For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo ...testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial screening, but it is not presently a complete or surrogate approach to determine whether a chemical is a DNT in humans. By itself, the DNT IVB does not have the ability to capture nuances and complexity of the developing nervous system and associated outcomes including behavioral ontogeny, motor activity, sensory function, and learning/memory. Presently, such developmental landmarks cannot be adequately assessed in the DNT IVB or by other NAMs. The expert panel (all who serve as co-authors of this review) recommended that additional data generation and validation is required before the DNT IVB can be considered for application within global regulatory frameworks for decision-making.
•An expert panel of developmental neurotoxicologists and risk assessors was assembled.•Panelists provided input on interpretation of in vitro DNT screening studies.•DNT IVB is currently best suited for prioritization.•Test should be validated/harmonized across labs and within test systems.•Exposure/PBPK parameters should be considered to determine relevance of in vitro data.
Over 100 free-ranging adult California sea lions (Zalophus californianus) and one Northern fur seal (Callorhinus ursinus), predominantly adult females, were intoxicated by domoic acid (DA) during ...three harmful algal blooms between 1998 and 2000 in central and northern California coastal waters. The vector prey item was Northern anchovy (Engraulis mordax) and the primary DA-producing algal diatom was Psuedonitzschia australis. Postmortem examination revealed gross and histologic findings that were distinctive and aided in diagnosis. A total of 109 sea lions were examined, dying between 1 day and 10 months after admission to a marine mammal rehabilitation center. Persistent seizures with obtundation were the main clinical findings. Frequent gross findings in animals dying acutely consisted of piriform lobe malacia, myocardial pallor, bronchopneumonia, and complications related to pregnancy. Gross findings in animals dying months after intoxication included bilateral hippocampal atrophy. Histologic observations implicated limbic system seizure injury consistent with excitotoxin exposure. Peracutely, there was microvesicular hydropic degeneration within the neuropil of the hippocampus, amygdala, pyriform lobe, and other limbic structures. Acutely, there was ischemic neuronal necrosis, particularly apparent in the granular cells of the dentate gyrus and the pyramidal cells within the hippocampus cornu ammonis (CA) sectors CA4, CA3, and CA1. Dentate granular cell necrosis has not been reported in human or experimental animal DA toxicity and may be unique to sea lions. Chronically, there was gliosis, mild nonsuppurative inflammation, and loss of laminar organization in affected areas.
Background
The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral ...chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment.
Case Series
We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16‐year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT).
Literature Review and Discussion
A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT‐negative staining and a good response to temozolomide (OR 9·35, P = 0·0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.
...he was commenced on block and replace therapy with 25 mug thyroxine. ...albumin becomes the main binding protein, especially as it is available in a large quantity compared to TBG, but binding of ...thyroxine to triiodothyronine is normal. 1, 3, 6, 10, 11 In 1994, Peterson et al showed that the increased binding is due to substitution of arginine to histidine at position 218 on the albumin protein. 12 The incidence of FDH is not known, mainly due to the fact that the condition is diagnosed by chance when thyroid function tests are ordered. 1 Patients who are anxious when examined in the clinic may show signs such as tachycardia and sweating.
OBJECTIVE To examine the cycle length of the junctional tachycardia often seen during successful slow pathway ablation for atrioventricular (AV) node re-entrant tachycardia, to determine whether ...shorter cycle lengths predict imminent atrioventricular block. DESIGN Retrospective analysis of consecutive patients undergoing slow pathway modification. Intracardiac recordings were analysed after digital storage to determine the development of junctional tachycardia, its duration and maximum, minimum, and mean cycle length, occurrence of heart block, persistent slow pathway conduction, or later confirmed recurrence of AV node re-entrant tachycardia. SETTING Regional cardiac centre. PATIENTS 136 consecutive patients undergoing electrophysiological study found to have typical “slow-fast” AV node re-entrant tachycardia and subject to 137 slow pathway modification procedures. RESULTS During successful temperature feedback controlled radiofrequency energy application, junctional tachycardia developed in 133 of 137 procedures. During ablation, 10 patients had evidence of AV block (first degree in seven patients and third degree in three), and 17 others had retrograde junctional atrial (JA) block. In these 27 patients, the junctional tachycardia was rapid, with a minimum (SD) cycle length 291 (47) ms. Conduction recovered quickly in all but two patients, one of whom required permanent pacing. Junctional tachycardia with normal AV and JA conduction in the other 111 patients was of a significantly slower minimum cycle length (537 (123) ms; p < 0.0001). CONCLUSIONS Fast junctional tachycardia with cycle lengths under 350 ms seen during slow pathway modification is a predictor of conduction block, suggesting proximity to the compact node. Radiofrequency energy application should be terminated immediately to prevent development of AV block. An “auto cut off” facility for cycle lengths shorter than 350 ms could be built into radiofrequency ablation systems to increase safety.
We characterize intercalative complexes as either "high charge" and "low charge". In low charge complexes, stacking interactions appear to dominate stability and structure. The dominance of stacking ...is evident in structures of daunomycin, nogalamycin, ethidium, and triostin A/echinomycin. By contrast in a DNA complex with the tetracationic metalloporphyrin CuTMPyP4 copper (II) meso-tetra(N-methyl-4-pyridyl)porphyrin, electrostatic interactions appear to draw the porphyrin into the duplex interior, extending the DNA along its axis, and unstacking the DNA. Similarly, DNA complexes of tetracationic ditercalinium and tetracationic flexi-di show significant unstacking. Here we report x-ray structures of complexes of the tetracationic bis-intercalator D232 bound to DNA fragments d(CGTACG) and d(BrCGTABrCG). D232 is analogous to ditercalinium but with three methylene groups inserted between the piperidinium groups. The extension of the D232 linker allows it to sandwich four base pairs rather than two. In comparison to CuTMPyP4, flexi-di and ditercalinium, stacking interactions of D232 are significantly improved. We conclude that it is not sufficient to characterize intercalators simply by net charge. One anticipates strong electrostatic forces when cationic charge is focused to a small volume or region near DNA and so must consider the extent to which cationic charge is focused or distributed. In sum, ditercalinium, with a relatively short linker, focuses cationic charge more narrowly than does D232. So even though the net charges are equivalent, electrostatic charges are expected to be of greater structural significance in the ditercalinium complex than in the D232 complex.
The Community Land Model (CLM) is the land component of the Community Earth System Model (CESM) and is used in several global and regional modeling systems. In this paper, we introduce model ...developments included in CLM version 5 (CLM5), which is the default land component for CESM2. We assess an ensemble of simulations, including prescribed and prognostic vegetation state, multiple forcing data sets, and CLM4, CLM4.5, and CLM5, against a range of metrics including from the International Land Model Benchmarking (ILAMBv2) package. CLM5 includes new and updated processes and parameterizations: (1) dynamic land units, (2) updated parameterizations and structure for hydrology and snow (spatially explicit soil depth, dry surface layer, revised groundwater scheme, revised canopy interception and canopy snow processes, updated fresh snow density, simple firn model, and Model for Scale Adaptive River Transport), (3) plant hydraulics and hydraulic redistribution, (4) revised nitrogen cycling (flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake), (5) global crop model with six crop types and time‐evolving irrigated areas and fertilization rates, (6) updated urban building energy, (7) carbon isotopes, and (8) updated stomatal physiology. New optional features include demographically structured dynamic vegetation model (Functionally Assembled Terrestrial Ecosystem Simulator), ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Conclusive establishment of improvement or degradation of individual variables or metrics is challenged by forcing uncertainty, parametric uncertainty, and model structural complexity, but the multivariate metrics presented here suggest a general broad improvement from CLM4 to CLM5.
Plain Language Summary
The Community Land Model (CLM) is the land component of the widely used Community Earth System Model (CESM). Here, we introduce model developments included in CLM version 5 (CLM5), the default land component for CESM2 which will be used for the Coupled Model Intercomparison Project (CMIP6). CLM5 includes many new and updated processes including (1) hydrology and snow features such as spatially explicit soil depth, canopy snow processes, a simple firn model, and a more mechanistic river model, (2) plant hydraulics and hydraulic redistribution, (3) revised nitrogen cycling with flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake, (4) expansion to six crop types (global) and time‐evolving irrigated areas and fertilization rates, (5) improved urban building energy model, and (6) carbon isotopes. New optional features include a demographically structured dynamic vegetation model, ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Model performance is generally improved for most assessed variables and metrics, though clear establishment of improvement or degradation is challenging due to model complexity as well as observational data limitations. Nonetheless, CLM5 is increasingly suited for research into a broad range of societally relevant scientific questions related to the terrestrial system.
Key Points
Updated Community Land Model has more hydrological and ecological process fidelity and more comprehensive representation of land management.
The model is systematically evaluated using International Land Model Benchmarking system and shows marked improvement over prior versions.
THE COMMUNITY EARTH SYSTEM MODEL Hurrell, James W.; Holland, M. M.; Gent, P. R. ...
Bulletin of the American Meteorological Society,
09/2013, Letnik:
94, Številka:
9
Journal Article
Recenzirano
Odprti dostop
The Community Earth System Model (CESM) is a flexible and extensible community tool used to investigate a diverse set of Earth system interactions across multiple time and space scales. This global ...coupled model significantly extends its predecessor, the Community Climate System Model, by incorporating new Earth system simulation capabilities. These comprise the ability to simulate biogeochemical cycles, including those of carbon and nitrogen, a variety of atmospheric chemistry options, the Greenland Ice Sheet, and an atmosphere that extends to the lower thermosphere. These and other new model capabilities are enabling investigations into a wide range of pressing scientific questions, providing new foresight into possible future climates and increasing our collective knowledge about the behavior and interactions of the Earth system. Simulations with numerous configurations of the CESM have been provided to phase 5 of the Coupled Model Intercomparison Project (CMIP5) and are being analyzed by the broad community of scientists. Additionally, the model source code and associated documentation are freely available to the scientific community to use for Earth system studies, making it a true community tool. This article describes this Earth system model and its various possible configurations, and highlights a number of its scientific capabilities.
The Greenland ice sheet is one of the largest contributors to global mean sea-level rise today and is expected to continue to lose mass as the Arctic continues to warm. The two predominant mass loss ...mechanisms are increased surface meltwater run-off and mass loss associated with the retreat of marine-terminating outlet glaciers. In this paper we use a large ensemble of Greenland ice sheet models forced by output from a representative subset of the Coupled Model Intercomparison Project (CMIP5) global climate models to project ice sheet changes and sea-level rise contributions over the 21st century. The simulations are part of the Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6). We estimate the sea-level contribution together with uncertainties due to future climate forcing, ice sheet model formulations and ocean forcing for the two greenhouse gas concentration scenarios RCP8.5 and RCP2.6. The results indicate that the Greenland ice sheet will continue to lose mass in both scenarios until 2100, with contributions of 90±50 and 32±17 mm to sea-level rise for RCP8.5 and RCP2.6, respectively. The largest mass loss is expected from the south-west of Greenland, which is governed by surface mass balance changes, continuing what is already observed today. Because the contributions are calculated against an unforced control experiment, these numbers do not include any committed mass loss, i.e. mass loss that would occur over the coming century if the climate forcing remained constant. Under RCP8.5 forcing, ice sheet model uncertainty explains an ensemble spread of 40 mm, while climate model uncertainty and ocean forcing uncertainty account for a spread of 36 and 19 mm, respectively. Apart from those formally derived uncertainty ranges, the largest gap in our knowledge is about the physical understanding and implementation of the calving process, i.e. the interaction of the ice sheet with the ocean.
BACKGROUND:We assessed whether 7 days of zidovudine + lamivudine postpartum with single-dose nevirapine at labor decreases nevirapine resistance in HIV-infected women in Malawi.
METHODS:HIV-infected ...pregnant women receiving intrapartum single-dose nevirapine and 7 days of zidovudine + lamivudine (n = 132) and women receiving intrapartum single-dose nevirapine alone (n = 66) were followed from an antenatal visit through 6 weeks postpartum. Plasma specimens at 2 and 6 weeks postpartum were tested for genotypic resistance to nevirapine by population sequencing and sensitive real-time polymerase chain reaction. Poisson regression was used to determine predictors of postpartum nevirapine resistance.
RESULTS:Median HIV RNA was similar at entry (4.27 log vs. 4.35 log, P = 0.87), differed at 2 weeks postpartum (2.67 log vs. 3.58 log, P < 0.0001) but not at 6 weeks postpartum (4.49 log vs. 4.40 log, P = 0.79), between single-dose nevirapine/zidovudine + lamivudine and single-dose nevirapine groups, respectively. Nevirapine resistance, measured by population sequencing and sensitive real-time polymerase chain reaction, was significantly less common in those receiving single-dose nevirapine/zidovudine + lamivudine compared with single-dose nevirapine, respectively, at 2 weeks 10% (4 of 40) vs. 74% (31 of 42), P < 0.0001 and 6 weeks postpartum 10% (11 of 115) vs. 64% (41 of 64), P < 0.0001; adjusted relative risk = 0.18, 95% confidence interval (0.10 to 0.34).
CONCLUSIONS:The significant decrease in nevirapine resistance conferred by 1 week of zidovudine + lamivudine should help policymakers optimize peripartum HIV prophylaxis recommendations.
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