Cardiovascular effects of the combination of levosimendan and valsartan in hypertensive Dahl/Rapp rats.

Hypertension is the main risk factor for left ventricular hypertrophy and development of diastolic heart failure. There is no yet treatment, which can effectively reduce mortality in patients suffering from heart failure with preserved systolic function. We tested whether the calcium sensitizer levosimendan and the AT1-receptor antagonist valsartan could protect from salt-induced hypertension, cardiovascular mortality and heart failure in Dahl/Rapp salt-sensitive rats fed for 7 weeks with a high salt diet (8% NaCl). Levosimendan (1 mg/kg/day via drinking water) and valsartan (30 mg/kg in the food) monotherapies and their combination prevented mortality in Dahl/Rapp rats. The drug combination evoked an additive effect on blood pressure, cardiac hypertrophy, cardiomyocyte cross-sectional area, target organ damage and myocardial ANP mRNA expression. There was a close correlation between systolic blood pressure and cardiac hypertrophy, cardiac and renal damage. As compared to Dahl/Rapp controls kept on low-salt diet (NaCl 0.3%). The high salt rats exhibited impaired diastolic relaxation as assessed by isovolumic relaxation time. Levosimendan alone and in combination with valsartan, improved diastolic relaxation without significantly improving systolic function. Our findings are evidence for an additive effect between levosimendan and valsartan on blood pressure and a blood pressure-dependent protection against the development of salt-induced target organ damage. The present study also demonstrates that levosimendan, alone or in combination with valsartan, can correct diastolic dysfunction induced by salt-dependent hypertension.

Cell death and production of reactive oxygen species by murine macrophages after short term exposure to phthalates.

The effects of four phthalates, i.e., di-2-ethylhexyl phthalate (DEHP), butyl benzyl phthalate (BBP), dibutyl phthalate (DBP) and diisobutyl phthalate (DIBP) on necrotic and apoptotic cell death, and production of reactive oxygen species (ROS) were studied on mouse macrophage cell line RAW 264.7. All the phthalates caused negligible and non-dose-dependent ROS production compared to control experiment. DEHP and BBP did not cause significant necrotic nor apoptotic cell death at any of the studied doses. Both DIBP and DBP caused dose-dependent necrotic cell death at the two highest concentrations (100 microM and 1 mM). Both doses (500 microM and 1 mM) of DIBP increased apoptosis by 31- and 60-fold, respectively, whereas the increase in apoptotic cell death caused by DBP was only two and fourfold, that however, was not statistically significant. In conclusion, DIBP caused a substantially different apoptotic cell death effect on murine macrophages from the three other phthalates, and this effect was not related to ROS production. Thus, toxicological and health risks of DIBP and DBP should be assessed separately in the future.

A multi-faceted approach to risk assessment of laboratory animal allergens at two facilities.

BACKGROUND: Risk assessment of exposure to allergens is difficult because the relationship between exposure, sensitization, and symptoms has not been fully established. Laboratory animal allergens (LAA) are an important occupational health risk factor; 10-32% of workers exposed to these allergens develop allergic diseases. This article introduces a versatile approach to assessing the risks posed by LAA at two laboratory animal facilities. METHODS: The risk assessment approach that was used at the laboratory animal facilities included questionnaires for management and employees, a hazard identification visit and measurements in the workplaces, as well as the creation of a list of generally recommended procedures to reduce allergen exposure. RESULTS: The prevalence of work-related allergic symptoms was 17%. Suggested countermeasures at the sites included changes in ventilation and work practices, reduction of unnecessary exposure, recommendations for more comprehensive use of personal protective equipment, and wider communication about LAA risks. CONCLUSIONS: The approach managed to identify critical points and potential means for controlling LAA exposure.

Acute effects of Aspergillus versicolor aerosols on murine airways.

Mice were exposed to aerosols from Aspergillus versicolor extract by inhalation (for 15-20 min). Changes in respiratory function parameters were monitored during the exposure to evaluate acute effects on the upper and lower respiratory tracts and the conductive airways. The single inhalation exposure to A. versicolor aerosols at the range of 12-151 mg/m3 provoked upper respiratory tract irritation in the airways of mice. The higher the exposure concentration the higher was the increase in the sensory irritation (SI) response. No bronchoconstriction or pulmonary irritation was observed. The causative agents for the SI response in the fungal extract are not known.

Slight respiratory irritation but not inflammation in mice exposed to (1-->3)-beta-D-glucan aerosols.

Airway irritation effects after single and repeated inhalation exposures to aerosols of beta-glucan (grifolan) were investigated in mice. In addition, the effects on serum total immunoglobulin E (IgE) production and histopathological inflammation in the respiratory tract were studied. The beta-glucan aerosols provoked slight sensory irritation in the airways, but the response was not concentration dependent at the levels studied. Slight pulmonary irritation was observed after repeated exposures. No effect was found on the serum total IgE levels, and no signs of inflammation were seen in the airways 6 h after the final exposure. The results suggest that, irrespective of previous fungal sensitization of the animals, inhaled beta-glucan may cause symptoms of respiratory tract irritation but without apparent inflammation. Respiratory tract irritation reported after inhalation of fungi may not be entirely attributed to beta-glucan.

Sensory irritating potency of some microbial volatile organic compounds (MVOCs) and a mixture of five MVOCs.

The authors investigated the ability/potencies of 3 microbial volatile organic compounds and a mixture of 5 microbial volatile organic compounds to cause eye and upper respiratory tract irritation (i.e., sensory irritation), with an animal bioassay. The authors estimated potencies by determining the concentration capable of decreasing the respiratory frequency of mice by 50% (i.e., the RD50 value). The RD50 values for 1-octen-3-ol, 3-octanol, and 3-octanone were 182 mg/m3 (35 ppm), 1359 mg/m3 (256 ppm), and 17586 mg/m3 (3360 ppm), respectively. Recommended indoor air levels calculated from the individual RD50 values for 1-octen-3-ol, 3-octanol, and 3-octanone were 100, 1000, and 13000 microg/m3, respectively-values considerably higher than the reported measured indoor air levels for these compounds. The RD50 value for a mixture of 5 microbial volatile organic compounds was also determined and found to be 3.6 times lower than estimated from the fractional concentrations and the respective RD50s of the individual components. The data support the conclusion that a variety of microbial volatile organic compounds may have some synergistic effects for the sensory irritation response, which constrains the interpretation and application of recommended indoor air levels of individual microbial volatile organic compounds. The results also showed that if a particular component of a mixture was much more potent than the other components, it may dominate the sensory irritation effect. With respect to irritation symptoms reported in moldy houses, the results of this study indicate that the contribution of microbial volatile organic compounds to these symptoms seems less than previously supposed.

Volatile compounds originating from mixed microbial cultures on building materials under various humidity conditions.

We examined growth of mixed microbial cultures (13 fungal species and one actinomycete species) and production of volatile compounds (VOCs) in typical building materials in outside walls, separating walls, and bathroom floors at various relative humidities (RHs) of air. Air samples from incubation chambers were adsorbed on Tenax TA and dinitrophenylhydrazine cartridges and were analyzed by thermal desorption-gas chromatography and high-performance liquid chromatography, respectively. Metabolic activity was measured by determining CO2 production, and microbial concentrations were determined by a dilution plate method. At 80 to 82% RH, CO2 production did not indicate that microbial activity occurred, and only 10% of the spores germinated, while slight increases in the concentrations of some VOCs were detected. All of the parameters showed that microbial activity occurred at 90 to 99% RH. The microbiological analyses revealed weak microbial growth even under drying conditions (32 to 33% RH). The main VOCs produced on the building materials studied were 3-methyl-1-butanol, 1-pentanol, 1-hexanol, and 1-octen-3-ol. In some cases fungal growth decreased aldehyde emissions. We found that various VOCs accompany microbial activity but that no single VOC is a reliable indicator of biocontamination in building materials.