bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequence‐selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons
Authors: Chatterjee Sukalyan , Zaman Khalequz , Ryu Hoon , Conforto Adriana , Ratan Rajiv R.
Published: November 2004

Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G‐C‐rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apoptosis induced by glutathione depletion‐induced oxidative stress or the DNA‐damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate “G‐C” box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence‐selective DNA‐binding drugs as neurological therapeutics. Ann Neurol 2001;49:345–354
DYT13, a novel primary torsion dystonia locus, maps to chromosome 1p36.13–36.32 in an Italian family with cranial‐cervical or upper limb onset
Authors: Valente Enza Maria , Bentivoglio Anna Rita , Cassetta Emanuele , Dixon Peter H. , Davis Mary B. , Ferraris Alessandro , Ialongo Tamara , Frontali Marina , Wood Nicholas W. , Albanese Alberto
Published: November 2004

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb‐onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical dystonia. Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was characterized by prominent cranial‐cervical and upper limb involvement and mild severity. A genome‐wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667. Ann Neurol 2001;49:362–366
Reduction of Menkes mRNA and copper in leukocytes of patients with primary adult‐onset dystonia
Authors: Kruse Niels , Berg Daniela , Francis Michael J. , Naumann Markus , Rausch Wolf‐Dieter , Reiners K. , Rieckmann Peter , Weishaupt Andreas , Becker Georg
Published: November 2004

Studies on postmortem tissue of patients with primary adult‐onset dystonia revealed a significant increase in copper levels and a reduction of copper transporting Menkes protein of the lentiform nuclei. Here we demonstrate that patients with idiopathic adult‐onset cervical dystonia (n = 14) have reduced Menkes mRNA copies and lower copper levels in leukocytes compared to controls (n = 17; U test, p < 0.05). Changes were less distinct in patients with blepharospasm. Therefore, disturbances of copper metabolism in focal dystonia may not be restricted to the basal ganglia. Ann Neurol 2001;49:405–408
Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease
Authors: Chan Dennis , Fox Nick C. , Scahill Rachael I. , Crum William R. , Whitwell Jennifer L. , Leschziner Guy , Rossor Alex M. , Stevens John M. , Cipolotti Lisa , Rossor Martin N.
Published: November 2004

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left‐sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role. Ann Neurol 2001;49:433–442
A novel autosomal dominant distal myopathy with early respiratory failure: Clinico‐pathologic characteristics and exclusion of linkage to candidate genetic loci
Authors: Chinnery Patrick F. , Johnson Margaret A. , Walls Timothy J. , Gibson G. John , Fawcett Peter R. W. , Jamieson Sarra , Fulthorpe John J. , Cullen Michael , Hudgson Peter , Bushby Kate M. D.
Published: November 2004

We describe a novel autosomal dominant myopathy presenting in mid–adult life with tibialis anterior weakness. We carried out a detailed clinical assessment of 24 individuals spanning three generations, documenting pathologic features of the muscles in 7 of the 11 affected individuals, including an autopsy study on one case. The second generation of affected individuals presented at an earlier age, and the disease progressed more rapidly than in the first generation. Lung function tests revealed progressive global respiratory muscle weakness detectable from the time of presentation, with preferential diaphragmatic involvement in some cases. Hip girdle and shoulder girdle weakness appeared later in the disease course. We observed a striking correlation between the clinical and pathological features. Clinically unaffected muscles had minimal pathologic change. Fiber splitting, eosinophilic inclusions, and vacuoles with basophilic rims were seen in moderately affected muscles, and fat and fibrous connective tissue replaced muscle fibers in the severely involved muscles. The inclusions were Congophilic and reacted with antibodies to desmin, β‐amyloid, and phosphorylated tau protein. The disease was not linked to any of the known loci associated with distal myopathies, confirming that the disorder in this family is both genetically and phenotypically distinct. Ann Neurol 2001;49:443–452
α‐adrenergic supersensitivity of the sudomotor nerve in complex regional pain syndrome
Authors: Chémali Kamal R. , Gorodeski Revital , Chelimsky Thomas C.
Published: November 2004

α‐adrenoreceptor supersensitivity in many tissues has been described in patients with complex regional pain syndrome type I (CRPS I). Because excessive sweating of the affected limb is an important feature of CRPS I, we investigated whether this supersensitivity also occurs in the sudomotor system. We compared the sweat response to iontophoresis of an α‐adrenergic agent (phenylephrine) in 4 patients with acute CRPS I and 3 patients with resolved CRPS I with that in 9 control subjects using the methodology of the quantitative sudomotor axon reflex test (QSART). A significantly higher sweat response was observed in the affected limb of patients with acute CRPS I compared to their unaffected limb (p = 0.03), to control subjects (p > 0.018), and to the affected or unaffected limbs of patients with resolved CRPS I (p = 0.02), whose sweat response was not significantly different from that of control subjects. We conclude that the abnormal response in patients with acute CRPS I is most likely mediated by an axon reflex and that α‐adrenoreceptor supersensitivity occurs in the presynaptic portion of the postganglionic sudomotor axon. This supersensitivity is reversed when CRPS I resolves. Ann Neurol 2001;49:453–459
Stroke magnetic resonance imaging within 6 hours after onset of hyperacute cerebral ischemia
Authors: Schellinger Peter D. , Fiebach Jochen B. , Jansen Olav , Ringleb Peter A. , Mohr Alexander , Steiner Thorsten , Heiland Sabine , Schwab Stefan , Pohlers Olivia , Ryssel Henning , Orakcioglu Berk , Sartor Klaus , Hacke Werner
Published: November 2004

We studied the diagnostic and prognostic value of diffusion‐ and perfusion‐weighted magnetic resonancce imaging (DWI and PWI) for the initial evaluation and follow‐up monitoring of patients with stroke that had ensued less than 6 hours previously. Further, we examined the role of vessel patency or occlusion and subsequent recanalization or persistent occlusion for further clinical and morphological stroke progression so as to define categories of patients and facilitate treatment decisions. Fifty‐one patients underwent stroke magnetic resonance imaging (DWI, PWI, magnetic resonance angiography, and T2‐weighted imaging) within 3.3 ± 1.29 hours, and, of those, 41 underwent follow‐up magnetic resonance imaging on day 2 and 28 on day 5. In addition, we assessed clinical scores (on the National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, Barthel Index, and Modified Rankin Scale) on days 1, 2, 5, 30, and 90 and performed volumetric analysis of lesion volumes. In all, 25 patients had a proximal, 18 a distal, and 8 no vessel occlusion. Furthermore, 15 of 43 patients exhibited recanalization on day 2. Vessel occlusion was associated with a PWI‐DWI mismatch on the initial magnetic resonance imaging, vessel patency with a PWI‐DWI match (p < 0.0001). Outcome scores and lesion volumes differed significantly between patients experiencing recanalization and those who did not (all p < 0.0001). Acute DWI and PWI lesion volumes correlated poorly with acute clinical scores and only modestly with outcome scores. We have concluded on the basis of this study that early recanalization saves tissue at risk of ischemic infarction and results in significantly smaller infarcts and a significantly better clinical outcome. Patients with proximal vessel occlusions have a larger amount of tissue at risk, a lower recanalization rate, and a worse outcome. Urgent recanalization seems to be of utmost importance for these patients. Ann Neurol 2001;49:460–469
Electrically active axons degenerate when exposed to nitric oxide
Authors: Smith Kenneth J. , Kapoor Raju , Hall Susan M. , Davies Meirion
Published: November 2004

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders. Ann Neurol 2001;49:470–476
Characterization of lipids from human brain tissues by multinuclear magnetic resonance spectroscopy
Authors: Tugnoli V. , Tosi M. R. , Tinti A. , Trinchero A. , Bottura G. , Fini G.
Published: November 2004

Multinuclear (1H, 13C, and 31P) magnetic resonance spectroscopy are applied to the biochemical characterization of the total lipid fraction of healthy and neoplastic human brain tissues. Lipid extracts from normal brains, glioblastomas, anaplastic oligodendrogliomas, oligodendrogliomas, and meningiomas are examined. Moreover, the unknown liquid content of a cyst adjacent to a meningioma is analyzed. Two biopsies from glioblastomas are directly studied by 1H‐NMR without any treatment (ex vivo NMR). The 1H‐ and 13C‐NMR analysis allows full characterization of the lipid component of the cerebral tissues. In particular, the presence of cholesteryl esters and triglycerides in the extracts of high grade tumors is correlated to the vascular proliferation degree, which is different from normal brain tissue and low grade neoplasms. The 31P spectra show that phosphatidylcholine is the prominent phospholipid and its relative amount, which is higher in gliomas, is correlated to the low grade of differentiation of tumor cells and an altered membrane turnover. The ex vivo 1H‐NMR data on the glioblastoma samples show the presence of mobile lipids that are correlated to cell necrotic phenomena. Our data allow a direct correlation between biochemical results obtained by NMR and the histopathological factors (vascular and cell proliferations, differentiation, and necrosis) that are prominent in determining brain tumor grading. © 2001 John Wiley & Sons, Inc. Biopolymers (Biospectroscopy) 62: 297–306, 2001
Analysis of single‐chain antibody production in Pichia pastoris using on‐line methanol control in fed‐batch and mixed‐feed fermentations
Authors: Hellwig Stephan , Emde Frank , Raven Nicole P. G. , Henke Mario , van der Logt Paul , Fischer Rainer
Published: November 2004

In the last few years the Pichia pastoris expression system has been gaining more and more interest for the expression of recombinant proteins. Many groups have employed fermentation technology in their investigations because the system is fairly easy to scale up and suitable for the production in the milligram to gram range. A large number of heterologous proteins from different sources has been expressed, but the fermentation process technology has been investigated to a lesser extent. A large number of fermentations are carried out in standard bioreactors that may be insufficiently equipped to meet the demands of high‐cell‐density fermentations of methylotrophic yeasts. In particular, the lack of on‐line methanol analysis leads to fermentation protocols that may impair the optimal expression of the desired products. We have used a commercially available methanol sensor to investigate in detail the effects of supplementary glycerol feeding while maintaining a constant methanol concentration during the induction of a Mut+ strain of Pichia pastoris. Specific glycerol feed rates in the range of 38–4.2 mg · g−1 · h−1 (mg glycerol per gram fresh weight per hour) were investigated. Expression of the recombinant scFv antibody fragment was only observed at specific feed rates below 6 mg · g−1 · h−1. At low specific feed rates, growth was even lower than with methanol as the sole carbon source and the harvest expression level of the scFv was only half of that found in the control fermentation. These results show that glycerol inhibits expression driven by the AOX1 promoter even at extremely limited availability and demonstrate the benefits of on‐line methanol control in Pichia fermentation research. © 2001 John Wiley & Sons, Inc. Biotechnol Bioeng 74: 344–352, 2001.
Mutations in the second C2 domain of synaptotagmin disrupt synaptic transmission at Drosophila neuromuscular junctions
Authors: Mackler Jennifer M. , Reist Noreen E.
Published: November 2004

The synaptic vesicle protein, synaptotagmin, has been hypothesized to mediate several functions in neurotransmitter release including calcium sensing, vesicle recycling, and synaptic vesicle docking. These hypotheses are based on evidence from in vitro binding assays, peptide and antibody injection experiments, and genetic knockout studies. Synaptotagmin contains two domains that are homologous to the calcium ion (Ca2+)‐binding C2 domain of protein kinase C. The two C2 domains of synaptotagmin have broadly differing ligand‐binding properties. We have focused on the second C2 domain (C2B) of synaptotagmin I, in particular, on a series of conserved lysine residues on β‐strand 4 of C2B. This polylysine motif binds clathrin‐adapter protein AP‐2, neuronal calcium channels, and inositol high polyphosphates. It also mediates Ca2+‐dependent oligomerization. To investigate the importance of these lysine residues in synaptic transmission, we have introduced synaptotagmin I (syt) transgenes harboring specific polylysine motif mutations into flies otherwise lacking the synaptotagmin I protein (sytnull). Electrophysiological analyses of these mutants revealed that evoked transmitter release is decreased by ≈36% and that spontaneous release is increased approximately twofold relative to sytnull flies that express a wild type syt transgene. Synaptotagmin expression in both the mutant and the wild type transgenic lines was equivalent, as measured by semiquantitative Western blot analysis. Thus, the alteration in synaptic transmission was due to the mutation and not to the level of synaptotagmin expression. We conclude that synaptotagmin interactions mediated by the C2B polylysine motif are required to attain full synaptotagmin function in vivo. J. Comp. Neurol. 436:4–16, 2001. © 2001 Wiley‐Liss, Inc.
Zona incerta: Substrate for contralateral interconnectivity in the thalamus of rats
Authors: Power Brian D. , Mitrofanis John
Published: November 2004

We have shown previously that the zona incerta (ZI), a small nucleus deriving from the ventral thalamus, has extensive ipsilateral connections with the higher order and intralaminar nuclei of the dorsal thalamus and that there are many ipsilateral interconnections between the different cytoarchitectonic sectors of the ZI. In this study, we explore the contralateral connections that the ZI has with its opposing nucleus as well as with the other nuclei of the thalamus. Injections of biotinylated dextran or cholera toxin subunit B were made into each of the different ZI sectors (rostral, dorsal, ventral, and caudal) and into intralaminar and higher order dorsal thalamic nuclei of Sprague‐Dawley rats by using stereotaxic coordinates. Brains were fixed in aldehyde and processed using standard methods. Our results show that, after injections limited to a given ZI sector, labelled terminal‐like elements and cells were seen across the other sectors of the ZI of the contralateral side. Furthermore, after each of these ZI injections, labelling was seen in the intralaminar (e.g., parafascicular, central lateral, and central medial) and higher order (e.g., posterior thalamic, lateral posterior, and lateral dorsal) nuclei of the contralateral side. These patterns of labelling were confirmed after tracer injections into intralaminar and higher order nuclei; after such injections, labelling was seen in the contralateral ZI. In all cases, there was labelling on the ipsilateral side as well, and this was generally heavier than on the contralateral side. Overall, our results indicate that there is a network of interconnections between the ZI of both sides of the thalamus and that the ZI has contralateral connections with the intralaminar and higher order nuclei. Hence, the ZI furnishes a substrate that spreads activity to both sides of the brain. J. Comp. Neurol. 436:52–63, 2001. © 2001 Wiley‐Liss, Inc.
Localization of neuropeptide Y mRNA and peptide in the chicken hypothalamus and their alterations after food deprivation, dehydration, and castration
Authors: Kameda Yoko , Miura Masaaki , Nishimaki Toshiyuki
Published: November 2004

Localization of neuropeptide Y (NPY) mRNA in the hypothalamus of chickens was studied by in situ hybridization with digoxigenin‐labeled chicken NPY cRNA probe. The largest number of perikarya‐expressing NPY mRNA was found within the mediobasal hypothalamus, including the infundibular nucleus, inferior hypothalamic nucleus, and median eminence. Many NPY perikarya were noted to surround the nucleus rotundus and to be present in the supraoptic nucleus. Moreover, some perikarya were detected in the nucleus of basal optic root, bed nucleus pallial commissure, and nucleus striae terminalis close to the lateral forebrain bundle. NPY‐immunoreactive nerve fibers were densely distributed in these regions containing the NPY mRNA‐expressing perikarya. Following food deprivation for four days, perikarya‐expressing NPY mRNA and peptide were markedly increased in the mediobasal hypothalamus and particularly so in the infundibular nucleus. No changes, however, were detected in other regions containing NPY‐positive perikarya. Water deprivation induced less increase in NPY‐positive perikarya in the mediobasal hypothalamus compared to food deprivation. After gonadectomy, the number of NPY‐positive perikarya in the mediobasal hypothalamus was unaltered. Northern blot analysis with 32P‐labeled chicken NPY cDNA probe demonstrated that a 2.7‐fold increase of NPY mRNA was induced by starvation and a 1.5‐fold increase was induced by dehydration, whereas the NPY mRNA band remained unchanged after gonadectomy. Thus, it seems that NPY neurons located in the mediobasal hypothalamus are involved in feeding behavior but not reproductive activity. J. Comp. Neurol. 436:376–388, 2001. © 2001 Wiley‐Liss, Inc.
Immunocytochemical analysis of basket cells in rat piriform cortex
Authors: Ekstrand Jeffrey J. , Domroese Mark E. , Feig Sherry L. , Illig Kurt R. , Haberly Lewis B.
Published: November 2004

Basket cells, defined by axons that preferentially contact cell bodies, were studied in rat piriform (olfactory) cortex with antisera to γ‐aminobutyric acid (GABA)ergic markers (GABA, glutamate decarboxylase) and to peptides and calcium binding proteins that are expressed by basket cells. Detailed visualization of dendritic and axonal arbors was obtained by silver‐gold enhancement of staining for vasoactive intestinal peptide (VIP), cholecystokinin (CCK), parvalbumin, and calbindin. Neuronal features were placed into five categories: soma‐dendritic and axonal morphologies, laminar distributions of dendritic and axonal processes, and molecular phenotype. Although comparatively few forms were distinguished within each category, a highly varied co‐expression of features from different categories produced a “combinatorial explosion” in the characteristics of individual neurons. Findings of particular functional interest include: dendritic distributions suggesting that somatic inhibition is mediated by feedforward as well as feedback pathways, axonal variations suggesting a differential shaping of the temporal aspects of somatic inhibition from different basket cells, evidence that different principal cell populations receive input from different combinations of basket cells, and a close association between axonal morphology and molecular phenotype. A finding of practical importance is that light microscopic measurements of boutons were diagnostic for the molecular phenotype and certain morphological attributes of basket cells. It is argued that the diversity in basket cell form in the piriform cortex, as in other areas of the cerebral cortex, reflects requirements for large numbers of specifically tailored inhibitory processes for optimal operation that cannot be met by a small number of rigidly defined neuronal populations. J. Comp. Neurol. 434:308–328, 2001. © 2001 Wiley‐Liss, Inc.
Bi‐level image coding for digital printing using genetic algorithm
Authors: Tanaka Masaharu , Sakanashi Hidenori , Mizoguchi Masanobu , Higuchi Tetsuya
Published: November 2004

We propose a bi‐level image coding method for digital printing images, using Genetic Algorithms (GAs). These images have resolutions as high as those of photographs; therefore, the coding method is required to achieve high compression ratios. Our GA‐based method can obtain higher compression ratios by optimizing the coding algorithm according to the features of the printing images. We have confirmed that our method is 1014 times as fast as a full search, and that the compression ratio is 9.26% better than that of conventional methods. In addition, the compression ratio is 42% higher than that of the JBIG standard. © 2001 Scripta Technica, Electron Comm Jpn Pt 3, 84(9): 1–10, 2001
Applying mixed methods under the framework of theory‐driven evaluations
Authors: Chen Huey‐tsyh
Published: November 2004

The application of mixed methods under the framework of theory‐driven evaluations can minimize the potential tension and conflict of mixing qualitative and quantitative methods, as well as compensate for each method's weaknesses. Mixed methods should not be applied indiscriminantly, however, but rather contingently under particular conditions as described in this chapter.
Genetic imbalances in 26 cases of penile squamous cell carcinoma
Authors: Alves Gilda , Heller Anita , Fiedler Wolfgang , Campos Mércia Mendes , Claussen Uwe , Ornellas Antônio Augusto , Liehr Thomas
Published: November 2004

To obtain more information on chromosomal changes in the up‐to‐now poorly studied tumor class of penile squamous cell carcinoma (SCC), we performed a comparative genomic hybridization study of 26 cases of this rare tumor. DNA sequence copy number alterations (CNAs) very similar to those detected in other SCC types, such as oral and esophageal SCC, were noted. The most common copy number gains were found in 8q24, 16p11–12, 20q11–13, 22q, 19q13, and 5p15, and the most common deletions were detected in 13q21–22, 4q21–32, and along the X chromosome. Classifying the patients according to the number of CNAs showed a possible correlation with clinical outcome. © 2001 Wiley‐Liss, Inc.
The sedimentary records in Mediterranean rockshelters and caves: Archives of environmental change
Authors: Woodward Jamie C. , Goldberg Paul
Published: November 2004

It is important to develop rigorous methods and robust conceptual models for the interpretation of rockshelter and cave sediment records so that the cultural sequences they contain can be considered in their proper environmental context. Much of what we know about the prehistory of the Mediterranean region and adjacent areas has largely been pieced together from materials excavated from sedimentary sequences in these environments. The rockshelters and caves of the region form important environmental and sedimentary archives. Recent work has begun to consider if the remarkable climatic variability evident in the high resolution lacustrine and ice core records is manifest in the rockshelter and cave sediment records of the area. In this context, the two main characteristics of a rockshelter or cave site which control its usefulness as an archive of environmental change are the temporal resolution of the sedimentary record and the environmental sensitivity of the site. Many rockshelters and caves can be described as either Active Karst Settings (AKS) or Passive Karst Settings (PKS) and site type is an important influence on climatic sensitivity with a direct influence upon the usefulness of the sedimentary sequence as a proxy record of climate change. It is now clear that some sites may preserve detailed paleoclimatic records and the climatic signal may be represented by distinctive suites of micromorphological features, by variations in the input of allogenic sediment, or by fluctuations in the mineral magnetic properties of the fine sediment fraction. It can be argued that data derived from the analysis of bulk coarse‐grained samples often lacks the stratigraphic resolution and environmental sensitivity that can be obtained from other approaches. The most favorable sites for detailed paleoclimatic reconstruction appear to be in active karst settings such as Theopetra Cave (Greece) and Pigeon Cave (Morocco) where micromorphological analyses offer insights into the stratigraphic record that are not otherwise obtainable. The temporal resolution of a site can only be established through a rigorous stratigraphic analysis and a comprehensive dating program. These are fundamental considerations in the study of rockshelter sediment records, especially when attempting to correlate between sites and draw comparisons with other proxy records of environmental change derived from sedimentary environments with rather different characteristics. Rockshelters and caves are part of a wider sediment system, and their investigation must be accompanied by detailed geomorphological, sedimentological, paleoecological, and geochronological studies of the off‐site Quaternary record. © 2001 John Wiley & Sons, Inc.
Advanced hypopharyngeal carcinoma treatment results according to treatment modalities
Authors: Kim Suzy , Wu Hong‐Gyun , Heo Dae‐Seog , Kim Kwang Hyun , Sung Myung‐Whun , Park Charn Il
Published: November 2004

Background

The purpose of this retrospective study is to compare the treatment results of locally advanced hypopharyngeal carcinoma according to treatment modalities.

Methods

Seventy‐three patients with locally advanced hypopharyngeal carcinoma treated at the Department of Therapeutic Radiology, Seoul National University Hospital, between August 1979 and July 1997 were retrospectively analyzed. Twenty‐three patients were treated with radiotherapy (RT) alone, 18 patients were treated with surgery and postoperative RT, and 32 patients were treated with neoadjuvant chemotherapy (CTx) and RT. Median follow‐up period was 28 months.

Results

The overall 5‐year survival rates were 15.7% for the RT alone group, 46.8% for surgery and postoperative RT group, and 43.0% for neoadjuvant CTx and RT group. The 5‐year disease‐free survival rates were 13.9%, 47.4%, and 30.7%, respectively. Surgery and postoperative RT or neoadjuvant CTx and RT showed superiority over RT alone in terms of both overall survival and disease‐free survival rates. No significant differences were found in overall and disease‐free survival rates between the surgery and postoperative RT group and neoadjuvant CTx and RT group (p= .15,p= .13). In the neoadjuvant CTx and RT group, 12 patients (38%) retained their larynx more than 5 years.

Conclusion

Neoadjuvant CTx and RT is an effective strategy to achieve organ preservation without compromising the survival of patients with locally advanced hypopharyngeal carcinoma. © 2001 John Wiley & Sons, Inc. Head Neck 23: 713–717, 2001.
Observer error in the assessment of nodal disease in head and neck cancer
Authors: Alderson David J. , Jones Terry M. , White Sarah J. , Roland Nicholas J.
Published: November 2004

Background

There is no previously published information on clinicians' abilities to accurately differentiate between different stages of node positive disease in head and neck cancer.

Methods

Forty‐two surgeons examined standardized nodes in a model neck and estimated nodal size. Each recorded their confidence in their ability to perform the task using a visual analogue scale. Reference nodes of known size were provided for comparison during a second examination of each node. The study was repeated after 1 month.

Results

Accuracy was poor and was not dependent on experience or confidence. There was a tendency to underestimate the size of smaller nodes. Estimates were strongly influenced by volume independent of largest diameter (p < .001). Reference nodes aided accuracy (p = .031). Subjects were not consistent on repeated testing (p < .001).

Conclusions

Both trainees and specialists are poor at accurately staging nodal disease using palpation alone. © 2001 John Wiley & Sons, Inc. Head Neck 23: 739–743, 2001.
Incidence of cervical node involvement in metastatic cutaneous malignancy involving the parotid gland
Authors: O'Brien Christopher J. , McNeil Edward B. , McMahon Jeremy D. , Pathak Irvin , Lauer Christopher S.
Published: November 2004

Background

The parotid lymph nodes represent an important group of nodes at risk for metastatic involvement from cutaneous malignancies of the head and neck. When treating patients with metastatic disease in the parotid gland it has been our custom to also remove the lymph nodes of the neck on the basis that these nodes represent other nodal groups at risk for metastatic involvement. The aim of this study is to determine the incidence of cervical node involvement among patients with clinical metastatic SCC or melanoma of the parotid to determine whether treatment of the clinically negative neck is warranted.

Methods

The study group consists of 123 prospectively accessioned patients with clinical metastatic cutaneous squamous cell carcinoma (SCC) (n = 73) or melanoma (n = 50) involving the parotid gland and a minimum of 2 years of follow up, irrespective of the clinical status of the neck.

Results

Among 73 patients with metastatic SCC in the parotid, 19 (26%) had clinical neck involvement, and 16 of these were pathologically positive (84%). A total of 37 patients had elective neck dissections, and 13 were pathologically positive, which is an overall rate of 52% neck involvement among patients having neck dissection. Among 50 patients with metastatic melanoma in the parotid, 19 (38%) patients were initially seen with clinical neck disease, and all were pathologically positive. Among 31 patients with clinically negative necks, 26 had neck dissections and seven had positive nodes (27%). Overall, 58% of patients with melanoma who had a neck dissection had positive nodes.

Conclusion

Patients with metastatic cutaneous SCC and melanoma involving the parotid gland had a high incidence of clinical (26% and 38%, respectively) and occult neck disease (35% and 27%). Treatment of the clinically negative neck in the presence of clinical metastatic parotid cancer should be considered to reduce the likelihood of failure in cervical nodes, to define the extent of disease, and to assist with patient selection for adjuvant therapy. © 2001 John Wiley & Sons, Inc. Head Neck 23: 744–748, 2001.
Cancer of retromolar trigone: Long‐term radiation therapy outcome
Authors: Huang Chih‐Jen , Chao K. S. Clifford , Tsai Jason , Simpson Joseph R. , Haughey Bruce , Spector Gershon J. , Sessions Donald G.
Published: November 2004

Background

Cancer of the retromolar trigone is an uncommon head and neck cancer. In this retrospective study, we identified the prognostic factors and evaluated the therapeutic outcomes of patients treated with preoperative radiation therapy (RT), postoperative RT, and RT alone.

Methods

Between 1971 and 1994, 65 patients with histologically proven epidermoid carcinoma of the retromolar trigone were treated at the Mallinckrodt Institute of Radiology; 10 patients received preoperative RT (30–55.2 Gy), 39 received postoperative RT (46–66.6 Gy), and 15 were treated with RT alone (63–74 Gy). Surgery included 44 composite resections and 7 wide excisions. The minimum follow‐up was 5 years.

Results

The 5‐year disease‐free survival rates were 90% with preoperative RT, 63% with postoperative RT, and 31% with RT alone. The 5‐year disease‐free survival rates were 76% for patients with T1 disease, 50% for T2, 72% for T3, and 54% for T4. The 5‐year disease‐free survival rates were 69% for patients with NO disease, 56% for N1, and 26% for N2. The locoregional recurrence rates were 10% (1 of 10) for preoperative RT, 23% (9 of 39) for postoperative RT, and 44% (7 of 16) for RT alone. On multivariate analysis, the significant factors for disease‐free survival were treatment modality (p = .002) and N stage (p = .012); for locoregional control it was treatment modality (p = .046); and for distant metastasis it was N stage (p = .002). The incidence of bone necrosis, soft tissue necrosis, and severe trismus was 12% with postoperative RT, 11% with RT alone, and none with preoperative RT.

Conclusions

Combination surgery with postoperative or preoperative RT offers better locoregional control and disease‐free survival than RT alone for epidermoid carcinoma of the retromolar trigone. Lymph node status significantly influences the disease‐free survival and distant metastasis rates. © 2001 John Wiley & Sons, Inc. Head Neck 23: 758–763, 2001.
Effects of chemotherapy on invasion and metastasis of oral cavity cancer in mice
Authors: Kawashiri Shuichi , Kojima Kiyoshi , Kumagai Shigehiro , Nakagawa Kiyomasa , Yamamoto Etsuhide
Published: November 2004

Background

Using an orthotopic implantation model in which oral cancer invasion and metastasis can be reproduced, we investigated the inhibitory effects of anticancer agents on invasion and metastasis.

Methods

A highly invasive and metastatic human oral squamous cell carcinoma cell line, OSC‐19, was implanted into the oral floor of nude mice, and cisplatin or peplomycin was administered to the mice 7 or 14 days after implantation. The effects of each anticancer drug and different administration timings on cancer invasion and metastasis were investigated.

Results

Tumor size and the ratio of proliferating cell nuclear antigen–positive cells was significantly reduced. In the control group, the tumors showed grade 4C mode of invasion, whereas in the groups treated with anticancer drugs, grade 3 was observed in 77.3% of the mice, with an inhibitory effect on tumor invasion being observed. The rate of metastasis in the cervical lymph node was significantly decreased in the groups treated with the cisplatin or peplomycin on day 7 after implantation. The tumor stage progression in the metastatic lymph nodes was also inhibited.

Conclusions

Chemotherapy is effective not only for tumor diminution but also for inhibiting invasion and metastasis. In light of these effects, administration of anticancer drugs may be clinically useful in this regard. 23: 764–771, 2001.
Do nodal metastases from cutaneous melanoma of the head and neck follow a clinically predictable pattern?
Authors: Pathak Irvin , O'Brien Christopher J. , Petersen‐Schaeffer Karin , McNeil Edward B. , McMahon Jeremy , Quinn Michael J. , Thompson John F. , McCarthy William H.
Published: November 2004

Background

Potential lymphatic drainage patterns from cutaneous melanomas of the head and neck are said to be variable and frequently unpredictable. The aim of this article is to correlate the anatomic distribution of pathologically involved lymph nodes with primary melanoma sites and to compare these findings with clinically predicted patterns of metastatic spread.

Methods

A prospectively documented series of 169 patients with pathologically proven metastatic melanoma was reviewed by analyzing the clinical, operative, and pathologic records. Clinically, it was predicted that melanomas of the anterior scalp, forehead, and face could metastasize to the parotid and neck levels I–III; the coronal scalp, ear, and neck to the parotid and levels I–V; the posterior scalp to occipital nodes and levels II–V; and the lower neck to levels III–V. Minimum follow up was 2 years.

Results

There were 141 therapeutic (97 comprehensive, 44 selective) and 28 elective lymphadenectomies (4 comprehensive dissections, 21 selective neck dissections, and 3 cases in which parotidectomy alone was performed). Overall, there were 112 parotidectomies, 44 of which were therapeutic and 68 elective. Pathologically positive nodes involved clinically predicted nodal groups in 156 of 169 cases (92.3%). The incidence of postauricular node involvement was only 1.5% (3 cases). No patient was initially seen with contralateral metastatic disease; however, 5 patients (2.9%) failed in the contralateral neck after therapeutic dissection. In 68% of patients, metastatic disease involved the nearest nodal group, and in 59% only a single node was involved.

Conclusions

Cutaneous malignant melanomas of the head and neck metastasized to clinically predicted nodal groups in 92% of patients in this series. Postauricular and contralateral metastatic node involvement was uncommon. © 2001 John Wiley & Sons, Inc. Head Neck 23: 785–790, 2001.
Salvage treatment for persistent and recurrent T1–2 nasopharyngeal carcinoma by stereotactic radiosurgery
Authors: Chua Daniel T. T. , Sham Jonathan S. T. , Hung Kwan‐Ngai , Leung Lucullus H. T. , Cheng Pui‐Wai , Kwong Philip W. K.
Published: November 2004

Objective

To study the efficacy of stereotactic radiosurgery in salvaging early‐stage persistent and recurrent nasopharyngeal carcinoma (NPC) after primary radiotherapy.

Methods

A prospective single‐arm study evaluating the response and outcome of patients with rT1–2 NPC treated by stereotactic radiosurgery. Eleven patients with rT1–2 were treated by radiosurgery between March 1998 and March 2000. Four patients were treated for persistent disease occurring within 4 months after primary radiotherapy, six were treated for first recurrence, and one for third recurrence. Six patients had rT1 disease and five had rT2 disease. Most patients had disease not amenable to brachytherapy, surgery, or external re‐irradiation. The median target volume was 5.8 cc (range, 3.3–16.9). Radiosurgery was performed with multiple noncoplanar arcs of photon, with a median dose of 12.5 Gy delivered to the 80% isodose line (range, 12–14 Gy). Median follow‐up time after radiosurgery was 18 months (range, 9–30).

Results

Nine patients had complete regression of tumor as assessed by imaging, nasopharyngoscopy, and biopsy; one patient had partial regression of tumor; whereas one patient had static disease. The overall response rate was 91% (10 of 11) and the complete response rate was 82% (9 of 11). Two patients with complete response subsequently had local relapse develop, with one recurrence outside the treated volume 8 months after radiosurgery, and the other within the treated volume 6 months after radiosurgery. One patient with a partial response had neck node recurrence develop. Temporal lobe necrosis occurred in one patient but probably represents sequelae of primary radiation after reviewing the dosimetry. Ten patients are still alive, whereas one patient with local relapse had distant metastases develop and died. The estimated 1‐year local control rate after radiosurgery was 82%.

Conclusions

Our preliminary results indicate that stereotactic radiosurgery is an effective treatment modality for persistent and recurrent T1–T2 NPC, and early control rate seems to be comparable to other salvage treatments. More clinical experiences and longer follow‐up are still needed to validate our results and to address fully the role of radiosurgery in salvaging local failures of NPC. © 2001 John Wiley & Sons, Inc. Head Neck 23: 791–798, 2001.
Evidence for a direct projection from the postrhinal cortex to the subiculum in the rat
Authors: Naber Pieterke A. , Witter Menno P. , Lopes da Silva Fernando H.
Published: November 2004

Behavioral data indicate that three of the areas which form the parahippocampal region in the rat, i.e., the entorhinal, perirhinal, and postrhinal cortices, have different, although related functions that also differ from those of the hippocampal formation. These functional differences might be related to differences in connectivity, on the one hand with parts of the association cortex, and on the other with the hippocampal formation. In a previous study, we showed the existence of both a direct and an indirect projection from the perirhinal cortex to areas CA1 and subiculum of the hippocampus. Here we present the result of a second study, demonstrating a similarly organized projection from the postrhinal cortex to the subiculum, comprising both a direct and an indirect route.

Electrical stimulation of the postrhinal cortex in vivo evoked field potentials throughout the subiculum and the dentate gyrus. Current source density analysis in both the subiculum and dentate gyrus revealed the presence of sink‐source pairs, indicative of a synaptic termination. Based on comparison with the sink‐source pairs found after stimulation of the medial entorhinal cortex, we conclude that the connection between the postrhinal cortex and the dentate gyrus most likely is formed by a polysynaptic pathway mediated via the medial entorhinal cortex, while the pathway from the postrhinal cortex to the subiculum is likely monosynaptic. In order to substantiate these findings, we carried out several tracer experiments. Anterograde tracer injections in the postrhinal cortex resulted in labeled fibers in limited parts of the subiculum, but no anatomical evidence for a projection of the postrhinal cortex to the dentate gyrus was found. Additional retrograde tracer injections in the subiculum also showed evidence for a direct postrhinal‐to‐subiculum projection with a strong topological organization. Based on these combined anatomical and electrophysiological data, we conclude that the postrhinal cortex indeed can reach the subiculum via both a direct and an indirect pathway. Hippocampus 2001;11:105–117. © 2001 Wiley‐Liss, Inc.