bluuebunny/crossref_metadata_2025 huggingface dataset:
The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif
Authors: WALKER Steven M. , LESLIE Nick R. , PERERA Nevin M. , BATTY Ian H. , DOWNES C. Peter
Published: April 2004

The PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour-suppressor protein is a phosphoinositide 3-phosphatase which antagonizes phosphoinositide 3-kinase-dependent signalling by dephosphorylating PtdIns(3,4,5)P3. Most tumour-derived point mutations of PTEN induce a loss of function, which correlates with profoundly reduced catalytic activity. However, here we characterize a point mutation at the N-terminus of PTEN, K13E from a human glioblastoma, which displayed wild-type activity when assayed in vitro. This mutation occurs within a conserved polybasic motif, a putative PtdIns(4,5)P2-binding site that may participate in membrane targeting of PTEN. We found that catalytic activity against lipid substrates and vesicle binding of wild-type PTEN, but not of PTEN K13E, were greatly stimulated by anionic lipids, especially PtdIns(4,5)P2. The K13E mutation also greatly reduces the efficiency with which anionic lipids inhibit PTEN activity against soluble substrates, supporting the hypothesis that non-catalytic membrane binding orientates the active site to favour lipid substrates. Significantly, in contrast to the wild-type enzyme, PTEN K13E failed either to prevent protein kinase B/Akt phosphorylation, or inhibit cell proliferation when expressed in PTEN-null U87MG cells. The cellular functioning of K13E PTEN was recovered by targeting to the plasma membrane through inclusion of a myristoylation site. Our results establish a requirement for the conserved N-terminal motif of PTEN for correct membrane orientation, cellular activity and tumour-suppressor function.
Diversity of folds in animal toxins acting on ion channels
Authors: MOUHAT Stéphanie , JOUIROU Besma , MOSBAH Amor , DE WAARD Michel , SABATIER Jean-Marc
Published: April 2004

Animal toxins acting on ion channels of excitable cells are principally highly potent short peptides that are present in limited amounts in the venoms of various unrelated species, such as scorpions, snakes, sea anemones, spiders, insects, marine cone snails and worms. These toxins have been used extensively as invaluable biochemical and pharmacological tools to characterize and discriminate between the various ion channel types that differ in ionic selectivity, structure and/or cell function. Alongside the huge molecular and functional diversity of ion channels, a no less impressive structural diversity of animal toxins has been indicated by the discovery of an increasing number of polypeptide folds that are able to target these ion channels. Indeed, it appears that these peptide toxins have evolved over time on the basis of clearly distinct architectural motifs, in order to adapt to different ion channel modulating strategies (pore blockers compared with gating modifiers). Herein, we provide an up-to-date overview of the various types of fold from animal toxins that act on ion channels selective for K+, Na+, Ca2+ or Cl− ions, with special emphasis on disulphide bridge frameworks and structural motifs associated with these peptide folds.
Repression of Smad4 transcriptional activity by SUMO modification
Authors: LONG Jianyin , WANG Guannan , HE Dongming , LIU Fang
Published: April 2004

Smad4 plays a key role in TGF-β (transforming growth factor β)/Smad-mediated transcriptional responses. We show that Smad4 is sumoylated both in vivo and in vitro. Recent studies showed that sumoylation of Smad4 regulated its stability, but the effect of sumoylation on the intrinsic transcriptional activity of Smad4 was not defined. We show that overexpression of SUMO (small ubiquitin-related modifier)-1 and Ubc9 can inhibit a TGF-β-responsive reporter gene, whereas co-transfection with SUMO-1 protease-1 (SuPr-1) can increase the TGF-β response. We show further that mutation of the Smad4 sumoylation sites or co-transfection with SuPr-1 greatly increases Smad4 transcriptional activity. Moreover, direct fusion of SUMO-1 to the sumoylation mutant Smad4 potently inhibits its transcriptional activity. Thus, as it is being rapidly discovered that sumoylation inhibits the activities of many transcription factors, sumoylation also represses Smad4 transcriptional activity. The net effect of sumoylation of Smad4 can therefore be either stimulatory or inhibitory, depending on the target promoter that is analysed.
Nuclear factor-kappaB motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells
Authors: NASCHBERGER Elisabeth , WERNER Thomas , VICENTE Ana B. , GUENZI Eric , TÖPOLT Kristin , LEUBERT René , LUBESEDER-MARTELLATO Clara , NELSON Peter J. , STÜRZL Michael
Published: April 2004

The large GTPase GBP-1 (guanylate-binding protein-1) is a major IFN-γ (interferon-γ)-induced protein with potent anti-angiogenic activity in endothelial cells. An ISRE (IFN-α-stimulated response element) is necessary and sufficient for the induction of GBP-1 expression by IFN-γ. Recently, we have shown that in vivo GBP-1 expression is strongly endothelial-cell-associated and is, in addition to IFN-γ, also activated by interleukin-1β and tumour necrosis factor-α, both in vitro and in vivo [Lubeseder-Martellato, Guenzi, Jörg, Töpolt, Naschberger, Kremmer, Zietz, Tschachler, Hutzler, Schwemmle et al. (2002) Am. J. Pathol. 161, 1749–1759; Guenzi, Töpolt, Cornali, Lubeseder-Martellato, Jörg, Matzen, Zietz, Kremmer, Nappi, Schwemmle et al. (2001) EMBO J. 20, 5568–5577]. In the present study, we identified a NF-κB (nuclear factor κB)-binding motif that, together with ISRE, is required for the induction of GBP-1 expression by interleukin-1β and tumour necrosis factor-α. Deactivation of the NF-κB motif reduced the additive effects of combinations of these cytokines with IFN-γ by more than 50%. Importantly, NF-κB p50 rather than p65 activated the GBP-1 promoter. The NF-κB motif and ISRE were detected in an almost identical spatial organization, as in the GBP-1 promoter, in the promoter regions of various inflammation-associated genes. Therefore both motifs may constitute a cooperative inflammatory cytokine response module that regulates GBP-1 expression. Our findings may open new perspectives for the use of NF-κB inhibitors to support angiogenesis in inflammatory diseases including ischaemia.
A functional chimaeric S-layer-enhanced green fluorescent protein to follow the uptake of S-layer-coated liposomes into eukaryotic cells
Authors: ILK Nicola , KÜPCÜ Seta , MONCAYO Gerald , KLIMT Sigrid , ECKER Rupert C. , HOFER-WARBINEK Renate , EGELSEER Eva M. , SLEYTR Uwe B. , SÁRA Margit
Published: April 2004

The chimaeric gene encoding a C-terminally truncated form of the S-layer protein SbpA of Bacillus sphaericus CCM 2177 and the EGFP (enhanced green fluorescent protein) was ligated into plasmid pET28a and cloned and expressed in Escherichia coli. Just 1 h after induction of expression an intense EGFP fluorescence was detected in the cytoplasm of the host cells. Expression at 28 °C instead of 37 °C resulted in clearly increased fluorescence intensity, indicating that the folding process of the EGFP moiety was temperature sensitive. To maintain the EGFP fluorescence, isolation of the fusion protein from the host cells had to be performed in the presence of reducing agents. SDS/PAGE analysis, immunoblotting and N-terminal sequencing of the isolated and purified fusion protein confirmed the presence of both the S-layer protein and the EGFP moiety. The fusion protein had maintained the ability to self-assemble in suspension and to recrystallize on peptidoglycan-containing sacculi or on positively charged liposomes, as well as to fluoresce. Comparison of fluorescence excitation and emission spectra of recombinant EGFP and rSbpA31-1068/EGFP revealed identical maxima at 488 and 507 nm respectively. The uptake of liposomes coated with a fluorescent monomolecular protein lattice of rSbpA31-1068/EGFP into HeLa cells was studied by confocal laser-scanning microscopy. The major part of the liposomes was internalized within 2 h of incubation and entered the HeLa cells by endocytosis.
Intracerebroventricular leptin regulates hepatic cholesterol metabolism
Authors: VanPATTEN Sonya , KARKANIAS George B. , ROSSETTI Luciano , COHEN David E.
Published: April 2004

To elucidate the control of hepatic cholesterol metabolism by leptin, rats were administered IV (intravenous) leptin, ICV (intracerebroventricular) leptin or saline. A single low dose of ICV leptin was as effective as a continuous IV infusion of highdose leptin at decreasing the activities of 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7α-hydroxylase. These results indicate that the hepatic response to leptin is transduced via the central nervous system.
Probing nucleotide-binding effects on backbone dynamics and folding of the nucleotide-binding domain of the sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase
Authors: ABU-ABED Mona , MILLET Oscar , MacLENNAN David H. , IKURA Mitsuhiko
Published: April 2004

In muscle cells, SERCA (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase) plays a key role in restoring cytoplasmic Ca2+ levels to resting concentrations after transient surges caused by excitation–coupling cycles. The mechanism by which Ca2+ is translocated to the lumen of the ER (endoplasmic reticulum) involves major conformational rearrangements among the three cytoplasmic domains: actuator (A), nucleotide-binding (N) and phosphorylation (P) domains; and within the transmembrane Ca2+-binding domain of SERCA. CD, fluorescence spectroscopy and NMR spectroscopy were used in the present study to probe the conformation and stability of the isolated N domain of SERCA (SERCA-N), in the presence and absence of AMP-PNP (adenosine 5´-[β,γ-imido]triphosphate). CD and tryptophan fluorescence spectroscopy results established that the effects of nucleotide binding were not readily manifested on the global fold and structural stability of SERCA-N. 15N-backbone-relaxation experiments revealed site-specific changes in backbone dynamics that converge on the central β-sheet domain. Nucleotide binding produced diverse effects on dynamics, with enhanced mobility observed for Ile369, Cys420, Arg467, Asp568, Phe593 and Gly598, whereas rigidifying effects were found for Ser383, Leu419, Thr484 and Thr532. These results demonstrate that the overall fold and backbone motional properties of SERCA-N remained essentially the same in the presence of AMP-PNP, yet revealing evidence for internal counter-balancing effects on backbone dynamics upon binding the nucleotide, which propagate through the central β-sheet.
Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma
Authors: ZHOU Xiao-Dong , YU Jie-Ping , LIU Jin , LUO He-Sheng , CHEN Hong-Xia , YU Hong-Gang
Published: April 2004

The aim of the present study was to investigate the prevalence of c-FLIP [cellular FLICE-inhibitory protein, where FLICE is Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme] expression in gastric adenocarcinoma and its possible implications for the progression of the cancer. Expression of c-FLIP in 48 gastric adenocarcinomas and their normal counterparts was analysed by reverse transcriptase PCR, Western blotting and immunohistochemistry. In situ cell apoptosis was detected by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. As a result, c-FLIP transcripts were constitutively expressed in gastric adenocarcinomas and their levels were significantly higher than those in matched normal tissues (P<0.01). Immunohistochemically, the c-FLIP protein was also found to be expressed in all gastric adenocarcinomas (48/48), and 68.8% (33/48) showed an intense immunostaining; in contrast, only 75% (36/48) of normal gastric mucosa showed positive staining and none of them immunostained intensely. The abundance of c-FLIP protein was significantly higher in carcinoma than in normal gastric mucosa (6.93±0.58 versus 3.19±0.26, P<0.01) and showed a reverse correlation with apoptotic index in adenocarcinoma, but not in normal mucosa. In addition, abundance of c-FLIP was significantly associated with lymph node metastasis at both mRNA level (P<0.05) and protein level (P<0.01). Western-blot analysis showed that the expression levels of the long form of c-FLIP and the short form of c-FLIP in adenocarcinomas were 2.6-fold and 2.8-fold (P<0.01) higher than those in normal tissues respectively. However, no significant difference was found between the expression levels of the two isoforms in both adenocarcinomas or normal tissues. In conclusion, overexpression of c-FLIP is tumour specific, which may be one of the in vivo mechanisms by which tumour cells escape from apoptotic death during the malignant transformation, and plays an important role in lymph node metastasis of gastric adenocarcinoma, which ultimately contributes to the tumour progression.
Correction of cardiac output obtained by Modelflow® from finger pulse pressure profiles with a respiratory method in humans
Authors: TAM Enrico , KENFACK Marcel AZABJI , CAUTERO Michela , LADOR Federic , ANTONUTTO Guglielmo , DI PRAMPERO Pietro Enrico , FERRETTI Guido , CAPELLI Carlo
Published: April 2004

The beat-by-beat non-invasive assessment of cardiac output (Q, litre·min-1) based on the arterial pulse pressure analysis called Modelflow® can be a very useful tool for quantifying the cardiovascular adjustments occurring in exercising humans. Q was measured in nine young subjects at rest and during steady-state cycling exercise performed at 50, 100, 150 and 200 W by using Modelflow® applied to the Portapres® non-invasive pulse wave (QModelflow) and by means of the open-circuit acetylene uptake (QC2H2). Q values were correlated linearly (r=0.784), but Bland–Altman analysis revealed that mean QModelflow-QC2H2 difference (bias) was equal to 1.83 litre·min-1 with an S.D. (precision) of 4.11 litre·min-1, and 95% limits of agreement were relatively large, i.e. from -6.23 to +9.89 litre·min-1. QModelflow values were then multiplied by individual calibrating factors obtained by dividing QC2H2 by QModelflow for each subject measured at 150 W to obtain corrected QModelflow (Qcorrected) values. Qcorrected values were compared with the corresponding QC2H2 values, with values at 150 W ignored. Data were correlated linearly (r=0.931) and were not significantly different. The bias and precision were found to be 0.24 litre·min-1 and 3.48 litre·min-1 respectively, and 95% limits of agreement ranged from -6.58 to +7.05 litre·min-1. In conclusion, after correction by an independent method, Modelflow® was found to be a reliable and accurate procedure for measuring Q in humans at rest and exercise, and it can be proposed for routine purposes.
Changes in pulmonary vascular function after acute methionine loading in normal men
Authors: O'DOCHARTAIGH Conor , ONG Hean , LOVELL Sharon , DONNELLY Ronan , HANRATTY Colm , RILEY Marshall , FRENNEAUX Michael , YOUNG Ian , NICHOLLS Paul
Published: April 2004

Elevated blood levels of Hcy (homocysteine) are associated with endothelial dysfunction in the systemic and coronary arterial beds. We wished to know if similar changes could be detected in the pulmonary circulation, using non-invasive tests. We studied ten normal young men aged 23–31 years, in whom acute hyperhomocysteinaemia was induced by oral ingestion of methionine. Cardiopulmonary exercise testing [including measurement of exhaled breath NO (nitric oxide)] was performed on two occasions, with and without methionine loading. In addition, blood samples for vWf (von Willebrand factor) and factor VIIIc were taken as markers of endothelial function. After oral methionine, plasma Hcy increased from 11.8±3.1 to 31.2±10.3 µmol/l (values are means±S.D.; P<0.0001), whereas there was no increase after placebo. After exercise there was an increase in VNO (NO production) and circulating plasma levels of vWf and factor VIIIc, but these were similar in the two tests. Exercise time, HR (heart rate) and BP (blood pressure) responses and PVO2 (peak achieved O2 uptake) were also similar in the two tests. VE (expiratory minute ventilation)/VCO2 (CO2 production) was similar in the two groups at rest (methionine, 31.9±3.9; placebo, 30.5±3.9; P=0.11), but increased during exercise after methionine (at peak, 32.2±4.6 compared with 29.9±2.8; P=0.016). PETCO2 (end-tidal partial pressure of CO2) was also similar in the two groups at rest (35.1±2.9 compared with 36.8±3.2; P=0.11), but decreased throughout the methionine test (peak 34.1±4.4 compared with 36.7±3.5; P=0.006). VE vs VCO2 slope also increased in the methionine test (25.2±2.4 compared with 22.8±2.3; P=0.003). In conclusion, small, but consistent and significant, changes in respiratory gas exchange were seen after methionine loading, compatible with a V/Q (ventilation/perfusion) mismatch due to pulmonary vascular endothelial dysfunction.
Can mild-to-moderate hyperhomocysteinaemia impair endothelial function in the absence of other risk factors for cardiovascular disease?
Authors: HONING Marina L. H. , STEHOUWER Coen D. A.
Published: April 2004

The majority of clinical studies demonstrate that patients with hyperhomocysteinaemia have an increased risk of atherothrombotic events. However, there is a striking and poorly understood heterogeneity in the severity of clinical features in individuals with hyperhomocysteinaemia. This observation suggests that other factors must exist that modulate the relationship between hyperhomocysteinaemia and clinical disease. Therefore identifying factors that inhibit or enhance the vasculotoxic effects of homocysteine is important, as is elucidation of how homocysteine damages blood vessels. This comment discusses the study of Woodman and colleagues in this issue of Clinical Science in which they investigate the effects of hyperhomocysteinaemia on endothelial function.
Novel Approach to Diagnosis of a Wide‐Complex Tachycardia
Authors: GULA LORNE J. , SKANES ALLAN , KRAHN ANDREW D. , KLEIN GEORGE J.
Published: April 2004

Despite sophisticated atrial and ventricular pacing techniques used during electrophysiologic study, the exact mechanism of some tachycardias remain elusive. In this situation, eliminating conduction from specific tissue and observing the effect on the tachycardia can be diagnostic. Such a maneuver can be performed using the technique of ice mapping, which entails reversible cooling of tissue to test function prior to delivery of a permanent ablation lesion. We present a case of wide‐complex tachycardia with inconclusive results from diagnostic electrophysiologic study. Using ice mapping, cooling at the region of the compact AV node resulted in block in the ascending fast pathway. When cooling subsequently was applied to the region of the slow pathway, tachycardia broke in the descending limb; thus AV nodal reentrant tachycardia was diagnosed on an anatomic and functional basis. (J Cardiovasc Electrophysiol, Vol. 15, pp. 466‐469, April 2004)
Restitution Dynamics During Pacing and Arrhythmias in Isolated Pig Hearts
Authors: BANVILLE ISABELLE , CHATTIPAKORN NIPON , GRAY RICHARD A.
Published: April 2004

Introduction: The dependence of action potential duration (APD) on the preceding diastolic interval (DI), i.e., restitution, has been purported to predict the development of alternans and reentrant arrhythmias. However, restitution depends on the history of activation (i.e., memory), and its relevance to arrhythmia induction and maintenance is unknown.

Methods and Results: Using a dual‐camera video imaging system, we recorded action potentials from thousands of sites on the surface of the isolated pig heart. A steady‐state pacing (SSP) protocol was performed to generate the SSP APD restitution curve. During SSP, the minimum DI and APD were 57 ± 6 ms and 107 ± 6 ms, respectively. The restitution slope was >1 for DIs <85 ± 5 ms; however, alternans were not observed. Abrupt decreases in cycle length (CL) resulted in a rapid (<5 beats) decrease in APD followed by a slower decrease to “steady state.” DI, APD pairs for the initial beats following these rate changes were significantly above the SSP restitution curve. DI, APD pairs measured during sustained ventricular fibrillation clustered significantly below the SSP restitution curve, at significantly shorter APDs (57 ± 4 ms) and DIs (49 ± 6 ms) than could be achieved during SSP. In addition, abrupt increases in CL following SSP resulted in APDs significantly shorter than those predicted from the SSP restitution curve.

Conclusion: Our results indicate that the responses of APD and DI to sudden rate changes and during arrhythmias are not predicted by the SSP restitution relationship. Acute dynamics act to damp out the proarrhythmic oscillations predicted from the SSP restitution curve. (J Cardiovasc Electrophysiol, Vol. 15, pp. 455‐463, April 2004)
Inhibitors of the Na+/H+ Exchanger Cannot Prevent Atrial Electrical Remodeling in the Goat
Authors: BLAAUW YURI , BEIER NORBERT , VAN DER VOORT PEPIJN , VAN HUNNIK ARNE , SCHOTTEN ULRICH , ALLESSIE MAURITS A.
Published: April 2004

Introduction: It has been suggested that blockade of the Na+/H+ exchanger (NHE1) can prevent atrial fibrillation (AF)‐induced electrical remodeling and the development of AF.

Methods and Results: AF was maintained by burst pacing in 10 chronically instrumented conscious goats. Intravenous and oral dosages of two NHE1 blockers (EMD87580 and EMD125021) resulted in plasma levels several magnitudes higher than required for effective NHE1 blockade. Shortening of atrial refractoriness immediately after 5 minutes of AF was not prevented by NHE1 blockade. In remodeled atria, increasing dosages of EMD87580 and EMD125021 did not reverse shortening of the atrial refractory period or reduce the duration of AF episodes. The cycle length during persistent AF also was not affected. Oral pretreatment with EMD87580 (8 mg/kg bid) starting 3 days before AF could not prevent electrical remodeling. After 24 and 48 hours of remodeling, the duration of AF paroxysms was 47 ± 32 seconds and 135 ± 63 seconds compared to 56 ± 17 seconds and 136 ± 52 seconds in placebo‐treated animals (P > 0.8), respectively.

Conclusion: In the goat model of AF, the Na+/H+ exchanger inhibitors EMD87580 and EMD125021 did not prevent or revert AF‐induced electrical remodeling. This indicates that activation of the Na+/H+ exchanger is not involved in the intracellular pathways of electrical remodeling. This does not support the suggestion that blockers of the Na+/H+ exchanger may be beneficial for prevention and treatment of AF. (J Cardiovasc Electrophysiol, Vol. 15, pp. 440‐446, April 2004)
Low‐Affinity Nerve Growth Factor Receptor p75NTR Immunoreactivity in the Myocardium with Sympathetic Hyperinnervation
Authors: ZHOU SHENGMEI , CAO JI‐MIN , SWISSA MOSHE , GONZALEZ‐GOMEZ IGNACIO , CHANG CHE‐MING , CHIEN KAI , MIYAUCHI YASUSHI , FU KATHERINE J. , YI JOHNNY , ASOTRA KAMLESH , KARAGUEUZIAN HRAYR S. , FISHBEIN MICHAEL C. , CHEN PENG‐SHENG , CHEN LAN S.
Published: April 2004

Introduction: We previously demonstrated the relationship between sympathetic nerve density in myocardium and the occurrences of ventricular arrhythmia. Nerve growth factor (NGF) regulates myocardial sympathetic innervation. However, it is unclear whether the NGF high‐affinity receptor tyrosine kinase A (TrkA) and the NGF low‐affinity receptor p75NTR are altered in the state of sympathetic hyperinnervation in the heart. The aim of this study was to determine the density and location of TrkA and p75NTR in canine ventricles with sympathetic hyperinnervation.

Methods and Results: Myocardial sympathetic hyperinnervation was induced by local infusion of NGF into myocardium or left stellate ganglia, or chronic subthreshold electric stimulation to the left stellate ganglia. The results showed that TrkA immunoreactivity was absent in the myocardium. Low‐affinity receptor p75NTR immunoreactivity was present in axons, Schwann cells, and interstitial cells of sympathetic nerves, as well as in interstitial cells of the myocardium. The density of p75NTR immunolabeled myocardial interstitial cells at the NGF infusion site was lower than that at the site remote from NGF infusion, yet the sympathetic nerve density was higher at the infusion site than the remote area. The density of p75NTR also was lower in the myocardium with high sympathetic nerve density, induced by NGF infusion or chronic electric stimulation of the left stellate ganglia, compared to control groups.

Conclusion: The data indicate that p75NTR may be the main NGF receptor in the myocardium, and p75NTR immunopositive interstitial cells may have a role in regulating sympathetic nerve growth in canine heart. (J Cardiovasc Electrophysiol, Vol. 15, pp. 430‐437, April 2004)
Drug‐Induced Torsades de Pointes and Implications for Drug Development
Authors: FENICHEL ROBERT R. , MALIK MAREK , ANTZELEVITCH CHARLES , SANGUINETTI MICHAEL , RODEN DAN M. , PRIORI SILVIA G. , RUSKIN JEREMY N. , LIPICKY RAYMOND J. , CANTILENA LOUIS R. ,   Independent Academic Task Force
Published: April 2004

Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug‐induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug‐induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to‐benefit interpretation of drug‐induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug‐related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug‐induced torsades within the larger evaluation of drug‐related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475‐495, April 2004)
High‐Resolution Mapping Around the Crista Terminalis During Typical Atrial Flutter:
Authors: TAI CHING‐TAI , HUANG JIN‐LONG , LEE PI‐CHANG , DING YU‐AN , CHANG MAU‐SONG , CHEN SHIH‐ANN
Published: April 2004

Introduction: The aim of this study was to delineate activation patterns around the crista terminalis (CT) using high‐resolution noncontact mapping.

Methods and Results: Twenty‐six patients with typical atrial flutter (20 counterclockwise and 6 clockwise) were enrolled in the study. A noncontact mapping system was used to map atrial flutter. There were three activation patterns around the line(s) of block. Type I (n = 6) showed activation around a single complete line of block located in the CT. Type II (n = 17) showed activation around a single incomplete line of block with a conduction gap in the CT. Type III (n = 3) showed activation around double lines of block, one located in the CT and the other located in the sinus venosa region. Simultaneous activation around the tricuspid annulus and through the CT gap could result in double loop reentry (n = 12). After successful ablation of the cavotricuspid isthmus (CTI) in 24 patients, upper loop reentry was still induced in 12 patients with double loop reentry. Subsequent ablation of the CT gap was performed successfully in these 12 patients, and no arrhythmia was inducible thereafter. During the follow‐up period of 8.4 ± 4.1 months, there was no recurrence of atrial flutter in any patient.

Conclusion: During typical atrial flutter, the CT might be an incomplete barrier. Simultaneous conduction through the CTI and CT gap could result in double loop reentry. Radiofrequency ablation of the CTI and CT gap was effective in eliminating this arrhythmia. (J Cardiovasc Electrophysiol, Vol. 15, pp. 406‐414, April 2004)
Isolated Sphenoid Lesions: Diagnosis and Management
Authors: Sethi Dharambir S.
Published: April 2004

Isolated sphenoid lesions are rare. It is likely that isolated sphenoid sinus disease is underreported for a number of reasons. First, the presenting symptoms are often nonspecific; second, the inaccessibility of the sinus precludes optimal physical examination; and third, before the advent of CT and MRI scanning, radiologic examination of the sinus was inadequate. Endoscopic evaluation and current imaging techniques with CT or MRI have contributed to an increase in diagnosis of these lesions. Twenty‐one patients with isolated sphenoid lesions that I treated in a 4‐year period are presented. The pathology was unilateral sphenoid sinusitis (8), sphenoid mucoceles (4), inflammatory spheno‐choanal polyp (3), inverting papilloma (2), invasive pituitary adenoma (1), carcinoma (1), aspergilloma (1), and fibrous dysplasia (1). Endoscopic biopsy was carried out in 7 patients (33.3%). A precise diagnosis after endoscopy, biopsy, and imaging studies was established in all patients. Definitive treatment included an endoscopic sphenoidotomy in 15 (71.4%). Five patients (23.8%) were treated with other therapeutic modalities. One patient did not require any definitive treatment. The combined use of imaging techniques and diagnostic nasal endoscopy allows for an accurate diagnosis and enables minimally invasive techniques to be tailored to the patient's disease.
Effect of Uvulopalatopharyngoplasty and Genial and Hyoid Advancement on Swallowing in Patients with Obstructive Sleep Apnea Syndrome
Authors: Altman Jerald S. , Halpert Robert D. , Mickelson Samuel A. , Senior Brent A.
Published: April 2004

OBJECTIVE

Uvulopalatopharyngoplasty (UPPP) and genial and hyoid advancement (GHA) are surgical techniques for the treatment of obstructive sleep apnea. These techniques enlarge the oropharyngeal and hypopharyngeal airway, reducing collapse at these levels. This study evaluated the effect of these procedures on swallowing.

METHODS

Fifteen patients who had undergone UPPP and GHA were evaluated with a modified barium swallow to assess biomechanical changes in swallowing. Specifically, velopharyngeal insufficiency; changes in tongue‐base movement, laryngeal elevation, and closure; epiglottic movement; and pharyngoesophageal opening were examined. A brief swallowing questionnaire was administered to assess for subjective changes in swallowing.

RESULTS

Nine of 15 patients demonstrated abnormal objective swallow, of whom 5 reported normal subjective swallowing. Six of 15 demonstrated normal objective swallowing. Of these, 5 reported subjective change.

CONCLUSION

UPPP with GHA may alter biomechanical events during deglutition. However, little correlation exists between subjective symptoms and objective findings. Further studies that include preoperative and postoperative modified barium swallows are needed to identify a cause‐and‐effect relationship. (Otolaryngol Head Neck Surg 1999;120:454‐7.)
Direct Round Window Membrane Application of Gentamicin in the Treatment of Meniere's Disease
Authors: Silverstein Herbert , Arruda Johnny , Rosenberg Seth I. , Deems Daniel , Hester T. Oma
Published: April 2004

OBJECTIVE

To evaluate the effectiveness of the round window membrane (RWM) Gelfoam gentamicin technique in patients with Meniere's disease who were unresponsive to medical management or in whom surgical therapy failed.

STUDY DESIGN

Protocol 1, single intratympanic gentamicin infusion; protocol 2 (the best method), 2 infusions, 5 days apart with reevaluation at 1 month; and protocol 3, multiple infusions 1 to 4 weeks apart.

PATIENTS

In total, 32 patients (19 male, 13 female) were enrolled in the study. The mean age was 65 years (range 34 to 94 years). Seven of these patients were surgical salvage cases.

INTERVENTIONS

Laser‐assisted otoendoscopy with a 1.7‐mm otoendoscope (Smith‐Nephew Richards, Memphis, TN) was performed first. If the RWM was obscured by mucosa or adhesions, these were cleared before placing a 2 × 3 mm piece of dry Gelfoam against the RWM. Buffered gentamicin (26.7 mg/mL) was then injected into the middle ear (0.2 to 0.3 mL).

RESULTS

Overall, vertigo was controlled in 75% of the patients after the completion of the treatment, with subtotal vestibular ablation in two thirds of patients. Hearing was preserved in 90% of the patients (within 15 dB pure‐tone average or 15% speech discrimination score), tinnitus improved in 48%, and aural pressure improved in 62.5%.
Gastroesophageal Reflux: A Critical Factor in Pediatric Subglottic Stenosis
Authors: Halstead Lucinda A.
Published: April 2004

Gastroesophageal reflux (GER) plays a causative role in the development of subglottic stenosis (SGS) in children. This study examined the impact of aggressive antireflux therapy on the clinical outcomes of 35 children. Since 1994, 25 children were treated aggressively with omeprazole and cis‐apride before endoscopic surgical repair of their stenoses, which ranged from Cotton grades 1 to 3. Nine patients became asymptomatic on antireflux therapy alone. Endoscopic repair was performed in 16 patients. Endoscopic repair failed in only 1, who required tracheotomy. Before 1994, all children undergoing endoscopic repair of SGS were treated perioperatively for reflux. Endoscopic repair failed in 10 of the 57 children, and all required tracheotomy. The clinical outcome of these 10 patients after aggressive antireflux therapy is described. Five of the 10 have been decannulated. The role of double pH probe testing and the importance of the pharyngeal probe for monitoring the response to antireflux medication are described. The probe data suggest that in some instances GER may be limited to perioperative stress, but in many cases, especially in premature infants with SGS, GER can persist unabated for years and is not outgrown as the patient matures.
Expression of Major Histocompatibility Complex Antigens in Squamous Cell Carcinomas of the Head and Neck: Effects of Interferon Gene Transfer
Authors: Arosarena Oneida A. , Baranwal Seema , Strome Scott , Wolf Gregory T. , Krauss John C. , Bradford Carol R. , Carey Thomas E.
Published: April 2004

The effect of retroviral‐mediated interferon‐γ (IFN‐γ) gene transfer on major histocompatibility complex (MHC) class I and II antigen expression was investigated in 13 head and neck squamous carcinoma cell lines. Six cell lines exhibited increased MHC class I expression, and 10 exhibited increased MHC class II expression after IFN‐γ gene transfer. Differences in MHC antigen expression between parental and transduced cell lines were significant (P = 0.002) only for cell lines that upregulated MHC class II expression. After incubation in medium containing 100 U/mL recombinant IFN‐γ, or in medium from IFN‐γ retrovirus‐transduced NIH 3T3 cells, 12 cell lines significantly upregulated MHC class I expression, and 9 significantly upregulated MHC class II expression. Only cell lines that exhibited increased MHC class II expression after retroviral transduction also upregulated class II expression with exogenous IFN‐γ treatment. Thus some head and neck squamous carcinoma cell lines can upregulate MHC class I and II expression after exogenous application of either IFN‐γ or IFN‐γ retro‐viral transduction. These are promising findings for head and neck cancer immunotherapy and gene therapy.
Pharyngeal pH Monitoring in Patients with Posterior Laryngitis
Authors: Ulualp Seckin O. , Toohill Robert J. , Hoffmann Raymond , Shaker Reza
Published: April 2004

OBJECTIVE

To evaluate the diagnostic value of 3‐site 24‐hour ambulatory pH monitoring in patients with posterior laryngitis (PL) and the prevalence of esophageal abnormalities in this patient group.

METHODS

Twenty patients with PL and 17 healthy volunteers were studied as controls. Control subjects had transnasal esophagogastroduodenoscopy (T‐EGD) and ambulatory pH monitoring. Patients underwent T‐EGD, ambulatory pH monitoring, and barium esophagram.

RESULTS

T‐EGD documented no abnormality in controls. Esophagitis was present in 2 PL patients, and hiatal hernia in 3. Ambulatory pH monitoring showed that 15 PL patients and 2 controls exhibited pharyngeal acid reflux. Barium esophagram documented gastroesophageal reflux in 5 PL patients. However, none of these barium reflux events reached the pharynx. All PL patients with barium esophagram evidence of gastroesophageal reflux also showed pharyngeal acid reflux by pH monitoring.

CONCLUSION

Pharyngeal acid reflux is more prevalent in patients with PL than in healthy controls. Patients with PL infrequently have esophageal sequelae of reflux disease. Ambulatory 24‐hour simultaneous 3‐site pharyngoesophageal pH monitoring detects gastroesophagopharyngeal acid reflux events in most patients with PL.
Time Course of Hearing Loss in an Animal Model of Pneumococcal Meningitis
Authors: Kesser Bradley W. , Hashisaki George T. , Spindel Jonathan H. , Ruth Roger A. , Scheld W. Michael
Published: April 2004

A leading cause of morbidity from bacterial meningitis is an irreversible, usually profound sensorineural hearing loss, with an incidence as high as 30% in some studies. Bacterial meningitis remains the most common cause of acquired postnatal sensorineural deafness. Although several clinical studies have examined the long‐term outcome of hearing in meningitis, few studies have examined the time course of hearing loss during the acute course of the disease. We have developed an animal model of meningogenic hearing loss in the rat and have plotted the time course of that hearing loss. Serial auditory brain stem responses (ABRs) were measured in rats inoculated in the cisterna magna (subarachnoid space) with Streptococcus pneumoniae (105 to 107 colony‐forming units). All rats injected developed meningitis as evidenced by increased cerebrospinal fluid (CSF) white cell counts and positive CSF cultures. Serial ABR measurements taken 6, 12, 15, 18, 21, and 24 hours after inoculation demonstrated significant threshold shifts and eventual loss of the ABR waveform as compared with measurements in control rats injected with sterile culture medium. Hearing loss began approximately 12 to 15 hours after inoculation and progressed to complete loss by 24 hours (17 of 18 animals). No correlation was found between the magnitude of hearing loss and CSF white cell count or bacterial titer. Temporal bone histology of rats with meningitis shows a dense inflammatory cell infiltrate throughout the subarachnoid space. Labyrinthine inflammatory cells were confined to the scala tympani.
Stage Grouping Reliability: TNM '97 versus TANIS in Laryngeal Cancer
Authors: Carinci Francesco , Farina Antonio , Pelucchi Stefano , Pastore Antonio , Longhini Luca , Urso Richard G. , Calearo Carlo
Published: April 2004

PURPOSE

To compare the correlation of TANIS and TNM '97 with the survival rate in laryngeal cancer.

METHODS AND MATERIAL

From 1970 to 1990, 599 patients at the ENT Clinic, University of Ferrara, had a complete follow‐up and met the criteria of enrollment. Data were analyzed by means of survival analyses (Kaplan‐Meier and Cox algorithms).

RESULTS

Both systems showed a significant correlation with the survival rate. TANIS advanced subcategories were better correlated with the mortality rate than TNM stages IVa and IVb. Again, in the final statistical model, TANIS was more highly correlated with survival rate than TNM.
Reverse Impact Assessment Using a Regional Social Accounting Matrix
Authors: Cardenete Manuel Alejandro , Sancho Ferran
Published: April 2004

Unlike traditional impact analysis, that measures the influence of a sector, or a set of like sectors, on the overall economy, we present in this note a simple reverse procedure that attempts to quantify the impact of activity changes in the overall regional economy over a specific subset of firms. We apply the procedure to a specific enclave of the chemical and basic industry sectors, which has been and still is of special significance for the development of the region. Because we feel that interdependency effects should be adequately captured, we rely on a 1995 regional social accounting matrix (SAM) of Andalusia, Spain, to establish the empirical structural support for the analysis. We proceed by setting up a linear SAM model to obtain extended multipliers, then we decompose them in three categories of effects (direct, indirect, and induced) under different hypotheses about the classification of endogenous and exogenous sectors. The decomposed multipliers are then apportioned to measure and distinguish the effects on the economic enclave. The results are seen to be quite robust to the exogeneity assumptions.
Consumer Citizens and the Cities for Climate Protection Campaign
Authors: Slocum Rachel
Published: April 2004

The Cities for Climate Protection campaign, an effort to lower greenhouse-gas emissions at the city scale, operates within the neoliberal state. Two features characterize the interaction of the state and the public via this campaign: a lack of public involvement, and the construction of the citizen as a passive consumer. The author emphasizes a tension that exists between two readings of the consumer citizen: the pliable figure who listens to neoliberal bottom-line arguments, and the political economic actor who identifies not with consumerism but with political change. Citizens thus cannot be wholly embodied by constructions such as the consumer, and consumerist activism has potential. Citizens, though often interpellated as consumers, can position themselves as reasoning publics who see climate change, their cities, and themselves in relational perspective. The author enlists Foucauldian and deliberative-democracy theory to explore the making of citizens through the Cities for Climate Protection campaign.
Sign Value, Topophilia, and the Locational Component in Property Prices
Authors: Kauko Tom
Published: April 2004

Over the last few decades a certain fragmentation of economy and society has taken place on a global scale. A related observation is that the marketplace for landed property has become more complex, involving more actors and informal networks. The consequence is a cultural and behavioural reorientation of the conceptual model of property-value formation, which traditionally is anchored in equilibrium economics. This postulate is especially relevant for the residential sector as households and their preferences, as well as external factors forcing their mobility, are factors that contribute to the formation of house prices. However, from the early 1970s there was literature that pointed to a multidimensional theoretical framework on aesthetic and other values that ‘make the place’. Using more multiple and idiosyncratic perspectives of value conceptualisation is therefore not a completely new trend, only a neglected line of research. With these potentially powerful formulations as the background, this contribution presents evidence of property-value formation from the 1990s Helsinki housing market. Using the analytic hierarchy process, quality ranks for different bundles of locational attributes were generated based on interactive data, and compared with actual market-outcome data. Both the theoretical and the empirical material compiled for this paper suggest that, to remain a valid concept, equilibrium needs to be treated at the level of market price together with stated actor choice—not just on the level of the first concept.
International Water Resources Allocation and Conflicts: The Case of the Euphrates and Tigris
Authors: Kucukmehmetoglu Mehmet , Guldmann Jean-Michel
Published: April 2004

This paper presents a linear programming model that allocates the waters of the Euphrates and Tigris rivers to irrigation, urban consumption, and on-stream hydroelectricity production in the three riparian countries (Turkey, Syria, and Iraq), by maximizing the aggregate net benefits from water uses while accounting for water-conveyance costs. The model represents, in network form, the system made of the two rivers and their various consumption, supply, and transshipment nodes, and accounts for evaporation and return flows. The constraints include water-conservation balances and maximum and minimum water consumption. The model is used to assess the economic consequences of various cooperation and noncooperation strategies that may be adopted by the riparian countries. Cooperative game-theory concepts (core and Shapley value) are used to identify stable water allocations, under which all three countries find it beneficial to cooperate. The results suggest that an allocation of the total benefits exists, under various scenarios of future energy prices and agricultural productivities, that makes this global cooperation attractive to all countries. Various research extensions are outlined.
ICT and Substitution Between Out-of-Home and at-Home Work: The Importance of Timing
Authors: de Graaff Thomas , Rietveld Piet
Published: April 2004

This paper investigates the determinants of at-home and out-of-home labor supply in the Netherlands in the 1990s, focusing on the presence of information and computer technology (ICT) in households—in particular modem possession. To investigate these determinants, a sequential hurdle model is estimated in which people first decide to work and then decide to divide total labor supply in at-home and out-of-home labor supply. To correct for possible endogeneity, the modem variable is estimated by means of instrumental variables. When we consider only office hours, possession of ICT facilities at home stimulates both at-home and out-of-home labor supply. Thus, the two may be called complements from the ICT perspective. However, outside office hours, modem possession leads to less work out of home. During this part of the day the time worked less on the job is partly substituted by work at home. Thus, during this part of the week we find that substitution dominates. However, because labor supply during office hours dominates labor supply during the rest of the week we find complementarity as the main feature of overall labor supply. These results underline the importance of timing issues.
Facilitated Processing of Visual Stimuli Associated with the Body
Authors: Whiteley Louise , Kennett Steffan , Taylor-Clarke Marisa , Haggard Patrick
Published: April 2004

Recent work on tactile perception has revealed enhanced tactile acuity and speeded spatial-choice reaction times (RTs) when viewing the stimulated body site as opposed to viewing a neutral object. Here we examine whether this body-view enhancement effect extends to visual targets. Participants performed a speeded spatial discrimination between two lights attached either to their own left index finger or to a wooden finger-shaped object, making a simple distal–proximal decision. We filmed either the finger-mounted or the object-mounted lights in separate experimental blocks and the live scene was projected onto a screen in front of the participants. Thus, participants responded to identical visual targets varying only in their context: on the body or not. Results revealed a large performance advantage for the finger-mounted stimuli: reaction times were substantially reduced, while discrimination accuracy was unaffected. With this finding we address concerns associated with previous work on the processing of stimuli attributed to the self and extend the finding of a performance advantage for such stimuli to vision.