bluuebunny/crossref_metadata_2025 huggingface dataset:
FIRE, SACRIFICE,
IPHIGÉNIE
Authors: Wygant Amy
Published: August 2006

Gluck's
Iphigénie en Aulide
(1774), his first opera written for the French stage, never settled on an ending. In order to analyse the historical conditions of this musical reluctance, this argument reads the opera's literary source, Jean Racine's
Iphigénie
, developing a three-fold link: to the fireworks that followed the first performance of Racine's tragedy in 1674 in the garden of Versailles, to the discovery in 1774 by Joseph Priestley of oxygen and related developments in the poetics of fire, and to changes in the political culture of sacrifice and so necessarily in the ends of tragedy. Racine's cosmic storm around a sacrificial pyre that auto-ignites, the self-immolation of the monarch created by the garden festival, and this opera which now ends with a chorus of soldier-workers crowned as kings all point to music's fabled ability to predict and determine the political, a danger recognized by governments from the Greek city-state to the present. In the course of a revolution that had been precisely figured in Gluck's music, Iphigénie the victim becomes the young queen who had been Gluck's singing pupil in Vienna, Marie-Antoinette.
Cochleosaccular Dysplasia Associated With a Connexin 26 Mutation in Keratitis–Ichthyosis–Deafness Syndrome
Authors: Griffith Andrew J. , Yang Yandan , Pryor Shannon P. , Park Hong‐Joon , Jabs Ethylin Wang , Nadol Joseph B. , Russell Laura J. , Wasserman Daniel I. , Richard Gabriele , Adams Joe C. , Merchant Saumil N.
Published: August 2006

Objective: The objective of this study was to characterize the temporal bone phenotype associated with a mutation of GJB2 (encoding connexin 26).

Study Design: The authors conducted correlative clinical, molecular genetic, and postmortem histopathologic analysis.

Methods: The study subject was a male infant with keratitis–ichthyosis–deafness (KID) syndrome. We performed a nucleotide sequence analysis of GJB2 and a histopathologic analysis of the temporal bones.

Results: The subject was heterozygous for G45E, a previously reported KID syndrome mutation of GJB2. The primary inner ear abnormality was dysplasia of the cochlear and saccular neuroepithelium.

Conclusions: GJB2 mutations can cause deafness in KID syndrome, and possibly in other GJB2 mutant phenotypes, by disrupting cochlear differentiation.
STI‐571 (Gleevec) Potentiates the Effect of Cisplatin in Inhibiting the Proliferation of Head and Neck Squamous Cell Carcinoma In Vitro
Authors: Wang‐Rodriguez Jessica , Lopez Jay Patrick , Altuna Xabier , Chu Theresa S. , Weisman Robert A. , Ongkeko Weg M.
Published: August 2006

Objective: The objective of this study was to determine whether STI‐571 (Gleevec; imatinib mesylate) could sensitize established head and neck squamous cell carcinoma (HNSCC) cell lines to the effects of cisplatin.

Methods: Western blot analysis and immunofluorescence were used to examine the expression of the tyrosine kinases that are known targets of Gleevec, including c‐kit, c‐Abl, and platelet‐derived growth factor receptor, on the cell lines, and immunohistochemistry was performed to determine the expression of these kinases in human HNSCC tissue. Once these targets were confirmed, clonogenic cell survival assays were performed to determine the effect STI‐571 had on growth and proliferation when used in combination with cisplatin compared with STI‐571 alone or cisplatin alone. Cells were incubated with a range of doses of STI‐571 24 hours before the addition of cisplatin. Flow cytometry analysis was performed to determine cell‐cycle distribution and to measure apoptosis caused by the various treatments. An annexin V assay was also used to further measure apoptosis.

Results: Our results indicate that STI‐571 potentiates the effect of cisplatin and leads to a significant decrease in cell proliferation and colony formation compared with cisplatin alone in a dose‐dependent fashion. Surprisingly, there was a slight decrease in the level of apoptosis when Gleevec was used in combination with cisplatin compared with cisplatin alone. Gleevec alone resulted in a slight increase in G1 phase of the cell cycle, whereas cisplatin alone resulted in a G2 arrest. The addition of Gleevec to cisplatin resulted in an enhanced S/G2 phase accumulation. Although we did not demonstrate an increase in cisplatin‐induced cell death, we postulate that the increased S/G2 arrest resulting from the DNA damage in the presence of Gleevec results in decreased proliferation of HNSCC, resulting in a net decrease in colony formation.

Conclusions: The small molecule inhibitor Gleevec, which targets specific tyrosine kinases that are expressed in HNSCC, can significantly potentiate the antiproliferative effects of cisplatin. Because Gleevec alone has minimal side effects, treatment with the combination treatment of cisplatin and Gleevec may result in increased efficacy of cisplatin in treating this cancer. Additional studies are warranted, keeping in mind that drug combinations may result in unexpected toxicities that are not frequently seen with either drug alone.
Detection of Osteoprotegerin and TNF‐alpha mRNA in Ankylotic Stapes Footplates in Connection With Measles Virus Positivity
Authors: Karosi Tamás , Jókay István , Kónya József , Szabó László Z. , Pytel József , Jóri József , Szalmás Anita , Sziklai István
Published: August 2006

Hypothesis: Otosclerosis is a bone remodeling disorder of the otic capsule causing conductive and sensorineural hearing loss. Persistent measles virus infection of the temporal bone with increased tumor necrosis factor (TNF)‐alpha and decreased osteoprotegerin mRNA expression is supposed to be the main etiologic factor in otosclerosis.

Background: Determinants of measles virus infection and reactive inflammation were studied in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse transcriptase‐polymerase chain reaction (RT‐PCR) amplification of the viral RNA. No report is available, however, about the role and interactions of bone‐specific cytokines in otosclerosis.

Methods: Nucleic acid was extracted from stapes footplates of clinically otosclerotic patients. Measles virus nucleoprotein RNA was amplified by seminested RT‐PCR. TNF‐alpha and osteoprotegerin mRNA coexpression was detected by RT‐PCR in otosclerotic bone and was correlated to measles virus positivity.

Results: Among 154 clinically stapes fixation otosclerotic patients, 99 stapedes contained measles virus RNA. TNF‐alpha mRNA was detectable in 88 virus‐positive and in 6 virus‐negative stapes footplates. Osteoprotegerin mRNA expression was significantly lower in the TNF‐alpha‐positive specimens (P < .0001) that was independent from virus positivity.

Conclusion: Detection of TNF‐alpha mRNA demonstrates activated osteoclast functions and inflammatory pathways in otosclerotic stapes footplates associated with measles virus presence. Increased expression of TNF‐alpha and its action on RANK production inhibits the protective functions of osteoprotegerin on normal bone turnover in the otic capsule.
Massive Enlargement of the Nasolacrimal Canal Causing Epiphora and Chronic Maxillary Sinusitis
Authors: Schloegel Luke , Sindwani Raj
Published: August 2006

Objectives: Enlargement of the nasolacrimal canal (NLC) is a rare anatomic variant. We present the first report of a massively dilated NLC causing epiphora and chronic sinusitis.

Methods: The authors conducted a literature review and case report.

Results: A 65‐year‐old man with refractory sinonasal symptoms and a remote history of a dacryocystorhinostomy was found to have a massively dilated, air‐filled NLC. Using a combined endoscopic transnasal and endoscope‐assisted Caldwell‐Luc approach, the posterolateral wall of the NLC was removed. The patient's symptoms were improved 10 months postoperatively.

Conclusions: Symptoms suggestive of nasolacrimal dysfunction should prompt a search for potential sinonasal pathology.
Coblation versus Unipolar Electrocautery Tonsillectomy: A Prospective, Randomized, Single‐Blind Study in Adult Patients
Authors: Noordzij J Pieter , Affleck Brian D.
Published: August 2006

Objectives: To determine if the coblation tonsillectomy (subcapsular dissection) results in less postoperative pain, equivalent intraoperative blood loss, equivalent postoperative hemorrhage rates, and faster healing compared with tonsillectomy was performed using unipolar electrocautery in adult patients.

Study Design: The authors conducted a prospective clinical trial.

Methods: Forty‐eight patients underwent tonsillectomy and were randomly assigned to have one tonsil removed with coblation and the other with unipolar electrocautery. Outcome measures included time to remove each tonsil, intraoperative blood loss, patient‐reported pain, postoperative hemorrhage, and amount of healing 2 weeks after surgery.

Results: Mean time to remove a single tonsil with coblation and electrocautery was 8.22 minutes and 6.33 minutes, respectively (P = .011). Mean intraoperative blood loss for each technique was less than 10 mL. Postoperative pain was significantly less with coblation as compared with electrocautery: 18.6% less painful during the first week of recovery. Seventy percent of blinded patients identified the coblation side as less painful during the overall 14‐day convalescent period. Postoperative hemorrhage rates (2.1% for coblation and 6.2% for electrocautery) were not significantly different. No difference in tonsillar fossa healing was observed between the two techniques 2 weeks after surgery. During nine of the 48 surgeries, wires on the tip of the coblation handpiece experienced thinning to the point of discontinuity while removing a single tonsil.

Conclusions: Coblation subcapsular tonsillectomy was less painful than electrocautery tonsillectomy in this 48‐patient group. On average, intraoperative blood loss was less than 10 mL for both techniques. Postoperative hemorrhage rates and the degree of tonsillar fossa healing were similar between the two techniques. The coblation handpiece experienced degradation of vital wires in 18% of cases necessitating the use of a second, new handpiece.
In Vivo and In Vitro Characterization of Bone Marrow‐Derived Stem Cells in the Cochlea
Authors: Matsuoka Akihiro J. , Kondo Takako , Miyamoto Richard T. , Hashino Eri
Published: August 2006

Objectives/Hypothesis: Stem cell replacement therapy has the potential to treat or cure an array of degenerative neurologic disorders, including sensorineural deafness. However, little is known about the potential for marrow‐derived stem cells (MSCs) to take on properties of spiral ganglion neurons. The main purpose of this prospective animal study was to evaluate the survival of MSCs transplanted into the gerbil cochlea.

Methods: Eight 3‐ to 4‐month‐old Mongolian gerbils were used as recipients. The animals received an intraperilymphatic transplantation of 100,000 green fluorescent protein (GFP)‐positive MSCs with scala tympani injection and modiolar injection. Seven days after transplantation, MSC survival was evaluated by microscopic examination of frozen sections cut through the cochleae of the recipient animals.

Results: MSCs isolated from the TgN (ACTbEGFP) mouse line used in this study exhibited bright green florescence after five to seven passages in vitro. Seven days after postoperatively, most transplanted MSCs were found in the scala tympani and scala vestibule and only a small number located in the scala media in animals that received both forms of injection. There were no GFP‐positive MSCs in the modiolus in animals with scala tympani injection. In contrast, the mean profile count in animals with modiolar injection was 28, which was the highest in all regions. Although MSCs have the potential to migrate, the anatomic barrier between the perilymphatic space and the modiolus might account for the absence of GFP‐positive MSCs in this region.

Conclusion: These findings may have important clinical implications as a means of delivering MSCs in the cochlea for cell replacement therapy.
Transoral Robotic Surgery (TORS) for Base of Tongue Neoplasms
Authors: O'Malley Bert W. , Weinstein Gregory S. , Snyder Wendy , Hockstein Neil G.
Published: August 2006

Objective: To develop a minimally invasive surgical technique for the treatment of base of tongue neoplasms using the optical and technical advantages of robotic surgical instrumentation.

Study Design: Ten experimental procedures including tongue base exposure and dissections were performed on three cadavers and two mongrel dogs. Transoral robotic surgery (TORS) was then performed on three human patients with tongue base cancers in a prospective human trial.

Methods: Using the da Vinci Surgical Robot (Intuitive Surgical, Inc., Sunnyvale, CA), we performed a total of 10 base of tongue resections on edentulous and dentate cadavers as well as live mongrel dogs. In the cadaver models, exposure was evaluated using three different retractors, the Dingman, Crowe Davis, and FK retractors. The three human patients underwent TORS surgery of their tongue base cancers under an institutional review board approved prospective clinical trial. The ability to identify and preserve or resect key anatomic structures such as the glossopharyngeal, hypoglossal, and lingual nerves as well as techniques for identifying the lingual artery and achieving hemostasis were developed.

Results: The da Vinci Surgical Robot provided excellent visualization and enabled removal of the posterior one third to one half of the oral tongue in cadavers, dogs, and human patients. Among the three retractors evaluated, the FK retractor offered the greatest versatility and overall exposure for robotic instrument maneuverability. Complete resection to negative surgical margins with excellent hemostasis and no complications was achieved in the live patient surgeries.

Conclusions: TORS provided excellent three‐dimensional visualization and instrument access that allowed successful surgical resections from cadaver models to human patients. TORS is a novel and minimally invasive approach to tongue neoplasms that has significant advantages over classic open surgery or endoscopic transoral laser surgery.
Advanced Stage of Head and Neck Cancer at a Tertiary‐Care County Hospital
Authors: Patel Urjeet A. , Lynn‐Macrae Alastair , Rosen Fred , Holloway Nathaniel , Kern Robert
Published: August 2006

Background: Public hospitals provide health care for uninsured and medically underserved patients in large metropolitan areas. Outcomes for head and neck cancer patients within this population are perceived as being worse than outcomes for the general population, perhaps because of advanced stage at presentation.

Objective: This study assesses the initial cancer stage in patients with head and neck carcinoma presenting to an urban tertiary‐care county hospital compared with data for the general population.

Study Design: Prospective study of 209 consecutive patients newly diagnosed with head and neck cancer by the Division of Otolaryngology/Head and Neck Surgery from October 2003 to April 2005.

Methods: Clinical and pathologic data were obtained as patients presented and underwent treatment. Demographic data were obtained retrospectively. Staging analysis was performed on 186 patients with squamous cell carcinoma. Normative data were obtained from the National Cancer Database.

Results: The mean age was 55, with a 4:1 male to female ratio. Over 95% of patients reported being unemployed. The racial composition was white 27%, African American 52%, Hispanic 11%, Asian 7%, and 3% “other.” Staging revealed that 68% of patients were stage IV, and 85% would be considered “advanced” disease (stage III/IV). This is significantly worse than what national data demonstrates, where only 39% are stage IV, and 55% have advanced stage of disease at presentation.

Conclusion: Although the perceived poor outcome of uninsured and underserved cancer patients is multifactorial, advanced stage at presentation is a critical factor. These statistics demonstrate the need for increased patient education and screening for this underserved population as an initial step to improve outcome.
Sphenopalatine Endoscopic Ganglion Block: A Revision of a Traditional Technique for Cluster Headache
Authors: Felisati Giovanni , Arnone Flavio , Lozza Paolo , Leone Massimo , Curone Marcella , Bussone Gennaro
Published: August 2006

The diagnosis of chronic cluster headache (CH), the most painful form of headache, is based on typical clinical features characterized by strictly unilateral pain with no side shift and ipsilateral oculofacial autonomic phenomena. The attacks occur several times a day for periods of 1 to 2 months in the episodic form of the disease or less frequently on a daily basis in the chronic form. The pathogenesis of CH involves the activation of parasympathetic nerve structures located within the sphenopalatine ganglion (SPG), which explains many of the associated symptoms, whereas the activation of the ipsilateral hypothalamic gray matter may explain its typical circadian and circannual periodicity. A number of surgical approaches have been tried in cases of chronic CH resistant to pharmacologic therapy, of which SPG blockade has been shown to have certain efficacy. We have adopted a new technique based on endoscopic ganglion blockade that approaches the pterigo‐palatine fossa by way of the lateral nasal wall and consists of the injection of a mixture of local anesthetics and corticosteroids, which was performed in 20 selected patients with chronic CH, according to the International Headache Society criteria (18 male, 2 female; mean age 40 yr), who were selected for SPG blockade because they were totally drug resistant. The symptoms improved significantly, but always only temporarily, in 11 cases. These results should be considered rather good because, unlike other frequently used techniques, SPG blockade is not invasive and should therefore always be attempted before submitting patients to more invasive surgical approaches.
Three‐Dimensional Fluid‐Attenuated Inversion Recovery Magnetic Resonance Imaging Findings in Patients with Sudden Sensorineural Hearing Loss
Authors: Sugiura Makoto , Naganawa Shinji , Teranishi Masaaki , Nakashima Tsutomu
Published: August 2006

Objective:To evaluate the inner ear in sudden sensorineural hearing loss (SNHL) using three‐dimensional fluid‐attenuated inversion recovery (3D‐FLAIR) magnetic resonance imaging (MRI) at 3 Tesla (T).

Background:3D‐FLAIR MRI has recently been developed to detect high concentrations of protein or hemorrhage. Application of this method to sudden SNHL has not been described.

Methods:We used 3D‐FLAIR at 3 T with and without gadolinium enhancement to evaluate eight patients with sudden SNHL.

Results:In four of eight ears with idiopathic sudden SNHL, high precontrast signals were observed within the inner ear on 3D‐FLAIR. The high‐signal areas observed on 3D‐FLAIR were not detected by T1‐ or T2‐weighted MRI in any of these patients. In one of these four ears, significant gadolinium enhancement was observed on 3D‐FLAIR.

Conclusion:Half the patients with sudden SNHL examined had high signals in the SNHL‐affected ear on 3D‐FLAIR at 3 T. High precontrast signals in the inner‐ear fluid space may reflect minor hemorrhage, or an increased concentration of protein that had passed through blood vessels with increased permeability, or had originated from disrupted cells in the inner ear. Gadolinium enhancement in one ear suggested the breakdown of the blood–labyrinth barrier. 3D‐FLAIR MRI should contribute markedly to the elucidation of pathologic conditions in the inner ears of patients with idiopathic sudden SNHL.
Marine animal behaviour: neglecting ocean currents can lead us up the wrong track
Authors: Gaspar Philippe , Georges Jean-Yves , Fossette Sabrina , Lenoble Arnaud , Ferraroli Sandra , Le Maho Yvon
Published: August 2006

Tracks of marine animals in the wild, now increasingly acquired by electronic tagging of individuals, are of prime interest not only to identify habitats and high-risk areas, but also to gain detailed information about the behaviour of these animals. Using recent satellite-derived current estimates and leatherback turtle (Dermochelys coriacea) tracking data, we demonstrate that oceanic currents, usually neglected when analysing tracking data, can substantially distort the observed trajectories. Consequently, this will affect several important results deduced from the analysis of tracking data, such as the evaluation of the orientation skills and the energy budget of animals or the identification of foraging areas. We conclude that currents should be systematically taken into account to ensure the unbiased interpretation of tracking data, which now play a major role in marine conservation biology.
The organic preservation of fossil arthropods: an experimental study
Authors: Gupta Neal S , Michels R , Briggs Derek E.G , Evershed Richard P , Pancost Richard D
Published: August 2006

Modern arthropod cuticles consist of chitin fibres in a protein matrix, but those of fossil arthropods with an organic exoskeleton, particularly older than Tertiary, contain a dominant aliphatic component. This apparent contradiction was examined by subjecting modern cockroach, scorpion and shrimp cuticle to artificial maturation (350 °C/700 bars/24 h) following various chemical treatments, and analysing the products with pyrolysis–gas chromatography/mass spectrometry (Py–GC/MS). Analysis of artificially matured untreated cuticle yielded moieties related to phenols and alkylated substituents, pyridines, pyrroles and possibly indenes (derived from chitin).
n
-Alkyl amides, C
16
and C
18
fatty acids and alkane/alk-1-ene homologues ranging from C
9
to C
19
were also generated, the last indicating the presence of an
n
-alkyl component, similar in composition to that encountered in fossil arthropods. Similar pyrolysates were obtained from matured pure C
16
and C
18
fatty acids. Py–GC/MS of cuticles matured after lipid extraction and hydrolysis did not yield any aliphatic polymer. This provides direct experimental evidence that lipids incorporated from the cuticle were the source of aliphatic polymer. This process of
in situ
polymerization appears to account for most of the fossil record of terrestrial arthropods as well as marine arthropods that lacked a biomineralized exoskeleton.
Intracellular control of developmental and regenerative axon growth
Authors: Zhou Feng-Quan , Snider William D
Published: August 2006

Axon growth is a highly regulated process that requires stimulating signals from extracellular factors. The extracellular signals are then transduced to regulate coordinately gene expression and local axon assembly. Growth factors, especially neurotrophins that act via receptor tyrosine kinases, have been heavily studied as extracellular factors that stimulate axon growth. Downstream of receptor tyrosine kinases, recent studies have suggested that phosphatidylinositol-3 kinase (PI3K) regulates local assembly of axonal cytoskeleton, especially microtubules, via glycogen synthase kinase 3β (GSK-3β) and multiple microtubule binding proteins. The role of extracellular signal regulated kinase (ERK) signalling in regulation of local axon assembly is less clear, but may involve the regulation of local protein translation. Gene expression during axon growth is regulated by transcription factors, among which cyclic AMP response element binding protein and nuclear factors of activated T-cells (NFATs) are known to be required for neurotrophin (NT)-induced axon extension. In addition to growth factors, extracellular matrix molecules and neuronal activity contribute importantly to control axon growth. Increasingly, evidence suggests that these influences act to enhance growth via coordinating with growth factor signalling. Finally, evidence is emerging that developmental versus regenerative axon growth may be mediated by distinct signalling pathways, both at the level of gene transcription and at the level of local axon assembly.
Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells
Authors: Shivraj Sohur U , Emsley Jason G , Mitchell Bartley D , Macklis Jeffrey D
Published: August 2006

Recent work in neuroscience has shown that the adult central nervous system (CNS) contains neural progenitors, precursors and stem cells that are capable of generating new neurons, astrocytes and oligodendrocytes. While challenging the previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them the future possibilities for development of novel neural repair strategies. The purpose of this review is to present the current knowledge about constitutively occurring adult mammalian neurogenesis, highlight the critical differences between ‘neurogenic’ and ‘non-neurogenic’ regions in the adult brain, and describe the cardinal features of two well-described neurogenic regions—the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampus. We also provide an overview of presently used models for studying neural precursorsin vitro, mention some precursor transplantation models and emphasize that, in this rapidly growing field of neuroscience, one must be cautious with respect to a variety of methodological considerations for studying neural precursor cells bothin vitroandin vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims towards molecular and cellular manipulation of endogenous neural precursorsin situ, without transplantation. We conclude this review with a discussion of what might be the function of newly generated neurons in the adult brain, and provide a summary of present thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease.
Sprouting, regeneration and circuit formation in the injured spinal cord: factors and activity
Authors: Maier Irin C , Schwab Martin E
Published: August 2006

Central nervous system (CNS) injuries are particularly traumatic, owing to the limited capabilities of the mammalian CNS for repair. Nevertheless, functional recovery is observed in patients and experimental animals, but the degree of recovery is variable. We review the crucial characteristics of mammalian spinal cord function, tract development, injury and the current experimental therapeutic approaches for repair. Regenerative or compensatory growth of neurites and the formation of new, functional circuits require spontaneous and experimental reactivation of developmental mechanisms, suppression of the growth-inhibitory properties of the adult CNS tissue and specific targeted activation of new connections by rehabilitative training.
Plant hormone receptors: perception is everything
Authors: Chow Brenda , McCourt Peter
Published: August 2006

Despite the bewildering ability of higher plants to change their development with respect to the environment, there appear to be only a few hormones that function to organize growth and development. With the recent identification of three plant hormone receptors, the molecular identities of all the major plant receptors are now known. Some plant hormones such as cytokinins, ethylene, and brassinosteroids (BR) use well-characterized signaling modules such as those involving receptor kinases, but in the case of the ethylene and BR receptors, there appear to be additional functions aside from the hormone they perceive. Auxin and gibberellin perception require unique mechanisms where the receptors are components involved in ubiquitination-dependent proteolysis. With plant hormone receptors in hand, comparisons can now be made between plants and other kingdoms as to how hormones control growth and development.
Neural representations of location outside the hippocampus
Authors: Knierim James J.
Published: August 2006

Place cells of the rat hippocampus are a dominant model system for understanding the role of the hippocampus in learning and memory at the level of single-unit and neural ensemble responses. A complete understanding of the information processing and computations performed by the hippocampus requires detailed knowledge about the properties of the representations that are present in hippocampal afferents and efferents in order to decipher the transformations that occur to these representations in the hippocampal circuitry. Neural recordings in behaving rats have revealed a number of brain areas that contain place-related firing properties in the parahippocampal regions and in other brain regions that are thought to interact with the hippocampus in certain behavioral tasks. Although investigators have just begun to scratch the surface in terms of understanding these properties, differences in the precise nature of the spatial firing between the hippocampus and these other regions promise to reveal important clues regarding the exact role of the hippocampus in learning and memory and the nature of its interactions with other brain systems to support adaptive behavior.
Aversive memory reactivation engages in the amygdala only some neurotransmitters involved in consolidation
Authors: Bucherelli Corrado , Baldi Elisabetta , Mariottini Chiara , Passani Maria Beatrice , Blandina Patrizio
Published: August 2006

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a “reconsolidation” process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and that the amygdala is critically involved. Cholinergic and histaminergic systems seem to modulate only consolidation, whereas cannabinoids are involved in both consolidation and reactivation. The lability of retrieved memory affords opportunities to treat disorders such as phobias, post-traumatic stress, or chronic pain, and these results help searching for appropriate therapeutic targets.
Solution structure of GOPC PDZ domain and its interaction with the C‐terminal motif of neuroligin
Authors: Li Xiang , Zhang Jiahai , Cao Zanxia , Wu Jihui , Shi Yunyu
Published: August 2006

GOPC (Golgi‐associated PDZ and coiled‐coil motif‐containing protein) represents a PDZ domain‐containing protein associated with the Golgi apparatus, which plays important roles in vesicular trafficking in secretory and endocytic pathways. GOPC interacts with many other proteins, such as the Wnt receptors Frizzled 8 and neuroligin via its PDZ domain. Neuroligin is a neural cell‐adhesion molecule of the post‐synapse, which binds to the presynapse molecule neurexin to form a heterotypic intercellular junction. Here we report the solution structure of the GOPC PDZ domain by NMR. Our results show that it is a canonical class I PDZ domain, which contains two α‐helices and six β‐strands. Using chemical shift perturbation experiments, we further studied the binding properties of the GOPC PDZ domain with the C‐terminal motif of neuroligin. The observations showed that the ensemble of the interaction belongs to fast exchange with low affinity. The 3D model of the GOPC PDZ domain/neuroligin C‐terminal peptide complex was constructed with the aid of the molecular dynamics simulation method. Our discoveries provide insight into the specific interaction of the GOPC PDZ domain with the C‐terminal peptide of Nlg and also provide a general insight about the possible binding mode of the interaction of Nlg with other PDZ domain‐containing proteins.
Peptide deformylase is a potential target for anti‐Helicobacter pylori drugs: Reverse docking, enzymatic assay, and X‐ray crystallography validation
Authors: Cai Jianhua , Han Cong , Hu Tiancen , Zhang Jian , Wu Dalei , Wang Fangdao , Liu Yunqing , Ding Jianping , Chen Kaixian , Yue Jianmin , Shen Xu , Jiang Hualiang
Published: August 2006

Colonization of human stomach by the bacterium Helicobacter pylori is a major causative factor for gastrointestinal illnesses and gastric cancer. However, the discovery of anti‐H. pylori agents is a difficult task due to lack of mature protein targets. Therefore, identifying new molecular targets for developing new drugs against H. pylori is obviously necessary. In this study, the in‐house potential drug target database (PDTD, http://www.dddc.ac.cn/tarfisdock/) was searched by the reverse docking approach using an active natural product (compound 1) discovered by anti‐H. pylori screening as a probe. Homology search revealed that, among the 15 candidates discovered by reverse docking, only diaminopimelate decarboxylase (DC) and peptide deformylase (PDF) have homologous proteins in the genome of H. pylori. Enzymatic assay demonstrated compound 1 and its derivative compound 2 are the potent inhibitors against H. pylori PDF (HpPDF) with IC50 values of 10.8 and 1.25 μM, respectively. X‐ray crystal structures of HpPDF and the complexes of HpPDF with 1 and 2 were determined for the first time, indicating that these two inhibitors bind well with HpPDF binding pocket. All these results indicate that HpPDF is a potential target for screening new anti‐H. pylori agents. In addition, compounds 1 and 2 were predicted to bind to HpPDF with relatively high selectivity, suggesting they can be used as leads for developing new anti‐H. pylori agents. The results demonstrated that our strategy, reverse docking in conjunction with bioassay and structural biology, is effective and can be used as a complementary approach of functional genomics and chemical biology in target identification.
Residue centrality, functionally important residues, and active site shape: Analysis of enzyme and non‐enzyme families
Authors: del Sol Antonio , Fujihashi Hirotomo , Amoros Dolors , Nussinov Ruth
Published: August 2006

The representation of protein structures as small‐world networks facilitates the search for topological determinants, which may relate to functionally important residues. Here, we aimed to investigate the performance of residue centrality, viewed as a family fold characteristic, in identifying functionally important residues in protein families. Our study is based on 46 families, including 29 enzyme and 17 non‐enzyme families. A total of 80% of these central positions corresponded to active site residues or residues in direct contact with these sites. For enzyme families, this percentage increased to 91%, while for non‐enzyme families the percentage decreased substantially to 48%. A total of 70% of these central positions are located in catalytic sites in the enzyme families, 64% are in hetero‐atom binding sites in those families binding hetero‐atoms, and only 16% belong to protein–protein interfaces in families with protein–protein interaction data. These differences reflect the active site shape: enzyme active sites locate in surface clefts, hetero‐atom binding residues are in deep cavities, while protein–protein interactions involve a more planar configuration. On the other hand, not all surface cavities or clefts are comprised of central residues. Thus, closeness centrality identifies functionally important residues in enzymes. While here we focus on binding sites, we expect to identify key residues for the integration and transmission of the information to the rest of the protein, reflecting the relationship between fold and function. Residue centrality is more conserved than the protein sequence, emphasizing the robustness of protein structures.
Long‐term survival in post‐transplant lymphoproliferative disorders with a dose‐adjusted ACVBP regimen
Authors: Fohrer Cécile , Caillard Sophie , Koumarianou Argyro , Ellero Bernard , Woehl‐Jaeglé Marie‐Lorraine , Meyer Carole , Epailly Eric , Chenard Marie‐Pierre , Lioure Bruno , Natarajan‐Ame Shanti , Maloisel Frédéric , Lutun Philippe , Kessler Romain , Moulin Bruno , Bergerat Jean‐Pierre , Wolf Philippe , Herbrecht Raoul
Published: August 2006

Post‐transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long‐term tolerance rate. Currently, most centres use anthracycline‐based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose‐adjusted ACVBP (doxorubicin reduced to 50 mg/m2, cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites (P = 0·007), clinical stage III/IV (P = 0·004), bulky tumour (P < 0·0001), B symptoms (P = 0·03), decreased serum albumin (P = 0·03) and poor performance status (P = 0·06). Both the international and the PTLD prognostic index were predictive for survival (P = 0·001 and P = 0·002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty‐one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose‐adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long‐term survival.
Diagnosis of iodinated contrast media hypersensitivity: results of a 6‐year period
Authors: Kvedariene V. , Martins P. , Rouanet L. , Demoly P.
Published: August 2006

Background
Iodinated contrast media (ICM) hypersensitivity reactions represent a serious problem. Very few clinical data concerning systematic skin testing to ICM are available.

Objective
To evaluate the utility of ICM skin testing in patients with ICM hypersensitivity.

Material and methods
All patients referred over a 6‐year period for ICM hypersensitivity past reactions were skin tested for (a) the implicated ICM, or (b) a set of ICM if they were positive for the implicated ICM or if its name was unknown.

Results
Forty‐four patients, with a median age of 56 years, were studied (15 males, 29 females). The ICM skin tests were positive in 10 patients (23%): one had a positive skin prick test, seven an immediate positive intradermal test (IDT) and two a delayed positive IDT. Skin tests were more often positive in patients with immediate (9/32) as compared with those with non‐immediate reactions (1/11). The time interval between the reaction and skin testing was shorter for those patients with an immediate ICM reaction and a positive skin test result (3 months [2.5–174.0]) as compared with those with an immediate ICM reaction and a negative skin test (48 months [6.8–159.0]), (P<0.05). Respiratory allergy was more frequent in the positive group (6/10 vs. 7/34, P<0.05).

Conclusions
Skin tests with ICM are positive in a subgroup of patients with ICM hypersensitivity and may play an important role in the diagnosis of ICM allergy.
Pathophysiology of nasal obstruction and meta‐analysis of early and late effects of levocetirizine
Authors: Patou J. , De Smedt H. , Van Cauwenberge P. , Bachert C.
Published: August 2006

Nasal obstruction, also referred to as congestion, blockage or stuffiness, is a crucial symptom in allergic rhinitis (AR) and may affect sleep as well as quality of life. Early‐ and late‐phase‐allergic reactions both contribute to nasal obstruction, although it primarily represents a major symptom in the chronic allergic reaction. A complex network of inflammatory and neurogenic phenomena relates to chronic nasal obstruction, including the subepithelial accumulation of inflammatory cells, particularly mast cells and eosinophils, and the release of neuropeptides. Nasal obstruction is a difficult‐to‐treat symptom. Vasoconstrictors (decongestants) and intranasal corticosteroids, due to their anti‐inflammatory properties, have mainly been used for relieving the nasal passages from the congested mucosa. However, there is accumulating evidence recently that the latest‐generation potent antihistamines have decongestant properties in AR. This paper aims to review the pathophysiologic background of nasal obstruction and the evidence for an antihistamine, levocetirizine, in relieving nasal congestion. A meta‐analysis on the early and late effects of levocetirizine on nasal obstruction under artificial and natural allergen exposure conditions is presented, demonstrating convincingly that levocetirizine shows a consistent effect on nasal obstruction as early as over the first 2 h and sustained over 6 weeks.
A reproducible method for the enumeration of functional (cytokine producing)versusnon-functional peptide-specific cytotoxic T lymphocytes in human peripheral blood
Authors: Markovic S N , Nevala W K , Uhl C B , Celis E , McKean D J
Published: August 2006

One of the most difficult laboratory challenges in the field of therapeutic cancer vaccines has been the development of uncomplicated/reproducible methods for the quantification of vaccine immunization efficacy in peripheral blood of cancer patients. Existing methods are limited by lack of functional information (tetramers), difficulties with standardization/reproducibility [enzyme-linked immunosorbent spot (ELISPOT)] and reliance on endogenous (sample-specific) antigen presentation (cytokine flow cytometry). Herein we present a reproducible method utilizing an artificial antigen-presenting cell platform for flow cytometry-based quantification of the frequency and activation status of peptide-specific cytotoxic T lymphocytes. The methodology [currently presented for cytomegalovirus human leucocyte antigen (HLA)-A2 cognant peptide antigens] allows simultaneous ex vivo quantification of activated (cytokine-producing) and inactive tetramer-positive T cells following HLA class I/peptide/CD28 stimulation independent of endogenous antigen presentation. The simplicity and reliability of the assay provide for high-throughput applications and automation. The utility and application of this method are discussed.
Survival in patients with pulmonary arterial hypertension treated with first‐line bosentan
Authors: McLaughlin V. V.
Published: August 2006

Background  Pulmonary arterial hypertension (PAH) is a devastating disease of the small pulmonary arteries and arterioles, characterized by intimal fibrosis, medial hypertrophy and plexiform lesions. When untreated both the idiopathic form (IPAH, formerly termed primary pulmonary hypertension, PPH) and PAH related to various other conditions such as scleroderma (SSc) often take a progressive course with high mortality. There is ongoing search for disease‐specific treatments that are able to improve survival in these patients. The oral dual endothelin (ETA/ETB) antagonist bosentan has been shown to improve exercise capacity, time to clinical worsening, haemodynamics and quality of life in short‐term studies.

Materials and methods  To determine the long‐term effects of bosentan on survival, patients from the two double‐blind, randomized trials and their open‐label extensions, treated with first‐line bosentan, were followed for up to 3 years. Data on survival were collected between September 1999 (first patient included in the placebo‐controlled trials) and December 2002. Vital status was verified in each patient. The survival cohorts of these patients were compared with either the predicted survival for each patient based on an equation from the National Institutes of Health (NIH) PPH registry or with historical controls.

Results  Observed survival up to 36 months was reported as a Kaplan‐Meier estimate in three cohorts: (1) In 169 PPH patients treated with first‐line bosentan, 1‐ and 2‐year survival was 96% and 89%, respectively, vs. predicted untreated survival at 1 and 2 years of 69% and 57%, respectively; (2) in 50 patients with PAH associated with SSc (PAH‐SSc), 1‐, 2‐ and 3‐year survival was 82%, 67% and 64%, respectively, vs. ∼45%, ∼35% and ∼28%, respectively, from registry data of untreated PAH‐SSc patients; and (3) in 139 PPH patients in WHO functional class III, 1‐ and 2‐year survival was 97% and 91%, respectively, vs. 91% and 84% in a historical cohort of 346 patients treated with epoprostenol in five major referral centres.

Conclusions  The present analyses suggest that first‐line bosentan therapy, followed by the addition of other disease‐specific therapies as required, improves survival in patients with advanced PAH.
Role of endothelin and endothelin receptor antagonists in renal disease
Authors: Neuhofer W. , Pittrow D.
Published: August 2006

Endothelin (ET)‐1 is a potent vasoconstrictor peptide with pro‐inflammatory, mitogenic, and pro‐fibrotic properties that is closely involved in both normal renal physiology and pathology. ET‐1 exerts a wide variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix production, and inhibition of sodium and water reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders. These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition, ET‐1 is causally linked to renal disorders characterized by increased renal vascular resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and others. Furthermore, derangement of the ET system may be involved in conditions associated with inappropriate sodium and water retention; for example, in congestive heart failure and hepatic cirrhosis. Both selective and non‐selective ET receptor antagonist have been developed and tested in animal models with promising results. As key events in progressive renal injury like inflammation and fibrosis are mediated via both ETA and ETB receptors, while constrictor effects are primarily transduced by ETA receptors, dual ET receptor blockade may be superior over selective ETA antagonism. Several compounds have been developed with remarkable effects in several models of acute and progressive renal injury. Thus, clinical studies are required to assess whether these results can be confirmed in humans, hopefully leading to novel and effective therapeutic options with few side effects.
SOME SARAWAK SOILS
Authors: WOOD T. W. W. , BECKETT P. H. T.
Published: August 2006

The sub‐mature landscape of the country rock (Miocene fine sandstones and shales) along the coast north of Bintulu gives rise under a mean annual rainfall of 150 in. to highly leached yellow soils, comparable to Kellogg's Red‐Yellow Latosols, associated with lowland Dipterocarp rain forest. Areas of level or nearly level coarse‐textured marine or estuarine deposits marking successive stages of the fall in sea‐level during the Pleistocene are associated with ground‐water podzols supporting various forms of the characteristic kerangas forest, which give rise to ‘blackwater’ streams