bluuebunny/crossref_metadata_2025 huggingface dataset:
Multidrug-Resistant Acinetobacter Infections: An Emerging Challenge to Clinicians
Authors: Jain Rupali , Danziger Larry H
Published: July 2004

OBJECTIVE:

To review and evaluate clinically relevant epidemiology, microbiology, and clinical studies regarding the treatment of multidrug-resistant Acinetobacter infections.

DATA SOURCES:

Pertinent literature was identified by a MEDLINE search (1966-September 2003) and through secondary bibliographies of pertinent articles.

STUDY SELECTION AND DATA EXTRACTION:

All English-language articles identified from data sources were evaluated for clinical relevance.

DATA SYNTHESIS:

Acinetobacter baumannii has emerged as a worldwide problem as a nosocomial pathogen in hospitalized patients. Acinetobacter spp. can cause a multitude of infections including pneumonia, bacteremia, meningitis, urinary tract infections, and skin and soft tissue infections, and the mortality associated with these infections is high. Isolates resistant to almost all commercially available antimicrobials have been identified, thus limiting treatment options. The development of new agents and reappraisal of older compounds (ie, polymyxins, ampicillin/sulbactam) are necessary as we consider the optimal treatment of these multidrug-resistant organisms.

CONCLUSIONS:

There is no simple answer to the treatment of Acinetobacter infections. Eradication of Acinetobacter spp. requires adherence to good infection control practices and prudent antibiotic use, as well as effective antimicrobial therapy. Alternative therapies such as colistin, ampicillin/sulbactam, and tetracycline are potential options, but prospective, randomized, controlled trials are still lacking.
CD40 Ligand: A Novel Target in the Fight against Cardiovascular Disease
Authors: Vishnevetsky Diana , Kiyanista Vladimir A , Gandhi Pritesh J
Published: July 2004

OBJECTIVE:

To discuss the role of CD40 ligand (CD40L) in atherosclerosis and acute coronary syndromes (ACS), as well as describe relevant clinical literature evaluating the effects of pharmacotherapeutic agents on CD40L expression and soluble CD40L levels.

DATA SOURCES:

A MEDLINE and EMBASE search (1966–September 2003) was conducted using the key terms CD40, CD40 ligand, platelets, inflammation, and drug therapy. Additional primary literature was identified by reviewing the reference lists of relevant original and review papers.

STUDY SELECTION AND DATA EXTRACTION:

All articles identified in the search were evaluated, and those deemed relevant were incorporated into the review.

DATA SYNTHESIS:

CD40L is a transmembrane protein expressed on T cells, B cells, mast cells, basophils, eosinophils, natural killer cells, macrophages, endothelial cells, vascular smooth muscle cells, and activated platelets. It is also found in plasma as a soluble protein, sCD40L. As a consequence of CD40L binding to its receptor (CD40), several inflammatory processes are initiated. Studies have demonstrated elevated CD40L levels in patients with hypercholesterolemia and ACS, and elevated sCD40L levels have been associated with increased risk of cardiovascular events. Statins, glitazones, glycoprotein IIb/IIIa inhibitors, and clopidogrel have been demonstrated to effectively reduce CD40L levels both in vitro and in vivo. Abciximab has been shown to reduce the occurrence of death or myocardial infarction during 6 months of follow-up in patients with ACS who had the highest levels of sCD40L.

CONCLUSIONS:

The proinflammatory and procoagulant protein CD40L represents a novel target in the treatment of atherosclerosis and ACS. A number of therapeutic agents have been shown to modulate the expression of CD40L, findings that could have important clinical applications.
Alfuzosin-Induced Acute Hepatitis in a Patient with Chronic Liver Disease
Authors: Yolcu Ömer Faruk , Köklü Seyfettin , Köksal Aydin Ş , Yüksel Osman , Beyazit Yavuz , Başar Ömer
Published: July 2004

OBJECTIVE:

To report a new case of probable alfuzosin-induced hepatitis.

CASE SUMMARY:

An 80-year-old man was evaluated because of jaundice and pruritus. He was diagnosed as having Child-Pugh A chronic liver disease due to hepatitis B virus. Other etiologies of hepatitis were appropriately ruled out, and the hepatitis B was non-replicative. Therefore, elevated liver enzyme levels were ascribed to alfuzosin treatment.

DISCUSSION:

Although alfuzosin-related mixed-type hepatotoxicity has been previously reported, this is the first published case describing probable hepatocellular-type hepatotoxicity resulting from use of alfuzosin in a patient with underlying chronic liver disease. According to the Naranjo probability scale, alfuzosin was a probable cause of the hepatotoxicity. The mechanism of alfuzosin-induced liver damage is unknown. Several features, such as absence of predictable dose-dependent toxicity of alfuzosin in previous studies and absence of hypersensitivity manifestations in our case, are suggestive of a metabolic type of idiosyncratic toxicity.

CONCLUSIONS:

Alfuzosin rarely causes hepatotoxicity; however, clinicians must be alert for this adverse effect while using alfuzosin.
Fatal Venous Thromboembolism Associated with Antipsychotic Therapy
Authors: Farah Raymond E , Makhoul Nicola M , Farah Rola E , Shai Moshe D
Published: July 2004

OBJECTIVE:

To describe the occurrence of pulmonary embolism (PE) as a rare adverse effect of clozapine that is treatable, but sometimes fatal, and survey the literature on the subject in the hope of increasing awareness of the potential danger that may result from drug interactions.

CASE SUMMARY:

A 47-year-old woman treated with clozapine and paroxetine was admitted to the hospital with dyspnea and swelling of the leg. The patient was diagnosed as having PE and was treated with intravenous heparin. On hospital day 7, sudden acute respiratory failure developed and the patient died. Postmortem examination confirmed the existence of massive PE.

DISCUSSION:

The woman had no identifiable risk factors other than receiving a combination of clozapine and paroxetine, with a demonstrated elevated clozapine blood concentration. Use of the Naranjo probability scale revealed a probable likelihood that the adverse reaction was drug related.

CONCLUSIONS:

The association of antipsychotic drugs and venous thromboembolism has been previously described, but is still a rare finding. This case highlights the importance of monitoring and possibly discontinuing treatment when venous thrombosis is suspected. There should be careful monitoring, especially in patients with risk factors for thrombosis. Finally, antidepressant—antipsychotic drug combinations can increase the risk of rare adverse effects, such as venous thromboembolism, even in the absence of other risk factors.
Transactivation of Trk Neurotrophin Receptors by G-Protein-Coupled Receptor Ligands Occurs on Intracellular Membranes
Authors: Rajagopal Rithwick , Chen Zhe-Yu , Lee Francis S. , Chao Moses V.
Published: July 2004

Neurotrophins, such as NGF and BDNF, activate Trk receptor tyrosine kinases through receptor dimerization at the cell surface followed by autophosphorylation and intracellular signaling. It has been shown that activation of Trk receptor tyrosine kinases can also occur via a G-protein-coupled receptor (GPCR) mechanism, without involvement of neurotrophins. Two GPCR ligands, adenosine and pituitary adenylate cyclase-activating polypeptide (PACAP), can activate Trk receptor activity to increase the survival of neural cells through stimulation of Akt activity. To investigate the mechanism of Trk receptor transactivation, we have examined the localization of Trk receptors in PC12 cells and primary neurons after treatment with adenosine agonists and PACAP. In contrast to neurotrophin treatment, Trk receptors were sensitive to transcriptional and translational inhibitors, and they were found predominantly in intracellular locations particularly associated with Golgi membranes. Biotinylation and immunostaining experiments confirm that most of the transactivated Trk receptors are found in intracellular membranes. These results indicate that there are alternative modes of activating Trk receptor tyrosine kinases in the absence of neurotrophin binding at the cell surface and that receptor signaling may occur and persist inside of neuronal cells.
Voltage Imaging from Dendrites of Mitral Cells: EPSP Attenuation and Spike Trigger Zones
Authors: Djurisic Maja , Antic Srdjan , Chen Wei R. , Zecevic Dejan
Published: July 2004

To obtain a more complete description of individual neurons, it is necessary to complement the electrical patch pipette measurements with technologies that permit a massive parallel recording from many sites on neuronal processes. This can be achieved by using voltage imaging with intracellular dyes. With this approach, we investigated the functional structure of a mitral cell, the principal output neuron in the rat olfactory bulb. The most significant finding concerns the characteristics of EPSPs at the synaptic sites and surprisingly small attenuation along the trunk of the primary dendrite. Also, the experiments were performed to determine the number, location, and stability of spike trigger zones, the excitability of terminal dendritic branches, and the pattern and nature of spike initiation and propagation in the primary and secondary dendrites. The results show that optical data can be used to deduce the amplitude and shape of the EPSPs evoked by olfactory nerve stimulation at the site of origin (glomerular tuft) and to determine its attenuation along the entire length of the primary dendrite. This attenuation corresponds to an unusually large mean apparent “length constant” of the primary dendrite. Furthermore, the images of spike trigger zones showed that an action potential can be initiated in three different compartments of the mitral cell: the soma-axon region, the primary dendrite trunk, and the terminal dendritic tuft, which appears to be fully excitable. Finally, secondary dendrites clearly support the active propagation of action potentials.
Dominance Hierarchy Influences Adult Neurogenesis in the Dentate Gyrus: Figure 1.
Authors: Kozorovitskiy Yevgenia , Gould Elizabeth
Published: July 2004

Many mammalian species form dominance hierarchies, but it remains unknown whether differences in social status correspond to structural differences in the brain. Stressful experiences may arise naturally during the establishment of dominance, and stress has been linked to adult neurogenesis in the hippocampus. To determine whether position in a dominance hierarchy leads to changes in adult neurogenesis in the hippocampus, we examined the brains of rats housed in a visible burrow system (VBS), a seminaturalistic environment with opportunities for social interaction. Dominance hierarchies emerged among the males in all colonies within 3 d of living in the VBS. Although cell proliferation in the dentate gyrus did not differ between the groups, more new neurons were observed in the dentate gyrus of the dominant males compared with both subordinates and controls. Dominant and subordinate animals showed similar basal, stress, and recovery from stress levels of corticosterone, as well as similar thymus, adrenal gland, and body weights, suggesting that variables other than stress are responsible for the observed changes in adult neurogenesis. The differences in brain structure persisted among the animals that had no access to the burrow system after the dominance hierarchy stabilized, suggesting that social status rather than living in a complex environment accounts for the effect of dominance on adult neurogenesis.
A Neural Representation of Pitch Salience in Nonprimary Human Auditory Cortex Revealed with Functional Magnetic Resonance Imaging
Authors: Penagos Hector , Melcher Jennifer R. , Oxenham Andrew J.
Published: July 2004

Pitch, one of the primary auditory percepts, is related to the temporal regularity or periodicity of a sound. Previous functional brain imaging work in humans has shown that the level of population neural activity in centers throughout the auditory system is related to the temporal regularity of a sound, suggesting a possible relationship to pitch. In the current study, functional magnetic resonance imaging was used to measure activation in response to harmonic tone complexes whose temporal regularity was identical, but whose pitch salience (or perceptual pitch strength) differed, across conditions. Cochlear nucleus, inferior colliculus, and primary auditory cortex did not show significant differences in activation level between conditions. Instead, a correlate of pitch salience was found in the neural activity levels of a small, spatially localized region of nonprimary auditory cortex, overlapping the anterolateral end of Heschl's gyrus. The present data contribute to converging evidence that anterior areas of nonprimary auditory cortex play an important role in processing pitch.
Blockade of Nociceptin/Orphanin FQ Receptor Signaling in Rat Substantia Nigra Pars Reticulata Stimulates Nigrostriatal Dopaminergic Transmission and Motor Behavior
Authors: Marti Matteo , Mela Flora , Veronesi Carlo , Guerrini Remo , Salvadori Severo , Federici Mauro , Mercuri Nicola B. , Rizzi Anna , Franchi Gianfranco , Beani Lorenzo , Bianchi Clementina , Morari Michele
Published: July 2004

A multidisciplinary approach was followed to investigate whether the opioid-like peptide nociceptin/orphanin FQ (N/OFQ) regulates the nigrostriatal dopaminergic pathway and motor behavior. Nigrostriatal dopaminergic cells, which express N/OFQ peptide (NOP) receptors, are located in the substantia nigra pars compacta and extend their dendrites in the substantia nigra pars reticulata, thereby modulating the basal ganglia output neurons.In vitroelectrophysiological recordings demonstrated that N/OFQ hyperpolarized the dopaminergic cells of the substantia nigra pars compacta and inhibited their firing activity.In vivodual-probe microdialysis showed that N/OFQ perfused in the substantia nigra pars reticulata reduced dopamine release in the ipsilateral striatum, whereas UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ(1-13)-NH2) (a selective NOP receptor peptide antagonist) stimulated it. N/OFQ microinjected in the substantia nigra pars reticulata impaired rat performance on a rotarod apparatus, whereas UFP-101 enhanced it. Electromyography revealed that N/OFQ and UFP-101 oppositely affected muscle tone, inducing relaxation and contraction of triceps, respectively. The selective NOP receptor nonpeptide antagonist J-113397 (1-[3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one), either injected intranigrally or given systemically, also elevated striatal dopamine release and facilitated motor activity, confirming that these effects were caused by blockade of endogenous N/OFQ signaling. The inhibitory role played by endogenous N/OFQ on motor activity was additionally strengthened by the finding that mice lacking the NOP receptor gene outperformed wild-type mice on the rotarod. We conclude that NOP receptors in the substantia nigra pars reticulata, activated by endogenous N/OFQ, drive a physiologically inhibitory control on motor behavior, possibly via modulation of the nigrostriatal dopaminergic pathway.
TheDrosophilaReceptor Guanylyl Cyclase Gyc76C Is Required for Semaphorin-1a-Plexin A-Mediated Axonal Repulsion
Authors: Ayoob Joseph C. , Yu Hung-Hsiang , Terman Jonathan R. , Kolodkin Alex L.
Published: July 2004

Cyclic nucleotide levels within extending growth cones influence how navigating axons respond to guidance cues. Pharmacological alteration of cAMP or cGMP signalingin vitrodramatically modulates how growth cones respond to attractants and repellents, although how these second messengers function in the context of guidance cue signaling cascadesin vivois poorly understood. We report here that theDrosophilareceptor-type guanylyl cyclase Gyc76C is required for semaphorin-1a (Sema-1a)-plexin A repulsive axon guidance of motor axonsin vivo. Our genetic analyses define a neuronal requirement for Gyc76C in axonal repulsion. Additionally, we find that the integrity of the Gyc76C catalytic cyclase domain is critical for Gyc76C function in Sema-1a axon repulsion. Our results support a model in which cGMP production by Gyc76C facilitates Sema-1a-plexin A-mediated defasciculation of motor axons, allowing for the generation of neuromuscular connectivity in the developingDrosophilaembryo.
External Tufted Cells: A Major Excitatory Element That Coordinates Glomerular Activity
Authors: Hayar Abdallah , Karnup Sergei , Ennis Matthew , Shipley Michael T.
Published: July 2004

The glomeruli of the olfactory bulb are the first site of synaptic processing in the olfactory system. The glomeruli contain three types of neurons that are referred to collectively as juxtaglomerular (JG) cells: external tufted (ET), periglomerular (PG), and short axon (SA) cells. JG cells are thought to interact synaptically, but little is known about the circuitry linking these neurons or their functional roles in olfactory processing. Single and paired whole-cell recordings were performed to investigate these questions. ET cells spontaneously fired rhythmic spike bursts in the theta frequency range and received monosynaptic olfactory nerve (ON) input. In contrast, all SA and most PG cells lacked monosynaptic ON input. PG and SA cells exhibited spontaneous, intermittent bursts of EPSCs that were highly correlated with spike bursts of ET cells in the same but not in different glomeruli. Paired recording experiments demonstrated that ET cells provide monosynaptic excitatory input to PG/SA cells; the ET to PG/SA cell synapse is mediated by glutamate. ET cells thus are a major excitatory linkage between ON input and other JG cells. Spontaneous bursting is highly correlated among ET cells of the same glomerulus, and ET cell activity remains correlated when all fast synaptic activity is blocked. The findings suggest that multiple, synchronously active ET cells synaptically converge onto single PG/SA cells. Synchronous ET cell bursting may function to amplify transient sensory input and coordinate glomerular output.
Slow Actions of Neuroactive Steroids at GABAAReceptors
Authors: Shu Hong-Jin , Eisenman Lawrence N. , Jinadasa Deepani , Covey Douglas F. , Zorumski Charles F. , Mennerick Steven
Published: July 2004

Neuroactive steroids are potent and efficacious modulators of GABAAreceptor activity and are potent sedatives and anesthetics. These positive modulators of GABAAreceptors both potentiate the actions of GABA at the receptor and, at higher concentrations, directly gate the channel. The contribution of direct gating to the cellular and behavioral effects of neuroactive steroids is considered of little significance because it has been generally found that concentrations well above those needed for anesthesia are required to gate channels. By studying solitary glutamatergic neurons devoid of synaptic GABA input, we show that direct gating occurs and significantly alters membrane excitability at concentrations ≤100 nm. We propose that the relevance of direct gating has been overlooked partly because of the extremely slow kinetics of receptor activation and deactivation. We show that slow deactivation of directly gated currents does not result from an inherently tight ligand-receptor interaction because the slow deactivation is markedly accelerated by γ-cyclodextrin application. We hypothesize that steroids access the relevant GABAAreceptor site from a non-aqueous reservoir, likely the plasma membrane, and that it is slow reservoir accumulation and departure that accounts for the slow kinetics of receptor gating by neuroactive steroids.
On the Activity of the Corticostriatal Networks during Spike-and-Wave Discharges in a Genetic Model of Absence Epilepsy
Authors: Slaght Seán J. , Paz Tamar , Chavez Mario , Deniau Jean-Michel , Mahon Séverine , Charpier Stéphane
Published: July 2004

Absence seizures are characterized by impairment of consciousness associated with widespread bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram (EEG), which reflect highly synchronized oscillations in thalamocortical networks. Although recent pharmacological studies suggest that the basal ganglia could provide a remote control system for absence seizures, the mechanisms of propagation of epileptic discharges in these subcortical nuclei remain unknown. In the present study, we provide the first description of the electrical events in the corticostriatal pathway during spontaneous SWDs in the genetic absence epilepsy rats from Strasbourg (GAERS), a genetic model of absence epilepsy. In corticostriatal neurons, the SWDs were associated with suprathreshold rhythmic depolarizations in-phase with local EEG spikes. Consistent with this synchronized firing in their excitatory cortical afferents, striatal output neurons (SONs) exhibited, during SWDs, large-amplitude rhythmic synaptic depolarizations. However, SONs did not discharge during SWDs. Instead, the rhythmic synaptic excitation of SONs was shunted by a Cl--dependent increase in membrane conductance that was temporally correlated with bursts of action potentials in striatal GABAergic interneurons. The reduced SON excitability accompanying absence seizures may participate in the control of SWDs by affecting the flow of cortical information within the basal ganglia circuits.
Lipid Rafts Mediate the Synaptic Localization of α-Synuclein
Authors: Fortin Doris L. , Troyer Matthew D. , Nakamura Ken , Kubo Shin-ichiro , Anthony Malcolm D. , Edwards Robert H.
Published: July 2004

α-Synuclein contributes to the pathogenesis of Parkinson's disease (PD), but its precise role in the disorder and its normal function remain poorly understood. Consistent with a presumed role in neurotransmitter release and its prominent deposition in the dystrophic neurites of PD, α-synuclein localizes almost exclusively to the nerve terminal. In brain extracts, however, α-synuclein behaves as a soluble, monomeric protein. Using a binding assay to characterize the association of α-synuclein with cell membranes, we find that α-synuclein binds saturably and with high affinity to characteristic intracellular structures that double label for components of lipid rafts. Biochemical analysis demonstrates the interaction of α-synuclein with detergent-resistant membranes and reveals a shift in electrophoretic mobility of the raft-associated protein. In addition, the A30P mutation associated with PD disrupts the interaction of α-synuclein with lipid rafts. Furthermore, we find that both the A30P mutation and raft disruption redistribute α-synuclein away from synapses, indicating an important role for raft association in the normal function of α-synuclein and its role in the pathogenesis of PD.
Common Genetic Effects on Variation in Impulsivity and Activity in Mice
Authors: Isles Anthony R. , Humby Trevor , Walters Eurof , Wilkinson Lawrence S.
Published: July 2004

Impulsivity is a complex psychological construct that impacts on behavioral predispositions in the normal range and has been shown to have a genetic element through the examination of hereditary patterns of abnormal conditions such as attention deficit/hyperactivity disorder and obsessive compulsive disorder. In this study, we took advantage of the isogenic nature of inbred strains of mice to determine the contribution of genes to impulsive behaviors by examining the performance of four separate mouse strains in a novel murine delayed-reinforcement paradigm, during which the animals had to choose between rewards that were relatively small but available immediately and larger but progressively delayed rewards. To control for maternal effects, all the mice were cross-fostered to a common strain immediately after birth. Under these conditions, we found significant differences between the strains on behaviors indexing impulsive choice and on independent measures of locomotor activity, which subsequent heritability analysis showed could be related, in part, to genetic effects. Moreover, the two aspects of behavior were found to co-vary, with the more active animals also displaying more impulsive behavior. This was not attributable to mundane confounds related to individual task requirements but instead indicated the existence of common genetic factors influencing variation in both impulsivity and locomotor activity. The data are discussed in terms of the coexistence of impulsivity and hyperactivity, interactions between environmental and genetic effects, and possible candidate genes.
Mechanosensory Activation of a Motor Circuit by Coactivation of Two Projection Neurons
Authors: Beenhakker Mark P. , Nusbaum Michael P.
Published: July 2004

Individual neuronal circuits can generate multiple activity patterns because of the influence of different projection neurons. However, in most systems it has been difficult to identify and assess the relative contribution of all upstream neurons responsible for the activation of any single activity pattern by a behaviorally relevant stimulus. To elucidate this issue, we used the stomatogastric nervous system (STNS) of the crab. The STNS includes the gastric mill (chewing) motor circuit in the stomatogastric ganglion (STG) and no more than 20 projection neurons that innervate the STG. We previously identified at least some (four) of the projection neurons that are activated directly by the ventral cardiac neuron (VCN) system, a population of mechanosensory neurons that activates the gastric mill circuit. Here we show that two of these projection neurons, the previously identified modulatory commissural neuron 1 (MCN1) and commissural projection neuron 2 (CPN2), are necessary and likely sufficient for the initiation/maintenance of the VCN-elicited gastric mill rhythm. Selective inactivation of either MCN1 or CPN2 still enabled a VCN-elicited gastric mill rhythm. However, because MCN1 and CPN2 have different actions on gastric mill neurons, these manipulations resulted in rhythms distinct from each other and from that occurring in the intact system. After removal of both MCN1 and CPN2, VCN stimulation failed to activate the gastric mill rhythm. Selective conjoint stimulation of MCN1 and CPN2, approximating their VCN-elicited activity patterns and firing frequencies, elicited a VCN-like gastric mill rhythm. Thus the VCN mechanosensory system elicits the gastric mill rhythm via its activation of a subset of the relevant projection neurons.
cAMP Response Element-Binding Protein Is Required for Stress But Not Cocaine-Induced Reinstatement
Authors: Kreibich Arati S. , Blendy Julie A.
Published: July 2004

Reinstatement of previously extinguished conditioned place preference (CPP) is precipitated by stress or drug exposure. Here, we show that acute exposure to forced swim stress (FS), in a context distinct from conditioning, induces reinstatement of cocaine CPP in wild-type mice. This behavior is accompanied by a pattern of phosphorylated cAMP response element-binding protein (pCREB) activation in discrete brain regions that is distinct from the pattern observed after cocaine-induced reinstatement. For example, previous cocaine conditioning increases pCREB levels in the amygdala, and acute exposure to FS, but not to cocaine, further augments these changes. In contrast, previous cocaine conditioning does not alter levels of pCREB in the nucleus accumbens, but acute exposure to FS increases pCREB levels in this region on reinstatement day. Furthermore, to determine whether these alterations of CREB are necessary in FS or cocaine-induced reinstatement, we examined the effect of these stimuli on reinstatement behavior in mice deficient in α and Δ isoforms of CREB. The CREBαΔmutant mice show deficits in FS-induced reinstatement of conditioned place preference. In contrast, they show robust cocaine-induced reinstatement. This deficit in stress but not drug-induced reinstatement indicates a specific requirement for CREB in stress-induced behavioral responses to drugs of abuse.
Promotion of Axon Regeneration by Myelin-Associated Glycoprotein and Nogo through Divergent Signals Downstream of Gi/G
Authors: Hasegawa Yuiko , Fujitani Masashi , Hata Katsuhiko , Tohyama Masaya , Yamagishi Satoru , Yamashita Toshihide
Published: July 2004

Several myelin-derived proteins have been identified as components of the CNS myelin that prevents axonal regeneration in the adult vertebrate CNS. Activation of RhoA has been shown to be an essential part of the signaling mechanism of these proteins. Here we report an additional signal, which determines whether these proteins promote or inhibit axon outgrowth. Myelin-associated glycoprotein (MAG) and Nogo trigger the intracellular elevation of Ca2+as well as the activation of PKC, presumably mediated by Gi/G. Neurite outgrowth inhibition and growth cone collapse by MAG or Nogo can be converted to neurite extension and growth cone spreading by inhibiting conventional PKC, but not by inhibiting inositol 1,4,5-triphosphate (IP3). Conversely, neurite growth of immature neurons promoted by MAG is abolished by inhibiting IP3. Activation of RhoA is independent of PKC. Thus, a balance between PKC and IP3is important for bidirectional regulation of axon regeneration by the myelin-derived proteins.
β-Amyloid Peptide at Sublethal Concentrations Downregulates Brain-Derived Neurotrophic Factor Functions in Cultured Cortical Neurons
Authors: Tong Liqi , Balazs Robert , Thornton Phillip L. , Cotman Carl W.
Published: July 2004

The accumulation of β-amyloid (Aβ) is one of the etiological factors in Alzheimer's disease (AD). It has been assumed that the underlying mechanism involves a critical role of Aβ-induced neurodegeneration. However, low levels of Aβ, such as will accumulate during the course of the disease, may interfere with neuronal function via mechanisms other than those involving neurodegeneration. We have been testing, therefore, the hypothesis that Aβ at levels insufficient to cause degeneration (sublethal) may interfere with critical signal transduction processes. In cultured cortical neurons Aβ at sublethal concentrations interferes with the brain-derived neurotrophic factor (BDNF)-induced activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. The effect of sublethal Aβ1-42on BDNF signaling results in the suppression of the activation of critical transcription factor cAMP response element-binding protein and Elk-1 and cAMP response element-mediated and serum response element-mediated transcription. The site of interference with the Ras/ERK and PI3-K/Akt signaling is downstream of the TrkB receptor and involves docking proteins insulin receptor substrate-1 and Shc, which convey receptor activation to the downstream effectors. The functional consequences of Aβ interference with signaling are robust, causing increased vulnerability of neurons, abrogating BDNF protection against DNA damage- and trophic deprivation-induced apoptosis. These new findings suggest that Aβ engenders a dysfunctional encoding state in neurons and may initiate and/or contribute to cognitive deficit at an early stage of AD before or along with neuronal degeneration.
Opposing Extracellular Signal-Regulated Kinase and Akt Pathways Control Schwann Cell Myelination
Authors: Ogata Toru , Iijima Satoru , Hoshikawa Shinya , Miura Toshiki , Yamamoto Shin-ichi , Oda Hiromi , Nakamura Kozo , Tanaka Sakae
Published: July 2004

Schwann cells are the myelinating glia of the peripheral nervous system, and their development is regulated by various growth factors, such as neuregulin, platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). However, the mechanism of intracellular signaling pathways following these ligand stimuli in Schwann cell differentiation remains elusive. Here, we demonstrate that in cultured Schwann cells, neuregulin and PDGF suppressed the expression of myelin-associated protein markers, whereas IGF-I promoted it. Although these ligands activated common downstream signaling pathways [i.e., extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways], the profiles of activation varied among ligands. To elucidate the function of these pathways and the mechanisms underlying Schwann cell differentiation, we used adenoviral vectors to selectively activate or inactivate these pathways. We found that the selective activation of Erk pathways suppressed Schwann cell differentiation, whereas that of PI3K pathways promoted it. Furthermore, lithium chloride, a modulator of glycogen synthase kinase-3β (GSK-3β) promoted Schwann cell differentiation, suggesting the involvement of GSK-3β as a downstream molecule of PI3K-Akt pathways. Selective activation of PI3K pathways in Schwann cells by gene transfer also demonstrated increased myelination inin vitroSchwann cell-DRG neuron cocultures andin vivoallogenic nerve graft experiments. We conclude that signals mediated by PI3K-Akt are crucial for initiation of myelination and that the effects of growth factors are primarily dependent on the balance between Erk and PI3K-Akt activation. Our results also propose the possibility of augmenting Schwann cell functions by modulating intracellular signals in light of future cell therapies.
A patient with Prader–Willi syndrome and a supernumerary marker chromosome r(15)(q11.1‐13p11.1)pat and maternal heterodisomy
Authors: Werner Marion , Ben‐Neriah Ziva , silverstein Shira , Lerer Israela , Dagan Yudith , Abeliovich Dvorah
Published: July 2004

We report on a Prader–Willi patient with a de novo supernumerary marker chromosome (SMC) in 16% of the cells. The SMC was a ring chromosome and it included the PWS/AS critical region as was demonstrated by FISH. Segregation analysis indicated that the SMC originated from a paternal chromosome 15 and the two normal chromosomes 15 of the patients were of the maternal homologues. Namely, the patient had maternal heterodisomy in 85% of the cells and triplication of the PWS/AS region in 15% of the cells. The Prader–Willi features were the result of the low mosaicism of the SMC. The evolution of the maternal heterodisomy and the SMC were two unrelated events, the occurrence of both events in the same embryo rescued it from lethality. © 2004 Wiley‐Liss, Inc.
Paternal uniparental disomy of chromosome 14: Confirmation of a clinically‐recognizable phenotype
Authors: Stevenson David A. , Brothman Arthur R. , Chen Zhong , Bayrak‐Toydemir Pinar , Longo Nicola
Published: July 2004

We report on a girl with a dicentric chromosome 14 [45,XX,inv(9)(p11q13),dic(14;14)(p11.1;p11.1)] with paternal uniparental disomy (UPD) for chromosome 14. Clinical findings include severe hypotonia, thoracic dystrophy, diastasis recti, swallowing difficulties with aspiration, developmental delay, and multiple minor anomalies. UPD for chromosome 14 has been documented with paternal UPD much less commonly than with maternal UPD. There have been ten cases of paternal UPD for chromosome 14 and one case of segmental paternal isodisomy of chromosome 14. Many of the findings are nonspecific, but the radiographic rib findings (referred to as the “coat‐hanger” sign) are characteristic for this condition. UPD 14 studies should be performed in children thought to have Jeune asphyxiating thoracic dystrophy or other related osteochondrodysplasias when the diagnosis is in question. Our patient and the previously reported cases support a discrete recognizable phenotype for paternal UPD for chromosome 14. © 2004 Wiley‐Liss, Inc.
Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population
Authors: Brown Abraham M. , Gordon Derek , Lee Hsinhwa , Caudy Michael , Hardy John , Haroutunian Vahram , Blass John P.
Published: July 2004

Abundant biochemical evidence links deficient activity of mitochondrial α‐ketoglutarate dehydrogenase with neuropathologically confirmed Alzheimer's disease (AD). Reduced α‐ketoglutarate dehydrogenase activity has also been associated with anti‐mortem measures of clinical disability. One of the genes encoding this complex, namely, DLD, lies within a chromosome 7 region that is in linkage disequilibrium with AD. We therefore examined the hypothesis that variation in DLD is associated with AD risk. Denaturing HPLC was used to search for sequence variations in the coding and flanking regions of all exons of DLD, but no abundant variants that alter protein sequence were found. However, four common SNPs were identified and genotyped in a case‐control series of 297 Caucasians from New York City, including 229 residents of a Jewish nursing home. Logistic regression analysis was performed for the four‐locus DLD genotype, sex, and ApoE4 status to determine the association of these independent variables with AD. Significant associations with AD were observed for ApoE4 (P < 10−6) and sex combined with DLD genotype (P = 0.013). The association with the DLD genotypes appears only in the male population in both the Caucasian series (P = 0.0009, n = 83) and the Ashkenazi Jewish subseries (P = 0.017, n = 49). The DLD genotype appears to operate independently of APOE in conferring AD risk. © 2004 Wiley‐Liss, Inc.
Osteoarchaeological evidence for leprosy from western Central Asia
Authors: Blau Soren , Yagodin Vadim
Published: July 2004

Published reports of palaeopathological analyses of skeletal collections from Central Asia are, to date, scarce. During the macroscopic examination of skeletal remains dating to the early first millennium AD from the Ustyurt Plateau, Uzbekistan, diagnostic features suggestive of leprosy were found on one individual from Devkesken 6. This adult female exhibited rhinomaxillary changes indicative of leprosy: resorption of the anterior nasal spine, rounding and widening of the nasal aperture, erosion of the alveolar margin, loss of a maxillary incisor, and inflammatory changes in the hard palate. While it is unclear whether the bones of the hands and the feet from this individual were absent as a result of collection strategy or poor preservation, lesions affecting the tibia and fibula were recorded, and the ways in which they may be related to a diagnosis of leprosy are discussed. This is the first skeletal evidence of leprosy from Central Asia and raises questions not only about the spread of the disease in the past, but also about the living conditions of what traditionally were thought of as nomadic peoples. Am J Phys Anthropol 126:150–158, 2005. © 2004 Wiley‐Liss, Inc.
Genotype determines phenotype in experimental Lyme borreliosis
Authors: Pachner Andrew R. , Dail Donna , Bai Yunhong , Sondey Marie , Pak Lena , Narayan Kavitha , Cadavid Diego
Published: July 2004

Borrelia burgdorferi sensu lato, the causative organism of Lyme borreliosis, is a heterogeneous group of spirochetes, consisting of at least three pathogenic species. To test the hypothesis that the genetic heterogeneity is the reason for the clinical differences, we investigated whether the experimental disease induced by European isolates is different from that induced by American isolates. Two American isolates of species B. burgdorferi sensu stricto were compared with three European isolates, two of species B. garinii, and one of species B. afzelii. The patterns of infection, immunity, and inflammation induced by the different species was distinctive. Inflammatory cells and levels of antibody in B. garinii– and B. afzelii–infected animals were lower than in B. burgdorferi s.s.–infected animals, whereas levels of spirochetal infection in the skin and nervous system were higher in the former group of animals. These data demonstrate that B. burgdorferi s.s. strains are more infective and inflammatory, whereas B. garinii and B. afzelii strains can survive the adaptive immune response to a greater degree and persist at greater numbers in the skin and nervous system. The results explain to a large extent the disparities between LNB in humans in the United States and Europe. Ann Neurol 2004
Syntheses and biological activities of polymers containing methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid or 5‐fluorouracil
Authors: Lee Sun‐Mi , Lee Neung‐Ju , Ha Chang‐Sik , Cho Won‐Jei
Published: July 2004

A series of novel copolymers, poly(methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid‐co‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalic acid) [poly(MTCA‐co‐ETAc)], poly(methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid‐co‐hydrogenethyl‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalate) [poly(MTCA‐co‐HEET)], and poly(methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid‐co‐α‐ethoxy‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthaloyl‐5‐fluorouracil) [poly(MTCA‐co‐EETFU)], were prepared from corresponding monomers by photopolymerizations at 25°C for 48 h. The polymers were identified by FTIR, 1H‐NMR, and 13C‐NMR spectroscopies. The number‐average molecular weights of the fractionated polymers determined by GPC were in the range from 9400 to 14,900 and polydispersity indices were 1.2–1.4. The in vitro IC50 values of polymers against mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937) as cancer cell lines and mouse liver cells (AC2F) as a normal cell line were much higher compared to that of 5‐fluorouracil (5‐FU). The in vivo antitumor activities of monomers and polymers against mice bearing sarcoma 180 tumor cell line were better than those of 5‐FU. The inhibition of DNA replication and antiangiogenesis activities of MTCA and copolymers were better compared to those of 5‐FU. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 57–64, 2004
Interfacial adhesion in model bioblends
Authors: Biresaw G. , Carriere C. J. , Willett J. L.
Published: July 2004

Model bioblends were investigated for interfacial adhesion using the asymmetric double cantilever beam (ADCB) fracture method. The model bioblends comprised two synthetic polymer components, one of which was the nonbiodegradable polymer polystyrene (PS). The second component was a synthetic biodegradable polyester, which was either polycaprolactone (PCL) or Eastar Bio Copolyester® (EBU). The critical strain energy release rate (GIc) data from the ADCB fracture experiments on the model bioblends decreased in the order: PCL/PS > EBU/PS. This was opposite to the reported order in the interfacial tension of these bioblends. It is concluded that the relative interfacial adhesion of the model bioblends was due to better compatibility in PCL/PS blends over that in EBU/PS blends. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 65–73, 2004
Design and development of low‐cost optical‐fiber sensors for temperature metrology: Process monitoring of an epoxy resin system
Authors: Degamber B. , Tetlow J. , Fernando G. F.
Published: July 2004

This article reports the design and deployment of two optical‐fiber temperature sensors based on the fiber Fabry–Perot etalon. The first involved the use of an extrinsic fiber Fabry–Perot sensor, but in this instance, the coefficient of thermal expansion of the reflector and/or capillary was chosen to offer a mismatch. Hence, the cavity length could increase or decrease according to the coefficient of thermal expansion of the fiber and/or capillary. For comparison, single‐mode and multimode optical‐fiber Bragg gratings were also used as temperature sensors. The Fabry–Perot sensors operated from −50 to 410°C. The accuracy of the measurements was up to ±0.5°C with a low‐cost charged‐coupling‐device spectrometer. The sensors also worked effectively in a microwave oven and in a composite panel in an autoclave. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 83–95, 2004
Potential of the luminol reaction in the sensitive detection of pesticide residues by ﬂow injection analysis
Authors: Huertas‐Pérez José Fernando , García‐Campaña Ana M. , González‐Casado Antonio , Gámiz‐Gracia Laura
Published: July 2004

This study presents the ﬁrst analytical application of the luminol chemiluminescence (CL) reaction for the sensitive detection of carbamate residues. Some experiments have been carried out to check the inﬂuence of the presence of traces of a N‐methylcarbamate (carbaryl) on the CL emission produced from the oxidation of luminol using different oxidants, showing a signiﬁcant enhancing effect on the CL emission when the oxidation of luminol is produced by potassium permanganate in alkaline medium, this enhancement being proportional to the carbaryl concentration. This fact has permitted the establishment of a sensitive chemiluminescence ﬂow‐injection (CL‐FIA) method for the direct determination of carbaryl. The optimization of instrumental and chemical variables inﬂuencing the CL response has been carried out by applying experimental designs. Under the optimal conditions, the CL intensity was linear for a carbaryl concentration over the range 5–100 ng/mL with a detection limit of 4.9 ng/mL. This luminol–KMnO4‐based FIA‐CL system in basic medium shows an easy, fast and cheap alternative detection mode for the analysis of carbaryl residues in environmental water samples. Copyright © 2004 John Wiley & Sons, Ltd.
Angiogenesis and neoplastic transformation of Barrett's epithelium
Authors: Stein H J , Möbius C
Published: July 2004

Angiogenesis has significance in neoplastic transformation, prognosis and future therapy
Using information technology to improve surgical safety
Authors: Bates D W
Published: July 2004

Patient Safety Leading Article Series, 2004 Dr David W Bates of Harvard Medical School, and Brigham and Women's Hospital, Boston, has for some years had a major interest in information technology in healthcare. Here, he continues our ‘Patient Safety’ series of leading articles, exploring how the tools of the modern era can help avoid harm in the surgical arena.
Critical evaluation of the different staging systems for hepatocellular carcinoma (Br J Surg 2004; 91: 400-408)
Authors: Vauthey Jean-Nicolas , Pawlik Timothy M , Lauwers Gregory Y , Nagorney David M , Roh Mark S , Curley Steven A , Poon Ronnie T , Belghiti Jacques , Greene Frederick , Michael Henderson J
Published: July 2004

The Editors welcome topical correspondence from readers relating to articles published in the Journal. Responses can be sent electronically via the BJS website (www.bjs.co.uk) or by post. All letters will be reviewed and, if approved, appear on the website. A selection of these will be edited and published in the Journal. Letters must be no more than 250 words in length. Letters submitted by post should be typed on A4-sized paper in double spacing and should be accompanied by a disk.
Synthesis, Linear, and Quadratic‐Nonlinear Optical Properties of Octupolar D3 and D2d Bipyridyl Metal Complexes
Authors: Maury Olivier , Viau Lydie , Sénéchal Katell , Corre Brigitte , Guégan Jean‐Paul , Renouard Thierry , Ledoux Isabelle , Zyss Joseph , Le Bozec Hubert
Published: July 2004

A series of D3 (FeII, RuII, ZnII, HgII) and D2d (CuI, AgI, ZnII) octupolar metal complexes featuring different functionalized bipyridyl ligands has been synthesized, and their thermal, linear (absorption and emission), and nonlinear optical (NLO) properties were determined. Their quadratic NLO susceptibilities were determined by harmonic light scattering at 1.91 μm, and the molecular hyperpolarizability (β0) values are in the range of 200–657×10−30 esu for octahedral complexes and 70–157×10−30 esu for tetrahedral complexes. The octahedral zinc(II) complex 1 e, which contains a 4,4′‐oligophenylenevinylene‐functionalized 2,2′‐bipyridine, exhibits the highest quadratic hyperpolarizability ever reported for an octupolar derivative (λmax=482 nm, β1.91(1 e)=870×10−30 esu, β0(1 e)=657×10−30 esu). Herein, we demonstrate that the optical and nonlinear optical (NLO) properties are strongly influenced by the symmetry of the complexes, the nature of the ligands (donor endgroups and π linkers), and the nature of the metallic centers. For example, the length of the π‐conjugated backbone, the Lewis acidity of the metal ion, and the increase of ligand‐to‐metal ratio result in a substantial enhancement of β. The contribution of the metal‐to‐ligand (MLCT) transition to the molecular hyperpolarizability is also discussed with respect to octahedral d6 complexes (M=Fe, Ru).