Risk for lung-related diseases associated with welding fumes in an occupational population: Evidence from a Cox model.

Background: Welding fumes are a risk factor for welder pneumoconiosis. However, there is a lack of population information on the occurrence of welding fume-induced lung cancer, and little is known about the welding fume pathogenesis. Methods: Welding fume and metal ion concentrations were assessed in a vehicle factory in Wuhan. A Cox regression model estimated lung-related disease risk in workers by independent and combined factors. Results: Workers' exposures were divided into four grades; the highest exposure was among the welders in the maintenance workshop, the highest Mn and Fe exposure was 4 grades, and the highest Cr exposure was 3 grades. Subgroup analysis found that the risk of lung-related disease was 2.17 (95% CI: 1.31-3.57, p < 0.05) in welders compared with non-welders, and the risk of pulmonary disease in male welders was 2.24 (95% CI: 1.34-3.73, p < 0.05) compared to non-welders. Smoking welders had a 2.44 (95% CI: 1.32-4.51, p < 0.01) higher incidence of lung-related diseases than non-welders. Total years of work as an independent protective factor for lung-related disease risk was 0.72 (95% CI: 0.66-0.78, p < 0.01). As an independent risk factor, high-high and high-low exposure had a 5.39 (95% CI: 2.52-11.52, p < 0.001) and 2.17 (95% CI: 1.07-4.41, p < 0.05) higher risk for lung-related diseases, respectively. Conclusions: High welding fume exposure is a significant risk factor for lung-related disease in workers.

Synthesis and evaluation of hydrazinyl-containing pyrrolo[2,3-d]pyrimidine series as potent, selective and oral JAK1 inhibitors for the treatment of rheumatoid arthritis.

Selective inhibition of JAK kinases within the JAK family has been a desired goal of research in order to maximize efficacy while reducing undesired off target effect. Aiming to minimize adverse effects such as anemia, a promising new class of pyrrolo[2,3-d]pyrimidine series containing a hydrazinyl moiety were synthesized and profiled. Among them compound 8m and 8o showed the best enzymatic activity against JAK1 with IC50 value of 0.16 nM and 0.3 nM respectively, and with selectivity over JAK2 by 40.6 and 10 folds respectively. In addition, 8o had an improved PK profile and demonstrated better in vivo efficacy than Tofacitinib in CIA model.

Stress hormone biosynthesis-based genes and lifestyle moderated the association of noise exposure with blood pressure in a cohort of Chinese tobacco factory workers: A cross-sectional analysis.

When evaluating noise-related cardiovascular risk, noise is generally solely assessed as the major stressor. However, cardiovascular effect of other simultaneous exposure events, such as unhealthy lifestyle and genetic variation, is easily neglected. The aim of this study is to estimate the combined effect of noise and lifestyle on blood pressure alteration, particularly under different genetic background. This study included 536 workers from a tobacco factory in Wuhan, China, who were divided into high exposure group and low exposure group according to noise measurement in their working area. All participants took annual physical examination and questionnaire survey to provide information on individual systolic and diastolic blood pressure (SBP and DBP) and lifestyle (smoking, drinking and physical activity). Single nucleotide polymorphism at genes related to stress hormone production were determined. Moderated moderation models were constructed to investigate the interaction effect of noise exposure and lifestyle factors on blood pressure with regard to different genetic background. We identified an expected trend in association between noise exposure and SBP among active smokers (P = 0.086). The moderated moderation analysis showed significant three-way interaction effect (COMT rs4680 × smoking status × noise exposure levels) on SBP or DBP (both P < 0.05). For COMT rs4680 GA+AA genotype carriers, active smoking significantly moderated the association between noise exposure and SBP or DBP (both P < 0.05). The results indicated that for COMT rs4680 A allele carriers, tobacco and noise exposure contribute collectively to blood pressure alteration, supporting that stress hormone production may play a certain role in the smoke-and-noise-induced cardiovascular effect.

Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6).

Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 µM) profile.