Faculty Bibliography

Impaired repair of skin defects is a major complication of diabetes; yet, the pathophysiology of diabetic (db) wound healing remains largely opaque. Here, we investigate the role of humoral factors in modulating db wound repair by generating chimeric animals through parabiotic joining of wild-type (wt) and diabetic (db/db) mice. This strategy allows wounds on healing-deficient db/db mice to be exposed to factors derived from the wt circulation at physiologically appropriate concentrations. When compared with db controls, chimeric db/db animals showed significantly improved healing of full-thickness, cutaneous wounds, with enhanced granulation tissue formation, angiogenesis, cell proliferation, and collagen deposition. Glycemic control was unaffected by parabiosis; however, the distribution of circulating leukocytes, altered in db controls, normalized in db-chimeras. Both wt and db cells were recruited from circulation into db wounds, but wt cells never exceeded 20% of total cells. Improved angiogenesis persisted in db-chimeras separated 24 hours after wounding, suggesting the existence of long-term normalizing factors. This study establishes a new model for studying db wound healing, and shows a key role for circulating factors in normalizing wound repair in diabetes.

OBJECTIVE: To evaluate the mouth-motion step-stress fatigue behavior of two porcelain-zirconia all-ceramic crown systems. METHODS: The average dimensions of a mandibular first molar crown were imported into CAD software; a tooth preparation was modeled by reducing proximal walls by 1.5 mm and occlusal surface by 2.0 mm. The CAD-based tooth preparation was made by rapid prototyping and used as a master die to fabricate all-ceramic crowns with 1.0 mm porcelain veneered on 0.5 mm Y-TZP cores (LAVA veneer+LAVA frame, 3M/ESPE, and Vita veneer+CERCON frame, Dentsply). Crowns were cemented on aged (60 days in water) composite (Z100, 3M/ESPE) reproductions of the die. Three crowns from the LAVA group were subjected to single cycle load to failure for stress profile design; remainder subjected to step-stress mouth-motion fatigue (three step-stress profiles). All mechanical testing was performed by sliding a WC indenter of 6.25 mm diameter 0.7 mm lingually down the mesio-distal cusp. Master Weibull curves and reliability for missions of 50,000 cycles at 200 N load were calculated (Alta Pro 7, Reliasoft). RESULTS: Single load to failure showed fractures through the zirconia core. Reliability for a 200 N x 50K cycle mission was not significantly different between systems. In fatigue, failure occurred by formation of large chips within the veneer originating from the contact area without core exposure. CONCLUSIONS: LAVA and CERCON ceramic systems present similar fatigue behavior; fatigue loading of both systems reproduces clinically observed failure modes

Clinical detection of free flap failure lacks sensitivity. Failure is likely accompanied by altered gene expression; however, a genomic approach that identifies potential biomarkers and therapeutic targets has not been described. This study identifies genetic RNA expression alterations via microarray in a free flap failure animal model. A free tissue transfer rat model based on the inferior epigastric vessels was utilized. After microscopic anastomosis, the vein was occluded and RNA extracted from flap tissue of failure and control groups. Gene expression of 3 experimental and control group samples was assessed with the Affymetrix GeneChip Rat 230 v2.0 microarray. Quantitative reverse transcription polymerase chain reaction was performed on RNA of genes identified on an additional 6 experimental and 7 control group flaps. Eight hundred ninety of 28,000 genes had greater than 2-fold expression differences between experimental and controls. Student t test and 2-way analysis of variance filtering with equal variance identified 53 genes with statistically significant differences. Hierarchical clustering by gene ontology identified 4 genes with likely involvement in failure pathogenesis: RT1 class II, locus Bb, secreted frizzled-related protein 1, platelet/endothelial cell adhesion molecule, and Claudin 5. Validation performed by quantitative reverse transcription polymerase chain reaction revealed statistically significant expression alterations in locus Bb, platelet/endothelial cell adhesion molecule, and Claudin 5 of the failure group. Utilizing expression thresholds for test positivity, venous occlusion was predicted with 100% sensitivity and 86% specificity. Three highly sensitive and specific novel genes predictive of flap failure from venous occlusion were identified with altered expression in an animal model.

OBJECTIVE: Determine long-term loss of mandible height with use of stress-shielding reconstruction plates for free fibula flap mandible reconstruction. DESIGN: Retrospective single-blinded medical record review. SUBJECTS: Seventy patients who had fibula free flap mandible reconstructions performed for 10 years. Patients who underwent radiotherapy were excluded. METHODS: Review of 70 fibula free flap mandible reconstructions performed for the last 10 years in a city hospital revealed 7 patients (10%) who had resections for benign odontogenic diseases. All had a three-dimensional cast model made, on which the reconstruction plate was bent to the desired shape preoperatively. Free fibula height on panoramic x-ray images taken preoperatively and at 2 and 12 months postoperatively. RESULTS: Seven (10%) patients met criteria for the study. Bone height was maintained at 2 months postoperatively, but at 12 months, there was a statistically significant loss of fibular bone height averaging 20% in the anterior, body, and ramus areas (P < 0.05). Despite this, all patients were considered eligible for dental rehabilitation, and 4 of 7 patients have had osseointegrated implants placed. CONCLUSIONS: As opposed to miniplates, increased resorption may have been due to the stress-shielding phenomenon unique to a reconstruction plates. However, this did not seem to affect the ability to place osseointegrated implants.

The Allen test is used to diagnose the relative contribution of the ulnar and radial arteries to each hand. We modified this test to investigate the relative vascular contributions to distal perfusion of the lower extremity. With the patient supine, a handheld Doppler is used to locate the first dorsal metatarsal artery. The posterior tibial artery (PT) and dorsalis pedis artery (DP) pulses are compressed. A persistent signal indicates collateral flow through the peroneal artery (PA). Sequential decompression is then used to evaluate the relative contribution of the PT and DP to distal circulation. We report a case in which angiography failed to predict reliance on the PT. In this case, performance of the lower-extremity Allen test (LEAT) led to an alternative recipient vessel choice. The LEAT is simple to perform and provides a valuable adjunct to angiographic data

BACKGROUND: The purpose of this investigation was to determine the response of the osteotomized Le Fort III midface bony segment to variations in the location and direction, or vector, of force application on using the rigid external distraction device. METHODS: This retrospective study involved 18 consecutive syndromic craniosynostotic patients (average age, 5.7 years) who underwent Le Fort III midface advancement distraction. Various cephalometric and novel landmarks, located on the mobilized Le Fort III segment and on the components of the distraction device, were identified before activation and at mid-activation. The direction and magnitude of change for these points were recorded. RESULTS: Based on the observed change in the position of the midface during distraction, the sample was divided into the following groups. In group 1 (n = 5), the Le Fort III segment translated forward and no rotation was noted. In group 2 (n = 3), the Le Fort III segment rotated clockwise and showed downward displacement. In group 3 (n = 6), the Le Fort III segment showed forward displacement and rotated counterclockwise. In group 4 (n = 4), the Le Fort III segment translated forward and downward. CONCLUSIONS: Direction of movement and resultant change in position of the Le Fort III segment during distraction are directly related to the location and direction of force application. Translation forward, with minimal rotation, was achieved when the force was applied at a location 55 percent above the occlusal plane (between the occlusal plane and the nasion) and in a direction parallel to the maxillary occlusal plane

In this study, we hypothesize that local sustained release of vascular endothelial growth factor (VEGF), using adenovirus vector (ADV)-mediated gene transfer, accelerates experimental wound healing. This hypothesis was tested by determining the specific effects of VEGF(165) application on multiple aspects of the wound healing process, that is, time to complete wound closure and skin biomechanical properties. After showing accelerated wound healing in vivo, we studied the mechanism to explain the findings on multiple aspects of the wound healing cascade, including epithelialization, collagen deposition, and cell migration. Intradermal treatment of wounds in non-obese diabetic and db/db mice with ADV/VEGF(165) improves healing by enhancing tensile stiffness and/or increasing epithelialization and collagen deposition, as well as by decreasing time to wound closure. VEGF(165), in vitro, stimulates the migration of cultured human keratinocytes and fibroblasts, thus revealing a non-angiogenic effect of VEGF on wound closure. In conclusion, ADV/VEGF is effective in accelerating wound closure by stimulating angiogenesis, epithelialization, and collagen deposition. In the future, local administration and sustained, controlled release of VEGF(165) may decrease amputations in patients with diabetic foot ulcers and possibly accelerate closure of venous ulcers and pressure ulcers.Journal of Investigative Dermatology advance online publication, 12 March 2009; doi:10.1038/jid.2009.26

PURPOSE: We examined preoperative factors that could predict successful microdissection testicular sperm extraction in men with azoospermia and nonmosaic Klinefelter's syndrome. We also analyzed the influence of preoperative hormonal therapy on the sperm retrieval rate. MATERIALS AND METHODS: A total of 91 microdissection testicular sperm extraction attempts were done in 68 men with nonmosaic Klinefelter's syndrome. Men with serum testosterone less than 300 ng/dl received medical therapy with aromatase inhibitors, clomiphene or human chorionic gonadotropin before microdissection testicular sperm extraction. Preoperative factors of patient age and endocrinological data were compared in those in whom the procedure was and was not successful. The sperm retrieval rate was the main outcome. Clinical pregnancy (pregnancy with heartbeat) and the live birth rate were also calculated. RESULTS: Testicular spermatozoa were successfully retrieved in 45 men (66%), representing 62 (68%) attempts. Increasing male age was associated with a trend toward a lower sperm retrieval rate (p = 0.05). The various types of preoperative hormonal therapies did not have different sperm retrieval rates but men with normal baseline testosterone had the best sperm retrieval rate of 86%. Patients who required medical therapy and responded to that treatment with a resultant testosterone of 250 ng/dl or higher had a higher sperm retrieval rate than men in whom posttreatment testosterone was less than 250 ng/dl (77% vs 55%). For in vitro fertilization attempts in which sperm were retrieved the clinical pregnancy and live birth rates were 57% and 45%, respectively. CONCLUSIONS: Microdissection testicular sperm extraction is an effective sperm retrieval technique in men with Klinefelter's syndrome. Men with hypogonadism who respond to medical therapy may have a better chance of sperm retrieval.

BACKGROUND: The objective of this study was 2-fold: (1) document the presence and degree of vascularity in gliomas of different pathologic grades and (2) determine whether the presence of abnormal vascularity, determined by catheter angiography, correlates with a shortened survival. METHODS: As part of a protocol for radiographic data acquisition that was used in a computer-assisted, stereotactic system, all patients who underwent biopsy or resection of a newly diagnosed glioma between 1994 and 2000 at our institution routinely underwent preoperative catheter angiography. The presence and degree of tumor vascularity were recorded and then correlated with survival and pathologic grade. The confounding effects of age, KPS, adjuvant treatment, and extent of resection on survival were considered. RESULTS: Two hundred thirty-one patients were included in this study. The mean follow-up of survivors was 7.8 years. Tumor vascularity correlated with a shortened survival (proportional hazards RR for survival, 0.69; 95% CI, 0.58-0.82). This correlation persisted after correction for age, KPS score, adjuvant therapy, and extent of resection (RR, 0.81; 95% CI, 0.68-0.97). Abnormal vascularity was present in 25 (30%) of 82 low-grade (WHO grade 2) gliomas. Overall, the extent of vascularity (none [120 patients, 52%], blush [63 patients, 27%], neovessels [25 patients, 11%], and arteriovenous shunting [23 patients, 10%]) correlated with worse WHO tumor grade (P < .0001). CONCLUSIONS: The presence of abnormal vascularity correlates with both a shortened survival and higher grade of malignancy. These findings underscore the importance of antiangiogenesis factor investigation and drug development for the treatment of gliomas, regardless of their pathologic grade