Effects of Changing Meteoric Precipitation Patterns on Groundwater Temperature in Karst Environments.

Climate predictions indicate that precipitation patterns will change and average air temperatures will increase across much of the planet. These changes will alter surface water and groundwater temperatures which can significantly affect the local and regional environment. Here, we examine the role of precipitation timing in changes to groundwater temperature in carbonate-karst aquifers using measured groundwater level and temperature data from the Konza Prairie Long-Term Ecological Research Site, Kansas. We demonstrate that shifts to increased cool-season precipitation may mitigate the increases in groundwater temperature produced by increases in average annual air temperature. In karst, the solution-enlarged conduits allow faster and focused recharge, and the recharge-event temperature can strongly influence the groundwater temperature in the aquifer. Our field data and analysis show that predictions of future groundwater conditions in karst aquifers need to consider changes in precipitation patterns, in addition to changes to average annual air temperature.

Muteins of human interleukin-1 that show enhanced bioactivities.

Using recombinant DNA techniques, we have made a series of amino-terminal muteins of human interleukin-1 (IL-1). Two of the muteins demonstrated 4-7-fold increase in bioactivity as compared to that of the native IL-1. The enhanced biological potency coincides with an increase in both receptor binding affinity and in vivo tumor inhibitory activity. By site specific mutagenesis, we have shown that the arginine at the fourth position of IL-1 is one of the key residues in the function of IL-1. Circular dichroism studies of the amino-terminus analogs showed little structural rearrangement. The change in bioactivity might be due to a change in the stability of the muteins, in the side chain interactions with receptors or in the minor change in folding near the receptor binding site.

Antiinflammatory 4,5-diarylpyrroles. 2. Activity as a function of cyclooxygenase-2 inhibition.

The antiinflammatory activity of a series of 2-substituted- and 2,3-disubstituted-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H- pyrroles was previously shown by quantitative structure-activity relationship (QSAR) studies to be correlated with the molar refractivity and inductive field effect of the 2-substituent and the lipophilicity of the 3-substituent. The present study demonstrates that much of the antiinflammatory activity of these pyrroles could be correlated with the inhibition of the inducible isoform of cyclooxygenase (COX2). Additional QSAR studies have been used to identify the molecular parameters necessary for maximizing COX2 inhibition while simultaneously minimizing the inhibition of constitutively expressed cyclooxygenase-1. Such an effort should facilitate the discovery and development of selective COX inhibitors that should lead to safer nonsteroidal antiinflammatory drugs.

2'-substituted chalcone derivatives as inhibitors of interleukin-1 biosynthesis.

A series of 2'-substituted chalcone derivatives has been found to show potent inhibition of the production of IL-1 beta from human peripheral blood monocytes stimulated with lipopolysaccharide (LPS), with IC50 values in the 0.2-5.0-microM range. Some members of the series have also shown inhibition of septic shock induced in mice by injection of LPS, although with low potency. Qualitative structure-activity relationships have shown that the enone is required for activity, which may be mediated by conjugate addition of a biological nucleophile to the chalcone. Electron-poor aromatic rings beta to the ketone give enhanced potency. Although electronic effects in the other ring (directly attached to the ketone) are minimal, this ring must possess an ortho substituent for good activity without cytotoxicity, suggesting a degree of selectivity which would not be expected for simple, nonspecific alkylating agents.

Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors.

A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.

Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release.

SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.

Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.

To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of

Photon-assisted tunneling in electron pumps

We measure photon-assisted tunneling in 4- and 6-junction electron pumps at photon frequencies up to 60 GHz. We determine the microwave voltage at the pumps using noise thermometry. The standard theory of leakage in the electron pump, modified to include photon-assisted tunneling, describes our experiments well. From this test of theory we argue that, in the absence of external microwaves, photon-assisted tunneling driven by 1/f noise is an important error mechanism in electron pumps.

Range highlight facility within region of interest for air-CT cisternography and canalography.

Air-CT cisternography and canalography have improved the radiographic diagnosis of small acoustic neuromas. Institutions that do not have an Independent Viewing System with their CT unit can improve their technique by data manipulation using the Range Highlight Facility within the Region of Interest as a part of their existing commercial unit.

Pituicytoma, spindle cell oncocytoma, and granular cell tumor: clarification and meta-analysis of the world literature since 1893.

BACKGROUND AND PURPOSE: Pituicytoma, SCO, and GCT are poorly understood entities with confusing nomenclature and undetermined imaging characteristics. Our purpose was to confirm published cases of pituicytoma, SCO, and GCT with the newest 2007 World Health Organization criteria and elucidate imaging findings that distinguish these tumors from common entities such as pituitary adenoma. MATERIALS AND METHODS: A literature search identified 145 published cases (81 GCTs, 48 pituicytomas, and 16 SCOs). Case diagnoses were blindly reviewed by a neuropathologist according to the latest WHO criteria, resulting in 112 pathologically documented cases (64 GCTs, 35 pituicytomas, and 13 SCOs). Imaging illustrations from proved cases were reviewed to determine location, configuration, attenuation and signal intensity, and enhancement characteristics. RESULTS: Only pituicytomas presented as purely intrasellar lesions (7/33). Most GCTs were purely suprasellar (28/45). All SCOs were both intra- and suprasellar (13/13). Twenty-five percent of pituicytomas (6/22) and GCTs (7/30) appeared separate from the pituitary gland. All SCOs were infiltrating. Seventy-nine percent of entities appeared isointense to brain on T1-weighted image (34/43). Seventy-four percent of pituicytomas enhanced homogeneously (14/19). Twelve of 23 GCTs and 5/7 SCOs enhanced heterogeneously. Most GCTs were hyperattenuated to brain on CT (18/20). Eleven of 13 cases enhanced homogeneously. Visual disturbances were common symptoms for all entities (67/112). Diabetes insipidus was rare (4/112). CONCLUSIONS: Pituicytoma may be considered for purely intrasellar masses that are clearly separate from the pituitary gland. GCT should receive consideration for purely suprasellar lesions that are hyperattenuated to brain on CT. SCO should be considered for infiltrating pituitary masses with a mixed intra- and suprasellar location. A history of diabetes insipidus helps to exclude these tumors.

The financial costs of healthcare treatment for people with Type 1 or Type 2 diabetes in the UK with particular reference to differing severity of peripheral neuropathy.

AIMS: To characterize symptom severity of diabetic peripheral neuropathy (DPN) in people with diabetes and to characterize its association with healthcare resource use. METHODS: The study was undertaken in Cardiff and the Vale of Glamorgan, UK. A postal survey was posted to subjects identified as having diabetes. Demography, quality of life (EQ-5D and SF-36) and symptoms of neuropathy (NTSS-6 and QOL-DN) data were collected. These data were linked to routine healthcare data coded into healthcare resource groups (HRGs) and subsequently costed according to UK National reference costs. RESULTS: Survey responses were received from 1298 patients, a 32% response rate. For patients with a clinically confirmed diagnosis of DPN, the mean NTSS-6-SA score was 6.16 vs. 3.19 (P < 0.001). Duration of diabetes did not change across groups defined by severity of neuropathy symptoms, but mean HbA(1c) and body mass index values did increase with symptom severity (range 7.6-8.1%, P = 0.023; and 28.0-30.9 kg/m(2), P < 0.001, respectively). General linear modelling showed that the NTSS-6-SA score was a significant predictor of both annual health resource costs and yearly prescribed drug costs. On average, each 1-point increase in NTSS-6-SA score predicted a 6% increase in primary and secondary care costs and a 3% increase in log transformed drug costs. CONCLUSION: This study demonstrated that severity of DPN symptoms was associated with increased healthcare resource use, thus costs.

The health-related utility and health-related quality of life of hospital-treated subjects with type 1 or type 2 diabetes with particular reference to differing severity of peripheral neuropathy.

AIMS/HYPOTHESIS: We characterised symptom severity of diabetic peripheral neuropathy (DPN) in people with diabetes, and correlated this with health-related utility and health-related quality of life. MATERIALS AND METHODS: The study was undertaken in Cardiff and the Vale of Glamorgan, Wales. A postal survey was mailed to a random sample of subjects identified as having diabetes. Data were collected on the symptoms of neuropathy using the Neuropathic Total Symptom Score (self-administered) (NTSS-6-6A) and on quality of life using the Quality of Life in Diabetes Neuropathy Instrument (QoL-DN), EueroQoL five dimensions (EQ5D) and Short Form 36 (SF36). Other information, such as demographics and self-reported drug use, was also collected. The anonymised data were linked to routine inpatient and outpatient healthcare data. RESULTS: Responses were received from 1,298 patients. For patients with a clinically confirmed diagnosis of DPN, the mean NTSS-6-SA score was 6.16 vs 3.19 in patients without DPN (p<0.001). Four categories of severity were defined, ranging from none to severe. All quality of life measures showed a deterioration between these groups: the EQ5D(index) fell from an average of 0.81 in those without symptoms to 0.25 in those with severe symptoms, the SF36 general health profile fell from 59.9 to 25.5 (p<0.001) and the QoL-DN increased from 25.8 to 48.1 (p<0.001). Multivariate models also demonstrated that this relationship remained after controlling for other factors. CONCLUSIONS/INTERPRETATION: This study demonstrated that severity of DPN symptoms was predictive of poor health-related utility and decreased quality of life. Furthermore, it provides detailed utility data for economic evaluation of treatment of typical diabetes-related morbidity states. Reducing DPN morbidity should be a priority.

Goal theory, motivation, and school achievement: an integrative review.

The purpose of this review is to document the directions and recent progress in our understanding of the motivational dynamics of school achievement. Based on the accumulating research it is concluded that the quality of student learning as well as the will to continue learning depends closely on an interaction between the kinds of social and academic goals students bring to the classroom, the motivating properties of these goals and prevailing classroom reward structures. Implications for school reform that follow uniquely from a motivational and goal-theory perspective are also explored.

Receipt of recommended prenatal interventions and birth weight among African-American women: analysis of data from the 1988 National Maternal and Infant Health Survey.

OBJECTIVES: While the importance of exploring and better measuring elements of prenatal care have been noted in the public health literature, the components and timing of such services have been poorly examined for the overall pregnant population and specifically for African-Americans, who traditionally have had higher rates of low birth weight and premature delivery. This study explores the association between patient receipt of selected recommended prenatal care interventions and infant birth weight in a nationally representative sample of African-American women, while controlling for the influence of low birth weight risk indicators. METHOD: This is a retrospective case-control analysis using survey data of women who delivered normal birth weight, moderate low birth weight, and very low birth weight newborns in 1988. A sample of 3905 African-American women who responded to the 1988 National Maternal and Infant Health Survey is examined based on maternal recall of receipt of six clinical screening procedures and seven health-promotion recommendations. Birth weight measures were obtained from linked 1988 birth certificate data. RESULTS: The initial results indicated that women who do not receive all of the recommended health-promotion advice are more likely to deliver very low birth weight infants than women who receive all of the advice in the content of their prenatal care, after controlling for low birth weight risks (OR = 1.28; 95% CI = 1.01, 1.7). However, when breast-feeding advice is removed from the aggregation of health-promotion advice, the significant effect of advice on very low birth weight is negated. No other significant group variations in the receipt of clinical screening procedures or health-promotion advice for women who gave birth in the remaining birth weight categories are observed. CONCLUSIONS: Nationally recommended initial clinical screening procedures and health-promotion advice in prenatal care content do not appear to be associated with a reduction in low birth weight for African-American women. More research is needed to better assess the impact of other antenatal interventions, particularly those given to women with a higher prevalence of poor birth outcomes.

The activation of human fibroblast prostaglandin E production by interleukin 1.

We have examined the induction of prostaglandin E2 (PGE2) release from fibroblasts by human interleukin 1 (IL-1). A number of fibroblast cell lines appear to respond to IL-1 in a fashion similar to that seen with synovial fibroblast cultures. Using the Gin-1 primary fibroblast cell line, the earliest time where a significant increase in PGE2 release can be detected is 2 hr. Thereafter PGE2 appears to increase dramatically, with levels after 5 hr increased over 50-fold above baseline. IL-1 appears to directly induce the increase in PGE2 since removal of other proteins from culture medium does not affect induction. PGE2 induction by IL-1 also does not require cell proliferation. The induction appears to involve the synthesis of new protein since the enhanced release can be completely blocked by addition of actinomycin D or cycloheximide. Arachidonic acid mobilization in cells does not appear to be altered following IL-1 addition. However, the ability to convert arachidonic acid to PGE2 is increased following 5 hr of culture with IL-1. While increasing the release of PGE2, the addition of phorbol esters, alone or in combination with calcium ionophores, does not mimic the protein synthesis-dependent increase seen with IL-1. Taken together these results suggest that IL-1 induction of fibroblast PGE2 involves the synthesis of new protein or proteins involved in the conversion of free arachidonic acid to PGE2.

Time-resolved measurement of propagating spin waves in ferromagnetic thin films.

We measure the propagation of spatially localized spin waves in NiFe thin films through local inductive detection of the dynamic magnetization. A pulsed magnetic field excites a linear superposition of spin wave modes with a distribution that is predominantly driven by the spatial dependence of the in-plane excitation field. The results of numerical micromagnetic calculations exhibit excellent agreement with experiment and show that a comprehensive account of spatial nonuniformity and propagation is necessary to accurately measure the intrinsic damping rate.

The distribution and clearance of radiolabeled human interleukin-1 beta in mice.

Mice were injected with radiolabeled human interleukin-1 beta (IL-1) and monitored for tissue localization and route of clearance. IL-1 was labeled with no apparent loss of in vitro biological activity. Mice were injected by intravenous (i.v.), intraperitoneal (i.p.), and subcutaneous (s.c.) routes with either low dose (10 ng radiolabeled) or high dose (10 ng radiolabeled with 10 micrograms unlabeled) IL-1. Blood and urine were monitored and various tissues were counted for radioactivity after 2, 24 or 48 hours. Injection of either dose of IL-1 by i.v. route demonstrates a rapid initial loss of IL-1 from the circulation followed by a slower loss over the next hour. Injection by i.p. or s.c. routes gives an initial peak in circulating IL-1 after 10 minutes which is sustained over at least the next 7 hours with the high dose. Circulating IL-1 is associated with the plasma fraction and is not cell associated. Two hours after injection, most tissues examined were found to contain an equal amount of IL-1 on a weight basis with the exception of bone, which contains half the level found in other tissues, and kidney, which contains 4-8 fold more IL-1. The major route of clearance is the kidney with 10-20% of label found in the urine within hours of injection. IL-1 found in the urine contains intact 17 kD IL-1.