bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Impact of Breast Cancer by Age at Diagnosis
Authors: Kroenke Candyce H. , Rosner Bernard , Chen Wendy Y. , Kawachi Ichiro , Colditz Graham A. , Holmes Michelle D.
Published: May 2004

Purpose

To explore changes in physical and psychosocial function before and after breast cancer by age at diagnosis.

Patients and Methods

A total of 122,969 women from the Nurses' Health Study (NHS) and NHS 2, ages 29 to 71 years, who responded to pre- and postfunctional status assessments were included; 1,082 women were diagnosed with breast cancer between 1992 and 1997. Functional status was measured using the Medical Outcomes Study Short Form 36 (SF-36). Mean change in health-related quality of life (HRQoL) scores was computed across categories representing the combination of incident breast cancer (yes or no) and age at diagnosis (≤ 40, 41 to 64, or 65+ years).

Results

Compared with women ≤ 40 years without breast cancer, women with breast cancer experienced significant functional declines. Young (age ≤ 40) women who developed breast cancer experienced the largest relative declines in HRQoL (as compared with middle-aged and elderly women) in multiple domains including physical roles (−18.8 v −11.5 and −7.5 points, respectively), bodily pain (−9.0 v −2.7 and −2.7 points), social functioning (−11.3 v −4.3 and −4.4 points) and mental health (−3.1 v 0.0 and +0.4 points). Much of the decline in HRQoL among elderly (age ≥ 65) women with breast cancer was age related.

Conclusion

Young women may fare worse than middle-aged or elderly women in both physical and psychosocial dimensions after breast cancer diagnosis. The needs of women facing breast cancer may be better understood within a life stage framework.
The Prognostic Significance of Phosphatidylinositol 3-Kinase Pathway Activation in Human Gliomas
Authors: Chakravarti Arnab , Zhai Gary , Suzuki Yoshiyuki , Sarkesh Sormeh , Black Peter M. , Muzikansky Alona , Loeffler Jay S.
Published: May 2004

Purpose

The objectives of this study were to examine activation patterns of the phosphatidylinositol 3-kinase (PI3K) pathway in gliomas and to examine the prognostic significance of PI3K pathway activation using snap-frozen clinical specimens.

Materials and Methods

Levels of expression of PI3K pathway members were assessed in 92 prospectively collected gliomas through quantitative Western analysis using total and phospho-specific antibodies for PI3K, Akt, and p70s6k. Both expression and expression levels of these PI3K pathway members were correlated with histology, markers of apoptosis (cleaved caspase 3), and with clinical outcome (eg, overall survival).

Results

It was determined that activation of all three PI3K pathway members were significantly more frequent in glioblastoma multiforme than in non-glioblastoma multiforme tumors. Levels of phospho-PI3K, phospho-Akt, and phospho-p70s6k were all found to be inversely associated with cleaved caspase 3 levels, suggesting PI3K pathway activation is associated with reduced levels of apoptosis. Perhaps most importantly, activation of PI3K pathway members was found to be significantly associated with reduced survival times when all glioma cases were considered in aggregate. When glioblastoma cases were considered separately, the prognostic value of PI3K activation remained significant, suggesting that PI3K activation may directly be associated with radiation resistance, given that this was the only adjuvant therapy administered to this subset of patients.

Conclusion

Activation of the PI3K pathway is significantly associated with increasing tumor grade, decreased levels of apoptosis, and with adverse clinical outcome in human gliomas. Molecular pathways regulating PI3K activation would appear to be promising targets in the clinical management of glioma patients.
Diagnosis of Deep Septic Thrombophlebitis in Cancer Patients by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Scanning: A Preliminary Report
Authors: Miceli Marisa , Atoui Rola , Walker Ronald , Mahfouz Tahsine , Mirza Nadeem , Diaz Jose , Tricot Guido , Barlogie Bart , Anaissie Elias
Published: May 2004

Purpose

To determine the role of the fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan in the diagnosis and management of deep septic thrombophlebitis (STP).

Patients and Methods

We conducted a prospective observational evaluation of FDG-PET in patients with cancer and suspected STP. Retrospective evaluation of patients with cancer and deep venous thrombosis (DVT) who underwent FDG-PET and extremity duplex scan (DS) was also performed.

Results

Strong venous uptake was observed in FDG-PET of nine STP episodes versus 0 of 27 DVT episodes (P < .001). FDG-PET identified central vein STP in five patients, whereas DS and venography were negative in five and two of these patients, respectively. FDG-PET diagnosis of STP resulted in therapeutic changes in all patients. In four patients, follow-up FDG-PET confirmed resolution.

Conclusion

In cancer patients, FDG-PET identifies STP even in areas not optimally visualized by DS or venography, distinguishes STP from DVT, and leads to significant therapeutic changes.
The Urge to Splurge: A Terror Management Account of Materialism and Consumer Behavior
Authors: Arndt Jamie , Solomon Sheldon , Kasser Tim , Sheldon Kennon M.
Published: May 2004

This article presents terror management theory (TMT) as a way to understand how the human awareness of death affects materialism, conspicuous consumption, and consumer decisions. The pursuit of wealth and culturally desired commodities are hypothesized to reinforce those beliefs that function to protect people from existential anxieties. Following a brief overview of TMT and research, evidence is reviewed that explicates how intimations of mortality increase materialism as a way to enhance self‐esteem and affects consumer decisions that support one's cultural worldview. Adverse consequences of materialistic and consumeristic worldviews are described and the challenges for future research to discover ways to alleviate them are considered.
Dogmas and controversies in the handling of nitrogenous wastes:5-HT2-like receptors are involved in triggering pulsatile urea excretion in the gulf toadfish,Opsanus beta
Authors: McDonald M. Danielle , Walsh Patrick J.
Published: May 2004

When injected arterially, serotonin (5-hydroxytryptamine; 5-HT) has been shown to elicit naturally sized urea pulse events in the gulf toadfish, Opsanus beta. The goal of the present study was to determine which 5-HT receptor(s) was involved in mediating this serotonergic stimulation of the pulsatile excretion mechanism. Toadfish were surgically implanted with caudal arterial catheters and intraperitoneal catheters and injected with either 8-OH-DPAT (1 μmol kg–1), a selective 5-HT1A receptor agonist, α-methyl-5-HT (1 μmol kg–1), a 5-HT2 receptor agonist, or ketanserin, a 5-HT2 receptor antagonist (0.01, 0.1, 1 and 10 μmol kg–1) plus α-methyl-5-HT. 8-OH-DPAT injection did not mediate an increase in urea excretion, ruling out the involvement of 5-HT1A receptors in pulsatile excretion. However, within 5 min,α-methyl-5-HT injection caused an increase in the excretion of urea in>95% (N=27) of the fish injected, with an average pulse size of 652±102 μmol N kg–1 (N=26). Withα-methyl-5-HT injection there was no corresponding increase in ammonia or [3H]PEG 4000 permeability. Urea pulses elicited byα-methyl-5-HT were inhibited in a dose-dependent fashion by the 5-HT2 receptor antagonist ketanserin, which at low doses caused a significant inhibition of pulse size and at higher doses significantly inhibited the occurrence of pulsatile excretion altogether. However, neither 8-OH-DPAT nor α-methyl 5-HT injection had an effect on plasma cortisol or plasma urea concentrations. These findings suggest the involvement of a 5-HT2-like receptor in the regulation of pulsatile urea excretion.
Variation in temperature increases the cost of living in birds
Authors: Pendlebury C. J. , MacLeod M. G. , Bryant D. M.
Published: May 2004

The effect of temperature variability on laying birds was studied experimentally, using Japanese quail. Two aspects of temperature variability were investigated: the effects of regular daily variation in temperature, and of a sudden change in temperature. Both of these may become more common as a consequence of climate change. These manipulations were carried out at two levels of food supply. Energy expenditure increased with higher daily temperature variation, and also after a sudden change in temperature, taking several days to settle to a constant level. Manipulating daily temperature variation also resulted in smaller eggs being laid under more variable temperatures, when food quality was also low. The results demonstrate that day-to-day variation in temperature, as well as mean temperature, affects energy expenditure, which can have consequences for egg production.
Fyn Kinase Modulates Synaptotoxicity, But Not Aberrant Sprouting, in Human Amyloid Precursor Protein Transgenic Mice
Authors: Chin Jeannie , Palop Jorge J. , Yu Gui-Qiu , Kojima Nobuhiko , Masliah Eliezer , Mucke Lennart
Published: May 2004

Alzheimer's disease (AD), the most common neurodegenerative disorder, results in progressive degeneration of synapses and aberrant sprouting of axon terminals. The mechanisms underlying these seemingly opposing cellular phenomena are unclear. We hypothesized that Fyn kinase may play a role in one or both of these processes because it is increased in AD brains and because it is involved in synaptic plasticity and axonal outgrowth. We investigated the effects of Fyn on AD-related synaptotoxicity and aberrant axonal sprouting by ablating or overexpressing Fyn in human amyloid precursor protein (hAPP) transgenic mice.

On thefyn+/+background, hAPP/amyloid β peptide (Aβ) decreased hippocampal levels of synaptophysin-immunoreactive presynaptic terminals (SIPTs), consistent with previous findings. On thefyn-/-background, hAPP/Aβ did not affect SIPTs. SIPT reductions correlated with hippocampal Aβ levels in hAPP/fyn+/+, but not hAPP/fyn-/-, mice suggesting that Fyn provides a critical link between hAPP/Aβ and SIPTs. Furthermore, overexpression of Fyn exacerbated SIPT reductions in hAPP mice. We also found that the susceptibility of mice to hAPP/Aβ-induced premature mortality was decreased by Fyn ablation and increased by Fyn overexpression. In contrast, axonal sprouting in the hippocampus of hAPP mice was unaffected. We conclude that Fyn-dependent pathways are critical in AD-related synaptotoxicity and that the pathogenesis of hAPP/Aβ-induced neuronal alterations may be mechanistically heterogenous.
Cortical Synaptic IntegrationIn VivoIs Disrupted by Amyloid-β Plaques
Authors: Stern Edward A. , Bacskai Brian J. , Hickey Gregory A. , Attenello Frank J. , Lombardo Julianne A. , Hyman Bradley T.
Published: May 2004

The accumulation of amyloid-β protein into plaques is a characteristic feature of Alzheimer's disease. However, the contribution of amyloid-β plaques to neuronal dysfunction is unknown. We compared intracellular recordings from neocortical pyramidal neuronsin vivoin APP-Sw (Tg2576 transgenic mice overexpressing amyloid precursor protein with the Swedish mutation) transgenic mice to age-matched nontransgenic cohorts at ages either before or after deposition of cortical plaques. We show that the evoked synaptic response of neurons to transcallosal stimuli is severely impaired in cortex containing substantial plaque accumulation, with an average 2.5-fold greater rate of response failure and twofold reduction in response precision compared with age-matched nontransgenic controls. This effect correlated with the presence of amyloid-β plaques and alterations in neuronal process geometry. Responses of neurons in younger APP-Sw animals, before plaque accumulation, were similar to those in nontransgenic controls. In all cases, spontaneous membrane potential dynamics were similar, suggesting that overall levels of synaptic innervation were not affected by plaques. Our results show that plaques disrupt the synchrony of convergent inputs, reducing the ability of neurons to successfully integrate and propagate information.
ADrosophilaTemperature-Sensitive Seizure Mutant in Phosphoglycerate Kinase Disrupts ATP Generation and Alters Synaptic Function
Authors: Wang Ping , Saraswati Sudipta , Guan Zhuo , Watkins Carol J. , Wurtman Richard J. , Littleton J. Troy
Published: May 2004

A novel paralytic mutant,nubian, was identified in a behavioral screen for conditional temperature-sensitive seizure mutants inDrosophila melanogaster. nubianmutants display reduced lifespan, abnormal motor behavior, altered synaptic structure, and defective neurotransmitter release. Thenubianmutant disrupts phosphoglycerate kinase (PGK), an enzyme required for ATP generation in the terminal stage of the glycolytic pathway. Consistent with altered ATP generation innubiananimals, brain extracts show a threefold reduction in resting ATP levels compared with controls. Microarray analysis ofnubianmutants reveals altered transcription of genes implicated in glucose and lipid metabolism. Disruption of ATP generation innubiananimals is accompanied by temperature-dependent defects in neuronal activity, with initial seizure activity, followed by an activity-dependent loss of synaptic transmission.nubianmutants also display structural defects at the synapse, with larger varicosity size but normal varicosity number, indicating that these synaptic parameters are regulated independently. Both exocytotic (NSF) and endocytotic (dynamin) ATPase/GTPase activity are required for normal synaptic transmission. Biochemical and physiological analyses indicate that synaptic defects innubiananimals are secondary to defective endocytosis, suggesting that endocytotic pathways may be generally more sensitive to altered ATP levels than those used for exocytosis. Alterations in ATP metabolism likely disrupt similar pathways in humans, because PGK deficiency is associated with mental retardation, seizures, and exercise intolerance. Given the behavioral similarities between disruptions of PGK function inDrosophilaand humans, the analysis ofnubiananimals may reveal conserved neuronal responses associated with altered ATP generation within the brain.
The Function of Neurotrophic Factor Receptors Expressed by the Developing Adductor Motor PoolIn Vivo
Authors: Gould Thomas W. , Oppenheim Ronald W.
Published: May 2004

We examined the spatio-temporal relationship between neurotrophic factor receptor (NTF-R) expression and motoneuron (MN) survival in the developing avian spinal cord and observed heterogeneity in the expression of NTF-Rs between, but not within, pools of MNs projecting to individual muscles. We then focused on the role of NTFs in regulating the survival of one motor pool of MNs, all of which innervate a pair of adductor muscles in the thigh and hence compete for survival during the period of programmed cell death (PCD). The complete NTF-R complement of these MNs was analyzed and found to include many, but not all, NTF-Rs. Treatment with exogenous individual NTFs rescued some, but not all, adductor MNs expressing appropriate NTF-Rs. In contrast, administration of multiple NTFs completely rescued adductor MNs from PCD. Additionally, adductor MNs were partially rescued from PCD by NTFs for which they failed to express receptors. NTF-Rs expressed by the nerve but not in the muscle target were capable of mediating survival signals to MNsin trans. Finally, the expression of some NTF-Rs by adductor MNs was not required for MN survival. These studies demonstrate the complexity in NTF regulation of a defined subset of competing MNs and suggest that properties other than NTF-R expression itself can play a role in mediating trophic responses to NTFs.
KCNQ/M Channels Control Spike Afterdepolarization and Burst Generation in Hippocampal Neurons
Authors: Yue Cuiyong , Yaari Yoel
Published: May 2004

KCNQ channel subunits are widely expressed in peripheral and central neurons, where they give rise to a muscarinic-sensitive, subthreshold, and noninactivating K+current (M-current). It is generally agreed that activation of KCNQ/M channels contributes to spike frequency adaptation during sustained depolarizations but is too slow to influence the repolarization of solitary spikes. This concept, however, is based mainly on experiments with muscarinic agonists, the multiple effects on membrane conductances of which may overshadow the distinctive effects of KCNQ/M channel block. Here, we have used selective modulators of KCNQ/M channels to investigate their role in spike electrogenesis in CA1 pyramidal cells. Solitary spikes were evoked by brief depolarizing current pulses injected into the neurons. The KCNQ/M channel blockers linopirdine and XE991 markedly enhanced the spike afterdepolarization (ADP) and, in most neurons, converted solitary (“simple”) spikes to high-frequency bursts of three to seven spikes (“complex” spikes). Conversely, the KCNQ/M channel opener retigabine reduced the spike ADP and induced regular firing in bursting neurons. Selective block of BK or SK channels had no effect on the spike ADP or firing mode in these neurons. We conclude that KCNQ/M channels activate during the spike ADP and limit its duration, thereby precluding its escalation to a burst. Consequently, down-modulation of KCNQ/M channels converts the neuronal firing pattern from simple to complex spiking, whereas up-modulation of these channels exerts the opposite effect.
Retarded Axonal Transport of R406W Mutant Tau in Transgenic Mice with a Neurodegenerative Tauopathy
Authors: Zhang Bin , Higuchi Makoto , Yoshiyama Yasumasa , Ishihara Takeshi , Forman Mark S. , Martinez Dan , Joyce Sonali , Trojanowski John Q. , Lee Virginia M.-Y.
Published: May 2004

Intracellular accumulations of filamentous tau inclusions are neuropathological hallmarks of neurodegenerative diseases known as tauopathies. The discovery of multiple pathogenictaugene mutations in many kindreds with familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau abnormalities in the etiology of neurodegenerative disorders. To examine the effects of tau gene mutations and the role of tau abnormalities in neurodegenerative tauopathies, transgenic (Tg) mice were engineered to express the longest human tau isoform (T40) with or without the R406W mutation (RW and hWT Tg mice, respectively) that is pathogenic for FTDP-17 in several kindreds. RW but not hWT tau Tg mice developed an age-dependent accumulation of insoluble filamentous tau aggregates in neuronal perikarya of the cerebral cortex, hippocampus, cerebellum, and spinal cord. Significantly, CNS axons in RW mice contained reduced levels of tau when compared with hWT mice, and this was linked to retarded axonal transport and increased accumulation of an insoluble pool of RW but not hWT tau. Furthermore, RW but not hWT mice demonstrated neurodegeneration and a reduced lifespan. These data indicate that the R406W mutation causes reduced binding of this mutant tau to microtubules, resulting in slower axonal transport. This altered tau function caused by the RW mutation leads to increased accumulation and reduced solubility of RW tau in an age-dependent manner, culminating in the formation of filamentous intraneuronal tau aggregates similar to that observed in tauopathy patients.
Evidence that Climbing Fibers Control an Intrinsic Spike Generator in Cerebellar Purkinje Cells
Authors: Cerminara Nadia L. , Rawson John A.
Published: May 2004

It is well established that the climbing fiber (CF) input to a cerebellar Purkinje cell (PC) can exert a controlling influence on the background simple spike (SS) activity of the cell, in that repetitive stimulation of CFs causes a decrease in SS activity, and removal or inactivation of CFs is followed by a rise in activity. In the present study, the effects of inactivation of CFs in the short term and longer term (hours) were investigated in anesthetized rats to determine how the CFs control the PC SS activity. Inactivation of the CF input to a PC was accomplished by either reversibly inactivating with lignocaine or by microlesioning the inferior olive. Consistent with previous findings, CF removal caused a transformation of the PC firing pattern, with SSs discharging more regularly and rising to an exceptionally high level. In cases in which CF activity resumed, SS rate declined to control levels within a few seconds. However, with sustained CF inactivation (30 min to 5 hr), SS activity continues to rise progressively and develops an oscillating firing pattern, consisting of alternating bursts of high-frequency discharge at up to 100-150 Hz followed by 10-20 sec periods of electrical quiescence. No accompanying changes in the threshold for evoking SSs via the parallel fibers were seen to accompany the increases in tonic SS activity. We conclude that the increase in SS activity that follows CF inactivation could be caused by the removal of an inhibitory action that CFs exert on the intrinsic pacemaker present in PCs under normal conditions.
Local Sensory Cues and Place Cell Directionality: Additional Evidence of Prospective Coding in the Hippocampus
Authors: Battaglia Francesco P. , Sutherland Gary R. , McNaughton Bruce L.
Published: May 2004

In tasks involving goal-directed, stereotyped trajectories on uniform tracks, the spatially selective activity of hippocampal principal cells depends on the animal's direction of motion. Principal cell ensemble activity while the rat moves in opposite directions through a given location is typically uncorrelated. It is shown here, with data from three experiments, that multimodal, local sensory cues can change the directional properties of CA1 pyramidal cells, inducing bidirectionality in a significant proportion of place cells. For a majority of these bidirectional place cells, place field centers in the two directions of motion were displaced relative to one another, as would be the case if the cells were representing a position in space ∼5-10 cm ahead of the rat or if place cells were subject to strong accommodation or inhibition in the latter half of their input fields. However, place field density was not affected by the presence of local cues, but in the experimental condition with the most salient sensory cues, the CA1 population vectors in the “cue-rich” condition were sparser and changed more quickly in space than in the “cue-poor” condition. These results suggest that “view-invariant” object representations are projected to the hippocampus from lower cortical areas and can have the effect of increasing the correlation of the hippocampal input vectors in the two directions, hence decreasing the orthogonality of hippocampal output.
Metabotropic Regulation of Intrinsic Excitability by Synaptic Activation of Kainate Receptors
Authors: Melyan Zare , Lancaster Barrie , Wheal Howard V.
Published: May 2004

Prolonged modification of intrinsic neuronal excitability is gaining prominence as an activity-dependent form of plasticity. Here we describe a potential synaptic initiation mechanism for these changes in which release of the transmitter glutamate acts on kainate receptors to regulate the postspike slow afterhyperpolarization (sAHP). This action of synaptically released glutamate was occluded by previous kainate application. Furthermore, inhibition of glutamate uptake enhanced the effects of synaptic activation. Glutamate-mediated kainate receptor inhibition of sAHP current (IsAHP) was blocked by the PKC inhibitor calphostin C, confirming the requirement for a metabotropic signaling cascade. These data describe a new physiological function for glutamate release: activation of metabotropic kainate receptors, which control directly the excitability of pyramidal cells and probably contribute to prolonged excitability changes.
Interaction between Perirhinal and Medial Prefrontal Cortex Is Required for Temporal Order But Not Recognition Memory for Objects in Rats
Authors: Hannesson Darren K. , Howland John G. , Phillips Anthony G.
Published: May 2004

The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).
Ca2+-Binding Protein-1 Facilitates and Forms a Postsynaptic Complex with Cav1.2 (L-Type) Ca2+Channels
Authors: Zhou Hong , Kim Seong-Ah , Kirk Elizabeth A. , Tippens Alyssa L. , Sun Hong , Haeseleer Françoise , Lee Amy
Published: May 2004

Ca2+-binding protein-1 (CaBP1) is a Ca2+-binding protein that is closely related to calmodulin (CaM) and localized in somatodendritic regions of principal neurons throughout the brain, but how CaBP1 participates in postsynaptic Ca2+signaling is not known. Here, we describe a novel role for CaBP1 in the regulation of Ca2+influx through Cav1.2 (L-type) Ca2+channels. CaBP1 interacts directly with the α1subunit of Cav1.2 at sites that also bind CaM. CaBP1 binding to one of these sites, the IQ domain, is Ca2+dependent and competitive with CaM binding. The physiological significance of this interaction is supported by the association of Cav1.2 and CaBP1 in postsynaptic density fractions purified from rat brain. Moreover, in double-label immunofluorescence experiments, CaBP1 and Cav1.2 colocalize in numerous cell bodies and dendrites of neurons, particularly in pyramidal cells in the CA3 region of the hippocampus and in the dorsal cortex. In electrophysiological recordings of cells transfected with Cav1.2, CaBP1 greatly prolonged Ca2+currents, prevented Ca2+-dependent inactivation, and caused Ca2+-dependent facilitation of currents evoked by step depolarizations and repetitive stimuli. These effects contrast with those of CaM, which promoted strong Ca2+-dependent inactivation of Cav1.2 with these same voltage protocols. Our findings reveal how Ca2+-binding proteins, such as CaM and CaBP1, differentially adjust Ca2+influx through Cav1.2 channels, which may specify diverse modes of Ca2+signaling in neurons.
Neuropathic Pain Activates the Endogenous κ Opioid System in Mouse Spinal Cord and Induces Opioid Receptor Tolerance
Authors: Xu Mei , Petraschka Michael , McLaughlin Jay P. , Westenbroek Ruth E. , Caron Marc G. , Lefkowitz Robert J. , Czyzyk Traci A. , Pintar John E. , Terman Gregory W. , Chavkin Charles
Published: May 2004

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [κ opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the κ agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.
Relay Based Closed-Loop Tuning of PID Controllers (Adaption der PID-Reglerparameter im geschlossenen Kreis durch Einkopplung eines Zweipunktreglers)
Authors: Majhi Somanath , Litz Lothar
Published: May 2004

A relay based on-line tuning method for PID controllers is presented. Due to a new structure to use the relay for identification reasons the method is well appropriate for a large class of linear and non-linear processes which may have load and noise disturbances. The new structure inserts a relay in parallel to a conventional P, PI or PID controller inducing limit cycle oscillations of small amplitude around the process value. With the limit cycle measurements, a transfer function model of the process dynamics is obtained by a robust identification method. Using a model based tuning algorithm the controller settings are retuned to achieve enhanced performance without disrupting the closed-loop control. The performance of the proposed scheme is discussed by different simulations to show the benefits of the new method.
Priorisierung von Asset Managementaktivitäten für chemische Anlagenausrüstungen: Aussagen aus Ereignisstatistiken (Prioritizing Asset Management Activities for Chemical Plants: Learning from Event Statistics)
Authors: Kroll Andreas
Published: May 2004

Verbesserungsmöglichkeiten des Betriebs chemischer Anlagen sind oft zahlreicher und umfangreicher als die zur Entwicklung und Umsetzung zur Verfügung stehenden Ressourcen. Dies macht eine Priorisierung der Alternativen wünschenswert. Ein im Beitrag untersuchter Teilaspekt einer solchen Priorisierung ist die Vermeidung von unerwünschten Ereignissen. Zur Identifizierung und Gewichtung von möglichen Angriffspunkten erfolgte eine Auswertung von Ereignisstatistiken für die chemische Industrie. Insbesondere wurden Statistiken von Versicherern, Risikoberatern und Störfallmeldestellen analysiert. Es zeigt sich, dass Mineralölraffination und Chlor-Alkali-Produktion interessante Zielbranchen sind. Rohre und Rohrleitungen sowie Tanks führen die Liste der verursachenden Anlagenkomponenten an. Korrosion spielt eine wichtige Rolle bei den Ursachen. Etwa ein Viertel der Ereignisse tritt im Nichtnormalbetrieb auf. Menschliche Bedienfehler sind im Durchschnitt am teuersten und verursachen ungefähr ein Viertel aller Störungen. Einige mögliche Beiträge insbesondere der Automatisierungs- und Informationstechnologie zur Verbesserung der Situation werden beschrieben.
Effects of Didanosine Formulations on the Pharmacokinetics of Amprenavir
Authors: Shelton Mark J. , Giovanniello Angela A. , Cloen Denise , Berenson Charles S. , Keil Kim , DiFrancesco Robin , Hewitt Ross G.
Published: May 2004

Study Objectives. To determine the effects of concurrent, single doses of didanosine (both buffered and encapsulated enteric‐coated bead formulations) on amprenavir steady‐state pharmacokinetics, and to determine the effect of staggered dosing of the buffered formulation.

Design. Two‐period, single‐sequence, prospective, open‐label drug interaction study with a 10‐day washout interval.

Setting. Clinical research unit.

Subjects. Sixteen healthy volunteers without human immunodeficiency virus infection.

Intervention. Amprenavir 600 mg twice/day was given for the first 4 days of each treatment period, with 12‐hour pharmacokinetic evaluations conducted on the last 2 days of each period. Amprenavir was administered according to the following sequential treatments (all fasting): amprenavir alone, concurrent with buffered didanosine, 1 hour before buffered didanosine, and concurrent with the encapsulated enteric‐coated bead formulation of didanosine.

Measurements and Main Results. Plasma was collected 0, 1, 2, 3, 4, 6, 8, and 12 hours after dosing and assayed for amprenavir by using high‐performance liquid chromatography. Noncompartmental pharmacokinetic parameters were determined. Geometric mean ratios for each treatment relative to amprenavir alone were determined and reported with 90% confidence intervals (CIs). No significant trends were noted in predose concentrations measured during either period. Area under the concentration‐time curve during one 12‐hour dosing interval (AUC12) was found to be bioequivalent for all treatments. Peak drug concentration (Cmax) was reduced by 15% on average with concurrent administration of buffered didanosine, and bioequivalence was not demonstrated for this parameter. For concurrent enteric‐coated didanosine, geometric mean ratios for Cmax and AUC12 were 0.93 and 0.94, respectively. For buffered didanosine given 1 hour after amprenavir, geometric mean ratios were 1.06 and 1.10 for the same parameters, respectively. No differences were observed in 12‐hour concentration (C12) with concurrent administration of buffered or enteric‐coated didanosine.

Conclusion. Amprenavir AUC12 and C12 are not significantly affected by concurrent administration of the buffered or enteric‐coated formulations of didanosine. Therefore, amprenavir may be administered concurrently with either the buffered or the encapsulated enteric‐coated bead formulation of didanosine in the fasting state.
Statin‐Associated Memory Loss: Analysis of 60 Case Reports and Review of the Literature
Authors: Wagstaff Leslie R. , Mitton Melinda W. , Arvik Beth McLendon , Doraiswamy P. Murali
Published: May 2004

Objective. To review case reports of statin‐associated memory loss as well as the available published evidence for and against such a link.

Methods. We searched the MedWatch drug surveillance system of the Food and Drug Administration (FDA) from November 1997‐February 2002 for reports of statin‐associated memory loss. We also reviewed the published literature (using MEDLINE) and prescribing information for these drugs.

Results. Of the 60 patients identified who had memory loss associated with statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the patients noted cognitive adverse effects within 2 months of therapy. Fourteen (56%) of 25 patients noted improvement when the statin was discontinued. Memory loss recurred in four patients who were rechallenged with the drug. None of the 60 reported cognitive test results. Two placebo‐controlled trials found no benefits for statins on cognition or disability. One randomized controlled trial of simvastatin found no effects on cerebrospinal amyloid levels. In one small, randomized study, patients receiving statins showed a trend toward lower cognitive performance than those receiving placebo. Five observational studies found a lower risk of dementia among patients receiving statins.

Conclusion. Current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; observational studies indicate that patients receiving statins have a reduced risk of dementia. However, available prospective studies show no cognitive or antiamyloid benefits for any statin. In addition, case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain.
Pontine hypoplasia in Carey–Fineman–Ziter (CFZ) syndrome
Authors: Maheshwari Akhil , Calhoun Darlene A. , Lacson Atilano , Pereda Lourdes , Nelson Robert M. , Saste Monisha D. , Kousseff Boris , Gieron‐Korthals Maria
Published: May 2004

We describe an infant with multiple congenital anomalies including cleft palate and micrognathia, Möbius sequence, developmental delay, myopathy, hydronephrosis, and bilateral clubfeet. These features are consistent with Carey–Fineman–Ziter (CFZ) syndrome (MIM 254940), which has been previously reported in six children (including two sibling pairs). Cranial magnetic resonance imaging (MRI) revealed an unusually small pons, a finding not previously described in CFZ syndrome. © 2004 Wiley‐Liss, Inc.
Internet searching and browsing in a multilingual world: An experiment on the Chinese Business Intelligence Portal (CBizPort)
Authors: Chung Wingyan , Zhang Yiwen , Huang Zan , Wang Gang , Ong Thian‐Huat , Chen Hsinchun
Published: May 2004

The rapid growth of the non‐English‐speaking Internet population has created a need for better searching and browsing capabilities in languages other than English. However, existing search engines may not serve the needs of many non‐English‐speaking Internet users. In this paper, we propose a generic and integrated approach to searching and browsing the Internet in a multilingual world. Based on this approach, we have developed the Chinese Business Intelligence Portal (CBizPort), a meta‐search engine that searches for business information of mainland China, Taiwan, and Hong Kong. Additional functions provided by CBizPort include encoding conversion (between Simplified Chinese and Traditional Chinese), summarization, and categorization. Experimental results of our user evaluation study show that the searching and browsing performance of CBizPort was comparable to that of regional Chinese search engines, and CBizPort could significantly augment these search engines. Subjects' verbal comments indicate that CBizPort performed best in terms of analysis functions, cross‐regional searching, and user‐friendliness, whereas regional search engines were more efficient and more popular. Subjects especially liked CBizPort's summarizer and categorizer, which helped in understanding search results. These encouraging results suggest a promising future of our approach to Internet searching and browsing in a multilingual world.
Popular music access: The Sony music browser
Authors: Pachet François , La Burthe Amaury , Zils Aymeric , Aucouturier Jean‐Julien
Published: May 2004

The intentionally ambiguous expression “Popular Music Browser” reflects the two main goals of this project, which started in 1998, at Sony Computer Science Laboratories. First, we are interested in human‐centered issues related to browsing “Popular Music.” Popular here means that the music accessed is distributed widely and known to many listeners. Second, we consider “popular browsing” of music, i.e., making music accessible to nonspecialists (music lovers) and allowing sharing of musical tastes and information within communities, departing from the usual, single‐user view of digital libraries. This research project covers all areas of the music‐to‐listener chain, from music description, descriptor extraction from the music signal, or data mining techniques, similarity‐based access, and novel music retrieval methods such as automatic sequence generation, and to user interface issues. This article describes the scientific and technical issues at stake and the results obtained, and is illustrated by prototypes developed within the European IST projectCuidado.
Application of soft computing to automatic music information retrieval
Authors: Kostek Bozena
Published: May 2004

There are many problems in the musical signal domain that have not been solved yet. Among such problems are automatic recognition and editing of musical sound patterns, retrieval of audio material, detection of transient states, and articulation features in sounds. It seems that the key challenge is in building inexpensive browsers to retrieve audio material contained in multimedia bases and Internet sites. This overview shows motivation and intermediate and long‐term goals of the research projects that have conducted for several years in the Multimedia Systems Department, Gdansk University of Technology, Poland.
An unforgettable surgery
Authors: Cowden Sharon
Published: May 2004

For more than 50 years, Cancer has explored every facet of malignant disease, including morphology, therapy, epidemiology, biology, historical perspective, and basic science. However, the Editors of Cancer believe that the human beings who bear the burden of this illness have much to teach us, and we now solicit essays from patients and family members about their experience. Cancer 2004. © 2004 American Cancer Society.
Nitroxide Radicals Interacting with Polyamine‐Phenolic Ligands and Their Metal Complexes
Authors: Cangiotti Michela , Formica Mauro , Fusi Vieri , Giorgi Luca , Micheloni Mauro , Ottaviani M. Francesca , Sampaolesi Sonia
Published: May 2004

We have analyzed the interactions of a series of nitroxide radicals with ligands containing a phenol moiety coupled with different polyamine fragments, and their CuII and ZnII complexes, by EPR experiments. Nitroxide radicals are good mimics of the properties of pollutant molecules, e.g., organic compounds having different polarities and charges, surfactants, and polyaromatics. Charged, polar, and low‐polarity sites in the ligands and complexes are all available for interactions; in particular, the ability to entrap the radicals in a vice‐like structure, by the formation of phenyl sandwich complexes, determines the type of selective interaction that occurs when a chain or planar aromatic structure is present. For closely packed complexes, ZnII has a cooperative effect in the interaction with the radical; it allows both the entrance of low‐polarity radicals at the low‐polarity sites of the complex and the interactions of polar or charged radicals at the polar sites of the complexes. Conversely, CuII coordinates to the amino groups of the ligands and blocks the entry of radicals, which, thus, impedes their insertion into the structure of the complexes. The opposite behavior, with respect to that of CuII and ZnII, was found for the complexes that have more open structures. The complexes that have cyclic ligands exhibit a poor ability to interact with radicals, but, for the ligands in the absence of the coordinating metals, the interactions are significantly enhanced as a result of the entrance of the radicals into the cyclic structures. In all cases, stronger interactions occur when both hydrophilic and hydrophobic sites are involved. The neutral‐surfactant probe forms aggregates mainly with the cooperative effect of the copper complexes. UV/Vis measurements confirmed the results obtained by EPR and indicate that weak interactions occur between the radicals and the complexes or ligands; they also confirmed the formation of 1:1 adducts. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Tris(trimethylsilyl)‐Substituted Heavy Group 14‐Element‐Centered Anions: Unsolvated Trimeric Germyllithium and Solvated Dimeric Silyl‐ and Stannyllithiums
Authors: Nanjo Masato , Nanjo Emi , Mochida Kunio
Published: May 2004

Tris(trimethylsilyl)‐substituted group 14‐element‐centered anion monomers [LiE(SiMe3)3·3THF] (E = Si, Ge, and Sn) can be distilled under reduced pressure to give dimeric silyllithium 4 and stannyllithium 6, and trimeric germyllithium 5 without pyrolysis products such as dilithiometallanes. The molecular structures of 4, 5, and 6 were unequivocally determined by X‐ray diffraction. Dimer 4 has a symmetrical bent four‐membered‐ring structure consisting of two anionic silicon atoms and two cationic lithium atoms with coordinated THF molecules. Dimer 6 has an unsymmetrical distorted four‐membered‐ring structure consisting of two anionic tin atoms, a bridged unsolvated lithium atom, and a bridged lithium atom solvated by a THF molecule. Interestingly, 6 aggregates to form dimers of dimers by an intermolecular CH3···Li interaction. Trimeric germyllithium 5 forms an equilateral triangular lithium cluster without solvation. Compound 5 has a crystallographic threefold axis with three anionic germanium atoms and three cationic lithium atoms lying in the same plane. The lithium atoms in 5 are stabilized by an intramolecular CH3···Li interaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis, Crystal Structure and Thermal Reactivity of New Copper(I) Halide Pyrimidine‐Containing Coordination Polymers
Authors: Näther Christian , Jeß Inke
Published: May 2004

Reaction of copper(I) chloride with pyrimidine in acetonitrile leads to the formation of the ligand‐rich 1:1 compound poly[CuCl(μ2‐pyrimidine‐N,N′)] (1). “Zig‐zag”‐like CuCl chains are found in the crystal structure that are connected by the pyrimidine ligands to form layers. This compound loses half of its ligands upon heating and transforms into the new l2:1 coordination polymer poly[(CuCl)2(μ2‐pyrimidine‐N,N′)] (2). In this structure, ladder‐like CuCl double chains occur which are connected by the pyrimidine ligands to form layers. If copper(I) iodide is used in the synthesis, the new 1:1 coordination polymer poly[CuI(μ2‐pyrimidine‐N,N′)] (3) forms. In contrast to compound 1, CuI single chains and (CuI)2 dimers are found as the CuX substructure, and these are connected by the ligands to form sheets. On heating this compound a similar behaviour as for compound 1 is observed, and a transformation into the new 2:1 compound poly[(CuI)2(μ2‐pyrimidine‐N,N′)] (4) occurs. This compound is not isotypic to 2 even though the topology of the coordination network is identical (CuI double chains are connected into layers by the pyrimidine ligands). The thermal behaviour of the known compounds poly[CuBr(μ2‐pyrimidine‐N,N′)] (5) and poly[(CuBr)2(μ2‐pyrimidine‐N,N′)] (6) was also investigated. A transformation of the ligand‐rich 1:1 compound 5 into the 2:1 compound 6 is also observed in the thermal decomposition reaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis and Characterization of [OsCl2(=C=CHR)(PPh3)2] and Related Complexes
Authors: Wen Ting Bin , Hung Wai Yiu , Zhou Zhong Yuan , Lo Man Fung , Williams Ian D. , Jia Guochen
Published: May 2004

Treatment of [OsCl2(PPh3)3] with HC≡CR (R = Ph, p‐tolyl, CMe3) in the presence of HCl gives the corresponding trichloro(carbyne) complexes [OsCl3(≡CCH2R)(PPh3)2] in good yields. The vinylidene complexes [OsCl2(=C=CHR)(PPh3)2] (R = Ph, p‐tolyl, CMe3) are, in turn, prepared from the reactions of the carbyne complexes [OsCl3(≡CCH2R)(PPh3)2] with NEt3. These new vinylidene complexes are hygroscopic and react with H2O to give (aqua)(vinylidene) complexes [OsCl2(H2O)(=C=CHR)(PPh3)2]. The structures of several of these new complexes have been determined by X‐ray diffraction studies. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)