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A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

A full description of the terminal architecture of sympathetic axons innervating the gastrointestinal (GI) tract has not been available. To label sympathetic fibers projecting to the gut muscle wall, dextran biotin was injected into the celiac and superior mesenteric ganglia (CSMG) of rats. Nine days postinjection, animals were euthanized and stomachs and small intestines were processed as whole mounts (submucosa and mucosa removed) to examine CSMG efferent terminals. Myenteric neurons were counterstained with Cuprolinic Blue; catecholaminergic axons were stained immunohistochemically for tyrosine hydroxylase. Essentially all dextran-labeled axons (135 of 136 sampled) were tyrosine hydroxylase-positive. Complete postganglionic arbors (n = 154) in the muscle wall were digitized and analyzed morphometrically. Individual sympathetic axons formed complex arbors of varicose neurites within myenteric ganglia/primary plexus and, concomitantly, long rectilinear arrays of neurites within circular muscle/secondary plexus or longitudinal muscle/tertiary plexus. Very few CSMG neurons projected exclusively (i.e., ∼100% of an arbor's varicose branches) to myenteric plexus (∼2%) or smooth muscle (∼14%). With less stringent inclusion criteria (i.e., ≥85% of an axon's varicose branches), larger minorities of neurons projected predominantly to either myenteric plexus (∼13%) or smooth muscle (∼27%). The majority (i.e., ∼60%) of all individual CSMG postganglionics formed mixed, heterotypic arbors that coinnervated extensively (>15% of their varicose branches per target) both myenteric ganglia and smooth muscle. The fact that ∼87% of all sympathetics projected either extensively or even predominantly to smooth muscle, while simultaneously contacting myenteric plexus, is consistent with the view that these neurons control GI muscle directly, if not exclusively. J. Comp. Neurol. 524:2577-2603, 2016. © 2016 Wiley Periodicals, Inc.

The feasibility of monitoring erosion and settlement of earthen covers on uranium mill tailings impoundment was evaluated using synthetic aperture radar (SAR) coherence analysis, differential radar interferometry (DInSAR) and multi-temporal interferometry. A total of 13 ERS-1/-2 SAR images were acquired between August 22, 1996 and December 14, 2000 over two uranium mill tailings sites located in north-western New Mexico, USA. These SAR datasets were screened based on meteorological conditions at the time of acquisition, eliminating those acquired during (a) rain and thunderstorms, (b) mist or fog or, (c) during overcast conditions. Preliminary coherence analysis allowed us to better understand the dynamics of land disposal sites, to identify useful and relevant time domains and define the appropriate parameters for subsequent InSAR analyses. DInSAR allowed us to measure differential settlement of tens of mm over two 3 to 4 month periods. The Small BAseline Subset (SBAS) technique identified spatial variations in the rate of settlement ranging from approximately 1 mm/yr to 10 mm/yr. Although the extent of the analysis was limited by the availability of archived SAR data, the results demonstrated that monitoring using on-demand SAR data should yield reliable measurements of surface displacements earthen covers.

Analysis of satellite-acquired synthetic aperture radar (SAR) data provides a way to rapidly survey road conditions over large areas. This capability could be useful for identifying road segments that potentially require repair or at least onsite inspection of their condition due to changes in vehicular traffic associated with change in land use. We conducted a feasibility study focused on urban roads near the Southwest Research Institute (SwRI) campus in San Antonio, Texas. The roads near SwRI were affected by heavy truck traffic, they were easily inspected, and the age and construction of the pavement was known. TerraSAR-X (TSX) SpotLight (ST) satellite data were used to correlate radar backscattering response to pavement age and condition. Our preliminary results indicate that TSX radar imagery can be useful for detecting changes in pavement type, damage to pavement, such as cracking and scaling, and, occasionally, severe rutting. In addition, multitemporal interferometric analysis showed patches of settlement along two roads south of the SwRI campus. Further development of an automated approach to detect degradation of roads could allow transportation departments to prioritize inspection and repair efforts. The techniques also could be used to detect surreptitious heavy truck traffic in areas where direct inspection is not possible.

[1] An uncertainty distribution is developed to describe areal-average infiltration at Yucca Mountain averaged over the next million years. The distribution uses Infiltration Tabulator for Yucca Mountain (ITYM) model results to estimate uncertainty in net infiltration given decadal-average climate, driven with two independent estimates for potential future climatic sequences. Both future climatic sequences use orbital mechanics linked to paleoclimatic proxies to estimate future climate states, but one uses primarily biotic indicators and the other uses primarily abiotic indicators to link paleoclimate to orbital stage. Abiotic indicators suggest that present-day climate variation by latitude in the Great Basin is reasonably analogous to glacial-scale climate variation at a single location once orographic, lake effect, and insolation influences are accounted for. In the southern Sierra Nevada, abiotic indicators suggest that mean annual precipitation was 1.7–1.9 times larger than present and mean annual temperature was 5.6–7°C cooler than present at the last glacial maximum. The influence of decadal to millennial-scale variability is estimated using the 8000 year Methuselah Walk tree-ring record, which suggests that even large inferred fluctuations over the Holocene only modestly increase 8000-year-average infiltration. Combining the future-climate projections with the infiltration model uncertainty distribution yields approximately lognormal uncertainty distributions for projected million-year areal-average net infiltration, with a mean of 41 mm/yr and coefficient of variation of 0.81. Even if anthropogenic effects significantly alter climatic patterns relative to past climate cycles, the projected anthropogenic period is sufficiently brief that million-year averages are not likely to be substantially influenced.

The flow synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced via a reverse “tube-in-tube” flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions.

The flow synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced via a reverse “tube-in-tube” flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions.

Recharge through intermittent and ephemeral stream channels is believed to be a primary aquifer recharge process in arid and semiarid environments. The intermittent nature of precipitation and flow events in these channels, and their often remote locations, makes direct flow and loss measurements difficult and expensive. Airborne and satellite optical images were interpreted to evaluate aquifer recharge due to stream losses on the Frio River in south-central Texas. Losses in the Frio River are believed to be a major contributor of recharge to the Edwards Aquifer. The results of this work indicate that interpretation of readily available remote sensing optical images can offer important insights into the spatial distribution of aquifer recharge from losing streams. In cases where upstream gauging data are available, simple visual analysis of the length of the flowing reach downstream from the gauging station can be used to estimate channel losses. In the case of the Frio River, the rate of channel loss estimated from the length of the flowing reach at low flows was about half of the loss rate calculated from in-stream gain-loss measurements. Analysis based on water-surface width and channel slope indicated that losses were mainly in a reach downstream of the mapped recharge zone. The analysis based on water-surface width, however, did not indicate that this method could yield accurate estimates of actual flow in pool and riffle streams, such as the Frio River and similar rivers draining the Edwards Plateau.

Dystrophic axons and terminals are common in the myenteric plexus and smooth muscle of the gastrointestinal (GI) tract of aged rats. In young adult rats, alpha-synuclein in its normal state is abundant throughout the myenteric plexus, making this protein-which is prone to fibrillization-a candidate marker for axonopathies in the aged rat. To determine if aggregation of alpha-synuclein is involved in the formation of age-related enteric neuropathies, we sampled the stomach, small intestine and large intestine of adult, middle-aged, and aged virgin male Fischer 344 rats stained for alpha-synuclein in both its normal and pathological states. Alpha-synuclein-positive dystrophic axons and terminals were present throughout the GI tract of middle-aged and aged rats, with immunohistochemical double labeling demonstrating co-localization within nitric oxide synthase-, calretinin-, calbindin-, or tyrosine hydroxylase-positive markedly swollen neurites. However, other dystrophic neurites positive for each of these four markers were not co-reactive for alpha-synuclein. Similarly, a subpopulation of alpha-synuclein inclusions contained deposits immunostained with an anti-tau phospho-specific Ser(262) antibody, but not all of these hyperphosphorylated tau-positive aggregates were co-localized with alpha-synuclein. The presence of heteroplastic and potentially degenerating neural elements and protein aggregates both positive and negative for alpha-synuclein suggests a complex chronological relationship between the onset of degenerative changes and the accumulation of misfolded proteins. Additionally, proteins other than alpha-synuclein appear to be involved in age-related axonopathies. Finally, this study establishes the utility of the aging Fischer 344 rat for the study of synucleopathies and tauopathies in the GI tract.

Depending on the substitution of the α-carbon to the cyano group of the nitrile educts, either 2-substituted thiazoles or 2-substituted aminothiophenes are obtained.

Well testing procedures, such as the Tier 3 methodology specified in the U.S. Code of Federal Regulations (CFR) Subtitle D, are commonly used for directly estimating landfill gas (LFG) emissions at municipal solid waste (MSW) landfills. Similar procedures are also used to estimate LFG generation rates for the design of LFG-to-energy projects. These methodologies assume that the LFG generation rate equals the extraction rate of a test gas well within its radius of influence (ROI). The ROI is defined as the distance from the extraction well at which the induced pressure drop is immeasurable by some standard of precision. Based on fluid dynamic principles, Tier 3 and similar methodologies are demonstrated to be incapable of providing reliable estimates of the LFG generation rate. These tests may either over- or underestimate the LFG generation rate depending on the precision with which the ROI is determined, but they will only coincidentally produce an estimate that accurately represents the actual LFG generation rate. Fluid dynamic principles dictate that the actual LFG generation rate can only be estimated if the pneumatic properties of the refuse and cover materials as well as the excess pressure in the refuse caused by LFG generation are known or can be estimated.

The capture zone or contributing area of a ground water extraction well can be defined as that portion of the aquifer from which the well draws its water. Accurate delineation of capture zones is important in many ground water remediation applications and in the definition of wellhead protection areas. Their mathematical delineation is often simplified by using quasi-steady-state models based on time-weighted average pumping rates and background hydraulic gradients. We present a new semianalytic approach for the definition of capture zones under transient-flow conditions. We then use this approach to evaluate the effects of time variations in the direction of the background hydraulic gradient on capture. Results are presented in the form of capture efficiency maps (CEMs). Although the area contributing to a given well is found to generally expand relative to the steady-state average capture zone when the gradient direction varies, the zone of 100% capture may expand or contract depending on site-specific conditions. We illustrate our CEM approach by applying it to the design of a plume containment system.

Dramatic increases in the development of oil and natural gas from shale formations will result in large quantities of drill cuttings, flowback water, and produced water. These organic-rich shale gas formations often contain elevated concentrations of naturally occurring radioactive materials (NORM), such as uranium, thorium, and radium. Production of oil and gas from these formations will also lead to the development of technologically enhanced NORM (TENORM) in production equipment. Disposal of these potentially radium-bearing materials in municipal solid waste (MSW) landfills could release radon to the atmosphere. Risk analyses of disposal of radium-bearing TENORM in MSW landfills sponsored by the Department of Energy did not consider the effect of landfill gas (LFG) generation or LFG control systems on radon emissions. Simulation of radon emissions from landfills with LFG generation indicates that LFG generation can significantly increase radon emissions relative to emissions without LFG generation, where the radon emissions are largely controlled by vapor-phase diffusion. Although the operation of LFG control systems at landfills with radon source materials can result in point-source atmospheric radon plumes, the LFG control systems tend to reduce overall radon emissions by reducing advective gas flow through the landfill surface, and increasing the radon residence time in the subsurface, thus allowing more time for radon to decay. In some of the disposal scenarios considered, the radon flux from the landfill and off-site atmospheric activities exceed levels that would be allowed for radon emissions from uranium mill tailings.Increased development of hydrocarbons from organic-rich shale formations has raised public concern that wastes from these activities containing naturally occurring radioactive materials, particularly radium, may be disposed in municipal solid waste landfills and endanger public health by releasing radon to the atmosphere. This paper analyses the processes by which radon may be emitted from a landfill to the atmosphere. The analyses indicate that landfill gas generation can significantly increase radon emissions, but that the actual level of radon emissions depend on the place of the waste, construction of the landfill cover, and nature of the landfill gas control system.

Leaks from hazardous liquid pipelines can have significant impacts on safety and the environment. The detection of such leaks in their infancy is important to the overall integrity management of pipelines. The traditional means of detecting leaks on this infrastructure typically involve visual inspection or computational monitoring. However, such methods are often inadequate for detecting and locating small discharges that can result in damage to the environment. One potential alternative technology is distributed temperature sensing (DTS). The analytical work in this paper details near-field thermal effects surrounding the pipeline, seasonal and diurnal impacts on temperature as a function of buried depth, and the impact of transient temperature response from batch product operations. The analysis demonstrated that DTS employed on a buried transmission line would be immune from many of these effects and would not generate numerous false alarms due to these conditions. Laboratory testing was conducted on both Brillouin and Raman-based DTS systems; a total of four different manufacturer’s products were utilized. The testing characterized any limitations of such systems as a function of wetted length. The testing demonstrated that such technology could accurately detect small temperature fluctuations over distances exceeding 12 km (7.5 mi) to a location with a resolution of one meter. In addition to sensitivity testing of the systems, the automated alarm systems were tested to ensure that the systems could detect leaks without generating numerous false alarms.

An extensive literature review of statistical studies on merger, acquisition and takeover activities in various sectors is presented. It reveals a large number of efforts, models and pitfalls to classify and predict acquired or bankrupt vs. non-acquired or healthy firms. In this study we considered twenty endogenous bank variables in order to determine the most important characteristics that differentiate US bank mergers/acquisitions with or without federal assistance. We developed several logistic regression models, with only three to five significant variables, which classified correctly about 93% of the 299 actual 1987–1988 cases (and 89% in the 56 case 1989 holdout sample).

Abstract Arctic regions have been determined to be particularly sensitive to a warming global climate both on the basis of climatic modeling and observation of dramatic changes in arctic landscapes and sea ice. As early as the 1990s, air temperatures in interior northwest Alaska were warming at a rate of 0.75 °C per decade. The resulting thawing of permafrost causes significant damage to buildings, roadways, and can lead to increased mass wasting (e.g., active layer detachments and thaw slumps) by melting the soil ice that " cements?? the grains together to resist soil movement, as well as ground subsidence. These climate-induced ground movements can threaten infrastructure, such as road, bridges, and pipelines, either by direct physical damage or indirectly, such as through changes in drainage patterns, increased risk of flooding and forest fires. Because these geohazards often occur in remote locations with harsh weather conditions and limited access, and the precursor conditions for initiating them can occur gradually, methods for remotely monitoring changes in ground conditions and estimating ground failure risks have significant engineering and economic value. The research described in this paper addresses this need by developing techniques for detecting changes in permafrost and seasonally frozen soil terrains using satellite and airborne remote sensing data, and combining these data with mathematical models to estimate the risk of ground failures due to soil thawing. The methodology consists of combining multiple sources of satellite-acquired synthetic aperture radar (SAR) data with high resolution optical-band data and aerial photography to map frozen ground and associated changes in soil moisture, and to detect vertical and lateral ground movements. The remote sensing data interpretations along with traditional soil and vegetation mapping are used to inform mathematical models of permafrost and frozen soil stability. These models are used to develop maps of the probability of ground movements associated with permafrost degradation and seasonally frozen soil under current and future climate conditions. The models and slope stability risk algorithm were applied to a portion of Kobuk Valley National Park, Alaska for which soil and vegetation land cover maps were available. The cryosphere model results suggest that the same relative change in active-layer thickness occurs across the landscape, but warmer locations experience a larger absolute change in active-layer thickness and may experience permafrost loss as a consequence. The slope failure risk algorithm indicates that the upland areas are most susceptible to slope failure, particularly south-facing slopes, but low-cohesion low-land soils and steep river banks are also susceptible to failure.

A vertical circulation well is a well completed in two intervals with extraction induced in one interval and injection induced in the other, generating a circulating flow field near the well. A vertical circulation well may be used to remediate contaminated ground water by air stripping the extracted water and then reinjecting the clean water; by introducing oxygen and/or nutrients to the extracted water before reinjecting it, thereby stimulating the natural bioremediation of the water; or by injecting appropriate chemicals or microbes, effecting remediation of the circulated water. This paper summarizes an analytical technique for predicting the steady-state hydraulic head and flow fields caused by the operation of multiple vertical circulation wells in a confined aquifer with a regional gradient. The method begins with the hydraulic head solution for a point sink in an infinite aquifer. The point sink is then integrated to derive the solution for a line sink. Linear superposition is applied to obtain the hydraulic head resulting from multiple line sinks and sources in a homogeneous confined aquifer. This solution is then differentiated to obtain the hydraulic head gradient and three-dimensional velocity field. The velocity field is numerically integrated by an adaptive Runge-Kutta scheme to obtain the pathlines of three-dimensional flow.

We developed a novel method to quantify subtle rates of landscape evolution using two satellite imaging systems with different viewing angles and spectral sensitivities. We selected the slowly migrating, high-latitude, subarctic Great Kobuk Sand Dunes (GKSD), Kobuk Valley National Park, Alaska (USA), for our study. The COSI-Corr technique was used for precise orthorectification, co-registration, and subpixel correlation of satellite data. ASTER Visible Near Infrared (VNIR) and SPOT Panchromatic images with a 5-year temporal separation were correlated to measure the horizontal velocity of the GKSD. To reduce correlation noise, ASTER VNIR bands were linearly mixed to match the SPOT Panchromatic band, and raw correlation measurements were projected onto a local robust migration direction to estimate unbiased velocity magnitudes. The results show that the most likely migration rate for the GKSD ranges from 0.5 to 1.5 m/year, with peak velocities up to 3.8 m/year, and uncertainty of approximately 0.16 m/year. The unprecedented ability to measure slow migration rates, including those that may occur over a relatively short time interval, illustrates the value of this method to reliably detect and monitor subtle ground movements including dune migration, glacier flow, mass movements, and other small-scale processes.

Recent progress in understanding visceral afferents, some of it reviewed in the present issue, serves to underscore how little is known about the aging of the visceral afferents in the gastrointestinal (GI) tract. In spite of the clinical importance of the issue--with age, GI function often becomes severely compromised--only a few initial observations on age-related structural changes of visceral afferents are available. Primary afferent cell bodies in both the nodose ganglia and dorsal root ganglia lose Nissl material and accumulate lipofucsin, inclusions, aggregates, and tangles. Additionally, in changes that we focus on in the present review, vagal visceral afferent terminals in both the muscle wall and the mucosa of the GI tract exhibit age-related structural changes. In aged animals, both of the vagal terminal types examined, namely intraganglionic laminar endings and villus afferents, exhibit dystrophic or regressive morphological changes. These neuropathies are associated with age-related changes in the structural integrity of the target organs of the affected afferents, suggesting that local changes in trophic environment may give rise to the aging of GI innervation. Given the clinical relevance of GI tract aging, a more complete understanding both of how aging alters the innervation of the gut and of how such changes might be mitigated should be made research priorities.

The effects of systemic hypothermia (33.5 degrees C) on the ischemia-evoked release of the neurotransmitter amino acids, glutamate, aspartate, gamma-amino-butyric acid (GABA) and glycine into rat cerebral cortical superfusates were evaluated in the rat four vessel occlusion model. Glutamate, aspartate and GABA, but not glycine, levels were enhanced during and following a 20 min period of ischemia. However, when compared with normothermic ischemic animals, no reductions in glutamate, aspartate or GABA levels in the superfusates were apparent either prior to, during or following forebrain ischemic episodes. Indeed, the superfusate levels of aspartate and GABA were transiently increased immediately following ischemia. Glycine levels were significantly depressed, both pre- and post-ischemia, in cortical superfusates from hypothermic animals in comparison with normothermic rats.

The effects of a potent adenosine deaminase inhibitor, deoxycoformycin, on purine and amino acid neuro-transmitter release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (20 min) was elicited by four-vessel occlusion. Purine and amino acid releases were compared from control ischemic animals and deoxycoformycin-pretreated ischemic rats. Ischemia enhanced the release of glutamate, aspartate, and gamma-aminobutyric acid into cortical perfusates. The levels of adenosine, inosine, hypoxanthine, and xanthine in the same perfusates were also elevated during and following ischemia. Deoxycoformycin (500 micrograms/kg) enhanced ischemia-evoked release of adenosine, indicating a marked rise in the adenosine content of the interstitial fluid of the cerebral cortex. Inosine, hypoxanthine, and xanthine levels were depressed by deoxycoformycin. Deoxycoformycin pretreatment failed to alter the pattern of amino acid neurotransmitter release from the cerebral cortex in comparison with that observed in control ischemic animals. The failure of deoxycoformycin to attenuate amino acid neurotransmitter release, even though it markedly enhanced adenosine levels in the extracellular space, implies that the amino acid release during ischemia occurs via an adenosine-insensitive mechanism. Inhibition of excitotoxic amino acid release is unlikely to be responsible for the cerebroprotective actions of deoxycoformycin in the ischemic brain.

None of the anterograde tracers used to label and investigate vagal preganglionic neurons projecting to the viscera has proved optimal for routine and extensive labeling of autonomic terminal fields. To identify an alternative tracer protocol, the present experiment evaluated whether dextran conjugates, which have produced superior results in the CNS, might yield widespread and effective labeling of long, fine-caliber vagal efferents in the peripheral nervous system. The dextran conjugates that were evaluated proved reliable and versatile for labeling the motor neuron pool in its entirety, for single- and multiple-labeling protocols, for both conventional and confocal fluorescence microscopy, and for permanent labeling protocols for brightfield microscopy of the projections to the gastrointestinal (GI) tract. Using a standard ABC kit followed by visualization with DAB as the chromagen, Golgi-like labeling of the vagal efferent terminal fields in the GI wall was achieved with the biotinylated dextrans. The definition of individual terminal varicosities was so sharp and detailed that it was routinely practical to examine the relationship of putative vagal efferent contacts (by the criteria of high magnification light microscopy) with the dendritic and somatic architecture of counterstained neurons in the myenteric plexus. Overall, dextran conjugates provide high-definition labeling of an extensive vagal motor pool in the GI tract, and offer considerable versatility when multiple-staining protocols are needed to elucidate the complexities of the innervation of the gut.

This short note describes the synthesis of the title compound through spontaneous aerobic oxidation of ethyl 2-phenyl-2-(thiazol-2-yl)acetate. Due to the prevalence of such functional motifs in biologically active substances, we believe the oxidation encountered highlights an important degradation pathway worthy of note.

Allowing disposal of technologically enhanced naturally occurring radioactive materials (TENORM) from petroleum exploration and production in non-hazardous waste landfills was proposed in a U.S. Deparment of Energy study. TENORM often contains radium that is a source of radon. Diffusion through soil and other cover materials is commonly regarded as the dominant radon transport process from land disposal units. Biogas generation in landfills may increase radon emissions relative to diffusion-dominated sites. A numerical gas flow and transport model was used to simulate potential radon emissions from radium-bearing TENORM in solid waste landfills and land disposal sites where TENORM is co-disposed with oily waste. The landfill scenarios considered the effect of landfill gas generation potential and rate, cover construction, TENORM disposal method, and gas control methodology on radon emissions. The co-disposal scenarios investigated the effect of biogas generation rate, organic carbon partitioning, and cover construction on radon emissions. Gas generation was found to significantly increase radon emissions from landfills. Depending on the nature of the gas management system, atmospheric radon concentrations could exceed background level both on-site and off-site. The effect of biogas generation on radon emissions from co-disposal sites was found to be strongly dependent on the hydrocarbon content of the waste. The results of this investigation provide guidance for selecting appropriate TENORM disposal options and for evaluating the potential environmental liabilities associated with the options.

The levels of adenosine in rat cerebral cortical superfusates were studied in rats prior to, and after, the administration of saline or d -glucose (3 g/kg). Hypoxia-evoked increases in purine release were significantly attenuated after glucose administration. After glucose administration, the falls in arterial blood pressure, which normally accompany systemic hypoxia, were reduced. To ensure that this was not the reason for the decrease in adenosine release, blood was withdrawn from a second group of hyperglycemic rats so that the post-glucose hypoxia was equivalent to the original control. Adenosine release was still significantly attenuated. This decrease in the levels of adenosine, a cerebroprotective agent, in the cerebral cortical extracellular space, may be a contributing factor to the detrimental effects of hyperglycemia on recovery from cerebral ischemia.

An HMG-CoA reductase inhibition assay was developed and validated for quantitation of atorvastatin in human, dog, rat, and mouse plasma. Atorvastatin was isolated from plasma by protein precipitation. Rat-liver microsomes were used to provide the reductase enzyme. The method was validated by assaying calibration standards and quality controls in triplicate on each of the 3 days. A customized computer program was used for data calculation. Quantitation of the assay ranged from 0.36 to 16 ng/ml of atorvastatin in different plasma matrices. Assay precision and accuracy, based on the coefficient of variation and percent relative error, respectively, of quality controls were 10.4% to 14.5% and within +/- 6.25% in human; 4.89% to 10.6% (+/- 8.13%) in dog; 2.68% to 8.62% (+/- 5.00%) in rat; and 3.68% to 8.96% (+/- 5.38%) in mouse plasma. The method has been applied to pharmacokinetic studies of atorvastatin in human and toxicokinetic studies in dog, rat, and mouse after atorvastatin administration. Atorvastatin equivalent concentrations in a set of plasma samples from subjects receiving single and multiple doses of atorvastatin were determined by validated HMG-CoA reductase inhibition assays at four different laboratories. Results were compared using linear regression and concordance correlation statistical procedures. Good agreements among these data indicated that results from different laboratories with the same validated method can be used interchangeably.

CI-980, a 1-deaza-7,8-dihydropteridine, is a novel anticancer agent that is a potent mitotic inhibitor acting as a tubulin binder similar to the vinca alkaloids. CI-980 has shown equivalent or superior anticancer activity in vitro compared to vincristine and retains full activity against vincristine resistant tumors in vitro. A high-performance liquid chromatographic (HPLC) assay was developed and validated for human plasma and urine to support Phase 1 clinical trials. CI-980 and PD 080658, internal standard, were isolated from 2-ml samples of human plasma and urine by solid-phase extraction with Bond-Elut C18 cartridges. Urine samples must be pretreated with bovine serum albumin (BSA) to minimize the binding of CI-980 to glass and some plastics. The eluate from the cartridges for both matrices was evaporated to dryness and taken up in mobile phase. Zorbax RX C18 columns, mobile phase buffer of 10 mM ammonium dihydrogen phosphate at pH 7.5 and a flow-rate of 0.75 ml/min were used for both matrices. Column dimensions, column temperature and mobile phase acetonitrile-buffer ratio were 300 mm x 4.6 mm I.D., 30 degrees C and 38:62 (v/v), respectively, for the plasma assay and 250 mm x 4.6 mm I.D., 35 degrees C and 40:60 (v/v), respectively, for the urine assay. Column effluent was monitored fluorometrically for the plasma method using excitation and emission wavelengths of 388 nm and 473 nm, respectively. Ultraviolet detection at 380 nm was used for the urine method. Peak-area ratios were proportional to CI-980 concentrations from 0.2 to 25 ng/ml and 1 to 100 ng/ml for plasma and urine, respectively. CI-980 in water will bind to glass and plastics but not PTFE or stainless steel. Urine calibration standards were frozen prior to use in order to compensate for loss of CI-980 due to freezing in this matrix. The accuracy of the assay was within 4.7%, with a precision of 5.6% for both matrices. Recoveries ranged from 93.8 to 102% and 90.7 to 92.3% for plasma and urine, respectively. CI-980 was stable in plasma and urine for at least 275 and 217 days, respectively, when stored at -70 degrees C. The assay is suitable for studying the clinical pharmacokinetics of CI-980.

A new technique for achieving repeated sampling of fourth ventricular cerebrospinal fluid (CSF) from the cisterna magna of unanesthetized rats is described. The sampling cannula is positioned extracranially, in contrast to previously published techniques which require insertion through the skull. CSF samples, withdrawn from unanesthetized rats before, during and after a 25 min period of inhalation of 5% oxygen in nitrogen, were analyzed for their adenosine and inosine contents by high pressure liquid chromatography. Adenosine and inosine levels increased during the hypoxic episode and were even higher 1 h later. They had declined, but were still above basal levels, 2–3 h after the hypoxic episode. Elevated CSF adenosine concentrations may be responsible for the generation of such persistent effects of hypoxia as post-hypoxic respiratory depression.

The effects of the adenosine deaminase inhibitor, deoxycoformycin, on purine release from the rat cerebral cortex were studied with the cortical cup technique. Deoxycoformycin (5 and 500 μg/kg i.v.) enhanced the hypoxia/ischemia-evoked release of adenosine from the cerebral cortex, indicating a marked rise in the adenosine content of interstitial fluid in the cerebral cortex. Inosine and hypoxanthine release were attenuated at the higher dose of deoxycoformycin, acid release into the cortical perfusates was enhanced at the higher dose level. These results demonstrate that low doses of deoxycoformycin can be used to elevate interstitial levels of adenosine in the brain during hypoxia, and to depress the formation of some of its metabolites. The elevation of hypoxia/ischemia-evoked adenosine levels can account for the previously reported potentiation of hypoxia-evoked increases in rat cerebral blood flow after deoxycoformycin administration. The potential therapeutic utility of these findings is discussed.

The [2+2] cycloaddition of keteniminium ions and alkenes followed by in situ reduction of the resultant iminium ions gives cyclobutylamines in good yields.

Existing methods for the determination of horizontal aquifer anisotropy by means of pumping tests require a minimum of four wells, one for water withdrawal and three for drawdown observations. This paper shows how the same methods can be used to determine anisotropy with as few as three wells, if at least two of them can be pumped in sequence. A field example is included. A method of analyzing data from more wells than the above minimum, by least squares, is also described.

gamma-Aminobutyric acid (GABA) and glycine levels in rat cerebral cortical superfusates rose during a 10-min period to reach stable concentrations of approximately 0.55 microM and approximately 12.3 microM, respectively. In cerebrospinal fluid withdrawn from the fourth ventricle, the GABA concentration was 0.1 microM, and that of glycine, 10.55 microM. GABA, and to a lesser extent glycine, concentrations increased in the cortical superfusates during and immediately following exposure of the rats to a 5-min period of 5% oxygen in nitrogen inhalation.

Isocratic reverse-phase high performance liquid chromatography techniques were developed to resolve and quantitate the purine nucleosides adenosine (Ado) and inosine (Ino) and their metabolites hypoxanthine (Hyp), xanthine (Xan), and uric acid (UA) in the cerebrospinal fluid of the rat. The moving phase composition for resolving hypoxanthine, xanthine and uric acid was a 0.22 M, pH 5.8 phosphate buffer. The moving phase composition for resolving adenosine and inosine was a 0.22 M, pH 6.8 phosphate buffer, 7% methanol (v/v) and 2.5 mM tetrabutylammonium phosphate. The observed cerebrospinal fluid concentrations in the rat were: Ado = 35 ± 9 nM (s.e.m.), Ino = 359 ± 85 nM, Hyp = 243 ± 77 nM, Xan = 1340 ± 423 nM and UA = 6130 ± 678 nM.

The relationship between physiological response patterns.and task difficulty was investigated by evaluating heart rate and respiratory responses during a choice reaction lime tusk with three levels of task difficulty. The data fit a two-component model or attention containing reactive and sustained responses. There were two reactive responses: An immediate deceleration which was independent of task manipulation; and a short latency response, monotonically paralleling task difficulty, which was characterized by acceleration and an increase in heart rate variability. The sustained component exhibited task dependent deceleration and u generalized reduction in heart rate variability and respiration amplitude variability. A stepwise discriminant analysis was performed on the task conditions using physiological responses to determine responses sensitive to task demands. Physiological response patterns were monotonically ordered as a function of task difficulty, suggesting that this technique may have advantages for determining physiological responses most sensitive to psychological manipulation.

The effects of the purine precursor 5-aminoimidazole-4-carboxamide riboside (AICAriboside) on the release of purines from cerebral cortices of normoxic and hypoxic/hypotensive rats was studied with the cortical cup technique. AICAriboside was administered either intravascularly (50 mg/kg) or intraperitoneally (500 mg/kg) to ascertain whether this agent can be used to enhance adenosine levels in the cerebral cortical interstitial fluid. Following its intraperitoneal administration AICAriboside appeared rapidly in the cortical superfusates at concentrations of up to 9 μM and remained at this level for a 90 min period. After intravascular administration, AICAriboside levels peaked at 2 μM, and then declined rapidly. No increases in basal (normoxic) or hypoxia-elicited adenosine levels in the cortical superfusates were observed. Increases did occur in the basal and hypoxia-evoked levels of hypoxanthine, xanthine and, especially, of uric acid. AICAriboside administration appears to have caused an increase in adenosine metabolite, rather than in adenosine, levels in the cerebral interstitial fluid and it may therefore be of little benefit as a precursor for adenosine formation and release in the treatment of cerebral ischemic damage.

The advent of newer generation high resolution computed tomography (CT) scanners has revolutionized diagnostic evaluation in head and neck cancer. Since the development of conservation surgical techniques for the larynx, a precise preoperative evaluation of the extent of laryngeal involvement by carcinoma has been of prime importance. No single diagnostic study now yields more information regarding the anatomic extent of tumor than high resolution CT scanning. This study was designed to evaluate the reliability of CT scanning in determining extent of disease at several laryngeal levels by comparing preoperative CT scans with corresponding postoperative pathology obtained by serially sectioning laryngeal specimens. We found very good correlation in the inferior larynx and good correlation in the superior larynx. Determination of cartilage invasion proved very difficult, and scanning was unreliable at all levels when severe postradiation reactions were present.

The cerebral cortical cup technique was used to monitor changes in adenosine and inosine levels in the rat cerebral cortex during periods of hypoxia, anoxia, or hemorrhagic hypotension. Basal levels of adenosine and inosine in cortical perfusates stabilized within 10 min at concentrations of 30–50 and 75–130 n M, respectively. Comparable levels were observed in normal CSF collected from the cisterna magna. Reductions in the oxygen content of the inspired air (14, 12, 8, and 5% oxygen) resulted in increases in the adenosine and inosine levels in the cortical perfusates, the magnitude of the increase being progressively more pronounced with greater reductions in the oxygen content. Cerebral anoxia/ischemia, induced by 100% nitrogen inhalation, caused a rapid increase in the adenosine and inosine contents of the cortical perfusates. Hemorrhagic hypotension (46.1 ± 1.7 mm Hg) of 5 min duration did not result in an elevated adenosine or inosine release. The results suggest that interstitial fluid adenosine levels are likely to be in the low n M range in the normoxic animal and are capable of rapid increases during hypoxic or anoxic episodes. The findings support the adenosine hypothesis of CBF regulation.

The [2+2] cycloaddition of keteniminium ions and alkenes followed by in situ reduction of the resultant iminium ions gives cyclobutylamines in good yields.

Desalivate rats were tested in two-bottle preference tests for a 0.4% NaCl solution under different dietary conditions. Two effects were seen. A loss in preference may occur because of the prandial drinking pattern desalivates show. Elimination of prandial drinking abolished this effect. An enhancement in preference is seen with a diet that presumably initiates a prandial drinking pattern insufficient for taste masking, or when food is absent. Apparently desalivation has a direct enhancing effect on salt preference that may be exaggerated under appropriate dietary conditions.

The effects of two nucleoside transport inhibitors, dipyridamole and soluflazine, on adenosine, inosine and oxypurine release from the normoxic and hypoxic/ischemic rat cerebral cortex have been studied. Dipyridamole (500 micrograms/kg) enhanced adenosine release during hypoxic/ischemic challenges in comparison with saline-injected controls. It decreased the hypoxia/ischemia-elicited releases of inosine, hypoxanthine and xanthine. Both basal and hypoxia/ischemia-elicited releases of uric acid were elevated. Soluflazine, administered topically or systemically, failed to enhance adenosine release and did not consistently alter the hypoxia/ischemia-evoked releases of inosine, hypoxanthine and xanthine. Basal release of uric acid was elevated. The failure of either drug to elevate the basal or hypoxia/ischemia-evoked releases of adenosine above predrug levels illustrates one of the problems which may be inherent in the use of bidirectional nucleoside transport inhibitors for the manipulation of adenosine levels in the cerebral interstitial fluid.