Does the initiation of urate lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review

Objectives: To systematically review the literature on effect of initiating urate lowering treatment (ULT) during an acute attack of gout on duration of index attack and persistence on ULT. Methods: OVID (MEDLINE), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation during acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardised mean difference (SMD) and relative risk (RR) were used to pool continuous and categorical data. Meta-analysis was carried out using STATA v14. Results: 537 studies were selected. 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evidence from two high quality studies that early initiation of allopurinol did not increase pain severity at days 10 to 15 (SMDpooled (95%CI) 0.18(-0.58, 0.93)). Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with drop-outs (RRpooled (95%CI) 1.16(0.58, 2.31)). Conclusion: There is moderate-quality evidence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT discontinuation. Larger studies are required to confirm these findings so that patients with acute gout can be initiated on ULT with confidence

A preliminary study of Argiope argentata as indicators of southern California metal contamination

This study describes a novel test for 16 metals using Argiope argentata as indicators of environmental pollution. Our results suggest that A. argentata from a relatively isolated California island suffer a more diverse metal burden than those from the California mainland. Metal burdens of Cd, Cs, Ni, Sr, Tl, and U were greater in Santa Catalina specimens. Only the metal burdens of As and V were greater in the mainland Encinitas specimens. The metal burdens of Be, Bi, Co, Cr, Ga, In, Li, and Pb were not different between the sites. Soil samples taken later from the same sampling locations confirm higher concentrations of Cd, Ni and Sr on Santa Catalina, while cactus plants from the sites had a different pattern of metal accumulation. The effect of metal burden on spider body weight was examined, and Santa Catalina A. argentata had significantly increased mass compared to Encinitas spiders. This indicates that, despite a more diverse burden of metals, A. argentata spiders from Santa Catalina may have a higher fitness than those from Encinitas

Development and performance evaluation of a minimum input model calibration methodology for residential buildings

Energy simulations of existing dwellings are often impeded by the complexity of assigning appropriate model inputs. While data-driven calibration is an effective method to reduce variance between measured and simulated datasets, significant effort is required for monitoring and auditing. A new minimum input calibration method is proposed, where the number of inputs is greatly reduced through a three-step sensitivity analysis creating an input set with the most influential parameters on internal temperatures. The reduction in input parameters simplifies calibration and reduces the likelihood of unrealistic solutions. The proposed method is verified on two dwellings where conventional calibration techniques were compared to the minimum input calibration method using sub-hourly internal temperatures. Compared to baseline models, the variance of minimum input models reduced from 9.9% and 9.7% to 3.3% and 3.8% (CVRMSE (%)). Results indicate that minimum input model calibration can sufficiently predict thermal performance and could be applied to retrofit optimization. Acronyms: BoM: Bureau of Meteorology; BPS: building performance simulation; CD: cooling dominant; CDH: cooling-degree hours; CVRMSE: coefficient of variation of the root mean square error; D: discrete; ECM: energy conservation measure; HD: heating dominant; HDH: heating-degree hours; MAE: mean absolute error; MBE: mean bias error; MIM: minimum input model; MIS: minimum input set; MOAT: manual one at a time; N: normal distribution; NRMSE: normalized root mean square error; RMSE: root mean square error; RMY: reference meteorological year; SHGC: solar heat gain coefficient; U: uniform distribution

Metabolism and Lung Toxicity of Inhaled Naphthalene: Effects of Postnatal Age and Sex.

Human exposure to naphthalene (NA), an acute lung toxicant and possible human carcinogen, is primarily through inhalation. Acute lung toxicity and carcinogenesis are thought to be related because the target sites for both are similar. To understand susceptibility of the developing lung to cytotoxicity of inhaled NA, we exposed neonatal (7 days), juvenile (3 weeks), and adult mice to 5 or 10 ppm NA vapor for 4 h. We measured vacuolated airway epithelium morphometrically, quantified NA and NA-glutathione levels in plasma and lung, and quantified gene expression in microdissected airways. NA inhalation caused airway epithelial cytotoxicity at all ages, in both sexes. Contrary to a previous study that showed the greatest airway epithelial cytotoxicity in neonatal mice following intraperitoneal NA injection, we observed the most extensive airway epithelial toxicity in older, juvenile, animals exposed to NA by inhalation. Juvenile female animals were the most susceptible. Furthermore, NA inhalation in juvenile animals resulted in damage to conducting airway Club cells that was greater in proximal versus distal airways. We also found NA tissue burden and metabolism differed by age. Gene expression pathway analysis was consistent with the premise that female juvenile mice are more predisposed to damage; DNA damage and cancer pathways were upregulated. Our data demonstrate special susceptibility of young, juvenile mice to NA inhalation-induced cytotoxicity, highlight the importance of route of exposure and airway location in toxicity of chemicals in the developing lung, and provide metabolic and molecular insights for further identification of mechanisms underlying age and sex differences in NA toxicity

Naphthalene DNA adduct formation and tolerance in the lung

Naphthalene (NA) is a respiratory toxicant and possible human carcinogen. NA is a ubiquitous combustion product and significant component of jet fuel. The National Toxicology Program found that NA forms tumors in two species, in rats (nose) and mice (lung). However, it has been argued that NA does not pose a cancer risk to humans because NA is bioactivated by cytochrome P450 monooxygenase enzymes that have very high efficiency in the lung tissue of rodents but low efficiency in the lung tissue of humans. It is thought that NA carcinogenesis in rodents is related to repeated cycles of lung epithelial injury and repair, an indirect mechanism. Repeated in vivo exposure to NA leads to development of tolerance, with the emergence of cells more resistant to NA insult. We tested the hypothesis that tolerance involves reduced susceptibility to the formation of NA-DNA adducts. NA-DNA adduct formation in tolerant mice was examined in individual, metabolically-active mouse airways exposed ex vivo to 250 μΜ 14C-NA. Ex vivo dosing was used since it had been done previously and the act of creating a radioactive aerosol of a potential carcinogen posed too many safety and regulatory obstacles. Following extensive rinsing to remove unbound 14C-NA, DNA was extracted and 14C-NA-DNA adducts were quantified by AMS. The tolerant mice appeared to have slightly lower NA-DNA adduct levels than non-tolerant controls, but intra-group variations were large and the difference was statistically insignificant. It appears the tolerance may be more related to other mechanisms, such as NA-protein interactions in the airway, than DNA-adduct formation

Naphthalene genotoxicity: DNA adducts in primate and mouse airway explants

Naphthalene (NA) is a ubiquitous environmental pollutant and possible human carcinogen that forms tumors in rodents with tissue/regional and species selectivity. This study seeks to determine whether NA is able to directly adduct DNA in an ex vivo culture system. Metabolically active lung tissue was isolated and incubated in explant culture with carbon-14 labeled NA (0, 25, 250 μM) or 1,2-naphthoquinone (NQ), followed by AMS analyses of metabolite binding to DNA. Despite relatively low metabolic bioactivation in the primate airway, dose-dependent NA-DNA adduct formation was detected. More airway adducts were detected in female mice (4.7-fold) and primates (2.1-fold) than in males of the same species. Few adducts were detected in rat airway or nasal epithelium. NQ, which is a metabolic product of NA, proved to be even more potent, with levels of adduct formation 70-80-fold higher than seen when tissues were incubated with the parent compound NA. This is the first study to demonstrate NA-DNA adduct formation at a site of carcinogenesis, the mouse lung. Adducts were also detected in non-human primate lung and with a NQ metabolite of NA. Taken together, this suggests that NA may contribute to in vivo carcinogenesis through a genotoxic mechanism

Comparison of acute respiratory epithelial toxicity for 4-Methylimidazole and naphthalene administered by oral gavage in B6C3F1 mice

4-Methylimidazole (4MEI) is a contaminant in food and consumer products. Pulmonary toxicity and carcinogenicity following chronic dietary exposures to 4MEI is a regulatory concern based on previous rodent studies. This study examined acute pulmonary toxicity in B6C3F1 mice from 6 h to 5 days after oral gavage with a single dose of 150 mg/kg 4MEI, a double dose delivered 6 h apart, or vehicle controls. Oral gavage of 150 mg/kg naphthalene, a prototypical Club cell toxicant, was used as a positive control. Intrapulmonary conducting airway cytotoxicity was assessed in fixed-pressure inflated lungs using qualitative histopathology scoring, quantitative morphometric measurement of vacuolated and exfoliating epithelial cells, and immunohistochemistry. 4MEI treatment did not change markers of cytotoxicity including the mass of vacuolated epithelium, the thickness of the epithelium, or the distributions of epithelial proteins: secretoglobin 1A1, proliferating cell nuclear antigen, calcitonin gene-related peptide, and myeloperoxidase. 4MEI and vehicle controls caused slight cytotoxicity with rare vacuolization of the epithelium relative to the severe bronchiolar epithelial cell toxicity found in the naphthalene exposed mice at terminal bronchioles, intrapulmonary airways, or airway bifurcations. In summary, 4MEI caused minimal airway epithelial toxicity without characteristic Club Cell toxicity when compared to naphthalene, a canonical Club Cell toxicant

Novel multi-functional europium-doped gadolinium oxide nanoparticle aerosols facilitate the study of deposition in the developing rat lung.

Ambient ultrafine particulate matter (UPM), less than 100 nm in size, has been linked to the development and exacerbation of pulmonary diseases. Age differences in susceptibility to UPM may be due to a difference in delivered dose as well as age-dependent differences in lung biology and clearance. In this study, we developed and characterized aerosol exposures to novel metal oxide nanoparticles containing lanthanides to study particle deposition in the developing postnatal rat lung. Neonatal, juvenile and adult rats (1, 3 and 12 weeks old) were nose only exposed to 380 μg m(-3) of ∼30 nm europium doped gadolinium oxide nanoparticles (Gd2O3:Eu(3+)) for 1 h. The deposited dose in the nose, extrapulmonary airways and lungs was determined using inductively-coupled plasma mass spectroscopy. The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng per g body weight compared to 1.47 ng per g and 0.097 ng per g for the adult and neonate rats, respectively. Toxicity was investigated in bronchoalveolar lavage fluid (BALF) by quantifying recovered cell types, and measuring lactate dehydrogenase activity and total protein. The toxicity data suggests that the lanthanide particles were not acutely toxic or inflammatory with no increase in neutrophils or lactate dehydrogenase activity at any age. Juvenile and adult rats had the same mass of deposited NPs per gram of lung tissue, while neonatal rats had significantly less NPs deposited per gram of lung tissue. The current study demonstrates the utility of novel lanthanide-based nanoparticles to study inhaled particle deposition in vivo and has important implications for nanoparticles delivery to the developing lung either as therapies or as a portion of particulate matter air pollution

Additional file 1 of CITEViz: interactively classify cell populations in CITE-Seq via a flow cytometry-like gating workflow using R-Shiny

Additional file 1. Back-gate schemes for B-cells and platelets, and an example gate using scRNA-Seq data