Asthma on the job: work-related factors in new-onset asthma and in exacerbations of pre-existing asthma.
(17/539)
Occupational asthma (OA) can be defined as variable airways narrowing causally related to exposure in the working environment to airborne dusts, gases, vapours or fumes. There are many agents in the work-place that can induce asthma or cause substantial deterioration in pre-existing asthma. It has been estimated that 5-15% of adult-onset asthma can be attributed to occupational exposures. Hence adult patients, especially those with new-onset asthma, must be investigated with regard to occupational risk factors for disease. The prognosis for OA is improved if the causal exposure is controlled either by controlling the exposure at the workplace or by moving the patient out of the workplace. (+info)
Transbuccal delivery of acyclovir (II): feasibility, system design, and in vitro permeation studies.
(18/539)
PURPOSE: To design a buccal mucoadhesive system for systemic delivery of acyclovir using a novel mucoadhesive, copolymers of acrylic acid and poly(ethylene glycol), and to determine the feasibility of transbuccal delivery of acyclovir using this system. METHODS: The buccal delivery system was prepared using an adhesive, a copolymer of acrylic acid and poly(ethylene glycol) monomethylether monomethacrylate, and an impermeable membrane to prevent excessive washout by saliva and to attain unidirectional release. Acyclovir was loaded into the copolymer film prior to lamination of backing material. In vitro drug release studies were conducted in isotonic McIlvaine buffer solution. Buccal permeation of acyclovir was investigated using porcine buccal mucosa with side-by-side flow through diffusion cells at 37;C. Acyclovir was quantified using HPLC. RESULTS: Buccal permeation of acyclovir from the mucoadhesive delivery system was controlled for up to 20 hours with a time lag (t(lag)) of 10.4 hours and a steady state flux of 144.2 microg/cm(2)/h. With the incorporation of NaGC into the system t(lag) was shortened to 5.6 hours with an enhanced steady state flux of 758.7 microg/cm(2)/h. Sustained delivery of acyclovir across bucccal mucosa using this mucoadhesive system was maintained for up to 22 hours. CONCLUSIONS: The mucoadhesive system of P(AA-co-PEG) was shown to be a good candidate for controlled oral mucosal delivery of acyclovir. Buccal delivery of acyclovir was proven feasible based on in vitro permeation studies. (+info)
Mitochondrial electron transfer in the wheat pathogenic fungus Septoria tritici: on the role of alternative respiratory enzymes in fungicide resistance.
(19/539)
Certain phytopathogenic fungi are able to express alternative NADH- and quinol-oxidising enzymes that are insensitive to inhibitors of the mitochondrial respiratory Complexes I and III. To assess the extent to which such enzymes confer tolerance to respiration-targeted fungicides, an understanding of mitochondrial electron transfer in these species is required. An isolation procedure has been developed which results in intact, active and coupled mitochondria from the wheat pathogen Septoria tritici, as evidenced by morphological and kinetic data. Exogenous NADH, succinate and malate/glutamate are readily oxidised, the latter activity being only partly (approx. 70%) sensitive to rotenone. Of particular importance was the finding that azoxystrobin (a strobilurin fungicide) potently inhibits fungal respiration at the level of Complex III. In some S. tritici strains investigated, a small but significant part of the respiratory activity (approx. 10%) is insensitive to antimycin A and azoxystrobin. Such resistant activity is sensitive to octyl gallate, a specific inhibitor of the plant alternative oxidase. This enzyme, however, could not be detected immunologically. On the basis of the above findings, a conceptual mitochondrial electron transfer chain is presented. Data are discussed in terms of developmental and environmental regulation of the composition of this chain. (+info)
Application of a hybrid CFD-PBPK nasal dosimetry model in an inhalation risk assessment: an example with acrylic acid.
(20/539)
The available inhalation toxicity information for acrylic acid (AA) suggests that lesions to the nasal cavity, specifically olfactory degeneration, are the most sensitive end point for developing a reference concentration (RfC). Advances in physiologically based pharmacokinetic (PBPK) modeling, specifically the incorporation of computational fluid dynamic (CFD) models, now make it possible to estimate the flux of inhaled chemicals within the nasal cavity of experimental species, specifically rats. The focus of this investigation was to apply an existing CFD-PBPK hybrid model in the estimation of an RfC to determine the impact of incorporation of this new modeling technique into the risk assessment process. Information provided in the literature on the toxicity and mode of action for AA was used to determine the risk assessment approach. A comparison of the approach used for the current U.S. Environmental Protection Agency (U.S. EPA) RfC with the approach using the CFD-PBPK hybrid model was also conducted. The application of the CFD-PBPK hybrid model in a risk assessment for AA resulted in an RfC of 79 ppb, assuming a minute ventilation of 13.8 l/min (20 m(3)/day) in humans. This value differs substantially from the RfC of 0.37 ppb estimated for AA by the U.S. EPA before the PBPK modeling advances became available. The difference in these two RfCs arises from many factors, with the main difference being the species selected (mouse vs. rat). The choice to conduct the evaluation using the rat was based on the availability of dosimetry data in this species. Once these data are available in the mouse, an assessment should be conducted using this information. Additional differences included the methods used for estimating the target tissue concentration, the uncertainty factors (UFs) applied, and the application of duration and uncertainty adjustments to the internal target tissue dose rather than the external exposure concentration. (+info)
Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells.
(21/539)
BACKGROUND: Multidrug resistance-associated protein (MRP) 1 and canalicular multispecific organic anion transporter (cMOAT or MRP2) are adenosine triphosphate-binding cassette transporters that confer resistance to anticancer agents. In addition to these two transporters, there are at least four other human MRP subfamily members (MRP3 through MRP6). We and others reported previously that MRP3 is capable of conferring resistance to certain anticancer agents. In this study, we investigated whether MRP4 (MOAT-B), whose transcript accumulates to the highest levels in prostate tissue, has the capacity to confer drug resistance. METHODS: MRP4-transfected NIH3T3 cells were generated, and their drug sensitivity was analyzed. The subcellular localization of MRP4 was assessed by immunohistochemical analysis in transfected cells and in prostate tissue. Statistical tests were two-sided. RESULTS: MRP4 was detected as a 170-kd protein that was localized in the plasma membrane and cytoplasm of transfected cells. The MRP4 transfectants displayed 5.5-fold increased resistance to methotrexate in short-term drug-exposure assays (P=.022) and exhibited decreased cellular accumulation of this agent at 4 hours (P=.006) and 24 hours (P<.001). In continuous-exposure assays, however, the MRP4 transfectants did not display increased resistance for either methotrexate or natural product cytotoxic agents (anthracyclines, etoposide, vinca alkaloids, and paclitaxel [Taxol]). However, the transfectants did show increased resistance (2.3-fold) for the anti-acquired immunodeficiency syndrome nucleoside analogue 9-(2-phosphonylmethoxyethyl)adenine (PMEA) (P=.022) in continuous-exposure assays. Consistent with MRP4's plasma membrane localization in transfected cells, analysis of prostate tissue showed that MRP4 protein was localized primarily in the basolateral plasma membranes of tubuloacinar cells. CONCLUSIONS: These results indicate that MRP4 confers resistance to short-term methotrexate and continuous PMEA treatment. Given its structure, drug resistance profile and subcellular localization, MRP4 probably functions as an amphipathic anion efflux pump whose substrate range includes glutamate and phosphate conjugates. (+info)
Workers' dermal exposure to UV-curable acrylates in the furniture and Parquet industry.
(22/539)
The use of ultraviolet radiation-curable coatings (UV-coatings) has increased rapidly in the parquet and furniture industry. Work with UV-coatings involves risk from skin exposure to chemically reactive, concentrated acrylates that are known skin contact irritants and sensitizers. Yet, the methods and tools for measuring and quantifying dermal exposure from hazardous chemicals directly on the skin are limited and methods to measure skin exposure to UV-coatings in occupational or environmental settings have been lacking. Skin exposure to UV-coatings was measured employing a quantitative tape stripping method that we have developed for this purpose. A pilot study was performed at three workplaces. In the main study, workers' skin exposure to uncured UV-coatings was measured at seven workplaces and on two separate workdays (rounds 1 and 2) within a six-month period to determine exposure variation. Skin exposure was measured at four standardized sites on the hand, 3-4 times per work shift. The forehead was sampled once. A questionnaire was carried out with the workers in both rounds to find out factors that can affect skin exposure to UV-coatings. The pilot study indicated that both skin and surface contamination to TPGDA-containing UV-coatings were common and varied up to 2110 microgram on the sampling area of 10cm(2). In the main study skin contamination due to TPGDA was found on 16 of 23 workers, at 6 out of the 7 workplaces, and from 36 (5. 4%) of the 664 samples. In round one 8.6% (n=383) of the samples contained TPGDA and in round two 1.1 % (n=281). The average TPGDA mass on all the positive samples (n=36) was 30.4+/-77.0 microgram for the first and second rounds alone this mass was 30.6+/-80 (n=33) and 28.3+/-16.5 microgram (n=3), respectively. Despite the limited sampling area and sampling sites, we could find residues of TPGDA at all sampling times, even at the beginning of the work shift. This may be due to transfer of UV-coatings through contaminated equipment, shoes and surfaces. Our study indicates that there is a risk of harmful skin exposure to UV-coatings in the furniture and parquet industry. (+info)
Influence of intraocular lens material and design on postoperative intracapsular cellular reactivity.
(23/539)
PURPOSE: To evaluate the influence of intraocular lens (IOL) material and design on the outcome of postoperative lens epithelial cell proliferation within the capsular bag after cataract surgery. METHODS: A total of 5,079 human globes containing rigid and foldable posterior chamber IOL styles commonly implanted in the United States (n = 8) were analyzed in this study. Each globe, fixated in 10% formalin, was sectioned at the equator and analyzed using the Miyake-Apple posterior technique. The study consisted of 3 parts: First, to evaluate posterior capsule opacification (PCO); the Nd:YAG laser posterior capsulotomy rate (%) was documented and plotted on a monthly basis, creating a computerized trend line for each IOL style. Second, to evaluate anterior capsule opacification (ACO); 460 globes were processed for histologic examination. Anterior capsule fibrosis was scored from 0 to III, according to the thickness of proliferative tissue/cells on the inner surface of the anterior capsule at the capsulorhexis margin. Third, interlenticular opacification (ILO) was studied by analysis of 3 pairs of acrylic piggyback lenses that had been explanted because of opacification between their optics. Each IOL pair was processed for histologic examination, and scanning electron microscopy was performed on 1 of the lenses. RESULTS: In the first study, relatively higher Nd:YAG laser posterior capsulotomy rates (19.1% to 32.8%) were noted with the 4 oldest IOL designs in this study (2 foldable lenses, 1 3-piece polymethyl methacrylate [PMMA] design, and 1 single-piece all-PMMA design). Four modern lenses, 1 acrylic lens, and 3 silicone foldable IOL designs had Nd:YAG rates ranging from 1.3% to 14.6% (P < .0001). In the second study, mean ACO scores were highest with silicone-plate lenses (1.77 +/- 0.86 and 1.28 +/- 0.77). The lowest mean score was observed with the acrylic lens (0.51 +/- 0.52; P < .0001). In study 3, the analyses of the 3 pairs of explanted acrylic piggyback lenses showed that the opacification between them (ILO) may have different forms. CONCLUSIONS: Control of postoperative intracapsular cellular proliferation is important in avoiding 3 significant clinical complications. Postoperative lens epithelial cell proliferation is involved in the pathogenesis of PCO, ACO, and ILO, the latter being a newly described form of opacification within the capsular bag related to piggyback IOL implantation. IOL material and design are important factors influencing the outcome of these complications. (+info)
Direct effects of candesartan and eprosartan on human cloned potassium channels involved in cardiac repolarization.
(24/539)
In the present study, we analyzed the effects of two angiotensin II type 1 receptor antagonists, candesartan (0.1 microM) and eprosartan (1 microM), on hKv1.5, HERG, KvLQT1+minK, and Kv4.3 channels expressed on Ltk(-) or Chinese hamster ovary cells using the patch-clamp technique. Candesartan and eprosartan produced a voltage-dependent block of hKv1.5 channels decreasing the current at +60 mV by 20.9 +/- 2.3% and 14.3 +/- 1.5%, respectively. The blockade was frequency-dependent, suggesting an open-channel interaction. Eprosartan inhibited the tail amplitude of HERG currents elicited on repolarization after pulses to +60 mV from 239 +/- 78 to 179 +/- 72 pA. Candesartan shifted the activation curve of HERG channels in the hyperpolarizing direction, thus increasing the current amplitude elicited by depolarizations to potentials between -50 and 0 mV. Candesartan reduced the KvLQT1+minK currents elicited by 2-s pulses to +60 mV (38.7 +/- 6.3%). In contrast, eprosartan transiently increased (8.8 +/- 2.7%) and thereafter reduced the KvLQT1+minK current amplitude by 17.7 +/- 3.0%. Eprosartan, but not candesartan, blocked Kv4.3 channels in a voltage-dependent manner (22.2 +/- 3.5% at +50 mV) without modifying the voltage-dependence of Kv4.3 channel inactivation. Candesartan slightly prolonged the action potential duration recorded in guinea pig papillary muscles at all driving rates. Eprosartan prolonged the action potential duration in muscles driven at 0.1 to 1 Hz, but it shortened this parameter at faster rates (2--3 Hz). All these results demonstrated that candesartan and eprosartan exert direct effects on Kv1.5, HERG, KvLQT1+minK, and Kv4.3 currents involved in human cardiac repolarization. (+info)