bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Established Tumor Is Associated with ICAM-1 Upregulation and Reversed by CD8 Depletion in a Tumor Necrosis Factor-Alpha Gene Transfected Mouse Mammary Tumor
Authors: Matory Yvedt L. , Dorfman David M. , Wu Lei , Chen Man , Goedegebuure Peter , Eberlein Timothy J.
Published: April 2003

Introduction: We have performed TNF-α gene transfection in a mouse mammary cancer line and found significant antitumor effects. We hypothesize that the antitumor effects observed in this model are mediated by ICAM-1 and by the recruitment of CD4+ and CD8+ T cells. In vivo (Balb/c mice) tumor growth inhibition, treatment of established tumor and the effects of ICAM-1 and CD4+ and CD8+ T cells were evaluated. Methods and Results: Gene transfection with highly efficient vectors resulted in secretion of large amounts of TNF-α (ELISA). In vivo antitumor effects were tested. The number of cells required to generate palpable tumor 7–10 days after subcutaneous injection was determined (1 × 106). The same number of transfected cells were injected subcutaneously and compared to nontransfected controls. Tumors were measured blindly and size was analyzed on day 30 by the Wilcoxon rank sum test. Mean tumor size after injection of transfected cells is compared to that of controls. Control tumors reached the maximum allowable size by day 30 (4 cm2). On day 30 EMT6-TNF-α tumors were 0.48 cm2 (p < 0.05). The effect of repeat injection (challenge was also tested. Animals were injected with transfected cells or wild-type control on day –6 and challenged with the same number of wild-type tumor cells on day 0. Significant immune protection against subsequent challenge was seen after first time injection with EMT6-TNF-α but not after first time EMT6 wild-type injection (1.62 vs. 4 cm2). Treatment of 6-day-old tumor was also evaluated. On day 30, mean tumor size in animals treated with EMT6-TNF-α was 0.9 cm2 compared to 4 cm2 for controls. In all experiments, CD8+ T cell depletion and CD4+ T cell depletion caused a reversal of TNF-α-induced inhibitory effects. In addition, in vivo antibody blocking of ICAM-1 in tumor growth experiments reversed antitumor effects (control 4 cm2, TNF-α 0.2 cm2 and ICAM-1 blocking 3.14 cm2). Using flow cytometry, MHC class I and II and ICAM-1 adhesion molecule expression of transfected tumor was tested. ICAM-I expression was significantly upregulated. MHC class II antigen expression was also increased. TNF-α-transfected human breast cancer was also evaluated. Three cell lines and fresh tumor were transfected to express TNF-α. In vitro analysis revealed ICAM-1 upregulation following transfection. Histologic analysis and immunohistochemical staining revealed TNF-α and ICAM-1 in transfected tumors and not in wild-type tumors. Conclusion: Highly significant in vivo tumor growth inhibition and immune protection after injection with TNF-α-transfected tumors appears to be mediated predominantly by CD8+ T cells and ICAM-1 upregulation. These findings suggest that TNF-α increases recruitment and adhesion of effector T cells.
The p16/Cdkn2a/Ink4a Gene Is Frequently Deleted in Nitrosourea-Induced Rat Glial Tumors
Authors: Schlegel Jürgen , Piontek Guido , Kersting Michael , Schuermann Marcus , Kappler Roland , Scherthan Harry , Weghorst Christopher , Buzard Gregory , Mennel Hans-Dieter
Published: April 2003

The present study investigates nitrosourea-induced rat (Rattus norvegicus) glioma cell lines for the functional status of the p16/Cdkn2a/Ink4a gene, which encodes the p16 cdk4 inhibitor and the alternative reading frame protein, p19ARF. We detected homozygous deletions of the p16/Cdkn2a/Ink4a gene locus in 4 of 5 glioma cell lines (C6, F98, RG2, and RGL.3), but not in the 9L gliosarcoma cell line or in a rat primary fibroblast cell line. RT-PCR demonstrated expression of the p16 and p19ARF mRNAs only in 9L cells and in rat fibroblasts. Comparative genomic in situ hybridization showed that the copy number of rat chromosome RNO5 was not altered in any of the glioma cell lines investigated, indicating that the deletions result from a discrete loss in the region of the p16/Cdkn2a/Ink4a locus. This is the first report of p16/Cdkn2a/Ink4a deletions present in nitrosourea-induced rat glioma cell lines. Since this genetic alteration is also commonly observed in human malignant glial tumors, our results validate the use of chemically induced rat glioma cell lines as an experimental model in the development of gene therapy strategies.
Magnesium Fortification of Drinking Water Suppresses Atherogenesis in Male LDL-Receptor-Deficient Mice
Authors: Sherer Yaniv , Shaish Aviv , Levkovitz Hana , Keren Pnina , Janackovic Zora , Shoenfeld Yehuda , Harats Dror
Published: April 2003

Magnesium, an important cofactor of more than 300 enzymes, has previously been found to modulate blood lipid levels, atherogenesis and atherosclerosis in rabbits, when added to their diet. The aim of this study was to examine whether magnesium fortification of drinking water, without a change in diet content, can affect atherogenesis. The study included six groups of LDL-receptor-deficient mice. The mice received either distilled water or water containing 50 g of magnesium sulfate per liter. In the first (12 weeks) and second (6 weeks) stages of the experiment, the mice received low- and high-cholesterol diets, respectively. At the end of each stage, blood was drawn for the determination of plasma magnesium, calcium and lipid levels. In addition, the extent of atherosclerosis was determined at the aortic sinus. In both males and females, magnesium fortification was associated with higher levels of plasma magnesium (50 and 37% increase, respectively), without any differences in plasma calcium content. The extent of atherosclerosis at the aortic sinus in the male mice that received high levels of magnesium was a third of that of the male mice that received distilled water. However, these differences were not found in the female groups. Surprisingly, the female mice that received water fortified with magnesium had higher levels of cholesterol after stage 2, whereas no differences regarding plasma lipid levels were found among the male mice. These results confirm that magnesium fortification of drinking water is capable of inhibiting atherogenesis in male LDL-receptor-deficient mice. The mechanisms of action are yet to be discovered, and are probably not related to diminished lipid excretion, but possibly to the prevention of calcium influx into vascular smooth muscle cells, elevated antioxidative capacity, or other yet undetermined mechanisms.
Mitochondrial tRNACys Mutation A5823G in a Patient with Motor Neuron Disease and Temporal Lobe Epilepsy
Authors: Kirches E. , Winkler K. , Vielhaber S. , Michael M. , Warich-Kirches M. , von Bossanyi P. , Plate I. , Kunz W.S. , Szibor R. , Feistner H. , Dietzmann K.
Published: April 2003

We discovered a new homoplasmic mutation in the mitochondrial cysteine tRNA of a 60-year-old Caucasian male suffering from asymmetrical pure lower motor neuron disease (MND) and temporal lobe epilepsy (TLE). Furthermore, titrations with Amytal, an inhibitor of NADH:CoQ oxidoreductase, revealed mild mitochondrial dysfunction in skeletal muscle tissue, which was described in patients with MND in an earlier report. The mutation was undetectable in 155 Caucasian controls of both sexes, in 40 MND patients and in 13 individuals suffering from TLE. It was, however, detected in a heteroplasmic state in the patient’s mother, who did not suffer from a neurological disorder. Since this rare mutation affected a nonconserved base position and was not observed in MND or TLE materials, its relation to disease remains unclear.
Regulation of Macrophage Gene Expression by Pro- and Anti-Inflammatory Cytokines
Authors: Hamilton T.A. , Ohmori Y. , Tebo J.M. , Kishore R.
Published: April 2003

The anti-inflammatory cytokines IL-4 and IL-10 are well recognized as important negative regulators of proinflammatory gene expression in mononuclear phagocytes. The intracellular mechanisms which mediate these responses appear to be multifactorial. IL-4 is able to markedly suppress transcriptional activation of IFNγ-responsive genes and the promoter sequences required for both IFNγ and IL-4 sensitivity are identical. IFNγ-activated STAT1 and IL-4-activated STAT6 can both form complexes on the same regulatory sequence element; while STAT1 functions to promote transcription, STAT6 is inactive. STAT6 is, however, required for the suppressive activity of IL-4. In this model, IL-4 appears to suppress IFNγ-inducible proinflammatory gene expression through the ability of STAT6 to compete with STAT1 for occupancy of promoter sites necessary for IFNγ-induced transcriptional initiation. In a second model, IL-10 suppresses the expression of genes induced in LPS-stimulated macrophages through a pathway involving destabilization of specific mRNAs. We have demonstrated that nucleotide sequences in the 3′-untranslated region of an IL-10-sensitive gene can both destabilize a stable reporter mRNA (CAT) and confer sensitivity to IL-10-mediated destabilization. Deletion and site-specific mutagenesis have mapped this to an AU-rich sequence motif similar to that found in many cytokine and growth factor mRNAs. IL-10 is able to modulate the activity of proteins capable of binding to this sequence and one or more of these may regulate the rate of mRNA degradation. Thus mechanisms through which IL-10 and IL-4 act to dampen inflammatory responses are mechanistically distinct and involve diverse intracellular signaling pathways.
Phenotypic Analysis of IL-10-Treated Macrophages Using the Monoclonal Antibodies RFD1 and RFD7
Authors: Taams Leonie S. , Poulter Len W. , Rustin Malcolm H.A. , Akbar Arne N.
Published: April 2003

Suppressive or tolerogenic antigen-presenting cells (APC) might play an important role in the control of auto/hyperreactivity and the resolution of the immune response. Recent studies have provided evidence that tolerogenic APC can be induced by anergic T cells or interleukin-10 (IL-10). The aim of this study is to investigate how anergic T cells and IL-10 induce the suppressive APC phenotype and how this affects the immune response. Previously, two monoclonal antibodies (RFD1 and RFD7) were described by our lab which distinguish inductive (RFD1+RFD7–), phagocytic (RFD1–RFD7+) and suppressive (RFD1+RFD7+) macrophages. RFD1 recognizes an MHC class II-associated epitope which has restricted expression, and RFD7 recognizes a predominantly cytoplasmic antigen. Macrophages were derived from the adherent fraction of peripheral blood mononuclear cells from healthy donors. At day 5, IL-10 or IFNγ (a cytokine which should lead to the inductive APC phenotype) was added to the cultures. At day 7, the macrophages were harvested and their phenotypes were assessed by immunohistochemical staining and FACS analysis. Upon culture of macrophages with IL-10 RFD1 staining and HLA class II expression were reduced, whereas RFD7 staining was increased. Incubation of APC with IFNγ led to upregulation of RFD1 and HLA class II, without affecting RFD7 staining. This suggests that IL-10 induced the suppressive RFD1+RFD7+ APC population, whereas IFNγ treatment led to the inductive RFD1+RFD7– APC subset. Thus the use of IL-10 and/or IFNγ, and the discrimination offered by mAbs RFD7 and RFD1 represent a model whereby APC function in terms of T cell stimulation or T cell anergy can be assessed.
Increased Muscarinic Receptor Blockade by Atropine in Tracheal Chains of Ovalbumin-Sensitized Guinea Pigs
Authors: Boskabady M.H. , Adel-Kardan S.
Published: April 2003

Drug delivery to the receptor sites and receptor affinity could be determinant factors for increased bronchial responsiveness seen in asthma. Competitive antagonism blockade which is measured as dose ratio – 1 (DR-1) depends only on these two factors. Therefore, in this study we examined the muscarinic receptor blockade by atropine on isolated tracheal chains of sensitized compared to control guinea pigs. An experimental model of asthma was induced in guinea pigs by sensitization of animals with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of sensitized and control animals (for each group n = 10) to cumulative concentrations of methacholine in the absence and presence of 5 nmol/l atropine were measured, and the effective concentrations of methacholine causing 50% of maximum response (EC50 M) were obtained. The atropine blockade (DR-1) was calculated by: (post-atropine EC50 M/EC50 M) – 1. The responses of tracheal chains to 0.1% OA, relative to contraction obtained by 10 mmol/l methacholine, were also measured. The tracheal responses of sensitized guinea pigs were significantly higher than those of control animals to both OA (mean ± SEM, 55.94 ± 5.22 vs. 2.59 ± 0.85%, p < 0.001) and methacholine (EC50 M for asthmatic and control animals were 0.88 ± 0.27 and 2.00 ± 0.26 μmol, respectively, p < 0.01). The muscarinic receptor blockade by atropine (DR-1) was also significantly higher in tracheas of asthmatic compared to that of control animals (131.12 ± 19.82 vs. 24.50 ± 3.19, p < 0.001). There were significant correlations between tracheal response to OA and EC50 M (r = –0.644, p = 0.002) and also between DR-1 and tracheal responses to both OA (r = 0.738, p < 0.001) and EC50 M (r = –0.679, p < 0.001). This enhanced muscarinic receptor blockade in tracheal chains of sensitized animals confirms our previous findings which was predicted to be due to the increased drug delivery to the receptors. Drug delivery could also be a determinant factor for bronchial responsiveness to stimuli in asthma.
Cyclosporine A Preparations and Their Vehicles Induce Contraction of the Guinea Pig Gallbladder in vitro: The Role of Cyclooxygenase Metabolites
Authors: Yasar U. , Erdem S.R. , Tuncer M.
Published: April 2003

The aim of this study was to establish whether prostanoids play a role in the contraction induced by cyclosporine A (CyA) preparations in the guinea pig isolated gallbladder strips. It was also aimed to study the effects of the preparations and their solvents on the acetylcholine-evoked rhythmic contractions of the guinea pig isolated sphincter of Oddi (SO). Isometric contractions were recorded. CyA parenteral and oral preparations and their vehicles, Cremophor-EL and Labrafil caused concentration-dependent and sustained contractions (74.2 ± 6.2, 58.4 ± 6.3, 88.9 ± 4.9 and 47.5 ± 6.2% of maximum KCl contraction, respectively) of gallbladder strips, but not of SO. Quinacrine, indometacin and ridogrel inhibited the contraction induced by CyA preparations and their vehicles in gallbladder strips (for CyA parenteral preparation, 34.7 ± 6.7, 1.4 ± 0.9, 19.0 ± 6.4% of maximum KCl contraction, respectively). The drug and its vehicles changed neither the initial contraction nor the amplitude and frequency of the phasic contractions induced by acetylcholine in SO preparations. The results indicate that the drug is able to contract the gallbladder strips and the vehicles contribute to the contracting effect of CyA. Prostanoids may be responsible for the CyA-induced contraction of the gallbladder.
Endothelial Modulation of Vasoconstrictor Responses in the Perfused Rabbit Ovarian Vascular Bed
Authors: Yousif M.H. , Oriowo M.A. , Williams K.I.
Published: April 2003

The purpose of this study was to investigate the effects of endothelial denudation, inhibitors of nitric oxide (NO) and prostanoid synthesis on vasoconstrictor responses in the perfused rabbit ovarian vascular. The experiments were conducted using an in vitro perfusion system, where the ovarian vascular bed (en bloc) was perfused with Krebs’ solution delivered at a constant flow rate using a peristaltic pump. Changes in perfusion pressure, which reflected peripheral resistance, were measured. Results showed that noradrenaline (NA) (10–9 to 10–6 mol) induced reproducible dose-dependent vasoconstrictor responses. Vasoconstrictor effects of low doses of noradrenaline were not affected by perfusion of the vascular bed with CHAPS (4.7 mg/ml for 30 s) to remove the endothelium. The same treatment however, significantly reduced responses induced by the higher doses of noradrenaline, thus depressing the maximum response. KCl-induced vasoconstriction was not affected by CHAPS. L-NG-nitroarginine (L-NOARG) (10–5 mol/l) enhanced NA-induced vasoconstriction. D-NOARG, the inactive isomer of L-NOARG and aminoguanidine, an inhibitor of inducible nitric oxide synthase reduced rather than enhanced noradrenaline-induced responses. Methylene blue (3 × 10–5 mol/l) and LY 83583 (10–5 mol/l) produced a potentiation of NA-induced vasoconstrictor responses. Indomethacin (3 × 10–6 mol/l) did not significantly enhance NA-induced vasoconstriction. The nonselective endothelin antagonist, SB 209670 (10–7 and 10–6 mol/l) did not inhibit the vasoconstriction to NA. In conclusion, results are interpreted to suggest that NA-induced vasoconstriction in the perfused rabbit ovarian vascular bed is accompanied by a release of NO and possibly endothelium-derived contracting factor. There was no evidence for a modulation of vasoconstrictor responses by products of arachidonic acid metabolism or endothelins released from the endothelium.
Effect of TEI-6720, a Xanthine Oxidase Inhibitor, on the Nucleoside Transport in the Lung Cancer Cell Line A549
Authors: Yamamoto Tetsuya , Moriwaki Yuji , Fujimura Yoshihiro , Takahashi Sumio , Tsutsumi Zenta , Tsutsui Takahiko , Higashino Kazuya , Hada Toshikazu
Published: April 2003

To examine the effect of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (TEI-6720), an inhibitor of xanthine oxidase, on purine metabolism in the lung cancer cell line A549, the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine guanine phosphoribosyltransferase, xanthine oxidase, and guanase together with pyrimidine nucleoside phosphorylase were measured with or without the addition of TEI-6720, and the extracellular concentrations of hypoxanthine, xanthine, inosine, uracil, and uridine were measured after the addition of inosine or uridine to the incubation medium with or without TEI-6720. Moreover, the Na-indepenent nucleoside transport was determined in A549 cells with or without TEI-6720. TEI-6720 inhibited the activity of xanthine oxidase in A549 cells, but did not affect other enzymes. During incubation, TEI-6720 not only prevented a decrease in the inosine concentration in inosine-containing medium, but also a decrease in the uridine concentration in uridine-containing medium. Furthermore, the Na-independent transport of uridine was inhibited by TEI-6720 with a Ki value of 4.1 μmol/l. These results indicate that TEI-6720 is an inhibitor of the Na-independent nucleoside transport of uridine and inosine, as well as xanthine oxidase.
Antinociceptive/Anti-Edema Effects of Liposomal Morphine during Acute Inflammation of the Rat Paw
Authors: Planas Eulalia , Sánchez Silvia , Rodriguez Leocadio , Pol Olga , Puig Margarita M.
Published: April 2003

We evaluated the anti-edema/antinociceptive effects of subcutaneous free and liposomal morphine in rats with carrageenan-induced inflammation of the paw. We assessed antinociception by the paw pressure test and edema by plethysmography. Unilamellar liposomes (150–200 nm) with 0.3% morphine hydrochloride were used; encapsulation signifcantly reduced the rate for release of morphine in vitro. During inflammation, the antinociceptive potency of free, but not liposomal morphine increased 2.5 times; moreover, duration of the effects was prolonged by encapsulation (p < 0.001). The anti-edema effects of liposomal morphine were more pronounced (p < 0.001) and of longer duration (p < 0.05). All the effects were reversed by naloxone. The results show that morphine encapsulation enhances the anti-edema effects and prolongs antinociception.
Differential Involvement of Opioid Receptors in Stress-Induced Antinociception Caused by Repeated Exposure to Forced Walking Stress in Mice
Authors: Onodera Kenji , Sakurada Shinobu , Furuta Seiichi , Yonezawa Akihiko , Arai Kinue , Hayashi Takafumi , Katsuyama Sou , Sato Takumi , Miyazaki Shuichi , Kisara Kensuke
Published: April 2003

We examined the effects of repeated exposure to forced walking stress for 6 h once a day for 0, 6 and 9 consecutive days on formalin-induced paw licking in mice. In each observation period, stress-induced antinociception (SIA) was observed only in the late phase (from 10 to 30 min), but not in the early phase (from 0 to 10 min) of formalin-induced paw licking in mice. Moreover, it was hard to develop tolerance even by daily exposure to stress for 6 days, although SIA for 9 days decreased compared with those for 0 and 6 days. Naloxone (10 mg/kg), an opioid-receptor antagonist, was effective in reducing the SIA induced by forced walking stress for 6 days and/or 9 days, but not for 0 days. Furthermore, the experiments with selective opioid-receptor antagonists, β-funaltrexamine (μ) naltrindol (δ), or nor-binaltorphimine (κ) demonstrated that SIA induced by forced walking stress for 9 successive days may be mediated through opioid δ- and κ-receptors. Finally, although SIA seemed to be a unitary phenomenon, the present results strengthened the idea that SIA is induced by exposure to forced walking stress with characteristics dependent on the duration of exposure.
Vasodilatory Effect of Adrenomedullin in Mouse Aorta
Authors: Ashton Daryl , Hieble Paul , Gout Bernard , Aiyar Nambi
Published: April 2003

Human adrenomedullin (AM) and human calcitonin gene-related peptide (CGRP) produced a concentration-dependent relaxation in mouse aorta, precontracted with noradrenaline. EC50 values for AM and CGRP were 9.8 ± 2.4 and 4.2 ± 0.1 nmol/l, respectively. AM-mediated vasorelaxation was partially (3-fold) shifted by AM(22–52), the C-terminal AM fragment, but not by CGRP(8–37), a selective CGRP1 antagonist. Both AM(22–52) and CGRP(8–37) failed to inhibit CGRP-mediated vasorelaxation of mouse aorta rings. Binding of rat [125I]AM to these membranes was specific. Both human AM and AM(22–52) displaced rat [125I]AM binding in a concentration-dependent manner with IC50 values of 12.0 ± 4 and 19.4 ± 8 nmol/l, respectively. In contrast, both human CGRP and CGRP(8–37) were weak in displacing [125I]AM binding. Very little specific binding was observed with [125I]CGRP. In conclusion, the data presented here demonstrate that the mouse aorta displays AM receptors that mediate vasorelaxation.
Pharmacogenetics of Beta-1- and Beta-2-Adrenergic Receptors
Authors: Liggett Stephen B.
Published: April 2003

β1- and β2-adrenergic receptors are G protein-coupled receptors expressed throughout the body and serve as receptors for the catecholamines epinephrine and norepinephrine. They are targets for therapeutive agonists and/or antagonists in treatment of heart failure and asthma. Nonsynonymous coding and promoter polymorphisms of both receptors have been identified in the general population. These have been mimicked in transfected cell systems and transgenic mice, and show altered expression, ligand binding, coupling, or regulation phenotypes. Clinical studies to date have revealed that some of these polymorphisms have a significant disease modifying effect or alter the response to treatment. These are some of the first G protein coupled receptor polymorphisms to undergo extensive in vitro study and clinical validation; there are likely to be polymorphisms of other receptors of the superfamily that will have clinical relevance as well.
Molecular Genetics of Cancer Susceptibility
Authors: Brockmöller Jürgen , Cascorbi Ingolf , Henning Stefan , Meisel Christian , Roots Ivar
Published: April 2003

Studies on the role of genetically polymorphic enzymes like cytochrome P450 1A1, arylamine N-acetyltransferase 2 or glutathione S-transferase M1 as cancer susceptibility factors date back more than 20 years, and some associations have been confirmed in several studies and meta-analyses. Overall, the extent of risk modulation due to these polymorphisms is only moderate but remains epidemiologically relevant. The role of some of these polymorphisms in human health may even be ambiguous: rapid acetylation, for example, protects from urinary bladder cancer but appears to increase the risk of laryngeal, lung and colon cancer. The first genetic polymorphisms in xenobiotics transporters such as P-gp (MDR1) and MRP2 have recently been identified. These polymorphisms may have great impact as cancer susceptibility factors as well as factors modulating the outcome of cancer treatment. Enzymes involved in generation or detoxification of reactive oxygen species also have to be considered; one of these enzymes, myeloperoxidase, constitutes a relatively strong lung cancer risk factor, as confirmed in 4 independent studies. Other genes, including those coding for DNA repair enzymes, signal transduction and cell growth regulation, may ultimately prove more important than the metabolic enzymes as cancer susceptibility factors. Study designs in molecular genetic epidemiology are evolving; large ongoing prospective trials increasingly allow confirmatory nested case control studies to be performed. However, carefully controlled, large case-control studies will remain the mainstay in molecular genetic epidemiology. Molecular genetic epidemiological evaluation of response to chemoprevention as well as response to the adverse events of cancer chemotherapy are likely to provide results that may be useful for individualized prevention and treatment in the near future. Since routine genotyping of all persons is now feasible, something like a genotype passport may soon become reality, and molecular and clinical epidemiological studies will have to provide the basis for understanding how to use genotype data for the benefit of the population.
Vowel Change in Australian English
Authors: Cox Felicity
Published: April 2003

The dynamic nature of vowel systems has recently been investigated in several English dialects confirming that phonetic disruptions often have systemic consequences and suggesting that change follows predictable patterns of movement. The present paper examines the nature of vowel change in Australian English by comparing two sets of data from different subjects at each end of a 25-year interval. A series of multivariate analyses of variance reveals significant acoustic differences between the two sets of data providing strong evidence for systemic effects. The analysis also indicates the presence of chain and parallel shifts within vowel classes as well as a close correspondence between monophthong and diphthong movement in phonetic space. The observed monophthong/diphthong relationships suggests that change in one class of vowels impacts on the other in a parallel fashion in this dialect of English.
The C/D Model and Prosodic Control of Articulatory Behavior
Authors: Fujimura Osamu
Published: April 2003

The Converter and Distributor (C/D) model is a generative description of articulatory gesture organization for utterances. Its input comprises specifications for syllables by features, a paraphonologically augmented metrical structure, and system parameters for utterance conditions. A syllable-boundary pulse train is computed as a time function representing the skeletal rhythmic structure of the utterance. Control functions for articulators are computed by superimposing consonantal elemental gestures onto the base function, which includes voicing, vocalic, mandibular, and tonal functions associated with the pulse train. A preliminary analysis of microbeam data for experimental dialogues, using jaw opening as an approximate measure of the syllable magnitude, inferred syllable and boundary durations consistently with durational characteristics observed in the acoustic waveform.
Diverse Acoustic Cues at Consonantal Landmarks
Authors: Stevens Kenneth N.
Published: April 2003

The consonantal segments that underlie an utterance are manifested in the acoustic signal by abrupt discontinuities or dislocations in the spectral pattern. There are potentially two such discontinuities for each consonant, corresponding to the formation and release of a constriction in the oral cavity by the lips, the tongue blade, or the tongue body. Acoustic cues for the various consonant features of place, voicing and nasality reside in the signal in quite different forms on the two sides of each acoustic discontinuity. Examples of these diverse cues and their origin in acoustic theory are reviewed, with special attention to place features and features related to the laryngeal state and to nasalization. A listener appears to have the ability to integrate these diverse, brief acoustic cues for the features of consonants, although the mechanism for this integration process is unclear.
The Construction of a First Phonology
Authors: Vihman Marilyn M. , Velleman Shelley L.
Published: April 2003

Although it is generally accepted that phonological development is grounded in phonetic learning, there is less agreement for the proposition supported here, that the first phonological structuring constitutes a developmental discontinuity. Data from the phonetic and lexical learning of Finnish consonant duration are presented to illustrate the role of (1) child selection of adult words for early context-supported production based on phonetic learning and (2) child adaptation of adult words to an idiosyncratic template for later production as part of an incipient system. We argue that the latter, but not the former, reflects the construction of a first phonology.
Imitation and the Emergence of Segments
Authors: Studdert-Kennedy Michael
Published: April 2003

The paper argues that the discrete phonetic segments on which language is raised are subjective gestural structures that emerge ontogenetically (and perhaps emerged evolutionarily) from the process of imitating a quasi-continuous acoustic signal with a neuroanatomically segmented and somatotopically organized vocal machinery. Evidence cited for somatotopic organization includes the perceptual salience in the speech signal of information specifying place of articulation, as revealed both by sine wave speech and by the pattern of errors in children’s early words.Copyright © 2000 S. Karger AG, Basel‘Almost every insight gained by modern linguistics, from Grimm’s Law to Jakobson’s distinctive features, depends crucially on the assumption that speech is a sequence of discrete entities.’Morris Halle [1964, p. 325]
Developmental Origins of Adult Phonology: The Interplay between Phonetic Emergents and the Evolutionary Adaptations of Sound Patterns
Authors: Lindblom Björn
Published: April 2003

In this paper fragments of a theory of emergent phonology are presented. Phonological patterns are seen as products of cultural evolution adapted to universal biological constraints on listening, speaking and learning. It is proposed that children develop adult phonology thanks to the interaction of the emergent patterning of phonetic content and the adaptive organization of sound structure. Emergence – here used in the technical sense of qualitatively new development – is illustrated with examples from the study of perception, motor mechanisms and memory encoding. In this framework, there is no split between ‘behavioral phonetics’ and ‘abstract phonology’. Phonology differs qualitatively from phonetics in that it represents a new, more complex and higher level of organization of speech behavior. Accordingly, the phonology that the child ends up with as an adult is neither abstract nor independent of use. It represents an emergent patterning of phonetic content.
Surgical Management of Cutis Aplasia with High-Flow Sinus pericranii
Authors: Madsen Joseph R. , Robertson Richard L. , Bartlett Richard
Published: April 2003

Cutis aplasia (cutis aplasia congenita cystica) is a rare congenital disorder with failure of completion of the extracerebral coverings, involving a defect in the scalp and often a cranial defect. A case of cutis aplasia is reported with an associated high-flow venous fistula or sinus pericranii, resulting in altered venous drainage of sagittal sinus blood through dilated scalp veins. Radiological workup to ensure patency of the superior sagittal sinus was critical to the surgical management in this case.
Subdural Empyema due to Salmonella Infection
Authors: Jain K.C. , Mahapatra A.K.
Published: April 2003

A case of a 6-month-old child with a Salmonella subdural empyema is reported. The causative organism was never suspected until the culture report was available. The child responded well to surgical drainage and antibiotic therapy.
Severe Pediatric Head Injury: Myth, Magic, and Actual Fact
Authors: Johnson Dennis L. , Krishnamurthy Satish
Published: April 2003

Reports of low mortality rate for severely head-injured children have led to the myth that children have a better outcome than adults after severe head injury. This was examined in the present study by comparing the outcome of 4,041 severely head-injured children with 14,789 adults from five Level I trauma centers in the Pennsylvania Trauma Systems Foundation from 1986 to 1996. Severe head injury was defined as GCS <8, and outcome was defined by mortality. The overall mortality rate for children (<18 years) was 36.5% and for adults 47.6%. However, for patients involved in motor vehicle accidents, there was no clinically significant difference between children age 3–11 years (35%), age 12–18 years (31.4%) and adults (32.5%). The unprecedented low mortality rate for severe head injury in children was probably due to the selection bias of the patient population. We conclude that children involved in motor vehicle accidents are just as likely to die from severe head injury as adults.
Endoscopic Third Ventriculostomy: An Outcome Analysis
Authors: Brockmeyer Douglas , Abtin Keyvan , Carey Lyn , Walker Marion L.
Published: April 2003

Endoscopic third ventriculostomy (ETV) has gained widespread acceptance as an effective way to manage hydrocephalus in selected patients. To determine which patient groups have the highest chance of successful ETV, a retrospective case review was performed. From June 1992 to December 1996, 97 patients underwent a total of 98 ETVs at our institution. There were 59 males and 38 females with a mean age of 8.1 years (range 1 day to 29.5 years). Twenty-six of 98 procedures (26%) were abandoned due to either unfavorable anatomy, inability to perform a cisternostomy, or hemorrhage. Follow-up data was available in 92 patients for a mean of 24.2 months. The rate of successful ETV in 71 patients, with either complete shunt avoidance or removal, varied widely by diagnosis and patient age. The highest success rates were achieved in patients with aqueductal stenosis, tectal plate tumor, myelomeningocele and posterior fossa tumor. Complications included one transient herniation syndrome, one basilar artery perforation, 2 cases of ventriculitis, one transient decrease in level of consciousness, and one transient hemiparesis. We feel these results support the continued use of ETV in only carefully selected patients with hydrocephalus.
Serial Radiography in the Infant Shaken Impact Syndrome
Authors: Dias Mark S. , Backstrom James , Falk Michael , Li Veetai
Published: April 2003

Certain CT and/or MRI abnormalities have been used medicolegally to time intracranial injuries from the infant shaken impact syndrome (ISIS). For example, parenchymal hypodensities on CT scans are said to arise only after 6–48 h have elapsed postinjury, and the presence of chronic or mixed subdural hematomas suggests injury that occured 1–4 weeks prior. However, these statements are based largely upon inference from data obtained in other conditions such as ischemic anoxic injury and chronic subdural hemorrhage in adults. Direct evidence about the evolution of intracranial injuries in infants with ISIS is sparse, and the radiographic changes following ISIS have never been systematically studied on serial imaging studies. One hundred-seventeen serial CT and MRI scans obtained from 33 infants with ISIS were reviewed retrospectively. The exact scan dates and times were obtained directly from the scans. Acute subdural hemorrhage was the most common intracranial abnormality and was present in 27 (81%) of the 33 infants. Other intracranial abnormalities included chronic subdural collections, subarachnoid hemorrhage, epidural hematomas, parenchymal hypodensities, edema and contusions, and atrophy and encephalomalacia. In 15 of the 33 infants, the injury could be timed with reasonable certainty, and the evolution of the radiographic changes followed over time. Six of the 15 infants had evidence of prior cranial trauma such as chronic subdural collections (5 infants) or mild atrophy (1 infant). Of the remaining 9 infants, parenchymal abnormalities such as hypodensities, edema and contusion appeared in virtually all of the initial scans performed approximately 3 h following the report of injury. One ‘chronic’ subdural collection was absent on the first scan performed 2.75 h postinjury, but appeared on a second scan performed 17 h later, suggesting that some ‘chronic’ subdural fluid collections may arise much sooner than previously thought. These findings challenge some of the current dogma about the timing of radiographic changes following abuse and are important in timing the alleged abuse for legal purposes.
Neurocytoma Presenting with Intraparenchymal Cerebral Hemorrhage
Authors: Taylor Christopher L. , Cohen Mark L. , Cohen Alan R.
Published: April 2003

Neurocytomas are uncommon intracranial neoplasms that have only recently been characterized pathologically. Neurocytomas are histologically benign neoplasms that are often quite large when diagnosed, and previous reports have commonly described presentation with mass effect or cerebrospinal fluid outflow obstruction. We describe the first case of neurocytoma presenting with intraparenchymal cerebral hemorrhage.
Spontaneous Involution of a Diencephalic Astrocytoma
Authors: Kernan Jennifer C. , Horgan Michael A. , Piatt Joseph H. , D’Agostino Anthony
Published: April 2003

We present the case of a child with a symptomatic diencephalic astrocytoma which involuted after needle biopsy without any adjuvant therapy. A tendency for certain childhood astrocytomas to regress after partial resection has been previously suggested. However, some authors have doubted whether or not such regression actually occurs. Our case radiographically documents the spontaneous involution of a low-grade astrocytoma.
High-Field Strength Interventional Magnetic Resonance Imaging for Pediatric Neurosurgery
Authors: Hall Walter A. , Martin Alastair J. , Liu Haiying , Pozza Christopher H. , Casey Sean O. , Michel Eduard , Nussbaum Eric S. , Maxwell Robert E. , Truwit Charles L.
Published: April 2003

Background: Interventional magnetic resonance (MR) imaging allows neurosurgeons to interactively perform surgery using MR guidance. High-field (1.5-Tesla) strength imaging provides exceptional visualization of intracranial and spinal pathology. The full capabilities of this technology for pediatric neurosurgery have not been defined or determined. Materials and Methods: From January 1997 through June 1998, 10 of 85 cases performed in the interventional MR unit were in the pediatric population (mean age 8.3, median 8, range 2–15 years). Procedures included 2 brain biopsies, 5 craniotomies for tumor, 2 thoracic laminectomies for syringomyelia, and placement of a reservoir into a cystic brainstem tumor. The biopsies and reservoir placement were performed using MR-compatible equipment. Craniotomies and spinal surgery were performed with conventional instrumentation outside the 5-Gauss magnetic footprint. Interactive and intraoperative imaging was performed to assess the goals of surgery. Results: Both brain biopsies were diagnostic for cerebral infarct and anaplastic astrocytoma and the reservoir was optimally placed within the tumor cyst. Of the 5 tumor resections, all were considered radiographically complete. One biopsy patient and 1 tumor resection patient experienced transient neurological deficits after surgery. The patient with the thoracic syrinx required reoperation when the syringosubarachnoid shunt migrated into the syrinx 3 months after initial placement. No patient sustained a postoperative hemorrhage. Tumor histologies found at craniotomy were craniopharyngioma, ganglioglioma, and 3 low-grade gliomas. No evidence of tumor progression has been seen in any of these patients at a mean follow-up of 5.3 (range 4–8) months. The goals of the procedure were achieved in all 10 cases. There were no untoward events experienced related to MR-compatible instrumentation or intraoperative patient monitoring, despite the present inability to monitor core body temperature. Conclusions: 1.5-Tesla interventional MR is a safe and effective technology for assisting neurosurgeons to achieve the goals of pediatric neurosurgery. Preliminary results suggest that surgical resection of histologically benign tumors is enhanced in the interventional MR unit. The incidence of surgically related morbidity is low.
Fusiform Dilatations of the Internal Carotid Artery following Surgery for Pediatric Suprasellar Tumors
Authors: Bendszus M. , Sörensen N. , Hofmann E. , Röll E. , Solymosi L.
Published: April 2003

Fusiform dilatations of the internal carotid artery (FDCA) represent a vascular complication following surgery for suprasellar tumors in children. In a long-term follow-up of 62 children we identified 7 children (11.3%) with a FDCA. In all children the FDCA was present within 15 months following surgery. It was not related to radiotherapy or a distinct histology. In 3 children the FDCA remained unchanged during the follow-up, in 3 children there was a progression and 1 child revealed a regression within 6 months. Clinically the FDCA was inapparent in all cases and not treated. In a follow-up study of an adult population who underwent surgery for suprasellar tumors no case of FDCA was encountered. Potential pathomechanisms and indications for treatment are discussed.
A Method of Cranioplasty Using Coralline Hydroxyapatite
Authors: Choi Soo Ho , Levy Michael L. , McComb J. Gordon
Published: April 2003

Introduction: Current cranioplasty materials include autologous or homologous bone grafts, wire mesh and methyl methacrylate, either alone or in combination. However, each material has its own unique disadvantages. Although hydroxyapatite has been used extensively in other specialties as a bone substitute, the coralline form has rarely been used to repair cranial bone defects. Coralline hydroxyapatite, similar to that found in bone, provides a matrix on which living tissue can form and grow. Because it is an ideal bioimplant, a method of cranioplasty using coralline hydroxyapatite was employed. Methods: The hydroxyapatite granules are mixed with Avitene and autologous blood to form a paste which can be countoured as needed. Results: Over the past few years, we have used hydroxyapatite either alone or in combination with tantalum mesh in 19 pediatric patients for a variety of conditions. The cosmetic results were good to excellent. Furthermore, postoperative CT scans have documented bony substitution of the hydroxyapatite granules. Follow-up ranged from 1 to 43 months with a mean of 26 months. Conclusion: In neurosurgical procedures when a bone substitute is needed, hydroxyapatite is an effective alternative to other currently available materials.
High-Grade Pediatric Spinal Cord Tumors
Authors: Merchant ThomasE. , Nguyen Duyen , Thompson StephenJ. , Reardon DavidA. , Kun LarryE. , Sanford RobertA.
Published: April 2003

Our institutional experience with high-grade pediatric spinal cord tumors includes 11 children treated during the period of 1981-1997. All patients underwent a biopsy or an attempt at resection and received postoperative radiation therapy. Three patients had a gross-total resection of their primary tumor, 6 patients had a subtotal resection and the remaining 2 were biopsied. Histologically, these tumors were characterized as anaplastic astrocytoma (n = 6), glioblastoma multiforme (n = 3) or anaplastic oligodendroglioma (n = 2). Three patients were treated with craniospinal irradiation (38-48 Gy) in addition to a boost to the residual tumor. The median dose to the primary site for all patients was 48.6 Gy (range 38-55 Gy). The median overall survival was 13 months (range 8-149 months). Only 2 patients were alive at 138 and 149 months following radiation therapy. The median progression-free survival following radiation therapy was 10 months (range 2-80 months). There was no difference in progression-free or overall survival for those diagnosed with glioblastoma multiforme when compared to patients diagnosed with anaplastic astrocytoma or anaplastic oligodendroglioma. The pattern of failure was either diffuse or local. For the patients who failed diffusely (n = 6), the median progression-free survival was 2 months compared to 23 months for those whose failure was entirely local (p < 0.01). The median overall survival was significantly shorter for those who failed diffusely compared to those who failed locally (10 vs. 37 months, p < 0.01). High-grade spinal cord tumors in children have a poor prognosis based on this report. It is important to document the extent of disease accurately prior to the initiation of radiation therapy, since a subset of these patients progress rapidly outside of the field of irradiation.
Third Ventriculostomy versus Cerebrospinal Fluid Shunt as a First Procedure in Pediatric Hydrocephalus
Authors: Tuli Sagun , Alshail Essam , Drake James
Published: April 2003

Background: Third ventriculostomy (TV) has been reported to be efficacious for diverse causes of obstructive hydrocephalus in pediatric patients, and preferable to a first CSF shunt (CS) in those eligible. We reviewed the respective failure rates in a prospective cohort of patients at our institution. Method: All patients having either TV or CS (i.e ventriculoperitoneal shunt) over the period 1987 to 1997 were prospectively entered into a database. To compare homogeneous patients, only diagnoses of either aqueductal stenosis or tumor were considered. Failure was defined as any subsequent surgical procedure for CSF diversion. Kaplan-Meier curves were constructed to determine survivorship. A multivariable Cox model using time-dependent covariates was constructed. Results: There were 32 TV and 210 CS patients: 14 (44%) and 95 (45%) failed, respectively. TV patients were older (median age = 8.1 vs. 3.6 years) and had a higher incidence of aqueductal stenosis (53 vs. 25%). There was no statistically significant difference between the two procedures based on bivariate analysis (p = 0.87) and on multivariable analysis using the Cox model after adjusting for the potential confounders (p = 0.66, hazard ratio = 1.19, 95% confidence interval = 0.55-2.56). Conclusion: Failure from TV is not unlike that of CS when analyzed by survival methods. Larger prospective series are needed to look at specific subgroups who may benefit from TV. Quality of life and clinical outcome measures are also required to analyze the difference between these two procedures.
An Unusual Case of Cephalocele Associated with Lipoma of Corpus Callosum
Authors: Ergün Rüçhan , Ökten Ali İhsan , Bostanci Uǧur
Published: April 2003

Cephalocele is a part of the family of neural tube defects. Although the frequency has ranged from 1 per 2,400 to 1 per 12,500 live births, the true incidence has been hidden in stillborns, underreferral of massive defects and early pregnancy losses. It has been suggested that the size, the content of the sac and associated hydrocephalus were unfavorable factors for the prognosis. Cephaloceles may occur as isolated malformations or together with other anomalies, and associated abnormalities are present in up to 50% of the cases. We report an unusual case of encephalocele associated with lipoma of corpus callosum, and the features of magnetic resonance imaging are discussed.