Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Evaluation of Eimeria krijgsmanni as a murine model for testing the efficacy of anti-parasitic agents.

Murine Eimeria spp. have been used as effective models of disease instead of large mammalian hosts such as cattle. We attempted to establish in vivo and in vitro assays using a murine intestinal protozoan, Eimeria krijgsmanni, which we previously isolated, to test anti-parasitic agents. Consequently, when mice were treated with sulfur drugs or toltrazuril, which are commercially available for livestock. Furthermore, sporulated oocysts and excysted sporozoites of E. krijgsmanni were treated with naturally occurring substances (lactoferrin, longicin, and curcumin). Although exposure to these substances did not affect oocyst infectivity, sporozoite viability decreased by 60% with longicin. However, direct injection of sporozoites treated with longicin into mice ceca did not result in any changes in the oocyst shedding pattern compared with control mice. The results suggest that E. krijgsmanni could be resistant to these anti-parasitic agents and might therefore have different characteristics to other apicomplexan parasites.

Case of granulomatosis with polyangiitis (Wegener's granulomatosis) manifested with asymptomatic intracerebral hemorrhage.

A 46-year-old man, who had had sinusitis, developed bilateral omalgia, petechiae on his lower extremities and a congested right eye. A blood test detected elevated serum C-reactive protein level. Computed tomography incidentally found an acute lesion of thalamic hemorrhage without neurological symptoms and no specific therapy was given at the time. Thereafter, he developed vertigo, vomiting and pneumonia for which antibiotics were ineffective. He was referred and admitted to our hospital. Further, aural and renal lesions, and presence of serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) confirmed his diagnosis of granulomatosis with polyangiitis (Wegener's) (GPA). With corticosteroid and cyclophosphamide therapy, his symptoms disappeared in two months along with faded PR3-ANCA. Afterward he showed neither new cerebral lesion nor symptom. This is a rare case of GPA manifested with asymptomatic intracerebral hemorrhage. It should be noted that GPA could cause various manifestations in central nervous system such as a fatal or an asymptomatic hemorrhagic lesion, which might respond to immunosuppressive therapy.

Modeling of the changes in heart rate and blood pressure with characteristic respiratory waveform during surgery under local anesthesia.

We are developing a model that can represent the physiological and mental responses of a patient at each stage of a surgical procedure during endoscopic sinus surgery under local anesthesia. In this study, causal influence structures among changes in heart rate and blood pressure and characteristic shapes on respiratory waveform were constructed using a Bayesian network. We defined ten respiratory waveform indices indicating breath-holding behaviors and respiratory irregularities. According to the results of analysis and model construction, the defined indices demonstrate improvements in the ability to predict the changing direction of blood pressure in all patients.