Apoptosis is induced in Chlamydia trachomatis-infected HEp-2 cells by the addition of a combination innate immune activation compounds and the inhibitor wedelolactone

Citation Huston WM, Gloeckl S, de Boer L, Beagley KW, Timms P. Apoptosis is induced in Chlamydia trachomatis‐infected HEp‐2 cells by the addition of a combination innate immune activation compounds and the inhibitor wedelolactone. Am J Reprod Immunol 2011; 65: 460–465 Problem Innate immune activation of human cells, for some intracellular pathogens, is advantageous for vacuole morphology and pathogenic viability. It is unknown whether innate immune activation is advantageous to Chlamydia trachomatis viability. Method of study Innate immune activation of HEp‐2 cells during Chlamydia infection was conducted using lipopolysaccharide (LPS), polyI:C, and wedelolactone (innate immune inhibitor) to investigate the impact of these conditions on viability of Chlamydia. Results The addition of LPS and polyI:C to stimulate activation of the two distinct innate immune pathways (nuclear factor kappa beta and interferon regulatory factor) had no impact on the viability of Chlamydia. However, when compounds targeting either pathway were added in combination with the specific innate immune inhibitor (wedelolactone) a major impact on Chlamydia viability was observed. This impact was found to be due to the induction of apoptosis of the HEp‐2 cells under these conditions. Conclusion This is the first time that induction of apoptosis has been reported in C. trachomatis‐infected cells when treated with a combination of innate immune activators and wedelolactone.     

Total skin electron radiation in the management of mycosis fungoides: Consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group

Radiotherapy has been successfully implemented in the treatment of mycosis fungoides (MF) for almost a century. With the development of the modern linear accelerator, it has become possible to treat extended areas of the skin with accelerated electrons. Total skin electron beam radiation (TSEB) has been in use for several decades, and a number of technical modifications have been made with the goals of optimizing dose distribution and improving clinical outcome. Emerging evidence from recent studies suggests an association between TSEB techniques and efficacy in the treatment of MF. Based on this evidence, the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group, in association with experts from radiotherapy centers in North America, has reached a consensus on acceptable methods and clinical indications for TSEB in the treatment of MF. The aims of this report are to enhance accessibility of this highly efficacious treatment modality to patients with MF and to provide a point of reference for further clinical research.     

Psychotherapie und Gesellschaft/en

Psychotherapie Forum -     

Embolization treatment of bleeding complications in pancreatitis

Pseudoaneurysm following chronic pancreatitis is a severe complication that can lead to massive gastrointestinal bleeding. Surgical treatment means high risk for the patient. We report on two patients in whom the bleeding was managed by percutaneous transvascular embolization, a relatively non-invasive and successful method with low risk. The goal was either the definitive arrest of bleeding or stabilization of the patient to enable a surgical procedure. Embolization coils are the material most utilized for vessel occlusion. In patients with bleeding complication following pancreatitis, if sonography or computed tomography demonstrates a pseudoaneurysm, we recommend angiographic visualization and immediate subsequent embolization. Received for publication on Jan. 26, 1998; accepted on Feb. 23, 1998     

Combination treatment of cis- and carboplatin in cancers restricted to the peritoneal cavity in the rat

In the present study, cisplatin (cDDP) and carboplatin (CBDCA) were combined in different in vitro and in vivo assays to determine whether combined cDDP and CBDCA treatment would eventually lead to a better antitumor response. Co-incubation of CC531 cells with cDDP and CBDCA led to higher intracellular Pt concentrations (30.5±3.4 ng Pt/10⁶ cells) than did cDDP (16.9±9.4 ng Pt/10⁶ cells) or CBDCA (1.28±0.72 ng Pt/10⁶ cells) incubation alone. In survival assays an additive cell kill was seen after combined treatment with cDDP and CBDCA. DNA binding experiments using isolated salmon-sperm DNA exposed to the drugs separately or in combination were in agreement with the survival studies (for cDDP a binding of 12.42 g Pt/mg DNA; for CBDCA, 0.49 g Pt/mg DNA at 76 h). Toxicity studies in rats treated with cDDP plus CBDCA required a dose reduction for cDDP amounting to 20% of the MTD, whereas the CBDCA dose could be maintained. Pharmacokinetics studies showed higher AUCs andt _1/2 in plasma as well as the peritoneal cavity after combined treatment with cDDP and CBDCA (both given i.p.) or following cDDP given i.p. and CBDCA given i.v. Pt concentrations in peritoneal tumors corresponded with these observations, with higher Pt concentrations following combined treatment than after single-agent injection. In addition, combined adminstration of cDDP i.p. and CBDCA i.v. led to higher Pt concentrations in peritoneal tumors than did administration of both drugs i.p. (3.93±0.9 vs 2.76±0.2 mg Pt/g tissue). The higher Pt concentrations in the peritoneal tumors after combined treatment was associated with a significantly better antitumor response in comparison with that observed after single-agent treatment (a growth delay of 30.2±5.6 days for cDDP i.p. plus CBDCA i.v. vs 16.1±5.4 days for cDDP alone and 10.8±4.2 days for CBDCA alone).     

Gender: Diskurse und Perspektiven für die Psychotherapie

Psychotherapie Forum -     

Depressive and anxiety disorders and the association with obesity,physical, and social activities

Objective: There is evidence of more obesity among persons with depressive and depressive and anxiety disorders. However, the nature and the underlying mechanisms of the association are still unclear. This study examines the association between depressive and anxiety disorders and obesity, physical activity, and social activity, and examines whether social and physical activity are potential influencing factors in the association between depressive and anxiety disorders and obesity. Method: Cross‐sectional data were used from the Netherlands Study of Depression and Anxiety. A total of 1,854 women and 955 men aged 18–65 years were recruited from the community, general practices, and specialized mental health care. Depressive and anxiety disorders were determined with the Composite International Diagnostic Interview. Body mass index (BMI<30 kg/m²) was used to determine obesity. Physical and social activities were measured by self‐report. Results: The odds of obesity adjusted for covariates was significantly higher among those with a current pure Major Depressive Disorder (MDD;odds ratio [OR] OR:1.43; 95% CI:1.07–1.92) compared to controls. Physical activity and social activities were lower among persons with depressive and anxiety disorders compared to controls. The association between MDD and obesity was influenced by social and physical activities. Conclusion: This study confirmed a link between depressive disorders and obesity that was influenced by lower social and physical activities among the depressed. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease

Amyloid fibrils composed of peptides as short as six amino acids are therapeutic in experimental autoimmune encephalomyelitis (EAE), reducing paralysis and inflammation, while inducing several pathways of immune suppression. Intraperitoneal injection of fibrils selectively activates B-1a lymphocytes and two populations of resident macrophages (MΦs), increasing IL-10 production, and triggering their exodus from the peritoneum. The importance of IL-10–producing B-1a cells in this effective therapy was established in loss-of-function experiments where neither B-cell–deficient (μMT) nor IL10^−/− mice with EAE responded to the fibrils. In gain-of-function experiments, B-1a cells, adoptively transferred to μMT mice with EAE, restored their therapeutic efficacy when Amylin 28–33 was administered. Stimulation of adoptively transferred bioluminescent MΦs and B-1a cells by amyloid fibrils resulted in rapid (within 60 min of injection) trafficking of both cell types to draining lymph nodes. Analysis of gene expression indicated that the fibrils activated the CD40/B-cell receptor pathway in B-1a cells and induced a set of immune-suppressive cell-surface proteins, including BTLA, IRF4, and Siglec G. Collectively, these data indicate that the fibrils activate B-1a cells and F4/80⁺ MΦs, resulting in their migration to the lymph nodes, where IL-10 and cell-surface receptors associated with immune-suppression limit antigen presentation and T-cell activation. These mechanisms culminate in reduction of paralytic signs of EAE.Amyloid fibrils, composed of hexapeptides, when injected into the peritoneum of mice stimulate an immune-suppressive response of sufficient magnitude to reduce the paralytic signs of experimental autoimmune encephalomyelitis (EAE) (1, 2). Analysis of the differential gene-expression pattern in peripheral blood mononuclear cells revealed the amyloidogenic peptides (e.g., Tau 623–628) induced a type 1 interferon (IFN) response. Plasmacytoid dendritic cells were the source of type 1 IFN, which was induced by NETosis arising from neutrophil endocytosis of the amyloid fibrils. Production of the type 1 IFN was therapeutic in Th1-induced adoptive transfer EAE, but exacerbated the paralytic signs of Th17-induced disease, consistent with experiments by Axtell et al. (3). However, not all amyloidogenic peptides induced equivalent amounts of type 1 IFN. The induction of type 1 IFN appeared to correlate with the amount of fibril formation as measured by thioflavin T. A set of peptides with a polar fibril interface (e.g., Amylin 28–33) did not form measurable amounts of fibrils in physiological buffers, induced minimal amounts of type 1 IFN, but nevertheless were therapeutic, reducing IFN-γ, TNF-α, and IL-6 production by peripheral blood mononuclear cells, and thus providing evidence of a second immune-suppressive pathway (2). Further proof of the importance of this second immune-suppressive pathway was the ability of amyloidogenic peptides to be therapeutic in IFN-α/βR^−/− animals with EAE (2).To better define this second immune-suppressive pathway, the induced effects of the amyloid fibrils at the site of injection in the peritoneum were investigated. The peritoneal cavity contains a variety of specialized cells, including two types of resident macrophages (MΦs), large peritoneal MΦs (LPM) (CD11b^hiF4/80^hiMHC-II^–) and small peritoneal MΦs (SPM) (CD11b⁺F4/80^loMHC-II^hi), B-1a lymphocytes (CD19^hiCD5⁺CD23^–), and more common components of blood, including the B-2 lymphocytes (CD19⁺CD5^–CD23⁺), T lymphocytes, mast cells, neutrophils, eosinophils, and NK cells (4). The LPMs (F4/80^hi) are more prevalent than the SPMs (MHC-II^hi), representing ∼90% of peritoneal MΦs. The B-1a and MΦs (LPM+SPM) each comprise ∼30% of the total peritoneal cells (4). Several groups have established that B-1a lymphocytes are distinguishable from the more plentiful B-2 lymphocytes and are enriched in body cavities (5). The chemokines and integrins, which are responsible for B-1a localization to the peritoneal cavity and their exodus when activated, have also been defined (6, 7). The B-1a cell population is notable for its constitutive expression of IL-10 (8-10), a well-established immune-suppressive cytokine. IL-10–producing B cells, B10 cells, were shown initially by Janeway and colleagues to be necessary for the recovery from the signs of EAE (11) and were demonstrated subsequently to be immune-suppressive in animal models of multiple sclerosis (12, 13), inflammatory bowel disease (14), collagen-induced arthritis (15), lupus (16), stroke (17), insulin resistance (18), and allergic airway disease (19). The B10 cells in many of these studies were isolated from the spleen and not the peritoneal cavity, but several authors have argued the similarity of the cell types. Although not identical, the different cells appear to be physiologically similar (20–22).Maximal immune suppression by B10 cells is observed after the cells are activated through Toll-like receptor (TLR) (12, 23), CD40 (16), or IL-21 ligation (24), all of which induce both an increase in IL-10 production and an egress of the cells from the peritoneum into secondary lymph organs (21, 25). Reduction of symptoms in each of the inflammatory autoimmune diseases correlated with reduction of TNF-α, IL-6, and IFN-γ, a pattern similar to that seen with the administration of the amyloidogenic peptides.