The Chemotactic Response of Human Granulocytes to Clostridium difficile Toxin A is Age Dependent

Elderly patients are at high risk for developing diarrhea and colitis as a complication of antimicrobial therapy. Clostridium difficile, the causative agent of antibiotic-associated diarrhea and colitis produces an enterotoxin (toxin A) and a cytotoxin (toxin B). Of these two exotoxins, toxin A appears to be largely responsible for the inflammatory phenomena of C. difficile colitis, because it produces secretion, pronounced granulocytic infiltration, and epithelial cell necrosis and ulceration in ligated ileal loops of experimental animals. We have recently demonstrated that the inflammatory effects of C. difficile toxin A in the intestine may be related to its ability to mobilize intracellular calcium and elicit a chemotactic response by human granulocytes. In this study, in order to explain why the elderly are at greater risk for developing antibiotic-associated colitis, we investigated the effects of toxin A on activation of granulocytes from healthy elderly and young subjects. Highly purified toxin A and the chemotactic factor N-formyl-Met-Leu-Phe (FMLP) at concentrations of 10(-7) M both elicited a significant (p less than 0.001) and comparable chemotactic and chemokinetic response in human granulocytes from both age groups. A significantly (p less than 0.001) increased chemotactic effect in elderly subjects compared with young subjects was elicited by toxin A and not by FMLP. These findings suggest that the enhanced intestinal inflammatory effects of C. difficile in the elderly, compared with the young, may be related to the ability of its enterotoxin to elicit a more pronounced chemotactic response by granulocytes.     

Clostridium difficile toxin A triggers human colonocyte IL-8 release via mitochondrial oxygen radical generation

BACKGROUND & AIMS: Clostridium difficile toxin A causes mitochondrial dysfunction resulting in generation of oxygen radicals and adenosine triphosphate (ATP) depletion. We investigated whether mitochondrial dysfunction is involved in nuclear factor kappaB (NF-kappaB) activation and interleukin (IL)-8 release from toxin A-exposed enterocytes. METHODS: NF-kappaB activation and IL-8 release in response to toxin A were correlated with reactive oxygen intermediate (ROI) generation and ATP production in HT-29 monolayers or HT-29 cells exposed to ethidium bromide (EB) to inhibit mitochondrial function. RESULTS: HT-29 cells exposed to EB showed damaged mitochondria and diminished resting levels of ATP. ROI production in EB-treated cells exposed to toxin A for 30 minutes was significantly reduced. Exposure of wild-type HT-29 cells to toxin A resulted in increased oxygen radical generation and IL-8 production (P < 0.01 vs. control) that was inhibited by antioxidant pretreatment. Degradation of IkappaB was observed within 30 minutes of toxin exposure, before ras homologue (Rho) glucosylation, and was followed by nuclear translocation of NF-kappaB. Toxin A did not increase IL-8 levels in EB-treated cells, whereas IL-8 release in response to IL-1beta was not affected. CONCLUSIONS: Our data support an early role for mitochondria-derived ROIs in stimulation of IL-8 release from colonocytes by toxin A. ROI generation is independent of Rho inactivation and involves nuclear translocation of NF-kappaB before release of IL-8.     

Leiomyosarcomas of the oral tissues: clinicopathologic analysis of 50 cases.

PURPOSE: Primary oral leiomyosarcomas are rare tumors. Information regarding the biological behavior, prognosis, and appropriate management of this neoplasm is lacking in the literature. The purpose of this report was to summarize the data of isolated case reports of primary oral leiomyosarcoma that have been published in the English literature during the past 25 years. The cases of 4 additional new patients who have been treated in our department during the past 10 years are also presented. PATIENTS AND METHODS: The data for 46 patients obtained from 32 individual articles retrieved from the English literature were added to our 4 cases and produced a total number of 50 cases of primary leiomyosarcomas of the oral tissues. Patients were analyzed according to demographic data, anatomic location, type of treatment, and survival. RESULTS: Primary oral leiomyosarcoma may affect any age with peaks of occurrence in the third, sixth, and seventh decades of life. There is no gender predilection. Female patients presented the higher incidence in the third decade, whereas males had an even age distribution. The tumor arises in approximately 70% of the cases in the maxillary and mandibular bones. Radical surgery was the treatment of choice. Radiotherapy and chemotherapy when applied in recurrent tumors had little effect. The most adverse prognostic factor was the positive surgical margins. The 5-year survival was 62% (62.9% for females and 52.6% for males, P > .1968). CONCLUSIONS: Cases of oral leiomyosarcoma appear to be associated with major neurovascular structures of the facial skeleton, as evidenced from the imaging studies of our 4 patients. Primary oral leiomyosarcoma is a rare tumor that should be managed with aggressive surgical resection in order to safeguard curability. Histopathologic diagnosis is greatly facilitated with positive immunohistochemical staining for smooth muscle antigenic markers.     

Recent advances in Saccharomyces boulardii research

This review summarizes the probiotic mechanisms of action of Saccharomyces boulardii (S. boulardii) against inflammatory and non-inflammatory diarrheal conditions. S. boulardii is distributed in lyophilized form in many countries and used for the prevention of diarrhea in children and adults, including Clostridium difficile (C. difficile) associated infection. The main mechanisms of action of S. boulardii include inhibition of activities of bacterial pathogenic products, trophic effects on the intestinal mucosa, as well as modification of host signaling pathways involved in inflammatory and non-inflammatory intestinal diseases. S. boulardii inhibits production of pro-inflammatory cytokines by inhibiting main regulators of inflammation, including nuclear factor κB (NF-κB), and mitogen-activated protein kinases (MAP kinases), ERK1/2 and p38, but stimulates production of anti-inflammatory molecules such as peroxisome proliferator-activated receptor-gamma (PPAR-γ). Moreover, S. boulardii suppresses bacterial infection by inhibiting adhesion and/or overgrowth of bacteria, produces a serine protease that cleaves C. difficile toxin A, and stimulates antibody production against this toxin. Furthermore, S. boulardii may interfere with pathogenesis of Inflammatory Bowel Disease (IBD) by acting on T cells and acts in diarrheal conditions by improving the fecal biostructure in patients with diarrhea. These diverse mechanisms exerted by S. boulardii provide molecular clues for its effectiveness in diarrheal diseases and intestinal inflammatory conditions with an inflammatory component.     

Longterm persistence and nonrecurrence of depression treatment in Germany: a four‐year retrospective follow‐up using linked claims data

Objectives

To measure persistence and nonrecurrence of depression treatment and investigate potential risk factors.

Methods

We retrospectively observed a closed cohort of insurees with new‐onset depression treatment in 2007 and without most psychiatric comorbidity for 16 quarters (plus one to ascertain discontinuation). We linked inpatient/outpatient/drug‐data per person and quarter. Person‐quarters containing specified depression services were classified as depression‐treatment‐person‐quarters (DTPQ). We defined longterm‐DTPQ‐persistence as 16 + 1 continuous DTPQ and longterm‐DTPQ‐nonrecurrence as 12 continuous quarters without DTPQ and used multivariate logistic regression to explore associations with these outcomes.

Results

Within first 16 quarters, 28,348 patients' first period (total time) persisted for a mean/median 5.4/3 (8.7/8) quarters. Fourteen percent had longterm‐DTPQ‐persistence, associated (p < .05) with baseline hospital (odds ratio, OR = 1.80), psychotherapy/specialist‐interview and antidepressants (OR = 1.81), age (years, OR = 1.03), unemployment (OR = 1.21), retirement (OR = 1.31), and insured as a dependent (OR = 1.32). Thirty‐four percent had longterm‐DTPQ‐nonrecurrence, associated with psychotherapy/specialist‐interview (OR = 1.40), antidepressants (OR = 0.54), female sex (OR = 0.84), age (years, OR = 0.99), retirement (OR = 1.18), and insured as a dependent (OR = 0.88). Women differed for episodic and not chronic treatment.

Conclusion

Treatment measures compared to survey's symptoms measures. We suggest further research on “treatment‐free‐time.” Antidepressants(?) and psychotherapy/specialist‐interview(+) were significantly associated with longterm‐DTPQ‐nonrecurrence. This was presumably moderated by possible short‐time/low‐dosage antidepressants use(?) and selective therapy assignment(+). Sample selectivity limited data misclassification.