bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cribriform‐morular variant of Papillary Thyroid Carcinoma: Clue to Early Detection of Familial Adenomatous Polyposis‐associated Colon Cancer
Authors: Tomoda Chisato , Miyauchi Akira , Uruno Takashi , Takamura Yuuki , Ito Yasuhiro , Miya Akihiro , Kobayashi Kaoru , Matsuzuka Fumio , Kuma Seiji , Kuma Kanji , Kakudo Kennichi 
Published: September 2004

AbstractThe cribriform‐morular variant (CMV) of papillary thyroid carcinoma (PTC) is a rare histologic subtype of PTC that shows a combination of growth patterns including cribriform and spindle cell areas. The thyroid cancer with this unique histology was originally reported in patients with familial adenomatous polyposis (FAP), although it was later found in patients without polyposis as well. Because of its rarity, its clinical features are not clear. We reviewed seven patients with CMV‐PTC who were found among 4194 patients with PTC in our pathology files between June 1991 and March 2003. The prevalence of CMV was 0.16% among all PTCs. We invited these patients to our hospital so we could obtain a detailed family history and recommend colonoscopic examination and germline APC gene analysis. Two patients without subjective symptoms had polyposis of the colon and colon cancers. Germline APC gene mutations were found in both patients. The father of a patient who refused the invitation was revealed to have undergone surgery for colon polyposis. In the remaining four patients, neither polyposis nor APC gene mutation was found. Common clinical features included a young age (mean 25 years), predominance of females, circumscribed tumors, negative node metastasis, and no recurrence of the thyroid cancer after surgery. Two of the three patients with colon polyposis had bilateral multiple thyroid tumors, whereas the remaining four (without polyposis) had a solitary tumor. The histopathology of CMV in patients with PTC should arouse a suspicion of FAP, especially if there are multiple tumors. This finding can lead to early detection of colon cancer.
Sodium–calcium exchanger contributes to membrane hyperpolarization of intact endothelial cells from rat aorta during acetylcholine stimulation
Authors: Bondarenko Alexander 
Published: September 2004

The role of sodium–calcium exchanger in acetylcholine (Ach)‐induced hyperpolarization of intact endothelial cells was studied in excised rat aorta. The membrane potential was recorded using perforated patch‐clamp technique.
The mean resting potential of endothelial cells was −44.1±1.4 mV. A selective inhibitor of sodium–calcium exchanger benzamil (100 μM) had no significant effect on resting membrane potential, but reversibly decreased the amplitude of sustained Ach‐induced endothelial hyperpolarization from 20.9±1.4 to 5.7±1.1 mV when applied during the plateau phase.
The blocker of reversed mode of the exchanger KB‐R7943 (2‐[2‐[4‐(4‐nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate, 20 μM) reversibly decreased the amplitude of sustained Ach‐induced hyperpolarization from 20.5±2.9 to 7.5±1.8 mV.
Introduction of tetraethylammonium (10 mM) in the continuous presence of Ach decreased the sustained phase of hyperpolarization from 17.9±1.5 by 12.9±0.9 mV. Subsequent addition of 20 μM KB‐R7943 further depolarized endothelial cells by 4.8±1.1 mV.
Substituting external sodium with N‐methyl D‐glucamine during the plateau phase of Ach‐evoked hyperpolarization reversibly decreased the hyperpolarization from −61.8±2.7 to −54.2±1.9 mV. In the majority of preparations, the initial response to removal of external sodium was a transient further rise in the membrane potential of several mV. Sodium ionophore monensin hyperpolarized endothelium by 10.3±0.7 mV.
The inhibitory effect of benzamil on Ach‐induced endothelial sustained hyperpolarization was observed in endothelium mechanically isolated from smooth muscle.
These results suggest that the sodium–calcium exchanger of intact endothelial cells is able to operate in reverse following stimulation by Ach, contributing to sustained hyperpolarization. Myoendothelial electrical communications do not mediate the effect of blockers of sodium–calcium exchanger.

British Journal of Pharmacology (2004) 143, 9–18. doi:10.1038/sj.bjp.0705866
Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action
Authors: Taubert D , Berkels R , Grosser N , Schröder H , Gründemann D , Schömig E 
Published: September 2004

The study was designed to test the hypothesis that aspirin may stimulate nitric oxide (NO) release from vascular endothelium, a pivotal factor for maintenance of vascular homeostasis.
Clinical evidence suggests that low‐dose aspirin may improve vascular endothelial function. Since other cyclooxygenase (COX) inhibitors showed no beneficial vascular effects, aspirin may exhibit a vasculoprotective, COX‐independent mechanism.
Luminal NO release was monitored in real time on dissected porcine coronary arteries (PCA) by an amperometric, NO‐selective sensor. Additionally, endothelial NO synthase (eNOS) activity was measured in EA.hy 926 cell homogenates by an L‐[3H]citrulline/L‐[3H]arginine conversion assay. Superoxide scavenging capacity was assessed by lucigenin‐enhanced luminescence.
Aspirin induced an immediate concentration‐dependent NO release from PCA with an EC50 of 50 nM and potentiated the NO stimulation by the receptor‐dependent agonist substance P. These effects were independent of an increase in intracellular calcium and could be mimicked by stimulation with acetylating aspirin derivatives. The aspirin metabolite salicylic acid or the reversible cyclooxygenase inhibitor indomethacin failed to modulate NO release. Incubation of soluble eNOS for 15 min with 100 μM aspirin or acetylating aspirin analogues increased the L‐[3H]citrulline yield by 40–80%, while salicylic acid had no effect. Aspirin and salicylic acid showed a similar, but only modest, magnitude and velocity of superoxide scavenging.
Our findings demonstrate that therapeutically relevant concentrations of aspirin elicit NO release from vascular endothelium. This effect appears to be due to a direct acetylation of the eNOS protein, but is independent of COX inhibition or inhibition of superoxide‐mediated NO degradation.

British Journal of Pharmacology (2004) 143, 159–165. doi:10.1038/sj.bjp.0705907
GEA 3162 decomposes to co‐generate nitric oxide and superoxide and induces apoptosis in human neutrophils via a peroxynitrite‐dependent mechanism
Authors: Taylor Emma L , Rossi Adriano G , Shaw Catherine A , Dal Rio Francesco P , Haslett Christopher , Megson Ian L 
Published: September 2004

GEA 3162 (1,2,3,4,‐oxatriazolium, 5‐amino‐3‐(3,4‐dichlorophenyl)‐chloride), has powerful effects on neutrophil function and apoptosis, but the underlying mechanisms are unclear, particularly with respect to the possible roles of nitric oxide (NO) and/or peroxynitrite (ONOO−).
Our hypothesis was that GEA 3162 is a generator of ONOO− and that its biological effects on neutrophil apoptosis differ from those of a conventional NO donor. The effects of GEA 3162 were compared to those of the established ONOO− donor, 3‐morpholinosydnonimine (SIN‐1), and the NO donor, diethylamine diazeniumdiolate (DEA/NO) in neutrophils from healthy volunteers. Electrochemical detection and electron paramagnetic resonance were used to define the NO‐related species generated from these agents.
GEA 3162 and SIN‐1 influence neutrophil apoptosis differently from DEA/NO. All three compounds induced morphological neutrophil apoptosis. However, both GEA 3162 and SIN‐1 paradoxically inhibited internucleosomal DNA fragmentation, whereas DEA/NO induced fragmentation compared to control.
In contrast to DEA/NO, generation of free NO was not detectable in solutions of GEA 3162 or SIN‐1 (100 μM). However, Cu/Zn superoxide dismutase (SOD; 50–750 U ml−1) unmasked NO generated from these compounds in a concentration‐dependent manner. GEA 3162 and SIN‐1 oxidised the O2−‐ and ONOO−‐sensitive dye, dihydrorhodamine 123 (DHR 123; 1 μM), suggesting that ONOO− released from these compounds is responsible for oxidation of DHR 123.
We conclude that GEA 3162 is an ONOO− donor with pro‐apoptotic properties that more closely resemble SIN‐1 than the NO donor, DEA/NO. Moreover, unlike NO, ONOO− induces apoptosis in neutrophils via a mechanism that does not require DNA fragmentation.

British Journal of Pharmacology (2004) 143, 179–185. doi:10.1038/sj.bjp.0705909
Preclinical characterisation of 111In‐DTPA‐trastuzumab
Authors: Lub‐de Hooge Marjolijn N , Kosterink Jos G W , Perik Patrick J , Nijnuis Hugo , Tran Ly , Bart Joost , Suurmeijer Albert J H , de Jong Steven , Jager Pieter L , de Vries Elisabeth G E 
Published: September 2004

Trastuzumab (Herceptin®) is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), used for metastatic breast cancer treatment. Radiolabelled trastuzumab may have several future applications for diagnostic use. The aim of the present study was to develop clinical grade 111Indium (111In) radiolabelled trastuzumab, to evaluate the stability and immunoreactivity of the tracer and to perform a biodistribution study in human tumour‐bearing mice. Trastuzumab was radiolabelled with 111In using DTPA as a chelator. 111In‐DTPA‐trastuzumab (labelling yield 92.3±2.3%, radiochemical purity 97.0±1.5%) is stable in PBS when stored at 4°C for more than 14 days. The immunoreactive fraction determined by cell‐binding assays, using the HER2‐overexpressing human ovarian SK‐OV‐3 tumour cell line, was 0.87±0.06. Biodistribution and tumour targeting were studied in HER2 receptor‐positive and ‐negative tumour‐bearing athymic mice. The HER2‐positive tumour showed (9.77±1.14% injected dose per gram (ID g−1)) substantial uptake of the labelled antibody already after 5 h. The difference in uptake between HER2‐positive versus ‐negative tumours was even more pronounced 3 days after injection (16.30±0.64% ID g−1), and was visualised by radioimmunoscintigraphy. Liver, spleen and kidney showed marked tracer uptake. In summary, trastuzumab can be efficiently radiolabelled with 111In with high labelling yields and high stability. 111In‐DTPA‐trastuzumab selectively binds to the human HER2 receptor both in vitro and in vivo in animals. Therefore, 111In‐DTPA‐trastuzumab appears suitable for clinical use. British Journal of Pharmacology (2004) 143, 99–106. doi:10.1038/sj.bjp.0705915
P2X2 and P2Y1 immunofluorescence in rat neostriatal medium‐spiny projection neurones and cholinergic interneurones is not linked to respective purinergic receptor function
Authors: Scheibler Peter , Pesic Mihail , Franke Heike , Reinhardt Robert , Wirkner Kerstin , Illes Peter , Nörenberg Wolfgang 
Published: September 2004

The presence of ionotropic P2X receptors, targets of ATP in fast synaptic transmission, as well as metabotropic P2Y receptors, known to activate K+ currents in cultured neostriatal neurones, was investigated in medium‐spiny neurones and cholinergic interneurones contained in neostriatal brain slices from 5–26‐day‐old rats.
In these cells, adenosine‐5′‐triphosphate (ATP) (100–1000 μM), 2‐methylthioadenosine‐5′‐triphosphate (2MeSATP), α,β‐methyleneadenosine‐5′‐triphosphate (α,βmeATP, 30–300 μM, each) and adenosine‐5′‐O‐(3‐thiotriphosphate (ATPγS) (100 μM) failed to evoke P2X receptor currents even when 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 0.1 μM), apyrase (10 U ml−1) or intracellular Cs+ was used to prevent occluding effects of the ATP breakdown product adenosine, desensitisation of P2X receptors by endogenous ATP and an interference with the activation of K+ channels, respectively. P2X receptor agonists were also ineffective in outside‐out patches withdrawn from the brain slice tissue. Muscimol (10 μM) evoked GABAA receptor‐mediated currents under all these conditions.
When used as a control, locus coeruleus neurones responded with P2X receptor‐mediated currents to ATP (300 μM), 2MeSATP and α,βmeATP (100 μM, each).
ATP and adenosine‐5′‐diphosphate (ADP) (100 μM, each) did not activate K+ currents in the neostriatal neurones.
Despite the observed lack of function, P2X2 and P2Y1 immunofluorescence was found in roughly 50% of the medium‐spiny neurones and cholinergic interneurones.
A role of ATP in synaptic transmission to striatal medium‐spiny neurones and cholinergic interneurones appears unlikely, however, the otherwise silent P2X and P2Y receptors may gain functionality under certain yet unknown conditions.

British Journal of Pharmacology (2004) 143, 119–131. doi:10.1038/sj.bjp.0705916
Inhibitory pathways in the circular muscle of rat jejunum
Authors: Vanneste Gwen , Robberecht Patrick , Lefebvre Romain A 
Published: September 2004

Conflicting data have been reported on the contribution of nitric oxide (NO) to inhibitory neurotransmission in rat jejunum. Therefore, the mechanism of relaxation and contribution to inhibitory neurotransmission of NO, adenosine 5′‐triphosphate (ATP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase‐activating peptide (PACAP) was examined in the circular muscle of Wistar–Han rat jejunum.
Mucosa‐free circular muscle strips were precontracted with methacholine in the presence of guanethidine and exposed to electrical field stimulation (EFS) and exogenous NO, ATP, VIP and PACAP. All stimuli induced reduction of tone and inhibition of phasic motility. Only electrically induced responses were sensitive to tetrodotoxin (3 × 10−6M).
NO (10−6–10−4M)‐induced concentration‐dependent relaxations that were inhibited by the soluble guanylyl cyclase inhibitor 1H‐[1,2,4]‐oxadiazolo‐[4,3‐a]‐quinoxalin‐1‐one (ODQ; 10−5M) and the small conductance Ca2+‐activated K+‐channel blocker apamin (APA; 3 × 10−8M).
Relaxations elicited by exogenous ATP (10−4–10−3M) were inhibited by the P2Y purinoceptor antagonist reactive blue 2 (RB2; 3 × 10−4M), but not by APA and ODQ.
The inhibitory responses evoked by 10−7M VIP and 3 × 10−8M PACAP were decreased by the selective PAC1 receptor antagonist PACAP6–38 (3 × 10−6M) and APA. The VPAC2 receptor antagonist PG99‐465 (3 × 10−7M) reduced relaxations caused by VIP, but not those by PACAP, while the VPAC1 receptor antagonist PG97‐269 (3 × 10−7M) had no influence.
EFS‐induced relaxations were inhibited by the NO‐synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (3 × 10−4M), ODQ and APA, but not by RB2, PG97‐269, PG99‐465 and PACAP6–38.
These results suggest that NO is the main inhibitory neurotransmitter in the circular muscle of Wistar–Han rat jejunum acting through a rise in cyclic guanosine monophosphate levels and activation of small conductance Ca2+‐dependent K+ channels.

British Journal of Pharmacology (2004) 143, 107–118. doi:10.1038/sj.bjp.0705918
Ouabain‐induced hypertension alters the participation of endothelial factors in α‐adrenergic responses differently in rat resistance and conductance mesenteric arteries
Authors: Xavier Fabiano E , Rossoni Luciana V , Alonso María J , Balfagón Gloria , Vassallo Dalton V , Salaices Mercedes 
Published: September 2004

This study compares the role of endothelial factors in α‐adrenoceptor contractile responses in mesenteric resistance (MRA) and superior (SMA) mesenteric arteries from ouabain‐treated (8.0 μg day−1, 5 weeks) and untreated rats. The role of the renin–angiotensin system was also evaluated.
Ouabain treatment increased systolic blood pressure. In addition, ouabain reduced the phenylephrine response in SMA but did not alter noradrenaline responses in MRA.
Endothelium removal or the nitric oxide synthase (NOS) inhibitor (L‐NAME, 100 μM) increased the responses to α‐adrenergic agonists in both vessels. After ouabain treatment, both endothelial modulation and the L‐NAME effect were increased in SMA, while only the L‐NAME effect was increased in MRA. Endothelial NOS expression remained unaltered after ouabain treatment.
Indomethacin (10 μM) similarly reduced the noradrenaline contraction in MRA from both groups; in contrast, in SMA, indomethacin only reduced phenylephrine‐induced contractions in segments from untreated rats. Co‐incubation of L‐NAME and indomethacin leftward shifted the concentration–response curves for noradrenaline more in MRA from ouabain‐treated rats; tetraethylammonium (2 mM) shifted the noradrenaline curves further leftward only in MRA from untreated rats.
Losartan treatment prevents the development of hypertension but not all vascular changes observed after ouabain treatment.
In conclusion, a rise in endothelial NO and impaired prostanoid participation might explain the reduction in phenylephrine‐induced contraction in SMA after ouabain treatment. An increase in the modulatory effect of endothelial NO and impairment of endothelium‐dependent hyperpolarizing factor effect might explain why the ouabain treatment had no effect on noradrenaline responses in MRA.

British Journal of Pharmacology (2004) 143, 215–225. doi:10.1038/sj.bjp.0705919
Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences
Authors: Sun Y. V. , Boverhof D. R. , Burgoon L. D. , Fielden M. R. , Zacharewski T. R. 
Published: September 2004

AbstractComparative approaches were used to identify human, mouse and rat dioxin response elements (DREs) in genomic sequences unambiguously assigned to a nucleotide RefSeq accession number. A total of 13 bona fide DREs, all including the substitution intolerant core sequence (GCGTG) and adjacent variable sequences, were used to establish a position weight matrix and a matrix similarity (MS) score threshold to rank identified DREs. DREs with MS scores above the threshold were disproportionately distributed in close proximity to the transcription start site in all three species. Gene expression assays in hepatic mouse tissue confirmed the responsiveness of 192 genes possessing a putative DRE. Previously identified functional DREs in well-characterized AhR-regulated genes including Cyp1a1 and Cyp1b1 were corroborated. Putative DREs were identified in 48 out of 2437 human–mouse–rat orthologous genes between −1500 and the transcriptional start site, of which 19 of these genes possessed positionally conserved DREs as determined by multiple sequence alignment. Seven of these nineteen genes exhibited 2,3,7,8-tetrachlorodibenzo- p -dioxin-mediated regulation, although there were significant discrepancies between in vivo and in vitro results. Interestingly, of the mouse–rat orthologous genes with a DRE between −1500 and +1500, only 37% had an equivalent human ortholog. These results suggest that AhR-mediated gene expression may not be well conserved across species, which could have significant implications in human risk assessment.
Therapeutic Efficacy of the Epley Canalith Repositioning Maneuver
Authors: Ruckenstein Michael J. 
Published: September 2004

AbstractObjectives/Hypotheses The hypotheses of the current study are as follows: 1) That if the Epley canalith repositioning maneuver is an effective treatment for benign positional vertigo (BPV), relief from the vertigo should occur virtually immediately after the performance of the maneuver; 2) that the Epley canalith repositioning maneuver does provide almost immediate relief in BPV and should be the established treatment of choice for this disorder in both primary and tertiary care settings; and 3) that residual symptoms of lightheadedness and imbalance do persist after the resolution of the vertigo. The distinction of these symptoms from the vertigo is required for the accurate evaluation of the efficacy of positional maneuvers.Study Design Prospective cohort study in a tertiary care balance center.Methods Eighty‐six patients (95 cases) with a history and physical examination consistent with active BPV were entered in the study. Patients were treated with a modified Epley canalith repositioning maneuver. A modified 360° roll was used to treat those patients with horizontal canal BPV. Patients were provided with a preprinted diary in which they were to circle the answer most relevant to their symptoms for 14 days after the maneuver. Patients were then re‐evaluated in the office at 2 weeks after the maneuver.Results The mean duration of the BPV before treatment was 9 weeks. Seventy‐four percent of cases that were treated with one or two canalith repositioning maneuvers had a resolution of vertigo as a direct result of the maneuver. A resolution attributable to the first intervention was obtained in 70% of cases within 48 hours of the maneuver. An additional 14% of cases that were treated had a resolution of vertigo; however, it is not possible to say that these patients definitely benefited from the canalith repositioning maneuver. Only 4% of cases (three patients) manifested BPV that persisted after four treatments. Residual symptoms of lightheadedness or imbalance, or both, were frequent (47% of cases) but rarely required formal intervention with vestibular rehabilitation physical therapy.Conclusions The Epley canalith repositioning maneuver results in a resolution of vertigo in the majority of patients (70% of cases) immediately after one treatment. It is safe and requires no special equipment or investigations. It should be established as the treatment of choice for BPV in both primary and tertiary care settings.
Cause of Death in Patients With Well‐Differentiated Thyroid Carcinoma
Authors: Beasley Nigel J. P. , Walfish Paul G. , Witterick Ian , Freeman Jeremy L. 
Published: September 2004

AbstractObjectives The aim of this study is to examine in detail patients dying of well‐differentiated thyroid carcinoma.Study Design A retrospective chart review with follow‐up.Methods Data were collected from 522 consecutive cases of differentiated thyroid carcinoma treated by one endocrinologist and four surgeons at Mount Sinai Hospital, Toronto, Ontario, Canada, from 1964 to 1999.Results Ten patients died as a direct result of thyroid carcinoma; 19 other deaths were unrelated. Five of 102 patients were men (5%) and 5 of 420 were women (1%); the median age at diagnosis was 68.5 years (range, 49–82 y). No cases were stage I; three, stage II; two, stage III; and five, stage IV. Pathologically papillary carcinoma was found in six of the patients who died, follicular carcinoma in three patients, and Hurtle cell carcinoma in one patient. The causes of death were local invasion or compression of the trachea in two cases and distant metastases in eight patients. Median survival was 3.5 years (range, 1 mo–20 y).Conclusions All patients dying of well‐differentiated thyroid carcinoma had neck nodes, extrathyroidal spread, or distant metastases at presentation and were older than 49 years of age. Many presented because of their distant metastases. Death resulting from local disease was unusual, with most patients dying of distant metastases.