Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative motor neuron disease that involves activation of the immune system and inflammatory response in the nervous system. Reduced level of the immuno-modulatory and anti-inflammatory protein alpha-1-antitrypsin (AAT) is associated with inflammation-related pathologies. The objective of the present is to determine AAT levels and IL-23 in the cerebrospinal fluid (CSF) of ALS patients and control group. FINDINGS: CSF samples from newly diagnosed ALS patients and age-matched controls were analyzed for AAT and IL-23 by ELISA and magnetic luminex screening, respectively. A statistically significant reduction of 45 % in mean AAT levels was observed in the CSF of ALS patients (21.4 µg/ml) as compared to the control group (mean 38.8 µg/ml, p = 0.013). A statistically significant increase of 30.8 % in CSF mean levels of the pro-inflammatory cytokine IL-23 was observed in ALS patients (1647 pg/ml) in comparison to the controls (1259 pg/ml, p = 0.012). A negative correlation coefficient (r = -0.543) was obtained by linear regression analysis of the two measured parameters (p = 0.036). CONCLUSIONS: Reduced AAT and elevated IL-23 CSF levels support the notion of neuroinflammatory process occurring in ALS patients. Increasing AAT levels in the patients' nervous system should be further investigated as a new therapeutic approach and a novel potential tool for ALS treatment.

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes.

Methylmercury (MeHg) is an environmental neurotoxicant associated with aberrant central nervous system (CNS) functions. In this study, we examined the protective effect of a novel anti-inflammatory and cytoprotective nonapeptide, termed IIIM1, against MeHg-induced toxicity in cultured rat neonatal primary astrocytes. Astrocytes were pretreated for 66 h with 5 µg/ml IIIM1 (4.95 µM) followed by 6 h exposure to MeHg (5 µM). MeHg significantly increased F(2)-isoprostane generation, a lipid peroxidation biomarker of oxidative injury and this effect was significantly reduced upon pre-treatment with IIIM1. The MeHg-induced increase in levels of prostaglandin E(2) (PGE(2)), biomarkers of inflammatory responses, was also decreased in the peptide-treated cells. Mass spectrometry analysis revealed no chemical or binding interaction between MeHg and IIIM1, indicating that intracellular cytoprotective mechanism of action accounts for the neuroprotection rather than direct intracellular neutralization of the neurotoxicant with the peptide. These findings point to therapeutic potential for IIIM1 in a plethora of conditions associated with reactive oxygen species (ROS) generation. The implication of these findings may prove beneficial in designing new treatment modalities that efficiently suppress neurotoxicity, triggered not only by MeHg, but also by other metals and environmental agents, as well as chronic disease conditions that inherently increase reactive radical production and inflammatory signaling.

Pesticide exposure among pregnant women in Jerusalem, Israel: results of a pilot study.

BACKGROUND: Pesticides have been shown to disrupt neurodevelopment in laboratory animals and in human populations. To date, there have been no studies on exposure to pesticides in pregnant women in Israel, despite reports of widespread exposure in other populations of pregnant women and the importance of evaluating exposure in this susceptible sub-population. METHODS: We measured urinary concentrations of organophosphorus (OP) insecticide metabolites and plasma concentrations of OP and other pesticides in 20 pregnant women, recruited in Jerusalem, Israel in 2006, and collected questionnaire data on demographic factors and consumer habits from these women. We compared geometric mean concentrations in subgroups using the Mann-Whitney U-test for independent samples. We compared creatinine-adjusted OP pesticide metabolite concentrations, as well as plasma pesticide concentrations, with other populations of pregnant women. RESULTS: Creatinine-adjusted total dimethyl (DM) metabolite concentrations were between 4 and 6 times higher in this population compared to other populations of pregnant women in the United States while total diethyl (DE) metabolite concentrations were lower. Dimethylphosphate (DMP) was detected in 74% of the urine samples whereas dimethylthiophosphate (DMTP) was detected in 90% of the urine samples. The carbamate bendiocarb was detected in 89% of the plasma samples, while the OP insecticide chlorpyrifos was detected in 42% of the samples. Mean plasma concentrations of bendiocarb and chlorpyrifos in our sample were 4.4 and 3.9 times higher, respectively, than that of an urban minority cohort from New York City. Twelve women (63%) reported using some form of household pest control during their pregnancy and five (26%) reported using household pest control during the past month. Women with a graduate degree had significantly higher geometric mean concentrations of total urinary DM metabolite concentrations compared to other women (P=0.006). Finally, one woman in the study had exceptionally high concentrations of DMP, DMTP, DMDTP compared to the other women in the study, despite reporting no current occupational exposure to OP pesticides and no other significant exposure sources. CONCLUSIONS: Pregnant women in the Jerusalem area are exposed to OP pesticides and to the carbamate pesticide bendiocarb. It is unclear why total DM metabolites concentrations were much higher in this population compared to other populations of pregnant women in the United States and Netherlands. Finally, the finding of very high DM metabolite concentrations in one woman who reported being moved from her regular laboratory work to administrative work upon becoming pregnant, raises questions about the adequacy of measures to protect pregnant women from pesticide exposures during pregnancy.

Anti-inflammatory effects of peptide fragments of H2A histone and Oryza Sativa Japonica protein.

Anti-inflammatory drugs are often of limited use due to low efficacy and toxic effects. The present study describes the anti-inflammatory effects of a novel nonapeptide termed IIIM1, using the mouse hind paw edema as an experimental model of inflammation. Multiple prophylactic injections of IIIM1 resulted in a significant reduction in carrageenan-induced foot pad swelling, both in mice and rats. A single prophylactic treatment of the peptide caused the maximal effect at 7-9 days between the initial peptide treatment and the subsequent carrageenan injection. A reduced inflammatory reaction was observed in transgenic mice constitutively expressing the peptide. A marked decrease in oxidative burst was observed in activated peritoneal macrophages obtained from peptide-treated mice. Furthermore, the sera of IIIM1-treated mice caused a significant decrease in the oxidative burst of macrophages. In addition, the reduction of hind paw swelling in mice injected with the sera of IIIM1-treated mice strongly suggests the presence of a circulating inducible factor responsible for the anti-inflammatory effect of the peptide. Previous LC/MS/MS analysis revealed the presence of a new peptide, termed RA1, in the sera of IIIM1-treated mice. RA1 was identified as a fragment of the Oryza Sativa Japonica protein. The anti-inflammatory effect of RA1 as evidenced by the reduction in carrageenan-induced hind paw swelling corresponded with the decrease in the oxidative burst of macrophages treated in vitro with this peptide. In conclusion, both IIIM1 and RA1 represent potential agents for the efficient treatment of inflammatory diseases that are currently incurable using presently available drugs.

Peaceful use of disastrous neurotoxicants.

The increasing exposure to environmental neurotoxicants in the last decades caused serious health problems in the world population. Some of the neurotoxic agents are being used in agriculture and household such as insecticides and rodenticides and others are of natural origin like snake and scorpion venoms. Additional group of harmful substances is the chemical warfare agents including nerve and blistering agents that are known for their disastrous effects on neuronal tissues. The present paper presents a combination of epidemiological/clinical and molecular approaches for investigating the effect of certain groups of neurotoxicants on a variety of pathologies. The work of Finkelstein and coworkers describes epidemiological and clinical studies on acute and chronic organophosphate (OP)-induced neurotoxicity in certain populations in Israel. They mainly investigated the neurotoxic effects of low-level long-term exposure to OP in agricultural areas but also dealt with acute exposures as well. A molecular approach to OP mechanism of neuronal injury was described by Milatovic and coworkers. They demonstrated OP-induced oxidative injury in pyramidal neurons in the CA1 hippocampal area and its suppression by antioxidants. Lecht and coworkers described the novel snake venom angioneurins as important mediators of the physiological cross-talk between the cardiovascular and nervous systems. They also showed that under certain conditions these angioneurins may induce pathologies such as tumor development or disruption of the vascular barrier function during envenomation. Additional mechanistic/therapeutic approach was presented by Brodsky, Rosengarten, Proscura, Shapira and Wormser. They developed a novel anti-inflammatory peptide that reduced skin irritation induced by heat and sulfur mustard (SM) stimuli. Since SM causes neuropsychiatric symptoms and alterations in neurological functions this peptide may serve as a potential treatment of neuronal injuries caused by environmental neurotoxicants. These reviews highlight different aspects of neurotoxicity, addressing epidemiology and mechanisms of toxicity; and identifying novel potential therapies.

Amelioration of experimental autoimmune encephalitis by novel peptides: involvement of T regulatory cells.

The purpose of the present study was to develop a peptide for treatment of multiple sclerosis (MS). We have tested the effect of a novel anti-inflammatory peptide (KGHYAERVG, termed IIIM1) on experimental autoimmune encephalitis (EAE), an animal model of MS. Our findings demonstrate significant reduction in neurological score following oral administration of IIIM1. Structural studies revealed that the entire peptide is required for activity. The peptide caused significant reduction in IL17, interferon gamma, IL23 and IL12 production by isolated splenocytes and concomitant elevation of anti-inflammatory cytokines. IIIM1 elevated T regulatory cells (Tregs, CD4(+)CD25(+)FoxP3(+)) in brain and spleen of EAE mice. Similar proliferative effect was observed in isolated human and mouse Tregs in vitro. Stimulation of Tregs by IIIM1 caused production of a new peptide termed RA1 present in Oryza Sativa Japonica group. This Japanese rice peptide ameliorated neurological symptoms in the EAE model. Similar beneficial effect was observed upon oral administration of an extract of Japanese rice. In conclusion, oral treatment with IIIM1 ameliorates EAE symptoms via stimulation of Tregs to proliferate and produce RA1 which reduces EAE symptoms. RA1 might be involved in the relatively low prevalence of MS in Japan and other Japanese rice-eating populations.

Phthalate exposure among pregnant women in Jerusalem, Israel: results of a pilot study.

BACKGROUND: Phthalates can disrupt endocrine function and induce reproductive and developmental toxicity in laboratory animals. Few studies have evaluated exposure to phthalates in pregnant women, despite the potential sensitivity of the developing fetus to adverse effects of phthalates. METHODS: We measured urinary concentrations of 11 phthalate metabolites in 19 pregnant women, recruited in Jerusalem, Israel in 2006, and collected questionnaire data on demographic factors and consumer habits from these women. We compared geometric mean concentrations in subgroups and used the Mann-Whitney U-test for independent samples to determine significant differences between groups. RESULTS: Nine metabolites were detected in at least 95% of the samples: mono(2-ethyl-5-carboxypentyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, mono(3-carboxypropyl) phthalate, mono(n-butyl) phthalate, monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), mono(2-ethylhexyl) phthalate and monoisobutyl phthalate. Phthalate metabolite concentrations in these pregnant women were remarkably similar to those in the general United States female population. MBzP geometric mean concentrations were higher in women living in buildings existing 40 years or more (P=0.04). In women who used four or more personal care products (perfume, deodorant, lipstick, nail polish, or hand/face cream) in the 48 h prior to providing the urine sample, geometric mean MEP concentrations were more than 4 times higher than concentrations in women using only two or three of the aforementioned products (P=0.07). CONCLUSIONS: Pregnant women in Jerusalem are exposed to a wide range of phthalates. Building materials used in old constructions may be a source of exposure to benzylbutyl phthalate, the parent compound of MBzP. Personal care products may be sources of exposure to diethyl phthalate, the parent compound of MEP.

From topical antidote against skin irritants to a novel counter-irritating and anti-inflammatory peptide.

The primary purpose of the present study was to investigate the mechanism of the counter-irritating activity of topical iodine against skin lesions induced by chemical and thermal stimuli. The hypothesis that iodine exerts its activity by inducing an endogenous anti-inflammatory factor was confirmed by exposing guinea pig skin to heat stimulus followed by topical iodine treatment and skin extraction. Injection of the extract into naïve guinea pigs reduced heat-induced irritation by 69%. The protective factor, identified as a new nonapeptide (histone H2A 36-44, H-Lys-Gly-Asn-Tyr-Ala-Glu-Arg-Ileu-Ala-OH), caused reduction of 40% in irritation score in heat-exposed guinea pigs. The murine analog (H-Lys-Gly-His-Tyr-Ala-Glu-Arg-Val-Gly-OH, termed IIIM1) reduced sulfur mustard (SM)-induced ear swelling at a dose-dependent bell-shape manner reaching peak activity of 1 mg/kg. Cultured keratinocytes transfected with the peptide were more resistant towards SM than the control cells. The peptide suppressed oxidative burst in activated neutrophils in a concentration-dependent manner. In addition, the peptide reduced glucose oxidase-induced skin edema in mice at a dose-dependent bell-shape manner. Apart from thermal and chemical-induced skin irritation this novel peptide might be of potential use in chronic dermal disorders such as psoriasis and pemphigus as well as non-dermal inflammatory diseases like multiple sclerosis, arthritis and colitis.

Protection from toxicants.

Exposures to skin irritants frequently occur in daily life at the workplace, in laboratories and during housekeeping. Apart from the physical protective countermeasures, there is a need for pharmacological preparations for the topical treatment of the exposed skin to prevent the development of burns. Exposure of the skin to a chemical irritant initiates an inflammatory response which progressively intensifies, leading to epidermal and dermal lesions. Topical treatment with povidone-iodine (PI) or iodine ointment significantly reduced skin damage induced by mustard gas (sulfur mustard), hydrofluoric acid and other chemical irritants. Human studies showed the efficacy of PI and iodine against thermal burns. The combination of anti-inflammatory agents and iodine increased the counterirritating activity. Both human and experimental animal studies demonstrated that the ointment should be immediately applied after occurrence: the earlier the treatment, the better the therapeutic effect. In addition, the ointment should be left on the skin long enough for achieving the therapeutic effect. This simple topical treatment can prevent suffering, skin transplantation and complications associated with skin burns.

Topical iodine facilitates transdermal delivery of insulin.

Transdermal delivery of insulin is a non-invasive alternative to the subcutaneous injection of insulin in diabetic patients. It has been found that skin pretreatment with iodine followed by a dermal application of insulin results in reduced glucose and elevated hormone levels in the plasma. Topical iodine protects the dermally applied insulin presumably by inactivation of endogenous sulfhydryls such as glutathione and gamma glutamylcysteine which can reduce the disulfide bonds of the hormone. Thus, the effect of iodine is mediated by retaining the potency of the hormone during its penetration via the skin into the circulation. The proposed procedure might be applicable for additional disulfide-containing peptides such as calcitonin, somatostatin, oxytocin/vasopressin and their analogs.

Effect of different iodine formulations on the expression and activity of Streptococcus mutans glucosyltransferase and fructosyltransferase in biofilm and planktonic environments.

OBJECTIVES: The glucosyltransferase (GTF) and fructosyltransferase (FTF) enzymes play a pivotal role in dental biofilm formation as they synthesize polysaccharides that act as the extracellular matrix of the biofilm. Iodine is a unique antibacterial agent that has distinct properties from other conventional antibacterial agents. In this study we have examined the effect of iodine and povidone iodine (PI) on gtf and ftf expression in biofilm and planktonic environments and on immobilized and unbound GTF and FTF activity. METHODS: Real-time reverse transcription-PCR was used to investigate the effect of iodine and PI on ftf, gtfB and gtfC expression. The effect of iodine and PI on GTF and FTF activity was tested using radioactive assays. RESULTS: Our results indicate that iodine and PI in a tetraglycol carrier cause enhancement of expression of gtfB in Streptococcus mutans in biofilms but not in planktonic bacteria. PI in water induced expression of gtfB and gtfC in planktonic bacteria. However, iodine and PI strongly inhibit polysaccharide production by GTF and to a lesser extent by FTF activity. The inhibitory effect on GTF activity was similar in solution compared to its activity in the immobilized environment. This unique effect may be attributed to the distinct chemical properties of iodine compared with other antibacterial agents. CONCLUSIONS: This study indicates that iodine at sub-bactericidal concentrations demonstrates molecular and enzymatic effects that are highly associated with biofilm formation.

Toxic serum factor long after single exposure to organophosphate; a new approach for biomonitoring.

One of the major limitations of current methods of biological detection of exposure to hazardous environmental agents is their inability to detect long-term exposures. In the current study we examined the potential of a new bioassay based on the hypothesis that serum of exposed individuals contains a toxic factor(s) produced by an affected cell/tissue. The procedure included exposure of neuronal PC12 cell cultures to sera of rats treated once with the organophosphate chlorpyrifos. Samples taken 4 weeks after chlorpyrifos exposure reduced nerve growth factor (NGF)-induced neurite outgrowth by 40%. This effect lasted 6 weeks after treatment, whereas motor activity and cholinesterase activity returned to normal levels within 1 week. These results demonstrate the potential of the proposed method to detect environmental exposures long after they have occurred.

Early effects of iodine on DNA synthesis in sulfur mustard-induced skin lesions.

Sulfur mustard (SM) is powerful alkylator and highly cytotoxic blisterogen in both humans and animals. This study in male guinea pigs shows that, at an early stage (5 h) after SM exposure, a marked increase occurred in epithelial nuclear vacuolation, epidermal thickening, and dermal acute inflammation. Topical iodine treatment reduced the severity of these parameters. The rate of DNA synthesis expressed by incorporation of bromodeoxyuridine was reduced upon topical treatment with iodine only or SM only by 46 and 72%, respectively. Iodine treatment following SM exposure exerted an effect similar to that of SM only, indicating that DNA synthesis is not directly involved in the mechanism of action of iodine-induced protection.

Involvement of tumor necrosis factor-alpha in sulfur mustard-induced skin lesion; effect of topical iodine.

Sulfur mustard (SM), also termed mustard gas, is a potent vesicant that elicits an inflammatory response upon exposure of the skin. Evaluation of mouse ear 3 h after SM exposure revealed acute inflammatory-cell aggregates in the vascular beds accompanied by strongly TNF-alpha-positive neutrophils. Eight hours after SM exposure, this phenomenon became intensified and associated with infiltration into the adjacent dermis. In ear skin topically treated with iodine, however, no inflammatory cells were observed 3 h after SM exposure; 8 h postexposure, blood vessels contained very few TNF-alpha-positive inflammatory cells. Since TNF-alpha induction was shown to be associated with reactive oxygen species production, we studied the effect of iodine on activated peritoneal mouse neutrophils. Iodine elicited a concentration-dependent reduction in the oxidative burst of activated neutrophils. Iodine also scavenged hydroxyl radicals generated by glucose oxidase in a concentration-dependent manner. The involvement of TNF-alpha in SM-induced skin toxicity was confirmed by reduction of 49 and 30% in ear edema following administration of 1 and 2 mug anti-TNF-alpha antibodies, respectively. These findings were corroborated by quantitative analysis of the histological findings showing 46% reduction in acute inflammation and no signs of subacute inflammation in the treated group, in contrast to the control group treated with SM only. Other epidermal (microblister formation, ulceration, and necrosis) and dermal (neutrophilia, hemorrhage, and necrosis) parameters also showed marked reductions in the antibodies-treated group in comparison to controls. The combination of iodine and antiTNF-alpha antibodies might constitute a new approach for treatment of SM-exposed individuals.

Vitamin D3-based conjugates for topical treatment of psoriasis: synthesis, antiproliferative activity, and cutaneous penetration studies.

PURPOSE: The goals of the experiments reported in this paper were to explore skin bioavailability and cell growth inhibitory activity of new vitamin D3-based conjugates studied as a potential drug complex for psoriasis. METHODS: Conjugation was made between polyunsaturated fatty acids (PUFAs), such as linolenic acid or gamma-linolenic acid, and calcipotriol--a vitamin D3 analogue clinically used for topical treatment of psoriasis. These complexes were prepared by coupling the corresponding fatty acid with calcipotriol in the presence of dicyclohexyl-carbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) to obtain an ester bond. RESULTS: The conjugates were capable of enhancing the penetration of the vitamin into the skin as well as inhibiting proliferation of keratinocytes in cultures. The antiproliferative activity even increased after simulating the full hydrolysis of the conjugates. In vitro skin penetration studies revealed that the conjugates penetrated into the skin at higher levels relative to calcipotriol alone. It was also demonstrated that the conjugate containing n-3 fatty acid penetrated into the skin at higher levels as compared to the conjugate containing n-6 PUFA. High-performance liquid chromatography analysis has shown that after penetration, a major portion of calcipotriol-PUFA conjugate was first converted mainly into another isomer form, presumably by transesterification, and only then it was hydrolyzed to form apparently high local concentrations of both calcipotriol and PUFA. CONCLUSIONS: The unique biotransformation that occurred after penetration into the skin indicates that these conjugates are mutual prodrugs that are able to be bioprocessed in the skin and fully converted to the parent therapeutic agents.

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity.

The chemical warfare blistering agent, sulfur mustard (SM), is a powerful mutagen and carcinogen. Due to its similarity to the related chemotherapy agents nitrogen mustard (mechlorethamine), it is expected to act as a developmental neurotoxicant. The present study was designed to establish a chick model for the mechanisms of SM on neurobehavioral teratogenicity, free of confounds related to mammalian maternal effects. Chicken eggs were injected with SM at a dose range of 0.0017-17.0 microg/kg of egg, which is below the threshold for dysmorphology, on incubation days (ID) 2 and 7, and then tests were conducted posthatching. Exposure to SM elicited significant deficits in the intermedial part of the hyperstriatum ventrale (IMHV)-related imprinting behavior. Parallel decreases were found in the level of membrane PKCgamma in the IMHV, while eliciting no net change in cytosolic PKCgamma. The chick, thus, provides a suitable model for the rapid evaluation of SM behavioral teratogenicity and elucidation of the mechanisms underlying behavioral anomalies. The results obtained, using a model that controls for confounding maternal effects, may be replicated in the mammalian model and provide the groundwork for studies designed to offset or reverse the SM-induced neurobehavioral defects in both avian and mammals.

Reduced sulfur mustard-induced skin toxicity in cyclooxygenase-2 knockout and celecoxib-treated mice.

Sulfur mustard (SM), a potent vesicant and chemical warfare agent, induces tissue damage involving an inflammatory response, including vasodilatation, polymorphonuclear infiltration, production of inflammatory mediators, and cyclooxygenase activity. To evaluate the role of cyclooxygenase-1 and -2 (COX-1, COX-2) in sulfur mustard-induced skin toxicity, we applied the agent to the ears of wildtype (WT) and COX-1- and COX-2-deficient mice. In the latter, ear swelling 24 and 48 h after exposure was significantly reduced (P < 0.05) by 55% and 30%, respectively, compared to WT. Quantitative histopathology revealed no epidermal ulceration in COX-2-deficient mice but some degree of severity in WT. COX-2-deficient mice showed significant reductions (P < 0.05) in severity of epidermal necrosis (29%), acute inflammation (42%), and hemorrhage (25%), compared to the WT mice. COX-1 deficiency resulted in significant exacerbation (P < 0.05) in severity of some parameters, including increases of 4.6- and 1.2-fold in epidermal ulceration and epidermal necrosis, respectively, compared to WT. Postexposure treatment of normal male ICR mice with the selective COX-2 inhibitor celecoxib resulted in significant reductions of 27% (P < 0.05) and 28% (P < 0.01) in ear swelling at intervals of 40 and 60 min between exposure and treatment, respectively. Histopathological evaluation revealed significant reductions (P < 0.05) in subepidermal microblister formation (73%) and dermal necrosis (32%), compared to the control group. These findings may indicate that COX-2 participates in the early stages of sulfur mustard-induced acute skin toxicity and that COX-1 might exert some protective function against this chemical insult.

Low molecular weight antioxidants released from the skin's epidermal layers: an age dependent phenomenon in the rat.

Skin is one of the tissues most exposed to oxidative stress both from endogenous and exogenous sources. Therefore, it can be speculated that skin possesses an extremely efficient antioxidant defense mechanism, particularly in its epidermal layers. The present study shows that human and rat skins possess different and unique reducing antioxidant profiles. These reducing antioxidants can be washed out into the surrounding environment. Non-invasive measurements indicated that skin releases low molecular weight antioxidants (LMWA) from its epidermal layers. Cyclic voltammetry measurements have shown that rat skin releases three major groups of reducing antioxidants at peak potentials of 476 and 889 and 1044 mV while human skin releases two major groups at peak potentials of 779 and 1068 mV. In rat, the overall concentrations of the LMWA secreted decreased significantly with age. The major components of the LMWA composing the first anodic wave in rats were identified as uric acid and ascorbic acid. Uric acid and other as yet uncharacterized LMWA, but not ascorbic acid, were released in human skin. Differences in the ability to release high levels of uric acid among species were well correlated with their metabolic rates. It is suggested that in rat the released LMWA may serve as a possible marker for aging of the skin.

Protective effect of topical iodine containing anti-inflammatory drugs against sulfur mustard-induced skin lesions.

Previous studies have shown the antidotal efficacy of topical iodine at 15 and 30 min post-exposure to sulfur mustard (SM). Here we demonstrate efficacy at longer intervals (20, 30, 45, and 60 min, respectively, for data) using an improved topical povidone-iodine preparation termed N66, which contains steroidal and non-steroidal anti-inflammatory agents. In the mouse, N66 reduced severity of ear edema by 43, 47, 44, and 36%; ear epidermal ulceration by 74, 58, 45, and 58%; and epidermal necrosis by 54, 34, 26, and 31% at the respective time points. A similar effect was observed with encrustation. The healing marker, grade of acanthotic area, showed dramatic increases of 39.6-, 25.3-, 20.9-, and 22-fold. Severity of the dermal parameters, acute inflammation and dermal necrosis, was reduced by 63, 34, 34, and 38% and 80, 54, 54, and 59%, respectively. In guinea pig skin, topical treatment with N66 45 min post-exposure reduced the SM-induced ulceration area by 75%. The histological parameters subepidermal microblister formation, epidermal ulceration, epidermal necrosis, and encrustation were reduced by 63, 61, 41, and 41%, respectively. The healing marker, grade of acanthotic area, was elevated by 73%. N66 induced a statistically significant reduction in two dermal markers for tissue damage: acute inflammation (33%) and dermal necrosis (48%). Reduced skin damage was also observed in areas adjacent the treated sites. The pharmacologically active components of N66 showed additive effect. These findings suggest that the povidone-iodine preparation combined with anti-inflammatory agents functions as a potent antidote against skin lesions induced by SM at relatively long intervals between exposure and treatment.

[Ammonia and ammonium salts: remedy and poison, myth and time honored reality].

The public interest in ammonia and its salts has risen due to the recent water crisis in Israel. The focus on their regulatory and environmental aspects has been intensified due to the elevated levels of ammonium salts in the national water system, resulting in a banning of water use in the Dan district. To the public it is commonly known that ammonia is toxic. Nevertheless, the medical view regarding ammonium salts is very different from that of ammonia gas. In contrast to the hazardous ammonia gas, its salts (such as ammonium bicarbonate) are considered to be much less toxic and are widely used as medicaments and food additives. Thus, although the presence of ammonium salts in the drinking water may indicate contamination, this is not a case of poisoning associated with toxic side effects.