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Background and Objective Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects. Methods Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study. Results Following a single oral dose of tylerdipine of 5–30 mg, the mean maximum plasma concentration ( C max ) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas C max exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (R AUC ) of less than 1.65. All adverse events were assessed as mild or moderate. Conclusion Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5–30 mg increased in a greater than dose-proportional manner, while C max exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing. Study registrations CTR20140862 and CTR20150660.

Pyrosequencing and metagenomic profiling were used to assess the phylogenetic and functional characteristics of microbial communities residing in sediments collected from the estuaries of Rivers Oujiang (OS) and Jiaojiang (JS) in the western region of the East China Sea. Another sediment sample was obtained from near the shore far from estuaries, used for contrast (CS). Characterization of estuary sediment bacterial communities showed that toxic chemicals potentially reduced the natural variability in microbial communities, while they increased the microbial metabolic enzymes and pathways. Polycyclic aromatic hydrocarbons (PAHs) and nitrobenzene were negatively correlated with the bacterial community variation. The dominant class in the sediments was Gammaproteobacteria. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) enzyme profiles, dominant enzymes were found in estuarine sediments, which increased greatly, such as 2-oxoglutarate synthase, acetolactate synthase, inorganic diphosphatase, and aconitate hydratase. In KEGG pathway profiles, most of the pathways were also dominated by specific metabolism in these sediments and showed a marked increase, for instance alanine, aspartate, and glutamate metabolism, carbon fixation pathways in prokaryotes, and aminoacyl-tRNA biosynthesis. The estuarine sediment bacterial diversity varied with the polluted river water inputs. In the estuary receiving river water from the more seriously polluted River Oujiang, the sediment bacterial community function was more severely affected.

Background An earlier investigation found increased bladder cancer incidence among workers at a rubber chemical manufacturing plant that used o-toluidine, aniline and nitrobenzene. The cohort was expanded to include additional workers (n=1875) and updated through 2007 to assess bladder cancer with improved exposure characterisation. Methods Work histories were updated and exposure categories and ranks were developed for o-toluidine, aniline and nitrobenzene combined. Incident cancers were identified by linkage to six state cancer registries. Residency in time-dependent cancer registry catchment areas was determined. SIR and standardised rate ratios for bladder cancer were calculated by exposure category and cumulative rank quartiles for different lag periods. Cox regression was used to model bladder cancer incidence with estimated cumulative rank, adjusting for confounders. Indirect methods were used to control for smoking. Results Excess bladder cancer was observed compared to the New York State population (SIR=2.87, 95% CI 2.02 to 3.96), with higher elevations among workers definitely exposed (moderate/high) (SIR=3.90, 95% CI 2.57 to 5.68), and in the highest cumulative rank quartile (SIR=6.13, 95% CI 2.80 to 11.6, 10-year lag). Bladder cancer rates increased significantly with estimated cumulative rank (10-year lag). Smoking only accounted for an estimated 8% elevation in bladder cancer incidence. Conclusions Bladder cancer incidence remains elevated in this cohort and significantly associated with estimated cumulative exposure. Results are consistent with earlier findings in this and other cohorts. Despite other concurrent chemical exposures, we consider o-toluidine most likely responsible for the bladder cancer incidence elevation and recommend a re-examination of occupational exposure limits.

This investigation aimed to study the in vivo harmful effects of the subcutaneous injection of different methicillin resistance Staphylococcus aureus extracts (MRSA2, MRSA4, MRSA10, MRSA69, MRSA70, MRSA76, and MRSA78). Such strains represented the highest minimum inhibition concentration toward methicillin with various multidrug-resistant patterns. The obtained results revealed that rats injected with the MRSA4 extract died immediately after the last dose indicating the high cytotoxicity of MRSA4 strain (100% mortality). While the mortalities in other groups injected by the other MRSA extracts ranged from 50 to 75%. In comparison with the normal animal group, all MRSA extracts induced a hepatotoxic effect which was indicated from the significant ( p  < 0.01) increases in the activities of the serum alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) enzymes. Moreover, alkaline phosphatase (ALP) combined with a partial nephrotoxicity that was monitored from the significant elevation of serum urea concentration. While serum creatinine levels did not affect. Similarly, a significant elevation was recorded in serum levels of tumor biomarkers (alpha fetoprotein; AFP, carcinoembryonic antigen; CEA, and lactate dehydrogenase; LDH) reflecting their carcinogenic potential. On the other hand, the percentage of micronuclei (MN) in polychromatic erythrocytes from bone marrow cells was statistically significant in all groups as compared to the control group. The percentage of sperm abnormalities was statistically significant compared to the control. Different types of head abnormalities and coiled tail were recorded. Consequently, the current study focused on fighting MRSA virulence factors by the new compound ayamycin, which proved to be potent anti-virulence factor against all MRSA strains under study by significant decreasing of their streptokinase activities, hemolysin synthesis, biofilm formation, and their cell surface hydrophobicity.

To determine whether the carcinogenicity of dinitrotoluene (DNT) in rodent bioassays was predictive for humans, we examined the mortality experience of exposed workers at two ammunition plants. Cohorts of 156 and 301 men who had worked a month or more during the 1940s and 1950s at jobs with opportunity for substantial DNT exposure were followed through the end of 1980. Numbers of expected deaths and standardized mortality ratios (SMRs) were computed, using mortality rates of US white males as the standard. No evidence of a carcinogenic effect was found, but unsuspected excesses of mortality from ischémie heart disease were noted at both plants (SMRs 131 and 143; 95% confidence limits 65 to 234 and 107 to 187, respectively). Deaths from ischemic heart disease remained high even when compared with expected numbers derived using mortality rates of the counties in which the plants were located. Additional analyses revealed evidence of a 15-year latent period and suggested a relationship with duration and intensity of exposure. Epidemiologie investigations of other heavily exposed populations are needed to conñrm the etiologic signiñeance of the association between DNT and heart disease described here.

Dinitrotoluene (DNT) and toluene diamine (TDA) are intermediates in the production of toluene diisocyante and Polyurethane plastics. Some reproductive effects in rodents have been reported; and the National Institute for Occupational Safety and Health reported probable reproductive toxic effect to humans after a preliminary survey. Accordinglyr, 84 workers exposed to DNT/TDA (classified by intensity and recency of exposure) and 119 nonexposed workers were studied at Olin's chemical complex at Lake Charles, La. Each worker was the subject of a physician's urogenital examination, a reproductive and fertility questionnaire, an estimation of testicular volume, an assessment of serum follicile-stimulating hormone, and an analysis of semen for sperm count and morphology. No differences were found between the exposed and control groups among any of these variables. Although both TDA and DNT are readily absorbed (percutaneous, inhalation, ingestion), they did not present detectable reproductive hazard to the workers.

Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients. Cardiovascular disease: Averting a calcium catastrophe A therapeutic strategy for preventing calcium build-up in the heart could protect chronic kidney disease (CKD) patients from lethal cardiovascular complications. This accumulation is a common feature of late-stage CKD, resulting in obstruction of the aortic valve that can ultimately cause heart failure. A team led by Wei Sun and Xiangqing Kong of The First Affiliated Hospital of Nanjing Medical University in China has demonstrated that specific chemical modifications to histone proteins contribute to this process. Histones organize chromosomal DNA and can thereby regulate gene expression, and the researchers showed that a drug that inhibits histone-modifying acetyltransferase enzymes switches off biochemical pathways that promote calcium accumulation in cultured heart valve cells. They subsequently confirmed these protective effects in a mouse model of aortic valve calcification, indicating a potentially promising avenue for treating CKD.