Dragonfly larvae as biosentinels of Hg bioaccumulation in Northeastern and Adirondack lakes: relationships to abiotic factors.

Mercury (Hg) is a toxic pollutant, widespread in northeastern US ecosystems. Resource managers' efforts to develop fish consumption advisories for humans and to focus conservation efforts for fish-eating wildlife are hampered by spatial variability. Dragonfly larvae can serve as biosentinels for Hg given that they are widespread in freshwaters, long-lived, exhibit site fidelity, and bioaccumulate relatively high mercury concentrations, mostly as methylmercury (88% ± 11% MeHg in this study). We sampled lake water and dragonfly larvae in 74 northeastern US lakes that are part of the US EPA Long-Term Monitoring Network, including 45 lakes in New York, 43 of which are in the Adirondacks. Aqueous dissolved organic carbon (DOC) and total Hg (THg) were strongly related to MeHg in lake water. Dragonfly larvae total mercury ranged from 0.016-0.918 µg/g, dw across the study area; Adirondack lakes had the minimum and maximum concentrations. Aqueous MeHg and dragonfly THg were similar between the Adirondack and Northeast regions, but a majority of lakes within the highest quartile of dragonfly THg were in the Adirondacks. Using landscape, lake chemistry, and lake morphometry data, we evaluated relationships with MeHg in lake water and THg in dragonfly larvae. Lakewater DOC and lake volume were strong predictors for MeHg in water. Dragonfly THg Bioaccumulation Factors (BAFs, calculated as [dragonfly THg]:[aqueous MeHg]) increased as lake volume increased, suggesting that lake size influences Hg bioaccumulation or biomagnification. BAFs declined with increasing DOC, supporting a potential limiting effect for MeHg bioavailability with higher DOC.

Decadal trends reveal recent acceleration in the rate of recovery from acidification in the northeastern U.S.

Previous reports suggest variable trends in recovery from acidification in northeastern U.S. surface waters in response to the Clean Air Act Amendments. Here we analyze recent trends in emissions, wet deposition, and lake chemistry using long-term data from a variety of lakes in the Adirondack Mountains and New England. Sulfate concentration in wet deposition declined by more than 40% in the 2000s and sulfate concentration in lakes declined at a greater rate from 2002 to 2010 than during the 1980s or 1990s (-3.27 µeq L(-1)year(-1) as compared to -1.26 µeq L(-1)year(-1)). During the 2000s, nitrate concentration in wet deposition declined by more than 50% and nitrate concentration in lakes, which had no linear trend prior to 2000, declined at a rate of -0.05 µeq L(-1)year(-1). Base cation concentrations, which decreased during the 1990s (-1.5 µeq L(-1) year(-1)), have stabilized in New England lakes. Although total aluminum concentrations increased since 1999 (2.57 µg L(-1) year(-1)), there was a shift to nontoxic, organic aluminum. Despite this recent acceleration in recovery in multiple variables, both ANC and pH continue to have variable trends. This may be due in part to variable trajectories in the concentrations of base cations and dissolved organic carbon among our study lakes.

Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.

KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase.

The tumor necrosis factor-alpha (TNF-alpha) cytokine, secreted by activated monocytes/macrophages and T lymphocytes, is implicated in several diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, and osteoporosis. Monocyte/macrophage production of TNF-alpha is largely driven by p38alpha mitogen-activated protein kinase (MAP kinase), an intracellular soluble serine-threonine kinase. p38alpha MAP kinase is activated by growth factors, cellular stresses, and cytokines such as TNF-alpha and interleukin-l (IL-I). The primary contribution of p38alpha activation to excess TNF-alpha in settings of both chronic and acute inflammation has instigated efforts to find inhibitors of this enzyme as possible therapies for associated disease states. Analogue design, synthesis, and structure-activity studies led to the identification of 5-tert-butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino}-benzamide (KR-003048) as a potent inhibitor of the p38 MAP kinase signaling pathway in vitro and in vivo. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide (LPS)-induced p38 activation and subsequent TNF-alpha release is described. KR-00348 was demonstrated to be a potent inhibitor of inflammatory cytokine production ex vivo in rat and human whole blood, and showed good oral bioavailability. Additionally, efficacy in mouse and rat models of acute and chronic inflammation was obtained. KR-003048 possessed therapeutic activity in acute models, demonstrating substantial inhibition of carrageenan-induced paw edema and in vivo LPS-induced TNF release at 30mg/kg p.o. Collagen-induced arthritis in mice was significantly inhibited by 10 and 30mg/kg doses of KR-003048. Evidence for disease-modifying activity in this model was indicated by histological evaluation of joints.

Formocresol blood levels in children receiving dental treatment under general anesthesia.

PURPOSE: The purpose of this study was to determine the presence of formocresol in the plasma of children undergoing oral rehabilitation involving pulp therapy under general anesthesia. METHODS: Thirty 2- to 6-year-old preschool children were enrolled in the study. Preoperative, intra-operative, and postoperative peripheral venous samples were collected from each child. All samples were analyzed for formaldehyde and cresol levels using gas chromatography with mass spectrometry detection. RESULTS: Eighty-five pulpotomies were performed ranging from 1 to 5 per child. Three hundred twelve blood samples were collected. Analysis revealed that formaldehyde was undetectable above baseline plasma concentration and cresol was undetectable in all samples. Benzyl alcohol (a byproduct of cresol metabolism) was present in all samples except the baseline preoperative samples. Benzyl alcohol concentrations ranged from 0 to 1 mg/ml. CONCLUSIONS: Formaldehyde was undetectable above baseline plasma concentration, and cresol was undetectable in subjects receiving pulpotomy treatment under general anesthesia. Benzyl alcohol was detected in the plasma of all subjects receiving pulpotomy treatment. The levels present were far below the Food and Drug Administration's recommended daily allowance. It is unlikely that formocresol, when used in the doses typically employed for a vital pulpotomy procedure, poses any risk to children.

The design and synthesis of novel alpha-ketoamide-based p38 MAP kinase inhibitors.

We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.

Anthropogenically driven changes in chloride complicate interpretation of base cation trends in lakes recovering from acidic deposition.

Declines in Ca and Mg in low ANC lakes recovering from acidic deposition are widespread across the northern hemisphere. We report overall increases between 1984 and 2004 in the concentrations of Ca + Mg and Cl in lakes representing the statistical population of nearly 4000 low ANC lakes in the northeast U.S. Increases in Cl occurred in nearly all lakes in urbanized southern New England, but only 18% of lakes in more remote Maine had Cl increases. This spatial pattern implicates road salt application as the major source of the increased Cl salts. Among the 48% of the lake population classified as salt-affected, the median changes in Cl (+133 microeq/L) and Ca + Mg (+47 microeq/ L) were large and positive in direction over the 20 years. However, in the unaffected lakes, Cl remained stable and Ca + Mg decreased (-3 microeq/L), consistent with reported long-term trends in base cations of acid-sensitive lakes. This discrepancy between the Cl groups suggests that changes in ion exchange processes in salt-affected watersheds have altered the geochemical cycling of Ca and Mg. One policy-relevant implication is that waters influenced by Cl salts complicate regional assessments of surface water recovery from "acid rain" related to the passage of the Clean Air Act.

Nutrient export from watersheds on Mt. Desert Island, Maine, as a function of land use and fire history.

A study of 13 small (less than 7.5 km(2)) watersheds on Mt. Desert Island, Maine, was conducted from January 1999 to September 2000 to determine nutrient export delivery to coastal waters around the island, and to determine whether a series of wildfires in 1947 have affected nutrient export in burned watersheds. Nutrient export (nitrate-nitrogen, total nitrogen, total phosphorus) was determined for each watershed during the study period, and was normalized by watershed area. The yield of nitrate-nitrogen (N) ranged from 10 to 140 kg/km(2)/year. Total N yield ranged from 42 to 250 kg/km(2)/year. Total phosphorus (P) yield ranged from 1.4 to 7.9 kg/km(2)/year. Watersheds entirely within Acadia National Park (lacking human land-based nutrient sources) exported significantly less total N and total P than watersheds that were partly or entirely outside the park boundary. Nitrate-N export was not significantly different in these two groups of watersheds, perhaps because atmospheric deposition is a dominant source of nitrate in the study area. No relation was observed between burn history and nutrient export. Any effect of burn history may be masked by other landscape-level factors related to nutrient export.

Multiple focal nodular hyperplasia: atypical imaging characteristics in the setting of hepatic steatosis.

Focal nodular hyperplasia is an uncommon, benign lesion of the liver most often affecting women of childbearing age. It can present clinically with chronic, intermittent right upper quadrant pain and nausea, with associated liver enzyme abnormalities. The presence of characteristic sonographic and computed tomography imaging findings can help to differentiate this entity from other hepatic masses. This article describes an unusual case of multifocal disease that demonstrates atypical imaging findings in the background of hepatic steatosis.