Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton's Tyrosine Kinase.

Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation: (a) BWF1 lupus nephritis mice, (b) anti-GBM nephritis, (c) bleomycin-induced systemic sclerosis like skin disease, and (d) bleomycin-induced lung disease. In agreement with the previous studies, BTK inhibitor (BTKB66) treatment was effective in treating lupus nephritis in terms of reducing renal damage both functionally and histologically, accompanied by significant decrease in proteinuria. Both low-dose and high-dose BTKB66 profoundly blocked renal disease in the anti-GBM nephritis model, with efficacy that was comparable to that seen with dexamethasone. This study provides the first evidence that BTK inhibition has both therapeutic and preventative effects in bleomycin-induced SSc-like disease, in terms of reducing skin thickness, fibrosis, collagen deposition, and inflammation. Likewise, significantly lower lung inflammatory cell infiltration was observed after treatment with BTKB66. Therapeutic benefit was associated with lower numbers of macrophages, proliferating macrophages and activated T-cells in the respective injured organs. The observation that these immune cells play key roles in driving end organ inflammation in multiple systemic rheumatic diseases have broad implications for the use of BTKB66 in managing patients with systemic rheumatic diseases where multiple end organs are afflicted, including lupus and systemic sclerosis.

Epigallocatechin-3-Gallate Dampens Non-Alcoholic Fatty Liver by Modulating Liver Function, Lipid Profile and Macrophage Polarization.

Epigallocatechin-3-gallate (EGCG) has been shown to attenuate obesity, fatty liver disease, hepatic inflammation and lipid profiles. Here, we validate the efficacy of EGCG in a murine model of non-alcoholic fatty liver disease (NAFLD) and extend the mechanistic insights. NAFLD was induced in mice by a high-fat diet (HFD) with 30% fructose. EGCG was administered at a low dose (25 mg/kg/day, EGCG-25) or high dose (50 mg/kg/day, EGCG-50) for 8 weeks. In HFD-fed mice, EGCG attenuated body and liver weight by ~22% and 47%, respectively, accompanied by ~47% reduction in hepatic triglyceride (TG) accumulation and ~38% reduction in serum cholesterol, resonating well with previous reports in the literature. In EGCG-treated mice, the hepatic steatosis score and the non-alcoholic steatohepatitis activity score were both reduced by ~50% and ~57%, respectively, accompanied by improvements in hepatic inflammation grade. Liver enzymes were improved ~2-3-fold following EGCG treatment, recapitulating previous reports. Hepatic flow cytometry demonstrated that EGCG-fed mice had lower Ly6C+, MHCII+ and higher CD206+, CD23+ hepatic macrophage infiltration, indicating that EGCG impactedM1/M2 macrophage polarization. Our study further validates the salubrious effects of EGCG on NAFLD and sheds light on a novel mechanistic contribution of EGCG, namely hepatic M1-to-M2 macrophage polarization. These findings offer further support for the use of EGCG in human NAFLD.

Low dose Epigallocatechin Gallate Alleviates Experimental Colitis by Subduing Inflammatory Cells and Cytokines, and Improving Intestinal Permeability.

BACKGROUND: In this study, we investigate the impact of epigallocatechin gallate (EGCG), the most abundant and potent catechin in green tea, on a mouse model of inflammatory bowel disease (IBD) and the underlying mechanisms of action. METHODS: C57BL/6J mice were subjected to dextran sulfate sodium (DSS)-induced IBD-like disease and then randomly divided into three groups: Model group (MD), low-dose EGCG group (LE, 20 mg/kg/d), and high-dose EGCG group (HE, 50 mg/kg/d). DSS-induced clinical and macroscopic changes were monitored daily. Intestinal permeability was assessed by FITC-Dextran assay. RESULTS: Both high- and low-dose EGCG treatment alleviated clinical manifestations including body weight loss and disease activity index (DAI) of DSS-induced colitis. The DAI score was significantly improved after two days of EGCG treatment. At the end of the study, the macroscopic severity score (MSS) of HE and LE treatment groups were 2.4 ± 1.2, and 2.2 ± 1.0, respectively, significantly lower than that of the controls (5.0 ± 2.1). EGCG treatment also prevented colon shortening, and improved intestinal permeability and histopathological changes. In addition, EGCG treatment attenuated colon inflammation by suppressing colonic levels of pro-inflammatory cytokines IL-6, MCP-1, and TNF-alpha, and inhibited CD3+ T cell and CD68+ macrophage infiltration. CONCLUSION: EGCG is effective in inflammatory colitis because it reduces cellular and molecular inflammation, and reduces intestinal permeability.

Risk of asthmatic episodes in children exposed to sulfur dioxide stack emissions from a refinery point source in Montreal, Canada.

BACKGROUND: Little is known about the respiratory effects of short-term exposures to petroleum refinery emissions in young children. This study is an extension of an ecologic study that found an increased rate of hospitalizations for respiratory conditions among children living near petroleum refineries in Montreal (Canada). METHODS: We used a time-stratified case-crossover design to assess the risk of asthma episodes in relation to short-term variations in sulfur dioxide levels among children 2-4 years of age living within 0.5-7.5 km of the refinery stacks. Health data used to measure asthma episodes included emergency department (ED) visits and hospital admissions from 1996 to 2004. We estimated daily levels of SO2 at the residence of children using a) two fixed-site SO2 monitors located near the refineries and b) the AERMOD (American Meteorological Society/Environmental Protection Agency Regulatory Model) atmospheric dispersion model. We used conditional logistic regression to estimate odds ratios associated with an increase in the interquartile range of daily SO2 mean and peak exposures (31.2 ppb for AERMOD peaks). We adjusted for temperature, relative humidity, and regional/urban background air pollutant levels. RESULTS: The risks of asthma ED visits and hospitalizations were more pronounced for same-day (lag 0) SO2 peak levels than for mean levels on the same day, or for other lags: the adjusted odds ratios estimated for same-day SO2 peak levels from AERMOD were 1.10 [95% confidence interval (CI), 1.00-1.22] and 1.42 (95% CI, 1.10-1.82), over the interquartile range, for ED visits and hospital admissions, respectively. CONCLUSIONS: Short-term episodes of increased SO2 exposures from refinery stack emissions were associated with a higher number of asthma episodes in nearby children.

Generalized metabolic bone disease in Neurofibromatosis type I.

Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1) but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical and pathological level the bone involvement in NF1 patients. Using dual energy X-ray absorptiometry (DXA) we analyzed bone status in 73 unselected NF1 subjects, 26 males and 47 females, mainly children and adolescents (mean age: 16.6 years). In a subgroup of subjects with low bone mass, we measured indices of calcium-phosphate metabolism, bone turnover, and bone density before and after vitamin D and calcium treatment. We found statistically significant and generalized reduction in bone mass with the mean lumbar bone mineral density (BMD) z-score being -1.38+/-1.05 (CI 95% -1.62 to -1.13), and whole body bone mineral content (BMC) z-score -0.61+/-1.19 (CI 95% -0.94 to -0.29), both significantly reduced compared to normal controls (p<.001). PTH was moderately elevated and after 4 months of supplemental therapy with calcium and vitamin D, it decreased to the normal range. However, BMD z-scores did not significantly improve after 2 years of follow-up. Histological analysis of bone samples from NF1 patients revealed substantial alteration of bone microarchitecture due mainly to reduced trabecular bone. Our observations are consistent with a generalized bone metabolic defect due to loss of the function of neurofibromin. Early identification of patients with osteoporosis may permit more timely and aggressive treatments to prevent the likely substantial morbidity associated with increased fracture risk later in life.

Development of a health effects-based priority ranking system for air emissions reductions from oil refineries in Canada.

In Canada, the Canadian Council of Ministers for the Environment (CCME) is currently engaged in a process to determine how best to reduce air emissions from oil refineries. The National Framework for Petroleum Refineries Emissions Reduction (NFPRER) is being developed with the input of stakeholders, including nongovernment organizations (NGOs), industry, and regulatory jurisdictions. One component of this framework is the development of a tool to prioritize emissions for reduction based on estimated health impacts. HEIDI II (Health Effects Indicators Decision Index II) is a spreadsheet-based model that prioritizes a series of carcinogenic and noncarcinogenic air toxicicants and criteria air contaminants commonly emitted from Canadian oil refineries. A generic meteorological dispersion model was applied to reported annual emissions data for each of Canada's 20 refineries. Photodegradation rates and ambient levels of each substance were accounted for, and air concentrations were calculated for 20 geographic zones around each refinery. These were coupled to toxicity data derived mainly from Health Canada and the U.S. Environmental Protection Agency (EPA), and applied to target populations of children, adults and seniors. HEIDI II predicts incidence of relevant disease endpoints from each substance emitted, except for benzene, toluene, ethylbenzene, and xylene (BTEX) and polycyclic aromatic hydrocarbons (PAH), which were treated as chemical mixtures. Rankings were based on predicted case incidence or the application of a common health impact metric, disability-adjusted life years (DALYs), to the predicted incidence. Using the DALY approach, priority rankings can be made within each of the chemical classes, or across all three classes together. HEIDI II incorporates several switches that allow the user to investigate alternate scenarios based on stack height, average daily sunlight hours (for calculating photodegradation), and the possibility of emissions below regulatory reporting thresholds.

Biological factors in dental caries: role of remineralization and fluoride in the dynamic process of demineralization and remineralization (part 3).

Dental caries is a complex disease process that afflicts a large proportion of the world, regardless of gender, age and ethnicity, although it does tend to affect more with a low socioeconomic status to a greater extent. Remineralization may be enhanced by providing low levels of calcium and phosphate, in conjunction with minimal amounts of fluoride. It is truly remarkable the difference that a very small amount of fluoride (<1 ppm) has upon demineralization and remineralization. This is because fluoride acts as a catalyst and influences reaction rates with dissolution and transformation of various calcium phosphate mineral phases within tooth structure and resident within plaque adjacent to tooth surfaces. The incorporation of minimal amounts of fluoride into HAP yields FHAP that resists demineralization to similar level as FAP. New and emerging methods have been and are in the process of being developed. These hold great promise for preventing and reversing caries, especially in the one-fifth of the population that accounts for two-thirds of the caries experience. Still, the mainstay in caries prevention and remineralization is frequent exposure to low levels of fluoride. This may be accomplished with fluoridated toothpastes, supplemented with fluoride mouthrinses, CPP-ACP containing chewing gum and application of fluoride varnishes. The role of systemic fluorides appears to be limited and primarily has a topical effect.

In vivo caries formation in enamel following argon laser irradiation and combined fluoride and argon laser treatment: a clinical pilot study.

OBJECTIVE: This in vivo pilot study investigated the role of argon laser irradiation and combined fluoride and argon laser treatment in accelerated natural caries development in sound enamel surfaces beneath plaque-retentive orthodontic bands. METHOD AND MATERIALS: Five patients (3 female, 2 male, ages 19 to 28 years) requiring tooth extraction prior to orthodontic treatment, participated in the study. Buccal surfaces were treated with either: (1) argon laser (250 mW for 10 seconds, ARGO-MOD); (2) topical fluoride (0.5% fluoride ion, Thera-Flur-N) followed by argon lasing; or (3) no treatment (control). Orthodontic bands with plaque-retentive slots on buccal surfaces were placed on the teeth slated for extraction (n = 14). Following a minimum of 5 weeks of intraoral exposure, the teeth were extracted for laboratory analysis. The teeth underwent serial longitudinal sectioning (12 sections per tooth). The sections were imbibed in water, and lesion depths were determined with each section, using polarized light microscopy. Comparisons were made among treatment groups (analysis of variance, Duncan's multiple range test for paired samples). RESULTS: Mean lesion depths were: 261 +/- 24 microm for the no treatment control group (n = 84 sections); 147 +/- 18 microm for the argon laser group (n = 24 sections); and 99 +/- 12 microm for the fluoride and argon laser group (n = 60 sections). Both the argon laser (44%) and the fluoride and argon laser groups (62%) had significant lesion depth reductions compared to controls. The addition of fluoride treatment prior to argon lasing resulted in a 32% reduction in lesion depth compared to argon laser treatment alone. CONCLUSIONS: Within this clinical pilot study, in vivo natural caries formation was affected significantly by a single exposure to low fluence argon laser irradiation. Topical fluoride treatment in combination with argon lasing provided an even greater degree of resistance against in vivo enamel caries development. A simple technique for reducing the caries susceptibility of enamel may be a clinical reality.