bluuebunny/crossref_metadata_2025 huggingface dataset:
Micropatterning of costimulatory ligands enhances CD4+T cell function
Authors: Shen Keyue , Thomas V. Kaye , Dustin Michael L. , Kam Lance C.
Published: May 2008

Spatial organization of signaling complexes is a defining characteristic of the immunological synapse (IS), but its impact on cell communication is unclear. In T cell–APC pairs, more IL-2 is produced when CD28 clusters are segregated from central supramolecular activation cluster (cSMAC)-localized CD3 and into the IS periphery. However, it is not clear in these cellular experiments whether the increased IL-2 is driven by the pattern itself or by upstream events that precipitate the patterns. In this article, we recapitulate key features of physiological synapses using planar costimulation arrays containing antibodies against CD3 and CD28, surrounded by ICAM-1, created by combining multiple rounds of microcontact printing on a single surface. Naïve T cells traverse these arrays, stopping at features of anti-CD3 antibodies and forming a stable synapse. We directly demonstrate that presenting anti-CD28 in the cell periphery, surrounding an anti-CD3 feature, enhances IL-2 secretion by naïve CD4+T cells compared with having these signals combined in the center of the IS. This increased cytokine production correlates with NF-κB translocation and requires PKB/Akt signaling. The ability to arbitrarily and independently control the locations of anti-CD3 and anti-CD28 offered the opportunity to examine patterns not precisely attainable in cell–cell interfaces. With these patterns, we show that the peripheral presentation of CD28 has a larger impact on IL-2 secretion than CD3 colocalization/segregation.
Insights into the stator assembly of the
Vibrio
flagellar motor from the crystal structure of MotY
Authors: Kojima Seiji , Shinohara Akari , Terashima Hiroyuki , Yakushi Toshiharu , Sakuma Mayuko , Homma Michio , Namba Keiichi , Imada Katsumi
Published: May 2008

Rotation of the sodium-driven polar flagellum of
Vibrio alginolyticus
requires four motor proteins: PomA, PomB, MotX, and MotY. PomA and PomB form a sodium-ion channel in the cytoplasmic membrane that functions as a stator complex to couple sodium-ion flux with torque generation. MotX and MotY are components of the T-ring, which is located beneath the P-ring of the polar flagellar basal body and is involved in incorporation of the PomA/PomB complex into the motor. Here, we describe the determination of the crystal structure of MotY at 2.9 Å resolution. The structure shows two distinct domains: an N-terminal domain (MotY-N) and a C-terminal domain (MotY-C). MotY-N has a unique structure. MotY-C contains a putative peptidoglycan-binding motif that is remarkably similar to those of peptidoglycan-binding proteins, such as Pal and RmpM, but this region is disordered in MotY. Motility assay of cells producing either of the MotY-N and MotY-C fragments and subsequent biochemical analyses indicate that MotY-N is essential for association of the stator units around the rotor, whereas MotY-C stabilizes the association by binding to the peptidoglycan layer. Based on these observations, we propose a model for the mechanism of stator assembly around the rotor.
Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model
Authors: Cacucci Francesca , Yi Ming , Wills Thomas J. , Chapman Paul , O'Keefe John
Published: May 2008

Alzheimer's disease (AD) is associated with progressive memory decline. Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. We have recorded place cells in the Tg2576 mouse model of AD, and we report that aged (16 mo) but not young (3 mo) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals' (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Place cell recording provides a sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies.
Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system
Authors: Xue Mingshan , Stradomska Alicja , Chen Hongmei , Brose Nils , Zhang Weiqi , Rosenmund Christian , Reim Kerstin
Published: May 2008

Complexins (Cplxs) are key regulators of synaptic exocytosis, but whether they act as facilitators or inhibitors is currently being disputed controversially. We show that genetic deletion of all Cplxs expressed in the mouse brain causes a reduction in Ca
2+
-triggered and spontaneous neurotransmitter release at both excitatory and inhibitory synapses. Our results demonstrate that at mammalian central nervous system synapses, Cplxs facilitate neurotransmitter release and do not simply act as inhibitory clamps of the synaptic vesicle fusion machinery.
Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins
Authors: Krojer Tobias , Pangerl Karen , Kurt Juliane , Sawa Justyna , Stingl Christoph , Mechtler Karl , Huber Robert , Ehrmann Michael , Clausen Tim
Published: May 2008

Aberrant proteins represent an extreme hazard to cells. Therefore, molecular chaperones and proteases have to carry out protein quality control in each cellular compartment. In contrast to the ATP-dependent cytosolic proteases and chaperones, the molecular mechanisms of extracytosolic factors are largely unknown. To address this question, we studied the protease function of DegP, the central housekeeping protein in the bacterial envelope. Our data reveal that DegP processively degrades misfolded proteins into peptides of defined size by employing a molecular ruler comprised of the PDZ1 domain and the proteolytic site. Furthermore, peptide binding to the PDZ domain transforms the resting protease into its active state. This allosteric activation mechanism ensures the regulated and rapid elimination of misfolded proteins upon folding stress. In comparison to the cytosolic proteases, the regulatory features of DegP are established by entirely different mechanisms reflecting the convergent evolution of an extracytosolic housekeeping protease.
The PHD Domain of Np95 (mUHRF1) Is Involved in Large-Scale Reorganization of Pericentromeric Heterochromatin
Authors: Papait Roberto , Pistore Christian , Grazini Ursula , Babbio Federica , Cogliati Sara , Pecoraro Daniela , Brino Laurent , Morand Anne-Laure , Dechampesme Anne-Marie , Spada Fabio , Leonhardt Heinrich , McBlane Fraser , Oudet Pierre , Bonapace Ian Marc
Published: May 2008

Heterochromatic chromosomal regions undergo large-scale reorganization and progressively aggregate, forming chromocenters. These are dynamic structures that rapidly adapt to various stimuli that influence gene expression patterns, cell cycle progression, and differentiation. Np95-ICBP90 (m- and h-UHRF1) is a histone-binding protein expressed only in proliferating cells. During pericentromeric heterochromatin (PH) replication, Np95 specifically relocalizes to chromocenters where it highly concentrates in the replication factories that correspond to less compacted DNA. Np95 recruits HDAC and DNMT1 to PH and depletion of Np95 impairs PH replication. Here we show that Np95 causes large-scale modifications of chromocenters independently from the H3:K9 and H4:K20 trimethylation pathways, from the expression levels of HP1, from DNA methylation and from the cell cycle. The PHD domain is essential to induce this effect. The PHD domain is also required in vitro to increase access of a restriction enzyme to DNA packaged into nucleosomal arrays. We propose that the PHD domain of Np95-ICBP90 contributes to the opening and/or stabilization of dense chromocenter structures to support the recruitment of modifying enzymes, like HDAC and DNMT1, required for the replication and formation of PH.
P4-ATPase Requirement for AP-1/Clathrin Function in Protein Transport from the trans-Golgi Network and Early Endosomes
Authors: Liu Ke , Surendhran Kavitha , Nothwehr Steven F. , Graham Todd R.
Published: May 2008

Drs2p is a resident type 4 P-type ATPase (P4-ATPase) and potential phospholipid translocase of the trans-Golgi network (TGN) where it has been implicated in clathrin function. However, precise protein transport pathways requiring Drs2p and how it contributes to clathrin-coated vesicle budding remain unclear. Here we show a functional codependence between Drs2p and the AP-1 clathrin adaptor in protein sorting at the TGN and early endosomes of Saccharomyces cerevisiae. Genetic criteria indicate that Drs2p and AP-1 operate in the same pathway and that AP-1 requires Drs2p for function. In addition, we show that loss of AP-1 markedly increases Drs2p trafficking to the plasma membrane, but does not perturb retrieval of Drs2p from the early endosome back to the TGN. Thus AP-1 is required at the TGN to sort Drs2p out of the exocytic pathway, presumably for delivery to the early endosome. Moreover, a conditional allele that inactivates Drs2p phospholipid translocase (flippase) activity disrupts its own transport in this AP-1 pathway. Drs2p physically interacts with AP-1; however, AP-1 and clathrin are both recruited normally to the TGN in drs2Δ cells. These results imply that Drs2p acts independently of coat recruitment to facilitate AP-1/clathrin-coated vesicle budding from the TGN.
Characterization and classification of acoustically detected fish spatial distributions
Authors: Burgos Julian M. , Horne John K.
Published: May 2008

Burgos, J. M., and Horne, J. K. 2008. Characterization and classification of acoustically detected fish spatial distributions. – ICES Journal of Marine Science, 65: 1235–1247. High-resolution, two-dimensional measurements of aquatic-organism density are collected routinely during echo integration trawl surveys. School-detection algorithms are commonly used to describe and analyse spatial distributions of pelagic and semi-pelagic organisms observed in echograms. This approach is appropriate for species that form well-defined schools, but is limited when used for species that form demersal layers or diffuse pelagic shoals. As an alternative to metrics obtained from school-detection algorithms, we used landscape indices to quantify and characterize spatial heterogeneity in density distributions of walleye pollock (Theragra chalcogramma). Survey transects were divided into segments of equal length and echo integrated at a resolution of 20 m (horizontal) and 1 m (vertical). A series of 20 landscape metrics was calculated in each segment to measure occupancy, patchiness, size distribution of patches, distances among patches, acoustic density, and vertical location and dispersion. Factor analysis indicated that the metric set could be reduced to four factors: spatial occupancy, aggregation, packing density, and vertical distribution. Cluster analysis was used to develop a 12-category classification typology for distribution patterns. Visual inspection revealed that spatial patterns of segments assigned to each type were consistent, but that there was considerable overlap among types.
Fowler Award Presentation: Effects of ErbB2 Signaling on the Response of Vestibular Schwannoma Cells to γ‐Irradiation
Authors: Hansen Marlan R. , Clark J Jason , Gantz Bruce J. , Goswami Prabhat C.
Published: May 2008

Objective: For vestibular schwannomas (VSs) that require treatment, options are limited to microsurgery or irradiation (IR). Development of alternative therapies that augment or replace microsurgery or IR would benefit patients not suitable for current therapies. This study explored the ability of ErbB2 inhibitors to modulate the effects of IR on VS cells.

Study Design: Prospective study using primary cultures derived from human VSs.

Methods: Primary cultures of VS cells were derived from acutely resected tumors. Cultures received single escalating doses (15–40 Gy) of γ‐irradiation from a 137Cs γ‐irradiation source. Cell proliferation was determined by BrdU uptake and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Trastuzumab (Herceptin) and PD158780 were independently used to inhibit ErbB2 signaling while neuregulin‐1β (NRG‐1) was used to activate ErbB2.

Results: IR induces VS cell cycle arrest and apoptosis in doses greater than 20 Gy, demonstrating that VS cells are relatively radioresistant. This radioresistance likely arises from their low proliferative capacity as a sublethal dose of IR (10 Gy) strongly induces deoxyribonucleic acid (DNA) damage evidenced by histone H2AX phosphorylation. Inhibition of ErbB2, which decreases VS cell proliferation, protects VS cells from radiation‐induced apoptosis, while NRG‐1, an ErbB2 ligand and VS cell mitogen, increases radiation‐induced VS cell apoptosis.

Conclusions: Compared with many neoplastic conditions, VS cells are relatively radioresistant. The radio‐protective effect of ErbB2 inhibitors implies that the sensitivity of VS cells to IR depends on their proliferative capacity. These results hold important implications for current and future treatment strategies.
Staging and Survival Analysis for Nonsquamous Cell Carcinomas of the Larynx
Authors: Lin Harrison W. , Bhattacharyya Neil
Published: May 2008

Objective: Determine staging and comparative survival for nonsquamous cell carcinoma (SCC) of the larynx.

Study Design: Cross‐sectional population analysis.

Methods: Cases of non‐SCC supraglottic, glottic, and subglottic cancers were extracted from the Surveillance, Epidemiology and End Results database (1988–2003) and the staging distribution computed. For each site, Kaplan‐Meier survivals were compared according to histology, T‐stage, and N‐stage. Survival for non‐SCC cancers for each site were compared among histologies, T‐stage, and N‐stage as well as with age/sex/stage‐matched SCC cancers to determine differences in survival.

Results: One hundred forty supraglottic non‐SCC cases were identified (67% male, mean age 62.0 yr) consisting of 25 neuroendocrine, 25 small cell, and 22 lymphomas (among others), with mean survivals of 44.8, 52.1, and 80.5 months, respectively. Survival was not significantly different according to histology (log‐rank, P = .440) but was significantly different according to T‐stage (P = .029) and N‐stage (P < .001). Seventy‐eight glottic non‐SCC cases were identified (83% male, mean age 66.1 yr) consisting of 32 spindle cell, 13 sarcoma, and 10 small cell (among others), with mean survivals of 114.6, 89.8, and 39.2 months, respectively. Survival was not significantly different according to histology (P = .056) but was significantly different according to T‐stage (P = .002) and N‐stage (P = .022). Small numbers (26) precluded subglottic analysis. For both supraglottic and glottic sites including all histologies, survival was similar for matched non‐SCC and SCC cases (P = .510 and P = .930, respectively).

Conclusions: Non‐SCCs are more common in the supraglottic larynx. T‐stage and N‐stage influence survival more than histology alone for these cancers.
Simple and New Surgical Procedure for Laryngotracheal Separation in Pediatrics
Authors: Ninomiya Hiroshi , Yasuoka Yoshihito , Inoue Yoshihiro , Toyoda Minoru , Takahashi Katsumasa , Miyashita Motoaki , Furuya Nobuhiko
Published: May 2008

Objectives: In children with severe physical and mental disabilities who repeatedly develop aspiration pneumonia due to intractable aspiration, laryngotracheal separation/tracheoesophageal anastomosis or laryngotracheal separation has been performed in many institutions for the prevention of aspiration, and good results have been reported. However, families sometimes show a marked reluctance to give consent to these surgical techniques because of tracheal transection. A purpose of this study is to evaluate a new surgical procedure for laryngotracheal separation without tracheal transection.

Study Design: Case‐series study.

Methods: As a new, simple, less invasive surgical technique for the prevention of aspiration without tracheal transection, we performed tracheal closure (tracheal flap method) in six children. A U‐shaped flap of the tracheal anterior wall from the 2nd to the 4th/5th tracheal ring was produced, bent toward the tracheal lumen, and sutured to the tracheal posterior/lateral walls by mattress stitches for tracheal closure. In addition, the closure was covered with a cutaneous U‐shaped flap for reinforcement and a permanent tracheal stoma was constructed.

Results: In all six patients, aspiration pneumonia could be prevented without severe complications.

Conclusions: Tracheal closure (tracheal flap method) has effects comparable to those of other surgical techniques for the prevention of aspiration, and may be useful for aspiration prevention in children with severe physical and mental disabilities.
Endoscopic Removal of Juvenile Nasopharyngeal Angiofibromas: A Video Presentation
Authors: Joo Daekeun , Chhetri Dinesh K. , Wang Marilene B.
Published: May 2008

Objectives/Hypothesis: Juvenile nasal angiogibroma (JNA) is a relatively rare, benign neoplasm generally seen in prepubertal and adolescent males. In the past, surgical management included lateral rhinotomy, transpalatal and transmaxillary routes, and midface degloving approaches. Endoscopic approaches have become the treatment of choice, especially for tumors limited by size and location criteria. Our presentation demonstrates an endoscopic approach to excision of JNAs that are limited to the nasal cavity, nasopharynx, and paranasal sinuses. Through the use of a brief video presentation, participants will be able to visualize the endoscopic technique.

Study Design and Methods: A retrospective review of JNA patients treated at our institution identified 3 patients who underwent endoscopic removal. All patients underwent preoperative embolization followed by endoscopic resection.

Results: A video demonstration is presented of a patient with a 3.5 cm JNA who underwent successful endoscopic, endonasal excision. After medialization of the middle turbinate and anterior ethmoidectomy, the tumor could be mobilized using a Cottle elevator and microdebrider. The origin and attachment of the tumor were visualized and detached from the sphenopalatine foramen. The tumor was resected en bloc with minimal bleeding. There were no intraoperative complications, and postoperative bleeding was negligible. To date, there has been no evidence of recurrence of tumor in these individuals.

Conclusions: Endoscopic removal is the approach of choice for small to medium, limited‐extent JNAs.
The Effect of Topical Doxycycline in the Prevention of Experimental Tympanosclerosis
Authors: Ozcan Ibrahim , Selcuk Adin , Ozcan K Murat , Akdogan Ozgur , Giray Seren G. , Dere Huseyin , Ozogul Candan
Published: May 2008

Objectives: The aim of this study is to determine the effectiveness of topical doxycycline used in the process of experimental myringosclerosis and tympanosclerosis.

Study Design: A prospective experimental animal study.

Methods: Experimental tympanosclerosis was accomplished in 25 healthy adult guinea pigs by inoculation with 2.5 × 107 colony‐forming units of type‐3 Streptococcus pneumoniae microorganisms followed by bilateral myringotomy. While the animals' right ears received a topical doxycycline treatment daily, their left ears were left untreated and used as controls. Otomicroscopic examination was carried out weekly and healing tympanic membranes were remyringotomized. After a 6‐week follow‐up, the temporal bones of 24 of 25 animals were removed and light‐microscopy examination was done regarding tympanic membrane myringosclerosis and middle ear mucosal sclerosis.

Results: Myringosclerosis was noticed to a lesser extent in the doxycycline‐treated group when compared to the untreated control group. Light microscopy evaluation revealed a difference in the area and thickness of the sclerotic plaques of myringosclerosis of the tympanic membranes in the doxycycline‐treated group and the control group, being significantly smaller and thinner in the treated group (P < .001, P < .04, respectively). Similarly, the area and thickness of the sclerotic plaques in the middle ear mucosa were significantly smaller and thinner in the doxycycline treated group (P < .001, P < .03).

Conclusion: This study demonstrated that the potent matrix metallo‐proteinase inhibitor doxycycline plays a preventive role in the development of experimentally induced tympanosclerosis.
Is the Canine Fossa Puncture Approach Really Necessary for the Severely Diseased Maxillary Sinus during Endoscopic Sinus Surgery?
Authors: Lee Jae Yong , Lee Sang Hag , Hong Hyun Sook , Lee Jong Dae , Cho Sung Hoon
Published: May 2008

Objectives: To evaluate the necessity of canine fossa puncture (CFP) by comparing the symptom scores and postoperative computed tomography (CT) findings between patients with severe maxillary sinus disease who underwent CFP and those who underwent maxillary sinus clearance through a middle meatal antrostomy (MMA).

Study Design: A prospective, randomized study.

Materials and Methods: Fourteen patients met the inclusion criteria for each of the CFP and MMA groups. In both groups, all diseased sinuses were addressed in the same manner using the same surgical techniques; the only difference was management of the maxillary sinus. Most of the patients completed the Sinonasal Outcome Test 20 (SNOT‐20) and visual analogue scales (VAS) for the six main symptoms preoperatively and 3, 6, and 12 months postoperatively. The Lund‐Mackay scores for the maxillary sinus and for all sinuses were calculated from the preoperative CT scan and another scan taken 12 months postoperatively. The mucosal thickening as a percentage of the total volume of the maxillary sinus was also evaluated on the postoperative CT scans, and complications related to both procedures were investigated.

Results: Twenty‐four patients completed the follow‐up, questionnaires, and postoperative CT scans and were included in the analysis: 11 CFP patients and 13 MMA patients. All of the patients had chronic rhinosinusitis with nasal polyposis (NP). There were no significantdifferences in polyp extent or Lund‐Mackay score for the maxillary sinus and for all sinuses on the pre‐ and postoperative CT scans between the groups. The volume of mucosal thickening also did not differ significantly between the groups on the postoperative CT scans. The SNOT‐20 and VAS scores improved significantly 3, 6, and 12 months after the procedure in both groups. However, there were no significant differences between the two groups except for the VAS for postnasal drip 3 months postoperatively, which was better in the CFP group. Six of 11 patients in the CFP group experienced one or more complications after the procedure, although all of the symptoms resolved spontaneously within 3 months. In the MMA group, three patients had bleeding from the branches of the sphenopalatine artery during widening of the ostium, which was controlled intraoperatively with suction cauterization.

Conclusions: We could not find any benefits of the CFP procedure over the conventional MMA method in the present study. Although CFP is a useful method for removing severe mucosal disease that cannot be reached through the MMA, it does not guarantee a better subjective or objective surgical outcome in patients who have accompanying NP.
Daily Tympanometry for High‐Resolution Measurement of the Time between Onset Of Cold‐Like Illness and Middle Ear Effusion
Authors: Doyle William J. , Winther Birgit , Alper Cuneyt M.
Published: May 2008

Background: Tympanometry is a simple method to assess middle ear pressure (MEP) and the presence of middle ear effusion (MEE), a marker of otitis media (OM).

Objectives: To determine whether daily parental tympanometry and illness sign recording in their children can be used to define the time between onsets of cold‐like illness (CLI) and MEE at high resolution.

Study Design: Prospective, longitudinal, 7 month, daily follow‐up on 169 children aged 1 through 8.6 years.

Methods: Tympanograms and illness were recorded daily by a parent. Tympanograms were examined, rejected if artifactual, and MEP data were entered into a database, with “flat tympanograms” coded as −400 mm H2O = MEE. The incidence and burden of CLIs (>2 days) were calculated, and for each CLI, the presence/absence of concurrent MEE (>2 days) was determined. For each child, the average MEP for CLI and nonCLI days was calculated. Paired CLI and tympanometric results were aligned and the days between event onsets determined. Stepwise regression was used to assign risk predictors for the measured outcomes.

Results: A total of 566 CLIs were recorded, and the average CLI burden/child was 16%. Age was a significant predictor of CLI incidence/child, and age, history of colds, and daily environment were predictors of CLI‐burden/child. Of the 433 evaluable CLI episodes, MEE was a complication in 37%, and MEE with a CLI was predicted by age, OM history, and environment. MEP was significantly more negative during CLI episodes, and the magnitude was predicted by age, race, and OM history. The average difference in MEE‐CLI onsets was 1.2 ± 4.0 days; approximately 32% of MEEs occurred prior to CLI onset and 17% on the same day as CLI onset.

Conclusions: CLIs adversely affect the middle ear‐ambient pressure balance and are frequently associated with MEE episodes. The distribution in onsets between those events suggests that chemoprophylaxis of a child with a newly identified CLI to prevent MEE would have a low expected efficiency.
Medical Management Of Ménière's Disease
Authors: Coelho Daniel H. , Lalwani Anil K.
Published: May 2008

Objectives: Ménière's disease (MD) is poorly understood with respect to its etiology, pathophysiology, clinical course, and treatment. Furthermore, in the absence of controlled clinical studies, empiric treatments have been used with varying degrees of success. In this paper, the authors review the current medical management of MD.

Study Design: Literature review.

Results: Because of a dearth of well‐controlled studies, the medical management of MD remains empirical and is largely restricted to lifestyle changes, pharmacotherapy, and office‐based procedures. The development of transtympanic therapies represents a true therapeutic advance that has largely supplanted surgical intervention. A treatment algorithm for acute and chronic medical management is reviewed.

Conclusions: Despite absence of a complete understanding of MD, medical management or its natural history leads to control of vertigo in the majority of patients. Basic research is needed to understand its pathophysiology so that directed therapies can be developed and can be tested in well‐controlled clinical trials.
Outcomes of Patients with N3 Neck Nodes Treated with Chemoradiation
Authors: Ballonoff Ari , Raben David , Rusthoven Kyle E. , Bassetti Michael , Kane Madeleine , Song John I. , Chen Changhu
Published: May 2008

Objective: To evaluate the outcomes of patients with locally advanced head and neck squamous cell carcinoma with N3 neck nodes treated with definitive chemoradiation.

Study Design: Retrospective review.

Methods: Thirty‐two patients with nonmetastatic locally advanced head and neck squamous cell carcinoma and N3 neck disease treated with concurrent chemoradiation therapy were evaluated. Overall survival, disease‐ free survival, locoregional control, and distant control were recorded.

Results: Median follow‐up for surviving patients was 25 (range, 3–93) months. Seventeen of 32 (53%) patients failed, 13 in distant sites only, 2 in the neck only, 1 in the neck and a distant site, and 1 in the neck and primary site. The absolute rates of locoregional control and distant control were 88% and 56%, respectively. Actuarial overall survival and disease‐free survival at 2 years were 51% and 29%, respectively.

Conclusion: Patients with N3 neck disease treated with chemoradiation experience a very high rate of distant failure. Future studies investigating the role of additional systemic therapy in these patients are warranted.
Conservative Management of Vestibular Schwannomas: An Effective Strategy
Authors: Ferri Gian Gaetano , Modugno Giovanni Carlo , Pirodda Antonio , Fioravanti Antonio , Calbucci Fabio , Ceroni Alberto Rinaldi
Published: May 2008

Objectives: Stimulated by the availability of a larger sample of patients and a longer follow‐up period, we update our experience with conservative management of vestibular schwannomas.

Study Design: Patients with intracanalicular and small/medium‐sized tumors have been followed prospectively at a tertiary referral center.

Methods: One hundred twenty‐three patients affected by sporadic vestibular schwannoma were primarily observed by means of magnetic resonance imaging scans. In case of significant tumor growth (≥2 mm), patients were either surgically treated or submitted to radiotherapy, but, not rarely, they continued to follow the “wait‐and‐scan” policy. Tumor‐size changes over time were also evaluated with hearing function. Statistical analysis with predictive growth factors was performed.

Results: Almost two thirds (64.5%) of the cases did not show tumor growth during the entire period of observation (mean follow‐up period, 4.8 yrs). Among growing tumors, 16 patients were surgically treated with no complications or facial nerve palsy. Less than half (45.5%) of the patients presented useful hearing (classes A and B of the American Academy of Otolaryngology–Head and Neck Surgery classification) at diagnosis, and 41 (73.2%) patients had preserved hearing during follow‐up independently from the tumor growth rate.

Conclusions: Conservative management of vestibular schwannoma appears to be a safe procedure because most tumors do not grow and surgical outcomes are not affected by possible delays. In the great majority of cases, useful hearing is maintained over time. Because of the irregular behavior of the tumor, periodic neuroradiologic scans are mandatory to limit late surgical risks.
Deviated Nose Cartilaginous Dorsum Correction Using a Dorsal L‐Strut Cutting and Suture Technique
Authors: Song Hyung Min , Kim Ji‐Sun , Lee Bong‐Jae , Jang Yong Ju
Published: May 2008

Objective: A deviated nose with involvement of a severely deviated cartilaginous dorsum is a particular challenge for rhinoplasty surgeons. We applied a new approach for treating such cases, the “dorsal L‐strut cutting and suture technique,” and assessed its efficacy and the surgical outcomes.

Study Design: Retrospective chart review.

Methodss: The study population consisted of 27 patients who received the “cutting and suture technique of dorsal L‐strut” to control a severe cartilaginous dorsal deflection between February 2004 and September 2006. Two otolaryngologists who were not involved in surgeries assessed surgical outcomes. Preoperative and postoperative photographs were studied to evaluate outcomes, and anthropometric measurements were made. Postoperative complications were assessed.

Results: Postoperative assessments showed that 81.5% of patients had “excellent” or “good” deviation correction. Two (7.4%) patients experienced cephalic rotation of the tips and shortening of the nasal length. There were no reports of recurrence, saddling, or infection during follow‐up. Pre‐ and postoperative anthropometric measurements showed there was no significant change in tip projection, nasal length, nasofrontal angle, or nasolabial angle.

Conclusions: The dorsal L‐strut cutting and suture technique appears to be a useful method for correcting severe cephalocaudal convexity of the dorsal L‐strut in deviated noses.
OK‐432 Sclerotherapy of Cervical Chylous Lymphocele After Neck Dissection
Authors: Roh Jong‐Lyel , Park Chan Il
Published: May 2008

Backgound/Objectives: Postoperative cervical chylous lymphoceles are extremely rare circumscribed collections of lymph which are usually treated by drainage or surgical exploration, but rarely by sclerotherapy. We investigated the efficacy of OK‐432 (Picibanil, Chungai Pharmaceutical Co., Tokyo, Japan) sclerotherapy in the treatment of cervical lymphocele after neck dissection.

Methods: Four patients with postoperative lymphocele who could not be cured by repeated percutaneous needle aspiration and pressure dressing were treated with intralesional injection of 0.1–0.2 mg OK‐432 after aspiration of fluid. The aspirated fluid was assessed biochemically and cytologically, and regular palpation and ultrasonography/computed tomography were used to evaluate outcomes and recurrences.

Results: Two patients with chyle leak during neck dissection had lymphoceles in the left supraclavicular region 3 weeks later. The other two patients had lymphoceles on the right neck 9 and 12 months, respectively, after neck dissection. All aspirated fluids were chylous in origin without tumor cells. OK‐432 sclerotherapy scored all four lesions with no major complications except for fever and local pain for several days. No lymphocele recurrences or metastatic cancers were observed in any patient for >1 year after sclerotherapy.

Conclusions: Intralesional injection of OK‐432 may be a safe and effective alternative to surgical exploration in the treatment of cervical lymphocele after neck dissection.
Sonographically‐Directed Neck Dissection for Recurrent Thyroid Carcinoma
Authors: Lee Lisa , Steward David L.
Published: May 2008

Objective: To determine the effectiveness of sonographically‐directed compartmental neck dissection for recurrent differentiated thyroid carcinoma as confirmed by ultrasound surveillance and thyroid‐specific biochemical markers.

Study Design: Retrospective chart review.

Methods: Retrospective cohort study of 18 patients with sonographically localized and pathology‐confirmed recurrent differentiated thyroid carcinoma. Fifteen patients chose to undergo compartmental neck dissection by a single surgeon. Surgery involved central compartment (level VI) or functional lateral neck dissection (level II‐IV+/‐V). Three patients declined surgery despite proven recurrent lymph node disease.

Results: All 18 patients started out with sonographic evidence of recurrent lymph node disease. Preoperative thyroglobulin or thyroglobulin antibody levels were positive in 17 of 18 patients (94%). Postoperatively, all 15 patients who underwent compartmental lymph node dissections had no sonographic evidence of lymph node disease. Of the 14 patients with preoperative positive thyroglobulin or thyroglobulin antibody levels, 9 patients converted to negative levels (64%). Furthermore, two of four patients (50%) converted to thyroglobulin antibody negative status after surgery. All three patients who declined surgery had persistently detectable sonographic nodal disease in addition to positive thyroglobulin and/or thyroglobulin antibody levels (100%). Surgical complications were minimal and self‐limited as no patient experienced permanent cranial nerve deficits.

Conclusion: Ultrasound‐directed cranial nerve sparing compartmental lymph node dissection results in no sonographically detectable cervical lymph node disease and undetectable basal thyroglobulin or thyroglobulin antibody levels in the majority of patients with low morbidity.
Individual genetic diversity correlates with the size and spatial isolation of natal colonies in a bird metapopulation
Authors: Ortego Joaquín , Aparicio José Miguel , Cordero Pedro J , Calabuig Gustau
Published: May 2008

The genetic consequences of small population size and isolation are of central concern in both population and conservation biology. Organisms with a metapopulation structure generally show effective population sizes that are much smaller than the number of mature individuals and this can reduce genetic diversity especially in small sized and isolated subpopulations. Here, we examine the association between heterozygosity and the size and spatial isolation of natal colonies in a metapopulation of lesser kestrels (Falco naumanni). For this purpose, we used capture–mark–recapture data to determine the patterns of immigration into the studied colonies, and 11 highly polymorphic microsatellite markers that allowed us to estimate genetic diversity of locally born individuals. We found that individuals born in smaller and more isolated colonies were genetically less diverse. These colonies received a lower number of immigrants, supporting the idea that both reduced gene flow and small population size are responsible for the genetic pattern observed. Our results are particularly intriguing because the lesser kestrel is a vagile and migratory species with great movement capacity and dispersal potential. Overall, this study provides evidence of the association between individual heterozygosity and the size and spatial isolation of natal colonies in a highly mobile vertebrate showing relatively frequent dispersal and low genetic differentiation among local subpopulations.
MTA Is an Arabidopsis Messenger RNA Adenosine Methylase and Interacts with a Homolog of a Sex-Specific Splicing Factor
Authors: Zhong Silin , Li Hongying , Bodi Zsuzsanna , Button James , Vespa Laurent , Herzog Michel , Fray Rupert G.
Published: May 2008

N  6-Methyladenosine is a ubiquitous modification identified in the mRNA of numerous eukaryotes, where it is present within both coding and noncoding regions. However, this base modification does not alter the coding capacity, and its biological significance remains unclear. We show that Arabidopsis thaliana mRNA contains N  6-methyladenosine at levels similar to those previously reported for animal cells. We further show that inactivation of the Arabidopsis ortholog of the yeast and human mRNA adenosine methylase (MTA) results in failure of the developing embryo to progress past the globular stage. We also demonstrate that the arrested seeds are deficient in mRNAs containing N  6-methyladenosine. Expression of MTA is strongly associated with dividing tissues, particularly reproductive organs, shoot meristems, and emerging lateral roots. Finally, we show that MTA interacts in vitro and in vivo with At FIP37, a homolog of the Drosophila protein FEMALE LETHAL2D and of human WILMS' TUMOUR1-ASSOCIATING PROTEIN. The results reported here provide direct evidence for an essential function for N  6-methyladenosine in a multicellular eukaryote, and the interaction with At FIP37 suggests possible RNA processing events that might be regulated or altered by this base modification.
Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti‐NGF monoclonal antibody, using a repertoire of biosensors
Authors: Abdiche Yasmina Noubia , Malashock Dan Stephen , Pons Jaume
Published: May 2008

We describe the use of four complementary biosensors (Biacore 3000, Octet QK, ProteOn XPR36, and KinExA 3000) in characterizing the kinetics of human nerve growth factor (NGF) binding to a humanized NGF‐neutralizing monoclonal antibody (tanezumab, formerly known as RN624). Tanezumab is a clinical candidate as a therapy for chronic pain. Our measurements were consistent with the NGF/tanezumab binding affinity being tighter than 10 pM due to the formation of an extremely stable complex that had an estimated half‐life exceeding 100 h, which was beyond the resolution of any of our methods. The system was particularly challenging to study because NGF is an obligate homodimer, and we describe various assay orientations and immobilization methods that were used to minimize avidity in our experiments while keeping NGF in as native a state as possible. We also explored the interactions of NGF with its natural receptors, TrkA and P75, and how tanezumab blocks them. The Biacore blocking assay that we designed was used to quantify the potency of tanezumab and is more precise and reproducible than the currently available cell‐based functional assays.
NMR insights into a megadalton‐size protein self‐assembly
Authors: Chugh Jeetender , Sharma Shilpy , Hosur Ramakrishna V.
Published: May 2008

Protein self‐association is critical to many biological functions. However, atomic‐level structural characterization of these assemblies has remained elusive. In this report we present insights into the mechanistic details of the process of self‐association of the 136‐residue GTPase effector domain (GED) of the endocytic protein dynamin into a megadalton‐sized soluble mass. Our approach is based on NMR monitoring of regulated folding and association through Gdn‐HCl titration. The results suggest the evolution of a sequence–self‐association paradigm. Equally significantly, the study demonstrates an elegant bottom‐up strategy that can render large protein self‐assemblies accessible to NMR investigations that have remained difficult to date.
Tissue transglutaminase modulates α‐synuclein oligomerization
Authors: Segers‐Nolten Ine M.J. , Wilhelmus Micha M.M. , Veldhuis Gertjan , van Rooijen Bart D. , Drukarch Benjamin , Subramaniam Vinod
Published: May 2008

We have studied the interaction of the enzyme tissue transglutaminase (tTG), catalyzing cross‐link formation between protein‐bound glutamine residues and primary amines, with Parkinson's disease‐associated α‐synuclein protein variants at physiologically relevant concentrations. We have, for the first time, determined binding affinities of tTG for wild‐type and mutant α‐synucleins using surface plasmon resonance approaches, revealing high‐affinity nanomolar equilibrium dissociation constants. Nanomolar tTG concentrations were sufficient for complete inhibition of fibrillization by effective α‐synuclein cross‐linking, resulting predominantly in intramolecularly cross‐linked monomers accompanied by an oligomeric fraction. Since oligomeric species have a pathophysiological relevance we further investigated the properties of the tTG/α‐synuclein oligomers. Atomic force microscopy revealed morphologically similar structures for oligomers from all α‐synuclein variants; the extent of oligomer formation was found to correlate with tTG concentration. Unlike normal α‐synuclein oligomers the resultant structures were extremely stable and resistant to GdnHCl and SDS. In contrast to normal β‐sheet‐containing oligomers, the tTG/α‐synuclein oligomers appear to be unstructured and are unable to disrupt phospholipid vesicles. These data suggest that tTG binds equally effective to wild‐type and disease mutant α‐synuclein variants. We propose that tTG cross‐linking imposes structural constraints on α‐synuclein, preventing the assembly of structured oligomers required for disruption of membranes and for progression into fibrils. In general, cross‐linking of amyloid forming proteins by tTG may prevent the progression into pathogenic species.
Morphological variation ofNymphaea(Nymphaeaceae) in European Russia
Authors: Volkova Polina A. , Shipunov Alexey B.
Published: May 2008

The morphological variability of the genusNymphaeais described on the basis of detailed studies of fresh material from 49 populations in European Russia and southern Siberia.

Macromorphological characters in the field (including analysis of leaf shape using geometrical morphometry), pollen size and exine sculpture have been analyzed. One polymorphic widespread species,N. candida, grows in most of European Russia.Nymphaea tetragonaseems to be absent in the investigated waters and possibly in the whole central part of European Russia, whereasN. albawas found only in the Astrakhan Region (the delta of the River Volga). These three species are separated relatively well by several morphological characters in fresh plants.Nymphaea tetragonadiffers fromN. albaandN. candidaby the sculpture of the exine of the proximal part of the pollen grains, but the latter species do not seem to be differentiated by pollen characters. Size characters ofNymphaealeaves and flowers do not depend on organic content in water.
Sorbus×liljeforsii, a name for the S. aucuparia×intermedia hybrid (Rosaceae)
Authors: Rich Tim C. G.
Published: May 2008

The uncommon spontaneous hybrid between Sorbus aucuparia L. and S. intermedia (Ehrh.) Pers (Rosaceae) is described and named as Sorbus×liljeforsii.
Spatial extent of bird species response to landscape changes: colonisation/extinction dynamics at the community‐level in two contrasting habitats
Authors: Sirami Clélia , Brotons Lluis , Martin Jean‐Louis
Published: May 2008

Animal community dynamics in changing landscapes are primarily driven by changes in vegetation structure and ultimately by how species respond to these changes and at which spatial scale. We consider two major components of local community dynamics, species colonisation and extinction. We hypothesise that (1) the optimal spatial extent needed to accurately predict them will differ between these two processes; (2) it will also likely differ from species to species as a result of life history traits differences related to differences in habitat selection and (3) that a species' primary habitat will determine the spatial extent at which it perceives change in vegetation structure. We used data collected over 25 yr in a changing Mediterranean landscape to study bird species local colonisation and extinction patterns in two groups of species typical from two habitats: open farmland and woodland. Vegetation changes were measured at spatial extents ranging from 0.2 to 79 ha. Local species colonisation and extinction estimates were computed using a method accounting for heterogeneity in detection probability among species. We built linear models between local species colonisation/extinction estimates and vegetation changes and examined variations in model quality with respect to the spatial extent at which vegetation changes had been measured. Models for open habitat species showed that colonisation processes operated at the landscape scale (79 ha), while extinction was more tightly linked to local habitat requirements (0.2 ha). Models for woodland species presented a low and constant model quality whatever the spatial extent considered. Our results suggest that the dynamics of the woodland species considered responded to a combination of vegetation changes at several scales and, in particular, to changes in the vertical structure of the vegetation. We highlight the need to explicitly consider spatial extent in studies of habitat selection and of habitat and population dynamics to improve our understanding of the biological consequences of land use changes and guide more effective conservation efforts.