Outcome of rectus femoris muscle flaps performed by vascular surgeons for the management of complex groin wounds after femoral artery reconstructions.

OBJECTIVE: Groin wound complications after femoral artery reconstructions are highly morbid and notoriously difficult to treat. Successful techniques include long-term antibiotic therapy, operative débridement, and muscle flap coverage. Historically, more complex muscle flap coverage, such as a rectus femoris muscle flap (RFF), has been performed by plastic and reconstructive surgeons. In this study, the experience of vascular surgeons performing RFF in the management of wound complications after femoral artery reconstructions is reported. METHODS: Clinical data between 2012 and 2018 were retrospectively analyzed. Data were summarized, and standard statistical analysis was performed. RESULTS: There were 23 patients who underwent 24 RFFs for coverage of complex groin wounds after femoral artery reconstructions. One of the 23 patients underwent bilateral RFFs. In this study cohort, patients had a median age of 67.5 years, and 79% (n = 19) were male. Median body mass index was 28.0 kg/m2, and 38% of patients were classified as obese on the basis of body mass index criteria. A history of tobacco use was present in 88%; however, only 29% were current smokers. Diabetes was present in 38% of patients and chronic kidney disease in 29%. Of the 24 RFFs, 14 (58%) were constructed in patients with reoperative groin surgery resulting in the need for muscle flap coverage. Femoral endarterectomy was the most common index procedure (46%), followed by infrainguinal leg bypass surgery (17%) and aortobifemoral bypass (17%). Grafts used during the original reconstruction included 12 bovine pericardial patches (50%), 6 Dacron grafts (25%), 4 PTFE grafts (17%), and 2 autogenous reconstructions (8%). Microbiology data identified 33% of patients (n = 8) to have gram-positive bacterial infections alone, 21% (n = 5) to have gram-negative infections alone, and 29% (n = 7) to have polymicrobial infections; 4 patients (13%) had negative intraoperative culture data. Median hospital stay after RFF was 8 days, and median follow-up time was 29.3 months. Major amputation was avoided in 20 of 24 limbs (83%) undergoing RFF. Eight patients underwent intentional graft or patch explantation (33%) before RFF, whereas 14 of the remaining 15 patients (93%) had successful salvage of the graft or patch after RFF. Two of the patients (13%) who underwent RFF with the intention of salvaging a prosthetic graft or patch required later graft excision. After RFF, 30-day and 1-year survival was 96% and 87%, respectively. CONCLUSIONS: RFF coverage of complex groin wounds after femoral artery reconstructions may safely be performed by vascular surgeons with excellent outcomes.

A 3-year experience with necrotizing fasciitis: favorable outcomes despite operative delays in a busy acute care hospital.

Necrotizing fasciitis is a rare severe soft tissue infection that has historically been associated with high mortality. We sought to evaluate our experience with necrotizing fasciitis focusing on outcomes based on timing of operative intervention. Our study hypothesis was that delays in surgical management would negatively impact outcomes. Fifty-four patients were identified for a retrospective chart review from January 2008 to January 2011. Data analysis included demographics, admission laboratory values, imaging results, examination findings, timing and nature of operations, length of stay (LOS), and outcomes. Surgical intervention in 12 hours or more was considered a delay in care. Our study cohort was high risk based on a high prevalence of intravenous drug abuse, diabetes mellitus, hypertension, and end-stage liver disease. The average time to surgical intervention was 18±25 hours and the overall mortality rate was 16 per cent. A delay to surgery did not impact mortality or the number of débridements and LOS. Mortality was high, 45 per cent, in patients requiring amputation. We observed a high-risk population managed with aggressive surgical care for necrotizing fasciitis. Our mortality was low compared with historical data and surgical delays did not impact outcomes. Those patients requiring amputation had worse outcomes.

A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation.

Desquamation of the stratum corneum is a serine protease-dependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13, and KLK14 to desquamation by examining their interactions, in vitro, with: 1) colocalized SPI, lympho-epithelial Kazal-type-related inhibitor (LEKTI, four recombinant fragments containing inhibitory domains 1-6 (rLEKTI(1-6)), domains 6-8 and partial domain 9 (rLEKTI(6-9')), domains 9-12 (rLEKTI(9-12)), and domains 12-15 (rLEKTI(12-15)), secretory leukocyte protease inhibitor, and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1. KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13, and KLK14 were potently inhibited by rLEKTI(1-6), rLEKTI(6-9'), and rLEKTI(9-12) with Ki values in the range of 2.3-28.4 nm, 6.1-221 nm, and 2.7-416 nm for each respective fragment. Only KLK5 was inhibited by rLEKTI(12-15) (Ki = 21.8 nm). No KLK was inhibited by secretory leukocyte protease inhibitor or elafin. Apart from KLK13, all KLKs digested the ectodomain of desmoglein 1 within cadherin repeats, Ca2+ binding sites, or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.

The Wnt-inducible transcription factor Twist1 inhibits chondrogenesis.

Wnt signaling is essential for many developmental processes, including skeletogenesis. To investigate the effects of Wnt signaling during skeletogenesis we studied the effects of Wnt on cultured chondrocytic cells and differentiating limb-bud mesenchyme. We showed that Wnt3a strongly repressed chondrogenesis and chondrocyte gene expression. Canonical Wnt signaling was responsible for the repression of differentiation, as evidenced by results showing that inhibition of glycogen synthase kinase 3 or expression of beta-catenin caused similar repression of differentiation. Significantly, we showed that the transcription repressor Twist1 is induced by canonical Wnt signaling. Expression of Twist1 strongly inhibited chondrocyte gene expression and short hairpin RNA knockdown of Twist1 transcript levels caused increased expression of the chondrocyte-specific genes aggrecan and type II collagen. Interestingly, Twist1 interfered with BMP2-induced expression of aggrecan and type II collagen expression and knockdown of Twist1 augmented BMP2-induced aggrecan and type II collagen expression. These data support the conclusions that Twist1 contributes to the repression of chondrogenesis and chondrocyte gene expression resulting from canonical Wnt signaling and that Twist1 interferes with BMP-dependent signaling.

Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18.

Glycogen synthase kinase 3 (GSK3) inhibits signaling pathways that are essential for bone development. To study the requirement for GSK activity during endochondral bone development, we inhibited GSK3 in cultured metatarsal bones with pharmacological antagonists. Interestingly, we find that inhibition of GSK3 strongly repressed chondrocyte and perichondrial osteoblast differentiation. Moreover, chondrocyte proliferation was inhibited, whereas perichondrial cell proliferation was stimulated. These results mirror the effects of fibroblast growth factor signaling (FGF), suggesting the FGF expression is induced. Indeed, we showed that (1) FGF18 expression is stimulated following inhibition of GSK3 and (2) GSK3 regulates FGF18 expression through the control of beta-catenin levels. Stimulation of cultured metatarsal with FGF18 had similar effects on the differentiation and proliferation of chondrocytes and perichondrial cells as GSK3 repression. This suggests that the regulation of FGF18 expression is a major function of GSK3 during endochondral bone development. Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3.

FGF18 represses noggin expression and is induced by calcineurin.

Fibroblast growth factors (FGFs) and bone morphogenetic proteins strongly regulate chondrogenesis and chondrocyte gene expression. The interactions of the signaling pathways initiated by these factors are central to the control of chondrocyte differentiation. Here we show that calcium-dependent signals induce expression of FGF18, an essential regulator of bone and cartilage differentiation. The induction of FGF18 expression required the calcium-dependent phosphatase, calcineurin. The activated forms of calcineurin or the calcineurin-dependent transcription factor, NFAT4 (nuclear factor of activated T-cell 4), induced FGF18 expression. FGF18 or a constitutive active FGF receptor suppressed noggin gene induction and thereby increased chondrocyte gene expression and chondrogenesis by facilitating bone morphogenetic protein-dependent signals. These findings reinforce the interdependence of bone morphogenetic protein and FGF signaling and provide a rational explanation for abnormal bone development occurring in humans or mice with constitutively active FGF receptors.