Exercise training improves obesity-related lymphatic dysfunction.

KEY POINTS: Obesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells. ABSTRACT: Although previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, including VEGFR-3 and Prox1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity-induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications.

Obesity-induced lymphatic dysfunction is reversible with weight loss.

KEY POINTS: Obesity induces lymphatic leakiness, decreases initial lymphatic vessel density, impairs collecting vessel pumping and decreases transport of macromolecules. Obesity results in perilymphatic inducible nitric oxide synthase (iNOS) expression and accumulation of T cells and macrophages. Deleterious effects of obesity on the lymphatic system correlate with weight gain. Weight loss restores lymphatic function in obese animals and decreases perilymphatic iNOS and inflammatory cell accumulation. ABSTRACT: Although clinical and experimental studies have shown that obesity results in lymphatic dysfunction, it remains unknown whether these changes are permanent or reversible with weight loss. In the current study, we used a mouse model of diet-induced obesity to identify putative cellular mechanisms of obesity-induced lymphatic dysfunction, determine whether there is a correlation between these deleterious effects and increasing weight gain, and finally examine whether lymphatic dysfunction is reversible with diet-induced weight loss. We report that obesity is negatively correlated with cutaneous lymphatic collecting vessel pumping rate (r = -0.9812, P < 0.0005) and initial lymphatic vessel density (r = -0.9449, P < 0.005). In addition, we show a significant positive correlation between weight gain and accumulation of perilymphatic inflammatory cells (r = 0.9872, P < 0.0005) and expression of inducible nitric oxide synthase (iNOS; r = 0.9986, P < 0.0001). Weight loss resulting from conversion to a normal chow diet for 8 weeks resulted in more than a 25% decrease in body weight and normalized cutaneous lymphatic collecting vessel pumping rate, lymphatic vessel density, lymphatic leakiness, and lymphatic macromolecule clearance (all P < 0.05). In addition, weight loss markedly decreased perilymphatic inflammation and iNOS expression. Taken together, our findings show that obesity is linearly correlated with lymphatic dysfunction, perilymphatic inflammation and iNOS expression, and that weight loss via dietary modification effectively reverses these deleterious effects.

Regulation of inflammation and fibrosis by macrophages in lymphedema.

Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b-diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4(+) cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4(+) cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function.

Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema.

Although obesity is a major clinical risk factor for lymphedema, the mechanisms that regulate this effect remain unknown. Recent reports have demonstrated that obesity is associated with acquired lymphatic dysfunction. The purpose of this study was to determine how obesity-induced lymphatic dysfunction modulates the pathological effects of lymphatic injury in a mouse model. We used a diet-induced model of obesity in adult male C57BL/6J mice in which experimental animals were fed a high-fat diet and control animals were fed a normal chow diet for 8-10 wk. We then surgically ablated the superficial and deep lymphatics of the midportion of the tail. Six weeks postoperatively, we analyzed changes in lymphatic function, adipose deposition, inflammation, and fibrosis. We also compared responses to acute inflammatory stimuli in obese and lean mice. Compared with lean control mice, obese mice had baseline decreased lymphatic function. Lymphedema in obese mice further impaired lymphatic function and resulted in increased subcutaneous adipose deposition, increased CD45(+) and CD4(+) cell inflammation (P < 0.01), and increased fibrosis, but caused no change in the number of lymphatic vessels. Interestingly, obese mice had a significantly increased acute inflammatory reaction to croton oil application. In conclusion, obese mice have impaired lymphatic function at baseline that is amplified by lymphatic injury. This effect is associated with increased chronic inflammation, fibrosis, and adipose deposition. These findings suggest that obese patients are at higher risk for lymphedema due to impaired baseline lymphatic clearance and an increased propensity for inflammation in response to injury.

IL-6 regulates adipose deposition and homeostasis in lymphedema.

Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4(+) cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4(+) inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4(+) cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.

An Evidence-Based and Case-Based Comparison of Modern Face Lift Techniques.

BACKGROUND: Facial aging is a multifactorial process that affects each component of facial anatomy. The two general groups of face lift techniques are superficial musculoaponeurotic system (SMAS) elevation and SMAS manipulation. The purpose of this article is to describe and compare the advantages, disadvantages, and limitations of face lift techniques. METHODS: A systematic review was performed to describe current outcomes evidence for face lift techniques. A subcohort of articles was selected for case-based analysis based on designated facial assessment criteria. Analysis was performed to determine the advantages, disadvantages, and limitations of each respective technique. RESULTS: A total of 65 articles were selected for systematic review, of which 15 met criteria for case-based review. Patient satisfaction was found to be equivocal for various face lift techniques. Specific advantages and disadvantages for each face lift technique were dependent on the techniques' approach to skin shift vector along with its degree of mobilizing superficial facial fat. Facial fat grafting was universally applicable for restoration of deep malar volume. Facial fat grafting was also used differently depending on the SMAS technique to address its specific limitations. CONCLUSIONS: The authors' review confirms that there are many methods to obtain excellent outcomes in facial rejuvenation. Experienced surgeons are able to obtain consistent results through a variety of techniques based on understanding the aesthetic needs of the individual patient, the quality of the soft tissues being manipulated, and how to vary a specific technique to reach desired aesthetic end points.

Gender Considerations in Rhinoplasty.

SUMMARY: Precise nasofacial analysis ahead of rhinoplasty is imperative. Features common to the White masculine nose are reviewed in a stepwise fashion and contrasted with those of the White feminine nose. A solid understanding of the cisgender male, masculine nose enables the plastic surgeon to determine the changes required for a successful facial feminizing rhinoplasty as a part of facial gender confirmation surgery.

Subcutaneous Lateral Temporal Lift.

Over the past decades, the understanding of the nuances of forehead anatomy and facial aging has grown immensely. Safe and reliable options for forehead rejuvenation followed. Although noninvasive techniques are an important adjunct in forehead rejuvenation, the mainstay of treatment of the eyebrow is operative intervention. The senior author's technique has developed over many years, first focusing on the open coronal and anterior hairline approach to the forehead lift, then the endoscopic brow lift, and most recently, the lateral subcutaneous temporal lift. This technique allows for reliable and safe elevation of the lateral brow with minimal complications.

The Five-Step Rhinoplasty Dead Space Closure Technique.

SUMMARY: The creation of dead space in rhinoplasty creates a welcoming environment for erratic soft -tissue contraction. If rhinoplasty surgeons can control and reliably predict skin contraction and wound healing, rhinoplasty results will undoubtedly improve. Obliteration of dead space is a key component in rhinoplasty as it minimizes soft-tissue contraction, resulting in a more predictable outcome. In this article, the authors present a systematic five-step dead space closure surgical plan.

An Update on the Surgical Management of the Bulbous and Boxy Tip.

SUMMARY: The bulbous and box tips are two common morphologies encountered in rhinoplasty. Nasal tip reshaping is a challenging aspect of rhinoplasty. Understanding the classifications of nasal tip morphologies aids when performing a nasal-facial analysis. The management algorithm for both tip morphologies shares various techniques. These techniques include but are not limited to cephalic trim, transdomal sutures, and interdomal sutures. A graduated approach to managing the variations in bulbous and boxy tips will help in achieving consistent results. New concepts applied to the management include supporting alar rims with alar contour grafts, closing dead space through a series of techniques, and managing the soft-tissue envelope, which is often in excess.

A Novel Algorithm for Defining the Mandibular Border.

SUMMARY: Techniques for defining the mandibular angle are a particular focus for patients around the world. Developing the desirable sharp contours is a combination of reducing bulkiness around the mandible while augmenting the border. Invasive techniques (e.g., face lifts and chin augmentation) can help define the mandible; however, younger patients are demanding more affordable and less invasive procedures. The "Nefertiti lift," masseter neurotoxin, buccal fat excision, mandibular border augmentation with filler, and liposuction of the neck can all be done in the office and will produce excellent results. If the loss of definition is due to superior soft tissue, the next step is to determine if this is based on anterior or posterior soft-tissue excess. Posteriorly, it is caused by masseter hypertrophy, and anteriorly, it may be because of an enlarged or full buccal fat pad in the lower cheek area. If the loss of definition is inferior, the next step is to again define if it is anterior or posterior. Anterior excess tissue can be corrected with liposuction of the neck along with energy-based skin tightening technology. Posteriorly, the inferior pull of the platysma can be blunted with neurotoxin. Finally, once the soft tissues are adequate, the mandibular border can be augmented with filler. In this article, the authors propose an algorithm for when to utilize each of these procedures while reviewing proper technique.

The Alar Equalization Suture for Nasal Tip Refinement.

SUMMARY: Anatomic subtleties of the nasal tip have a dramatic impact on the overall appearance of the nose. Creation of the ideal nasal tip in rhinoplasty requires straight lower lateral cartilages, everted lateral crura, a higher caudal edge of the lower lateral cartilages relative to the cephalic margin, and a diamond-shaped tip. In this article, the authors describe the alar equalization suture, a suture technique that further refines nasal tip shaping after traditional maneuvers have been performed.

TGF-ß1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation.

BACKGROUND: Secondary lymphedema is a common complication of cancer treatment, and previous studies have shown that the expression of transforming growth factor-beta 1 (TGF-ß1), a pro-fibrotic and anti-lymphangiogenic growth factor, is increased in this disease. Inhibition of TGF-ß1 decreases the severity of the disease in mouse models; however, the mechanisms that regulate this improvement remain unknown. METHODS: Expression of TGF-ß1 and extracellular matrix molecules (ECM) was assessed in biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL). The effects of TGF-ß1 inhibition using neutralizing antibodies or a topical formulation of pirfenidone (PFD) were analyzed in mouse models of lymphedema. We also assessed the direct effects of TGF-ß1 on lymphatic endothelial cells (LECs) using transgenic mice that expressed a dominant-negative TGF-ß receptor selectively on LECs (LECDN-RII ). RESULTS: The expression of TGF-ß1 and ECM molecules is significantly increased in BCRL skin biopsies. Inhibition of TGF-ß1 in mouse models of lymphedema using neutralizing antibodies or with topical PFD decreased ECM deposition, increased the formation of collateral lymphatics, and inhibited infiltration of T cells. In vitro studies showed that TGF-ß1 in lymphedematous tissues increases fibroblast, lymphatic endothelial cell (LEC), and lymphatic smooth muscle cell stiffness. Knockdown of TGF-ß1 responsiveness in LECDN-RII resulted in increased lymphangiogenesis and collateral lymphatic formation; however, ECM deposition and fibrosis persisted, and the severity of lymphedema was indistinguishable from controls. CONCLUSIONS: Our results show that TGF-ß1 is an essential regulator of ECM deposition in secondary lymphedema and that inhibition of this response is a promising means of treating lymphedema.

Prediction of Facial Aging Using the Facial Fat Compartments.

SUMMARY: Facial aging is a multifactorial process governed by both intrinsic and extrinsic factors that impart a change to each component of the facial anatomy. Our understanding of the science of aging has evolved over the years. A recent and valuable addition to our understanding is the knowledge of both the superficial and deep facial fat compartments. The deep compartments provide structural support to the midface and the superficial fat compartments. Understanding the anatomy and the spectrum of their changes helps to tailor management options for facial rejuvenation. The authors present a review on facial aging as it relates to these fat compartments and provide a management algorithm based on the longitudinal changes seen during aging.

Secondary Rhinoplasty for Unilateral Cleft Nasal Deformity.

BACKGROUND: Secondary cleft rhinoplasty presents some of the most challenging cases of both cosmetic and functional nasal deformities. Understanding the anatomy and growth abnormality seen with the cleft nasal deformity helps to tailor surgical management. This article seeks to expand on the application of current concepts in secondary rhinoplasty for unilateral cleft lip nasal deformity. METHODS: The authors review nasal analysis in the cleft rhinoplasty patient and provide the surgical management for each aspect in the secondary cleft rhinoplasty. RESULTS: The secondary rhinoplasty was divided into seven areas: piriform hypoplasia, septal reconstruction, dorsal reshaping, tip reshaping, tip projection, alar reshaping, and alar repositioning. Surgical management for each is provided. CONCLUSION: Secondary cleft rhinoplasty requires an understanding of the structural dysmorphology, and the use of cosmetic, functional, and secondary rhinoplasty techniques for its successful management.

Nasal Tip Shaping Finesse in Rhinoplasty.

SUMMARY: Anatomic subtleties of the nasal tip have a dramatic impact on the overall appearance of the nose. Mastery of normal nasal aesthetics and anatomy is a critical prerequisite to adeptly performing nasal tip refinement during open rhinoplasty. This article and series of videos aim to provide a focused review of nasal tip analysis, anatomy, and surgical technique, with particular emphasis on pertinent tip sutures and cartilage grafts.

Why Primary Rhinoplasty Fails.

SUMMARY: Rhinoplasty remains one of the most challenging operations performed by plastic surgeons. The complexity lies in the ability to have a consistent and predictable aesthetic result. The unpredictability is mainly attributable to the interplay of manipulated internal structures and wound healing dynamics. In addition, setting realistic expectations with the patient is essential for achieving high postoperative patient satisfaction. An open rhinoplasty approach enables an accurate and in-depth evaluation and intervention. The authors provide a detailed analysis and discussion on why primary rhinoplasty fails, along with the surgical approach for preventing these failures.

Management of Patients with Textured Surface Breast Implants.

SUMMARY: The purpose of this special topic article is to present an evidence-based approach and provide recommendations for the management of both asymptomatic and symptomatic patients with textured surface breast implants. There are currently no scientific data to support complete removal of a benign capsule. When unnecessary capsulectomies are performed, the patient is at higher risk for developing postoperative complications. Ultimately, the decision to keep, exchange, or remove breast implants is the patient's decision and the procedure should be performed only by a qualified surgeon.

Revisiting Primary Otoplasty: Surgical Approach to the Prominent Ear.

SUMMARY: Prominent ears and other ear deformities are some of the most common congenital deformities of the head, affecting over 10 percent of the general population. In 2018, more than 10,000 otoplasties were performed in the United States, with over one-third performed on men. The goal of primary otoplasty is creation of a normal-appearing ear without evidence of surgical intervention. This article and video detail the authors' preferred technique for the treatment of prominent ears. This novel method allows for reduction of a hypertrophic concha and obtuse conchoscaphal angle, as well as creation of an adequate antihelical fold.