24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis.

BACKGROUND & AIMS: Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni infection. Based on previously observed substantial anti-fibrotic effects of 24-nor-ursodeoxycholic acid (norUDCA) in Abcb4/Mdr2(-/-) mice with cholestatic liver injury and biliary fibrosis, we hypothesized that norUDCA improves inflammation-driven liver fibrosis in S. mansoni infection. METHODS: Adult NMRI mice were infected with 50 S. mansoni cercariae and after 12 weeks received either norUDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) for 4 weeks. Bile acid effects on liver histology, serum biochemistry, key regulatory cytokines, hepatic hydroxyproline content as well as granuloma formation were compared to naive mice and infected controls. In addition, effects of norUDCA on primary T-cell activation/proliferation and maturation of the antigen-presenting-cells (dendritic cells, macrophages) were determined in vitro. RESULTS: UDCA as well as norUDCA attenuated the inflammatory response in livers of S. mansoni infected mice, but exclusively norUDCA changed cellular composition and reduced size of hepatic granulomas as well as TH2-mediated hepatic fibrosis in vivo. Moreover, norUDCA affected surface expression level of major histocompatibility complex (MHC) class II of macrophages and dendritic cells as well as activation/proliferation of T-lymphocytes in vitro, whereas UDCA had no effect. CONCLUSIONS: This study demonstrates pronounced anti-inflammatory and anti-fibrotic effects of norUDCA compared to UDCA in S. mansoni induced liver injury, and indicates that norUDCA directly represses antigen presentation of antigen presenting cells and subsequent T-cell activation in vitro. Therefore, norUDCA represents a promising drug for the treatment of this important cause of liver fibrosis.

Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice.

UNLABELLED: Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells (DCs) contribute to hepatic stellate cell (HSC) activation and liver fibrosis. We show for the first time that hepatic macrophages enhance myofibroblast survival in a nuclear factor kappa B (NF-κB)-dependent manner and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the NF-κB pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-κB activation in HSCs. Macrophage-induced activation of NF-κB in HSCs in vitro and in vivo was mediated by interleukin (IL)-1 and tumor necrosis factor (TNF). Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSCs in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in coculture experiments and genetic ablation of IL-1 and TNF receptor in vivo. Coculture and in vivo ablation experiments revealed only a minor contribution to NF-κB activation in HSCs by DCs, and no contribution of DCs to liver fibrosis development, respectively. CONCLUSION: Promotion of NF-κB-dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis.

Clinical experiences derived from implementation of an easy to use concept for treatment of wound healing by secondary intention and guidance in selection of appropriate dressings.

The main objective of this case-cohort-type observational study conducted at different Surgical Departments of the Charité-Universitätsmedizin in Berlin was to evaluate the sequential use concept first described by Systagenix Wound Management in 2007. Fifty-two patients with different wound healing by secondary intention were treated for 7 weeks at the Charité-Universitätsmedizin in Berlin. A multidisciplinary team worked together to reach consensus in wound assessment; in classification of infection status according to the criteria described by European Wound Management Association (EWMA); in treatment protocol and on dressings to be used to 'cover' wounds. Before dressing application, all wounds were cleaned from debris. Following the sequential use concept, wounds classified as stages 2 and 3 were dressed with SILVERCEL(®) and TIELLE(®) or TIELLE PLUS(®) to 'clean' the wounds. After 2-3 weeks, treatment was changed to PROMOGRAN PRISMA(®) and TIELLE(®) to 'close and cover' wounds, thus providing optimal wound healing. Wounds classified as non infected were dressed with PROMOGRAN PRISMA(®) and TIELLE(®) during the complete treatment period. Patients were asked to evaluate the treatment using a simplified questionnaire developed at the Charité-Universitätsmedizin in Berlin. Wounds comprised 37 surgical procedures, 8 chronic mixed ulcer, 4 pressure sores, 1 diabetic foot ulcer, 1 venous leg ulcer, and 1 mixed arterial/venous ulcer. At baseline, 12 wounds were classified as stage 3, 38 wounds as stage 2 and 2 wounds as stage 1. After 7 weeks of treatment, all patients showed a positive clinical response to the sequential use treatment. Results of wound size showed a high significant progression of wound healing expressed with a profound reduction of wound area (P in all measurements <0·001, chi-square test) and improved granulation. This study summarises the clinical experiences derived from the evaluation of the sequential use concept in the daily clinical practice of wound treatment. On the basis of the wound healing results, patients' evaluation of treatment and the clinicians' and staff experiences, this concept was implemented at different Surgical Departments of the Charité-Universitätsmedizin in Berlin.

Multimodal perioperative rehabilitation in elective conventional resection of colonic cancer: results from the German Multicenter Quality Assurance Program 'Fast-Track Colon II'.

AIM: Multimodal perioperative rehabilitation in patients undergoing curative conventional colonic resection for cancer has not yet been studied in a multicenter setting. In 2005, a nationwide quality assurance program was initiated in Germany in an unselected patient population. METHODS: The prospective multicenter data collection includes patients from 24 German hospitals. All hospitals had established 'fast-track' rehabilitation as the standard perioperative treatment in elective colonic resection, and all patients entered the registry. RESULTS: 748 of 2,047 fast-track patients (36.5%) underwent open resection of colonic cancer. The median age of the 380 female and 368 male patients was 71 (26-96) years. Compliance was high for epidural analgesia (89%), systemic basic nonopioid analgesia (93%), 'restrictive' intraoperative intravenous fluids (81%), oral feeding (73%) and enforced mobilization (84%) on the day of surgery. Surgical complications were diagnosed in 20%, general morbidity occurred in only 13% of all patients, and 3 patients (0.4%) died in the early postoperative period. Readmission within 30 days of discharge was necessary in 27 patients (4%). CONCLUSIONS: Compliance with fast-track measures was high, and general morbidity was low in a population of patients undergoing multimodal perioperative rehabilitation for conventional colonic cancer resection.

Squamous cell carcinoma arising on a skin graft 64 years after primary injury.

Malignant degeneration of a chronic wound is often described by the term, Marjolin's ulcer. We present a case of a squamous cell carcinoma that developed in a patient 64 years after the initial injury during World War II. Tissue contusion and detachment required repeated surgery and full skin grafting in several hospitals. The patient had a persistent ulcer in the right popliteal region for the last 3 years. Excisional biopsy in our department showed a bifocal low-grade invasive squamous cell carcinoma of the skin. Because of extensive inflammation and previous scar formation it was difficult to determine the status of the surgical margins. Therefore, we proceeded with amputation at the right thigh. Some 6 months after surgery the general condition of the patient remains excellent.

Application of a solid tumor model to evaluate tumor recurrence after an open or laparoscopic rectal resection in rats.

PURPOSE: We used a solid tumor model to evaluate the influence of laparotomy versus laparoscopy on tumor growth after curative resection for rectal cancer in rats. METHODS: Colon tumor cells (DHD/K12/TRb) were administered intraperitoneally in 15 rats, which were used as solid tumor donors. Twenty-one days later, a 20-mg piece was then implanted in the rectal submucosa of the study rats (n=45). Animals were randomized into 3 groups for rectal resection either open or laparoscopic using either carbon dioxide (CO2) or helium for pneumoperitoneum. Autopsy took place 21 days after resection and tumor recurrence was evaluated. RESULTS: Port-site metastasis was observed after laparoscopy with CO2 (1 animal) and helium (1), whereas intraperitoneal tumor growth was detected in 2 and 3 animals of these groups. No tumor recurrence was observed after open surgery. CONCLUSIONS: Our solid tumor model is a novel neoplastic model that might simulate the clinical situation of an upper rectal carcinoma. It might be helpful to develop new protocols in studying solid tumor biology and different surgical procedures for cancer to address problematic issues in oncologic research.