Inhibition of Neutral Amino Acid Transport Across the Human Blood-Brain Barrier by Phenylalanine

The delivery of large neutral amino acids (LNAAs) to brain across the blood-brain barrier (BBB) is mediated by the L-type neutral amino acid transporter present in the membranes of the brain capillary endothelial cell. In experimental animals, the L-system transporter is saturated under normal conditions, and therefore an elevation in the plasma concentration of one LNAA will reduce brain uptake of others. In this study, we used positron emission tomography (PET) to determine the effect of elevated plasma phenylalanine concentrations on the uptake of an artificial neutral amino acid, [ 11 C]-aminocyclohexanecarboxylate ([ 11 C]ACHC), in human brain. PET scans were performed on six normal male subjects after an overnight fast and again 60 min after oral administration of 100 mg/kg of phenylalanine. The plasma phenylalanine concentration increased by an average of 11-fold between the first and second scans. This increase produced a reduction in [ 11 C]ACHC uptake in all brain regions but not in scalp. The mean ± SD influx rate constant for whole brain decreased after phenylalanine ingestion from 0.036 ± 0.002 to 0.019 ± 0.004 ml/g/min. Kinetic analysis of the effect of plasma phenylalanine concentration on the rate of [ 11 C]ACHC uptake is compatible with a model of competitive inhibition so that large increases in the concentration of one LNAA in plasma will reduce the brain uptake of other LNAAs across the human BBB.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65880/1/j.1471-4159.1995.64031252.x.pd

New Governance for Rural America: Creating Intergovernmental Partnerships

Throughout the 1990s public demand for a fundamental shift in the relationship between government and its citizens has intensified. In response, a new governance model has emerged, emphasizing decreased federal control in favor of intergovernmental collaboration and increased involvement of state, local, and private agencies. As the authors of this volume show, one of the best examples of new governance can be found in the National and State Rural Development Councils (NRDC and SRDC), created in 1990 as the result of President Bush\u27s Rural Development Initiative and now called the Rural Development Partnership. This effort was part of a move within policymaking circles to redefine a rural America that was no longer synonymous with family farming and that required innovative new solutions for economic revival. By 1994 twenty-nine states had created and ten other states were in the process of forming such councils. In this first detailed analysis of the NRDC and SRDCs, the authors examine the successes and failures of the original eight councils in Kansas, Maine, Mississippi, Oregon, South Carolina, South Dakota, Texas, and Washington; as well as eight other councils subsequently created in Iowa, New Mexico, North Carolina, Vermont, New York, North Dakota, Utah, and Wyoming. Combining empirical analysis with current theories about networks and inter-organizational relations, this volume should appeal to academics and practitioners interested in rural development policy, public administration, public policy and management, and intergovernmental relations. Description Beryl A. Radin is professor of Public Administration and Policy in the Graduate School of Public Affairs at Rockefeller College of the State University of New York at Albany. This Kansas Open Books title is funded by a grant from the National Endowment for the Humanities and the Andrew W. Mellon Foundation Humanities Open Book Program.https://digitalcommons.pittstate.edu/kansas_open_books/1051/thumbnail.jp

Magnetic Resonance Imaging with laser polarized 129Xe129Xe

Magnetic Resonance Imaging with laser-polarized 129Xe129Xe can be utilized to trace blood flow and perfusion in tissue for a variety of biomedical applications. Polarized xenon gas introduced in to the lungs dissolves in the blood and is transported to organs such as the brain where it accumulates in the tissue. Spectroscopic studies combined with imaging have been used to produce brain images of 129Xe129Xe in the rat head. This work establishes that nuclear polarization produced in the gas phases survives transport to the brain where it may be imaged. Increases in polarization and delivered volume of 129Xe129Xe will allow clinical measurements of regional blood flow. © 1998 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87439/2/200_1.pd

Use of [1 or 3-3H, U-14c]glucose to estimate the synthesis of glycerolipids via acyl dihydroxyacetone phosphate

SummaryBHK-21-cl3 fibroblasts were incubated with [1-3H, U-14c]glucose or [3-3H, U-14c]glucose to produce intracellular [3H]NADPH via the phosphogluconate pathway. 3H and 14C were then determined at the three positions of glycerol in glycerol phosphate, saponifiable glycerolipids, alkyl ether glycerolipids and plasmalogens. The 3H/14C ratio at C-2 in glycerol of saponifiable glycerolipids is 2-10 fold greater than in glycerol phosphate and approaches the ratio found in ether-containing glycerolipids. This suggests that a significant fraction of the glycerolipids in BHK-21-cl3 fibroblasts is synthesized via acyl dihydroxyacetone phosphate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22025/1/0000441.pd

Effect of Aspartame-Derived Phenylalanine on Neutral Amino Acid Uptake in Human Brain: A Positron Emission Tomography Study

The possible effects of elevation of the plasma phe-nylalanine level secondary to the ingestion of aspartame on brain amino acid uptake in human subjects have been investigated by means of positron emission tomography (PET). 1-[ 11 C]Aminocyclohexanecarboxylate ([ 11 C]ACHC) is a poorly metabolized synthetic amino acid that crosses the blood-brain barrier by the same carrier that transports naturally occurring large neutral amino acids. Quantitative test-retest PET studies were performed on 15 individuals. Seven received two identical baseline scans, whereas eight received a baseline scan followed by a scan performed ∼40–45 min following ingestion of an orange-flavored beverage containing 34 mg/kg of body weight of the low-calorie sweetener aspartame, a dose equivalent to the amount in 5 L of diet soft drink consumed all at once by the study subjects, weighing an average of 76 kg. The 40–45-min interval was selected to maximize the detection of possible decreases in ACHC uptake resulting from increased competition for the carrier, because the plasma phenylalanine level is known to peak at this time. We observed an 11.5% decrease in the amino acid transport rate constant Kt and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65668/1/j.1471-4159.1991.tb02047.x.pd

Cerebral blood flow activation of the anterior cingulate gyrus studied with positron emission tomography

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30868/1/0000532.pd

Cerebral benzodiazepine receptor binding in vivo in patients with recurrent hepatic encephalopathy

Increased activation of the central benzodiazepine receptor (BZR) appears to play an important role in hepatic encephalopathy (HE). However, there is controversy regarding whether the density or affinity of BZRs is altered. A previous positron emission tomography (PET) study using the BZR antagonist [11C]flumazenil (FMZ) found two- to threefold greater cerebral cortical tracer uptake in recurrent HE, but did not account for impaired FMZ metabolism due to liver disease or assess the relative contributions of tracer delivery versus BZR binding. We hypothesized that correcting for these factors would affect estimations of BZR binding in HE. Nine patients with recurrent HE and 13 age-comparable controls were studied with [11C]FMZ PET. After intravenous administration of [11C]FMZ, arterial blood samples were collected, and PET images were acquired over 60 minutes. FMZ transport and binding maps were calculated for each subject by using a physiological tracer kinetic model. In agreement with the previous report, we found that FMZ reached a much higher level and was retained longer in the HE cerebral cortex despite similar total blood radioactivity levels in the two groups. However, the patients showed impaired hepatic metabolism of FMZ. After physiological modeling incorporating these data, significant increases in BZR binding were found in the thalamus (13%), cerebellum (20%), and pons (23%). There were minor, statistically insignificant increases in cerebral cortical (10%), putamen (12%), and whole brain (12%) BZR binding in patients with recurrent HE. These findings are in general agreement with results of autopsy studies, confirming a lack of major increases in cortical or basal ganglial BZR binding in HE. They emphasize that physiological tracer modeling should be used and altered peripheral radioligand metabolism considered in future PET studies of HE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34769/1/510260204_ftp.pd

Biomarkers for cystic fibrosis lung disease: Application of SELDI-TOF mass spectrometry to BAL fluid

AbstractBackgroundFor cystic fibrosis (CF) patients there is a lack of good assays of disease activity and response to new therapeutic interventions, including gene therapy. Current measures of airways inflammation severity are insensitive or non-specific.MethodsBronchoalveolar lavage fluid from 39 CF children and 38 respiratory disease controls was obtained at bronchoscopy and analysed by surface enhanced laser desorption ionisation time of flight (SELDI-TOF) mass spectrometry. Recognized proteins were assessed for CF disease specificity. Individual protein identification of specific peaks was performed.Results1277 proteins/peptides, >4 kDa, were detected using 12 different surfaces and binding conditions. 202 proteins/peptides were differentially expressed in the CF samples (p<0.001), 167 up-regulated and 35 down-regulated. The most discriminatory biomarker had a mass of 5.163 kDa. The most abundant, with a mass of 10.6 kDa, was identified as s100 A8 (calgranulin A).ConclusionsThe application of SELDI-TOF mass spectrometry allows evaluation of proteins in BAL fluid avoiding the limitations of only analysing predetermined proteins and potentially identifying proteins not previously appreciated as biomarkers. Its application to cystic fibrosis should enable appropriate evaluation of evolving illness, of gene therapy and other new therapies

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p