Immune response to systemic inflammation in the intestinal microcirculation.

Systemic inflammation is characterized by acute or chronic dysregulation of the host immune response. The intestine plays an important role in systemic inflammation. Disturbances in the intestinal microcirculation due to infiltration of immune cells during systemic inflammation can increase bacterial translocation from the gut to the circulation and aggravate the pathological condition. Therefore, the intestinal microcirculation is relevant with respect to two aspects - as pathophysiological trigger and therapeutic target in systemic inflammation. Experimental intravital microscopy represents a unique method to study the immune response in organs and tissues in vivo. Novel non-invasive imaging technologies facilitate the examination of the human microcirculation. Future developments are needed to miniaturize the imaging technologies and automate the time-consuming analyses of the in vivo data in order to make the intestinal microcirculation accessible for routine diagnostics and therapeutic monitoring.

Anti-inflammatory effects of a novel iron chelator, DIBI, in experimental sepsis.

BACKGROUND: Iron catalyzes the generation of reactive oxygen species (ROS) as part of the innate antimicrobial defense. During sepsis, the dysregulated systemic inflammatory response to infection, iron homeostasis becomes disrupted, generating an excess of ROS causing damage to tissues. This can be potentially suppressed using iron chelators that selectively bind iron to prevent its participation in ROS-related inflammatory reactions. OBJECTIVE: We hypothesize that administration of DIBI, a novel iron-chelator, attenuates the dysregulated systemic immune response and reduces tissue damage in experimental endotoxemia. METHODS: Five groups of animals (n = 5-10) were included in this study: control, untreated endotoxemia, and endotoxemia animals treated with either DIBI-A, MAHMP, or DIBI-B. Intravital microscopy was performed on the intestine of anesthesized mice to observe leukocyte endothelial interactions and evaluate the intestinal microcirculation. RESULTS: Treatment of endotoxemic mice with DIBI-B reduced the number of adhering leukocytes in submucosal collecting (V1) venules by 68%. DIBI-B, MAHMP, and DIBI-A were able to restore functional capillary density (FCD) in the intestinal muscle layer by 74%, 44%, and 11%, respectively. CONCLUSIONS: DIBI-B reduces leukocyte recruitment and improves FCD in experimental endotoxemia, outperforming other chelators tested. These findings suggest a potential role for DIBI-B as a candidate drug for sepsis treatment.

What false-negative rates of non-invasive testing are active surveillance patients and uro-oncologists willing to accept in order to avoid prostate biopsy?

INTRODUCTION: Repeat prostate biopsies in active surveillance patients are associated with significant complications. Novel imaging and blood/urine-based non-invasive tests are being developed to better predict disease grade and volume progression. We conducted a theoretical study to determine what test performance characteristics and costs would a non-invasive test(s) require in order for patients and their physicians to comfortably avoid biopsy. METHODS: Surveys were administered to two populations to determine an acceptable false-negative rate and cost for such test(s). Active surveillance patients were recruited at time of followup in clinic at Princess Margaret Cancer Centre. Physician members of the Society of Urological Oncology were targeted via an online survey. Participants were questioned about their demographics and other characteristics that might influence chosen error rates and cost. RESULTS: 136 patients and 670 physicians were surveyed, with 130 (95.6%) and 104 (15.5%) responses obtained, respectively. A vast majority of patients (90.6%) were comfortable with a non-invasive test(s) in place of biopsy, with 64.8% accepting a false-negative rate of 5-20%. Most physicians (93.3%) were comfortable with a non-invasive test, with 77.9% accepting a rate of 5-20%. Most patients and physicians felt that a cost of less than $1000 per administration would be reasonable. CONCLUSIONS: Most patients/physicians are comfortable with a non-invasive test(s). Although a 5% error rate seems acceptable to many, a substantial subset feels that 99% or higher negative predictive value is required. Thus, a personalized approach with shared decision-making between patients and physicians is essential to optimize patient care in such situations.