Granulomatous hepatitis, choroiditis and aortoduodenal fistula complicating intravesical Bacillus Calmette-Guérin therapy: Case report.

BACKGROUND: Intravesical instillation of Bacillus Calmette-Guérin (BCG) is the treatment of choice for superficial bladder carcinoma. Complications of BCG therapy include local infections and disseminated BCG infection with multiple endorgan complications. CASE PRESENTATION: We report a case of disseminated, post-treatment BCG infection that initially presented with granulomatous hepatitis and choroiditis. After successful anti-mycobacterial therapy and resolution of the hepatic and ocular abnormalities, the patient developed an acute upper gastrointestinal hemorrhage from an aortoduodenal fistula that required emergency surgery. The resection specimen revealed multifocal, non-caseating granulomas, indicating mycobacterial involvement. CONCLUSIONS: This case highlights the varied end organ complications of disseminated BCG infection, and the need for vigilance even in immuno-competent patients with a history of intravesical BCG treatment.

TWEAK is a novel arthritogenic mediator.

TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.

Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9.

Enhanced cardiac generation of peroxynitrite contributes to septic cardiomyopathy. Since matrix metalloproteinases (MMPs) are activated in vitro by peroxynitrite, we hypothezised that MMPs may contribute to cardiac mechanical dysfunction in sepsis. Rats were injected (i.p.) with either lipopolysaccharide (LPS, 4 mg/kg) or vehicle. MMP inhibitors, either Ro 31-9790 (20 mg/kg), doxycycline (4 mg/kg), or vehicle were administered i.p. 30 min after LPS. At 6 h, when the symptoms of endotoxemia peak, hearts were excised and perfused as working hearts with Krebs-Henseleit buffer at 37 degrees C. Cardiac work (cardiac output x peak systolic pressure product) was measured. Perfusate and ventricle samples were analyzed by gelatin zymography to quantify MMP activity. Cardiac function was significantly depressed in LPS-treated rats compared to control rats (control: 55 +/- 4, LPS: 26 +/- 6 mmHg*mL*min(-1)). LPS also caused a loss of 72 kDa MMP-2 activity in the ventricles and the perfusate. Although MMP-9 activity was not detected in the ventricles, LPS resulted in an increase in perfusate 92 kDa MMP-9 activity. The MMP inhibitors significantly improved cardiac function of LPS-treated rats (Ro 31-9790: 38 +/- 3, doxycycline: 51 +/- 3 mmHg*mL*min(-1)), had no effect on the loss of MMP-2 activity, and significantly reduced the MMP-9 activity in the perfusate. These results demonstrate, for the first time, that LPS induced cardiac dysfunction is associated with a loss in ventricular MMP-2 activity and the release of MMP-9 from the heart. MMP inhibitors can significantly preserve cardiac mechanical function during septic shock.

Metabolic labeling of human cells with tritiated nucleosides results in activation of the ATM-dependent p53 signaling pathway and acceleration of DNA repair.

We investigated the effects of metabolic labeling with [(3)H]thymidine, [(3)H]uridine, and [(14)C]thymidine on human cells in terms of cell growth, p53 signaling, and nucleotide excision repair. Labeling with [(3)H] nucleosides resulted in growth inhibition by both p53-dependent and -independent mechanisms. Tritium labeling also led to nuclear accumulation of p53 and induction of the p53-regulated gene p21(WAF1) and its encoded protein (p21). ATM-deficient cells, however, did not increase their p53 and p21 protein levels in response to radiolabeling. Thus, labeling of human cells with tritiated nucleosides activates the radiation-responsive, ATM-dependent, DNA-damage surveillance network. Labeling of normal cells with [(3)H]thymidine significantly accelerated the repair of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers, as monitored by a sensitive immunofluorescence assay. Unlike [(3)H] labeling, [(14)C] labeling did not produce any impact on proliferation, p53 signaling, or DNA repair. In the light of these findings, the validity of results obtained with nucleic acid synthesis and DNA repair assays that involve [(3)H] and [(14)C] labeling is discussed. Our immunofluorescence approach detected pyrimidine dimers after exposure to UV fluences as low as 1 J/m(2) (the lowest fluence examined). This approach may prove particularly useful for monitoring DNA damage and its repair following exposure to extremely low levels of genotoxic agents.

Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction.

OBJECTIVE: Pro-inflammatory cytokines depress myocardial contractile function by enhancing peroxynitrite production, yet the mechanism by which peroxynitrite does this is unknown. As matrix metalloproteinases (MMPs) can be activated by peroxynitrite and can proteolytically cleave troponin I in hearts, we determined whether this occurs in cytokine-induced myocardial dysfunction. METHODS: Isolated working rat hearts were perfused with buffer containing interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha. RESULTS: Cytokines induced a marked decline in mechanical function during 60-120 min of perfusion. This decline was accompanied by increased myocardial inducible NO synthase activity and perfusate dityrosine (a marker of peroxynitrite), compared to control hearts. Before the decline in mechanical function there was enhanced MMP-2 activity in the perfusate. This was accompanied by decreased tissue levels of MMP-2, tissue inhibitor of matrix metalloproteinases-4 and troponin I in cytokine-treated hearts. The collagen content of the heart was not affected by cytokine treatment. A neutralizing anti-MMP-2 antibody or the MMP inhibitors Ro31-9790 or PD166793 attenuated the decline in myocardial function. Moreover, the MMP-2 antibody prevented the decline in myocardial MMP-2 and troponin I levels. CONCLUSIONS: Myocardial contractile dysfunction caused by pro-inflammatory cytokines results in MMP-2 activation and a decline in tissue inhibitor of matrix metalloproteinases-4 in the heart. Troponin I is also a target for the proteolytic action of MMP-2 during acute heart failure triggered by pro-inflammatory cytokines. Inhibition of MMPs may be a novel pharmacological strategy for the treatment of acute inflammatory heart disease.