Sodium Butyrate Downregulates Implant-Induced Inflammation in Mice.

Sodium butyrate (NaBu), a histone deacetylase inhibitor, has shown to exert beneficial actions attenuating inflammation in a number of intestinal and extra-intestinal diseases. However, the effects of NaBu on persistent inflammatory processes as in a response to implantation of foreign material have not been investigated. Synthetic matrix of polyether-polyurethane sponge was implanted in mice's subcutaneous layer of the dorsal region, and the animals were treated daily with oral administration of NaBu (100 mg/kg). After 7 days, the implants were removed and processed for assessment of inflammatory markers. Butyrate treatment caused a significant attenuation of neutrophil and macrophage infiltration in implants, which was reflected by the reduction of myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities, respectively. Similar reduction was observed in intra-implants nitrite levels of NaBu-treated mice. NaBu treatment was also able to decrease mast cell recruitment/activation and the levels of CXCL1, CCL2, IL-6, TNF-ɑ, and TGF-ß1 in the implants but did not alter the levels of IL-10. In addition, NaBu administration decreased the concentration of proteins p65 and p50 in the nucleus as compared with the cytoplasm by western blot analysis. This result suggests that treatment with NaBu inhibited the NF-κB pathway. The circulating levels of TNF-ɑ and TGF-ß1 were also attenuated by NaBu. Persistent inflammation at sites of implanted devices very often impairs their functionality; therefore, our findings suggest that NaBu holds potential therapeutic value to control this adverse response to biomedical implants.

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor.

Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-d-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials.

Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case-control study.

OBJECTIVES: Glycol ethers (GE) are oxygenated solvents frequently found in occupational and consumer products. Some of them are well-known testicular and developmental animal toxicants. This study aims to evaluate the risk of male genital anomalies in association with prenatal exposure to GE using urinary biomarkers of exposure. METHODS: We conducted a case-control study nested in two joint mother-child cohorts (5303 pregnant women). Cases of cryptorchidism and hypospadias were identified at birth and confirmed during a 2-year follow-up period (n=14 cryptorchidism and n=15 hypospadias). Each case was matched to three randomly selected controls within the cohorts for region of inclusion and gestational age at urine sampling. Concentrations of five GE acidic metabolites were measured in spot maternal urine samples collected during pregnancy. ORs were estimated with multivariate conditional logistic regressions including a Firth's penalisation. RESULTS: Detection rates of urinary GE metabolites ranged from 8% to 93% and only two were sufficiently detected (>33%) in each cohort to be studied: methoxyacetic acid (MAA) and phenoxyacetic acid (PhAA). A significantly higher risk of hypospadias was associated with the highest tertile of exposure to MAA: OR (95% CI) 4.5(1.4 to 23.4). No association were observed with urinary concentration of PhAA, nor with the risk of cryptorchidism. CONCLUSIONS: In view of the toxicological plausibility of our results, this study, despite its small sample size, raises concern about the potential developmental toxicity of MAA on the male genital system and calls for thorough identification of current sources of exposure to MAA.

[Ethylene glycol and propylene glycol ethers - Reproductive and developmental toxicity]. / Etery glikolu etylenowego i glikolu propylenowego - toksycznosc reprodukcyjna i rozwojowa.

Both ethylene and propylene glycol alkyl ethers (EGAEs and PGAEs, respectively) are widely used, mainly as solvents, in industrial and household products. Some EGAEs demonstrate gonadotoxic, embriotoxic, fetotoxic and teratogenic effects in both humans and experimental animals. Due to the noxious impact of these ethers on reproduction and development of organisms EGAEs are replaced for considerably less toxic PGAEs. The data on the mechanisms of testicular, embriotoxic, fetotoxic and teratogenic effects of EGAEs are presented in this paper. Our particular attention was focused on the metabolism of some EGAEs and their organ-specific toxicities, apoptosis of spermatocytes associated with changes in the expression of various genes that code for oxidative stress factors, protein kinases and nuclear hormone receptors.

Diabetes alters inflammation, angiogenesis, and fibrogenesis in intraperitoneal implants in rats.

The increased prevalence of diabetes worldwide is associated with increasing numbers of diabetic individuals receiving synthetic matrices and biomedical implants to repair and/or replace biological tissues. This therapeutic procedure invariably leads to adverse tissue healing (foreign body reaction), thus impairing the biomedical device function of subcutaneous implants. However, the influence of diabetes on abnormal tissue healing in intraperitoneal implants is unclear. We investigated key components of foreign body reactions in diabetic rats. Polyether-polyurethane sponge discs were placed intraperitoneally in rats previously injected with streptozotocin for induction of diabetes and in non-diabetic rats. Implants removed 10 days after implantation were assessed by determining the components of the fibrovascular tissue (angiogenesis, inflammation, and fibrogenesis). In implants from diabetic rats, fibrous capsule thickness and fibrovascular tissue infiltration (hematoxylin & eosin and picrosirius staining) were reduced in comparison with implants from non-diabetic rats. Hemoglobin (Hb) content (vascular index) and VEGF levels (pro-angiogenic cytokine) were increased after diabetes. However, the number of vessels (H&E and CD31-immunostaining) in the fibrovascular tissue from diabetic rats was decreased when compared with vessel numbers in implants from non-diabetic animals. Overall, all inflammatory parameters (macrophage accumulation-NAG activity; TNF-α and MCP-1 levels) increased in intraperitoneal implants after diabetes induction. The pro-fibrogenic cytokine (TGFß-1) increased after diabetes, but collagen deposition remained unaltered in the implants from diabetic rats. These important diabetes-related changes (increased levels of pro-inflammatory and angiogenic and fibrogenic cytokines) in peritoneal implant healing provide an insight into the mechanisms of the foreign body response in the diabetic environment in rats.

[Mass-spectrometric control of compound A during minimal flow anesthesia and its influence on liver and kidneys functions].

The article contains results of mass-spectrometric control of sevoflurane and compound A concentrations during inhalation anesthesia with minimal flow (< or = 0.5 l/min) and its influence on liver and kidney function. 40 patients (ASA I-II) were included in the study. Transsphenoidal pituitary adenomectomy was performed in all cases. Patients didn't have any signs of liver or kidneys disfunctions preoperatively. We used quadrupole mass spectrometer "Prisma Plus" (Pfeiffer vacuum, Germany) to determine the real time concentration of sevoflurane and compound A. Intensity of m/z = 131 peak sevoflurane and m/z = 128 peak compound A were registered. Laboratory blood tests to assess liver and kidney function were carried out before anesthesia, after anesthesia, and on the 1st day after anesthesia. They included: AST, ALT, total bilirubin, total protein, urea, creatinine. Quantitative analysis of the compound A and blood test before and after anesthesia showed only a tendency to increase biochemical markers levels within normal range, except small, but significant, AST elevation and total protein reduction in postoperative period. We concluded that maximal registered level of compound A (275 ppm/h) during minimal flow anesthesia didn't associate with significant liver and kidneys injury in healthy patients.

[A survey of occupational health among polyether-exposed workers].

OBJECTIVE: To investigate the occupational health of the workers simultaneously exposed to acrylonitrile, epoxyethane, epoxypropane, and styrene. METHODS: A questionnaire survey was conducted in 70 front-line workers simultaneously exposed to acrylonitrile, epoxyethane, epoxypropane, and styrene (exposure group) and 50 managers (control group) in a polyether manufacturer; in addition, air monitoring at workplace and occupational health examination were also performed. The obtained data were analyzed. RESULTS: The female workers in exposure group and the spouses of male workers in exposure group had significantly higher spontaneous abortion rates than their counterparts in control group (P < 0.01). The exposure group had a significantly higher abnormal rate of blood urea nitrogen than the control group (P < 0.01). The workers with different polyether-exposed working years had significantly higher mean levels of DNA damage than the control group (P < 0.01); the workers with not less than 5 and less than 20 polyether-exposed working years and those with not less than 20 polyether-exposed working years had significantly higher mean micronucleus rates than the control group (P < 0.01); there were no significant differences in overall chromosome aberration rate and mean level of DNA damage between each two groups of workers with different polyether-exposed working years (P > 0.05); the workers with not less than 5 and less than 20 polyether-exposed working years and workers with not less than 20 polyether-exposed working years had significantly higher mean micronucleus rates than those with less than 5 polyether-exposed working years (P < 0.01). CONCLUSION: Simultaneous exposure to acrylonitrile, epoxyethane, epoxypropane, and styrene causes occupational hazards among the workers in polyether manufacturer.

A rare allergy to a polyether dental impression material.

Polyether impression materials have been used in dentistry for more than 40 years. Allergic reactions to these materials such as reported in the 1970s ceased after replacement of a catalyst. Very recently, however, patients have started to report symptoms that suggest a new allergic reaction from polyether impression materials. Here, we report on the results of allergy testing with polyether impression materials as well as with its components. Eight patients with clinical symptoms of a contact allergy (swelling, redness or blisters) after exposure to a polyether impression material were subjected to patch tests, two of them additionally to a prick test. A further patient with atypical symptoms of an allergy (nausea and vomiting after contact with a polyether impression material in the oral cavity) but with a history of other allergic reaction was also patch tested. The prick tests showed no immediate reactions in the two patients tested. In the patch tests, all eight patients with typical clinical symptoms showed positive reactions to the mixed polyether impression materials, to the base paste or to a base paste component. The patient with the atypical clinical symptoms did not show any positive patch test reactions. Polyether impression materials may evoke type IV allergic reactions. The causative agent was a component of the base paste. In consideration of the widespread use of this impression material (millions of applications per year) and in comparison to the number of adverse reactions from other dental materials, the number of such allergic reactions is very low. In very scarce cases, positive allergic reactions to polyether impression materials are possible.

2-Butoxyethanol model of haemolysis and disseminated thrombosis in female rats: a preliminary study of the vascular mechanism of osteoarthritis in the temporomandibular joint.

Female rats develop haemolytic anaemia and disseminated thrombosis and infarction in multiple organs, including bone, when exposed to 2-butoxyethanol (BE). There is growing evidence that vascular occlusion of the subchondral bone may play a part in some cases of osteoarthritis. The subchondral bone is the main weight bearer as well as the source of the blood supply to the mandibular articular cartilage. Vascular occlusion is thought to be linked to sclerosis of the subchondral bone associated with disintegration of the articular cartilage. The aim of this study was to find out whether this model of haemolysis and disseminated thrombosis supports the vascular hypothesis of osteoarthritis. Six female rats were given BE orally for 4 consecutive days and the two control rats were given tap water alone. The rats were killed 26 days after the final dose. The mandibular condyles showed histological and radiological features consistent with osteoarthritis in three of the four experimental rats and in neither of the control rats. These results may support the need to explore the vascular mechanism of osteoarthritis further.

Perfluoropolyether phosphate: a non-irritating acidic agent of cosmeceutical use.

Formulating at acidic pH is a route to improve the chemical or biological stability and the performances of cosmeceuticals. Unfortunately, its potential is limited by the poor differentiation of available acidic agents, and by the risk of skin irritation. Recently, a perfluoropolyether phosphate was proposed to formulate acidic gels and emulsions, with advantages related with the specific active ingredient. The safety of these compositions, evaluated on volunteers, was the main objective of several studies. On the basis of these tests, and of its activity as O/W emulsifier, antimicrobial agent and oil repellent material, it can be asserted that perfluoropolyether phosphate widens the potential of acidic compositions regarding safety and functionality.

Significant exposures to isoeugenol derivatives in perfumes.

BACKGROUND: Isoeugenol, an important fragrance allergen in consumers, has been restricted to 200 p.p.m. since 1998 according to guidelines issued by the fragrance industry. However, no decline in contact allergy to isoeugnol has been detected. It has been speculated that isoeugenol derivatives, especially isoeugenyl acetate, are used instead. Isoeugenyl acetate is probably metabolized in the skin to isoeugenol and gives positive patch test reactions in 1/3 of isoeugenol-sensitized individuals. OBJECTIVES: To investigate the content of isoeugenol, isoeugenyl acetate, and two isoeugenol ethers in perfumes/aftershaves. MATERIALS AND METHODS: 29 international brand perfumes/aftershaves were analysed for the target fragrance ingredient by gas chromatography-mass spectrometry. All samples were analysed in duplicate at detection levels of 1-5 p.p.m. RESULTS: 16 products (55%) contained isoeugenol. The maximum concentration was 202 p.p.m. 10 products (34%) contained isoeugenyl acetate, which in 9 cases occurred together with isoeugenol. The concentrations of isoeugenyl acetate ranged from 20 to 4689 p.p.m. 13 products (44%) contained 64.9-1755.0 p.p.m. isoeugenyl methyl ether. Isoeugenyl benzyl ether was not detected in any of the investigated products. CONCLUSIONS: Isoeugenyl acetate is present in perfumes/aftershaves, in some products in significant amounts. This may lead to elicitation of contact allergy in isoeugenol-sensitized individuals and may contribute to unchanged levels of isoeugenol sensitization.

Risco ambiental da aplicação de éteres de difenilas polibromadas como retardantes de chama / Environmental risks involved with the application of polybrominated diphenyl ethers as flame retardants

Flame retardants are additives of combustible materials, such as plastics, textile, electronic circuitry, wood and paper providing resistance to the combustion process when exposed to fire and high temperature. The main flame retardants used are inorganic chemicals (such as antimony oxides), organic phosphate esters with or without halogens, and chlorinated and brominated organic compounds. The brominated flame retardants (BFRs) are largely used due to its efficiency and low cost. The most used flame retardants are the polybrominated diphenyl ethers (PBDEs), produced inlarge-scale whose degradation is very difficult. Thus, they have been found in many different environmental samples. These observations suggest the current destination of these substances is still devoid of recycling or specific treatment. Despite the increased application in oil polymers, little is known about its impact upon the ecosystem. In this review, we provide an overview about the use and risks related to PBDEs as a recognized toxicants found in industries.

Os retardantes de chama, dentre os quais se destacam os éteres de difenilas polibromadas, são aditivos de materiais destinados a torná-los resistentes ao fogo ou a altas temperaturas, inibindo ou suprimindo o processo de combustão, dentre os quais se destacam os éteres de difenilas polibromadas (PBDEs, do inglês, polibromated diphenyl ethers). Devido a sua produção em grande escala e sua difícil degradação, os PBDEs têm sido um contaminante emergente frequentemente encontrados em diferentes amostras ambientais, demonstrando que o processo produtivo, em especial o destino desse material, requer medidas estratégicas que racionalize seu uso. Apesar da ampla utilização desses aditivos em polímeros (na maioria derivados de petróleo) e tecidos inflamáveis comumente utilizados, pouco se sabe a respeito do impacto dessas substâncias sobre o ecossistema. Nessa revisão, uma relação consistente a respeito do risco ambiental resultante do uso indiscriminado desses aditivos, ainda carentes de regulamentação específica, foi estabelecida com base na ação desses compostos bem como a prevalência de algumas classes, reconhecidamente tóxicas em alguns ambientes.

[Contribution of statistical analytic tools to risk assessment]. / Intérêt des outils statistiques analytiques dans l'évaluation des risques.

Risk assessment is an important aspect of health safety. The main basis of information comes from the identification of adverse effects observed in animal studies, in vitro models, or in silico computer models. These data are used to construct a proof scaffold with an inherent double uncertainty about its clinical pertinence and the probability of occurrence in man. This uncertainty can be reduced with statistical analytical tools, particularly factorial analysis and principal component analysis. Factorial analysis describes a group of variables using a linear combination of underlying common factors associated with a single variable summarizing the specific contribution of each initial variable, thus providing evidence demonstrating the probability of the undesirable effect under consideration. Principal component analysis consists in expressing a group of variables (undesirable effects) by linear combinations of uncorrelated factors. These factors account for a more or less extensive proportion of the data variability thus limiting loss of data pertinence.

Miconidin and miconidin methyl ether from Primula obconica Hance: new allergens in an old sensitizer.

Several chemical and clinical observations have suggested the presence of at least one more allergen in addition to primin in Primula obconica. The aim of this study was to investigate the allergenicity of the primin precursor miconidin and the related miconidin methyl ether, both isolated from P. obconica. 12 primin-positive persons were patch tested with miconidin 0.01% petrolatum (pet.), miconidin in 96% ethanol incorporated into 0.01% pet., and miconidin methyl ether 1.0% pet. All persons were positive to miconidin 0.01% pet., with the strength of reactions very similar to those of the individual primin reactions, and remained inexplicably negative while testing with miconidin in 96% ethanol and pet., while miconidin methyl ether elicited 7 positive reactions. Although both miconidin and miconidin methyl ether may be allergenic only due to their conversion to primin in the skin, the presence of these substances nevertheless has to be taken into account when assessing the allergenicity of new P. obconica cultivars.

Halogenated inhalational anaesthetics.

The halogenated inhalational anaesthetics halothane, enflurane, isoflurane and desflurane can produce metabolic hepatocellular injury in humans to a variable extent. During metabolism of these anaesthetics, tissue acetylation occurs due to the formation of reactive intermediates. Proteins modified by acetylation may constitute neo-antigens with a potential for triggering an antibody-mediated immune response. The likelihood of suffering post-operative immune hepatitis depends on the amount of the anaesthetic metabolized and is thereby considerably less with enflurane, isoflurane or desflurane compared with halothane. Plasma inorganic fluoride concentrations are regularly increased after sevoflurane. Elevated inorganic fluoride concentrations have been associated with nephrotoxicity following methoxyflurane anaesthesia but not after sevoflurane. Another source of concern is the products of degradation from reactions with carbon dioxide absorbents. Most important is compound A, which has been shown to exhibit nephrotoxicity in rodents. However, no significant changes in renal function parameters have been reported in surgical patients.

Predicted distribution and ecological risk assessment of a "segregated" hydrofluorrother in the Japanese environment.

An assessment of HFE-7500, a 'segregated' hydrofluoroether, was conducted to evaluate the potential for exposure to and subsequent effects on humans and wildlife in Japan. The segregated hydrofluoroethers belong to a class of fluorochemicals currently being proposed as replacements for traditional fluorochemicals (CFCs and PFCs) that are currently being used in several industries, in particular, the semiconductor industry. These traditional compounds have been implicated as ozone-depleting or potent "greenhouse gases". The segregated hydrofluoroethers have useful physical and chemical properties, but do not contribute to ozone depletion and have lower "global warming potential" (GWP) indices. Although the physical properties of these materials (low H2O solubility and high vapor pressure) suggest there would be a very low level of risk to aquatic systems, a thorough analysis had not been previously performed. Predicted environmental concentrations (PECs) of HFE-7500 in Japan were determined with the Higashino model, a Gausian puff and plume model that used an approximation of environmental releases to the atmosphere as input to the model. Allowable concentrations to protect aquatic life, wildlife, and humans from noncancer effects were determined as detailed in USEPA's final Water Quality Guidance for the Great Lakes Systems. Potential risk to ecological receptors and humans was determined by calculating hazard quotients and margins of safety. The results of the risk assessment indicate that HFE-7500 poses no significant risk to either aquatic or terrestrial wildlife species or humans living in the Japanese environment. The least margin of safety for any ecological receptor was 100,000, and a margin of safety greater than 100,000,000 for most receptors indicated that HFE-7500 poses no threat to human health. Because of a scarcity of toxicity and exposure data, the risk assessment was based on very conservative assumptions. Therefore, the actual margins of safety for both humans and wildlife could have been 100- to 1,000-fold greater if additional data were available such that less stringent uncertainty factors could be applied. These results suggest that the environmental impact of HFE-7500 should be inconsequential based on the marked improvement in its atmospheric properties relative to the traditional compounds currently in use. Given the short atmospheric lifetime and low global warming potential of this material, its replacement of CFCs and PFCs would result in a net improvement of environmental health and safety.

Comparison of plasma alpha glutathione S-transferase concentrations during and after low-flow sevoflurane or isoflurane anaesthesia.

BACKGROUND: We evaluated the effect of low-flow sevoflurane anaesthesia, in which compound A is generated, and isoflurane anaesthesia, in which compound A is not generated (n=13 in each group), on hepatocellular integrity using alpha glutathione S-transferase (GST). Alpha GST is a more sensitive and specific marker of hepatocellular damage than is aminotransferase activity and correlates better with hepatic histology. METHODS: Sevoflurane or isoflurane were delivered without nitrous oxide with a fresh gas flow of 1 l/min. Concentrations of compound A in the circuit were measured hourly, and plasma alpha GST concentrations were measured perioperatively. RESULTS: Mean duration of anaesthesia was 338+/-92 min in the sevoflurane group and 320+/-63 min in the isoflurane group. Mean compound A concentration in the sevoflurane group was 28.6+/-9.0 ppm. There was no significant difference in alpha GST concentrations between the sevoflurane and isoflurane groups during or after anaesthesia. CONCLUSION: These results indicate that low-flow sevoflurane and isoflurane anaesthesia have the same effect on hepatic function, as assessed by plasma alpha GST concentrations.