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BackgroundAlthough interest in sphincter-sparing treatments for anal fistulas is increasing, few large prospective studies of these approaches have been conducted.ObjectiveThe study assessed outcomes after implantation of a synthetic bioabsorbable anal fistula plug.DesignA prospective, multicenter investigation was performed.SettingThe study was conducted at 11 colon and rectal centers.PatientsNinety-three patients (71 men; mean age, 47 years) with complex cryptoglandular transsphincteric anal fistulas were enrolled. Exclusion criteria included Crohn's disease, an active infection, a multitract fistula, and an immunocompromised status.InterventionDraining setons were used at the surgeon's discretion. Patients had follow-up evaluations at 1, 3, 6, and 12 months postoperatively.Main outcome measuresThe primary end point was healing of the fistula, defined as drainage cessation plus closure of the external opening, at 6 and 12 months. Secondary end points were fecal continence, duration of drainage from the fistula, pain, and adverse events during follow-up.ResultsThirteen patients were lost to follow-up and 21 were withdrawn, primarily to undergo an alternative treatment. The fistula healing rates at 6 and 12 months were 41% (95% CI, 30%-52%; total n = 74) and 49% (95% CI, 38%-61%; total n = 73). Half the patients in whom a previous treatment failed had healing. By 6 months, the mean Wexner score had improved significantly (p = 0.0003). By 12 months, 93% of patients had no or minimal pain. Adverse events included 11 infections/abscesses, 2 new fistulas, and 8 total and 5 partial plug extrusions. The fistula healed in 3 patients with a partial extrusion.LimitationsThe study was nonrandomized and had relatively high rates of loss to follow-up.ConclusionImplantation of a synthetic bioabsorbable fistula plug is a reasonably efficacious treatment for complex transsphincteric anal fistulas, especially given the simplicity and low morbidity of the procedure.

Recent studies suggest that the skeletal muscle may be a significant site of IL-6 production in various conditions, including exercise, inflammation, hypoperfusion, denervation, and local muscle injury. The mediators and molecular mechanisms regulating muscle IL-6 production are poorly understood. We tested the hypothesis that IL-6 production in muscle cells is regulated by IL-1[beta] and that mitogen-activated protein (MAP) kinase signaling and NF-[kappa]B activation are involved in IL-1[beta]-induced IL-6 production. Cultured C2C12 cells, a mouse skeletal muscle cell line, were treated with different concentrations (0.1-2 ng/ml) of IL-1[beta] in the absence or presence of the p38 MAP kinase inhibitor SB-208350 or the p42/44 inhibitor PD-98059. Protein and gene expression of IL-6 were determined by ELISA and real-time PCR, respectively. NF-[kappa]B DNA binding activity was determined by electrophoretic mobility shift assay and by transfecting myocytes with a luciferase reporter plasmid containing a promoter construct with multiple repeats of NF-[kappa]B binding site. Treatment of myotubes with IL-1[beta] resulted in a dose- and time-dependent increase of IL-6 production accompanied by an ~25-fold increase in IL-6 mRNA levels. IL-1[beta] stimulated NF-[kappa]B DNA binding activity and gene activation. SB-208350 and PD-98059 inhibited the increase in IL-6 production induced by IL-1[beta]. The present results support the concept that skeletal muscle is an important site of IL-6 production. In addition, the results suggest the IL-1[beta] regulates muscle IL-6 production at least in part by activating the MAP kinase pathway and NF-[kappa]B. interleukin-6 production; cytokines; mitogen-activated protein kinase; nuclear factor-[kappa]B

Mucosal and enterocyte IL-6 production is increased during sepsis and endotoxemia. Recent studies suggest that cAMP potentiates IL-6 production in endotoxin- or IL-[beta]-stimulated enterocytes, but the molecular mechanisms are not known. We examined the role of the transcription factors NF-[kappa]B, activator protein (AP)-I, CCAAT/enhancer binding protein (C/ EBP), and cAMP response element-binding protein (CREB) in cAMP-induced IL-6 production in cultured Caco-2 cells, a human intestinal epithelial cell line. In addition, the role of the protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein (MAP) kinase signaling pathways was examined. Treatment of the cells with IL-[beta] increased IL-6 production and activated the IL-6 promoter in cells transfected with a luciferase reporter plasmid containing a wild-type IL-6 promoter. These effects of IL-[beta] were significantly potentiated by cAMP. When the binding sites for the individual transcription factors in the IL-6 promoter were mutated, results indicated that all four transcription factors may be involved in the cAMP-induced activation of the IL-6 gene. Treatment of the Caco-2 cells with cAMP increased the DNA binding activity of CREB, C/EBP, and AP-1, but not NF-[kappa]B. By using specific blockers, evidence was found that both PKA and p38 MAP kinase (but not PKC or p42/44 MAP kinase) may be involved in the cAMP-induced potentiation of IL-6 production. The present results suggest that cAMP activates multiple transcription factors involved in the regulation of the IL-6 gene and that the activation of these transcription factors may at least in part explain why cAMP potentiates IL-6 production in stimulated enterocytes. mucosa; inflammation; cytokines; mitogen-activated protein kinase

In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response. intestine; mucosa; enterocyte; stress response; cytokine