bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed Functional Expression of Neuronal Chemokine Receptors Following Focal Nerve Demyelination in the Rat: A Mechanism for the Development of Chronic Sensitization of Peripheral Nociceptors
Authors: Bhangoo Sonia , Ren Dongjun , Miller Richard J , Henry Kenneth J , Lineswala Jayana , Hamdouchi Chafiq , Li Baolin , Monahan Patrick E , Chan David M , Ripsch Matthew S , White Fletcher A
Published: December 2007

Background:

Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.

Results:

Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.

Conclusion:

These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.
Comparative genomic analysis of the odorant-binding protein family in 12 Drosophila genomes: purifying selection and birth-and-death evolution
Authors: Vieira Filipe G , Sánchez-Gracia Alejandro , Rozas Julio
Published: December 2007

Background

Chemoreception is a widespread mechanism that is involved in critical biologic processes, including individual and social behavior. The insect peripheral olfactory system comprises three major multigene families: the olfactory receptor (Or), the gustatory receptor (Gr), and the odorant-binding protein (OBP) families. Members of the latter family establish the first contact with the odorants, and thus constitute the first step in the chemosensory transduction pathway.

Results

Comparative analysis of the OBP family in 12 Drosophila genomes allowed the identification of 595 genes that encode putative functional and nonfunctional members in extant species, with 43 gene gains and 28 gene losses (15 deletions and 13 pseudogenization events). The evolution of this family shows tandem gene duplication events, progressive divergence in DNA and amino acid sequence, and prevalence of pseudogenization events in external branches of the phylogenetic tree. We observed that the OBP arrangement in clusters is maintained across the Drosophila species and that purifying selection governs the evolution of the family; nevertheless, OBP genes differ in their functional constraints levels. Finally, we detect that the OBP repertoire evolves more rapidly in the specialist lineages of the Drosophila melanogaster group (D. sechellia and D. erecta) than in their closest generalists.

Conclusion

Overall, the evolution of the OBP multigene family is consistent with the birth-and-death model. We also found that members of this family exhibit different functional constraints, which is indicative of some functional divergence, and that they might be involved in some of the specialization processes that occurred through the diversification of the Drosophila genus.
The Brain as a Target for Inflammatory Processes and Neuroprotective Strategies
Authors: SKAPER STEPHEN D.
Published: December 2007

The importance of glial cell–propagated inflammation (i.e., neuroinflammation) disorders such as Alzheimer's disease (AD) was viewed previously as a bystander effect, or epiphenomenon, with inflammation occurring when damaged neurons elicit an activation response by glia. However, an accumulating body of evidence has challenged this earlier perspective and indicates a more active role of neuroinflammation in the pathophysiology of progressive neurodegenerative disorders such as AD, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This insight into pathophysiology evolved in concert with the appreciation that the brain is not as immunologically privileged as once thought. The central nervous system (CNS) has its own resident immune system, in which glial cells (microglia, astrocytes, and oligodendrocytes) not only serve supportive and nutritive roles for neurons but also engage from time to time in several “inflammatory” processes that defend the CNS from pathogens and help it to recover from stress and injury. These otherwise “normal” glial functions can sometimes result in a more severe and chronic neuroinflammatory cycle that actually promotes or propagates neurodegenerative disease. Excessive glial cell activation may thus constitute a viable target for the discovery of and development of neurodegenerative disease therapeutics. Suggestive clinical evidence in support of neuroinflammation as a drug discovery target for chronic neurodegenerative diseases, such as AD, comes from epidemiological and genetic linkage data. For example, long‐term use of nonsteroidal anti‐inflammatory drugs is correlated with a protective effect against AD, and certain polymorphisms in the genes for interleukin 1 and other proinflammatory mediator genes are associated with increased risk. In AD and Parkinson's disease, activated microglia and complement proteins have been identified in the brain regions most affected in these disorders. This report will briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, as well as their neuroprotective potential.
Inhibition of T‐type Calcium Current in the Reticular Thalamic Nucleus by a Novel Neuroactive Steroid
Authors: JOKSOVIC PAVLE M. , COVEY DOUGLAS F. , TODOROVIC SLOBODAN M.
Published: December 2007

Neurons of the nucleus reticularis of the thalamus (nRT) serve as an important inhibitory gate that controls trafficking of thalamocortical sensory signals and states of sleep, arousal, and epilepsy. T‐type calcium channels in nRT play a crucial role in the subthreshold excitability of these neurons, but their modulation by neuroactive steroids has not been previously studied. Here we explored the effect of (3β,5β,17β)‐3‐hydroxyandrostane‐17‐carbonitrile (3β‐OH), a novel neuroactive steroid on T‐type currents recorded from nRT neurons in intact brain slices of young rats. We found in voltage‐clamp experiments that 3β‐OH potently and reversibly decreased T‐type Ca2+ current amplitude and stabilized inactive states of the channels. In current‐clamp experiments, 3β‐OH significantly decreased the frequency of action potential firing from negative membrane potentials and minimally changed passive membrane properties. Our results indicate that 5β‐reduced neuroactive steroids, through the mechanisms of inhibition of T‐type Ca2+ currents and diminished spike firing in nRT neurons, may be important agents in control of sensory information processing in physiological conditions and possibly pathological brain states associated with increased cellular excitability such as epilepsy and/or tissue ischemia/hypoxia.
Brain‐Derived Neurotrophic Factor Prevents Human Immunodeficiency Virus Type 1 Protein gp120 Neurotoxicity in the Rat Nigrostriatal System
Authors: MOCCHETTI ITALO , NOSHENY RACHEL L. , TANDA GIANLUIGI , REN KE , MEYER EDWIN M.
Published: December 2007

Human immunodeficiency virus type 1 (HIV‐1) causes neuronal degeneration and, at a late stage, creates HIV‐associated dementia (HAD) and other neurological abnormalities. Therefore, the need for neuroprotective agents is great. However, therapeutic agents that reduce HIV neurotoxicity are difficult to characterize and develop because rodents are not infected by HIV. This study was undertaken to develop an animal model of HIV neurotoxicity by using the HIV‐1 envelope glycoprotein 120 (gp120). Vehicle or gp120 was injected acutely in the striatum of adult rats. gp120 produced loss of nigrostriatal neurons, as shown both by histochemical analysis of brain sections for apoptosis and biochemical determination of dopamine. The neurotrophin brain‐derived neurotrophic factor (BDNF) delivered by a recombinant adeno‐associated viral vector prevented gp120 toxicity. This study's results support the notion that gp120 produces a widespread neurotoxicity similar to that observed in HIV‐positive individuals and that BDNF may be a suitable neuroprotective agent for HAD.
Neuroprotection at the Nanolevel—Part I
Authors: ANDREWS RUSSELL J.
Published: December 2007

Nanoneurosurgery demands a departure from the traditional “excise what you can see and touch” role of neurosurgeons. Moreover, there is a conceptual leap necessary for neuroscientists as well as neurosurgeons in developing and applying nanotechniques to neurosurgery at the nanolevel. After introducing the realm of nanotechnology and some unique properties of nanomaterials, I review several of the nanotechniques in development that are most likely to affect neuroprotection at the nanolevel. These techniques include quantum dot “nanobarcode” labeling of cellular and subcellular entities, as well as nanotechniques for following enzymatic reactions in real time. Nanoscaffolds offer mechanical enhancement of neurorepair; carbon nanotube electrode arrays can provide nanolevel electrical and chemical enhancement. Even traditional “cut and sew” surgery is being taken down to the micron, if not nano, level for single axon repair, and the technology can use capillaries to deliver therapeutics to virtually any portion of the nervous system with greater than pinpoint accuracy. In this report, I use these nanotechniques to introduce the multiplex nanodevices under development.
Neuroprotection at the Nanolevel—Part II
Authors: ANDREWS RUSSELL J.
Published: December 2007

Nanotechniques presented in this article's companion report are being multiplexed into nanodevices that promise to greatly advance our understanding and treatment of many nervous system disorders. Current neuromodulation techniques for deep brain stimulation have major drawbacks, such as large size (in comparison with ideal of small neuron group stimulation), lack of feedback monitoring of brain electrical activity, and high electrical current needs. Carbon nanotube nanoelectrode arrays address these drawbacks and offer the possibility of monitoring neurotransmitter levels at the synapse/neuronal level in real time. Such arrays can monitor and modulate electrochemical events occurring among neural networks, which should add greatly to our understanding of neuronal communication. A multiplex nanodevice for studying (and enhancing) axonal regeneration after spinal cord injury is also being developed. The nanotechniques described in the companion piece are combined in a micron‐sized neural growth tube lined with nanodevices through which the regenerating axon extends—allowing continuous monitoring and modulation of the axon's electrochemical environment plus directional guidance with a biodegradable nanoscaffold. Multifunction nanodevices provide opportunities for neuronal (and subneuronal) monitoring and modulation that will enhance neuroprotection and neurorepair far beyond the micro‐ and macrolevel techniques used heretofore.
Drug Delivery to the Spinal Cord Tagged with Nanowire Enhances Neuroprotective Efficacy and Functional Recovery following Trauma to the Rat Spinal Cord
Authors: SHARMA HARI SHANKER , ALI SYED F. , DONG W. , TIAN Z. RYAN , PATNAIK R. , PATNAIK S. , SHARMA ARUNA , BOMAN ARNE , LEK PER , SEIFERT ELISABETH , LUNDSTEDT TORBJÖRN
Published: December 2007

The possibility that drugs attached to innocuous nanowires enhance their delivery within the central nervous system (CNS) and thereby increase their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three compounds—AP173 (SCI‐1), AP713 (SCI‐2), and AP364 (SCI‐5) (Acure Pharma, Uppsala, Sweden)—were tagged with TiO2‐based nanowires using standard procedure. Normal compounds were used for comparison. SCI was produced by making a longitudinal incision into the right dorsal horn of the T10–T11 segments under Equithesin anesthesia. The compounds, either alone or tagged with nanowires, were applied topically within 5 to 10 min after SCI. In these rats, behavioral outcome, blood–spinal cord barrier (BSCB) permeability, edema formation, and cell injury were examined at 5 h after injury. Topical application of normal compounds in high quantity (10 μg in 20 μL) attenuated behavioral dysfunction (3 h after trauma), edema formation, and cell injury, as well as reducing BSCB permeability to Evans blue albumin and 131I. These beneficial effects are most pronounced with AP713 (SCI‐2) treatment. Interestingly, when these compounds were administered in identical conditions after tagging with nanowires, their beneficial effects on functional recovery and spinal cord pathology were further enhanced. However, topical administration of nanowires alone did not influence trauma‐induced spinal cord pathology or motor functions. Taken together, our results, probably for the first time, indicate that drug delivery and therapeutic efficacy are enhanced when the compounds are administered with nanowires.
Neuro‐ and Cardioprotective Effects of Blockade of Nitric Oxide Action by Administration of Methylene Blue
Authors: WIKLUND LARS , BASU SAMAR , MICLESCU ADRIANA , WIKLUND PER , RONQUIST GUNNAR , SHARMA HARI SHANKER
Published: December 2007

Methylene blue (MB), generic name methylthioninium (C16H18ClN3 S · 3H2O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well‐known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia–reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S‐100β, as well as troponin I and creatine kinase isoenzyme MB, respectively.
Valproate and Acetyl‐l‐carnitine Prevent Methamphetamine‐Induced Behavioral Sensitization in Mice
Authors: COCCURELLO ROBERTO , CAPRIOLI ANTONIO , GHIRARDI ORLANDO , VIRMANI ASHRAF
Published: December 2007

This study deals with the possible inhibitory role played by acetyl‐l‐carnitine (ALC) against methamphetamine (METH)‐induced behavioral sensitization. Because valproate (VAL) inhibits the behavioral sensitization exerted by different psychostimulants, we investigated ALC's potential to prevent the amplification of METH‐mediated psychomotor effects. We therefore evaluated the locomotor effects of VAL or ALC alone or in combination with METH after acute (day 1) as well as repeated (day 7) drug challenge. Finally, to assess the induction of behavioral sensitization, we also recorded the METH‐mediated locomotor response after 7 days of drug suspension (day 15). Results showed that both VAL and ALC prevented the METH‐induced sensitization. Another interesting observation was the significantly higher METH‐induced hyperactivity at day 15 (after a 7‐day drug‐free period), indicating that behavioral sensitization developed during the washout period. Results also showed that both the acute and repeated coadministration of METH with either VAL or ALC inhibited METH‐induced hyperactivity. We present different hypotheses concerning similar but also peculiar mechanisms that might underlie the preventive action of VAL and ALC. These data add to a growing body of literature that illustrates the potential of ALC in protecting against the insult of dysfunctional mitochondrial metabolism and psychostimulant‐mediated neurotoxicity. By demonstrating anin vivoaction against one of the most abused drugs, these results raise the possibility of beneficial effects of ALC in abuse behavior.
N‐Acetylcysteine Attenuates Arsenite‐Induced Oxidative Injury in Dorsal Root Ganglion Explants
Authors: CHAO P.L. , FAN S.F. , CHOU Y.H. , LIN ANYA M.Y.
Published: December 2007

Chronic exposure to arsenic causes health problems, including peripheral neuropathy. Oxidative stress is one of the mechanisms underlying arsenic‐induced neurotoxicity. For this report, we studied the protective effect of N‐acetylcysteine (NAC) on arsenic‐induced oxidative injury in dorsal root ganglion (DRG) explants. After 24‐h incubation, NAC concentration‐dependently attenuated arsenite‐induced depletion in glutathione (GSH) content and increases in the ratio of oxidized GSH/reduced GSH (GSSG/GSH ratio) in DRG explants. Furthermore, NAC inhibited arsenite‐induced elevation in the expression of stress proteins, such as heat shock protein 70 and heme oxygenase 1, as well as arsenite‐induced phosphorylation of p38 mitogen‐activated protein kinase. Incubation with NAC ameliorated arsenite‐induced apoptosis by abolishing both mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, NAC attenuated arsenite‐induced elevation in Bcl‐2 level and cytosolic cytochrome c, as well as arsenite‐induced reduction in procaspase‐3 levels. In the ER pathway, NAC suppressed arsenite‐induced increases in activating transcription factor 6 and C/EBP homologous protein in the nuclear fraction. Furthermore, arsenite‐induced reductions in procaspase‐12 and elevation in BIP and caspase‐12, an ER‐specific enzyme, were prevented after NAC incubation. Taken together, our results demonstrate that NAC is neuroprotective against arsenite‐induced oxidative injury in DRG explants. Furthermore, NAC inhibits arsenite‐induced toxicity by inhibiting ER and mitochondrion activation. Our data indicate that NAC is potentially therapeutic for arsenite‐induced peripheral neuropathy.
Three Novel Missense Mutations within the LHX4 Gene Are Associated with Variable Pituitary Hormone Deficiencies
Authors: Pfaeffle Roland W. , Hunter Chad S. , Savage Jesse J. , Duran-Prado Mario , Mullen Rachel D. , Neeb Zachary P. , Eiholzer Urs , Hesse Volker , Haddad Nadine G. , Stobbe Heike M. , Blum Werner F. , Weigel Johannes F. W. , Rhodes Simon J.
Published: December 2007

Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency.

Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations.

Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments.

Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study.

Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive.

Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.
Granulosa Cell Survival and Proliferation Are Altered in Polycystic Ovary Syndrome
Authors: Das M. , Djahanbakhch O. , Hacihanefioglu B. , Saridogan E. , Ikram M. , Ghali L. , Raveendran M. , Storey A.
Published: December 2007

Context: Polycystic ovary syndrome (PCOS) represents the most common endocrine abnormality in women of reproductive age. The cause of PCOS remains largely unknown, but studies suggest an intrinsic ovarian abnormality.

Objective: The objective of the study was to test our hypothesis that differences in granulosa cell proliferation and apoptosis may underlie abnormalities that affect follicular development.

Design: Granulosa cells were prepared from follicular fluid aspirated from 4- to 8-mm follicles of unstimulated ovaries during routine laparoscopy or laparotomy from women with anovulatory PCOS and those with regular ovulatory cycles.

Setting: The study was conducted at a university hospital.

Patients: Fourteen women with anovulatory PCOS and nine women with regular ovulatory cycles participated in the study.

Main Outcome Measures: Immunocytochemistry on granulosa cells to investigate apoptotic and proliferation rates, together with real-time RT-PCR to analyze gene expression profiles of apoptotic regulators, was measured.

Results: Significantly lower apoptotic rates were found in granulosa cells from patients with PCOS, compared with women with regular ovulatory cycles (P = 0.004). Lower apoptotic rates were associated with decreased levels of the apoptotic effector caspase-3 (P = 0.001) and increased levels of the anti-apoptotic survival factor cellular inhibitor of apoptosis proteins-2 in the PCOS group that were coupled to higher proliferation rates (P = 0.032). Gene expression profiling confirmed the immunocytochemical findings.

Conclusions: Our findings indicate that there are significant differences in the rate of cell death and proliferation in granulosa cell populations in PCOS patients. These are associated with decreased expression of apoptotic effectors and increased expression of a cell survival factor. These results provide new insights that may be useful in developing specific therapeutic intervention strategies in PCOS.
Antithyroperoxidase Antibody-Dependent Cytotoxicity in Autoimmune Thyroid Disease
Authors: Rebuffat Sandra A. , Nguyen Brigitte , Robert Bruno , Castex Françoise , Peraldi-Roux Sylvie
Published: December 2007

Context: Thyroid antibody-dependent cytotoxicity has been reported in autoimmune thyroid disease (AITD). Indeed, the role of thyroperoxidase (TPO) autoantibodies (aAbs) in complement-mediated damage by binding to TPO expressed on the surface of human thyroid cells was demonstrated, whereas their activity in antibody-dependent cell cytotoxicity (ADCC) is not well established.

Objective: The aim of this study was to define the partners involved in antibody and complement-dependent cytotoxicity (CDC) in AITD and characterize which effector cells are involved in cytotoxicity mediated by anti-TPO aAbs using a chromium release assay.

Results: The relative capability of anti-TPO aAbs to mediate ADCC using human thyroid cells in culture varies from 11 to 74.5%, depending on the effectors cells used. The human monocyte cell line HL60 gives a better lysis than the THP-1 cell line as effector cells. It seems obvious that the mechanism of ADCC is mediated quite exclusively by FcγRI. Indeed, the two effector cell lines differ by the level of the FcγRI expression (91.83% for HL-60 cells and 22.55%t for the THP-1). In addition to ADCC, the anti-TPO aAbs mediate the destruction of thyrocytes by CDC (56%).

Conclusions: These results demonstrate that anti-TPO aAbs can damage cultured thyroid cells by ADCC and CDC mechanisms. The monocytes, via their FcγRI, are important effector cells in ADCC mediated by anti-TPO aAbs and may contribute with T cells to the destruction of thyroid gland in AITD.
Generics: Cognition and Acquisition
Authors: Leslie Sarah-Jane
Published: December 2007

`Ducks lay eggs' is a true sentence, and `ducks are female' is a false one. Similarly, `mosquitoes carry the West Nile virus' is obviously true, whereas `mosquitoes don't carry the West Nile virus' is patently false. This is so despite the egg-laying ducks' being a subset of the female ones and despite the number of mosquitoes that don't carry the virus being ninety-nine times the number that do. Puzzling facts such as these have made generic sentences defy adequate semantic treatment. However complex the truth conditions of generics appear to be, though, young children grasp generics more quickly and readily than seemingly simpler quantifiers such as `all' and `some'.

I present an account of generics that not only illuminates the strange truth conditions of generics, but also explains how young children find them so comparatively easy to acquire. I then argue that generics give voice to our most cognitively primitive generalizations and that this hypothesis accounts for a variety of facts ranging from acquisition patterns to cross-linguistic data concerning the phonological articulation of operators. I go on to develop an account of the nature of these cognitively fundamental generalizations and argue that this account explains the strange truth-conditional behavior of generics.
The role of cGMP and the rear of the cell in Dictyostelium chemotaxis and cell streaming
Authors: Veltman Douwe M. , van Haastert Peter J. M.
Published: December 2007

During chemotaxis, pseudopod extensions lead the cell towards the source of attractant. The role of actin-filled pseudopodia at the front of the cell is well recognized, whereas the function of the rear of the cell in chemotaxis and cell-cell interactions is less well known. Dictyostelium cell aggregation is mediated by outwardly propagating waves of extracellular cAMP that induce chemotaxis and cell-cell contacts, resulting in streams of cells moving towards the aggregation centre. Wild-type cells efficiently retract pseudopodia in the rear of the cell during the rising flank of the cAMP wave and have a quiescent cell posterior. This polarization largely remains during the declining flank, which causes cells to continue their chemotactic movement towards the aggregation centre and to form stable streams of moving cells. The dominance of the leading-edge pseudopod rescues chemotaxis during the rising flank of the wave, but the cells move in random directions after the peak of the wave has passed. As a consequence, cell-cell contacts cannot be maintained, and the cell streams break up. The results show that a quiescent rear of the cell increases the efficiency of directional movement and is essential to maintain stable cell-cell contacts.
miR-122 targeting with LNA/2′-O-methyl oligonucleotide mixmers, peptide nucleic acids (PNA), and PNA–peptide conjugates
Authors: Fabani Martin M. , Gait Michael J.
Published: December 2007

MicroRNAs are small noncoding RNAs that regulate many cellular processes in a post-transcriptional mode. MicroRNA knockdown by antisense oligonucleotides is a useful strategy to explore microRNA functionality and as potential therapeutics. MicroRNA-122 (miR-122) is a liver-specific microRNA, the main function of which has been linked with lipid metabolism and liver homeostasis. Here, we show that lipofection of an antisense oligonucleotide based on a Locked Nucleic Acids (LNA)/2′-O-methyl mixmer or electroporation of a Peptide Nucleic Acid (PNA) oligomer is effective at blocking miR-122 activity in human and rat liver cells. These oligonucleotide analogs, evaluated for the first time in microRNA inhibition, are more effective than standard 2′-O-methyl oligonucleotides in binding and inhibiting microRNA action. We also show that microRNA inhibition can be achieved without the need for transfection or electroporation of the human or rat cell lines, by conjugation of an antisense PNA to the cell-penetrating peptide R6-Penetratin, or merely by linkage to just four Lys residues, highlighting the potential of PNA for future therapeutic applications as well as for studying microRNA function.
Speeding Up Dynamic Shortest-Path Algorithms
Authors: Buriol Luciana S. , Resende Mauricio G. C. , Thorup Mikkel
Published: December 2007

Dynamic shortest-path algorithms update the shortest paths taking into account a change in an arc weight. This paper describes a new generic technique that allows the reduction of heap sizes used by several dynamic single-destination shortest-path algorithms. For unit weight changes, the updates can be done without heaps. These reductions almost always reduce the computational times for these algorithms. In computational testing, several dynamic shortest-path algorithms with and without the heap-reduction technique are compared. Speedups of up to a factor of 1.8 were observed using the heap-reduction technique on random weight changes and of over a factor of five on unit weight changes. We compare as well with Dijkstra's algorithm, which recomputes the paths from scratch. With respect to Dijkstra's algorithm, speedups of up to five orders of magnitude are observed.
Matchings in Node-Weighted Convex Bipartite Graphs
Authors: Katriel Irit
Published: December 2007

Matchings in convex bipartite graphs correspond to the problem of scheduling unit-length tasks on a single disjunctive resource, given a release time and a deadline for every task. The unweighted case was studied by several authors since Glover first considered the problem in 1967 [Glover, F. 1967. Maximum matching in convex bipartite graphs. Naval Res. Logist. Quart. 14 313–316] and until 1996, when Steiner and Yeomans found an algorithm whose running time is linear in the number of tasks [Steiner, G., J. S. Yeomans. 1996. A linear time algorithm for determining maximum matchings in convex, bipartite graphs. Comput. Math. Appl. 31(12) 91–96]. We address a weighted variant of this problem. Given a node-weighted convex bipartite graph G=(X, Y, E) (where Y is linearly ordered and the neighborhood of each node of X is an interval of Y), we show that it is possible to find an X-perfect matching of maximum (or minimum) weight in O(|E| + |Y| log |X|) time and O(|X| + |Y|) space. For the case in which only the nodes of Y are weighted and their weights are positive, the algorithm can be used to find a maximum-weight (not necessarily X-perfect) matching.
Investigating the Risk–Return Relationship of Information Technology Investment: Firm-Level Empirical Analysis
Authors: Dewan Sanjeev , Shi Charles , Gurbaxani Vijay
Published: December 2007

This paper develops empirical proxy measures of information technology (IT) risk and incorporates them into the usual empirical models for analyzing IT returns: production function and market value specifications. The results suggest that IT capital investments make a substantially larger contribution to overall firm risk than non-IT capital investments. Further, firms with higher IT risk have a higher marginal product of IT relative to firms with low IT risk. In the market value specification, the impact of IT risk is positive and significant, and inclusion of the IT risk term substantially reduces the coefficient on IT capital. We estimate that about 30% of the gross return on IT investment corresponds to the risk premium associated with IT risk. Taken together, our results show that IT risk provides part of the explanation for the unusually high valuations of IT capital investment in recent research.
Customer Lifetime Value Measurement
Authors: Borle Sharad , Singh Siddharth S. , Jain Dipak C.
Published: December 2007

The measurement of customer lifetime value is important because it is used as a metric in evaluating decisions in the context of customer relationship management. For a firm, it is important to form some expectations as to the lifetime value of each customer at the time a customer starts doing business with the firm, and at each purchase by the customer. In this paper, we use a hierarchical Bayes approach to estimate the lifetime value of each customer at each purchase occasion by jointly modeling the purchase timing, purchase amount, and risk of defection from the firm for each customer. The data come from a membership-based direct marketing company where the times of each customer joining the membership and terminating it are known once these events happen. In addition, there is an uncertain relationship between customer lifetime and purchase behavior. Therefore, longer customer lifetime does not necessarily imply higher customer lifetime value.

We compare the performance of our model with other models on a separate validation data set. The models compared are the extended NBD–Pareto model, the recency, frequency, and monetary value model, two models nested in our proposed model, and a heuristic model that takes the average customer lifetime, the average interpurchase time, and the average dollar purchase amount observed in our estimation sample and uses them to predict the present value of future customer revenues at each purchase occasion in our hold-out sample. The results show that our model performs better than all the other models compared both at predicting customer lifetime value and in targeting valuable customers. The results also show that longer interpurchase times are associated with larger purchase amounts and a greater risk of leaving the firm. Both male and female customers seem to have similar interpurchase time intervals and risk of leaving; however, female customers spend less compared with male customers.
Demand Allocation in Systems with Multiple Inventory Locations and Multiple Demand Sources
Authors: Benjaafar Saif , Li Yanzhi , Xu Dongsheng , Elhedhli Samir
Published: December 2007

We consider the problem of allocating demand that originates from multiple sources among multiple inventory locations. Demand from each source arrives dynamically according to an independent Poisson process. The cost of fulfilling each order depends on both the source of the order and its fulfillment location. Inventory at all locations is replenished from a shared production facility with a finite production capacity and stochastic production times. Consequently, supply lead times are load dependent and affected by congestion at the production facility. Our objective is to determine an optimal demand allocation and optimal inventory levels at each location so that the sum of transportation, inventory, and backorder costs is minimized. We formulate the problem as a nonlinear optimization problem and characterize the structure of the optimal allocation policy. We show that the optimal demand allocations are always discrete, with demand from each source always fulfilled entirely from a single inventory location. We use this discreteness property to reformulate the problems as a mixed-integer linear program and provide an exact solution procedure. We show that this discreteness property extends to systems with other forms of supply processes. However, we also show that supply systems exist for which the property does not hold. Using numerical results, we examine the impact of different parameters and provide some managerial insights.
Designing Optimal Preannounced Markdowns in the Presence of Rational Customers with Multiunit Demands
Authors: Elmaghraby Wedad , Gülcü Altan , Keskinocak Pınar
Published: December 2007

We analyze the optimal design of a markdown pricing mechanism with preannounced prices. In the presence of limited supply, buyers who choose to purchase at a lower price may face a scarcity in supply. Our focus is on the structure of the optimal markdown mechanisms in the presence of rational or strategic buyers who demand multiple units. We first examine a complete information setting where the set of customer valuations is known but the seller does not know the valuation of each individual customer (i.e., cannot exercise perfect price discrimination). We then generalize our analysis to an incomplete valuation information setting where customer valuations are drawn from known distributions. For both settings, we compare the seller's profit resulting from the optimal markdown mechanism and the optimal single price. We provide a number of managerial insights into designing profitable markdown mechanisms.
Improved Bounds for the Symmetric Rendezvous Value on the Line
Authors: Han Qiaoming , Du Donglei , Vera Juan , Zuluaga Luis F.
Published: December 2007

A notorious open problem in the field of rendezvous search is to decide the rendezvous value of the symmetric rendezvous search problem on the line, when the initial distance between the two players is two. We show that the symmetric rendezvous value is within the interval (4.1520, 4.2574), which considerably improves the previous best-known result (3.9546, 4.3931). To achieve the improved bounds, we call upon results from absorbing Markov chain theory and mathematical programming theory—particularly fractional quadratic programming and semidefinite programming. Moreover, we also establish some important properties of this problem, which could be of independent interest and useful for resolving this problem completely. Finally, we conjecture that the symmetric rendezvous value is asymptotically equal to 4.25 based on our numerical calculations.
Xeroradiographic detection of foreign bodies
Authors: Thompson David H. , Stasney C. Richard , Miller Tom
Published: December 2007

A study was designed to assess the efficacy of xeroradiography for the identification of tracheal and esophageal foreign bodies. AP, lateral, and oblique conventional X‐rays and xeroradiograms were taken of non‐radio‐paque objects placed in the trachea and esophagus of a canine subject.

Randomly numbered foreign body projections shown by conventional and xeroradiography were presented to radiologists with a list of the foreign bodies employed in the study. Series of films were also presented to radiologists and otolaryngologists who had no prior knowledge of types of foreign bodies used.

There was no significant advantage of xeroradiography over conventional radiography in identification of the foreign bodies. Lateral and oblique projections were shown to be far superior to the AP projection for demonstration of foreign bodies.

Based on these data we do not feel that the increase in radiation exposure necessitated by xeroradiography justifies its routine use. It is recommended only as an adjunctive diagnostic tool in specific circumstances.
Xeroradiography and otolaryngology
Authors: Henderson John A. , Colburn James E. , Morioka Wilford T.
Published: December 2007

As a diagnostic tool, a new horizon in otolaryngology has become apparent in the past several years. It is known as xeroradiography and is a convenient technique requiring minimal patient cooperation and enjoying excellent acceptability for both patients and physicians. Speed, efficiency and consistently high image quality make xeroradiography suitable for otolaryngologic applications in the office, as well as in operating and emergency rooms. All tissue densities are represented in a single image, eliminating the need for taking two films of different densities, while radiation exposure is the same. Now popular for use in mammography, the technique is especially useful for detailed studies of the areas of interest to otolaryngologists. Certain inherent disadvantages in the technique are mentioned and guidelines are given to make these disadvantages an acceptable trade‐off in actual application.
Anesthesia of the human tympanic membrane by iontophoresis of a local anesthetic
Authors: Comeau Maurice , Brummett Robert
Published: December 2007

Iontophoresis has been reported as a safe method of tympanic membrane anesthesia but data concerning variations and advances in technique are not available. Normal volunteers were used to determine the effects of varying canal preparation, epinephrine concentration, current level and duration. The two optimal techniques were compared in two groups of ten volunteers. A similar duration of anestheia (90 to 115 min.) was found for both techniques.

Clinical application of two techniques for the purpose of myringotomy and/or ventilation tube placement was done in 60 ears of 49 selected private patients with middle ear effusions. Techniques were used at random in the first 23 ears with equal success. The newly developed dry canal preparation method using lower current and longer time was preferred, because of convenience and added safety, in the last 37 procedures. Failure of anesthesia occurred once with acute otitis media and once due to electrode displacement. Fifty‐eight procedures resulted in successful myringotomy and/or tube placement.

Proper case selection, prevention of technical problems, advantages, and practical limitations of this anesthesia method are discussed.
Melanotic neuroectodermal tumor of infancy
Authors: Zajtchuk Joan T. , Lunsford Thomas M. , Alford Thomas J.
Published: December 2007

The lack of knowledge regarding the histogenesis of the melanotic neuroectodermal tumor of infancy may account for the numerous names given to this neoplasm. The most appropriate nomenclature is melanotic neuroectodermal tumor of infancy as this term is both clinically descriptive and reflects its most likely histogenesis. The histological diagnosis of this neoplasm and its known benign biological behavior should be appreciated so that radical surgery or radiotherapy is not undertaken. Our case report includes an electron microscopic analysis which is in keeping with other reported cases. We have not confirmed high urinary VMA levels prior to resection of the lesion.
The use of upper eyelid skin grafts in the head and neck
Authors: Goode Richard L.
Published: December 2007

Full thickness upper eyelid skin obtained by an upper blepharoplasty may be the graft of choice for correcting a variety of head and neck defects. It is particularly useful in the lower eyelids, nasal vestibule, external ear canal, concha and anterior oral cavity because of its thinness, high take rate, minimal shrinkage and good color match.
Beliefs About Medicines and Adherence Among Swedish Migraineurs
Authors: Hedenrud Tove , Jonsson Pernilla , Linde Mattias
Published: December 2007

Background:

The problem of low adherence to drug therapy is as prevalent in migraine as in any other disorder, with important consequences for the patient, such as impaired quality of life and absence from work. Beliefs about medicines have been identified as one of the most significant factors for adherence.

Objective:

To analyze whether beliefs about medicines and medication-related factors are associated with adherence to prophylactic drug therapy among migraineurs at a Swedish tertiary care clinic.

Methods:

A questionnaire was distributed to migraineurs visiting a tertiary care clinic in Sweden. All participants had recently been prescribed prophylactic medicine. The questionnaire was comprised of background questions, questions about disease characteristics, perceived effects, and adverse effects of migraine medications used, the Beliefs about Medicines questionnaire, and the Medication Adherence Report Scale. Medication-related variables, collected from patients’ records with consent, were also included. Logistic regression analysis was performed to analyze the association between beliefs about medicines, medication-related variables, and adherence to prophylactic drugs.

Results:

Of the 174 participants in the study, 64% were considered to be adherent to their prescribed prophylactic medicine. Users of β-blockers were significantly more adherent compared with patients using other drugs (eg, tricyclic antidepressants [TCAs) or antiepileptics); the reverse was true for patients taking TCAs. Respondents with the lowest level of education (≤9 y) expressed less concern about drugs and had a higher necessity-concerns differential compared with respondents with a higher educational level. In the final regression model, no variable was significantly associated with adherence.

Conclusions:

About one-third of the migraineurs did not adhere to their prophylactic drugs. Beliefs about medicines and medication-related factors could not predict nonadherence. We recommend further research on medication-related variables in relation to adherence among migraineurs.
Medea: A Hint of Divinity?
Authors: Konstan David
Published: December 2007

In this article I argue that massive soundplay involving the name Medea in the opening verses of Euripides' tragedy may signal a special status for the heroine, perhaps even divinity (I compare the threefold invocation of a deity). In this way, the beginning of the play seems to anticipate Medea's divine or quasi-divine stature in the finale.
The Last Twenty-Five Years of CAAS
Authors: Heverly W. Gerald
Published: December 2007

The Classical Association of the Atlantic States (CAAS) has changed much since its diamond jubilee in 1981. While the number of individual members from the CAAS region has declined substantially, the association has grown considerably wealthier. In addition, it has undertaken a number of initiatives that fulfill its core mission to foster teaching and research in classics. The organizational structure of CAAS has also changed, with the creation of several new, specialized offices and the outsourcing of some administrative functions. Finally, meetings have decreased in frequency but have become longer, more varied, and more attractive to pre-college teachers.
Drugs and the Delphic Oracle
Authors: Lehoux Daryn
Published: December 2007

This paper critically examines several recent studies purporting to show that the priestesses of the oracle of Apollo at Delphi were intoxicated on gaseous fumes emitted as a result of geological processes. The two gaseous candidates offered, ethylene and benzene, are considered. Ethylene is shown to be impossible and benzene to be crucially underdetermined. Finally, the historical evidence on which any gaseous vent hypothesis must rest is reexamined.
Elegy on the Threshold: Generic Self-Consciousness in Propertius 1.16
Authors: Nappa Christopher
Published: December 2007

By including a paraclausithyron intended to mock the topos of the paraclausithyron, Propertius has made poem 1.16 a criticism of elegiac protocols and values. Yet the speaker of this poem, the door of the mistress' house, has its own problems, and the frame of the paraclausithyron not only introduces one putative view of erotic elegy and its value system but also destabilizes the moralizing position imputed to the door. Poem 1.16 undercuts the door's apparent assault on the poet-lover and suggests that readers are complicit in the very behavior which they are invited to turn up their noses at.