Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2.

Type 1 diabetes (T1D) is a T cell-dependent autoimmune disease that is characterized by the destruction of insulin-producing ß cells in the pancreas. The administration to patients of ex vivo-differentiated FoxP3(+) regulatory T (Treg) cells or tolerogenic dendritic cells (DCs) that promote Treg cell differentiation is considered a potential therapy for T1D; however, cell-based therapies cannot be easily translated into clinical practice. We engineered nanoparticles (NPs) to deliver both a tolerogenic molecule, the aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and the ß cell antigen proinsulin (NPITE+Ins) to induce a tolerogenic phenotype in DCs and promote Treg cell generation in vivo. NPITE+Ins administration to 8-week-old nonobese diabetic mice suppressed autoimmune diabetes. NPITE+Ins induced a tolerogenic phenotype in DCs, which was characterized by a decreased ability to activate inflammatory effector T cells and was concomitant with the increased differentiation of FoxP3(+) Treg cells. The induction of a tolerogenic phenotype in DCs by NPs was mediated by the AhR-dependent induction of Socs2, which resulted in inhibition of nuclear factor κB activation and proinflammatory cytokine production (properties of tolerogenic DCs). Together, these data suggest that NPs constitute a potential tool to reestablish tolerance in T1D and potentially other autoimmune disorders.

Bupivacaine Versus Liposomal Bupivacaine for Postoperative Pain Control after Augmentation Mammaplasty: A Prospective, Randomized, Double-Blind Trial.

BACKGROUND: The long-acting preparation of bupivacaine, liposomal bupivacaine (EXPAREL, Pacira Pharmaceuticals, Inc., San Diego, CA), was approved by the Food and Drug Administration in October 2011 and has been shown to be safe in breast augmentation. It remains to be established if liposomal bupivacaine provides superior pain control in this setting. OBJECTIVES: This study compares liposomal bupivacaine and standard bupivacaine for postoperative pain control. METHODS: Thirty-four patients undergoing cosmetic primary subpectoral breast augmentation were recruited. Each patient was treated with bupivacaine in one implant pocket and liposomal bupivacaine in the other prior to closure in a randomized fashion. Both patient and surgeon were blinded. A brief pain inventory was administered by telephone every 12 h up to 72 h postoperatively. RESULTS: Liposomal bupivacaine demonstrated a statistically significantly lower pain score at the 12, 36, and 48 h time points in the worst pain category, at the 24, 36, 48, and 60 h time points in the least pain category, at the 12, 24, 36, 48, 60, and 72 h time points in the average pain category, and at the 24, 48, and 72 h time points in the pain rated at the time of the survey. These differences, however, were small, ranging from 0.08 to 0.98 using a 10-point pain scale. When asked if the additional charge for the liposomal bupivacaine would have been worth the benefit, 70% of the patients surveyed said "no." CONCLUSIONS: Although there is a statistically significant decrease in postoperative pain with the use of liposomal bupivacaine, this may not translate to an appreciable clinical benefit that justifies the additional cost. LEVEL OF EVIDENCE 3: Therapeutic.

Inverted nipple repair revisited: a 7-year experience.

BACKGROUND: Nipple inversion in females can be congenital or acquired. Women who desire treatment for this condition often report difficulty with breastfeeding and interference with their sexuality. However, data are limited on the demographics of patients who undergo surgery to repair inverted nipples and the associated recurrence rates and complications. OBJECTIVES: The authors assessed outcomes of a 7-year experience with an integrated approach to the correction of nipple inversion that minimizes ductal disruption. METHODS: A retrospective chart review was performed for 103 consecutive patients who underwent correction of nipple inversion. (The correction technique was initially reported in 2004 and entailed an integrated approach.) Complication rates, breastfeeding status, and patient demographics were documented. RESULTS: Among the 103 patients, 191 nipple corrections were performed. Nine patients had undergone previous nipple-correction surgery. Recurrence was experienced by 12.6% of patients, 3 of whom had bilateral recurrence. Other complications were partial nipple necrosis (1.05%), breast cellulitis (1.57%), and delayed healing (0.5%). The overall complication rate was 15.74%. Fifty-seven percent of the patients had a B-cup breast size, and 59% were 21 to 30 years of age. CONCLUSIONS: Results of the authors' 7-year experience demonstrate the safety and effectiveness of their technique to correct inverted nipples. LEVEL OF EVIDENCE 4: Therapeutic.

Superior pedicle technique of reduction mammaplasty: a stepwise approach.

Numerous surgical options for breast reduction have been described, but in the current healthcare environment, efficiency is of the utmost importance. In this Featured Operative Technique, the authors describe an efficient, reproducible, and simple method for minimal to moderate reduction mammaplasty that utilizes a superior pedicle. The surgical maneuvers were developed and conveyed to the senior author (W.G.S.) by Dr John Bostwick. This approach preserves superior and medial breast fullness while providing appropriate resection of the breast parenchyma to ameliorate symptoms and produce a smaller, lifted breast with a more youthful appearance. The surgical technique maintains a reliable blood supply to the nipple-areola complex (NAC) from the internal mammary artery and its perforators, and involves minimal transposition of the NAC. The authors reviewed the charts of 62 consecutive patients who underwent this procedure and found the complication rate to be 11.3%. Complications included 1 hematoma, 1 standing cone deformity, 3 soft-tissue infections, 8 incisional breakdowns, and 1 unilateral necrosis of the NAC.

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation.

Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by ß-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.

Secondary augmentation-mastopexy: indications, preferred practices, and the treatment of complications.

Increasing the volume of the breast while simultaneously decreasing the skin envelope equates to surgery involving opposing forces. Increasing patient demand and the evolving perceptions of surgeons have led to the growing popularity of the combined augmentation-mastopexy operation. In turn, secondary augmentation-mastopexies and revisional surgeries of primary augmentation-mastopexies also have increased in popularity. In this article, the authors describe indications for secondary augmentation-mastopexy, techniques for performing this combined procedure safely and effectively, adjunctive procedures, potential pitfalls, and the treatment of complications.

IL-21 induces IL-22 production in CD4+ T cells.

Interleukin (IL)-22 produced by innate lymphoid cells (ILCs) and CD4+ T cells plays an important role in host defence and mucosal homeostasis, thus it is important to investigate the mechanisms that regulate IL-22 production. We investigated the regulation IL-22 production by CD4+ T cells. Here we show that IL-21 triggers IL-22, but not IL-17 production by CD4+ T cells. STAT3, activated by IL-21, controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Moreover, IL-21 and AhR signalling in T cells control IL-22 production and the development of dextran sodium sulphate-induced colitis in ILC-deficient mice. Thus, we have identified IL-21 as an inducer of IL-22 production in CD4+ T cells in vitro and in vivo.

Analysis of satisfaction and well-being following breast reduction using a validated survey instrument: the BREAST-Q.

BACKGROUND: Breast reduction surgery has been proven in the literature to have a high rate of patient satisfaction, with improvement in quality of life. However, few studies have used validated survey instruments. The BREAST-Q is the only questionnaire to evaluate breast reduction that meets international and federal standards for questionnaire development. Therefore, the aim of this study was to implement this survey to analyze patient-reported satisfaction and quality of life following breast reduction. METHODS: All patients seen in consultation for breast reduction between January of 2008 and May of 2009 were asked to fill out BREAST-Q surveys anonymously, both preoperatively and 6 weeks postoperatively. Statistical analysis was performed and a value of p < 0.05 was considered significant. RESULTS: Forty-nine patients underwent breast reduction performed by a single surgeon (A.T.) during the study period. Of these patients, 38 (78 percent) completed the prereduction survey and 38 (78 percent) completed the postreduction survey. Statistically significant improvements were observed in satisfaction with breast appearance, psychosocial well-being, sexual well-being, and physical well-being. Satisfaction with overall outcomes most strongly correlated to satisfaction with breast appearance. CONCLUSIONS: As the implementation of evidence-based medicine continues to grow in everyday practice, there is increasing pressure to use validated survey instruments to demonstrate patient-reported outcomes. In this study, we have shown that breast reduction significantly improves satisfaction with breast appearance and psychosocial, sexual, and physical well-being, and that overall patient satisfaction is most strongly correlated with satisfaction in appearance of their breasts CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Analysis of satisfaction and well-being in the short follow-up from breast augmentation using the BREAST-Q, a validated survey instrument.

BACKGROUND: Improvements in satisfaction and quality of life following breast augmentation have been shown in the literature. However, few studies have used validated survey instruments. The BREAST-Q is a strong and validated questionnaire for breast augmentation. OBJECTIVE: The authors implement the BREAST-Q to analyze patient-reported satisfaction and quality of life following breast augmentation. METHODS: In this prospective study, all patients who underwent breast augmentation with a single surgeon (AT) between January 2008 and May 2009 were asked to fill out BREAST-Q surveys anonymously during the preoperative and 6-week postoperative periods. Statistical analysis was performed and a P value of <.05 was considered significant. RESULTS: Of the 155 patients who underwent breast augmentation during the study time period, 59 (38%) completed the preoperative survey and 70 (45%) completed the postoperative survey. Significant improvements were seen for satisfaction with breast appearance (P < .001), psychosocial well-being (P < .001), and sexual well-being (P < .01) between pre- and postoperative surveys. Conversely, a significant decrease was seen in the physical well-being category (P < .001). Satisfaction with overall outcomes most strongly correlated to satisfaction with appearance of breasts (r = 0.8) and less strongly with psychosocial well-being and sexual well-being (r = 0.6). No correlation was found between satisfaction with overall outcomes and physical well-being (r = 0.0). CONCLUSIONS: As the implementation of evidence-based medicine continues to grow in everyday practice, there is increasing pressure to use validated survey instruments to demonstrate patient-reported outcomes. In this study, the authors have shown that breast augmentation significantly improves satisfaction with breast appearance, psychosocial well-being, and sexual well-being and that overall satisfaction is most strongly correlated with breast appearance satisfaction.

Aiolos promotes TH17 differentiation by directly silencing Il2 expression.

CD4(+) interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are instrumental in the immune response to pathogens. However, an overactive T(H)17 response results in tissue inflammation and autoimmunity, and therefore it is important to identify the molecular mechanisms that control the development of T(H)17 cells. IL-2 suppresses such development, but how IL-2 production is actively suppressed during T(H)7 differentiation is not understood. Here we report that under T(H)17-polarizing conditions, the transcription factors STAT3 and AhR upregulated the expression of Aiolos, a member of the Ikaros family of transcription factors. Using Aiolos-deficient mice, we demonstrated that Aiolos silenced the Il2 locus, promoting T(H)17 differentiation in vitro and in vivo. Thus, we have identified a module in the transcriptional program of T(H)17 cells that actively limits IL-2 production and promotes their differentiation.

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis.

The immune response is normally controlled by regulatory T cells (Tregs). However, Treg deficits are found in autoimmune diseases, and therefore the induction of functional Tregs is considered a potential therapeutic approach for autoimmune disorders. The activation of the ligand-activated transcription factor aryl hydrocarbon receptor by 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) or other ligands induces dendritic cells (DCs) that promote FoxP3(+) Treg differentiation. Here we report the use of nanoparticles (NPs) to coadminister ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG)(35)(-55) to promote the generation of Tregs by DCs. NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Tregs in vitro. Moreover, NPs carrying ITE and MOG(35-55) expanded the FoxP3(+) Treg compartment and suppressed the development of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis. Thus, NPs are potential new tools to induce functional Tregs in autoimmune disorders.

Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.

The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells (T(reg) cells) and interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells), but its role in human T cell differentiation is unknown. We investigated the role of AhR in the differentiation of human induced T(reg) cells (iT(reg) cells). We found that AhR activation promoted the differentiation of CD4(+)Foxp3(-) T cells, which produce IL-10 and control responder T cells through granzyme B. However, activation of AhR in the presence of transforming growth factor-beta1 induced Foxp3(+) iT(reg) cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional Foxp3(+) iT(reg) cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iT(reg) cells could be induced in human autoimmune disorders.