGF-beta1 levels in the conditioned media obtained from PF sutures remained elevated compared with the sagittal suture on days 7 and 9; however, these differences were not statistically significant. Increased production of TGF-beta in the conditioned media of fusing PF sutures is the first such quantitative demonstration of growth factor upregulation during suture fusion and supports the hypothesis that TGF-beta expression may be important in cranial suture fusion
PMID: 10340857
ISSN: 0148-7043
CID: 56439

Gene expression of insulin-like growth factors I and II in rat membranous osteotomy healing

Steinbrech DS; Mehrara BJ; Rowe NM; Dudziak ME; Saadeh PB; Gittes GK; Longaker MT
Poorly healing mandibular osteotomies can be a difficult problem in reconstructive surgery. Many therapies have been attempted to augment the healing of mandibular fractures, defects, or osteotomies, but these methods have substantial drawbacks or have been ineffective. The difficulty in treating poorly healing bony defects has led to the exploration of gene therapy as a possible approach to supplement or accelerate mandibular fracture healing. To understand at what point the introduction of a suitable gene candidate might be of benefit in mandibular healing, it is imperative to examine the temporal expression of bone growth factors in a model of membranous bone healing. Insulinlike growth factors (IGFs) I and II are two such bone growth factor candidates because of their known potent in vitro as well as in vivo effects on bone formation. In this study the authors demonstrate the temporal pattern of IGF I and IGF II gene expression during mandibular osteotomy healing using a rat model. Their data reveal that IGF I and IGF II were elevated 7 days after a mandibular osteotomy that was held in external fixation. The upregulation of IGF I and IGF II during mandibular bone healing underscores the importance of these growth factors in bone repair. Gene therapy utilizing recombinant viral constructs containing IGFs I and II may be of benefit during mandibular bone healing in an effort to augment clinical scenarios of poor or retarded bony repair
PMID: 10340855
ISSN: 0148-7043
CID: 12011

Human cartilage engineering: chondrocyte extraction, proliferation, and characterization for construct development

Saadeh PB; Brent B; Mehrara BJ; Steinbrech DS; Ting V; Gittes GK; Longaker MT
To date, many efforts to engineer cartilage have focused on matrix construction with the goal of producing a durable construct as cartilage replaces the resorbing matrix. However, the importance of matrix construction is at least matched by the challenge of efficient chondrocyte extraction, culture expansion, and prevention of dedifferentiation. This challenge is underscored by the large number of chondrocytes needed for a clinically significant construct such as an ear. Because human rib provides a large, readily available source of hyaline cartilage, the authors evaluated human rib chondrocyte extraction and found that maximum viable cell yield occurred after a 6-hour digestion. They also evaluated human microtic auricular remnant chondrocyte extraction and identified fibroblast contamination as a shortcoming of this potential source of chondrocytes. Initially, rib chondrocytes proliferated in vitro with a doubling time of approximately 1 week. As the cells were passaged, proliferation decreased such that the cells stopped proliferating and adopted a large, spindle-shaped morphology by passage 6. Interestingly, no increase in proliferation was noted when rib chondrocytes were stimulated with transforming growth factor beta 1, bone morphogenetic protein 2, and basic fibroblast growth factor. The major obstacles to the use of autologous rib chondrocytes in matrix construction are the low cell yield from a small piece of rib and the limited proliferation that these cells will undergo in vitro. Further investigation of culture systems and mitogenic cytokines may help resolve these limitations
PMID: 10340859
ISSN: 0148-7043
CID: 12010

Cranial vault deformity and intracranial hypertension secondary to cephalic molding at delivery: a case and its management

Bradley JP; Hollier LH Jr; Weiner HL; McCarthy JG
Cephalic molding at birth has been traditionally felt to be benign, resulting in only a transient and self-correcting cranial deformity. However, we report a 6-month-old infant who presented with extensive cephalic molding at birth in combination with persistent brachyturricephaly from unilateral coronal synostosis and occipital deformation. Helmet therapy over a 3-month period failed despite patient compliance and numerous adjustments. Intracranial hypertension developed, as documented by multiple occipital bony erosions on computed tomographic scan and by an elevated direct intracranial pressure reading. The cranial vault asymmetry was corrected in two surgical stages: (1) occipital bar advancement, temporoparietal bone remodeling, and midline sagittal strip compression to reduce vertical height, followed in 3 months by (2) fronto-orbital advancement and remodeling
PMID: 10530232
ISSN: 1049-2275
CID: 6224

Hypoxia upregulates VEGF production in keloid fibroblasts

Steinbrech DS; Mehrara BJ; Chau D; Rowe NM; Chin G; Lee T; Saadeh PB; Gittes GK; Longaker MT
The etiology of keloid formation is diverse. They are characterized grossly as thick scar tissue that extends beyond the boundaries of the original wound. Histologically, keloids are composed of excessive collagen with an abnormally large number of partially or totally occluded microvessels. This occlusion of keloid microvessels has been hypothesized to contribute to a hypoxic microenvironment within these pathological scars. Vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen, and proangiogenic cytokine have been implicated in normal and pathological wound healing. The purpose of this study was to evaluate the amount of VEGF protein production by fibroblast cell lines derived from keloids and normal human dermal skin in hypoxic compared with normoxic culture conditions. By enzyme-linked immunosorbent protein assay, VEGF was increased in both keloid and normal human dermal fibroblasts in hypoxia over normoxic controls. There was not, however, a significant difference between upregulation of VEGF protein when comparing the keloid and normal fibroblast groups. As the result of the data, alternative hypotheses for hypoxia-induced keloid formation were explored: (1) downstream modulation or signal transduction of VEGF, (2) VEGF production from cells other than fibroblasts, (3) the importance of matrix accumulation stimulated by hypoxia, or (4) increased migration of cells (other than fibroblasts) specific to keloid biology. These hypotheses may help explain the possible role of hypoxia in the pathogenesis of keloid formation. Future studies involving in situ hybridization or immunohistochemical analysis may offer greater insight into the mechanisms underlying keloid formation. Ultimately, our therapeutic goal is the utilization of biomolecular approaches for the suppression of keloid formation
PMID: 10340860
ISSN: 0148-7043
CID: 12009

Expression of high-affinity receptors for TGF-beta during rat cranial suture fusion

Mehrara BJ; Steinbrech DS; Saadeh PB; Gittes GK; Longaker MT
The etiology of craniosynostosis is unknown. The elucidation of the biological pathways responsible for this disorder has been hampered by an inability to evaluate cranial sutures before, during, and after cranial suture fusion. The programmed fusion of the rat posterofrontal (PF) suture postnatally provides an excellent model to study the molecular events that occur during cranial suture fusion. Previous experiments have implicated transforming growth factor beta (TGF-beta) growth factors in the regulation of PF suture fusion. The purpose of these experiments was to localize the expression of high-affinity receptors for these growth factors during cranial suture fusion. Four rats were sacrificed on postnatal days 8, 12, 17, and 40 (N = 16). The PF and sagittal sutures were harvested and prepared for immunohistochemical localization of TGF-beta receptor 1 and receptor 2 (Tbeta-RI, Tbeta-RII) protein. Results indicate that immunostaining for Tbeta-RI and Tbeta-RII is markedly increased in the dura mater and osteoblasts of the sutural margin of the PF suture during active suture fusion (on postnatal days 12, 17, and 40) compared with the osteoblasts and dura mater underlying the patent sagittal suture. These results, in combination with the authors' previous findings as well as studies supporting a role for TGF-beta molecules in the regulation of osteogenesis, implicate TGF-beta signaling in the regulation of suture fusion. The possible mechanisms of ligand-receptor interaction are discussed
PMID: 10340858
ISSN: 0148-7043
CID: 56440

Secretary general's message [Editorial]

Allen, RJ
ISI:000079810400011
ISSN: 0743-684x
CID: 722112

Optimal time for distraction osteogenesis in limbs with nerve repairs: experimental study in the rat

Vekris, M D; Bates, M; Terzis, J K
The optimal period of time between peripheral-nerve repair and initiation of limb lengthening procedures has never been precisely determined. In the clinical setting, the surgeon must decide how long the repaired nerves should be allowed to heal before subjecting them to the forces created by the limb-lengthening process. The authors designed a study to quantify and qualify the effects of different recovery periods between initial nerve repair and subsequent limb-lengthening via distraction osteogenesis. Forty-two Sprague-Dawley male rats were randomized in two different categories of nerve repair: end-to-end and nerve grafts. At 4, 8 and 12 weeks after nerve reconstruction, the femur was submitted to limb-lengthening at a rate of 1 mm/day (0.25 mm every 6 hr). Sciatic Function Index (SFI) evaluation indicated that the impact of distraction was detrimental in the grafted nerves, although they maintained their electrical and morphologic properties at comparable levels to the non-distracted nerves. Nerves with direct coaptation presented an overall superior regeneration pattern. The findings in end-to-end repairs distracted at 8 weeks and those of grafted nerves at 12 weeks were comparable to those in distracted normal nerves. The morphology of the distracted nerves appeared to be more organized than that observed in the non-distracted nerves
PMID: 10226954
ISSN: 0743-684x
CID: 115185

Primary leiomyosarcoma of the mandible in a 7-year-old girl: report of a case and review of the literature [Case Report]

Carter LC; Aguirre A; Boyd B; DeLacure MD
Leiomyosarcoma is a malignant neoplasm of smooth muscle origin that manifests itself uncommonly in the oral cavity because of the paucity of smooth muscle in that location. To the best of our knowledge, only 10 cases of leiomyosarcoma primary to the jawbones have been reported in the English language literature. We report the first pediatric case of leiomyosarcoma arising from the mandible. Facial asymmetry and swelling were accompanied by a rapidly growing exophytic soft tissue mass that caused buccal displacement of the mandibular left permanent first molar. The lesion, observed radiographically as an extensive ill-defined area of osteolytic alveolar destruction, perforated the lingual cortex, displaced the inferior alveolar nerve canal inferiorly, and produced a 'floating-in-air' appearance of the first molar. Diagnosis of leiomyosarcoma was made after initial incisional biopsy of the lesion. A 5-cm segmental mandibulectomy and supraomohyoid neck dissection were followed by reconstruction with a dynamic mandibular reconstruction plate and placement of a multidimensional mandibular distraction device in a transport rectangle of bone to promote bifocal distraction osteogenesis. Forty millimeters of distraction (the technical limit of the device) were performed; this was followed by terminal iliac crest bone grafting. Seventeen months after the definitive surgical procedure, the patient remains free of disease
PMID: 10225631
ISSN: 1079-2104
CID: 48964

Mandibular growth after distraction in patients under 48 months of age

Hollier LH; Kim JH; Grayson B; McCarthy JG
Distraction osteogenesis is an effective technique for reconstruction of the congenitally deficient mandible. However, the age at which it is best performed remains under discussion. Distraction performed at an early age, while possibly allowing the face to develop with a more normal functional matrix, may entail a higher rate of complications. Additionally, it is possible that subsequent asymmetric growth of the mandible may necessitate serial distraction. To address this issue, the clinical records and cephalometric radiographs of all patients less than 48 months of age undergoing mandibular distraction at New York University Medical Center between August of 1989 and August of 1997 were examined. There was a total of 14 patients ranging in age from 19 months to 43 months. Nine patients had a diagnosis of unilateral craniofacial microsomia, three had Treacher Collins syndrome, one had Nager syndrome, and one had bilateral developmental micrognathia. The average amount of distraction was 27 mm (range, 23 to 39 mm) in unilateral cases and 24 mm in bilateral cases (range, 15 to 31 mm). The period of clinical follow-up averaged 32.6 months (range, 12 to 92 months). All patients showed significant improvement in craniofacial appearance, and in four patients, long-term tracheostomy tubes were removed. There were two major complications. In one patient with craniofacial microsomia, there was a relapse in the early postretention phase related to the presence of a dentigerous cyst. This required removal of the cyst and repeat distraction. In the patient with Nager syndrome, a coronoid ankylosis developed requiring surgical release. There were no other major complications. The scars required revision in only two of the patients. Cephalometric analysis of the patients in the study revealed a differential in the rate of growth between the affected and the unaffected side in all cases of craniofacial microsomia. The affected side always grew at a slower rate than the contralateral side after the distraction process was complete. This led to a progressive asymmetry of the rami, clinically expressed by some degree of facial asymmetry and an occlusal cant. For this reason, secondary distraction was required in one patient and is planned in a second. Initial overcorrection of the patient would seem to minimize the likelihood that secondary distraction will be necessary. Distraction osteogenesis for reconstruction of the mandible in this subset of young patients was a safe and effective technique for improving the craniofacial skeletal form and appearance, with minimal associated morbidity. Longer follow-up is necessary to assess the full impact of growth in these cases
PMID: 10190432
ISSN: 0032-1052
CID: 6075