HIV/AIDS-related stigma felt by people living with HIV from Buea, Cameroon.

The universal access to treatment and care for people living with HIV (PLWHIV) is a major problem especially in Sub-Saharan Africa, where the majority of HIV infected people live. However, equally important is the fact that HIV/AIDS-related stigma is recognized to be a major obstacle to successfully control the spread of this disease. In this study we measured the HIV/AIDS-related stigma felt by PLWHIV in Cameroon using "The people living with HIV stigma index" questionnaire developed by UNAIDS, International Planned Parenthood Federation and Global Network of PLWHIV/AIDS among others. A total of 200 questionnaires were anonymously administered to PLWHIV in the HIV/AIDS treatment center of the Regional Hospital Annex Buea in the South West Region of Cameroon by trained academics who were themselves PLWHIV. In this setting the major problems faced by the PLWHIV with regard to stigmatization and discrimination were gossiping and verbal insults, which was felt by about half of the interviewees. Equally important was internal stigma, half of the PLWHIV felt ashamed and guilty to be HIV infected. This is the first report of this kind in Cameroon. These results will help to better understand HIV/AIDS-related stigma in this setting and in turn will improve the quality of life of PLWHIV by promoting their acceptance by the community.

Escherichia coli Nissle 1917 (Mutaflor): new insights into an old probiotic bacterium.

Probiotic bacteria are live microorganisms which contribute health benefits to their host. The numerous mechanisms of the probiotic-acting microorganisms include the induction of expression of certain cytokines and increasing the secretion of IgA and mucin. They activate lymphocytes and macrophages and inhibit the adhesion and invasion of epithelial cells. Escherichia coli Nissle 1917 (Mutaflor) is one of the most investigated probiotic bacteria. While the number of reports discussing the underlying mechanisms of Mutaflor has increased rapidly in recent years, novel clinical studies are missing. Here we provide an overview of the mechanisms of action and clinical studies related to Mutaflor. While most of the studies had positive outcomes, there are also a few in which Mutaflor did not perform to its expectations.

Effects of bacterial N-acyl homoserine lactones on human Jurkat T lymphocytes-OdDHL induces apoptosis via the mitochondrial pathway.

Diverse Gram-negative bacteria communicate with each other by using diffusible N-acyl-homoserine lactone (AHL) signaling molecules to coordinate gene expression with cell population density. This mechanism termed 'quorum sensing' is involved in the regulation of physiological functions as well as multiple virulence determinants. It becomes more and more evident, that bacteria communicate not only with each other but also with their host. Up to now, little is known about this interkingdom communication. The AHL quorum sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) from Pseudomonas aeruginosa has been shown to influence the immune system of the host. The role and potential influence of other AHL molecules from other bacteria have so far not been determined. In this paper, we investigated the role of 7 different AHLs on apoptosis of human Jurkat T lymphocytes. We found, that among all homoserine lactones tested, only OdDHL rapidly induced apoptosis which was accompanied by the breakdown of the mitochondrial transmembrane potential (DeltaPsi(m)). Since overexpression of anti-apoptotic Bcl-2 completely abrogated the apoptotic effect, we presume that OdDHL induces apoptosis by activation of the intrinsic mitochondrial apoptosis pathway. The reason that bacteria induce apoptosis is largely unknown. We suspect that through apoptosis an anti-inflammatory response is triggered.

Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial.

BACKGROUND: The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. METHODS: In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. RESULTS: Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. CONCLUSION: Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. TRIAL REGISTRATION: ISRCTN66478538.

First surgical tumour reduction of peritoneal surface malignancy in a rat's model.

Surgical therapy of peritoneal surface malignancy from colorectal origin in combination with Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) has now become an established treatment approach in very few specialised centres. A peritonectomy procedure is possible to perform with additional HIPEC in patients. An experimental model to simulate peritonectomy procedure and HIPEC does not exist so far in rats. Nevertheless, animal models seem to be very important for evaluation of new therapeutic opportunities and toxicity of different multimodal therapies. In a first step we analysed the surgical tumour debulking of peritoneal surface malignancy in rats. A peritoneal surface malignancy from colonic origin was induced in 75 male BD IX rats. Twenty one days after induction of peritoneal surface malignancy rats were randomised and animals intend to create an operation with surgical tumour debulking. There was no tumour growth in two animals. The aim of the peritonectomy procedure was the complete tumour reduction. In this study the results of the surgical approach will be described. A complete tumour reduction (R0) was achieved in 34 animals. In 39 rats a macroscopic tumour deposit was left behind (R2). The intraoperative experimental Peritoneal Cancer Index (ePCI) was used to describe tumour weight and number of tumour inoculations. Both parameters were found to be dependent factors of complete tumour reduction. Six animals died due to therapeutical interventions. Surgical tumour debulking in rats with peritoneal surface malignancy is possible with high reliability and a low mortality rate. This animal model could be an important step for investigation of multimodal treatment options and toxicity in treatment regimens of peritoneal surface malignancy.

Novel anti-angiogenic compounds for application in tumor therapy - COP9 signalosome-associated kinases as possible targets.

Preclinical studies revealed that curcumin, the yellow curry pigment, emodin, a compound derived from grapes, and taurolidine, derived from a biogenic amino acid, and some of their structural homologs possess anti-angiogenic and cancer chemopreventive properties. Whereas curcumin and emodin can act via inhibition of COP9 signalosome-associated kinases, taurolidine blocks protein biosynthesis.

Surgical treatment of gastroesophageal reflux disease and upside-down stomach using the Da Vinci robotic system. A prospective study.

So far, the impact of telematic surgical approach in Gastroesophageal Reflux Disease (GERD) is still obscure. In this prospective study, we analyzed the Da Vinci Intuitive Surgical robotic system for antireflux surgery. In April 2003, we set up a pilot study to evaluate the efficacy of laparoscopic telerobotic surgery using the three-arm Da Vinci system. Optimal trocar positions, operating and setup times, conversion rate, intraoperative complications, and perioperative morbidity, as well as mortality rate, were analyzed. The median age was 53 years (range 25-74) in 118 patients (52 female/66 male). In 17 patients, an upside-down stomach- and in 101 GERD was surgical indication. The median operating time has been reduced from 105 min to 91 min after 40 procedures and setup time from 24.5 min to 10.4 min after 10 procedures. The system is safe and it seems to be superior to traditional laparoscopy during dissection in the esophageal hiatus region. This compensates long setup- and operating times. Disadvantages are the high costs, the time to master the setup/system and the necessity of exact trocar positioning.

Robotic-assisted laparoscopic and thoracoscopic surgery with the da Vinci system: a 4-year experience in a single institution.

PURPOSE: We set up a pilot study to evaluate the efficacy of telerobotic surgery using the da Vinci system for several procedures for which traditional laparoscopy (or thoracoscopy) is a standard approach in a single institution. METHODS: We performed fundoplications (hiatal hernia repair and antireflux surgery, n=112), upside-down stomach (14), cholecystectomy (16), gastric banding (3), colectomy (5), esophagectomy (4), sub/total gastrectomy (2), gastrojejunostomy (2), along with thymectomy (100), thoracic symatectomy (11), lobectomy (5), mediastinal parathyroidectomy (5), and left pancreatic resection (1). RESULTS: The median set up time for all procedures was reduced from 25.0 to 10.4 minutes. Conversion to traditional laparoscopy or thoracoscopy occurred in 12 cases and in open surgery in 11 cases. There was no morbidity related to the telerobotic system. CONCLUSIONS: Robotically assisted laparoscopic and thoracoscopic surgery is feasible and safe for a variety of procedures in general, visceral, and thoracic surgery.

Noninvasive monitoring of myocardial function after surgical and cytostatic therapy in a peritoneal metastasis rat model: assessment with tissue Doppler and non-Doppler 2D strain echocardiography.

OBJECTIVE: We sought to evaluate the impact of different antineoplastic treatment methods on systolic and diastolic myocardial function, and the feasibility estimation of regional deformation parameters with non-Doppler 2D echocardiography in rats. BACKGROUND: The optimal method for quantitative assessment of global and regional ventricular function in rats and the impact of complex oncological multimodal therapy on left- and right-ventricular function in rats remains unclear. METHODS: 90 rats after subperitoneal implantation of syngenetic colonic carcinoma cells underwent different onclogical treatment methods and were diveded into one control group and five treatment groups (with 15 rats in each group): group 1 = control group (without operation and without medication), group 2 = operation group without additional therapy, group 3 = combination of operation and photodynamic therapy, group 4 = operation in combination with hyperthermic intraoperative peritoneal chemotherapy with mitomycine, and group 5 = operation in combination with hyperthermic intraoperative peritoneal chemotherapy with gemcitabine, group 6 = operation in combination with taurolidin i.p. instillation. Echocardiographic examination with estimation of wall thickness, diameters, left ventricular fractional shortening, ejection fraction, early and late diastolic transmitral and myocardial velocities, radial and circumferential strain were performed 3-4 days after therapy. RESULTS: There was an increase of LVEDD and LVESD in all groups after the follow-up period (P = 0.0037). Other LV dimensions, FS and EF as well as diastolic mitral filling parameters measured by echocardiography were not significantly affected by the different treatments. Values for right ventricular dimensions and function remained unchanged, whereas circumferential 2D strain of the inferior wall was slightly, but significantly reduced under the treatment (-18.1 +/- 2.5 before and -16.2 +/- 2.9 % after treatment; P = 0.001) without differences between the single treatment groups. CONCLUSION: It is feasible to assess dimensions, global function, and regional contractility with echocardiography in rats under different oncological therapy. The deformation was decreased under overall treatment without influence by one specific therapy. Therefore, deformation assessment with non-Doppler 2D strain echocardiography is more sensitive than conventional echocardiography for assessing myocardial dysfunction in rats under oncological treatment.

Retroperitoneal Castleman's tumor and paraneoplastic pemphigus: report of a case and review of the literature.

BACKGROUND: Castleman's disease is a rare lymphoproliferative syndrome. Its etiology and pathogenesis are unclear. The disease can be occasionally associated with a paraneoplastic pemphigus (PNP), an autoimmune mucocutaneous disorder commonly seen in neoplasms of lymphocytic origin. CASE PRESENTATION: We present a case of a 63-year old male patient who was referred for surgical treatment of a lately diagnosed retroperitoneal pelvic mass. The patient had been already treated for two years due to progressive diffuse cutaneous lesions histologically consistent with lichen ruber verucosus and pemphigus vulgaris. Intraoperatively a highly vascularized solid mass occupying the small pelvis was resected after meticulous vascular ligation and hemostasis. After surgery and following immunosuppressive treatment a clear remission of the skin lesions was observed. CONCLUSION: Castleman's tumor should be always suspected when a retroperitoneal mass is combined with PNP. In a review of the literature we found 37 additional cases. Complete surgical resection of the tumor can be curative in most of the cases.

Prevention of disease progression in a patient with a gastric cancer-re-recurrence. Outcome after intravenous treatment with the novel antineoplastic agent taurolidine. Report of a case.

BACKGROUND: Taurolidine (TRD) is a novel agent with multimodal antineoplastic effects. We present the case of a tumor remission after intravenous administration of taurolidine in a patient with gastric cancer re-recurrence. CASE PRESENTATION: A 58 years old male patient suffering from a gastric adenocarcinoma was submitted to partial gastrectomy and partial liver resection (pT2, pN1, pM1L (liver segment 2), N0, V0). 24 months later a local recurrence was diagnosed and the patient was reoperated. Postoperatively the patient underwent a palliative chemotherapy with eloxatin, FU, and leucovorin. A subsequent CT-revealed a liver metastasis and a recurrence adjacent to the hepatic artery. After successful radiofrequency ablation of the liver metastasis the patient was intravenously treated with 2% taurolidine. The patient endured the therapy well and no toxicity was observed. CT-scans revealed a stable disease without a tumor progression or metastatic spread. After 39 cycles the patient was submitted to left nephrectomy due to primary urothelial carcinoma and died 2 days later due to myocardial infarction. Postmortem histology of the esophageal-jejunal anastomosis and liver revealed complete remission of the known metastasized gastric adenocarcinoma. CONCLUSION: The intravenous treatment with 2% taurolidine led to a histological remission of the tumor growth without any toxicity for the patient.

Effects of increasing doses of a bolus injection and an intravenous long-term therapy of taurolidine on subcutaneous (metastatic) tumor growth in rats.

BACKGROUND: Experimental studies have shown that taurolidine suppresses intraperitoneal tumor growth following local application in rats. In opposite, a single intravenous therapy affected neither intraperitoneal nor subcutaneous growth of malignancies. Thus, an intravenous long-term therapy with taurolidine was investigated in rats after administration of a subcutaneous tumor load. VEGF and TNFalpha production and their effects on tumor growth have not been elucidated so far. METHODS: VEGF and TNFalpha levels of rat colon adenocarcinoma cells (DHD/K12/TRb) were analyzed in the supernatant undergoing treatment of increasing taurolidine doses in vitro. Besides the cell experiments rats were treated intravenously. At the beginning of the operation, 10 000 colon adenocarcinoma cells were applied subcutaneously at the back of the rats. Then the animals (n = 80, BD IX rats) were randomized into eight groups and underwent a standardized midline laparotomy for 30 min. At the end of the operation the animals were given either a bolus (1 ml Ringer's solution) or a long-term intravenous therapy (7 days, eight-hourly 1 ml 1%, 2%, or 3% taurolidine) were performed. For long-term therapy, a jugularis vein port catheter system was placed and left for 1 week. The influence on subcutaneous tumor growth, animal growth, general side effects and leukocyte/granulocyte levels were analyzed. Total tumor weights were determined 4 weeks after cell application. RESULTS: The VEGF and TNFalpha levels decreased rapidly after taurolidine therapy with low doses in vitro. The subcutaneous tumor growth showed a downtrend of tumor weight (P = 0.075) with a statistical significance in solid tumor counts (P = 0.04) at the back of the animals. A slight and temporary depression in animal growth was observed only in long-term therapy groups. Independent of the therapeutic agents and the application forms, the operation itself caused a slight leukopenia shortly after the operation compensated by a moderate leukocytosis in the following course. Fast injections of taurolidine led to a reduction of breathing rate. CONCLUSIONS: Only the intravenous long-term therapy of 3% taurolidine led to a slight downregulation in subcutaneous tumor growth. The changes of leukocyte counts were not affected by taurolidine. Fast injections have to be avoided. The findings prompted us to start new experiments to determine the influence of increasing doses of taurolidine on progressive tumor growth in rats.

Computer-assisted laparoscopic repair of "upside-down" stomach with the Da Vinci system.

Recently introduced telerobotic surgical systems attempt to elude the inherent limitations of traditional laparoscopic surgery. Four patients (3 male, 1 female) with mixed hiatal and paraesophageal hernias with fixed intrathoracic partial or complete displacement of the stomach were operatively treated using the Da Vinci robotic system. Tissue dissection, hiatoplasty, and anterior hemifundoplication (Dor) were performed with the telerobotic system. There were no surgical complications. The system broke down in the fourth patient due to a software defect. Advantages were seen in terms of the intrathoracic dissection of displaced stomach through a narrow hiatus, intracorporeal suturing due to 6 degrees of freedom plus grasping. At the moment, lack of the appropriate robotic instruments for abdominal surgery as well as the enormous functional cost of the robotic system are considered to be the most significant current impediment to the adoption of robotic abdominal surgery. The continuous evolution and upgrade of the system is quite promising so far. Telerobotic-assisted hiatal hernia operation is feasible with many advantages compared with the traditional laparoscopic approach, especially during the dissection in the mediastinum in patients with intrathoracic stomach. A prospective, randomized trial will be performed later to evaluate the advantages and limitations of robotic compared with traditional laparoscopy. Technological evolution will perhaps diminish the current problems and the cost associated with robotic surgery.

Local and systemic chemotherapy with taurolidine and taurolidine/heparin in colon cancer-bearing rats undergoing laparotomy.

Experimental studies in the therapy of malignant abdominal tumors have shown that different cytotoxic agents suppress the intraperitoneal tumor growth. Nevertheless, a general accepted approach to prevent tumor recurrences does not exist. Following subcutaneous and intraperitoneal injection of 10(4) colon adenocarcinoma cells (DHD/K12/TRb), the influences of both taurolidine or taurolidine/heparin on intraperitoneal and subcutaneous tumor growth was investigated in 105 rats undergoing midline laparotomy. The animals were randomized into 7 groups and operated on during 30 min. To investigate the intraperitoneal (local) influence of either taurolidine or heparin on tumor growth, the substances were applied intraperitoneally. Systemic and intraperitoneal effects were evaluated after intravenous injection of the substances. Both application forms were also combined to analyze synergistic effects. Tumor weights, as well as the incidence of abdominal wound metastases, were determined four weeks after the intervention. In order to evaluate the effects of the agents, blood was taken to determine the peripheral leukocytes counts. Intraperitoneal tumor growth in rats receiving intraperitoneal application of taurolidine (median 7.0 mg, P = 0.05) and of taurolidine/heparin (median 0 mg, P = 0.02) was significantly reduced when compared to the control group (median 185 mg). The simultaneous instillation of both agents also reduced the intraperitoneal tumor growth (median 4 mg, P = 0.04), while the intravenous injection of the substances caused no local effect. In contrast, the subcutaneous tumor growth did not differ among all groups. In all groups, abdominal wound recurrences were rare and did not differ. Independent of the agents and the application form, the operation itself caused a slight leukopenia shortly after the operation and a leukocytosis in the following course. Intraperitoneal therapy of either taurolidine or in combination with heparin inhibits local tumor growth and abdominal wound recurrences in rats undergoing midline laparotomy. Neither the intraperitoneal nor the intravenous application or the combination of the two agents influenced the subcutaneous tumor growth. The substances did not alter the changes of peripheral leukocytes.

Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and attenuates systemic disease sequelae in experimental pancreatitis.

BACKGROUND: The cytokines involved in the systemic inflammatory response in acute pancreatitis (AP) comprise lipid mediators (eg, prostanoids, thromboxanes, leukotrienes) generated from arachidonic acid (AA) and eicosapentaenoic acid (EPA). The AA-derived mediators are generated from omega-6-fatty acid (FA) and have strong proinflammatory effects and the EPA-derived mediators generated from omega-3-fatty acid are less active or even exhibit anti-inflammatory effects. Basic parenteral nutrition delivers omega-6-FA and omega-3-FA at a ratio of approximately 7:1. AIM: To investigate whether altering the FA composition by fish oil supplementation (omega-3-FA) affects cytokine production and the parameters reflecting systemic disease severity in experimental AP. METHODS: Severe AP was induced in 30 rats by standardized intraductal infusion of bile salt and IV cerulein. Six hours after AP induction, rats were randomized to TPN using commercial solutions with identical amounts of glucose, amino acids, and fat but different FA compositions: group 1 received a soybean-based fat solution without additional fish oil and group 2 was supplemented with 0.2 g/kg per day fish oil. TPN was continued for 2 days. Serum concentrations of IL-6 and IL-10 were measured before and after AP induction and at 24 and 48 hours after starting TPN. Routine cardiorespiratory and renal parameters were monitored to assess the systemic response at the organ level. RESULTS: Animals treated with fish oil had significantly higher IL-10 values (at 24 hours, 63 +/- 7 versus 46 +/- 3 pg/mL), produced more urine (28 +/- 0.9 versus 21 +/- 1.6 mL), and had significantly fewer episodes of respiratory dysfunction (defined as a pO2 < 80 mm Hg or pCO2 > 50 mm Hg for >15 minutes; 29% versus 67%) during the observation period. CONCLUSIONS: Altering eicosanoid mediator precursor availability by infusion of (omega-3 fatty acid increases anti-inflammatory cytokines in this model of AP. This together with improved renal and respiratory function suggests that the systemic response to pancreatic injury is attenuated.

Quorum sensing in the probiotic bacterium Escherichia coli Nissle 1917 (Mutaflor) - evidence that furanosyl borate diester (AI-2) is influencing the cytokine expression in the DSS colitis mouse model.

BACKGROUND: "Quorum sensing" (QS) is the phenomenon which allows single bacterial cells to measure the concentration of bacterial signal molecules. Two principle different QS systems are known, the Autoinducer 1 system (AI-1) for the intraspecies communication using different Acyl-homoserine lactones (AHL) and AI-2 for the interspecies communication. Aim of this study was to investigate QS of Escherichia coli Nissle 1917 (Mutaflor). RESULTS: While E. coli Nissle is producing AI-2 in a density dependent manner, no AI-1 was produced. To study the effect of AI-2 in the DSS (dextran sulphate sodium) induced mouse model of acute colitis, we silenced the corresponding gene luxS by intron insertion. The mutant bacterium E. coli Nissle::luxS was equally effective in colonizing the colon and the mutation turned out to be 100% stable during the course of the experiment. Isolating RNA from the colon mucosa and performing semiquantitative RT PCR, we were able to show that the expression of the pro-inflammatory cytokine IFN-y was suppressed in mice being infected with the E. coli Nissle wild type. Mice infected with the E. coli Nissle::luxS mutant showed a suppressed expression of IL-10 compared to uninfected mice, while the expression of the pro-inflammatory cytokines IL-6 and TNF-α was higher in these mice. The expression of mBD-1 was suppressed in mice being infected with the mutant in comparison to the mice not infected or infected with the wild type. No differences were seen in the histological examination of the colon sections in the different groups of mice. CONCLUSIONS: E. coli Nissle is producing AI-2 molecules, which are influencing the expression of cytokines in the mucosa of the colon in the DSS mice. However, if QS has a direct influence on the probiotic properties of E. coli Nissle remains to be elucidated.

Treating critically ill patients with probiotics: Beneficial or dangerous?

Probiotic bacteria are live microorganisms which confer to health benefits of the host. They help to maintain the integrity of the intestinal barrier function by modulating the mucosal and systemic immune response of the host. These bacteria have proven their beneficial effect in several conditions of ulcerative colitis. More recently probiotics/synbiotics have been included in the treatment of critically ill patients. However to date it remains uncertain whether probiotics/synbiotics are beneficial or even dangerous to the clinical outcome of this patient group. This article reviews the current evidence of the use of bacteria in critically ill patients in intensive care settings.

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.

Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis.

Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 DeltainvG mutant lacking a functional type 3 secretion system-1 (DeltainvG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c(+)CX3CR1(+) mucosal DCs. At later stages, the bacteria became associated with other (CD11c(-)CX3CR1(-)) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo.

The tumor suppressive reagent taurolidine inhibits growth of malignant melanoma--a mouse model.

BACKGROUND: The tumor suppressive agent taurolidine (TRD) inhibits tumor growth of more than 30 cell lines in vitro and reduces tumor load in early and advanced stages of neoplastic disease in animals. TRD has been shown to induce apoptosis of melanoma cells in vitro. Therefore, the effects of TRD on disseminated melanoma were evaluated in a mice model. METHODS: After general anesthesia, a midline laparotomy was performed and 1.5 million malignant melanoma cells (B78-D14) were applied in the spleen and 1 million cells at the back (C57BL/6). Animals were randomized and either treated intraperitoneally (i.p., n = 40, 7 days, 12 hourly) or intravenously (i.v., n = 40, 2 days, 12 hourly) with 1%, 2%, or 3% TRD or with Ringer's solution (control group). On day 28, all animals were sacrificed and the total tumor weight and the number of metastatic lesions were determined by two investigators blinded for randomization. RESULTS: The i.p. therapy caused a dose-dependent inhibition of total tumor growth (P = 0.003) and i.p. tumor growth (P = < 0.001), whereas subcutaneous (s.c.) tumor growth was not affected (P = 0.132) compared with the i.p. control group. The i.v. therapy reduced the total tumor growth (P = 0.013) and the s.c. tumor growth (P = 0.016), whereas the i.p. tumor load was not reduced (P = 0.122) compared with the control group. Both i.p. and i.v. therapy with 3% TRD significantly decreased the total number of metastatic lesions. The animal weight was not affected. CONCLUSIONS: The i.p. and i.v. therapies reduce total tumor weight and number of metastatic lesions of disseminated malignant melanoma in a dose-dependent fashion in mice. Our encouraging findings should be further confirmed in clinical studies examining the influence of TRD in patients with disseminated malignant melanoma for whom prognosis still remains dismal.