The Mycotoxin Deoxynivalenol Significantly Alters the Function and Metabolism of Bovine Kidney Epithelial Cells In Vitro.

Bovine mycotoxicosis is a disorder caused by the ingestion of fungal toxins. It is associated with chronic signs, such as reduced growth rate and milk yield, and causes significant economic cost to the dairy industry. The mycotoxins deoxynivalenol (DON), zearalenone (ZEN), and fumonisin B1 (FB1) are commonly found in grain fed to cattle. Patulin (PA) is a common grass silage contaminant but is also found in grain. The effects of these mycotoxins on cellular function at low concentrations are not well understood. Using Madin-Darby bovine kidney cells we evaluated the cellular response to these mycotoxins, measuring cytotoxicity, de novo protein synthesis, cell proliferation, cell cycle analysis, and also metabolic profiling by 1H NMR spectroscopy. DON, ZEN, and PA induced cytotoxicity, and PA and FB1 induced a decrease in metabolic activity in surviving cells. DON was the only mycotoxin found to have a significant effect on the metabolic profile, with exposed cells showing increased cellular amino acids, lactate, 2-oxoglutarate, 3-hydroxybutyrate, and UDP-N-acetylglucosamine and decreased ß-alanine, choline, creatine, taurine, and myo-inositol. Cells exposed to DON also showed reductions in protein synthesis. DON has previously been documented as being a ribotoxin; the results here suggest that exposure of bovine cells to DON causes a decrease in protein synthesis with corresponding cellular accumulation of precursors. Cell proliferation was also arrested without causing apoptosis. It is likely that exposure triggers hypoxic, hypertonic, and ribotoxic responses in bovine cells, and that these responses contribute to reduced productivity in exposed cattle.

Assessing the ability of silage lactic acid bacteria to incorporate and transform inorganic selenium within laboratory scale silos.

Selenium (Se) is a non-metallic trace element essential for normal cellular function, which has been linked with reduced risk of cancer, cardiovascular disease, cognitive decline and thyroid disease in humans. Se deficiency in livestock is associated with white muscle disease, retained placenta, ill-thrift and mastitis. Where Se status or bioavailability from the soil for plants is poor, livestock rely on supplemental Se in their diets predominantly as either sodium selenite (inorganic form) or selenised-yeast (organic form). As lactic acid bacteria (LAB) have been shown to incorporate Se as either organic or elemental (Nano-Se) there may be potential to use silage inoculant bacteria to improve the Se status of feed to provide the Se requirements of livestock. We screened twenty-seven LAB in MRS broth in the presence of sodium selenite for growth and uptake of Se as organic (selenocysteine and selenomethionine), inorganic (selenite and selenate) or/and Nano-Se, with the aim to identify potential candidates for a mini-silo study. Sodium selenite addition into the growth medium of LAB reduced growth rates but also resulted in the conversion of the inorganic sodium selenite into predominately Nano-Se and small quantities of organic-Se. Based on a rank analysis of growth and ability to take up (total Se content) and convert inorganic Se (Nano and organic Se content), three LAB were selected for further investigation as silage inoculants: L. brevis DSMZ (A), L. plantarum LF1 (B), and L. plantarum SSL MC15 (C). Each LAB was used as an inoculant within a grass mini-silo trial, either cultured in the presence of sodium selenite before inoculation or sodium selenite added to the inoculum at inoculation versus controls with no Se. The addition of sodium selenite either into the growth media of LAB or applied at inoculation of grass silage did not interfere with the ability of the LAB to act as a silage inoculant with no difference in silage fermentation characteristic between LAB with no Se added. The addition of sodium selenite either to the LAB growth medium or at inoculation resulted in the conversion of sodium selenite into Nano-Se and organic-Se (Nano-Se, ca. 103 higher than organic), as previously shown in the screening trial. There was no difference between the three LAB for incorporation of Se or in silage quality, indicating the potential to develop silage inoculants to increase the bioavailable form of Se (elemental and organic) to livestock through conversion of inorganic forms during ensiling.

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

Separation, Aspiration, and Fat Equalization: SAFE Liposuction Concepts for Comprehensive Body Contouring.

BACKGROUND: Separation, aspiration, and fatty equilibration (SAFE) liposuction uses a process approach to body contouring and minimizes injury to surrounding structures. The multistep process allows for (1) fat separation, (2) lipoaspiration, and (3) fat equalization. The purpose of this study was to review both outcomes and complications of primary SAFE liposuction. METHODS: Retrospective chart review was completed of patients undergoing SAFE liposuction from January of 2006 to January of 2011. Patient selection was limited to those undergoing liposuction alone with no adjuvant excisional procedures. Data were collected regarding demographics, body mass index, operative details, and outcomes. RESULTS: Seven hundred thirty-four patients were identified as having undergone SAFE liposuction. One hundred twenty-nine patients were found to have been treated with liposuction alone. Patient age ranged from 18 to 42 years and body mass index ranged from 18 to 42 kg/m (mean, 26.3 kg/m). Seven patients (5.4 percent) underwent treatment of the face and neck, six patients (4.7 percent) underwent treatment of upper extremities, 13 patients (10.1 percent) underwent treatment of the chest, 20 patients (15.5 percent) underwent treatment of lower extremities, 32 patients (24.8 percent) underwent treatment of the circumferential trunk, and 51 patients (39.5 percent) underwent treatment of circumferential trunk and additional area(s). No major complications occurred. Five of the 129 patients (3.87 percent) developed the minor complication of seroma formation. CONCLUSIONS: SAFE liposuction is a multistep process approach to body contouring consisting of (1) fat separation, (2) lipoaspiration, and (3) fat equalization. The results of this study show such technique to be safe and effective. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Inferior Turbinate Hypertrophy in Rhinoplasty: Systematic Review of Surgical Techniques.

BACKGROUND: Inferior turbinate hypertrophy is often encountered by plastic surgeons who perform rhinoplasty. Many treatment options are available to treat the inferior turbinate. The objective of this study was to systematically review outcomes of available techniques and provide guidance to surgical turbinate management. METHODS: A MEDLINE search was performed for means of treating inferior turbinate hypertrophy. Studies selected focused on treatment of the inferior turbinate in isolation and excluding patients with refractory allergic rhinitis, vasomotor rhinitis, or hypertrophic rhinitis. RESULTS: Fifty-eight articles were identified, collectively including the following surgical treatments of inferior turbinate hypertrophy: total turbinectomy, partial turbinectomy, submucosal resection, laser surgery, cryotherapy, electrocautery, radiofrequency ablation, and turbinate outfracture. Outcomes and complications were collected from all studies. Procedures such as turbinectomy (partial/total) and submucosal resection showed crusting and epistaxis at comparatively higher rates, whereas more conservative treatments such as cryotherapy and submucous diathermy failed to provide long-term results. Submucosal resection and radiofrequency ablation were shown to decrease nasal resistance and preserve mucosal function. No literature exists to support the belief that turbinate outfracture alone is an effective treatment for turbinate hypertrophy. CONCLUSIONS: Treatment of inferior turbinate hypertrophy is best accomplished with modalities that provide long-lasting results, preservation of turbinate function, and low complication rates. Submucosal resection and radiofrequency ablation appear to best fulfill these criteria. Turbinate outfracture should only be considered in combination with tissue-reduction procedures.

Technical Maneuvers to Decrease Warping of Peripheral Costal Cartilage Grafts.

BACKGROUND: Cartilage warping has plagued reconstructive and cosmetic rhinoplasty since the introduction of extraanatomical cartilage use. The authors' group theorized that, rather than focusing on the prevention of the innate tendency of rib graft warping, it may be possible to redirect the stressors toward themselves and use these forces with oppositional suturing techniques to compensate for these intrinsic characteristics. METHODS: Fresh cadaver cartilage was obtained from the costosternal junction of two rib cages (aged 77 and 99 years). The cartilage was cut manually into 4 × 2.5 × 20-mm cross-sections from the cephalic edges of each of the harvested specimens. The specimens from the right chest were used as the control and the left segments underwent an oppositional suturing technique (n = 10) of the cephalic peripheral segment of the cartilage. RESULTS: Overall, the control group experienced a 724.2 percent increase in the mean degree of warping (p < 0.001). In contrast, the oppositional suturing group experienced a mean decrease in warping angle relative to baseline of only 35.7 percent. At 1 month, the oppositional suturing group displayed significantly decreased warping compared with the control group. CONCLUSIONS: This is a novel cadaveric study evaluating the benefit of oppositional suturing techniques in peripheral costal cartilage grafts. Multiple techniques and maneuvers have been borne out of the frustration of these inherent characteristics of costal cartilage grafts. Oppositional suturing techniques are a useful tool available to surgeons performing nasal reconstruction and revision rhinoplasty to maximize the amount of useful costal cartilage graft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Digital Imaging in Secondary Rhinoplasty.

BACKGROUND: Rhinoplasty remains one of the most commonly performed operations in plastic surgery. Little is known regarding the use of imaging in secondary rhinoplasty. Secondary rhinoplasty is a far more complex operation than primary rhinoplasty. The objective of this study was to assess the role of software imaging in patients undergoing secondary rhinoplasty. METHODS: A retrospective review was performed to identify patients undergoing secondary rhinoplasty performed by the senior author (R.J.R.) from January of 2000 to August of 2013. Forty consecutive patients met inclusion criteria. The degree of improvement was graded in comparison with both the preoperative photographs and software imaging using a graded scale. RESULTS: A total of 40 patients met inclusion criteria. There were 35 women (87.5 percent) and five men (12.5 percent). The nasal dorsum was found to have an average rating of 2.36 between the two observers, the midvault had an average rating of 2.65, the nasal tip had an average rating of 2.27, the nasal alae had an average rating of 2.63, and the nasal base had an average score of 2.99 CONCLUSIONS:: Based on the results of this study, the authors have determined that preoperative digital imaging can provide a reasonable expectation for patients undergoing secondary rhinoplasty. However, digital imaging must be used with caution, as secondary rhinoplasty patients have heightened expectations and unknown anatomy from their previous operation. The nasal tip and dorsum are especially difficult to adequately predict, and this should be discussed with the patient before surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Prophylactic antibiotics in dermatological surgery.

This is a review of the common pathogens of surgical site infections, antibiotic coverage for particular anatomical sites, mechanisms by which surgical site infections occur and the latest data and recommendations for prophylactic antibiotics in the prevention of surgical site infections, infective endocarditis and haematogenous joint infections. Recent evidence-based guidelines on surgical prophylaxis is for restricted indications and a shorter duration of antibiotic prophylaxis in situations where no clinical benefit of prolonged therapy has been proven, in order to minimise the potential adverse ecological and clinical effects associated with antibiotic therapy. This review recommends the cautious use of prophylactic antibiotics in dermatological surgery to help prevent the growing problem of bacterial resistance as well as other morbidity and health-care costs.

Alar Contour Grafts in Rhinoplasty: A Safe and Reproducible Way to Refine Alar Contour Aesthetics.

BACKGROUND: Alar rim deformities such as retraction, notching, collapse, and asymmetry are common problems in rhinoplasty patients. Although alar rim deformities may be improved through rhinoplasty, this area is prone to late changes because of scarring of the soft triangles and a paucity of native structural support. The purpose of this study was to analyze the effect of alar contour grafts on primary rhinoplasty. METHODS: Fifty consecutive primary rhinoplasty patients with preoperative and postoperative photographs who received alar contour grafts were evaluated for alar aesthetics; 50 consecutive primary rhinoplasty patients without such grafts served as controls. Differences among alar retraction, notching, collapse, and asymmetry from anterior, lateral, and basal views were evaluated. Follow-up ranged from 1 to 4 years and was graded on a four-point scale. RESULTS: The average difference between the two groups' aggregate preoperative scores was 0.21 (p = 0.24). The average preoperative and postoperative scores in the nongraft group were significant for worsening retraction, notching, and collapse but insignificant for asymmetry. The preoperative and postoperative scores for the graft group were insignificant for retraction but improved significantly for notching, collapse, and asymmetry. Postoperatively, the aggregate average of the scores in the nongroup was 0.32 points worse (p < 0.01), whereas the graft group had a 0.33-point improvement (p < 0.01). CONCLUSIONS: Alar contour grafts have a clear and important impact on cosmetic results of primary rhinoplasty. Use of alar contour grafts has been shown to improve aesthetics, whereas there is a worsening of the measured parameters postoperatively without use of these grafts. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Type 1 diabetes immunotherapy using polyclonal regulatory T cells.

Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing ß cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo-expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 × 10(8) to 26 × 10(8) cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype long-term. There were no infusion reactions or cell therapy-related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy.

Anatomy and surgical treatment of the depressor septi nasi muscle: a systematic review.

BACKGROUND: Although the majority of nasal alterations in rhinoplasty result from either augmentation or reduction of bone and cartilaginous substructure, modifications of influential soft-tissue provide significant contribution to the final result. The depressor septi nasi muscle is a soft-tissue structure well known to influence the final result in rhinoplasty. The objective of this study was to perform a standardized, comprehensive review of relevant data published with regard to the depressor septi nasi muscle. METHODS: A comprehensive search of the terms "depressor septi muscle" and "depressor septi nasi muscle" was performed using the PubMed, MEDLINE, and Cochrane databases. Articles were reviewed for relevancy and included if criteria were met. A secondary review was performed of all articles cited, to maximize diligence. RESULTS: Forty-three articles were identified in the initial search. Thirteen of the 43 were found to meet inclusion criteria. Secondary search revealed additional studies meeting inclusion criteria. Altogether, there were 175 cadaver specimens and 821 surgically treated patients for which data were available. Anatomical reports and nomenclature were found to vary. Surgical approach and muscle treatment diverged, with objective data showing no superior method. CONCLUSIONS: Although variation exists in anatomical reports regarding the depressor septi nasi muscle, the prevailing thought is that it originates from the maxilla and/or orbicularis oris muscle. More importantly, the muscle inserts on the medial crura and adjacent soft tissue. Disruption of this relationship provides the basis for surgical treatment of tip descent on animation.

Evaluation of the 5α-reductase inhibitor finasteride on reproduction and gonadal development in medaka, Oryzias latipes.

5-α reductase (5αR) inhibitors have an anti-androgenic effect in mammals because they inhibit the conversion of testosterone to the potent androgen, dihydrotestosterone. Finasteride is a type-2 5αR inhibitor that is used as a human pharmaceutical for the treatment of prostate cancer, benign prostate hyperplasia and male pattern baldness. This study evaluated the impacts of finasteride (50, 500 and 5000µg/L) on the development and reproduction of medaka (Oryzias latipes) exposed continuously over multiple generations (F0, F1 and F2). The exposure was initiated with reproductively mature fish (F0 generation) and continued until the hatching of the F2 generation. There were no significant effects on survival, fecundity or fertility in the F0 (50, 500, 5000µg/L) and F1 (50, 500µg/L) generations. The F1 generation exposed to 5000µg/L exhibited significant mortality. Histopathology of the gonads demonstrated that medaka and pre-clinical species respond similarly to finasteride exposure. Intersex condition and maldeveloped gonads were observed in F0 generation males exposed to 5000µg/L and F1 generation males exposed to 500µg/L. F1 generation males exposed to 500µg/L displayed reduced gonadosomatic index with an increased incidence of testicular degeneration. Males in both generations exhibited an increased incidence of Leydig cell hyperplasia at concentrations ⩾500µg/L. F0 generation females exposed to 5000µg/L exhibited increased gonadosomatic index. An increased prevalence of accelerated post-ovulatory follicle involution was observed in females at concentrations ⩾500µg/L in both generations. The gonadal changes induced by finasteride support the idea that 5-α reductase inhibition impacts androgen signaling in fish. Results from this study are discussed in the context of differential expression of the androgen receptor between species of fish.

Forage polyphenol oxidase and ruminant livestock nutrition.

Polyphenol oxidase (PPO) is predominately associated with the detrimental effect of browning fruit and vegetables, however, interest within PPO containing forage crops (crops to be fed to animals) has grown since the browning reaction was associated with reduced nitrogen (N) losses in silo and the rumen. The reduction in protein breakdown in silo of red clover (high PPO forage) increased the quality of protein, improving N-use efficiency [feed N into product N (e.g., Milk): NUE] when fed to ruminants. A further benefit of red clover silage feeding is a significant reduction in lipolysis (cleaving of glycerol-based lipid) in silo and an increase in the deposition of beneficial C18 polyunsaturated fatty acid (PUFA) in animal products, which has also been linked to PPO activity. PPOs protection of plant protein and glycerol based-PUFA in silo is related to the deactivation of plant proteases and lipases. This deactivation occurs through PPO catalyzing the conversion of diphenols to quinones which bind with cellular nucleophiles such as protein reforming a protein-bound phenol (PBP). If the protein is an enzyme (e.g., protease or lipase) the complexing denatures the enzyme. However, PPO is inactive in the anaerobic rumen and therefore any subsequent protection of plant protein and glycerol based-PUFA in the rumen must be as a result of events that occurred to the forage pre-ingestion. Reduced activity of plant proteases and lipases would have little effect on NUE and glycerol based-PUFA in the rumen due to the greater concentration of rumen microbial proteases and lipases. The mechanism for PPOs protection of plant protein in the rumen is a consequence of complexing plant protein, rather than protease deactivation per se. These complexed proteins reduce protein digestibility in the rumen and subsequently increase undegraded dietary protein flow to the small intestine. The mechanism for protecting glycerol-based PUFA has yet to be fully elucidated but may be associated with entrapment within PBP reducing access to microbial lipases or differences in rumen digestion kinetics of the forage and therefore not related to PPO activity.

Soft-tissue composition of the columella and potential relevance in rhinoplasty.

BACKGROUND: The columella serves as the medial limb of the nasal tripod, with the medial crura functioning as the cartilaginous framework. Although soft-tissue of the columella may have both functional and aesthetic implications, it is a topic not often discussed in the rhinoplasty literature. The objective of this study was to evaluate soft-tissue histology of the columella and discuss findings that are pertinent to clinical rhinoplasty. METHODS: Ten fresh cadaver heads were obtained from The University of Texas Southwestern Willed Body Program. En bloc resections of the columella were harvested. Specimens were fixed in formalin and embedded in paraffin. Subsequently, specimens were sectioned serially and stained. Staining with hematoxylin and eosin was performed to evaluate collagen and fat composition. Van Gieson elastin stain was completed to assess for elastin fibers. RESULTS: Laterally, the columella was framed by stratified squamous epithelium, which transitioned to mucosa at the level of the membranous septum. An areolar tissue plane was found between the skin and adjacent medial crura. Much greater soft-tissue volume was present between the bilateral medial crura. Soft-tissue composition was found to be heterogenous, with varying distributions of tissue at different levels of the columella. Present in notable volume were fibroblasts, collagen fibers, elastin fibers, adipocytes, and neurovascular structures. CONCLUSIONS: Columella soft-tissue is remarkable for the presence of fibroblasts, collagen and elastin fibers, muscle fibers, and adipocytes. These findings may have significant implications regarding surgical maneuvers influencing tip projection, effects of aging on the nose, and columellar aesthetics and function.

The tissue-based triad: a process approach to augmentation mastopexy.

BACKGROUND: Among the most exigent operations in plastic surgery is the combination of augmentation and mastopexy. The surgical challenge is related to oppositional forces that complicate the operative predictability. The purpose of this study was to investigate use of the tissue-based triad process approach in patients undergoing augmentation mastopexy. Measured components of the approach include skin stretch, nipple to inframammary fold distance on maximal stretch, and vertical excess. METHODS: Patients were selected for the study if they had been treated with one- or two-stage augmentation mastopexy, or mastopexy alone. Data gathered included preoperative measurements, operative details, complications, and outcomes including reoperation rate. RESULTS: A total of 176 consecutive patients were identified as meeting study inclusion criteria. Mean follow-up was 1.5 years. Seventy-one of 176 patients underwent mastopexy alone. Of the 176 patients included, 105 were treated with augmentation mastopexy. Ninety-one of 105 augmentation mastopexy operations were performed in one stage. The average amount of vertical excess was 5 cm. Nine patients exhibited delayed wound healing, while six (6.5 percent) required reoperations for scar revision (n=1), delayed wound healing requiring revision (n=2), hematoma (n=1), seroma (n=1), and soft-tissue stretch (n=1). Fourteen of 105 patients were treated in two stages. Average vertical excess was 7.5 cm. CONCLUSIONS: Use of the tissue-based triad process approach provided objectivity in determining which patients should undergo one- versus two-stage augmentation mastopexy. Use of this approach helps guide surgical decision making and is associated with lower reoperation rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Decreasing nasal tip projection in rhinoplasty.

BACKGROUND: Decreasing nasal tip projection is occasionally required in rhinoplasty and requires a working knowledge of nasal support and function. Equally important is an understanding of the evolution to a more conservative and incremental approach when decreasing nasal tip projection. Such a conservative approach reserves the most aggressive and precarious maneuvers to be used only when absolutely required. METHODS: The authors review the history and evolution of techniques regarding decrease in nasal tip projection. Anatomy of the nasal tip with focus on tip support structures is reviewed. Distinguishing between pseudo-overprojection and true overprojection of the nasal tip is discussed. Methods of diagnosing nasal tip projection are reviewed and a suggested surgical approach is presented. RESULTS: Reduction of nasal tip projection requires a thorough knowledge of relevant anatomy and tissue interplay. Although a variety of techniques and algorithms exist in addition to those recommended in this article, the goal should be an incremental approach with constant reassessment. Tip truncation is rarely if ever indicated and is often associated with eventual contour deformity. CONCLUSION: The described approach in this article has been proven reliable for the vast majority of patients undergoing rhinoplasty with the overprojected nose.

Proximal peroneal perforator in dual-skin paddle configuration of fibula free flap for composite oral reconstruction.

BACKGROUND: Composite defects of the oral cavity are often the result of trauma or advanced-stage tumor extirpation. The resultant deformity frequently requires a three-dimensional reconstruction of bone and soft-tissue. The fibula free flap is the preferred method of reconstruction, with various modifications focused on providing supplemental soft-tissue coverage. The objective of this study was to ascertain both anatomic and clinical data regarding the proximal peroneal perforator and its contribution to the evolution of the fibula free flap. METHODS: Ten cadaver lower extremities were dissected to isolate the most proximal perforator supplying skin over the proximal lateral lower leg. Data were recorded regarding perforator presence, location, and course. Furthermore, review of clinical cases in which the proximal perforator was used in fibula free flap design was performed for operative data collection. RESULTS: Cadaveric dissections revealed the proximal perforator to be present in 90 percent of specimens. Most commonly, the perforator, originating from the peroneal artery, traveled a short intramuscular course through the soleus muscle prior to supplying the overlying skin. In all clinical cases, the perforator was easily located with Doppler prior to incision, and there were no cases of flap failure or skin paddle loss. Flap inset was found to be optimal in all cases, with no tethering or undue tension. CONCLUSIONS: The proximal peroneal perforator was found to be anatomically reliable and clinically useful in composite oral cavity reconstruction following tumor removal. The gained separation between skin paddles allows for greater versatility in flap design and inset. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.