bluuebunny/crossref_metadata_2025 huggingface dataset:
Diverse Effects of Methylseleninic Acid on the Transcriptional Program of Human Prostate Cancer Cells
Authors: Zhao Hongjuan , Whitfield Michael L. , Xu Tong , Botstein David , Brooks James D.
Published: November 2003

Methylseleninic acid (MSA) has been shown to have potent anticancer activity and is an excellent compound for studying the anticancer effects of selenium in vitro. To gain insights into the effects of MSA in prostate cancer, we characterized the global transcriptional response of LNCaP, an androgen-sensitive human prostate cancer cell line, to MSA by using high-density cDNA microarrays. We identified 951 genes whose expression shows striking dose- and time-dependent changes in response to 3-30 μM MSA over the time course of 48 h. Transcript levels of many cell cycle-regulated genes change in response to MSA, suggesting that MSA inhibits proliferation. Consistent with these gene expression changes, cell proliferation, monitored by carboxyfluoroscein succinimidyl ester staining, was decreased after MSA treatment, and an accumulation of cells at G0/G1 phase was detected by flow cytometry. Surprisingly, MSA also modulated expression of many androgen-regulated genes, suppressed androgen receptor (AR) expression at both mRNA and protein level, and decreased levels of prostate specific antigen secreted into the medium. Low concentrations of MSA also induced significant increases in transcript levels of phase 2 detoxification enzymes and induced NADPH dehydrogenase, quinone 1 enzymatic activity, a surrogate marker of global phase 2 enzyme activity. Our results suggest that MSA may protect against prostate cancer by inhibiting cell proliferation, by modulating the expression of AR and AR-regulated genes and by inducing carcinogen defenses.
HIV Nef-mediated Major Histocompatibility Complex Class I Down-Modulation Is Independent of Arf6 Activity
Authors: Larsen Jakob E. , Massol Ramiro H. , Nieland Thomas J. F. , Kirchhausen Tomas
Published: November 2003

HIV Nef has a number of important biological effects, including the down-modulation of several immunological important molecules (CD4, major histocompatibility complex [MHC] class I). Down-modulation of CD4 seems to be via clathrin-dependent endocytosis, whereas down-modulation of MHC class I remains unexplained. Several mutant proteins, including mutations in the small GTPase Arf6, have been used to probe membrane traffic pathways. One such mutant has recently been used to propose that Nef acts through Arf6 to activate the endocytosis of MHC class I. Here, we show that MHC class I down-modulation is unaffected by other Arf6 mutants that provide more specific perturbations in the GDP-GTP cycling of Arf6. Inhibition of phosphatidylinositol-3-phosphate kinase, an upstream activator of Arf6, also had no effect on the internalization step, but its activity is required to direct MHC class I to the trans-Golgi network. We conclude that the apparent Arf6 dependency of Nef-mediated MHC class I down-modulation is due to nonspecific perturbations in membrane traffic.
RNA Interference Inhibition of Mus81 Reduces Mitotic Recombination in Human Cells
Authors: Blais Veronique , Gao Hui , Elwell Cherilyn A. , Boddy Michael N. , Gaillard Pierre-Henri L. , Russell Paul , McGowan Clare H.
Published: November 2003

Mus81 is a highly conserved endonuclease with homology to the XPF subunit of the XPF-ERCC1 complex. In yeast Mus81 associates with a second subunit, Eme1 or Mms4, which is essential for endonuclease activity in vitro and for in vivo function. Human Mus81 binds to a homolog of fission yeast Eme1 in vitro and in vivo. We show that recombinant Mus81-Eme1 cleaves replication forks, 3′ flap substrates, and Holliday junctions in vitro. By use of differentially tagged versions of Mus81 and Eme1, we find that Mus81 associates with Mus81 and that Eme1 associates with Eme1. Thus, complexes containing two or more Mus81-Eme1 units could function to coordinate substrate cleavage in vivo. Down-regulation of Mus81 by RNA interference reduces mitotic recombination in human somatic cells. The recombination defect is rescued by expression of a bacterial Holliday junction resolvase. These data provide direct evidence for a role of Mus81-Eme1 in mitotic recombination in higher eukaryotes and support the hypothesis that Mus81-Eme1 resolves Holliday junctions in vivo.
Pex30p, Pex31p, and Pex32p Form a Family of Peroxisomal Integral Membrane Proteins Regulating Peroxisome Size and Number inSaccharomyces cerevisiae
Authors: Vizeacoumar Franco J. , Torres-Guzman Juan C. , Bouard David , Aitchison John D. , Rachubinski Richard A.
Published: November 2003

The peroxin Pex23p of the yeast Yarrowia lipolytica exhibits high sequence similarity to the hypothetical proteins Ylr324p, Ygr004p, and Ybr168p encoded by the Saccharomyces cerevisiae genome. Ylr324p, Ygr004p, and Ybr168p are integral to the peroxisomal membrane and act to control peroxisome number and size. Synthesis of Ylr324p and Ybr168p, but not of Ygr004p, is induced during incubation of cells in oleic acid-containing medium, the metabolism of which requires intact peroxisomes. Cells deleted for YLR324w exhibit increased numbers of peroxisomes, whereas cells deleted for YGR004w or YBR168w exhibit enlarged peroxisomes. Ylr324p and Ybr168p cannot functionally substitute for one another or for Ygr004p, whereas Ygr004p shows partial functional redundancy with Ylr324p and Ybr168p. Ylr324p, Ygr004p, and Ybr168p interact within themselves and with Pex28p and Pex29p, which have been shown also to regulate peroxisome size and number. Systematic deletion of genes demonstrated that PEX28 and PEX29 function upstream of YLR324w, YGR004w, and YBR168w in the regulation of peroxisome proliferation. Our data suggest a role for Ylr324p, Ygr004p, and Ybr168p—now designated Pex30p, Pex31p, and Pex32p, respectively—together with Pex28p and Pex29p in controlling peroxisome size and proliferation in Saccharomyces cerevisiae.
A Review of Computer-Aided Body Surface Area Determination
Authors: Neuwalder J. M. , Sampson C. , Breuing K. H. , Orgill D. P.
Published: November 2003

Estimates of percent body surface area (%BSA) burns correlate well with fluid needs, nutritional requirements, and prognosis. Most burn centers rely on the Lund Browder chart and “rule of nines,” to calculate the %BSA. Computer-based methods may improve precision and data analysis. We studied two new methods of determining %BSA: a two-dimensional Web-based program (Sage II) and a three-dimensional computer-aided design program (EPRI 3D Burn Vision). Members of our burn team found the Sage II program easy to use and found many of the features useful for patient care. The EPRI program has the advantage of 3D images and different body morphologies but required training to use. Computer-aided methods offer the potential for improved precision and data analysis of %BSA measurements.
A Pilot Study Comparing Percutaneous Decompression With Decompressive Laparotomy for Acute Abdominal Compartment Syndrome in Thermal Injury
Authors: Latenser Barbara A. , Kowal-Vern Areta , Kimball Douglas , Chakrin Alan , Dujovny Nadav
Published: November 2003

Abdominal Compartment Syndrome (ACS) has multiple causes, and decompressive laparotomy has been the most frequent modality to prevent worsening cardiovascular, respiratory, and renal function. This pilot study evaluated the utility of percutaneous drainage (PD) of peritoneal fluid compared with decompressive laparotomy in burn patients. A 26-month review was conducted. Nine of 13 (69%) study patients developed intra-abdominal hypertension (IAH) that progressed to abdominal compartment syndrome in 4 (31%). All were treated with PD using a diagnostic peritoneal lavage catheter. Peritoneal fluid analysis revealed a sterile plasma ultrafiltrate with electrolyte and other chemistries reflecting patient serum levels. Five patients underwent PD successfully, and their IAH did not progress to ACS. Four patients with greater than 80% TBSA and severe inhalation injury did not respond to PD and required decompressive laparotomy. There was no evidence of bowel edema, ischemia, or necrosis. All patients requiring decompressive laparotomies died either from sepsis or respiratory failure. Percutaneous decompression is a safe and effective method of decreasing IAH and preventing ACS in patients with less than 80% TBSA thermal injury.
The Development of an Educational Web Site for Burn Care: Burnsurgery.org
Authors: Orgill D. P. , Neuwalder J. M. , Arch M. , Orgill J. , Demling R.
Published: November 2003

Advances in burn care are well documented in the literature but often do not reach health care professionals who treat burn patients. The World Wide Web provides instant access to a wide variety of information globally. We describe the development of www.burnsurgery.org, a nonprofit Web site dedicated to the education of burn care professionals. Internet-based medical education is becoming a dominant method of information transfer and we believe that it will help to standardize and improve burn care throughout the world.
Predictors of Quality of Life as Measured by the Burn Specific Health Scale in Persons With Major Burn Injury
Authors: Cromes G. F. , Holavanahalli R. , Kowalske K. , Helm P.
Published: November 2003

To determine 1) change over time in Quality of Life (QOL) and 2) functional, community reentry, and psychosocial predictors of QOL, data were prospectively collected from adults with major burn injury 2 months after hospital discharge (n = 110) and 6 (n = 97) and 12 (n = 69) months after injury. The dependent QOL variable was the Burn Specific Health Scale (BSHS) and the predictor variables were Brief Symptom Inventory, Functional Assessment Screening Questionnaire, Functional Independence Measure, Pain Analog Scale, and Community Integration Questionnaire. BSHS global scores were unchanged across the measurement periods. Stepwise multiple-regression analyses resulted in statistically significant multiple R s of .79 at 2 months, .81 at 6 months, and .76 at 12 months. Variables predicting more favorable BSHS global score were less emotional distress and pain at 2 months, less emotional distress and pain and better community reentry at 6 months, and less emotional distress and better community reentry at 12 months.
Catheter Infection Risk Related to the Distance Between Insertion Site and Burned Area
Authors: Ramos Guillermo E. , Bolgiani Alberto N. , Patiño Osvaldo , Prezzavento Gustavo E. , Guastavino Paula , Durlach Ricardo , Fernandez Canigia Liliana B. , Benaim Fortunato
Published: November 2003

A prospective observational study of central venous catheters (CVC) was carried out in order to determine if a CVC inserted near an open burn wound increases catheter infection risk in burned patients. The study was carried out during a 12-month period (1998–1999) at the Benaim Foundation's Burn Unit in Buenos Aires (C.E.P.A.Q.). Eighty-three CVCs were inserted in 20 burned patients during the study period. Twenty-six catheters were inserted near an open wound (NOW) and 57 far from an open wound (FOW). NOW CVCs were considered when 25 cm2 surrounding the catheter's insertion site overlapped the wound. Colonization rates were 84% (22/26 CVCs) in those inserted NOW and 47% (27/57 CVCs) in FOW (P = 0.001). Colonization relative risk of NOW-CVCs was 1.79 (95% confidence interval, 1.3–2.46). Bacteremia rates were 27% (7/26 CVCs) in CVCs inserted NOW and 6% (3/57 CVCs) in FOW (P = 0.004). Bacteremic risk of NOW-CVCs was 5.12 (95% confidence interval, 1.44–18.22). Colonization rates were higher and sooner in NOW-CVCs than in FOW-CVCs. We suggest that insertion of catheters near an open burn wound should be avoided and, if inevitable, should not be left in place for period exceeding 3 days.
Effect of Exercise Training on Pulmonary Function in Children With Thermal Injury
Authors: Suman Oscar E. , Mlcak Robert P. , Herndon David N.
Published: November 2003

Severe thermal injury in children results in a decrease in pulmonary function (PF) which lasts well into convalescence. Exercise has been used successfully to improve PF in other populations exhibiting a compromised PF such as in chronic obstructive pulmonary disease. Yet, whether exercise training will induce improvements in PF in burned children is presently unknown. We therefore evaluated if an exercise program improved PF in severely burned children (BC). Twenty healthy controls, nonburn children (NB) age 7 to <18 and 31 severely burned children; ages 7 to <18 years old, with greater than 40% of total body surface area burned were enrolled in the study. Burned children were randomized into two groups. One to participate in a 12-week in-hospital physical rehabilitation program supplemented with an exercise-training program (REX, n = 17) and the other nonexercising group (R, n = 14) to participate in a 12-week, home-based physical rehabilitation program without exercise. Pulmonary function tests were performed for all groups at baseline, but only the REX and R groups were tested after 12 weeks of either exercise or no exercise. Baseline PF for the NB group was normal and no differences in PF were found between the R vs REX groups. However, PF was decreased in BC compared to NB children. There was a significant improvement in PF in the REX group. In contrast, PF in the R group remained relatively unchanged. Severely burned children improve PF as a result of an exercise program and such should be a fundamental component of a multidisciplinary outpatient treatment program for victims of thermal injury.
Insulin-Like Growth Factor-I Inhibits Lysosomal and Proteasome-Dependent Proteolysis in Skeletal Muscle After Burn Injury
Authors: Fang Cheng-Hui , Li Bing-Guo , Wray Curtis J. , Hasselgren Per-Olof
Published: November 2003

Previous studies suggest that insulin-like growth factor-I (IGF-I) inhibits burn-induced muscle wasting mainly by reducing muscle protein degradation. The intracellular mechanisms of this effect of IGF-I are not known. In the present study, we examined the influence of IGF-I on individual proteolytic pathways in muscles from burned rats. Extensor digitorum longus muscles from burned rats were incubated with specific blockers of lysosomal, calcium-calpain-dependent, and ubiquitin-proteasome-dependent proteolytic pathways in the absence or presence of IGF-I. In addition, cathepsin B and L activities and 20S proteasome activity were determined. IGF-I inhibited lysosomal and ubiquitin-proteasome-dependent protein breakdown in skeletal muscle from burned rats by 70 and 90%, respectively, but did not influence calcium-calpain-dependent protein breakdown. The hormone blocked the burn-induced increase in cathepsin B and L activities but did not reduce 20S proteasome activity. Results are important because they provide novel information about intracellular mechanisms by which IGF-I inhibits the catabolic response to burn injury in skeletal muscle.
Multicenter Postapproval Clinical Trial of Integra® Dermal Regeneration Template for Burn Treatment
Authors: Heimbach David M. , Warden Glenn D. , Luterman Arnold , Jordan Marion H. , Ozobia Nathan , Ryan Colleen M. , Voigt David W. , Hickerson William L. , Saffle Jeffrey R. , DeClement Frederick A. , Sheridan Robert L. , Dimick Alan R.
Published: November 2003

The safety and effectiveness of Integra® Dermal Regeneration Template was evaluated in a postapproval study involving 216 burn injury patients who were treated at 13 burn care facilities in the United States. The mean total body surface area burned was 36.5% (range, 1–95%). Integra® was applied to fresh, clean, surgically excised burn wounds. Within 2 to 3 weeks, the dermal layer regenerated, and a thin epidermal autograft was placed. The incidence of invasive infection at Integra®-treated sites was 3.1% (95% confidence interval, 2.0–4.5%) and that of superficial infection 13.2% (95% confidence interval, 11.0–15.7%). Mean take rate of Integra® was 76.2%; the median take rate was 95%. The mean take rate of epidermal autograft was 87.7%; the median take rate was 98%. This postapproval study further supports the conclusion that Integra® is a safe and effective treatment modality in the hands of properly trained clinicians under conditions of routine clinical use at burn centers.
Burns Caused by Carburetors
Authors: Still Joseph , Law Edward , Orlet Hermann , Wilson Joan
Published: November 2003

During a 10-year period 4645 patients were admitted to the Joseph M. Still Burn Center with acute burns. Of these, 83 (1.79%) were caused by carburetor-related accidents. There were 79 males and 4 females. Ages ranged from 10 to 72 years. Burn size ranged from 1 to 97.5% (mean, 12.3%). There was one death in the group. Eighteen patients required only topical care; 65 patients required a total of 108 operations for debridement and grafting. Length of stay ranged from 1 to 63 days (mean, 11 days). The mechanism of injury was usually the same; in 81 cases the accident occurred while someone was pouring gasoline into a carburetor. In 63 cases the vehicle was an automobile or pickup truck. Explosions resulted in 12 instances; in 65 instances fires were started. These injuries are serious, expensive, fairly common, and may be life threatening. Proper handling of gasoline is stressed. Newer vehicles have fuel injector systems, which may gradually eliminate the problem over time, because pouring gasoline is not required.
Nonparametric Analysis of Statistic Images from Functional Mapping Experiments
Authors: Holmes A. P. , Blair R. C. , Watson J. D. G. , Ford I.
Published: November 2003

The analysis of functional mapping experiments in positron emission tomography involves the formation of images displaying the values of a suitable statistic, summarising the evidence in the data for a particular effect at each voxel. These statistic images must then be scrutinised to locate regions showing statistically significant effects. The methods most commonly used are parametric, assuming a particular form of probability distribution for the voxel values in the statistic image. Scientific hypotheses, formulated in terms of parameters describing these distributions, are then tested on the basis of the assumptions. Images of statistics are usually considered as lattice representations of continuous random fields. These are more amenable to statistical analysis. There are various shortcomings associated with these methods of analysis. The many assumptions and approximations involved may not be true. The low numbers of subjects and scans, in typical experiments, lead to noisy statistic images with low degrees of freedom, which are not well approximated by continuous random fields. Thus, the methods are only approximately valid at best and are most suspect in single-subject studies. In contrast to the existing methods, we present a nonparametric approach to significance testing for statistic images from activation studies. Formal assumptions are replaced by a computationally expensive approach. In a simple rest-activation study, if there is really no activation effect, the labelling of the scans as “active” or “rest” is artificial, and a statistic image formed with some other labelling is as likely as the observed one. Thus, considering all possible relabellings, a p value can be computed for any suitable statistic describing the statistic image. Consideration of the maximal statistic leads to a simple nonparametric single-threshold test. This randomisation test relies only on minimal assumptions about the design of the experiment, is (almost) exact, with Type I error (almost) exactly that specified, and hence is always valid. The absence of distributional assumptions permits the consideration of a wide range of test statistics, for instance, “pseudo” t statistic images formed with smoothed variance images. The approach presented extends easily to other paradigms, permitting nonparametric analysis of most functional mapping experiments. When the assumptions of the parametric methods are true, these new nonparametric methods, at worst, provide for their validation. When the assumptions of the parametric methods are dubious, the nonparametric methods provide the only analysis that can be guaranteed valid and exact.
Temporal Correlation Analysis of Penumbral Dynamics in Focal Cerebral Ischemia
Authors: Lo E. H. , Rogowska J. , Bogorodzki P. , Trocha M. , Matsumoto K. , Saffran B. , Wolf G. L.
Published: November 2003

A novel temporal correlation technique was used to map the first-pass transit of iodinated contrast agents through the brain. Transit profiles after bolus injections were measured with dynamic computed tomography (CT) scanning (1 image/s over 50 s). A rabbit model of focal cerebral ischemia (n = 6) was used, and dynamic CT scans were performed at 30, 60, 90, and 120 min postocclusion. Within the ischemic core, no bolus transit was detectable, demonstrating that complete ischemia was present after arterial occlusion. In the periphery of the ischemic distribution, transit dynamics showed smaller peaks, broadened profiles, and overall delay in bolus transit. A cross-correlation method was used to generate maps of delays in ischemic transit profiles compared with normal transit profiles from the contralateral hemisphere. These maps showed that penumbral regions surrounding the ischemic core had significantly delayed bolus transit profiles. Enlargement of the ischemic core over time (from 30 to 120 min postocclusion) was primarily accomplished by the progressive deterioration of the penumbral regions. These results suggest that (a) temporal correlation methods can define regions of abnormal perfusion in focal cerebral ischemia, (b) peripheral regions of focal cerebral ischemia are characterized by delays in bolus transit profiles, and (c) these regions of bolus transit delay deteriorate over time and thus represent a hemodynamic penumbra.
Effects of Hypoxia-Ischemia on GLUT1 and GLUT3 Glucose Transporters in Immature Rat Brain
Authors: Vannucci Susan J. , Seaman Lisa B. , Vannucci Robert C.
Published: November 2003

Cerebral hypoxia-ischemia produces major alterations in energy metabolism and glucose utilization in brain. The facilitative glucose transporter proteins mediate the transport of glucose across the blood–brain barrier (BBB) (55 kDa GLUT1) and into the neurons and glia (GLUT3 and 45 kDa GLUT1). Glucose uptake and utilization are low in the immature rat brain, as are the levels of the glucose transporter proteins. This study investigated the effect of cerebral hypoxia-ischemia in a model of unilateral brain damage on the expression of GLUT 1 and GLUT3 in the ipsilateral (damaged, hypoxic-ischemic) and contralateral (undamaged, hypoxic) hemispheres of perinatal rat brain. Early in the recovery period, both hemispheres exhibited increased expression of BBB GLUT1 and GLUT3, consistent with increased glucose transport and utilization. Further into recovery, BBB GLUT1 increased and neuronal GLUT3 decreased in the damaged hemisphere only, commensurate with neuronal loss.
Calcium Movements in Traumatic Brain Injury: The Role of Glutamate Receptor-Operated Ion Channels
Authors: Nilsson P. , Laursen H. , Hillered L. , Hansen A. J.
Published: November 2003

Ion-selective microelectrodes were used to study acute effects of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor blockade on posttraumatic calcium disturbances. An autoradiographic technique with 45Ca2+ was used to study calcium disturbances at 8, 24, and 72 h. Compression contusion trauma of the cerebral cortex was produced by a 21-g weight dropped from a height of 35 cm onto a piston that compressed the brain 2 mm. Pre- and posttrauma interstitial [Ca2+] ([Ca2+]e) concentrations were measured in the perimeter, i.e., the shear stress zone (SSZ) and in the central region (CR) of the trauma site. For the [Ca2+]e studies the animals were divided into controls and groups pretreated with dizocilipine maleate (MK-801) or with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[F]quinoxaline (NBQX). In all groups, [Ca2+]e decreased from pretrauma-values of approximately 1 m M to posttraumatic values of 0.1 m M in both the CR and the SSZ. This was followed by a slow restitution toward pretraumatic levels during the 2-h observation period. There was no significant difference in recovery pattern between controls and pretreated animals. Accumulation of 45Ca2+ and serum proteins was seen in the entire SSZ, while neuronal necrosis was confined to a narrow band within the SSZ. The CR was unaffected apart from occasional eosinophilic neurons and showed no accumulation of 45Ca2+. Posttraumatic treatment with MK-801 or NBQX had no obvious effect on neuronal injury in the SSZ. We conclude that (a) acute [Ca2+]e disturbances in compression contusion brain trauma are not affected by blockade of NMDA or AMPA receptors, (b) 45Ca2+ accumulation in the SSZ reflects mainly protein accumulation due to blood–brain barrier breakdown rather than cell death, and (c) acute cellular Ca2+ overload per se does not seem to be a major determinant of cell death after cerebral trauma in our model.
In Vivo Quantification of Cerebral Muscarinic Receptors in Normal Human Aging Using Positron Emission Tomography and [11C]Tropanyl Benzilate
Authors: Lee Kien S. , Frey Kirk A. , Koeppe Robert A. , Buck Alfred , Mulholland G. Keith , Kuhl David E.
Published: November 2003

Regional cerebral muscarinic cholinergic receptor binding was quantified in normal young and elderly subjects employing the muscarinic antagonist radioligand [11C]tropanyl benzilate (TRB). Binding was determined by kinetic analyses of positron emission tomographic (PET) determinations of cerebral activity in conjunction with radial arterial blood sampling following intravenous radiotracer injection. A significant, but minor (8%), loss of frontal cortical receptors relative to whole brain average receptor density was found with advancing age. Parametric estimates of binding suggest small reductions in cerebral cortex binding as well as increases in brain stem and cerebellar binding underlying the observed pattern difference. However, these latter changes did not achieve statistical significance. We conclude that cerebral muscarinic receptor availability, as depicted by antagonist binding, does not undergo a major decline during normal aging of the adult human brain. The cerebral cortical cholinergic dysfunction in elderly subjects, suggested by prior clinical evidence, is not attributable to major loss of total muscarinic cholinoceptive capacity.
Noninvasive Quantification of rCBF Using Positron Emission Tomography
Authors: Watabe H. , Itoh M. , Cunningham V. , Lammertsma A. A. , Bloomfield P. , Mejia M. , Fujiwara T. , Jones A. K. P. , Jones T. , Nakamura T.
Published: November 2003

This study proposes a new method for the pixel-by-pixel quantification of regional CBF (rCBF) with positron emission tomography and H215O by using a reference tissue region. No arterial blood is required. Simulation studies revealed that the calculation of rCBF was fairly stable provided that the frame time was relatively short compared with total scan time. In practice, calculated CBF images correlated significantly with those obtained with the dynamic/integral method. Because the method accurately detects changes in CBF, it is particularly suitable for brain activation studies.
Cerebral Metabolism of Patients with Stenosis of the Internal Carotid Artery before and after Endarterectomy
Authors: van der Grond J. , Balm R. , Klijn C. J. M. , Kappelle L. J. , Eikelboom B. C. , Mali W. P. Th. M.
Published: November 2003

Occlusion or severe stenosis, with a reduction in the diameter of more than 70% of the extracranial arteries may lead to hypoperfusion of the brain with an increased risk of cerebral infarction. The aim of this study was to investigate whether endarterectomy of stenosed internal carotid arteries leads to alterations in cerebral metabolism in regions in which no infarcts were visible with magnetic resonance imaging (MRI). We studied 10 healthy control subjects and 20 patients with transient or nondisabling cerebral ischemia with MRI and 1H magnetic resonance spectroscopic imaging. All patients underwent carotid endarterectomy. Patients were examined 1 week before and 3–6 months after carotid endarterectomy. The N-acetyl aspartate (NAA)/choline ratio in the symptomatic hemisphere before endarterectomy (2.29 ± 0.42) was significantly ( p < 0.001) lower than for control subjects (3.18 ± 0.32). In five of the patients lactate was detected preoperatively in regions that were not infarcted. The NAA/choline ratio in the symptomatic hemisphere of these five patients did not increase significantly after endarterectomy (1.99 ± 0.22 vs. 2.23 ± 0.48). The NAA/choline ratio in patients without lactate preoperatively increased significantly ( p < 0.01) after endarterectomy to a normal level (from 2.39 ± 0.42 to 2.92 ± 0.52). These results indicate that the presence of cerebral lactate may predict whether the NAA/choline ratio increases after carotid endarterectomy.
Increased Blood–Brain Permeability with Hyperosmolar Mannitol Increases Cerebral O2 Consumption and O2 Supply/Consumption Heterogeneity
Authors: Chi Oak Za , Wei Hwu Meei , Lu Xiaowen , Weiss Harvey R.
Published: November 2003

This study was performed to evaluate whether increasing the permeability of the blood–brain barrier by unilateral intracarotid injection of hyperosmolar mannitol would alter O2 consumption and the O2 supply/consumption balance in the ipsilateral cortex. Rats were anesthetized with 1.4% isoflurane using mechanical ventilation. Retrograde catheterization of a unilateral external carotid artery was performed to administer 25% mannitol at a rate of 0.25 ml/kg/s for 30 s. The blood–brain barrier transfer coefficient ( K of 14C-α aminoisobutyric acid was measured in one group (N = 7) after administering mannitol. Regional cerebral blood flow (rCBF), regional arterial and venous O2 saturation and O2 consumption were measured in another group using a 14C-iodoantipyrine autoradiographic technique and micro-spectrophotometry (N = 7). Vital signs were similar before and after administering mannitol. K i was significantly higher in the ipsilateral cortex (IC) (22.3 ± 8.4 μl/g/min) than in the contralateral cortex (CC) (4.4 ± 1.1). rCBF was similar between the IC (105 ± 21 ml/g/min) and the CC (93 ± 20). Venous O2 saturation was lower in the IC (43 ± 7%) than in the CC (55 ± 4%). The coefficient of variation (100 × SD/mean) of venous O2 saturation was significantly elevated in the IC (32.3) compared with the CC (18.2), indicating increased heterogeneity of O2 supply/consumption balance. O2 consumption was higher in the IC (9.6 ± 3.0 ml O2/100 g/min) than in the CC (6.7 ± 1.5). Our data suggested that increasing permeability of the blood–brain barrier increased cerebral O2 consumption and the heterogeneity of local O2 supply/consumption balance.
Functional Cerebral Activity during Regeneration from Entorhinal Lesions in the Rat
Authors: Beck Thomas , Weber Michael , Horváth Ervin , Wree Andreas
Published: November 2003

The consequences of an unilateral electrolytic entorhinal lesion on the functional activity in all major anatomically defined brain regions were evaluated in the rat. The 14C-2-deoxyglucose method served as a tool to quantify alterations of local cerebral glucose utilization (LCGU) ipsilateral and contralateral to the lesion at 4 days, 2 weeks, or 3 months after stereotaxic surgery. Apart from a few minor increases in the contralateral hemisphere, the predominant pattern consisted of reductions in the range of 10–40% in the ipsilateral hemisphere. Ipsilaterally, in extrahippocampal areas, LCGU had regained control levels at 2 weeks postlesion in contrast to hippocampal regions, where reductions were more pronounced than in other brain areas and partially persisted for up to 3 months. Interestingly, the termination zones of entorhinal fibers in the dentate gyrus did not regain control levels within 3 months. We conclude from the data that functional recovery of denervated primary target areas does not occur within 3 months after entorhinal lesions and that altered functional activity may be found beyond the primary target areas predominantly during the acute recovery period after the lesion. The data suggest that sprouting fibers do not reestablish a fully functional neuronal network during the recovery period.
Combined Study of Cerebral Glucose Metabolism and [11C]Methionine Accumulation in Probable Alzheimer's Disease Using Positron Emission Tomography
Authors: Salmon E. , Gregoire M. C. , Delfiore G. , Lemaire C. , Degueldre C. , Franck G. , Comar D.
Published: November 2003

There is a characteristic decrease in glucose metabolism in associative frontal and temporo-parietal cortices of patients suffering from Alzheimer's disease (AD). The decrease in metabolism might result from local neuronal loss or from a decrease of synaptic activity. We measured in vivo [11C]methionine accumulation into proteins with positron emission tomography (PET) to assess cortical tissue loss in AD. Both global regional activity and compartmental analysis were used to express [11C]methionine accumulation into brain tissue. Glucose metabolism was measured with [18F]fluorodeoxyglucose and autoradiographic method. Combined studies were performed in 10 patients with probable AD, compared to age-matched healthy volunteers. There was a significant 45% decrease of temporo-parietal glucose metabolism in patients with AD, and frontal metabolism was lowered in most patients. Temporo-parietal metabolism correlated to dementia severity. [11C]methionine incorporation into temporo-parietal and frontal cortices was not significantly decreased in AD. There was no correlation with clinical symptoms. Data suggest that regional tissue loss, assessed by the decrease of [11C]methionine accumulation, is not sufficient to explain cortical glucose hypometabolism, which reflects, rather, reduced synaptic connectivity.
Positron Emission Tomographic Imaging of Serotonin Activation Effects on Prefrontal Cortex in Healthy Volunteers
Authors: Mann J. John , Malone Kevin M. , Diehl David J. , Perel James , Nichols Thomas E. , Mintun Mark A.
Published: November 2003

Serotonergic system abnormalities have been implicated in major depression, suicide, violence, alcoholism, and other psychopathologies. The prolactin response to fenfluramine has been widely used as a neuroendocrine probe to study brain serotonin responsivity. We have extended this methodology by using the positron emission tomography (PET) 18F-fluorodeoxyglucose (18FDG) method to examine the fenfluramine-induced changes in regional cerebral glucose metabolism (rCMRglu), an indicator of changes in regional neuronal activity. We report results on 16 healthy controls, each of whom underwent two PET studies. One group of six subjects had a placebo on day 1 and a single 60 mg oral dose of fenfluramine on day 2. The second group, of 10 subjects, was tested on two consecutive occasions without drug or placebo. Data were analyzed for significant rCMRglu changes on day 2 vs day 1 using the statistical parametric mapping method ( p < 0.01). Subjects who did not receive drugs showed no statistically significant areas of rCMRglu increase or decrease on day 2 versus day 1. In contrast, the group that received fenfluramine showed significant fenfluramine-induced responses. Areas of rCMRglu increases involved mainly the left prefrontal and left temperoparietal cortex. Within the prefrontal cortex, two major areas of rCMRglu increase included, first, an area centered on the anterior cingulate and, second, an area in the lateral prefrontal cortex involving principally the inferior, middle, and superior frontal gyri. Some decreases in rCMRglu were observed, principally in the right hemisphere. This PET-fenfluramine paradigm is a potentially useful method for studying abnormalities of serotonin function in the prefrontal cortex.
Influence of Glucose Supply and Demand on Determination of Brain Glucose Content with Labeled Methylglucose
Authors: Nakanishi Hajime , Cruz Nancy F. , Adachi Keiji , Sokoloff Louis , Dienel Gerald A.
Published: November 2003

The equilibrium brain/plasma distribution ratio for 3- O-methyl-D-glucose (methylglucose) varies with plasma and tissue glucose contents and can be used to determine local glucose levels in brain. This ratio was previously found to rise as brain glucose concentration fell in response to lowered plasma glucose content. The ratios, however, differed with the same tissue glucose levels in conscious and pentobarbital-sedated rats, suggesting that changes in metabolic demand might alter the quantitative relationship between the methylglucose distribution ratio and brain glucose concentration. To examine this possibility, metabolic rate was varied by focal drug application, and hexose concentrations measured in treated and surrounding tissue. When tissue glucose levels were reduced by raised metabolic demand, methylglucose distribution ratios also fell. When brain glucose levels rose due to reduced consumption, the methylglucose distribution ratio also rose. Thus, in contrast to the inverse relationship between brain/plasma methylglucose ratio and brain glucose concentration when brain glucose content is altered secondarily to changes in plasma glucose level, changes in brain glucose content induced by altered glucose utilization cause the brain glucose level and methylglucose distribution ratio to rise and fall in a direct relationship. Determination of brain glucose content from methylglucose distribution ratios must take into account rates of glucose delivery and consumption.
Stress Proteins and Tolerance to Focal Cerebral Ischemia
Authors: Chen Jun , Graham Steven H. , Zhu Raymond L. , Simon Roger P.
Published: November 2003

Stress proteins are induced after a variety of neuronal injuries. The inducible 72-kDa heat shock protein (hsp70) is a stress protein that protects neurons from glutamate toxicity in vitro. Hsp70 has also been proposed to underlie the phenomenon of ischemic tolerance whereby brief sublethal intervals of global ischemia protect the hippocampus from subsequent lethal prolonged ischemia. To determine if the phenomenon of tolerance occurs in cortex after focal ischemia, the rat middle cerebral artery (MCA) was occluded by the suture method. Three 10-min intervals of transient ischemia (3 × 10-isc) separated by 45-min periods of reperfusion made up the most effective paradigm of preconditioning ischemia studied, and substantially reduced the volume of infarction 72 h after subsequent 100-min MCA occlusion. This approach induced protection if the interval between the 3 × 10-isc and the 100-min ischemia was 2, 3, or 5 days but not 1 or 7 days. Three 10-min intervals of transient ischemia alone produced minimal histological changes in the cortex at 72 h. Moreover, there were no significant changes in regional cerebral blood flow in the tolerant regions at 72 h after 3 × 10-isc before or during MCA occlusion. To explore the role of stress proteins in the induction of tolerance, expression of hsp70 and the glucose-regulated proteins grp75 and grp78 were studied. Samples from tolerant regions of the brain that had undergone preconditioning ischemia were evaluated at 1, 2, 3, 5, 7, and 14 days after 3 × 10-isc by Western blot analysis. The time course of hsp70 expression most closely correlated with tolerance. Hsp70 protein expression increased during times when tolerance was present (at 2–5 days) but did not increase thereafter (at 7 and 14 days). However, hsp70 was also increased before tolerance was present (at 1 day). Immunocytochemistry showed that hsp70 protein was expressed in neurons in the tolerant regions 24 h after 3 × 10-isc and was expressed in both neurons and glia after 72 h. Although immunocytochemistry suggested that there was increased neuronal expression of grp75 and grp78, no significant differences were found in protein expression as determined by Western blot before (at 1 day), during (at 2–5 days), and after (at 7 days and thereafter) tolerance. Thus, the time course of grp75 and grp78 expression did not correlate with that of tolerance. This model of ischemic tolerance is a useful method by which mechanisms of endogenous neuroprotection may be explored.
MR-Based Correction of Brain PET Measurements for Heterogeneous Gray Matter Radioactivity Distribution
Authors: Meltzer Carolyn Cidis , Zubieta Jon Kar , Links Jonathan M. , Brakeman Paul , Stumpf Martin J. , Frost J. James
Published: November 2003

Partial volume and mixed tissue sampling errors can cause significant inaccuracy in quantitative positron emission tomographic (PET) measurements. We previously described a method of correcting PET data for the effects of partial volume averaging on gray matter (GM) quantitation; however, this method may incompletely correct GM structures when local tissue concentrations are highly heterogeneous. We have extended this three-compartment algorithm to include a fourth compartment: a GM volume of interest (VOI) that can be delineated on magnetic resonance (MR) imaging. Computer simulations of PET images created from human MR data demonstrated errors of up to 120% in assigned activity values in small brain structures in uncorrected data. Four-compartment correction achieved full recovery of a wide range of coded activity in GM VOIs such as the amygdala, caudate, and thalamus. Further validation was performed in an agarose brain phantom in actual PET acquisitions. Implementation of this partial volume correction approach in [18F]fluorodeoxyglucose and [11C]-carfentanil PET data acquired in a healthy elderly human subject was also performed. This newly developed MR-based partial volume correction algorithm permits the accurate determination of the true radioactivity concentration in specific structures that can be defined by MR by accounting for the influence of heterogeneity of GM radioactivity.
Radiofluorinated L-m-Tyrosines: New In-Vivo Probes for Central Dopamine Biochemistry
Authors: Barrio Jorge R. , Huang Sung-Cheng , Yu Dan-Chu , Melega William P. , Quintana Javier , Cherry Simon R. , Jacobson Andrew , Namavari Mohammad , Satyamurthy Nagichettiar , Phelps Michael E.
Published: November 2003

In this work, we introduce 6-[18F]fluoro-L- m-tyrosine (6-FMT) and compare its in-vivo kinetic and biochemical behaviors in monkeys and rodents with those of 4-FMT and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (DOPA) (FDOPA). These radiofluorinated m-tyrosine presynaptic dopaminergic probes, resistant to peripheral 3- O-methylation, offer a nonpharmacological alternative to the use of catechol- O-methyltransferase inhibitors. Like FDOPA, 4-FMT and 6-FMT are analogs that essentially follow the L-DOPA pathway of central metabolism. After i.v. administration in nonhuman primates and rodents, these new radiofluorinated m-tyrosine analogs accumulate selectively in striatal structures and allow for the detection of additional innervation sites (e.g., brain stem) rich in aromatic amino acid decarboxylase. Biochemical analyses in rodents and monkeys revealed the specificity of their central and peripheral metabolism. Molecular and enzymatic mechanisms involved in their retention in central brain structures are consistent with involvement of dopaminergic neurons. The high signal-to-noise ratios observed make these radiofluorinated m-tyrosine analogs outstanding candidates for probing the integrity of central dopaminergic mechanisms in humans.
Effect of Smoking on Cerebrovascular Reactivity
Authors: Silvestrini Mauro , Troisi Elio , Matteis Maria , Cupini Letizia Maria , Bernardi Giorgio
Published: November 2003

Current smoking is a risk factor for stroke. The aim of this study was to evaluate the effect of smoking one cigarette on cerebral hemodynamics. Using transcranial Doppler ultrasound, we studied the changes of flow velocity after hypercapnia in the middle cerebral arteries (MCAs) of 24 healthy young smokers and 24 healthy controls matched for age and sex. We obtained hypercapnia with breath-holding and evaluated cerebrovascular reactivity with the breath-holding index. In smokers, the evaluation was performed during basal condition, immediately after smoking one cigarette, and at 10-, 20-, and 30-min intervals thereafter. In controls, the evaluation was performed at corresponding time intervals. Breath-holding index (BHI) values at rest were similar for both controls and smokers. In the former, breath-holding index values remained constant for each of the different evaluations. On the contrary, in smokers, breath-holding index values were significantly lower immediately ( p < 0.0001), at 10 min ( p < 0.001), and at 20 min ( p < 0.0001) after smoking with respect to baseline values. Smoking also caused more short-lasting changes, in this case increases in mean flow velocity (MFV), heart rate (HR), and mean blood pressure (MBP). These results suggest that a failure of cerebrovascular regulation occurs after smoking. This phenomenon might contribute to the increased risk of cerebrovascular disease in current smokers.
Cerebral [15O]Water Clearance in Humans Determined by PET: I. Theory and Normal Values
Authors: Ohta Shinsuke , Meyer Ernst , Fujita Hitoshi , Reutens David C. , Evans Alan , Gjedde Albert
Published: November 2003

When used to measure blood flow in the brain, water leaves a residue in the vascular bed that influences the estimation of blood flow by current methods. To assess the magnitude of this influence, we developed a two-compartment model of blood flow with separate parameters for transport and vascular distribution of brain water. Maps of the water clearance, K1 into brain tissue, separated from the circulation by a measurably resistant blood–brain barrier (BBB), were generated by time-weighted integration. Depending on the validity of the assumptions underlying the two-compartment model presented here, the maps revealed a significant overestimation of the clearance of water when the vascular residue was ignored. Maps of Vo the estimate of the apparent vascular distribution volume of tracer H215O, clearly revealed major cerebral arteries. Thus, we claim that the accumulation of radioactive water in brain tissue also reflects the volume of the arterial vascular bed of the brain.
Rate Dependence of Regional Cerebral Activation during Performance of a Repetitive Motor Task: A PET Study
Authors: Blinkenberg Morten , Bonde Christian , Holm Søren , Svarer Claus , Andersen Jimmy , Paulson Olaf B. , Law Ian
Published: November 2003

Using repeated positron emission tomography (PET) measures of regional cerebral counts, we investigated the regional cortical activations induced in eight normal subjects performing eight different frequencies of fingertapping (0.5–4 Hz) with the right index finger. The task was auditorially cued and the performance recorded during the scanning procedure. Performance evaluation showed increased error rates, during fingertapping, of high and low frequencies, and the best tapping performance was measured in the midrange of frequencies. Significantly activated areas ( p < 0.05) of normalized cerebral counts were located in the left sensorimotor cortex (M1S1), right motor cortex, left thalamus, right insula, supplementary motor area (SMA), and bilaterally in the primary auditory cortex and the cerebellum. Statistical evaluation showed a significant ( p < 0.01) and positive dependence of cerebral activation upon movement rate in the contralateral M1S1. There was no significant rate dependence of cerebral activation in other activated motor areas. The SMA and the right cerebellar hemisphere showed a more uniform activation throughout the tapping frequency range. Furthermore, we found a stimulus rate dependence of cerebral activation in the primary auditory cortex. We believe that the present data provide useful information for the preparation and interpretation of future motor activation studies of normal human subjects and may serve as reference points for studies of pathological conditions.