Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa.

BACKGROUND: Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms. OBJECTIVE: To assess the effect and mechanism of action of metformin in HS. METHODS: To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism. RESULTS: We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis. CONCLUSIONS: Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS.

The capsular hammock flap for correction of breast implant ptosis.

UNLABELLED: A well-defined inframammary fold (IMF) is essential in providing an aesthetically pleasing and stable result in breast procedures. The position of the IMF on the chest wall determines the "footprint" of the breast, and hence the breast and chest aesthetic as a whole. Implant malposition is reported in the literature to occur in 5-8 % of primary breast augmentation patients. This occurs most commonly in a caudal direction, which is the most difficult problem to correct, as reported by Tebbett (Clin Plast Surg 28:425-434, 2001). Numerous surgical techniques to correct the malpositioned IMF have been described, including periosteal anchorage techniques as reported by Persichetti et al. (Ann Plast Surg 70:636-638, 2013), periareolar approaches that secure the IMF to the rib cage, and superiorly based capsular flaps. Here we describe a novel simple capsular flap technique using the lower anterior capsule, which is divided and formed into an inferiorly based flap and used as a "hammock" to re-establish the IMF and support the implant. As the capsule is made of a compact fibrous shell with a dense collagen network and excellent blood supply, using it as a flap to reposition and maintain the implant is ideal. Previous studies and tests have shown the reliability of capsule-based flap reconstruction due to the capsule's intrinsic strength and good vascularity, as shown by Rubino et al. (Ann Plast Surg 46:95-102, 2001). We describe our series of 12 primary breast augmentation patients with caudal implant malposition who underwent IMF reconstruction and implant repositioning with this technique. We explain our simple and repeatable technique that shows a stable and very durable result in repositioning the IMF and implant, with no recurrence of implant ptosis. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Importance of histological analysis of seroma fluid.

UNLABELLED: The recent observation of anaplastic large cell lymphoma (ALCL) in association with breast implants has initiated a large amount of literature recently, particularly in light of the issues with Poly Implant Prosthese implants. There are now approximately 35-50 reports of this lymphoma associated with breast implants. One of the presenting signs with this lymphoma is a late perimplant seroma. Given Kim et als recommendations for seroma fluid to be analysed, we suggest that all late seromas should be considered for analysis for the possible presence of a causative ALCL pathology, and add to the data currently available on this association. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Identification of sokotrasterol sulfate as a novel proangiogenic steroid.

The potential to promote neovascularization in ischemic tissues using exogenous agents has become an exciting area of therapeutics. In an attempt to identify novel small molecules with angiogenesis promoting activity, we screened a library of natural products and identified a sulfated steroid, sokotrasterol sulfate, that induces angiogenesis in vitro and in vivo. We show that sokotrasterol sulfate promotes endothelial sprouting in vitro, new blood vessel formation on the chick chorioallantoic membrane, and accelerates angiogenesis and reperfusion in a mouse hindlimb ischemia model. We demonstrate that sulfation of the steroid is critical for promoting angiogenesis, as the desulfated steroid exhibited no endothelial sprouting activity. We thus developed a chemically synthesized sokotrasterol sulfate analog, 2beta,3alpha,6alpha-cholestanetrisulfate, that demonstrated equivalent activity in the hindlimb ischemia model and resulted in the generation of stable vessels that persisted following cessation of therapy. The function of sokotrasterol sulfate was dependent on cyclooxygenase-2 activity and vascular endothelial growth factor induction, as inhibition of either cyclooxygenase-2 or vascular endothelial growth factor blocked angiogenesis. Surface expression of alpha(v)beta(3) integrin was also necessary for function, as neutralization of alpha(v)beta(3) integrin, but not beta(1) integrin, binding abrogated endothelial sprouting and antiapoptotic activity in response to sokotrasterol sulfate. Our findings indicate that sokotrasterol sulfate and its analogs can promote angiogenesis in vitro and in vivo and could potentially be used for promoting neovascularization to relieve the sequelae of vasoocclusive diseases.

Scar Wars: Preferences in Breast Surgery.

BACKGROUND: The uptake of breast reconstruction is ever increasing with procedures ranging from implant-based reconstructions to complex free tissue transfer. Little emphasis is placed on scarring when counseling patients yet they remain a significant source of morbidity and litigation. The aim of this study was to examine the scarring preferences of men and women in breast oncoplastic and reconstructive surgery. METHODS: Five hundred men and women were asked to fill out a four-page questionnaire in two large Irish centres. They were asked about their opinions on scarring post breast surgery and were also asked to rank the common scarring patterns in wide local excisions, oncoplastic procedures, breast reconstructions as well as donor sites. RESULTS: Fifty-eight percent of those surveyed did not feel scars were important post breast cancer surgery. 61% said that their partners' opinion of scars were important. The most preferred wide local excision scar was the lower lateral quadrant scar whilst the scars from the deep inferior epigastric artery perforator (DIEP) flap were most favoured. The superior gluteal artery perforator flap had the most preferred donor site while surprisingly, the DIEP had the least favourite donor site. CONCLUSIONS: Scars are often overlooked when planning breast surgery yet the extent and position of the scar needs to be outlined to patients and it should play an important role in selecting a breast reconstruction option. This study highlights the need for further evaluation of patients' opinions regarding scar patterns.

Dual pathology proximal median nerve compression of the forearm.

We report an unusual case of synchronous pathology in the forearm- the coexistence of a large lipoma of the median nerve together with an osteochondroma of the proximal ulna, giving rise to a dual proximal median nerve compression. Proximal median nerve compression neuropathies in the forearm are uncommon compared to the prevalence of distal compression neuropathies (eg Carpal Tunnel Syndrome). Both neural fibrolipomas (Refs. 1,2) and osteochondromas of the proximal ulna (Ref. 3) in isolation are rare but well documented. Unlike that of a distal compression, a proximal compression of the median nerve will often have a definite cause. Neural fibrolipoma, also called fibrolipomatous hamartoma are rare, slow-growing, benign tumours of peripheral nerves, most often occurring in the median nerve of younger patients. To our knowledge, this is the first report of such dual pathology in the same forearm, giving rise to a severe proximal compression of the median nerve. In this case, the nerve was being pushed anteriorly by the osteochondroma, and was being compressed from within by the intraneural lipoma. This unusual case highlights the advantage of preoperative imaging as part of the workup of proximal median nerve compression.

Cleft palate and congenital synechiae syndrome: a case report.

OBJECTIVE: A 1-day-old baby girl with a cleft of the secondary palate and a soft tissue band connecting the upper and lower jaws and preventing mouth opening was referred to the cleft lip and palate team by her pediatrician. This case represents a further example of an interesting but rare anomaly known as congenital alveolar synechia syndrome that requires early management to allow normal feeding and oral development.