bluuebunny/crossref_metadata_2025 huggingface dataset:
The Family Impact of Migraine: Population-Based Studies in the USA and UK
Authors: Lipton RB , Bigal ME , Kolodner K , Stewart WF , Liberman JN , Steiner TJ
Published: June 2003

Despite an extensive body of research on the individual burden of migraine, few studies have examined its impact on the family. We aimed to assess the impact of migraine on family life both from the perspective of those with migraine and from the perspective of their partners. A validated computer-assisted telephone interview (CATI) identified 574 people with migraine from a population sample of 4007 in mainland England, and 568 from 4376 in Philadelphia County, in the USA. Migraine cases with six or more migraine attacks per year and living as married with partners were asked, along with their partners, to participate in this study. In a follow-up interview, questions were asked of the proband (i.e. subject identified with migraine in the survey) about the impact of migraine. Similar questions were also asked of the probands' partners regarding the impact of the proband's migraine on their participation in social, family and leisure activities and on family relationships. The samples from the two countries showed similar characteristics, and were combined. Of 389 people with migraine living with a household partner, 85% reported substantial reductions in their ability to do household work and chores, 45% missed family social and leisure activities, and 32% avoided making plans for fear of cancellation due to headaches. One half believed that, because of their migraine, they were more likely to argue with their partners (50%) and children (52%), while majorities (52-73%) reported other adverse consequences for their relationships with their partner and children, and at work. A third (36%) believed they would be better partners but for their headaches. Participating partners ( n = 100) partly confirmed these findings: 29% felt that arguments were more common because of headaches and 20-60% reported other negative effects on relationships at home. Compared with subjects who did not have migraine regarding their work performance, a statistically significantly higher proportion of migraine partners were unsatisfied with work demands placed on them ( P = 0.02), with their level or responsibilities and duties ( P = 0.02), and with their ability to perform ( P = 0.001). Results from this study show that the impact of migraine extends to household partners and other family members.
Stress, Anxiety, Depression and Migraine
Authors: Wacogne C , Lacoste JP , Guillibert E , Hugues FC , Le Jeunne C
Published: June 2003

This study investigated the intensity of stress, anxiety and depression in a sample of 141 migraineurs compared with a control group of 109 non-migraine workers matched for age and sex. Stress was measured using the Perceived Stress Questionnaire, and anxiety and depression using the Hospital Anxiety and Depression Scale. Results indicated that stress and anxiety were higher in the migraine group than in the control group and above the clinical level. Depression scores remained low in both groups, under clinical relevance. Stress is a primordial factor in the triggering and perpetuation of migraine attacks. The high score of the items ‘morning fatigue’, ‘intrusive thoughts about work’, ‘feeling under pressure’, ‘impatience’, and ‘irritability’ of the stress questionnaire in the migraineurs is particularly significant in the intensive stress response. It seems necessary to manage stress to improve the daily life of migraineurs and to study the link between stress, anxiety and migraine.
Nitric Oxide Pathway and Response to Nitroglycerin in Cluster Headache Patients: Plasma Nitrite and Citrulline Levels
Authors: Costa A , Ravaglia S , Sances G , Antonaci F , Pucci E , Nappi G
Published: June 2003

Nitric oxide (NO) may participate in the mechanisms underlying vascular headaches, such as migraine and cluster headache (CH), by triggering neurogenic inflammation and activation of fibres conveying nociceptive inputs to the trigeminal ganglion. Similarly to migraine, the administration of the NO donor glyceryltrinitrate (GTN) to CH patients is a known model of inducing spontaneous-like attacks. We carried out a GTN test (0.9 mg, sublingually) in 18 patients with episodic CH in active phase and 12 controls. The plasma levels of NO metabolite nitrites (NO2-), after conversion of nitrates to NO2-, were measured spectrophotometrically at baseline, at the maximum intensity of the induced response (or 45 min after GTN in controls), and 120 min after GTN administration. The basal plasma levels of L-citrulline were also assayed in patients and controls using highperformance liquid chromatography. Basal NO2- levels, similar in GTN-responsive patients and controls (48.3 ± 10.6 and 44.6 ± 9.5 μmol/l, respectively) were found to be increased significantly at pain peak in patients (76.1 ± 10.2 μmol/l) and after 45 min in controls (78.2 ± 9.6 μmol/l) ( P < 0.01 vs. respective baseline values), but not after 120 min, without differences between groups. L-citrulline levels in basal conditions showed no differences between groups (patients 64.8 ± 11.7, controls 67.3 ± 10.8 μmol/l). These data do not support the presence of a basal hyperactivity of the L-arginine-NO pathway in CH patients. Increased NO production may be of importance in the mechanisms leading to CH attacks, but other factors are likely to render CH patients hyperresponsive to NO, and ultimately to cause the occurrence of pain and associated features.
Valproic acid inhibits substance P‐induced activation of protein kinase C epsilon and expression of the substance P receptor
Authors: Lieb Klaus , Treffurth Yvonne , Hamke Maike , Akundi Ravi Shankar , Von Kleinsorgen Matthias , Fiebich Bernd L.
Published: June 2003

The neuropeptide substance P (SP) has been hypothesized to be involved in the etiopathology of affective disorders. This hypothesis is based on the findings that neurokinin‐1‐receptor antagonists have antidepressant effects in depressed patients and that SP may worsen mood. In this study, we investigated the effect of the mood‐stabilizing agents valproic acid (VPA), carbamazepine, and lithium on SP‐induced gene expression. As a model system, we used primary rat astrocytes and human astrocytoma cells, which both express functional SP‐receptors and, upon stimulation with SP, synthesize interleukin‐6 (IL‐6), a cytokine which has been shown to be elevated during the acute depressive state. We found that VPA dose‐dependently inhibited SP‐induced IL‐6 synthesis which was seen with pre‐incubation periods of 30 min, 3, 7 and 14 days, whereas carbamazepine and lithium showed no inhibitory effect. The inhibitory effect of VPA was not mediated by inhibition of the stress‐regulated kinases p38 and p42/44 (Erk1/2) but by inhibition of protein kinase C epsilon activation. Furthermore, VPA down‐regulated the expression of the substance P receptor (neurokinin(NK)‐1‐receptor) as assessed by real‐time PCR. Whether both mechanisms contribute to the mood‐stabilizing properties of VPA has to be evaluated in further studies.
Tumour necrosis factor‐related apoptosis‐inducing ligand sequentially activates pro‐survival and pro‐apoptotic pathways in SK‐N‐MC neuronal cells
Authors: Milani Daniela , Zauli Giorgio , Rimondi Erika , Celeghini Claudio , Marmiroli Sandra , Narducci Paola , Capitani Silvano , Secchiero Paola
Published: June 2003

The SK‐N‐MC neuroblastoma cell line, which expresses surface tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) receptors TRAIL‐R2 and TRAIL‐R4, was used as a model system to examine the effect of TRAIL on key intracellular pathways involved in the control of neuronal cell survival and apoptosis. TRAIL induced distinct short‐term (1–60 min) and long‐term (3–24 h) effects on the protein kinase B (PKB)/Akt (Akt), extracellular signal‐regulated kinase (ERK), cAMP response element‐binding protein (CREB), nuclear factor kappa B (NF‐κB) and caspase pathways. TRAIL rapidly (from 20 min) induced the phosphorylation of Akt and ERK, but not of c‐Jun NH2‐terminal kinase (JNK). Moreover, TRAIL increased CREB phosphorylation and phospho‐CREB DNA binding activity in a phosphatidylinositol 3‐kinase (PI 3K)/Akt‐dependent manner. At later time points (from 3 to 6 h onwards) TRAIL induced a progressive degradation of inhibitor of κB (IκB)β and IκBε, but not IκBα, coupled to the nuclear translocation of NF‐κB and an increase in its DNA binding activity. In the same time frame, TRAIL started to activate caspase‐8 and caspase‐3, and to induce apoptosis. Remarkably, caspase‐dependent cleavage of NF‐κB family members as well as of Akt and CREB proteins, but not of ERK, became prominent at 24 h, a time point coincident with the peak of caspase‐dependent apoptosis.
The heterogeneous growth cone glycoprotein gp93 is identical to the signal regulatory protein SIRPα/SHPS‐1/BIT
Authors: Wang Xiaoxin X. , Dangott Lawrence J. , Pfenninger Karl H.
Published: June 2003

Growth cone gp93 is a highly heterogeneous membrane glycoprotein with an Mr of about 93 kDa. It was purified from adult rat brain and microsequenced. The sequences of four different peptide fragments of gp93 matched those of the ‘signal regulatory protein’ SIRPα (also known as SHPS‐1, BIT or P84), an Ig superfamily member. SIRPα contains a cytoplasmic tail that is a tyrosine kinase substrate and binds the protein tyrosine phosphatase SHP‐2. SIRPα and gp93 also were immunochemically cross‐reactive. A PCR strategy was used to determine whether gp93/SIRPα heterogeneity in the brain depended upon the presence of different transcripts and, thus, sequence heterogeneity. However, we observed only a single full‐length transcript. A short splice variant also was detected. These data identify gp93 as the Ig superfamily member SIRPα. Together with our previous results, the data also demonstrate that, in rat brain, gp93/SIRPα heterogeneity is the result of differential glycosylation (plus phosphorylation), rather than sequence heterogeneity.
Inhibition of NMDA‐induced striatal dopamine release and behavioral activation by the neuroactive steroid 3α‐hydroxy‐5β‐pregnan‐20‐one hemisuccinate
Authors: Sadri‐Vakili G. , Johnson D. W. , Janis G. C. , Gibbs T. T. , Pierce R. C. , Farb D. H.
Published: June 2003

Our laboratory has previously shown that the synthetic neuroactive steroid 3α‐hydroxy‐5β‐pregnan‐20‐one hemisuccinate (3α5βHS) is a negative modulator of NMDA receptors in vitro. Similarly, 3α5βHS exhibits rapid sedative, analgesic, anticonvulsive, and neuroprotective effects in vivo. Here we report a study designed to investigate whether a negatively charged neuroactive steroid, 3α5βHS, modulates the action of NMDA receptors in vivo. Our results indicate that peripherally administered 3α5βHS enters the CNS and inhibits NMDA‐mediated motor activity and dopamine release in the rat striatum. The increase in motor activity induced by intrastriatal microinjection of NMDA was blocked by the systemic administration of 3α5βHS and the NMDA‐induced increase in extracellular dopamine in the striatum was also attenuated by both systemically administered and intrastriatally administered (by in vivo microdialysis) 3α5βHS. These data indicate that 3α5βHS acts through striatal NMDA receptors in vivo. When taken together, these results suggest that neuroactive steroids may prove to be effective in the treatment of neurological and psychiatric disorders involving over‐stimulation of NMDA receptors in the mesotelencephalic dopamine system.
Amphetamine‐evoked c‐fos mRNA expression in the caudate‐putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context
Authors: Ferguson Susan M. , Norton Camille S. , Watson Stanley J. , Akil Huda , Robinson Terry E.
Published: June 2003

Dopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate‐putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine‐evoked c‐fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c‐fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA‐containing neurons (Dyn‐SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose‐dependently decreased c‐fos expression in Dyn‐SP+ cells. When given in a novel environment, amphetamine induced c‐fos mRNA in both Dyn‐SP+ and preproenkephalin mRNA‐containing neurons (Enk+ cells). In this condition, D1R and non‐selective NMDAR antagonists dose‐dependently decreased c‐fos expression in Dyn‐SP+ cells, but neither D2R nor NR2B‐selective NMDAR antagonists had no effect. Furthermore, amphetamine‐evoked c‐fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c‐fos expression only in these cells. Finally, novelty‐stress also induced c‐fos expression in both Dyn‐SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c‐fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn‐SP+ vs. Enk+ cells), and environmental context (home vs. novel cage).
Subcellular distributions of rat CaM kinase phosphatase N and other members of the CaM kinase regulatory system
Authors: Kitani Takako , Okuno Sachiko , Takeuchi Masayuki , Fujisawa Hitoshi
Published: June 2003

Ca2+/Calmodulin‐dependent protein kinase (CaM kinase) regulatory system is composed of multifunctional CaM kinases such as CaM kinases IV and I, upstream CaM kinases such as CaM kinase kinases α and β, which activate multifunctional CaM kinases, and CaM kinase phosphatases such as CaM kinase phosphatase and CaM kinase phosphatase N, which deactivate the activated multifunctional CaM kinases. To understand the combinations of CaM kinases I and IV, CaM kinase kinases α and β, and CaM kinase phosphatases, the locations of the enzymes in the cell were examined by immunocytochemical studies of cultured cells. The results indicate that CaM kinase I, CaM kinase kinase β, and CaM kinase phosphatase occur in the cytoplasm and that CaM kinase IV, CaM kinase kinase α (and CaM kinase kinase β in some cell types and tissues), and CaM kinase phosphatase N occur inside the cellular nucleus, suggesting that there are at least two different sets of CaM kinase regulatory systems, one consisting of CaM kinase I, CaM kinase kinase β, and CaM kinase phosphatase in the cytoplasm and the other consisting of CaM kinase IV, CaM kinase kinase α (and CaM kinase kinase β in some cell types and tissues), and CaM kinase phosphatase N in the nucleus.
Distribution, levels, and activation of MEK1 in Alzheimer's disease
Authors: Zhu Xiongwei , Sun Zheng , Lee Hyoung‐gon , Siedlak Sandra L. , Perry George , Smith Mark A.
Published: June 2003

Extracellular‐signal‐regulated kinase (ERK) has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to ERK activation has not been elucidated. In this study, we focused on one of the physiological activators of ERK, mitogen‐activated protein kinase (MAPK)/ERK kinase 1 (MEK1). Although there was no significant difference in the level and distribution of total MEK1 between AD and age‐matched control cases, increased levels of activated phospho‐MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (Braak stage V–VI). The considerable overlap between MEK1 and its downstream effector, phospho‐ERK, suggests both a functional and mechanistic link. Nuclear localization of phospho‐MEK1 was a prominent feature in both mild AD cases (Braak stage III–IV) and control cases with limited pathology (Braak stage I–II). Since MEK1 is normally cytoplasmic due to the active export from nucleus because of the presence of nuclear export signal in its amino‐terminus, we suspect that the apparent nuclear accumulation of phospho‐MEK1 in AD patients at early stages suggests that abnormal nuclear trafficking may contribute to the pathogenesis of AD. By immunoblot analyses, phospho‐MEK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the ERK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.
The influence of brain inflammation upon neuronal adenosine A2Breceptors
Authors: Rosi Susanna , McGann Kristin , Hauss‐Wegrzyniak Beatrice , Wenk Gary L.
Published: June 2003

Alzheimer's disease (AD) is associated with glial activation and increased levels of pro‐inflammatory cytokines. Epidemiological results suggest that anti‐inflammatory therapies can slow the onset of AD. Adenosine, acting at type‐2 receptors, is an effective endogenous anti‐inflammatory agent that can modulate inflammation both in the periphery and the brain. We investigated changes in the expression of adenosine type‐2B (A2B) receptors and a related intracellular second messenger during chronic brain inflammation and following treatment with the non‐steroidal anti‐inflammatory drug flurbiprofen and its nitric oxide (NO)‐donating derivative, HCT1026. Chronic infusion of lipopolysaccharide (LPS) into the 4th ventricle of young rats induced brain inflammation that was associated with microglial activation and reduced neuronal immunoreactivity for adenosine A2Breceptors in the cortex. Daily administration of HCT1026, but not flurbiprofen, reduced microglial activation, prevented the down‐regulation of A2Breceptors and elevated tissue levels of cAMP. The results suggest that a therapy using an NO‐releasing NSAID might significantly attenuate the processes that drive the pathology associated with AD and that this process may involve the activation of adenosine A2Breceptors.
Gene expression in human neural stem cells: effects of leukemia inhibitory factor
Authors: Wright Lynda S. , Li Jiang , Caldwell Maeve A. , Wallace Kyle , Johnson Jeffrey A. , Svendsen Clive N.
Published: June 2003

Human neural precursor cells grown in culture provide a source of tissue for drug screening, developmental studies and cell therapy. However, mechanisms underlying their growth and differentiation are poorly understood. We show that epidermal growth factor (EGF) responsive precursors derived from the developing human cortex undergo senescence after 30–40 population doublings. Leukemia inhibitory factor (LIF) increased overall expansion rates, prevented senescence and allowed the growth of a long‐term self renewing neural stem cell (ltNSCctx) for up to 110 population doublings. We established basal gene expression in ltNSCctx using Affymetrix oligonucleotide microarrays that delineated specific members of important growth factor and signaling families consistently expressed across three separate lines. Following LIF withdrawal, 200 genes showed significant decreases. Protein analysis confirmed LIF‐regulated expression of glial fibrillary acidic protein, CD44, and major histocompatibility complex I. This study provides the first molecular profile of human ltNSCctx cultures capable of long‐term self renewal, and reveals specific sets of genes that are directly or indirectly regulated by LIF.
Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3‐kinase (PI3) kinase‐dependent manner in Neuro2a cells
Authors: Van Der Heide L. P. , Hoekman M. F. , Biessels G. J. , Gispen W. H.
Published: June 2003

Insulin signalling is well studied in peripheral tissue, but not in neuronal tissue. To gain more insight into neuronal insulin signalling we examined protein kinase B (PKB) and extracellular regulated kinase 1 and 2 (ERK1/2) regulation in serum‐deprived Neuro2a cells. Insulin phosphorylated PKB in a dose‐dependent manner but reduced phosphorylation of ERK1/2. Both processes were phosphatidylinositol 3‐kinase (PI3K) dependent. Interestingly, blockade of PI3K in combination with insulin induced phosphorylation of ERK1/2. The phosphorylation of ERK1/2 could be blocked with a specific inhibitor of mitogen‐activated protein/ERK kinase (MEK), suggesting that it was mediated through the highly conserved Ras–Raf–MEK–ERK1/2 pathway. Prolonged exposure to high concentrations of insulin resulted in a desensitized PI3K–PKB route. The insulin‐induced inhibition of ERK1/2 phosphorylation was also diminished when the PI3K–PKB route was desensitized. Blockade of PI3K in combination with insulin, however, still resulted in an unaltered MEK‐dependent phosphorylation of ERK1/2. We conclude that PI3K is an important integrator of insulin signalling in Neuro2a cells as it regulates activation of PKB and inhibition of ERK1/2, and is sensitive to the duration of the insulin stimulus.
Secretion of interleukin‐1β by astrocytes mediates endothelin‐1 and tumour necrosis factor‐α effects on human brain microvascular endothelial cell permeability
Authors: Didier Nathalie , Romero Ignacio A. , Créminon Christophe , Wijkhuisen Anne , Grassi Jacques , Mabondzo Aloïse
Published: June 2003

Evidence suggests that endothelin‐1 (ET‐1) plays an essential role in brain inflammation. However, whether ET‐1 contributes directly to blood–brain barrier (BBB) breakdown remains to be elucidated. Using an in vitro BBB model consisting of co‐cultures of human primary astrocytes and brain microvascular endothelial cells (BMVECs), we first investigated the expression of ET‐1 by BMVECs upon stimulation with tumour necrosis factor (TNF)‐α, which plays an essential role in the induction and synthesis of ET‐1 during systemic inflammatory responses. Increased ET‐1 mRNA was detected in the human BMVECs 24 h after TNF‐α treatment. This was correlated with an increase in ET‐1 levels in the culture medium, as determined by sandwich immunoassay. Both TNF‐α and ET‐1 increased the permeability of human BMVECs to a paracellular tracer, sucrose, but only in the presence of astrocytes. The increase in BMVEC permeability by TNF‐α was partially prevented by antibody neutralization of ET‐1 and completely by monoclonal antibody against IL‐1β. Concomitantly, TNF‐α induced IL‐1β mRNA expression by astrocytes in co‐culture and this effect was partially prevented by ET‐1 antibody neutralization. In parallel experiments, treatment of human primary astrocytes in single cultures with ET‐1 for 24 h induced IL‐1β mRNA synthesis and IL‐1β protein secretion in the cell culture supernatant. Taken together, these results provide evidence for paracrine actions involving ET‐1, TNF‐α and IL‐1β between human astrocytes and BMVECs, which may play a central role in BBB breakdown during CNS inflammation.
Mitogen and stress response kinase‐1 (MSK1) mediates excitotoxic induced death of hippocampal neurones
Authors: Hughes Jane P. , Staton Penny C. , Wilkinson Marc G. , Strijbos Paul J. L. M. , Skaper Stephen D. , Arthur J. Simon C. , Reith Alastair D.
Published: June 2003

Activation of the mitogen‐activated protein kinase (MAPK/ERK) signal transduction pathway may mediate excitotoxic neuronal cell death in vitro and during ischemic brain injury in vivo. However, little is known, of the upstream regulation or downstream consequences of ERK activation under these conditions. Magnesium removal has been described to induce hyperexcitability and degeneration in cultured hippocampal neurones. Here, we show that neurotoxicity evoked by Mg2+ removal in primary hippocampal neurones stimulates ERK, but not p38, phosphorylation. Removal of Mg2+ also resulted in induction of the MAPK/ERK substrate mitogen‐ and stress‐response kinase 1 (MSK1) and induced phosphorylation of the MSK1 substrate, the transcription factor cAMP response element binding protein (CREB). Neuronal death and phosphorylation of components in this cascade were inhibited by the Raf inhibitor SB‐386023, by the MEK inhibitor U0126, or by the MSK1 inhibitors H89 and Ro318220. Importantly, this form of cell death was inhibited in hippocampal neurones cultured from MSK1–/– mice and inhibitors of Raf or MEK had no additive neuroprotective effect. Together, these data indicate that MSK1 is a physiological kinase for CREB and that this activity is an essential component of activity‐dependent neuronal cell death.
Pro‐apoptotic signaling in neuronal cells following iron and amyloid beta peptide neurotoxicity
Authors: Kuperstein Faina , Yavin Ephraim
Published: June 2003

In a previous report, we characterized several oxidative stress parameters during the course of amyloid beta (Aβ) peptide/Fe2+‐induced apoptotic death in neuronal cells. In extending these findings, we now report a marked decrease in protein kinase C (PKC) isoforms, reduced Akt serine/threonine kinase activity, Bcl 2‐associated death promoter (BAD) phosphorylation and enhanced p38 mitogen‐activated protein kinase (MAPK) and caspase‐9 and ‐3 activation, 12 h after addition of both 5 µm Aβ and 5 µm Fe2+. These activities reminiscent for a pro‐apoptotic cellular course were blocked in the presence of the iron chelator deferroxamine. Aβ alone, increased PKC isoform levels between three‐ and four‐fold after 12 h, enhanced Akt activity approximately eight‐fold and Ser136 BAD phosphorylation two‐fold, suggesting that by itself is not toxic. Fe2+ alone transiently enhanced p38 MAPK and caspase‐9 and ‐3 enzymes indicative for cell damage, but was not sufficient to cause cell death as previously indicated. GF, a PKC inhibitor or wortmannin, a blocker of the Akt pathway enhanced Aβ/Fe2+‐induced toxicity, while SB, a p38 MAPK inhibitor, prevented cell damage and apoptosis. These findings further support the hypothesis that metal ion chelation and inhibitors of pro‐apoptotic kinase cascades may be beneficial for Alzheimer's disease therapy.
Escalation of cocaine self‐administration does not depend on altered cocaine‐induced nucleus accumbens dopamine levels
Authors: Ahmed Serge H. , Lin Daniel , Koob George F. , Parsons Loren H.
Published: June 2003

Previous studies showed that prolonged access to cocaine or heroin self‐administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125–1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self‐administration. Self‐administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self‐administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.
Increased activin levels in cerebrospinal fluid of rabbits with bacterial meningitis are associated with activation of microglia
Authors: Michel Uwe , Gerber Joachim , E. O'Connor Anne , Bunkowski Stephanie , Brück Wolfgang , Nau Roland , Phillips David J.
Published: June 2003

Activin, a member of the transforming growth factor superfamily, is upregulated in a number of inflammatory episodes such as septicemia and rheumatoid arthritis. In the CNS, activin has been predominantly assessed in terms of a neuroprotective role. In this report we characterized the activin response in the CNS in a rabbit model of meningitis. In normal animals, cerebrospinal fluid (CSF) activin levels were higher than those in serum, indicating an intracranial secretion of this cytokine. Following intracisternal inoculation with Streptococcus pneumoniae, activin in CSF was unchanged for the first 12 h and then rose progressively; levels were increased approximately 15‐fold within 24 h. Activin levels were correlated positively with CSF protein content and with the number of apoptotic neurons in the dentate gyrus. No apparent correlation was observed between CSF activin concentrations and bacterial titer, lactate concentrations or leukocyte density. Using immunohistochemistry, activin staining was localized to epithelial cells of the choroid plexus, cortical neurons and the CA3 region of the hippocampus, with similar staining intensities in both normal and meningitic brains. However, in meningitic brains there was also strong staining in activated microglia and infiltrating macrophages. Taken together, these results demonstrate that activin forms part of the CNS response to immune challenge and may be an important mediator to modulate inflammatory processes in the brain.
α‐Synuclein protects naive but not dbcAMP‐treated dopaminergic cell types from 1‐methyl‐4‐phenylpyridinium toxicity
Authors: Jensen Penny J. , Alter Benedict J. , O'Malley Karen L.
Published: June 2003

The pre‐synaptic protein, α‐synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that α‐synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism‐inducing drug 1‐methyl‐4‐phenylpyridinium (MPP+), whereas it cannot protect from the dopaminergic toxin, 6‐hydroxydopamine, hydrogen‐peroxide, or the β‐amyloid peptide, A‐β. Protection from MPP+ was directly correlated with the preservation of mitochondrial function. Specifically, α‐synuclein rescued cells from MPP+ mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin‐induced activation of the creatine kinase/creatine phosphate system. Similarly, α‐synuclein protected cells from the complex I inhibitor rotenone and 3‐nitroproprionic acid, a complex II inhibitor. Wild‐type α‐synuclein‐mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP‐differentiated cells. These results suggest that the normal physiological role for α‐synuclein may change during development.
Characterization of a novel G‐protein coupled receptor from the parasitic nematode H. contortus with high affinity for serotonin
Authors: Smith Martin W. , Borts Tracy L. , Emkey Renee , Cook Carolyn A. , Wiggins Christina J. , Gutierrez Jesus A.
Published: June 2003

The neurotransmitter serotonin (5HT) has been shown to modulate mobility, feeding, egg‐laying, and defecation behaviors in the saprophytic nematode Caenorhabditis elegans. Although the effects of serotonin on these behaviors in parasitic nematodes is under study, little is known about the diversity, ontogeny, signaling, and pharmacology of serotonin receptors in these organisms. In an effort to increase our understanding of this system, we cloned and characterized a novel cDNA (5HT1Hc) from the parasitic nematode Haemonchus contortus that has high amino acid sequence homology with known G‐protein coupled 5HT1‐receptors from invertebrates and vertebrates. Transcript expression studies in four development stages (egg, L1/L2, L3, and adult) revealed the presence of the mRNA in the L1/L2, L3, and adult stages. Membranes from insect cells (Sf9) expressing the 5HT1Hc‐receptor cDNA displayed nanomolar binding affinity to serotonin and a unique pharmacological profile distinct from known invertebrate and mammalian 5HT‐receptors. Receptor signaling studies with mammalian AV12 cells expressing the 5HT1Hc‐receptor and the promiscuous G‐protein, Gα15, demonstrated dose‐dependent intracellular signals with serotonin acting as an agonist. Together, these studies describe a novel invertebrate 5HT‐receptor with high affinity for the indolealkylamine, serotonin, and pharmacological properties that do not conform to any known members of this superfamily of metabotropic receptors.
Selenium and selenoproteins in the brain and brain diseases
Authors: Chen Jun , Berry Marla J.
Published: June 2003

Over the past three decades, selenium has been intensively investigated as an antioxidant trace element. It is widely distributed throughout the body, but is particularly well maintained in the brain, even upon prolonged dietary selenium deficiency. Changes in selenium concentration in blood and brain have been reported in Alzheimer's disease and brain tumors. The functions of selenium are believed to be carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine. Several selenoproteins are expressed in brain, but many questions remain about their roles in neuronal function. Glutathione peroxidase has been localized in glial cells, and its expression is increased surrounding the damaged area in Parkinson's disease and occlusive cerebrovascular disease, consistent with its protective role against oxidative damage. Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival. Recent studies in cell culture and gene knockout models support a function for selenoprotein P in delivery of selenium to the brain. mRNAs for other selenoproteins, including selenoprotein W, thioredoxin reductases, 15‐kDa selenoprotein and type 2 iodothyronine deiodinase, are also detected in the brain. Future research directions will surely unravel the important functions of this class of proteins in the brain.
Restoration of a Mine Pit Lake from Aquacultural Nutrient Enrichment
Authors: Axler Richard , Yokom Shane , Tikkanen Craig , McDonald Michael , Runke Henry , Wilcox Dwight , Cady Bruce
Published: June 2003

Minnesota, the land of 10,000 lakes, also has more than 4000 abandoned quarry pits and over 200 deep, exhausted iron ore pits. In the past 25 years the iron ore pits have gradually filled with groundwater and surface water, forming lakes on the Cuyuna, Mesabi, and Vermillion Iron Ranges in northeastern Minnesota. Most remain abandoned, but besides creating a small number of recreational parks and fisheries, the regional economic development agency promoted approximately 20 of the pit lakes for economic reclamation by using them for salmonid aquaculture. Intensive net‐pen aquaculture was carried out from 1988 to 1995 in the Twin City–South and Sherman pit lakes on the Mesabi Range. A water quality controversy resulted over the potential for long‐term degradation of the lakes and regional aquifer. The Minnesota Pollution Control Agency then mandated that aquaculture be terminated in Twin City–South in May 1993 and the lake restored to preaquaculture conditions by 1996. With no management other than artificial aeration for one summer, the lake rapidly recovered to near baseline water quality and returned to an oligomesotrophic (unproductive) status. Within 18 months the phosphorus budget was typical of reference pit lakes in the area and dissolved oxygen in bottom water remained above ∼4 mg O2/L without artificial aeration. Algal growth was low in 1993, due to light limitation from artificial mixing, but it remained low in 1994 without any management due to renewed phosphorus limitation. Inorganic nitrogen initially decreased faster than expected, at a rate similar to its increase during intensive aquaculture. More rapid reductions in water column nutrients might have occurred in 1993 by reducing aeration to allow anoxia in the lower hypolimnion, promoting denitrification and minimizing sediment resuspension, but this was precluded by water quality standards. The “natural” burial of solid wastes under inorganic sediment eroded from the basin walls effectively minimized transport of sediment nutrients to the overlying water. Fallowing for several years provided a simple, effective method for restoration of these pit lakes from aquacultural impacts. No change attributable to aquaculture was observed in the water quality of three nearby pit lakes, including a drinking water source. This fact suggests that there were few or no impacts from off‐site migration of aquaculturally enriched water into the regional aquifer.
Plant‐Mycorrhizal Community Dynamics Associated with a Moisture Gradient within a Rehabilitated Prairie Fen
Authors: Turner Stephen D. , Friese Carl F.
Published: June 2003

Wetland ecosystems have ecological significance in areas such as natural waste purification and nutrient cycling. Much has been accomplished in determining the floristic and edaphic characteristics of wetlands, but little is known about key structure‐function relationships such as mycorrhizae. We collected descriptive data on the plant and mycorrhizal fungal community associated with a moisture gradient along a rehabilitated prairie fen to assist in ongoing restoration efforts (Zimmerman Prairie, Greene County, Ohio). Analysis of soil samples from the prairie fen indicated that significant levels of arbuscular mycorrhizal fungal infection occurred within both the prairie and fen plant species (infection level means ranging from 20% to 47%). Mycorrhizal root infection was significantly correlated with all edaphic factors tested—soil moisture, organic matter, potassium, phosphorus, calcium, magnesium and pH—from May to October 1994. The plant‐mycorrhizal data clearly indicate the presence of mycorrhizae in soils that are saturated or even inundated. The functional role of mycorrhizae in wetlands is still unclear, however. For example, is the species interaction we are observing truly mutualistic or of some other form due to environmental conditions? Arbuscular mycorrhizal fungal relationships in all classes of wetland ecosystems need to be studied further if we are to understand their potential role in the ecological restoration of wetland ecosystems.
Correlations between structure and optical properties in Jahn–Teller Mn3+ fluorides: A study of TlMnF4 and NaMnF4 under pressure
Authors: Rodriguez Fernando , Aguado Fernando
Published: June 2003

This work investigates the Jahn–Teller (JT) distortion in different Mn3+ fluoride series by optical absorption (OA) spectroscopy. The aim is to establish correlations between the local structure of the formed MnF63− derived from x-ray diffraction and the JT splitting associated with the parent octahedral Eg5(3z2−r2,x2−y2) and T2g5(xy,xz,yz) states, Δe and Δt, obtained from the OA spectrum. A salient feature is the linear relation exhibited by both Δe and Δt with the tetragonal coordinate Qθ along the whole series. From these relations we derive suitable electron-ion coupling coefficients related to the Eg5 and T2g5 states whose values play a key role in the e⊗E and e⊗T JT theory, respectively. The results of these correlations are applied to investigate the structural variations undergone by the two-dimensional compounds NaMnF4 and TlMnF4 under pressure using OA spectroscopy. Interestingly, the analysis carried out is relevant since it provides useful information on the Mn3+ local structure, a task that is difficult to achieve using extended x-ray-absorption fine structure under pressure due to the high absorption of the diamond anvils. We conclude that the effect of pressure in NaMnF4 is to reduce progressively the JT distortion of the complex, keeping its tetragonal symmetry. The pressure effects in TlMnF4 are more drastic, leading to pressure-induced structural phase transitions of low symmetry. At variance with NaMnF4, the high-pressure Mn3+ local structure seems to have significant rhombic distortions.
Three-dimensional simulations of reversible bimolecular reactions. III. The pseudo-unimolecular ABCD reaction
Authors: Popov Alexander V. , Agmon Noam
Published: June 2003

We report a microscopic simulation for the reversible A+B⇌C+D reaction in its pseudo-unimolecular limit. The simulations are used to assess the validity of various approximate theories for the time dependence of the approach to equilibrium, up to its long-time asymptotic behavior. To available theories we have added a new theory, the generalized multiparticle kernel 1 (GMPK1) theory. It is shown to be in very good agreement with our simulations than all other theories. The asymptotic behavior of both simulations and GMPK1 agrees with that derived by Gopich and Szabo [Chem. Phys. 284, 91 (2002)].
An experimental and theoretical study of the reaction of ethynyl radicals with nitrogen dioxide (HC≡C+NO2)
Authors: Carl Shaun A. , Nguyen Hue Minh Thi , Nguyen Minh Tho , Peeters Jozef
Published: June 2003

A pulsed laser photolysis/chemiluminescence (PLP/CL) technique was used to determine absolute rate constants of the reaction C2H+NO2→products over the temperature range 288–800 K at a pressure of 5 Torr (N2). The reaction has a large rate constant that decreases with increasing temperature. It may be expressed in simple Arrhenius form as k1(T)=(7.6±1.0)×10−11 exp[(130±50) K/T], although there is an indication of a downward curvature for T>700 K. A three-parameter Arrhenius fit to the data, which takes this into account gives k1(T)=(9.7±1.5)×10−9T−0.68 exp[(158±65) K/T]. Our experiments also show that the 293 K rate constant is invariant to pressure between 2 and 11 Torr (N2). We have also characterized the C2H+NO2 reaction theoretically. A large portion of the potential energy surface (PES) of the [C2,H,N,O2] system has been investigated in its electronic (singlet) ground-state using DFT with the B3LYP/6-311++G(3df,2p) method and MO computations at the CCSD(T)/6-311++G(d,p) level of theory. Seventeen isomers and thirty-two transition structures were found to connect reactants to products following eighteen different channels. Hydroxyl cyano ketone 11 and formylisocyanate 16 were found to be the most stable intermediates, although the reaction flux through them, as a fraction of the total, is likely to be small over the temperature range studied. A part of the PES corresponds with that of the HCCO+NO reaction [I. V. Tokmakov, L. V. Moskaleva, D. V. Paschenko, and M. C. Lin, J. Phys. Chem. A 167, 1066 (2003)], and the dominant product channels for C2H+NO2 proceed via the same nitrosoketene intermediate that is formed initially in the HCCO+NO reaction. However, unlike in the latter reaction, the fate of the much more highly excited nitrosoketene formed by C2H+NO2 is likely to be governed dynamically. We present arguments as to the likely product channels for C2H+NO2 based on both statistical and dynamical considerations. A statistical description overwhelmingly favors the product set HCCO+NO. Dynamical considerations on the other hand favor both the HCN+CO2 and HCCO+NO product sets. Formation of HCNO+CO appears unlikely. Energetically allowed paths, leading to five other product sets, namely, HNCO+CO, HOCN+CO, HOCC+NO, HONC+CO, and HNC+CO2, have also been identified, and are discussed.
First observation of autodetachment lifetimes of methide, CH3−
Authors: Mitchell Stephen E. , Conklin Philip M. , Farley John W.
Published: June 2003

The methide ion, CH3−, has been studied in a mass-selected ion beam. Two autodetachment lifetimes were observed that differ by three orders of magnitude. Infrared laser excitation near 3 micrometers reveals a vibrationally excited state with an autodetachment lifetime of 9–12 ns. This is the first resonant vibrational–rotational transition observed in methide. In addition, metastable ions were observed with a much longer autodetachment lifetime. For simplicity in the data analysis, all metastable ions are assumed to have a single autodetachment lifetime. This is an oversimplification, because the metastable ions decay by rotational autodetachment, and the metastable lifetime will therefore vary with rotational quantum number. The data analysis yields two possible values for the autodetachment lifetime: either 1.59±0.35 μs or 0.42±0.28 ms. The longer lifetime is much more plausible. The metastable states are attributed to rotationally excited states, which can only decay by channels with ΔJ⩾5. This interpretation is supported by modeling the energy manifold and populations of ions and neutrals. In contrast, the nanosecond lifetime arises from a vibrationally excited state. There are presently no theoretical calculations of the autodetachment mechanism or lifetimes for the methide ion.
Dynamics of the dissociative and nondissociative scattering of hyperthermal CS2+ from a self-assembled fluoroalkyl monolayer surface on gold substrate
Authors: Shukla Anil K. , Futrell Jean H. , Sen Atish D.
Published: June 2003

Dissociative and nondissociative scattering of low energy CS2+ ions from a self-assembled monolayer surface of fluorinated alkylthiol [CF3(CF2)9CH2CH2SH] on vapor deposited gold has been studied using a modified crossed-beam instrument. Dissociation of CS2+ ions begins at ∼30 eV ion kinetic energy, much higher than the thermochemical threshold of 4.7 eV for the lowest energy dissociation channel forming S+. This product channel is dominant up to the ion energy of ∼50 eV, the highest energy accessible by this instrument. Both inelastically scattered parent ions and product ions leave the surface with very low kinetic energies, demonstrating that most of the ions’ kinetic energy is taken up by the surface rather than transferred into internal modes of recoiling ions. The scattered ion intensity maximum is found between the specular angle and the surface parallel. At all energies studied, primary ion intensity remains higher than that of fragment ions. Also, the intensity of S+ fragment ions is higher than that of CS+ fragment ions, suggesting that the distribution of internal excitation of the recoiling CS2+ ions extends only slightly above the thresholds for the two product channels. A comparison of the relative intensities of the fragment ions with those from earlier collision-induced dissociation study of the CS2+ ions with xenon suggests that only ∼6.5 and ∼7.5 eV are transferred into internal modes for 30.6 and 49.8 eV energy collisions, respectively. This is lower than the energy transferred into internal modes in the gas phase collision-induced dissociation process, for which the center-of-mass collision energy is well defined. We infer from our observations that the effective mass of the surface collision partner is much less than that of the infinite mass which would apply to scattering from the gold substrate or the mass of the monolayer surface molecule. The experimental velocity vectors of scattered primary and fragment ions reveal that their maxima follow a circle whose center falls on the ion velocity vector, away from the laboratory collision center. From this collision center, we estimate the effective mass of the surface for surface-induced dissociation to be 150 corresponding to the CF3CF2CF end group of the SAM molecular chain.
Experimental verification of line- and band-shape asymmetry in the Schumann–Runge system of O2
Authors: Kono M. , Lewis B. R. , Baldwin K. G. H. , Gibson S. T.
Published: June 2003

High-resolution, laser-based photoabsorption cross-section measurements in the weakly absorbing windows between the (11,0) and (16,0) Schumann–Runge bands of O2 have been performed at liquid-nitrogen temperature and the results compared with corresponding coupled-channel Schrödinger-equation (CSE) and line-by-line model calculations. While the symmetric-line- shape-based line-by-line model cross sections differ significantly from experiment, the excellent agreement found between the CSE and experimental window cross sections serves to confirm clearly for the first time the CSE-model predictions of band shape asymmetry and quantum-mechanical interference effects, especially in the (11,0)–(14,0) band region.