Computer simulation in the daily practice of orthognathic surgery.

The availability of computers and advances in imaging, especially over the last 10 years, have allowed the adoption of three-dimensional (3D) imaging in the office setting. The affordability and ease of use of this modality has led to its widespread implementation in diagnosis and treatment planning, teaching, and follow-up care. 3D imaging is particularly useful when the deformities are complex and involve both function and aesthetics, such as those in the dentofacial area, and for orthognathic surgery. Computer imaging involves combining images obtained from different modalities to create a virtual record of an individual. In this article, the system is described and its use in the office demonstrated. Computer imaging with simulation, and more specifically patient-specific anatomic records (PSAR), permit a more accurate analysis of the deformity as an aid to diagnosis and treatment planning. 3D imaging and computer simulation can be used effectively for the planning of office-based procedures. The technique can be used to perform virtual surgery and establish a definitive and objective treatment plan for correction of the facial deformity. In addition, patient education and follow-up can be facilitated. The end result is improved patient care and decreased expense.

[Le Fort I osteotomies combined with post-operative bone grafts]. / Greffes osseuses réalisées à partir des résidus peropératoires lors des ostéotomies de Le Fort I.

INTRODUCTION: We present and assess a surgical technique for maxillary auto-bone grafting concomitantly with Le Fort I osteotomy. The graft has 2 main objectives: to fill in the space between the 2 advanced segments of the maxilla to help bone consolidation, and to increase the volume of the malar, para-nasal spaces to improve post-operative esthetic results. TECHNICAL NOTE: Bone fragments, removed during the Le Fort I osteotomy, are stored and wrapped in a Surgicel(®) sheet, then grafted in the space left by the osteotomy, or on the anterior maxilla in the para-nasal area or on the malar bone. One hundred and twenty-three patient records, operated from 2007 to 2012, were collected to assess the post-operative course retrospectively. The post-operative course was uneventful in 93.5% of cases. About 8.4% of patients (7 cases) presented with a persistent post-operative maxillary edema. 1 patient (1.2%) presented with a sinus infection without any determined etiology. The grafts were all osteointegrated at the end of follow-up. DISCUSSION: The technique is simple and quickly performed; it improves bone healing and cosmetic results, without increasing morbidity or surgical time. It is a good alternative to bone grafts from a secondary sample site. It can be applied to all Le Fort I osteotomies.

Airway changes in obstructive sleep apnoea patients associated with a supine versus an upright position examined using cone beam computed tomography.

OBJECTIVE: This study aimed to describe total volume and cross-sectional area measurement changes in obstructive sleep apnoea patients associated with a supine versus an upright position. METHOD: A retrospective chart review of patients who underwent cone beam computed tomography in upright and supine positions was performed, and the images were analysed. RESULTS: Five obstructive sleep apnoea patients (all male) underwent both upright and supine cone beam computed tomography imaging. Mean age was 35.0 ± 9.3 years, mean body mass index was 28.1 ± 2.7 kg/m2 and mean apnoea-hypopnoea index was 39.3 ± 23.0 per hour. The airway was smaller when patients were in a supine compared with an upright position, as reflected by decreases in the following airway measurements: total volume; posterior nasal spine, uvula tip, retrolingual and tongue base (not significant) cross-sectional areas; and site of the minimum cross-sectional area (of the overall airway). Total airway volume decreased by 32.6 per cent and cross-sectional area measurements decreased between 32.3 and 75.9 per cent when patients were in a supine position. CONCLUSION: In this case series, the airway of obstructive sleep apnoea patients was significantly smaller when patients were in a supine compared with an upright position.

Reliability of panoramic radiographs for the assessment of mandibular elongation after distraction osteogenesis procedures.

UNLABELLED: To determine whether panoramic radiographs could be used for evaluation of changes in the vertical and horizontal dimensions following internal curvilinear mandibular distraction osteogenesis. STUDY DESIGN: A retrospective cohort study included 25 patients who underwent bilateral mandibular distraction surgery. Three panoramic radiographs and lateral cephalograms from each patient were available: before distraction, immediately upon termination of the distraction process, and at the end of the follow-up period. The radiographs were traced by plotting Condylion, Gonion, and Menton. The linear distances between Condylion and Gonion and between Gonion and Menton were measured on each side, and the correlation was calculated. RESULTS: No significant differences were found between the values of the linear measurements determined by lateral cephalograms and panoramic radiographs (p ≥ 0.079), excluding one measurement. The correlation test for these radiographs showed very high, positive and statistically significant correlations, for both sides of the internal mandibular distraction (r > 0.77, p ≤ 0.0001), apart from three measurements. CONCLUSION: Panoramic radiographs, with mandibular length (Co-Go and Go-Me) measurements, can be used as an alternative to lateral cephalograms, i.e. as a reliable tool for assessing vertical and horizontal dimensional changes resulting from internal mandibular distraction achieved by a curvilinear distractor.

Dynamics of expression of apoptosis-regulatory proteins Bid, Bcl-2, Bcl-X, Bax and Bak during development of murine nervous system.

We have used immunohistochemistry and immunoblotting to examine the expression of Bid and four other Bcl-2 family proteins (Bcl-2, Bcl-X, Bax and Bak) in the developing and adult murine central nervous system (CNS). Bid protein is widespread in embryonic and postnatal brain, and its expression is maintained at a high level late into the adulthood. Bid is expressed both in the germ disc, early neural tube, proliferating stem cells of ventricular zones, and in postmitotic, differentiated neurons of the developing central and peripheral nervous system. As the differentiation proceeds, the neurons express higher levels of Bid than the stem cells of the paraventricular zone. Both in embryonic and postnatal life, Bid protein is present in the most vital regions of brain, such as the limbic system, basal ganglia, mesencephalic tectum, Purkinje cells in cerebellum, and the ventral columns of spinal cord. The p15 cleaved form of Bid was detectable in the brain specimens at fetal stages of development, consistent with caspase-mediated activation of this pro-apoptotic Bcl-2 family protein. Among the Bcl-2 family proteins only Bid and Bcl-XL continue to be expressed at high levels in the adult brain.

Virtual reality based surgical assistance and training system for long duration space missions.

Access to medical care during long duration space missions is extremely important. Numerous unanticipated medical problems will need to be addressed promptly and efficiently. Although telemedicine provides a convenient tool for remote diagnosis and treatment, it is impractical due to the long delay between data transmission and reception to Earth. While a well-trained surgeon-internist-astronaut would be an essential addition to the crew, the vast number of potential medical problems necessitate instant access to computerized, skill-enhancing and diagnostic tools. A functional prototype of a virtual reality based surgical training and assistance tool was created at our center, using low-power, small, lightweight components that would be easy to transport on a space mission. The system consists of a tracked, head-mounted display, a computer system, and a number of tracked surgical instruments. The software provides a real-time surgical simulation system with integrated monitoring and information retrieval and a voice input/output subsystem. Initial medical content for the system has been created, comprising craniofacial, hand, inner ear, and general anatomy, as well as information on a number of surgical procedures and techniques. One surgical specialty in particular, microsurgery, was provided as a full simulation due to its long training requirements, significant impact on result due to experience, and likelihood for need. However, the system is easily adapted to realistically simulate a large number of other surgical procedures. By providing a general system for surgical simulation and assistance, the astronaut-surgeon can maintain their skills, acquire new specialty skills, and use tools for computer-based surgical planning and assistance to minimize overall crew and mission risk.

Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route.

We investigated the mechanism of lysosome-mediated cell death using purified recombinant pro-apoptotic proteins, and cell-free extracts from the human neuronal progenitor cell line NT2. Potential effectors were either isolated lysosomes or purified lysosomal proteases. Purified lysosomal cathepsins B, H, K, L, S, and X or an extract of mouse lysosomes did not directly activate either recombinant caspase zymogens or caspase zymogens present in an NT2 cytosolic extract to any significant extent. In contrast, a cathepsin L-related protease from the protozoan parasite Trypanosoma cruzi, cruzipain, showed a measurable caspase activation rate. This demonstrated that members of the papain family can directly activate caspases but that mammalian lysosomal members of this family may have been negatively selected for caspase activation to prevent inappropriate induction of apoptosis. Given the lack of evidence for a direct role in caspase activation by lysosomal proteases, we hypothesized that an indirect mode of caspase activation may involve the Bcl-2 family member Bid. In support of this, Bid was cleaved in the presence of lysosomal extracts, at a site six residues downstream from that seen for pathways involving capase 8. Incubation of mitochondria with Bid that had been cleaved by lysosomal extracts resulted in cytochrome c release. Thus, cleavage of Bid may represent a mechanism by which proteases that have leaked from the lysosomes can precipitate cytochrome c release and subsequent caspase activation. This is supported by the finding that cytosolic extracts from mice ablated in the bid gene are impaired in the ability to release cytochrome c in response to lysosome extracts. Together these data suggest that Bid represents a sensor that allows cells to initiate apoptosis in response to widespread adventitious proteolysis.

Antiapoptotic proteins. The bcl-2 and inhibitor of apoptosis protein families.

The balance between pro- and antiapoptotic proteins can determine cellular fate. In this regard, the Bcl-2 and IAP protein families have evolved as highly conserved regulators of cell death. A further testament to their critical roles in maintaining balance between cell life and death may be the increasing implication of Bcl-2 and TAP proteins in the pathologies of human diseases. Although much has been learned about these families of proteins, future studies of the Bcl-2 and IAP families are sure to hold more exciting discoveries and will continue to reveal new strategies for combating human diseases.

Measuring pore formation by Bcl-2 family proteins.

Two methods for assaying Bcl-2 protein family-induced solute efflux from liposomes have been outlined. They utilize either ion-selective electrodes to follow ion efflux or fluorescence to monitor changes in fluorescence of the liposome-encapsulated dye SPQ or carboxyfluorescein. Both methods provide a simple means of determining protein activity. These methods do not have the capability to detect either single-channel conductivity or ion selectivity, but they indicate whether the bulk of the protein population is inducing solute efflux. Although in in vivo significance of Bcl-2 protein family pore formation remains to be determined, in vitro measurements of channel activity should provide a means to determine whether a given protein preparation has activity and whether mutations have an adverse effect on channel formation.

Unilateral cleft lip repair--state of the art.

OBJECTIVE: A number of surgical techniques are utilized to correct the unilateral cleft lip, including variations of the rotation-advancement technique. This attests to the variability of the original deformity and the esthetic and functional results from any one technique, especially those based on traditional geometric rearrangement of the skin and associated tissues. RESULTS: Most recent advances in cleft lip repair have occurred in two main areas. The morphological result has been improved by functional muscular reconstruction of the lip with or without orthopedic molding. Early correction of the nasal deformity has also been readvocated based on newer principles with excellent results demonstrated. CONCLUSION: Further work continues in these areas and improved outcomes will continue to be seen along with a clearer understanding of surgical affects on growth and development.

Development and application of a virtual environment for reconstructive surgery.

OBJECTIVE: This paper details the development and application of a Virtual Environment for Reconstructive Surgery (VERS). It addresses the technical and user-interface challenges in developing such a system, and the lessons learned during application of the system in the case of a 17-year-old boy with a severe facial defect arising from the removal of a soft-tissue sarcoma. MATERIALS AND METHODS: Computed tomography (CT) scans were segmented into bone and soft-tissue classifications using traditional and novel algorithms, a surface mesh was generated, and imaging artifacts were removed, yielding a mesh suitable for visualization. This patient-specific mesh was then used in a virtual environment by the surgeons for preoperative visualization of the defect, planning of the surgery, and production of a custom surgical template to aid in repairing the defect. RESULTS: This system was successfully used to plan the surgery of the patient and to produce a custom, patient-specific template that was used to harvest bone from a donor site in order to reconstruct the defect. CONCLUSION: Despite technical challenges, virtual-environment surgical planning is useful as a clinical tool for preoperative visualization, cephalometric analysis, and surgical intervention. It can provide a more precise surgical result than would otherwise be realized using traditional methods.

Ion channel activity of the BH3 only Bcl-2 family member, BID.

BID is a member of the BH3-only subgroup of Bcl-2 family proteins that displays pro-apoptotic activity. The NH(2)-terminal region of BID contains a caspase-8 (Casp-8) cleavage site and the cleaved form of BID translocates to mitochondrial membranes where it is a potent inducer of cytochrome c release. Secondary structure and fold predictions suggest that BID has a high degree of alpha-helical content and structural similarity to Bcl-X(L), which itself is highly similar to bacterial pore-forming toxins. Moreover, circular dichroism analysis confirmed a high alpha-helical content of BID. Amino-terminal truncated BIDDelta1-55, mimicking the Casp-8-cleaved molecule, formed channels in planar bilayers at neutral pH and in liposomes at acidic pH. In contrast, full-length BID displayed channel activity only at nonphysiological pH 4.0 (but not at neutral pH) in planar bilayers and failed to form channels in liposomes even under acidic conditions. On a single channel level, BIDDelta1-55 channels were voltage-gated and exhibited multiconductance behavior at neutral pH. When full-length BID was cleaved by Casp-8, it too demonstrated channel activity similar to that seen with BIDDelta1-55. Thus, BID appears to share structural and functional similarity with other Bcl-2 family proteins known to have channel-forming activity, but its activity exhibits a novel form of activation: proteolytic cleavage.

A single surgeon's experience with the Delaire palatoplasty.

The purpose of this review was to evaluate the clinical outcomes regarding velopharyngeal insufficiency and fistulization in patients with cleft palate who underwent primary repair with the one-stage Delaire palatoplasty. All patients who had a primary Delaire-type palatoplasty performed by the senior surgeon over a 10-year period (1988 to 1998) were studied. During this period, each consecutive patient with an open palatal cleft underwent the same type of repair by the same surgeon. Speech quality and velopharyngeal competence as determined by a single speech pathologist were recorded. A total of 95 patients were included in this series. The average length of follow-up was 31 months (range, 1 to 118 months). Average age at time of surgery was 13.3 months (range, 6 to 180 months). Thirty-one patients (32.6 percent) had significant associated anomalies. The average length of hospital stay was 1.9 days (range, 1 to 8 days) with a trend in recent years toward discharge on postoperative day 1. There were no intraoperative complications, either surgical or anesthetic. Three patients (3.2 percent) developed palatal fistula; none of them required repair. Six patients (6.3 percent) had velopharyngeal incompetence. In patients with more than 1 year of follow-up, the incidence of velopharyngeal incompetence was 9.2 percent (6 of 65). The incidence of fistula after the Delaire palatoplasty was lower than usually reported. The incidence of velopharyngeal incompetence requiring pharyngoplasty was equal to or lower than that seen after other types of palatoplasty, suggesting superior soft-palate muscle function attributable to approximation of the musculus uvulae. The Delaire palatoplasty results in a functional palate with low risk for fistula formation and velopharyngeal incompetence.

Basic fibroblast growth factor and transforming growth factor beta-1 expression in the developing dura mater correlates with calvarial bone formation.

Numerous studies have found dura mater-calvarial mesenchyme interactions during calvarial bone induction; however, the exact molecular mechanisms governing these inductive events remain unknown. Recent studies have implicated basic fibroblast growth factor (FGF-2) and transforming growth factor-beta1 (TGF-beta1) in regulating bone formation. The purpose of this study was, therefore, to investigate the expression of FGF-2 and TGF-beta1 during calvarial bone formation in rats. Eight rats were killed on embryonic days 14, 18, and 20 and neonatal day 1 (n = 32). Four animals at each time point were analyzed by in situ hybridization, and the remainder were analyzed by immunohistochemistry. The results indicated that the dura mater underlying the developing calvarial bone strongly expressed FGF-2 and TGF-beta1 mRNA at all time points examined. In contrast, minimal growth factor expression was noted in the overlying calvarial mesenchyme until embryonic day 18, but it increased significantly with increasing age. Importantly, FGF-2 and TGF-beta1 mRNA expression in the dura mater underlying the developing calvarium preceded and was significantly greater than expression in the calvarium mesenchyme (p < 0.05). Interestingly, minimal expression of FGF-2 and TGF-beta1 mRNA was noted for all time points in the dura mater underlying the posterior frontal suture and within the posterior frontal suture connective tissue (p < 0.01 when compared with the dura mater underlying the developing calvarium). Immunohistochemical findings closely paralleled mRNA expression, with intense staining for FGF-2 and TGF-beta1 in the dura mater underlying the developing calvarial mesenchyme. Increasing FGF-2 and TGF-beta1 staining was noted within calvarial osteoblasts with increasing age, particularly in cells located near the endocranial surface (i.e., in contact with the developing dura mater). These findings, together with the known biologic functions of FGF-2 and TGF-beta1, implicate these growth factors in the regulation of calvarial bone growth by the developing dura mater. The possible mechanisms of this interaction are discussed.

Cytoprotection by Bcl-2 requires the pore-forming alpha5 and alpha6 helices.

We explored whether the putative channel-forming fifth and sixth alpha-helices of Bcl-2 and Bax account for Bcl-2-mediated cell survival and Bax-induced cell death in mammalian cells and in the yeast Saccharomyces cerevisiae. When alpha5-alpha6 were either deleted or swapped with each other, the Bcl-2Deltaalpha5alpha6 deletion mutant and Bcl-2-Bax(alpha5alpha6) chimeric protein failed to block apoptosis induced by either Bax or staurosporine in human cells and were unable to prevent Bax-induced cell death in yeast, implying that the alpha5-alpha6 region of Bcl-2 is essential for its cytoprotective function. Additional experiments indicated that, although alpha5-alpha6 is necessary, it is also insufficient for the anti-apoptotic activity of Bcl-2. In contrast, deletion or substitution of alpha5-alpha6 in Bax reduced but did not abrogate apoptosis induction in human cells, whereas it did completely nullify cytotoxic activity in yeast, implying that the pore-forming segments of Bax are critical for conferring a lethal phenotype in yeast but not necessarily in human cells. BaxDeltaalpha5alpha6 and Bax-Bcl-2(alpha5alpha6) also retained the ability to dimerize with Bcl-2. Bax therefore may have redundant mechanisms for inducing apoptosis in mammalian cells, based on its ability to form alpha5-alpha6-dependent channels in membranes and to dimerize with and antagonize anti-apoptotic proteins such as Bcl-2.

Acidic pH promotes dimerization of Bcl-2 family proteins.

Several members of the apoptosis-regulating Bcl-2 family of proteins can homo- or heterodimerize with each other at neutral pH and can also form ion channels in synthetic membranes at low pH. The effects of low pH on dimerization among these proteins, however, have not heretofore been examined. Surface plasmon resonance was used to examine the kinetics of dimerization as a function of pH between the anti-apoptotic protein Bcl-XL (applied in the mobile phase) and three other members of the Bcl-2 family: Bcl-2, Bax, and Bid (immobilized on biosensor chips). In all cases, the relative affinity of dimerization was substantially increased at pH 4.0 compared to pH 7.0-7.4, ranging from a approximately 10-fold enhancement for Bcl-XL/Bcl-XL homodimers to >60-fold for Bcl-XL/Bid heterodimers. Comparison of the apparent association (ka) and dissociation (kd) rates at neutral and acidic pH revealed that the major contributor to increased affinity at low pH was a decreased rate of dimer dissociation. Thus, low pH stabilizes homo- and heterodimeric complexes comprised of Bcl-XL and these other Bcl-2 family proteins. At pH 4.0, the circular dichroism spectra of Bcl-XL and Bax were essentially unchanged relative to pH 7.0-7.4, indicating a complete retention of alpha-helical secondary structure at low pH and excluding gross denaturation of the proteins. Size-exclusion chromatography and bisANS (4,4'-dianilino-1, 1'-binaphthyl-5,5'-disulfonic acid) labeling studies provided indirect evidence that Bcl-XL may undergo conformational changes at low pH. The findings are discussed with respect to the mechanisms of ion-channel formation by Bcl-2 family proteins and the putative molten globule state that has been proposed for these and structurally similar proteins.

Studies in cranial suture biology: up-regulation of transforming growth factor-beta1 and basic fibroblast growth factor mRNA correlates with posterior frontal cranial suture fusion in the rat.

The mechanisms involved in normal cranial suture development and fusion as well as in the pathophysiology of craniosyostosis are not well understood. The purpose of this study was to investigate the expression of several cytokines--transforming growth factor-beta-1 (TGF-beta1), basic fibroblast growth factor (bFGF), and interleukin-6 (IL-6)--during cranial suture fusion. TGF-beta exists in three mammalian isoforms that are abundant in bone and stimulate calvarial bone formation when delivered locally. Other bone growth factors including basic fibroblast growth factor and the interleukins regulate bone growth and are mitogenic for bone marrow cells and osteoblasts. The involvement of growth factors in the pathophysiology of craniosynostosis is supported by recent genetics data linking fibroblast growth factor receptor mutations to syndromal craniosynostoses. In this experimental study, in situ hybridization was used to localize and quantify the gene expression of TGF-beta1, bFGF, and IL-6 during cranial suture fusion. In the Sprague-Dawley rat, the posterior frontal cranial suture normally undergoes fusion between 12 and 22 days of age, whereas all other cranial sutures remain patent. All in situ analyses of fusing posterior frontal sutures were compared with the patent, control, sagittal sutures. Posterior frontal and sagittal sutures, together with underlying dura, were harvested from rats at 8, 12, 16, and 35 days of postnatal life to analyze posterior frontal suture activity before, during, and after fusion. In situ hybridization was performed on frozen sections of these specimens using DNA probes specific for TGF-beta1, bFGF, and IL-6 mRNA. A negative control probe to IL-6 in the sense orientation was also used to validate the procedure. Cells expressing cytokine-specific mRNA were quantified (in cells positive per 10(-1) mm2) and analyzed using the unpaired Student's t test. Areas encompassing the fibrous suture and the surrounding bone plates were analyzed for cellular mRNA activity. IL-6 mRNA expression showed a minimal rise in the posterior frontal suture at days 12 and 16, with an average count of 10 and 6 cells per 10(-1) mm2, respectively. The sagittal suture remained negative for IL-6 mRNA at all time points. TGF-beta1 and bFGF analyses were most interesting, showing marked increases specifically in the posterior frontal suture during the time of active suture fusion. On postnatal day 8, a 1.5-fold increase in posterior frontal suture TGF-beta1 mRNA was found compared with sagittal sutures (p = 0.1890, unpaired Student's t test). This difference was increased 26-fold on day 12 in posterior frontal suture TGF-beta1 expression (p = 0.0005). By day 35, posterior frontal suture TGF-beta1 mRNA had nearly returned to prefusion levels, whereas TGF-beta1 mRNA levels in the sagittal suture remained low. A similar upregulation of bFGF mRNA, peaking at day 12, was observed in posterior frontal but not sagittal sutures (p = 0.0003). Furthermore, both TGF-beta1 and bFGF mRNA samples with intact dura showed an intense dural mRNA expression in the time preceding and during active posterior frontal suture fusion but not in sagittal tissues. Our data demonstrate that TGF-beta1 and bFGF mRNA are up-regulated in cranial suture fusion, possibly signaling in a paracrine fashion from dura to suture. TGF-beta1 and bFGF gene expression were dramatically increased both in and surrounding the actively fusing suture and followed the direction of fusion from endocranial to epicranial. These experimental data on bone growth factors support the recent human genetics data linking growth factor/fibroblast growth factor receptor deletions to syndromal craniosynostoses. The ultimate aim of these studies is to understand the underlying mechanisms regulating suture growth, development, and fusion so surgeons may one day manipulate the biology of premature cranial suture fusion.