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Objective: To observe the clinical efficacy and safety of Yanghe decoction Huacai for the repair of Yin syndrome wounds with slow-healing after anal fistula surgery., Methods: A total of 120 patients with slow-healing negative wounds with after low-grade anal fistula surgery who met the inclusion criteria were divided into a treatment group and a control group based on a random number table method, with 60 patients in the treatment group and 60 patients in the control group. The treatment group was given Yanghe decoction Huacai in combination with routine treatment; the control group was only given routine treatment, in which the wound surface was disinfected with iodine, and then covered with sterile gauze. The course of treatment in both groups was 10 d. After treatment, the wound secretion score, wound granulation tissue score, the expression levels of basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGF-β1), and epidermal growth factor (EGF) in the wound, wound healing time and clinical efficacy were compared., Results: There was no significant difference in age or gender between the two groups ( P > 0.05). On the 10th and 15th days after the surgery, the wound secretion scores were higher in the treatment group than in the control group ( P < 0.01). Comparing the two groups at the 10th and 15th day after surgery, the granulation tissue growth scores in the treatment group were better than the in control group ( P < 0.01). On the 10th and 15th day after operation, the expression levels of bFGF, TGF-β1 and EGF factors in the treatment group were stronger than those in the control group. The healing time of the wounds in the treatment group was significantly shorter than in the control group ( P < 0.01). The clinical efficacy of the two groups after treatment was compared, and the overall efficacy of the treatment group was significantly higher than that of the control group ( P < 0.01)., Conclusions: Yanghe decoction Huacai have significant efficacy in the treatment of slow-healing wounds with Yin syndrome after anal fistula surgery. It improves wound secretions, promotes the growth of wound granulation tissue, and shortens wound healing time. Its mechanism of action may be related to the control of wound inflammation. It is related to increasing the expression of bFGF, TGF-β1 and EGF in wound tissue, and promoting wound angiogenesis and fibroblast proliferation.

Background and Aims: Perianal fistula represents one of the most disabling manifestations of Crohn's disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation., Methods: Surgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed., Results: A markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial-mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli., Conclusions: By mediating changes in the ECM organization, TSG-6 triggers the epithelial-mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cord blood platelet gel is prepared by activation of coagulation in a platelet concentrate obtained from cord blood. During the process of clot formation, platelet alpha-granules release growth factors that promote tissue repair. However, in the form of gel, it is not possible to inject it into small, narrow and deep cavities. Therefore, we analyzed gelification kinetics and developed an application technique of platelet gel in liquid form. This semi-activated form provides for the activation of the coagulation process but not the gelification of the platelet concentrate. In this way, it can be easily inoculated in an endocavitary space, and then complete in vivo the gelification process. We report the successful use of this procedure to heal a recurrent perianal fistula.

Tumor necrosis factor (TNF) antagonists are considered the cornerstone therapy for fistulizing perianal Crohn's disease (PCD), yet a substantial proportion of patients fail to achieve healing. Therefore, we reviewed the evidence for strategies to enhance the efficacy of TNF antagonists for PCD. A systematic search of electronic databases through July 2018 was performed to identify studies that assessed the effectiveness of TNF antagonists combined with another medical or surgical intervention for PCD; or assessed the association between anti-TNF serum concentrations and fistula healing. Twelve studies compared anti-TNF therapy alone versus a combined approach: four with surgery, three with antibiotics, and five with immunomodulators. Only two studies, both with antibiotics, were rated high quality. The addition of antibiotics to anti-TNF therapy resulted in significantly higher rates of fistula response and healing in one study, and a trend toward reduction in fistula drainage in the other. Three of four studies found higher rates of fistula healing when surgery was combined with TNF antagonists. In contrast, one of five studies found a trend toward higher rates of fistula healing in patients treated concomitantly with immunomodulators. Five observational studies assessed the association between anti-TNF concentration and fistula healing. Higher infliximab serum concentrations were consistently associated with fistula healing. In conclusion, few high-quality studies assessing strategies to optimize anti-TNF therapy for PCD exist. Although antibiotics, possibly surgery, and higher serum infliximab concentrations appear to improve fistula healing, future prospective studies are needed to determine the optimal treatment strategy.

Ga-prostate-specific membrane antigen (PSMA) PET/CT scan for primary staging discovered increased Ga-PSMA uptake in a known anal fistula in a recently diagnosed high-risk prostate cancer patient. The patient had an ongoing history of surgical revisions of complex fistulas in the perianal region, contributing to active inflammation and infection. Recently, reports have demonstrated increased Ga-PSMA uptake in different benign inflammatory conditions. This case demonstrates another case of a benign condition associated with increased Ga-PSMA uptake.

Anal fistulas continue to be a problem for patients and surgeons alike despite scientific advances. While patient and anatomical characteristics are important to surgeons who are evaluating patients with anal fistulas, their development and persistence likely involves a multifaceted interaction of histological, microbiological, and molecular factors. Histological studies have shown that anal fistulas are variably epithelialized and are surrounded by dense collagen tissue with pockets of inflammatory cells. Yet, it remains unknown if or how histological differences impact fistula healing. The presence of a perianal abscess that contains gut flora commonly leads to the development of anal fistula. This implies a microbiological component, but bacteria are infrequently found in chronic fistulas. Recent work has shown an increased expression of proinflammatory cytokines and epithelial to mesenchymal cell transition in both cryptoglandular and Crohn's perianal fistulas. This suggests that molecular mechanisms may also play a role in both fistula development and persistence. The aim of this study was to examine the histological, microbiological, molecular, and host factors that contribute to the development and persistence of anal fistulas.

Aim: The pathogenesis of cryptoglandular anal fistula (AF) is still under debate. Tissue inflammation could play a primary role. The pathological process of epithelial mesenchymal transition (EMT) might be involved but has never been investigated., Method: In a prospective pilot study, 12 patients with an AF had a fistulectomy. The excised track was divided into proximal (intrasphincteric) and distal (extrasphincteric) parts which were subjected to standard histopathological examination. The cytokines IL-8 and IL-1beta were analysed as markers of inflammation, while EMT was evaluated by expression of TGF-beta, Vimentin, Zeb-1, Snail and E-cadherin. The mRNA and protein expression of these molecules was investigated by real-time PCR (RT-PCR), Western blot analysis and immunohistochemistry and was compared with that of the normal adjacent tissue., Results: Chronic inflammation and granulation tissue and a stratified epithelium were evident on standard histopathological examination. The cytokine IL-8 was more expressed in the proximal than the distal part of the track (fold increase 4.34 vs 3.60), while the reverse was found for IL-1beta (fold increase 1.33 vs 2.01); both were more intensely expressed compared with the normal anal mucosa. EMT was demonstrated, in both proximal and distal parts of the track, with an increase of TGF-beta, Vimentin, Zeb-1 and Snail and a mean decrease of E-cadherin. Western blot analysis and immunohistochemistry confirmed the protein expression., Conclusion: The study suggests that chronic inflammation is present in cryptoglandular fistulas. The inflammatory pattern might be different in the proximal than in the distal part of the fistula track. The cytokines IL-1beta and IL-8 could play a possible role in fistula formation. The study demonstrates for the first time the potential importance of EMT in the pathogenesis of cryptoglandular AF., (Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.)

Background: Sphincter-preserving procedures for the treatment of transsphincteric fistulas fail in at least one out of every three patients. It has been suggested that failure is due to ongoing disease in the remaining fistula tract. Cytokines play an important role in inflammation. At present, biologicals targeting cytokines are available. Therefore, detection and identification of cytokines in anal fistulas might have implications for future treatment modalities. The objective of the present study was to assess local production of a selected panel of cytokines in anal fistulas, including pro-inflammatory interleukin (IL)-1β and tumor necrosis factor α (TNF-α)., Methods: Fistula tract tissue was obtained from 27 patients with a transsphincteric fistula of cryptoglandular origin who underwent flap repair, ligation of the intersphincteric fistula tract or a combination of both procedures. Patients with a rectovaginal fistula or a fistula due to Crohn's disease were excluded. Frozen tissue samples were sectioned and stained using advanced immuno-enzyme staining methods for detection of selected cytokines, IL-1β, IL-8, IL-10, IL-12p40, IL-17A, IL-18, IL-36 and TNF-α. The presence and frequencies of cytokine-producing cells in samples were quantitated., Results: The key finding was abundant expression of IL-1β in 93 % of the anal fistulas. Frequencies of IL-1β-producing cells were highest (>50 positive stained cells) in 7 % of the anal fistulas. Also, cytokines IL-8, IL-12p40 and TNF-α were present in respectively 70, 33 and 30 % of the anal fistulas., Conclusions: IL-1β is expressed in the large majority of cryptoglandular anal fistulas, as well as several other pro-inflammatory cytokines., Competing Interests: The authors declare that they have no conflict of interest. Ethical approval Ethical approval for the study was obtained from the hospital's institutional review board. Informed consent All patients provided informed consent meeting the standards set by the hospital’s institutional review board.

Background: AST-120 (spherical carbon adsorbent) was previously reported to be effective for perianal fistula healing in Japanese patients with mild-to-moderate Crohn's disease., Methods: To evaluate the efficacy and safety of AST-120 in a Western population, a phase 3, multicenter, randomized, double-blind, placebo-controlled, study (FHAST-1) was conducted in adult patients with at least 1 draining perianal fistula and a Crohn's disease activity index <400. Patients received either AST-120 or matching placebo at a dose of 2 g 3 times daily for 8 weeks. The primary endpoint was the proportion of patients with treatment success, defined as a 50% reduction in the number of draining fistulae, at both weeks 4 and 8. A multivariate model was generated to assess covariates for treatment success among baseline variables., Results: Two hundred forty-nine patients were randomized (AST-120; n = 122; placebo, n = 127). The proportions of patients achieving the primary endpoint were no different between treatment groups (13.9% versus 16.5%, P = 0.6). No differences in fistula response were noted at week 4 (23.0% versus 25.2%, P = 0.77) or week 8 (27.0 versus 34.6%, P = 0.22). Serum C-reactive protein concentrations >0.6 mg/dL and Crohn's disease activity index scores >151 at baseline were associated with a reduced likelihood of treatment success (odds ratio, 0.40; confidence interval, 0.19-0.87; P = 0.02; and odds ratio, 0.45; confidence interval, 0.21-0.97; P = 0.04, respectively)., Conclusions: In this largest placebo-controlled trial to date to evaluate the impact of a therapeutic agent on perianal fistulae in Crohn's disease, the efficacy of AST-120 could not be confirmed. An inverse relationship was observed between both inflammatory and clinical disease activity and fistula response., Competing Interests: S. Hanauer, S. Travis, and M. S. Harris have previously served as consultants to Ocera Therapeutics. M. S. Harris owns stock in Ocera Therapeutics and was an empcloyee during the time this study was conducted. The remaining authors have no conflicts of interest to disclose.

Background: Fistulae represent an important clinical complication of Crohn's disease (CD). The fistula tracts are covered by flat, myofibroblast-like cells with an epithelial origin (transitional cells, TC). We recently demonstrated a role of epithelial mesenchymal transition (EMT) in the pathogenesis of CD-associated fistulae. EMT is associated with an increased migratory and invasive potential of epithelial cells in different tissues. Here we investigated whether cytokines or growth factors as well as EMT-associated SNAIL family transcription factors are expressed in CD fistulae., Methods: By immunohistochemistry we analyzed seven perianal fistulae from seven CD and two perianal fistulae from two non-inflammatory bowel disease (IBD) control patients. Hematoxylin and eosin staining or immunohistochemistry for the expression of tumor necrosis factor (TNF), TNF-receptor I (TNF-RI), SNAIL1, SLUG, fibroblast growth factors (FGF) 1, 2, 4, 7, epidermal growth factor (EGF), and TWIST were performed using standard techniques., Results: Immunohistochemical staining of surgical specimens from CD patients revealed a strong expression of TNF and TNF-RI in and around fistula tracts. While SNAIL1 was also heavily expressed in the nuclei of TC, indicative of transcriptionally active protein, SLUG, FGF-1, and FGF-2 were detected rather in the fibrotic periphery of CD fistulae than in TC. In contrast, we did not detect considerable protein staining for FGF-4 and FGF-7 nor of EGF or the transcription factor, TWIST., Conclusions: Our data demonstrate that SNAIL1 and TNF are strongly expressed in TC of CD-associated fistulae. These observations support our previous data and indicate the onset of EMT-associated events in the pathogenesis of CD fistulae., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Background/purpose: Retinoid-mediated signal transduction plays a crucial role in the embryonic development of various organs. We previously reported that retinoic acid induced anorectal malformations (ARM) in mice. GDF11 is a TGFβ superfamily molecule and is cleaved and activated by proprotein convertase subtilisin/kexin 5 (PCSK5). PCSK5 (PC5/6) mutations result in an abnormal expression of Hlxb9 and Hox genes, which include known GDF11 targets that are necessary for caudal development in vertebrate embryos. To determine a possible role of the retinoid-mediated signaling pathway in the pathogenesis of ARM, we investigated whether all-trans retinoic acid (ATRA) affected the expression patterns of PCSK5 and GDF11 in ARM-treated mouse embryos., Methods: Pregnant ICR-Slc mice were administered 100 mg/kg ATRA by gavage on embryonic day (E) 9.0. Embryos were harvested between days E12 and E18, and mid-sagittal sections of the hindgut region were prepared for immunohistochemistry using antibodies against PCSK5 (PC5/6) and GDF11 (GDF8/11)., Results: Over 95% of the embryos treated with ATRA showed ARM, with rectourethral fistula or rectocloacal fistula, and a short tail. Furthermore, most of these embryos exhibited sacral malformations, tethered spinal cords, and presacral masses resembling those malformations found in caudal regression syndrome. By E14, normal mouse embryos formed a rectum and anus, and the somites behind the hindgut were positive for PC5/6 and GDF8/11. In contrast, in ARM embryos, the somites behind the hindgut were negative for PC5/6 and GDF8/11., Conclusion: ATRA treatment affected the caudal development in mouse embryos, resulting in anorectal, sacral, and spinal malformations, and inhibited PCSK5 and GDF11 expression in the hindgut region. These findings indicate that the expression of PCSK5 and GDF11, which plays a crucial role in the organogenesis of the hindgut, was disturbed in the hindgut region when retinoid-mediated signaling was disrupted. This study offers a new insight into the pathogenesis of ARM in mice as affected by the interaction between ATRA and PCSK5/GDF11., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aims: Perianal fistulae are often observed in patients with Crohn's disease (CD), although the development of associated adenocarcinomas is very rare. The origin of adenocarcinomas in perianal fistulae associated with CD remains controversial and includes adjacent anal glands or rectal mucosa. Here, we attempted to determine the origin., Methods: We performed immunohistochemical analysis on seven cases of adenocarcinomas in perianal fistulae associated with CD using antibodies against mucins (MUCs), cytokeratins (CKs) and the intestine-specific transcription factor CDX2., Results: MUC2 and CK20 were expressed in all seven adenocarcinomas examined. MUC5AC/CLH2, MUC5AC/HGM and CDX2 were positive in four (57%), five (71%), and five (71%) adenocarcinomas, respectively. These proteins were positive in rectal mucosa, and negative in the anal glands. Six of seven adenocarcinomas (86%) were negative for CK7. CK7 was expressed in the anal glands, but not in rectal mucosa., Conclusions: Adenocarcinomas in perianal fistulae associated with CD showed immunohistochemical phenotypes similar to those of rectal-type mucosa, rather than the anal glands. The adenocarcinomas might originate from cells migrating from the adjacent rectal mucosa to the CD-associated perianal fistulae.

Objective: Anal fistulas are the result of chronic infection of an intersphincteric gland. Despite the passage through mesenchymal tissue, fistulas seldom lead to systemic infection. Antimicrobial peptides are secreted by a variety of epithelia, belonging to the innate immune system and are potential factors contributing to infection control. The aim of this study was to investigate whether epithelium is present in the fistulas and what the origin might be., Material and Methods: Forty-seven chronic anal fistulas from patients, excluding Crohn's disease, were compared with healthy rectal and perianal control tissue. Expression of antimicrobial peptide mRNA was analysed by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Tissue was further studied by cytokine and cytokeratin staining., Results: Chronic anal fistulas express high levels of hBD-2 and hBD-3 and the newly identified antimicrobial peptides RNase7 and psoriasin compared to rectal mucosa from control patients. Perianal skin has almost identical levels of RNase7 and psoriasin expression to those in fistulas. IL-1b and IL-8 were the only cytokines detectable in fistulas. Fistulas are lined with squamous epithelium that expresses identical cytokeratines as skin., Conclusions: Epithelialization and local production of antimicrobial peptides in anal fistulas serve as defence mechanisms to prevent local and systemic infection by microbes from faeces passing through the fistula tract.

Objective: Tumor necrosis factor-alpha (TNF-alpha) plays a key role in the inflammatory response and pathogenesis of Crohn's disease (CD). TNF-alpha -308A polymorphism within the TNF-alpha gene promoter has been associated with enhanced TNF-alpha production in vitro. The aim of this study was to investigate the effect of TNF-alpha promoter polymorphism at -308 on the susceptibility and phenotypic expression of fistulizing CD., Methods: The distribution of -308 TNF-alpha genotypes was analyzed in 50 patients with fistulizing CD and 100 healthy matched controls. TNF-alpha, interleukin-1beta, and interleukin-6 serum levels were measured by ELISA. Serum amyloid-A, C-reactive protein, alpha1-antitrypsin, alpha1-acid glycoprotein, and haptoglobin were measured by nephelometry., Results: No significant differences were found in the allele frequencies of the polymorphism between patients and controls. However, compared with -308GG patients, those carrying -308AG had a significant increase of serum levels of TNF-alpha (58 +/- 79 vs 8 +/- 19 pg/ml, p < 0.001), interleukin-1beta (36 +/- 45 vs 16 +/- 20 pg/ml, p = 0.048), and acute phase proteins (APPs). -308A carriers had also a higher frequency of arthritis (66% vs 26%, p = 0.039). The logistic regression model showed that the patients carrying -308A polymorphism had a relative risk for developing arthritis of 5.45 (95% CI = 1.1-25.6). No other clinical or analytical findings were predictive for the risk of development of arthritis., Conclusions: TNF-alpha -308A polymorphism is associated with enhanced TNF-alpha production, more intense inflammatory activity, and an increased risk for arthritis susceptibility in CD patients with fistulizing disease.

Objective: To observe the effect of Zhuhuang Frost (ZHF), an external preparation of Chinese herbal medicine, on level of hydroxy-proline (Hyp) in surgical wound after anal operation., Methods: Fifty postoperational patients after low position simple operation of anal fistula were randomly divided into two groups and treated with ZHF and Mayinglong Musk hemorrhoidal paste (MMHP) respectively. The level of Hyp in granulation of wound was tested using alkaline hydrolysis assay at the 3rd, 7th and 14th day after operation respectively., Results: The Hyp level tested at the 7th and 14th day after operation in the ZHF treated group was higher than that in the MMHP treated group, but those tested at the 3rd postoperational day in the two groups was not different significantly., Conclusion: ZHF could increase the Hyp level in postoperational granulation of wound after anal operation.

The anal gland pathology comprises cystic anal glands (so-called anal gland cyst hamartomas), anal gland carcinomas, and anal fistulas with or without carcinoma. The differential diagnosis of these conditions from other cysts and carcinomas of the anal region can be difficult. The authors have therefore compared conventional history with mucin histochemistry in normal and pathological anal glands. In contrast to normal rectal mucosa the mucus of anal glands was characterized by strong PAS-reactivity that was completely abolished after periodate borohydride saponification indicating scarcity of absence of O-acylated sialic acids in the anal gland mucus. A pattern similar to this was found in one of two tumours classified histologically as anal gland carcinomas, in four of eight colloid carcinomas arising in preexisting fistulas, and in two cases of mucoepidermoid carcinoma of the anal region. The results indicate that the method in some cases may be of value in differentiating between carcinomas arising in anal gland epithelium and in rectal mucosa. The cystic anal glands showed decreased secretion but no qualitative histochemical differences from anal glands. On the basis of the patients' histories it is suggested that the so-called anal gland cyst hamartoma at least in some cases could be an inclusion cyst of anal glands on the inflammatory basis.

A 58-year-old man had a persistent perineal sinus following an abdominoperineal resection. An excision of the sinus was performed. Histology revealed that the sinus tract was bordered by a granulation tissue exhibiting numerous vacuolated cells containing polyvinylpyrrolidone. The origin of polyvinylpyrrolidone was related to lengthy irrigation of the fistula with Betadine.

An infant with high anal atresia and transverse colostomy, in whom initial radiologic evaluation of the urinary tract had been normal, developed hyperchloremic metabolic acidosis at 24 days of age. Gastroenteritis and renal tubular acidosis as possible causes for this metabolic disturbance were excluded, which prompted a repeat investigation of the possibility of a communication between the urinary tract and the rectum. A recto-urethral fistula was demonstrated by urethrography. Analysis of the fluid obtained from the left colon as compared to urine in the bladder and voided urine demonstrated that electrolyte exchange was taking place in the colon, resulting in hyperchloremic hypokalemic acidosis. Treatment with oral sodium bicarbonate and daily lavage of the left colon resulted in normalization of the acid-base status and catch-up growth of the baby. Hyperchloremic acidosis associated with anal atresia and recto-urinary communication appears to be uncommon. However, early diagnosis and treatment of the metabolic derangement are of importance as it may determine the infant's overall prognosis.