Enhanced alveolar bone loss in a model of non-invasive periodontitis in rice rats

Oral Diseases (2012) 18 , 459–468 Objective: The rice rat (Oryzomys palustris) develops periodontitis‐like lesions when fed a diet rich in sucrose and casein (H‐SC). We aimed to establish whether this model can accurately mimic the development of human periodontitis. Materials and Methods: For this purpose, 28‐day‐old rice rats (15/group) were assigned to standard (STD) or H‐SC diets and sacrificed after 6, 12, and 18 weeks. Jaws were processed for morphometric, histometric, histologic, histomorphometric, and micro‐CT analyses. Results: We found a progressive increase in horizontal alveolar bone loss (ABL) with age in maxillae of rats fed the STD diet as determined by morphometry. The H‐SC diet exacerbated horizontal ABL at the palatal surface at 12 and 18 weeks. Furthermore, increased vertical ABL was detected in mandibles and maxillae of rats fed the H‐SC diet for 12 and/or 18 weeks by histometry and micro‐CT. Remarkably, the H‐SC diet significantly increased bone remodeling at the interproximal alveolar bone of mandibles from rats fed for 6 weeks, but not in those fed for longer periods. Conclusions: These findings indicate that the H‐SC diet induced a transient increase in alveolar bone remodeling, which is followed by ABL characteristic of moderate periodontitis.     

Variation in inflammatory/regulatory cytokines in secondary, tertiary, and quaternary challenges with dengue virus

Abstract. Secondary heterologous dengue infection is a risk factor for severe disease manifestations because of the immune-enhancement phenomenon. Succeeding clinical infections are seldom reported, and the clinical course of tertiary and quaternary dengue infections is not clear. Cuba represents a unique environment to study tertiary/quaternary dengue infections in a population with known clinical and serologic dengue markers and no dengue endemicity. We took advantage of this exceptional epidemiologic condition to study the effect of primary, secondary, tertiary, and quaternary dengue infection exposure on the expression of pro-inflammatory and regulatory cytokines, critical in dengue infection pathogenesis, by using a dengue infection ex vivo model. Whereas secondary exposure induced a high cytokine response, we found a significantly lower expression of tumor necrosis factor-α, interferon-γ, interleukin-10, and tumor growth factor-β after tertiary and quaternary infectious challenge. Significant differences in expression of the cytokines were seen between the dengue immune profiles, suggesting that the sequence in which the immune system encounters serotypes may be important in determining the nature of the immune response to subsequent infections.     

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ(10) preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ(10) significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS-induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ(10).     

Phase II study of sorafenib in patients with relapsed or refractory lymphoma

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.