Plerixafor for pathogen-agnostic treatment in murine thigh infection and zebrafish sepsis.

Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen-agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator-led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling. Here, we investigated whether plerixafor could be repurposed to treat sepsis or severe wound infections, either alone or as an adjunct therapy. In a Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced zebrafish sepsis model, plerixafor reduced sepsis mortality and morbidity assessed by tail edema. There was a U-shaped response curve with the greatest effect seen at 0.1 µM concentration. We used Acinetobacter baumannii infection in a neutropenic murine thigh infection model. Plerixafor did not show reduced bacterial growth at 24 h in the mouse thigh model, nor did it amplify the effects of a rifampin antibiotic therapy, in varying regimens. While plerixafor did not mitigate or treat bacterial wound infections in mice, it did reduce sepsis mortality in zebra fish. The observed mortality reduction in our LPS model of zebrafish was consistent with prior research demonstrating a mortality benefit in a murine model of sepsis. However, based on our results, plerixafor is unlikely to be successful as an adjunct therapy for wound infections. Further research is needed to better define the scope of plerixafor as a pathogen-agnostic therapy. Future directions may include the use of longer acting CXCR4 antagonists, biased CXCR4 signaling, and optimization of animal models.

The Role of Energy-Based Devices in Male Body Contouring.

Energy-based devices extend the indications of traditional procedures in male body contouring. Devices currently available in this space may be noninvasive or minimally invasive. These devices use heat to destroy fat or tighten soft tissue and electromagnetic energy to build muscle mass. Thoughtful deployment of these technologies in isolation or in combination with each other or more traditional approaches can improve outcomes in male body contouring without an increase in scar burden. Patient selection and education are essential in maximizing satisfaction with these procedures.

In Situ Hydrolysis of Block Copolymers at the Water-Oil Interface.

In situ manipulation of the chemical composition of block copolymers at the fluid interfaces affords a route by which the interfacial tension, the packing of the copolymers, and the penetration of the blocks into the two liquids can be controlled. Here, a series of linear block copolymers of poly(solketal methacrylate-b-styrene) (PSM-b-PS) are used, converting hydrophobic PSM block into a hydrophilic glycerol monomethacrylate (GM) block, that results in a marked decrease in the liquid-liquid interfacial tension. The kinetics of the first-order hydrolysis reaction was analyzed by monitoring the time-dependent interfacial tension as a function of pH, polymer concentration, molecular weight, and composition. Fluorescence recovery after photobleaching (FRAP) was used to measure the in-plane dynamics of the copolymers before and after hydrolysis. This work provides insights into a quantitative pathway by which in situ interfacial reactions may be performed and monitored in real time, completely changing the interfacial activity of the molecule.

Pediatric Dog Bite Prevention: Are We Barking Up the Wrong Tree or Just Not Barking Loud Enough?

OBJECTIVES: The objectives of this study were (1) to evaluate dog bite-related injuries and associated medical documentation and (2) to compare these results with a study of dog bites from the same institution 10 years prior. METHODS: Data were retrospectively collected from a pediatric emergency department from July 2007 to July 2011 for patients treated for dog bites. These data were then compared with data from the same institution from 10 years prior. RESULTS: A total of 1017 bite injuries were treated (average, 254.25 bites/year), which represents a 25% increase compared with 10 years prior. Comparing the 1997 and 2007 to 2011 cohorts, patient demographics, bite rate among children less than 5 years old, rate of dog breed documentation, and setting of injury were similar. Dog breed was reported in 47% (95% confidence interval [CI], 40.2-53.9) and 41% (95% CI, 38.0-44.0) of cases, respectively, in the 2 cohorts. Bites to the craniofacial region were most common (face only reported for 1997: 43.2%; 95% CI, 36.4-50 versus 2007-2011: 66.1%; 95% CI, 63.2-69.0). In both cohorts, the child's home was the most frequent setting, accounting for 43% of bites (1997: 95% CI, 30.2-55.9 and 2007-2011: 95% CI, 39.3-46.7). CONCLUSIONS: Pediatric dog bites continue to occur frequently, and the associated factors did not change over the 10-year period: young age of child, bites to the craniofacial region, and dogs familiar to the child. Although accurate medical documentation of dog bites is a prerequisite to develop effective prevention strategies, current medical documentation of dog bites may be misguided.

Biomechanical Integrity in Craniofacial Surgery: Calvarial Reconstruction in Favorable and Infected Defects with Bone Morphogenetic Protein 2.

BACKGROUND: The limitations of autologous and alloplastic reconstruction for craniofacial bone defects have created a clinical need for viable tissue-engineering strategies. Recombinant human bone morphogenetic protein-2 (rhBMP-2) has shown promise in this setting. The aim of this study was to determine the long-term biomechanical properties of rhBMP-2-mediated calvarial reconstruction. METHODS: Twelve-week-old New Zealand White rabbits underwent subtotal calvarectomy. Defects were repaired in one of several groups: immediate reconstruction with autologous graft, immediate reconstruction with cryopreserved bone graft, immediate reconstruction with rhBMP-2 (favorable), and delayed reconstruction with rhBMP-2 following infection and subsequent débridement (unfavorable). Cryopreserved reconstructions were measured at 6 weeks; autologous reconstructions were measured at 6 weeks and 6 months; and both favorable and unfavorable rhBMP-2 reconstructions were assessed at 6 weeks, 6 months, and 1 year after reconstruction. Healing was assessed with computed tomography. An unconfined compression test was performed for biomechanical analysis. Stress at 20 percent strain, percentage relaxation, tangent modulus, and final strain at 1800 N were compared between groups. RESULTS: Nearly complete radiographic coverage was achieved by 6 months for autologous reconstruction and by 6 weeks for rhBMP-2 reconstruction. Favorable rhBMP-2 reconstruction demonstrated a larger final strain at 1800 N through 1 year compared with native bone. Bone in unfavorable rhBMP-2 reconstruction was more compressible than native bone, with a larger final strain at 1800 N at 1 year. There were no significant differences between favorable and unfavorable groups. CONCLUSIONS: Despite providing radiographic coverage, the biomechanical properties of rhBMP-2 bone differ from those of native bone. Further studies are warranted to determine how these properties affect overall strength and structural integrity.

Application of Laser Capture Microdissection to Craniofacial Biology: Characterization of Anatomically Relevant Gene Expression in Normal and Craniosynostotic Rabbit Sutures.

OBJECTIVE: Fusion of the cranial sutures is thought to depend on signaling among perisutural tissues. Mapping regional variations in gene expression would improve current models of craniosynostosis. Laser capture microdissection (LCM) isolates discrete cell populations for gene expression analysis. LCM has rarely been used in the study of mineralized tissue. This study sought to evaluate the potential use of LCM for mapping of regional gene expression within the cranial suture. DESIGN: Coronal sutures were isolated from 10-day-old wild-type and craniosynostotic (CS) New Zealand White rabbits, and LCM was used to isolate RNA from the sutural ligament (SL), osteogenic fronts (OF), dura mater, and periosteum. Relative expression levels for Fibroblast Growth Factor 2 (FGF2), Fibroblast Growth Factor Receptor 2 (FGFR2), Transforming Growth Factor Beta 2 (TGFß-2), Transforming Growth Factor Beta 3 (TGFß-3), Bone Morphogenetic Protein 2 (BMP-2), Bone Morphogenetic Protein 4 (BMP-4), and Noggin were determined using quantitative real-time PCR. RESULTS: A fivefold increase in TGFß2 expression was detected in the CS SL relative to wild type, whereas 152-fold less TGFß-3 was detected within the OF of CS animals. Noggin expression was increased by 10-fold within the CS SL, but reduced by 13-fold within the CS dura. Reduced expression of FGF2 was observed within the CS SL and dura, whereas increased expression of FGFR2 was observed within the CS SL. Reduced expression of BMP-2 was observed in the CS periosteum, and elevated expression of BMP-4 was observed in the CS SL and dura. CONCLUSIONS: LCM provides an effective tool for measuring regional variations in cranial suture gene expression. More precise measurements of regional gene expression with LCM may facilitate efforts to correlate gene expression with suture morphogenesis and pathophysiology.

Repair of a Complicated Calvarial Defect: Reconstruction of an Infected Wound With rhBMP-2.

BACKGROUND: Management of the previously infected craniofacial defect remains a significant clinical challenge, posing obstacles such as wound healing complications, lack of donor site availability, and predisposition to failure of the repair. Optimal therapy would reconstruct like with like, without donor site morbidity. The purpose of this study was to compare the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2)-mediated bone regeneration with the current standard of autologous bone graft for repair of previously infected calvarial defects. METHODS: Nineteen adult New Zealand white rabbits underwent subtotal calvariectomy. Bone flaps were inoculated with Staphylococcus aureus and replanted. After 1 week of infection, bone flaps were removed, and wounds were debrided, followed by 10 days of antibiotic treatment. After 6 weeks, animals underwent scar debridement followed by definitive reconstruction in 1 of 4 groups: empty control (n = 3), vehicle control (buffer solution on absorbable collagen sponge [ACS], n = 3), autologous bone graft (n = 3), or rhBMP-2 repair (rhBMP-2/ACS, n = 10). Animals underwent computed tomography imaging at 0, 2, 4, and 6 weeks postoperatively, followed by euthanization and histological analysis. Percent healing was determined by 3-dimensional analysis. A (time × group) 2-way analysis of variance was performed on healing versus treatment group and postoperative time. RESULTS: At 6 weeks postoperatively, rhBMP-2/ACS and autologous bone graft resulted in 93% and 68% healing, respectively, whereas the empty and vehicle control treatment resulted in 27% and 26% healing (P < 0.001). Histologically, compared to autologous bone graft, bone in the rhBMP-2/ACS group was more cellular and more consistently continuous with wound margins. CONCLUSIONS: The rhBMP-2 therapy is effective in achieving radiographic coverage of previously infected calvarial defects.

Strategies for Aesthetic Reshaping of the Postpartum Patient.

UNLABELLED: Statistics reflect that pregnancies are occurring at a later age, multiple births are becoming more common, and a sizeable population--with a keen interest in nutrition, fitness, and a continued desire to retain a youthful figure--is aging. Consequently, postpartum reshaping is a priority for many women, enough so that the phrase "mommy makeover" has entered the vernacular. In this article, the senior author's practice was evaluated to explore patient goals, methods, and outcomes in reshaping the postpartum abdomen. A literature review was conducted to assess the state of the art in methods to meet these goals. The postpartum patient often uses her prepregnancy appearance as a barometer for her postpregnancy goals. Although aging is one force motivating women to pursue abdominoplasty, the majority desires the correction of changes related to pregnancy. The abdomen and breasts are the regions most visibly affected by pregnancy, although numerous aesthetic units of the trunk and surrounding regions concern patients seeking postpartum body contouring and they may be part of the patient's perception and idealization of her appearance. Abdominoplasty is central to postpartum body contouring, and numerous strategies such as concurrent flap, flank, or mons pubis liposuction and waistline enhancement methods are integral components of it. Consideration should also be given to the multiple body areas affected by pregnancy that may enhance the patient's overall appearance. In the appropriate context, multiple procedures can be safely and effectively combined to address the various regions affected by postpartum changes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Severe Pediatric Midface Trauma: A Prospective Study of Growth and Development.

Severe pediatric facial trauma is characterized by multiple, comminuted, and unstable fractures, frequently necessitating operative intervention. Disruption of facial growth is a primary concern in the long-term sequelae of such conditions. Children suffering from midface fractures were followed over time in a long-term growth and development study. Lateral cephalograms at longest-term follow-up were traced, digitized, and averaged. Seven landmarks of the midface (A point, ANS, orbitale, bridge of nose, distal U6, upper lip, stomion superius) were identified for comparative measurements with age and sex-matched superimposed Bolton norms as controls. Differences in x and y axes between test and control metrics were measured. Clinical significance was defined as a 2-mm discrepancy from the norm. Statistical significance for each patient was determined using t tests of the x and y arrays of patient values versus normal controls. Seven patients met the inclusion criteria with mean age of 8.9 years at the time of injury. Mean cephalometric follow-up was 4.6 years (range 2-10 years). Six out of 7 patients (86%) showed clinically significant impairment in growth in horizontal (29%), vertical (29%), or both planes (29%). T Tests confirmed statistical significance (P ≤ 0.05) for all clinically significant differences. Mean deficiency in growth for all landmarks was 3.7  mm (range -4.0 to 13.7  mm) in the x axis and 2.9  mm (range -1.1 to 8.8  mm) in the y axis. Severe pediatric midface trauma often results in compromised bone growth and permanent facial deformity. New methodologies of management that better allow for growth are needed.

Taking it on the chin: recognizing and accounting for lower face asymmetry in chin augmentation and genioplasty.

During the course of thousands of preoperative facial analyses, it has become apparent that the chin, in most individuals, appears weaker on the left than on the right. This previously unreported disparity spans age, sex, and ethnicity. To document this finding, frontal and lateral photographs of 20 random patients from the senior author's practice were subjected to a battery of soft-tissue measurements. Analysis of four celebrities further demonstrated the ubiquity of relative left chin weakness. Precedent for asymmetry in human anatomy is abundant (e.g., handedness). Asymmetry, moreover, often is conserved throughout the population (e.g., sidedness of visceral orientation). Left-sided chin weakness appears to be another example of well-preserved anatomical asymmetry. The presence of this asymmetry should be considered in planning chin augmentation and genioplasty.

Combined breast surgery and abdominoplasty: strategies for success.

Abdominoplasty and breast surgery are frequently appealing to patients as combined procedures. The practice of combining abdominoplasty with other procedures originates from abdominoplasty performed in conjunction with intraabdominal or gynecologic surgery. Initially, the focus of combined surgery was on ensuring safety and minimizing local (e.g., wound healing) complications. As surgeons began combining abdominoplasty with distant procedures such as breast surgery, because the individual procedures have little adverse impact on one another and are not altered because of the combination, concerns with systemic morbidity surpassed the initial focus on avoiding local complications. Prevention of venous thromboembolism became a paramount concern. The authors perform abdominoplasty in conjunction with other procedures more frequently than in isolation, reflecting broader societal demand. Indeed, because of the effects of pregnancy and aging, abdominoplasty is being performed in conjunction with breast surgery with frequency sufficient to have driven the term "mommy makeover" into mainstream parlance. Consideration regarding length of surgery and the other recommendations in this report allows for the safe and successful execution of this common combination.

Transforming growth factor beta 1 augments calvarial defect healing and promotes suture regeneration.

BACKGROUND: Repair of complex cranial defects is hindered by a paucity of appropriate donor tissue. Bone morphogenetic protein 2 (BMP2) and transforming growth factor beta 1 (TGFß1) have been shown separately to induce bone formation through physiologically distinct mechanisms and potentially improve surgical outcome for cranial defect repair by obviating the need for donor tissue. We hypothesize that a combination of BMP2 and TGFß1 would improve calvarial defect healing by augmenting physiologic osteogenic mechanisms. METHODS/RESULTS: Coronal suturectomies (3×15 mm) were performed in 10-day-old New Zealand White rabbits. DermaMatrix™ (3×15mm) patterned with four treatments (vehicle, 350 ng BMP2, 200 ng TGFß1, or 350 ng BMP2+200 ng TGFß1) was placed in suturectomy sites and rabbits were euthanized at 6 weeks of age. Two-dimensional (2D) defect healing, bone volume, and bone density were quantified by computed tomography. Regenerated bone was qualitatively assessed histologically. One-way analysis of variance revealed significant group main effects for all bone quantity measures. Analysis revealed significant differences in 2D defect healing, bone volume, and bone density between the control group and all treatment groups, but no significant differences were detected among the three growth factor treatment groups. Qualitatively, TGFß1 treatment produced bone with morphology most similar to native bone. TGFß1-regenerated bone contained a suture-like tissue, growing from the lateral edge of the defect margin toward the midline. Unique to the BMP2 treatment group, regenerated bone contained lacunae with chondrocytes, demonstrating the presence of endochondral ossification. CONCLUSIONS/SIGNIFICANCE: Total healing in BMP2 and TGFß1 treatment groups is not significantly different. The combination of BMP2+TGFß1 did not significantly increase bone healing compared with treatment with BMP2 or TGFß1 alone postoperatively at 4 weeks. We highlight the potential use of TGFß1 to regenerate calvarial bone and cranial sutures. TGFß1 therapy significantly augmented bony defect healing at an earlier time point when compared with control, regenerated bone along the native intramembranous ossification pathway, and (unlike BMP2 alone or in combination with TGFß1) permitted normal suture reformation. We propose a novel method of craniofacial bone regeneration using low-dose, spatially controlled growth factor therapies to minimize potentially harmful effects while maximizing local bioavailability and regenerating native tissues.

Bone morphogenetic protein 2­mediated mandible reconstruction successfully heals bony defects but inhibits concurrent inferior alveolar nerve grafting: a rabbit experimental model.

BACKGROUND: Bone morphogenetic protein 2 (BMP-2) has been used to reconstruct mandibular defects. An elegant addition to this reconstruction method would be incorporation of a nerve graft wrapped in a BMP-2 carrier to reconstitute the inferior alveolar nerve (IAN) and restore sensation to the lower face. We developed a rabbit model to determine the effect BMP-2 has on nerve regeneration following neurorrhaphy. METHODS: An inferior border mandibulectomy was created in 16 adult New Zealand white rabbits. The IAN was protected, divided, and repaired with either primary neurorrhaphy or reverse autografts. Bone defects were treated with no treatment controls (n = 2), absorbable collagen sponge (ACS) (vehicle controls) (n = 7), and ACS soaked in BMP-2 (treatment group) (n = 7). Animals underwent computed tomography (CT) 2 days and 6 weeks postoperatively. The percent bone defect healing was calculated using Amira 3D imaging software. At 6 weeks, IANs were harvested mesial to the reconstruction and were evaluated with toluidine blue histology to identify myelinated axons. Reconstructed mandible segments were evaluated with micro-CT and hematoxylin-eosin histology. RESULTS: Bone morphogenetic protein 2-treated animals demonstrated significantly more bone healing than did the ACS and empty defect groups (82%, 38%, 44%, respectively; P < 0.01). One hundred percent of ACS-treated nerves (n = 4) demonstrated axon regrowth, whereas only 25% of BMP-2-treated nerves (n = 4) did. Micro-CT and histology showed BMP-2 caused bone growth around the IAN, but regenerated bone infiltrated the repair site and created a physical barrier to axon growth. CONCLUSIONS: Bone morphogenetic protein 2 can successfully heal bone defects in the rabbit mandible, but ectopic bone growth can inhibit IAN recovery after repair. Level of Evidence: Not gradable.

Cleft palate repair.

The authors begin with a discussion of the anatomy relevant to palatoplasty. Perioperative considerations are then addressed. A broad range of surgical options has evolved over time; these are discussed in their historical context. The authors present a detailed description of their preferred surgical approach. Postoperative care is then described. An examination of recent trends and controversies in the field is then offered. Finally, an approach to outcomes assessment is discussed. It is hoped that this monograph will be of use in guiding others as they embark on the highly challenging, but equally rewarding, task of perfecting the palatoplasty.

Intraoperative high-dose epinephrine infiltration in cleft palate repair.

OBJECTIVE: Local infiltration of epinephrine before surgical procedures is a well-accepted technique to promote vasoconstriction. Typically, the dose of epinephrine is limited by the co-administration of local anesthetic as well as the risk for arrhythmogenesis and hemodynamic changes. In addition, some controversy exists regarding the acceptable dose of epinephrine given to children. This retrospective review examines the use and safety of "high-dose" epinephrine in palatoplasty at our cleft-craniofacial center. DESIGN: A retrospective review of epinephrine use in primary palatoplasty at a tertiary children's hospital from 2003 to 2007 was performed. Operative and anesthetic records were reviewed for hypertension (systolic blood pressure, >120 or diastolic blood pressure, >70) and tachycardia (>190 beats per min) as defined by the American Heart Association guidelines, as well as dysrhythmias, intraoperative complications, and postoperative complications. RESULTS: A total of 102 patients who underwent consecutive primary palatoplasties performed by a single surgeon were identified. After the induction of anesthesia and before incision, the patients received an initial epinephrine infiltration (without local anesthetic) up to a maximum 10 µg/kg. The average total dose of epinephrine administered during palatoplasty was 12.8 µg/kg (range, 3.2-75.0 µg/kg). Doses up to a maximum of 10 µg/kg were administered as needed at 30-minute intervals. No instances of clinically unstable tachycardia or hypertension occurred. A total of 21.6% of the patients (22/102) experienced an instance of hypertension, and only 13.7% of these (14/102) were related to epinephrine administration. One (1%) postoperative fistula was identified. CONCLUSIONS: Locally infiltrated high-dose epinephrine during palatoplasty can be safely used as a means of vasoconstriction. Doses reaching a maximum of 10 µg/kg, administered as needed at 30-minute intervals, do not seem to be a significant risk for hemodynamic instability, intraoperative complications, or postoperative complications.

BMP-2-regenerated calvarial bone: a biomechanical appraisal in a large animal model.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is gaining popularity in craniofacial applications. Calvarial defects are, under normal circumstances, subjected to only minimal levels of the biomechanical stresses known to play an important role in osteogenesis, yet regenerated calvarial bone must be capable of withstanding traumatic forces such that the underlying neurocapsule is protected. The aim of this study is to, for the first time, assess the biomechanical properties of calvarial bone regenerated with derivations of a commercially available rhBMP-2-based system. Standardized calvarial defects were created in 23 adult male canines. These defects were treated with rhBMP-2 on one of several carriers. After 24 weeks, the biomechanical properties of the rhBMP-2-generated bone were compared to those of controls with a modified punch-out test (Bluehill 2; Instron, Norwood, Mass) and compared using a paired nonparametric analyses (SPSS, 17.0, Chicago, Ill). In a previously published report, defects across all the rhBMP-2 therapy groups were observed to have a mean rate of 99.5% radio-opacity at 24 weeks indicating nearly full bony coverage of the calvarial defect (compared to 32.7% in surgical controls). For ultimate load, ultimate energy, and first peak energy, there were significant differences (P<0.05) with the control native bone having more robust biomechanical properties than the rhBMP-2-generated bone. We conclude from these findings that rhBMP-2-generated calvarial bone is significantly less protective against trauma than native bone at 6 months. Further investigation is required to assess the efficacy of rhBMP-2 in healing calvarial defects in the longer term.

215 mandible fractures in 120 children: demographics, treatment, outcomes, and early growth data.

BACKGROUND: Optimal management of pediatric mandible fractures demands that the practitioner balance reduction and fixation with preservation of growth potential and function. The ideal synthesis of these goals has not yet been defined. The authors catalogue their experience with pediatric mandible fractures at a major pediatric teaching hospital with reference to demographics, injury type, treatment, and outcomes to inform future management of these injuries. METHODS: Demographics, management, and outcomes of pediatric mandible fractures presenting over 10 years at a pediatric trauma center were assessed. Cephalometric analysis was conducted. Relationships among demographics, fracture type, management, outcomes, and growth were explored. RESULTS: Two hundred fifteen mandible fractures in 120 patients younger than 18 years were analyzed (average follow-up, 19.5 months). The condylar head and neck were fractured most frequently. Operative management was significantly more likely for children older than 12 years (p<0.05). Operative management and multiple fractures were significantly associated with a higher rate of adverse outcomes (p<0.05), but no adverse outcomes were considered to significantly affect mandibular function by patient or surgeon. No significant growth differences existed on cephalometric analysis between our cohort and age- and sex-matched controls (p>0.05). CONCLUSIONS: This study reports the demographics, treatment, and early follow-up of a sizable cohort of pediatric mandible fractures. Management principles for these injuries are outlined. Although definitive recommendations must be withheld until longer follow-up is available, the data presented here show that the treatment protocols used at the authors' center have yielded largely uncompromised mandibular function and growth thus far.