bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Sorting of the Yeast Uracil Permease to the Endosomal System Is Controlled by Uracil Binding and Rsp5p-dependent Ubiquitylation
Authors: Blondel Marie-Odile , Morvan Joëlle , Dupré Sophie , Urban-Grimal Danièle , Haguenauer-Tsapis Rosine , Volland Christiane
Published: December 2003

The yeast uracil permease, Fur4p, is downregulated by uracil, which is toxic to cells with high permease activity. Uracil promotes cell surface Rsp5p-dependent ubiquitylation of the permease, signaling its endocytosis and further vacuolar degradation. We show here that uracil also triggers the direct routing of its cognate permease from the Golgi apparatus to the endosomal system for degradation, without passage via the plasma membrane. This early sorting was not observed for a variant permease with a much lower affinity for uracil, suggesting that uracil binding is the signal for the diverted pathway. The FUI1-encoded uridine permease is similarly sorted for early vacuolar degradation in cells exposed to a toxic level of uridine uptake. Membrane proteins destined for vacuolar degradation require sorting at the endosome level to the intraluminal vesicles of the multivesicular bodies. In cells with low levels of Rsp5p, Fur4p can be still diverted from the Golgi apparatus but does not reach the vacuolar lumen, being instead missorted to the vacuolar membrane. Correct luminal delivery is restored by the biosynthetic addition of a single ubiquitin, suggesting that the ubiquitylation of Fur4p serves as a specific signal for sorting to the luminal vesicles of the multivesicular bodies. A fused ubiquitin is also able to sort some Fur4p from the Golgi to the degradative pathway in the absence of added uracil but the low efficiency of this sorting indicates that ubiquitin does not itself act as a dominant signal for Golgi-to-endosome trafficking. Our results are consistent with a model in which the binding of intracellular uracil to the permease signals its sorting from the Golgi apparatus and subsequent ubiquitylation ensures its delivery to the vacuolar lumen.
Meiosis-specific Failure of Cell Cycle Progression in Fission Yeast by Mutation of a Conserved β-Tubulin Residue
Authors: Paluh Janet L. , Killilea Alison N. , Detrich H. William , Downing Kenneth H.
Published: December 2003

The microtubule cytoskeleton is involved in regulation of cell morphology, differentiation, and cell cycle progression. Precisely controlled dynamic properties are required for these microtubule functions. To better understand how tubulin's dynamics are embedded in its primary sequence, we investigated in vivo the consequences of altering a single, highly conserved residue in β-tubulin that lies at the interface between two structural domains. The residue differs between the cold-adapted Antarctic fish and temperate animals in a manner that suggests a role in microtubule stability. Fungi, like the Antarctic fish, have a phenylalanine in this position, whereas essentially all other animals have tyrosine. We mutated the corresponding residue in fission yeast to tyrosine. Temperature effects were subtle, but time-lapse microscopy of microtubule dynamics revealed reduced depolymerization rates and increased stability. Mitotic exit signaled by breakdown of the mitotic spindle was delayed. In meiosis, microtubules displayed prolonged contact to the cell cortex during horsetail movement, followed by completion of meiosis I but frequent asymmetric failure of meiosis II spindle formation. Our results indicate that depolymerization dynamics modulated through interdomain motion may be important for regulating a subset of plus-end microtubule complexes in Schizosaccharomyces pombe.
Reassessing the Role and Dynamics of Nonmuscle Myosin II during Furrow Formation in EarlyDrosophilaEmbryos
Authors: Royou Anne , Field Christine , Sisson John C. , Sullivan William , Karess Roger
Published: December 2003

The early Drosophila embryo undergoes two distinct membrane invagination events believed to be mechanistically related to cytokinesis: metaphase furrow formation and cellularization. Both involve actin cytoskeleton rearrangements, and both have myosin II at or near the forming furrow. Actin and myosin are thought to provide the force driving membrane invagination; however, membrane addition is also important. We have examined the role of myosin during these events in living embryos, with a fully functional myosin regulatory light-chain-GFP chimera. We find that furrow invagination during metaphase and cellularization occurs even when myosin activity has been experimentally perturbed. In contrast, the basal closure of the cellularization furrows and the first cytokinesis after cellularization are highly dependent on myosin. Strikingly, when ingression of the cellularization furrow is experimentally inhibited by colchicine treatment, basal closure still occurs at the appropriate time, suggesting that it is regulated independently of earlier cellularization events. We have also identified a previously unrecognized reservoir of particulate myosin that is recruited basally into the invaginating furrow in a microfilament-independent and microtubule-dependent manner. We suggest that cellularization can be divided into two distinct processes: furrow ingression, driven by microtubule mediated vesicle delivery, and basal closure, which is mediated by actin/myosin based constriction.
Caveolae Are a Novel Pathway for Membrane-Type 1 Matrix Metalloproteinase Traffic in Human Endothelial Cells
Authors: Gálvez Beatriz G. , Matías-Román Salomón , Yáñez-Mó María , Vicente-Manzanares Miguel , Sánchez-Madrid Francisco , Arroyo Alicia G.
Published: December 2003

The extracellular matrix (ECM) distinctly modulates membrane type 1-matrix metalloproteinase (MT1-MMP) in human endothelial cells (ECs). Herein, ECM-dependent RhoA activation is shown to regulate MT1-MMP localization and activity as well as clathrin-independent internalization in confluent ECs. In this regard, caveolae are revealed as the major MT1-MMP endocytic pathway in human ECs. Thus, MT1-MMP is present at caveolae with caveolin-1 and both proteins together with αvβ3 integrin colocalize at endothelial motility-associated extensions. Remarkably, caveolae traffic is required for proper MT1-MMP localization, activity, and function in migratory ECs as demonstrated by both treatment with caveolae-disrupting agents or selective targeting caveolin-1 expression by interference RNA. Thus, caveolae-mediated traffic constitutes a novel mechanism for MT1-MMP regulation in ECs during angiogenesis.
Telomere Attachment, Meiotic Chromosome Condensation, Pairing, and Bouquet Stage Duration Are Modified in Spermatocytes Lacking Axial Elements
Authors: Liebe Bodo , Alsheimer Manfred , Höög Christer , Benavente Ricardo , Scherthan Harry
Published: December 2003

During the extended prophase to the meiosis I division, chromosomes assemble axial elements (AE) along replicated sister chromatids whose ends attach to the inner nuclear membrane (NM) via a specialized conical thickening. Here, we show at the EM level that in Sycp3-/-spermatocyte chromosomes lack the AE and the conical end thickening, but still they attach their telomeres to the inner NM with an electron-dense plate that contains T2AG3repeats. Immunofluorescence detected telomere proteins, SCP2, and the meiosis-specific cohesin STAG3 at the Sycp3-/-telomere. Bouquet stage spermatocytes were approximately threefold enriched, and the number of telomere but not centromere signals was reduced to the haploid in advanced Sycp3-/-spermatocytes, which indicates a special mode of homolog pairing at the mammalian telomere. Fluorescence in situ hybridization with mouse chromosome 8- and 12-specific subsatellite probes uncovered reduced levels of regional homolog pairing, whereas painting of chromosomes 13 revealed partial or complete juxtapositioning of homologs; however, condensation of Sycp3-/-bivalents was defective. Electron microscopic analysis of AE-deficient spermatocytes revealed that transverse filaments formed short structures reminiscent of the synaptonemal complex central region, which likely mediate stable homolog pairing. It appears that the AE is required for chromosome condensation, rapid exit from the bouquet stage, and fine-tuning of homolog pairing.
WRN Helicase and FEN-1 Form a Complex upon Replication Arrest and Together Process Branchmigrating DNA Structures Associated with the Replication Fork
Authors: Sharma Sudha , Otterlei Marit , Sommers Joshua A. , Driscoll Henry C. , Dianov Grigory L. , Kao Hui-I , Bambara Robert A. , Brosh Robert M.
Published: December 2003

Werner Syndrome is a premature aging disorder characterized by genomic instability, elevated recombination, and replication defects. It has been hypothesized that defective processing of certain replication fork structures by WRN may contribute to genomic instability. Fluorescence resonance energy transfer (FRET) analyses show that WRN and Flap Endonuclease-1 (FEN-1) form a complex in vivo that colocalizes in foci associated with arrested replication forks. WRN effectively stimulates FEN-1 cleavage of branch-migrating double-flap structures that are the physiological substrates of FEN-1 during replication. Biochemical analyses demonstrate that WRN helicase unwinds the chicken-foot HJ intermediate associated with a regressed replication fork and stimulates FEN-1 to cleave the unwound product in a structure-dependent manner. These results provide evidence for an interaction between WRN and FEN-1 in vivo and suggest that these proteins function together to process DNA structures associated with the replication fork.
A Conserved Mechanism for Bni1- and mDia1-induced Actin Assembly and Dual Regulation of Bni1 by Bud6 and Profilin
Authors: Moseley James B. , Sagot Isabelle , Manning Amity L. , Xu Yingwu , Eck Michael J. , Pellman David , Goode Bruce L.
Published: December 2003

Formins have conserved roles in cell polarity and cytokinesis and directly nucleate actin filament assembly through their FH2 domain. Here, we define the active region of the yeast formin Bni1 FH2 domain and show that it dimerizes. Mutations that disrupt dimerization abolish actin assembly activity, suggesting that dimers are the active state of FH2 domains. The Bni1 FH2 domain protects growing barbed ends of actin filaments from vast excesses of capping protein, suggesting that the dimer maintains a persistent association during elongation. This is not a species-specific mechanism, as the activities of purified mammalian formin mDia1 are identical to those of Bni1. Further, mDia1 partially complements BNI1 function in vivo, and expression of a dominant active mDia1 construct in yeast causes similar phenotypes to dominant active Bni1 constructs. In addition, we purified the Bni1-interacting half of the cell polarity factor Bud6 and found that it binds specifically to actin monomers and, like profilin, promotes rapid nucleotide exchange on actin. Bud6 and profilin show additive stimulatory effects on Bni1 activity and have a synthetic lethal genetic interaction in vivo. From these results, we propose a model in which Bni1 FH2 dimers nucleate and processively cap the elongating barbed end of the actin filament, and Bud6 and profilin generate a local flux of ATP-actin monomers to promote actin assembly.
Candidate's Thesis: Platelet‐Activating Factor–Induced Hearing Loss: Mediated by Nitric Oxide?
Authors: Rhee Chung‐Ku
Published: December 2003

Objectives/Hypothesis Platelet‐activating factor (PAF)in middle ear effusion is thought to induce hearing loss. The purpose of this study is to investigate the role of nitric oxide (NO) in the mechanism of PAF‐induced hearing loss by studying the effects of PAF application on the round window membrane (RWM) with and without PAF‐antagonist NO‐blocker.

Study Design Longitudinal study on randomized guinea pigs using PAF to induce hearing loss.

Methods Guinea pigs were divided into four groups: PBS, PAF, PAF‐antagonist, and L‐NAME. The PBS group received phosphate buffered saline (PBS) and the PAF groups received 10, 20, and 40 μg of PAF soaked into gelfoam and placed on the RWM. PAF‐antagonist (WEB 2170) and NOS inhibitor NG‐nitro‐l‐arginine‐methylester (L‐NAME) were injected intraperitoneally prior to PAF 20 μg application on the RWM. The following three tests were performed on each animal group: Hearing was tested with an auditory brainstem response (ABR) test over 24 hours. At the end of 24 hours, cochlear hair cells were examined by scanning electron microscopy (SEM) and immunohistochemistry was carried out on the cochlea to test the expression of inducible nitric oxide synthase (iNOS).

Results The PAF group developed significant elevation of ABR threshold and cochlear hair cell damage in the SEM group as compared with the PBS control group. The PAF‐antagonist (WEB 2170) and the L‐NAME groups did not show significant elevation of ABR threshold and cochlear hair cell damage compared with the group administered PAF 20 μg, but in the PAF‐antagonist group, the elevation of ABR threshold was significant compared with that of the PBS control group, whereas it was not significant compared with the PBS group in the L‐NAME group. Strong expression of iNOS on cochlea was observed in the PAF group and lighter expression was seen in PBS, WEB 2170, and L‐NAME groups.

Conclusions This study demonstrated that PAF placed on the RWM induced hearing loss and cochlear hair cell damage. The PAF‐antagonists and L‐NAME prevented the PAF‐induced hearing loss and inhibited iNOS expression in the cochlea. These findings suggest that the PAF‐induced hearing loss caused by cochlear hair cell damage may have been mediated by NO. PAF‐antagonists and L‐NAME may have future therapeutic implications in preventing sensorineural hearing loss associated with chronic otitis media. The results of this study have significant potential clinical application.
A Method to Intraoperatively Assess Stapes Prostheses for Magnetic Attraction
Authors: White David W.
Published: December 2003

Objective To present a technique used to assess metallic otologic protheses for magnetic susceptibility during surgery.

Study Design Description of a surgical technique.

Methods A sterile handheld pacemaker magnet is used to evaluate the prothesis prior to implantation. The magnet is placed over the prosthesis and the prosthesis is placed directly on the magnet. Any evidence of magnetic attraction and the prosthesis is rejected prior to implantation.

Results None of the prostheses screened showed any magnetic attraction. As a control, steel wire was cut into pieces with dimensions similar to prostheses. These sections of wire were readily attracted to the magnet.

Conclusions Intraoperative screening of metallic prostheses for magnetic susceptibility is possible using a sterile handheld pacemaker magnet.
Esthesioneuroblastoma: Endoscopic Nasal and Anterior Craniotomy Resection
Authors: Devaiah Anand K. , Larsen Christopher , Tawfik Ossama , O'Boynick Paul , Hoover Larry A.
Published: December 2003

Objectives/Hypothesis The objective was to illustrate the use of endoscopic techniques as an evolving surgical modality in excision of esthesioneuroblastoma. The authors advocate this method with excision with anterior craniotomy for removal of cribriform plate or anterior cranial fossa tumor extension.

Study Design A retrospective chart review of patients with esthesioneuroblastoma treated surgically at a tertiary care institution from 1991 to 2002 using this surgical paradigm.

Methods Patients were excluded for nonsurgical treatment or nasal and sinus tumor excision by nonendoscopic techniques. Patient demographics, tumor histological findings, presenting signs and symptoms, staging (Kadish and Dulguerov), postoperative complications, adjunct therapy, and recurrence were examined.

Results Seven of 13 patients with esthesioneuroblastoma met all inclusion criteria. The average patient age was 47 years, with a male‐to‐female distribution of 4 to 3. Patients were grouped by tumor stage using Kadish (stages A, B, and C included three, one, and three patients, respectively) and Dulguerov (stages T1, T2, and T4 included three, two, and two patients, respectively) methods. Average follow‐up was 62.3 months. All patients had an endoscopic excision of the nasal and sinus component with anterior craniotomy. The most common postoperative complication was temporary mental status change, which was seen in two patients. There were no postoperative deaths. All patients received radiation therapy, and one also received chemotherapy. Two of the seven patients had recurrences. At last follow‐up, six patients had no evidence of disease and one was alive with disease.

Conclusion Endoscopic excision of the nasal and sinus component with anterior craniotomy for cribriform or anterior cranial fossa extension is an effective treatment of esthesioneuroblastoma.
Clinical Course of Thyroid Carcinoma After Neck Dissection
Authors: Shah Manish D. , Hall Francis T. , Eski Spiro J. , Witterick Ian J. , Walfish Paul G. , Freeman Jeremy L.
Published: December 2003

Objectives/Hypothesis The objective was to compare the rate and site of recurrences in patients with well‐differentiated thyroid carcinoma who underwent a central compartment dissection, a posterolateral neck dissection, or a combination of both procedures.

Study Design Retrospective chart review.

Methods The charts of 522 consecutive patients with well‐differentiated thyroid carcinoma were reviewed, and 74 patients who had undergone a neck dissection were identified. The rates of recurrence in three sites were noted: the central compartment nodes (levels VI, superior mediastinum), posterolateral compartment neck nodes (levels II–V), and distant sites. These rates were compared in patients who underwent a central compartment dissection (level VI, superior mediastinum) and in patients who underwent a posterolateral neck dissection (levels II–V).

Results Six patients underwent only a central compartment dissection, 47 patients had only a posterolateral neck dissection, and 21 patients had both a central compartment and a posterolateral neck dissection. In these three groups there were zero, two, and two central compartment node recurrences; two, nine, and seven posterolateral neck recurrences; and zero, two, and three distant recurrences, respectively. There were no significant differences in the rate of recurrence in any of the three sites examined between any of the three treatment groups (Fisher's Exact test, all P values > .20).

Conclusion In patients with well‐differentiated thyroid carcinoma, dissection of only the central or posterolateral compartments of the neck with clinical or radiographic evidence of disease is advocated.
Topical Ciprofloxacin/Dexamethasone is Superior to Ciprofloxacin Alone in Pediatric Patients with Acute Otitis Media and Otorrhea through Tympanostomy Tubes
Authors: Roland Peter S. , Anon Jack B. , Moe Richard D. , Conroy Peter J. , Wall G. Michael , Dupre Sheryl J. , Krueger Kimberly A. , Potts Susan , Hogg Gail , Stroman David W.
Published: December 2003

Objective To determine whether topical administration of a corticosteroid improves resolution of acute tympanostomy tube otorrhea when combined with topical antibiotic drops.

Study Design Randomized, patient‐masked, parallel‐group, multicenter trial of topical otic ciprofloxacin/dexamethasone versus topical ciprofloxacin alone in 201 children aged 6 months to 12 years with acute otitis media with tympanostomy tubes (AOMT) of less than or equal to 3 weeks' duration and visible otorrhea.

Methods Eligible patients were randomized to receive three drops of either ciprofloxacin 0.3%/dexamethasone 0.1% or ciprofloxacin 0.3% into the affected ear or ears twice daily for 7 days. Clinical signs and symptoms of AOMT were evaluated on days 1 (baseline), 3, 8 (end‐of‐therapy), and 14 (test‐of‐cure), and twice‐daily assessments of otorrhea were recorded in patient diaries.

Results The mean time to cessation of otorrhea in the microbiologically culture‐positive patient population (n = 167) was significantly shorter with topical ciprofloxacin/dexamethasone than with ciprofloxacin alone (4.22 vs. 5.31 days; P = .004). This resulted in significantly better clinical responses on days 3 and 8 (P < .0001 and P = .0499, respectively). However, there were no significant differences between the two treatment groups in either the clinical response or the microbial eradication rate by day 14.

Conclusions Topical otic treatment with ciprofloxacin/dexamethasone is superior to treatment with ciprofloxacin alone and results in a faster clinical resolution in children with AOMT. The contribution of the corticosteroid in achieving a 20% reduction (1.1 day) in time to cessation of otorrhea is clinically meaningful and represents an important advance over single‐agent antibiotic therapy.
Immunohistochemical Demonstration of Vascular Endothelial Growth Factor in Vestibular Schwannomas Correlates to Tumor Growth Rate
Authors: Cayé‐Thomasen Per , Baandrup Lone , Jacobsen Grete Krag , Thomsen Jens , Stangerup Sven‐Eric
Published: December 2003

Objective Vascular endothelial growth factor (VEGF) is one of the most potent mediators of angiogenesis, which is a mandatory process during tumor growth. The present objectives were to determine expression of VEGF in vestibular schwannomas by immunohistochemistry and to examine a possible correlation with symptom duration, tumor size, or growth rate.

Study Design Retrospective patient file review; immunohistochemistry and light microscopy of vestibular schwannomas removed by surgery.

Methods Vestibular schwannomas from 18 patients were immunolabelled using a polyclonal antibody against VEGF, followed by light microscopy and blinded semiquantitation of VEGF expression. Fifteen patients had a well‐defined tumor growth rate defined by repeated preoperative magnetic resonance imaging scans.

Results All tumors showed expression of VEGF in the Schwann cell cytoplasm, with a more intense staining of the perinuclear region of some cells. The staining intensity varied from tumor to tumor, and semiquantitation revealed a significant correlation between VEGF expression and tumor growth rate, but not symptom duration or tumor size.

Conclusion VEGF is expressed in vestibular schwannomas and the level of expression correlates positively with tumor growth rate, but not with tumor size and symptom duration. We conclude that VEGF seems to be a factor involved in the growth of vestibular schwannomas.
Results of Caldwell‐Luc After Failed Endoscopic Middle Meatus Antrostomy in Patients With Chronic Sinusitis
Authors: Cutler Jeffrey L. , Duncavage James A. , Matheny Keith , Cross Jenny L. , Miman Murat C. , Oh Charles K.
Published: December 2003

Objectives/Hypothesis The Caldwell‐Luc operation for treatment of medically refractory chronic maxillary sinusitis has largely been replaced by functional endoscopic sinus surgery. Despite this change, the Caldwell‐Luc procedure still has well documented indications including treatment of both failed endoscopic middle meatus antrostomy and irreversible mucosal changes. The purpose of the study was to review the authors' experience and results of Caldwell‐Luc procedure after failed endoscopic middle meatus antrostomy in patients clinically deemed to have irreversible mucosal changes.

Study Design Retrospective review of preoperative and postoperative results of patients who underwent Caldwell‐Luc procedure for refractory chronic maxillary sinusitis after failed endoscopic middle meatus antrostomy.

Methods The preoperative and postoperative clinical course of patients treated with Caldwell‐Luc procedure performed by a single surgeon between 1996 and 2001 were reviewed. Only patients with a history of chronic sinusitis after failed maximal medical therapy, no prior Caldwell‐Luc procedure, prior endoscopic middle meatus antrostomy, and at least 6 months of follow‐up were included. Outcome measurements including documented endoscopic examinations and the need for repeat surgery, and postoperative computed tomography scan results were evaluated to assess treatment success.

Results The study involved 11 men and 26 women who underwent 50 Caldwell‐Luc procedures. Caldwell‐Luc procedure was performed bilaterally in 13 patients. The average number of prior endoscopic middle meatus antrostomies before Caldwell‐Luc procedure was 2. Of all patients, 92% responded to surgical treatment as demonstrated by an endoscopic examination or computed tomography scan revealing a disease‐free maxillary sinus. Repeat Caldwell‐Luc procedure was required in 8.0% (n = 3) because of continued sinusitis. Two of the three cases with repeat Caldwell‐Luc procedures demonstrated clinical improvement during follow‐up. Average follow‐up was 23.5 months.

Conclusion Caldwell‐Luc procedure seems to be highly effective in the management of medically refractory chronic sinusitis after failed endoscopic middle meatus antrostomy. Caldwell‐Luc procedure should remain in the otolaryngologist's surgical repertoire for these selected cases.
Endonasal Surgery for Contact Point Headaches: A 10‐Year Longitudinal Study
Authors: Welge‐Luessen Antje , Hauser Rolf , Schmid Nevenka , Kappos Ludwig , Probst Rudolf
Published: December 2003

Objective Some migraine and cluster headaches may be triggered by stimulation of intranasal contact points via the trigeminovascular system. Endonasal surgery is successful in some patients, but long‐term outcomes have not been reported.

Study Design Prospective

Methods This investigation included 20 patients with a mean 18‐year history of refractory cluster or migraine headaches who were selected for surgery. All had endoscopically visible endonasal contact as well as a positive preoperative cocaine test result. Changes in pain severity and frequency and duration of headache attacks were statistically rated using a MANOVA. Follow‐up averaged 112 months.

Results Almost 10 years after surgery, six patients remained completely free of pain, seven had significant symptom improvement, and seven received no benefit from surgery (65% improvement). Two patients had been free of all symptoms for 7 and 8 years, respectively, before complaints returned.

Conclusion Our data suggest that some patients with refractory headaches and endonasal contact areas benefit from surgery, thereby supporting the existence of a connection between the two. Even though it is clear that surgery should be considered only if all other treatments have failed, a success rate of 65% over almost 10 years justifies evaluation of this option. Preoperative patient selection remains crucial and warrants further investigation.
Pathogenetic Mechanism of Olfactory Cell Injury after Exposure to Sulfur Dioxide in Mice
Authors: Min Yang‐Gi , Kim Jeong‐Whun , Hong Seok‐Chan , Dhong Hun‐Jong , Jarin Peter R. , Jin Yulian
Published: December 2003

Objectives This study aimed to investigate the cellular pathogenetic mechanism involved in olfactory tissue injury and regeneration.

Study Design Adult male mice were exposed to 40 ppm SO2 for 2 hours.

Methods The mice were sacrificed immediately, 4 hours, and 1, 3, 5, 7, 10, 14, and 21 days after exposure to SO2. Olfactory neuroepithelium and bulbs were harvested at the time of sacrifice. Western blot and immunohistochemical staining were performed.

Results Injuries of the olfactory neuroepithelium were found 24 hours after exposure to SO2. The number of total olfactory neuroepithelial cells decreased after SO2 exposure and recovered after 3 weeks. In contrast, the number of proliferating cell nuclear antigen (PCNA)–positive cells increased after SO2 injury and then decreased. In the neuroepithelium, where PCNA expression increased, olfactory marker protein (OMP)–positive cells were sparse. The expression of inducible nitric oxide synthase (iNOS) was localized in the lateral half of the turbinates. However, there was no expression of iNOS in the medial half of the turbinates, in which PCNA was strongly expressed. There was increased immunoreactivity of neuronal NOS (nNOS) in the surviving cells after SO2 exposure. Immediately after exposure to SO2, the immunoreactivity to phosphorylated fraction of extracellular signal‐regulated kinases (phospho‐ERK)‐1/2 increased in the cytoplasm and nucleus of supporting cells. In Western blot analysis, nNOS expression increased 4 hours after SO2 exposure.

Conclusions These findings suggest that the regenerative activity of the neuroepithelium might be well demonstrated by PCNA immunoreactivity and that regeneration of the neuroepithelium can be activated several days after SO2 injury. The two NOS isoforms, iNOS and nNOS, might contribute to neuroprotection in the olfactory neuroepithelium.
Paranasal Sinus Bony Structures and Sinus Functioning During Viral Colds in Subjects With and Without a History of Recurrent Sinusitis
Authors: Alho Olli‐Pekka
Published: December 2003

Objectives/Hypothesis The objective was to assess the impact of ostial obstruction and anatomical variations on paranasal sinus functioning during viral colds with computed tomography (CT) in subjects with and without a history of sinusitis.

Study Design Cross‐sectional study.

Methods Twenty‐three volunteers with a history of recurrent sinusitis and 25 subjects without such history who had an early (symptoms for 2–4 d) natural cold were examined by taking viral specimens and CT scans and recording symptoms. The pathological sinus changes in the CT scans were scored, and several paranasal bony anatomical variations recorded.

Results Viral origin of the cold was identified in 32 (67%) subjects, similarly in the two groups. Ostiomeatal obstruction and anatomical variations were equally frequent in the subjects with and without a sinusitis history (17 of 23 vs. 17 of 25 for ostial obstruction and 17 of 23 vs. 20 of 25 for at least one variation, respectively). However, in the case of ostiomeatal obstruction the combined CT score of ethmoidal and maxillary sinuses was significantly higher in the subjects with a sinusitis history than in those without (mean ± SD, 3.0 ± 0.9 vs. 2.3 ± 1.2 [P = .05, t test]). In the sinusitis‐prone subjects, several variations were associated significantly with various pathological sinus CT changes (septal deviation, horizontally situated processus uncinatus, large concha bullosa, and laterally concave concha media), whereas in the control subjects, only the presence of Haller cells was related to sphenoidal sinus disease.

Conclusion Ostiomeatal complex obstruction and bony anatomical variations seem to have a greater impact on the functioning of paranasal sinuses during viral colds in sinusitis‐prone subjects than in subjects without a sinusitis history. These differences may be associated with the increased risk of bacterial sinusitis.
Postoperative Pain and Side Effects After Uvulopalatopharyngoplasty, Laser‐Assisted Uvulopalatoplasty, and Radiofrequency Tissue Volume Reduction in Primary Snoring
Authors: Rombaux Philippe , Hamoir Marc , Bertrand Bernard , Aubert Genevieve , Liistro Giuseppe , Rodenstein Daniel
Published: December 2003

Objectives We compared, in a prospective study, the side effects and the postoperative complications of three procedures commonly used for the treatment of primary snoring.

Method Forty‐nine patients underwent velopharyngeal surgery for primary snoring (17 for uvulopalatopharyngoplasty [UPPP]; 15 for laser‐assisted uvulopalatoplasty [LAUP], and 17 for radiofrequency tissue volume reduction [RFTVR]). Preoperative full polysomnographic studies ruled out obstructive sleep apnea syndrome. Each patient's evaluation encompassed postoperative pharyngeal pain (as measured by a 5‐point visual analogue scale) and use of narcotic drugs in the early postoperative period as well as a subjective evaluation of late postoperative complaints. A surgeon's examination was performed to report postoperative complications in the oropharynx.

Results Postoperative pharyngeal pain was less important in the RFTVR group than in the UPPP and LAUP groups. Mean scores at days 3, 7, 16 were as follows: 4.2, 4.0, and 2.4, respectively, for UPPP; 4.6, 3.8, and 1.6 for LAUP; and 2.4, 2.0, and 0.7 for RFTVR. Mean duration of pain with a score greater than 2 was calculated as follows: UPPP, 21.3 days; LAUP, 15.1 days; and RFTVR, 6.1 days. Mean duration of narcotic drug use for the patients who needed this medication was 10.1 days for UPPP, 7.2 days for LAUP, and 1.3 for RFTVR. Postoperative side effects (trouble with smell and taste, pharyngeal dryness, globus sensation, voice change, and pharyngonasal reflux) were more present in the UPPP and LAUP groups than in the RFTVR group. Surgeon's assessment for postoperative complications reported more wound infection, dehiscence, and posterior pillar narrowing in the UPPP and LAUP groups than in the RFTVR group.

Conclusion RFTVR is a safer and less painful procedure than UPPP and LAUP for the treatment of primary snoring. Postoperative discomfort after LAUP and after UPPP appears to be very similar.
Distribution of Collagen in the Lamina Propria of the Human Vocal Fold
Authors: Madruga de Melo Erich Christiano , Lemos Miriam , Aragão Ximenes Filho João , Sennes Luiz Ubirajara , Nascimento Saldiva Paulo Hilário , Tsuji Domingos Hiroshi
Published: December 2003

Objectives To describe the arrangement of collagen fibers in the lamina propria of the human vocal fold.

Study Design Analysis of the lamina propria of the vocal fold obtained from human cadavers.

Methods The Picrosirius‐polarization method was used to visualize collagen fibers.

Results Analysis of 20 human vocal folds by the Picrosirius‐polarization method permitted the visualization of two fiber populations arranged in three layers in the lamina propria: two layers of thick, strongly birefringent collagen fibers (collagen type I), one immediately below the epithelium and another more dense layer in the deep region superficially to the vocal muscle, penetrating between muscle fibers. The third layer consisted of fine, weakly birefringent fibers (collagen type III) located between the two layers of thick fibers. In addition, the collagen fibers in the lamina propria showed an intertwined network arrangement in the form of a “wicker basket.”

Conclusions This basket‐like configuration better explains how the vocal fold is able to stretch even though it contains nonstretchable fibers and to modulate the frequency of the voice under the action of the intrinsic musculature of the larynx. Segmental areas of disarray of the basket‐like structure of the collagen layers were systematically observed in older patients. Thus, it is possible that vocal alterations occurring in the elderly might be the result of a loss of histoarchitectural arrangement of the collagen system and its relationship with the lamina propria and underlying musculature.
Laryngeal Dystonia Causing Inspiratory Stridor in Children with Cerebral Palsy
Authors: Worley Gordon , Witsell David L. , Hulka Gregory F.
Published: December 2003

Objective To present three cases of inspiratory stridor caused by laryngeal dystonia (LD) in children with cerebral palsy (CP), one of whom is being treated by periodic botulinum toxin type A (BTX) injection into a vocalis muscle, thereby avoiding tracheostomy.

Study Design Case series.

Results and Conclusions Laryngeal dystonia was diagnosed in three children with CP who presented with inspiratory stridor associated with generalized dystonia, all of whom were thought previously to have had laryngomalacia. The inspiratory stridor was severe enough in one patient that a tracheostomy was planned. In common with the movement disorder of generalized dystonia, the inspiratory stridor caused by LD was present in our patients when they were awake, worse when they were excited or agitated, diminished when they were awake and calm, and absent when they were asleep. Although there is overlap between the symptoms of LD and laryngomalacia (and other structural causes of upper airway obstruction) in children with CP, structural causes result in inspiratory stridor that is often persistent when patients are awake and relaxed or when they are asleep. Fiberoptic laryngoscopy in an awake patient with LD reveals vocal cord adduction in inspiration causing inspiratory stridor in association with generalized dystonia. Baclofen and gabapentin used together relieved the inspiratory stridor and improved the generalized dystonia of two patients, confirming the clinical diagnosis of LD, but for the last 2 years the third patient (the one with the most severe inspiratory stridor) also has required a periodic BTX injection into a vocalis muscle (the major vocal cord adductor) to relieve her inspiratory stridor, alternating the side of injection. Her mother considers this is a small price to pay to avoid tracheostomy. This is the first report of LD causing inspiratory stridor in patients with CP and the first reported use of BTX injection into a vocalis muscle for relief of inspiratory stridor due to LD in a child.
Parathyroid Hormone: An Early Predictor of Postthyroidectomy Hypocalcemia
Authors: Lam Allen , Kerr Paul D.
Published: December 2003

Objective To determine whether there is a correlation between the level of parathyroid hormone (PTH) soon after thyroidectomy and the development of hypocalcemia.

Study Design Prospective series of 40 consecutive patients undergoing total thyroidectomy or completion thyroidectomy between January 2001 and October 2002.

Method Ionized calcium was measured before surgery and at 1, 6, 18, 30, and 42 hours after surgery. PTH was measured before surgery and at 1 and 6 hours after surgery using an assay that accurately measures low levels of PTH. Patients were followed up at 1 week and 3 months after surgery with respect to their symptoms and need for calcium supplementation. Clinically significant hypocalcemia was defined as an ionized calcium level of less than or equal to 0.9 mmol/L.

Results The incidence of postoperative hypocalcemia was 30% (12/40). The mean PTH level 1 hour after surgery was much lower in patients who ultimately became hypocalcemic than in those who remained normocalcemic (3.8± 1.9 vs. 33 ± 21 pg/mL, P = .001). All patients with a PTH level less than or equal to 8 pg/mL 1 hour after surgery developed hypocalcemia, whereas all those with greater than or equal to 9 pg/mL remained normocalcemic.

Conclusions A single PTH level of less than or equal to 8 pg/mL 1 hour postthyroidectomy is a strong predictor for the development of clinically significant hypocalcemia. Once validated, this test may serve to identify those who require more intensive monitoring, prompt early therapy in those deemed at risk, and enable confident early discharge in the majority of thyroidectomy patients.
Hypopharyngeal Acid Exposure: An Independent Risk Factor for Laryngeal Cancer?
Authors: Geterud Åke , Bove Mogens , Ruth Magnus
Published: December 2003

Objectives/Hypothesis Gastroesophageal reflux disease has in recent years been linked to a variety of extraesophageal conditions including laryngeal cancer. However, whether a causal relationship exists is still under debate. The present study aimed to compare the occurrence and severity of gastroesophago‐hypopharyngeal reflux in patients with laryngeal cancer with those of healthy volunteers.

Study Design Prospective, controlled study.

Methods Forty‐one consecutive patients with newly diagnosed laryngeal cancer were examined by esophageal manometry and an ambulatory, 24‐hour, double‐probe pH monitoring. Their results were compared with those of 40 healthy volunteers.

Results Hypopharyngeal acid exposure was registered mainly in the upright body position. A pathological acid exposure, as compared with the upper levels of normality among the healthy volunteers, was found in the hypopharynx in six (16%) patients with laryngeal cancer and in the distal esophagus in 10 (25%) patients. Pathological acid exposure in either location was found in 15 (37%) patients and in both locations in 1 (3%) patient. However, the mean acid exposure time and the mean value of the number of reflux events did not differ significantly between cancer patients and control subjects at either location. The exclusion of meal periods from the analysis did not alter these observations. Nonsmoking cancer patients (n = 5) and nonsmoking control subjects (n = 36) had similar acid exposure both in the hypopharynx and in the distal esophagus.

Conclusion The present results do not support gastroesophago‐hypopharyngeal reflux as being an independent risk factor for laryngeal cancer.
The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo
Authors: Relaix Frédéric , Polimeni Mariarosa , Rocancourt Didier , Ponzetto Carola , Schäfer Beat W. , Buckingham Margaret
Published: December 2003

Pax3 is a key transcription factor implicated in development and human disease. To dissect the role of Pax3 in myogenesis and establish whether it is a repressor or activator, we generated loss- and gain-of-function alleles by targeting an nLacZ reporter and a sequence encoding the oncogenic fusion protein PAX3-FKHR into the Pax3 locus. Rescue of the Pax3 mutant phenotypes by PAX3-FKHR suggests that Pax3 acts as a transcriptional activator during embryogenesis. This is confirmed by a Pax reporter mouse. However, mice expressing PAX3-FKHR display developmental defects, including ectopic delamination and inappropriate migration of muscle precursor cells. These events result from overexpression of c-met, leading to constitutive activation of Met signaling, despite the absence of the ligand SF/HGF. Haploinsufficiency of c-met rescues this phenotype, confirming the direct genetic link with Pax3. The gain-of-function phenotype is also characterized by overactivation of MyoD. The consequences of PAX3-FKHR myogenic activity in the limbs and cervical and thoracic regions point to differential regulation of muscle growth and patterning. This gain-of-function allele provides a new approach to the molecular and cellular analysis of the role of Pax3 and of its target genes in vivo.
Identifying the determinants of corporate managers’ perceived social obligations
Authors: Quazi Ali M.
Published: December 2003

Explores the determinants of perceived social obligations of corporate managers focusing on managerial and personal demographics. A survey of Australian corporate managers revealed that there is a significant relationship between the level of education, training status and religiosity of managers and their perception of corporate social responsibility (CSR). The findings indicate that managerial commitment to CSR is linked with the acquired qualities (education and training) rather than their inherent physical maturity (age). Furthermore, modernity reflected in achievement via hard work, rather than mere belief in luck, determines the pattern of managerial perception of CSR. Religious metaphors seem to influence managers’ perception of social commitment suggesting that theology is also an important determinant of the ethical perceptions of Australian corporate managers. These findings have important implications for personnel policies of socially responsive corporations. Addresses the limitations of the study and explores potential areas of further research.
The evolution of corporate governance and its impact on modern corporate America
Authors: Grant Gerry H.
Published: December 2003

History shows a repetitive cycle of corporations over‐reaching their boundaries and causing social turmoil. Governments are faced with the task of reining them in by enacting regulations. Investors are faced with the task of preserving their individual assets. Corporate governance remains the core issue in these battles. This paper examines the origins of corporate governance and the events during the twentieth century that have failed to align the interests of management and shareholders.
Marketing in the Internet age: what can we learn from the past?
Authors: Harris Lisa , Cohen Geraldine
Published: December 2003

Examines whether business really is undergoing a revolution or just the latest in a series of incremental changes with the universal and seemingly exponential spread of Internet technology. While it is tempting to regard the Internet as a unique challenge through its dual role as a driver of change and provider of tools for change, the article begins by drawing on a number of historical precedents in order to question some of the “hype” surrounding current Internet developments. By analysing relevant literature and primary data from a number of case studies in the UK and the USA, the particular challenges facing marketing are then examined to establish whether there are any parallels in marketing history from which lessons for the future may be learned. From our examples it is concluded that many “new” developments have in fact been practised for centuries and traditional processes are an important constituent of “evolutionary” rather than “revolutionary” innovation.
Whistleblowing: the UK experience. Part 1
Authors: Vinten Gerald
Published: December 2003

An historical saunter is taken through the development of approaches, legal and organisational, to deal with whistleblowing. Whistleblowing engenders strong emotions, and it is not surprising that some of the early pioneers met with stiff resistance. Some classic whistleblowing cases are analysed, notably Stanley Adams and charge nurse Graham Pink. Key developments and cases during the Thatcher period are outlined. Employment law was rather primitive, and failed to give much definitive protection to whistleblowers. The contribution of the Committee of Lord Nolan on Standards in Public Life is outlined. The area of higher education, and the pivotal territory of financial services, accounting and auditing also are treated.
Linking leaders’ beliefs to their behaviors and competencies
Authors: Emiliani M.L.
Published: December 2003

Discusses how competency models are used with the intent to improve managers’ leadership skills. Determines that competency models will not result in any substantive changes in behaviors because they fail to address managers’ fundamental beliefs about the practice of business. A new construct is presented for conventional management practice that shows how leader’s beliefs lead to behaviors, which, in turn, lead to competencies that most managers would find undesirable. The beliefs, behaviors, and competencies of leaders skilled in the lean management system are presented in contrast and shown to be remarkably different from that possessed by managers skilled in conventional management practices. The results illustrate important limitations of leadership competency models. The development of new leadership competencies is re‐framed as a change‐over problem. Coupled with kaizen, competencies that better serve the interests of a business and its key stakeholders can be more effectively realized.
A framework to implement strategies in organizations
Authors: Okumus Fevzi
Published: December 2003

The implementation of strategy, directly or indirectly, relates to all facets of management. Therefore, it is essential to follow a holistic approach when analyzing and evaluating complex issues of implementation. However, research in this area is still limited, and offers few practical propositions. Given this situation, this article proposes an implementation framework by identifying key elements/factors of implementation and categorizing them into different groups depending on their role and importance. The role and importance of each implementation factor, as well as its relationship with other factors, are explained. It is believed that the framework developed in this article can assist executives and researchers to better understand and evaluate complex factors of implementation and deal with challenges from a holistic perspective. Suggestions for practice and future research are also given.