Firing Increases Arsenic Leaching from Ceramic Water Filters via Arsenic and Iron Phase Transformations.

Ceramic water filters (CWFs) are produced globally using local clay sources and can effectively remove bacterial pathogens during point-of-use water treatment. The ceramic production process involves firing clay mixed with burnout material at temperatures of 800-1100 °C, which induces mineralogical changes leading to increased arsenic (As) leaching from CWF material compared to source clay. Unfired clay and fired CWFs from Cambodia, Canada, and Mexico, CWF from Laos, and test-fired clay from the United States were analyzed to determine the extent of As leaching from CWFs that range in As (<1 to 16 mg kg-1) and iron (Fe) (0.6 to 5%) content. Deionized water, NaOH, HCl, and oxalate extractions showed that firing increased As solubility and decreased Fe solubility compared to unfired clay, with up to 8 mg kg-1 of water-soluble As in Cambodian CWFs. X-ray absorption spectra of the Cambodian clay and CWF showed a decrease in the Fe-O distance from 2.01 to 1.91 Å and decreased Fe coordination number from 6.3 to 4.6 after firing, indicating a decrease in Fe-O coordination. Arsenic(V) was the dominant species in Cambodia clay and CWF, existing primarily as a surface complex with average As-Fe distance of 3.28 Å in clay while in CWF As was either an outer-sphere As(V) phase or a discrete arsenate phase with no significant As-Fe scattering contribution within the resolution of the data. Improved understanding of molecular-scale processes that cause increased As leaching from CWFs provides a basis for assessing As leaching potential prior to CWF factory capital investment as well as engineered solutions (e.g., modified firing temperature, material amendments, and leaching prior to distribution) to mitigate As exposure from CWFs.

Corneal Endothelial Cell Toxicity Determines Long-Term Outcome After Ocular Exposure to Sulfur Mustard Vapor.

PURPOSE: Ocular exposure to sulfur mustard (SM) vapor causes acute loss of corneal endothelial cells (CECs). Persistent corneal endothelial pathologies are observed in eyes that do not recover from SM exposure, suggesting that endothelial toxicity contributes to mustard gas keratopathy (MGK). Here, we evaluated the contributions of endothelial loss to acute and chronic corneal injuries in SM-exposed eyes. METHODS: Rabbit eyes were exposed in vivo to equivalent doses of SM using 9-, 11-, or 14-mm vapor caps. The effects of exposure area on corneal injury progression were longitudinally evaluated over 12 weeks using clinical evaluations. The effects of exposure area on CEC morphology, endothelial and epithelial ultrastructure, and endothelial barrier function were determined from 1 day to 12 weeks. RESULTS: SM exposure caused loss of CECs and failure of endothelial barrier integrity at 1 day, independent of exposure cap size. By 3 weeks, eyes exposed with the 14-mm vapor cap exhibited increased corneal permeability, repopulation of the endothelium by cells with fibroblastic morphology, and abnormal deposition of extracellular matrix. Eyes exposed with 9- or 11-mm vapor caps exhibited transient symptoms of injury that fully resolved, with the rate of recovery correlated with cap size. CONCLUSIONS: The nonlinear correlation between endothelial lesion size and probability of developing MGK suggests that the CEC loss is a determinative factor for emergence of MGK. These studies illustrate the importance of endothelial repair in preventing MGK. Furthermore, they exclude chemical modification of basement membrane as a mechanistic cause of recurrent epithelial erosions in MGK eyes.

Characterization and treatment of spontaneous recurrent seizures following nerve agent-induced status epilepticus in mice.

PURPOSE: To develop and characterize a mouse model of spontaneous recurrent seizures following nerve agent-induced status epilepticus (SE) and test the efficacy of existing antiepileptic drugs. METHODS: SE was induced in telemeterized male C57Bl6/J mice by soman exposure, and electroencephalographic activity was recorded for 4-6 weeks. Mice were treated with antiepileptic drugs (levetiracetam, valproic acid, phenobarbital) or corresponding vehicles for 14 d after exposure, followed by 14 d of drug washout. Survival, body weight, seizure characteristics, and histopathology were used to characterize the acute and chronic effects of nerve agent exposure and to evaluate the efficacy of treatments in mitigating or preventing neurological effects. RESULTS: Spontaneous recurrent seizures manifested in all survivors, but the number and frequency of seizures varied considerably among mice. In untreated mice, seizures became longer over time. Moderate to severe histopathology was observed in the amygdala, piriform cortex, and CA1. Levetiracetam provided modest improvements in neurological parameters such as reduced spike rate and improved histopathology scores, whereas valproic acid and phenobarbital were largely ineffective. CONCLUSIONS: This model of post-SE spontaneous recurrent seizures differs from other experimental models in the brief latency to seizure development, the occurrence of seizures in 100 % of exposed animals, and the lack of damage to CA4/dentate gyrus. It may serve as a useful tool for rapidly and efficiently screening novel therapies that would be effective against severe epilepsy cases.

Photocatalytic Oxidation of Sulfur Mustard and Its Simulant on BODIPY-Incorporated Polymer Coatings and Fabrics.

Sulfur mustard is one of the most toxic chemical warfare agents worldwide. We report the use of 4,4-difluoro-4-bora-3a,4a-diaza- s-indacene (BODIPY) photosensitizers as a fast and effective sulfur mustard decontaminant and their incorporation into various polymer coatings and fabrics, including army combat uniform. These BODIPY-embedded materials are capable of generating singlet oxygen under visible light irradiation and effectively detoxifying sulfur mustard by converting it into nontoxic sulfoxides as the major products. The rate of decontamination is found to be affected by the photosensitizer structure and concentration as well as the excitation wavelength. The most effective BODIPY-embedded self-decontamination material observed in this study shows a half-life of only 0.8 min. In comparison to the current methods, which use activated carbon as the adsorbent layer, these self-detoxifying coatings and fabrics provide constant destruction of and real-time protection against sulfur mustard.

The intracellular genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone mediates G2-M cell cycle arrest in cancer cells via modulation of the p38 signaling pathway.

The cellular actions of genistein are believed to mediate the decreased risk of breast cancer associated with high soy consumption. We have investigated the intracellular metabolism of genistein in T47D tumorigenic and MCF-10A nontumorigenic cells and assessed the cellular actions of resultant metabolites. Genistein selectively induced growth arrest and G2-M phase cell cycle block in T47D but not MCF10A breast epithelial cells. These antiproliferative effects were paralleled by significant differences in the association of genistein to cells and in particular its intracellular metabolism. Genistein was selectively taken up into T47D cells and was subject to metabolism by CYP450 enzymes leading to the formation of both 5,7,3',4'-tetrahydroxyisoflavone (THIF) and two glutathionyl conjugates of THIF. THIF inhibited cdc2 activation via the phosphorylation of p38 MAP kinase, suggesting that this species may mediate genistein's cellular actions. THIF exposure activated p38 and caused subsequent inhibition of cyclin B1 (Ser 147) and cdc2 (Thr 161) phosphorylation, two events critical for the correct functioning of the cdc2-cyclin B1 complex. We suggest that the formation of THIF may mediate the cellular actions of genistein in tumorigenic breast epithelial cells via the activation of signaling through p38.

Cationic polyamines inhibit anthrax lethal factor protease.

BACKGROUND: Anthrax is a human disease that results from infection by the bacteria, Bacillus anthracis and has recently been used as a bioterrorist agent. Historically, this disease was associated with Bacillus spore exposure from wool or animal carcasses. While current vaccine approaches (targeted against the protective antigen) are effective for prophylaxis, multiple doses must be injected. Common antibiotics that block the germination process are effective but must be administered early in the infection cycle. In addition, new therapeutics are needed to specifically target the proteolytic activity of lethal factor (LF) associated with this bacterial infection. RESULTS: Using a fluorescence-based assay to identify and characterize inhibitors of anthrax lethal factor protease activity, we identified several chemically-distinct classes of inhibitory molecules including polyamines, aminoglycosides and cationic peptides. In these studies, spermine was demonstrated for the first time to inhibit anthrax LF with a Ki value of 0.9 +/- 0.09 microM (mean +/- SEM; n = 3). Additional linear polyamines were also active as LF inhibitors with lower potencies. CONCLUSION: Based upon the studies reported herein, we chose linear polyamines related to spermine as potential lead optimization candidates and additional testing in cell-based models where cell penetration could be studied. During our screening process, we reproducibly demonstrated that the potencies of certain compounds, including neomycin but not neamine or spermine, were different depending upon the presence or absence of nucleic acids. Differential sensitivity to the presence/absence of nucleic acids may be an additional point to consider when comparing various classes of active compounds for lead optimization.

Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension.

BACKGROUND AND AIMS: Infants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), ß-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti-angiogenic factors and have abnormal lung vascular growth in utero. METHODS: Human fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis. RESULTS: The angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects. CONCLUSIONS: We conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti-angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and contributes to high risk for PAH during infancy.