bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translocation of Neuronal Nitric Oxide Synthase to the Plasma Membrane by ATP is Mediated by P2X and P2Y Receptors
Authors: Ohnishi Takayuki , Matsumura Shinji , Ito Seiji 
Published: July 2009

Background The translocation of neuronal nitric oxide synthase (nNOS) from the cytosol to the membrane is functionally coupled to the activation of N-methyl-D-aspartate (NMDA) receptors at synapses. Whereas there is abundant evidence indicating that ATP and nitric oxide are involved in nociceptive transmission, whether nNOS is activated by ATP remains unknown. We recently established a fluorescence imaging system for examining nNOS translocation in PC12 cells expressing a yellow fluorescence protein-tagged nNOS N-terminal mutant, nNOSNT-YFP, and examined the effect of ATP on nNOS translocation using the system. Results The translocation of nNOS was induced by ATP in the presence of NMDA and forskolin, an adenylate cyclase activator. The purinergic P2X receptor agonist 2-MeSATP and the P2Y agonist UTP significantly enhanced nNOS translocation; and simultaneous stimulation with 2-MeSATP and UTP exhibited the same concentration-response curve for the translocation as obtained with ATP. ATP, 2-MeSATP, and UTP increased the intracellular Ca2+ concentration ([Ca2+]i) in PC12 cells. Conversely, whereas the P2X receptor antagonist PPADS and the P2Y antagonist reactive blue-2 partially inhibited increases in the translocation of nNOS and [Ca2+]i by ATP, the non-selective P2 receptor antagonist suramin completely blocked them. In addition, the increase in the nNOS translocation by ATP was blocked by NMDA receptor antagonists and inhibitors of protein kinase A, protein kinase C, and Src kinase. Consistent with the expression of P2X and P2Y receptors in the spinal cord, ATP and UTP increased the [Ca2+]i in primary cultured spinal neurons. ATP potentiated and prolonged the [Ca2+]i increase produced by NMDA in the dorsal horn of the spinal cord. Furthermore, the selective P2X3/P2X2/3 antagonist A-317491 inhibited nNOS activation assessed by NO formation in spinal slices prepared from neuropathic pain model mice. Conclusion ATP is involved in nNOS translocation mediated by protein kinase C via activation of P2X and P2Y receptors and nNOS translocation may be an action mechanism of ATP in nocieptive processing in the spinal cord.
Drug use patterns among Thai illicit drug injectors amidst increased police presence
Authors: Werb Dan , Hayashi Kanna , Fairbairn Nadia , Kaplan Karyn , Suwannawong Paisan , Lai Calvin , Kerr Thomas 
Published: July 2009

Abstract
Thailand has traditionally pursued an aggressive enforcement-based anti-illicit drug policy in an effort to make the country "drug-free." In light of this ongoing approach, we sought to assess impacts of enforcement on drug use behaviors among a cohort of injection drug users (IDU) in Thailand. We examined drug use patterns among IDU participating in a cross-sectional study conducted in Bangkok (n = 252). Participants were asked to provide data regarding patterns of drug use in the previous six months, including types of drugs consumed, method of consumption, frequency of use, and weekly income spent on drugs. We also conducted bivariate analyses to identify a possible effect of a reported increase in police presence on measures of drug use and related risk behaviors among study participants. One hundred fifty-five (61.5%) individuals reported injection heroin use and 132 (52.4%) individuals reported injection midazolam use at least daily in the past six months. Additionally, 86 (34.1%) individuals reported at least daily injection Yaba and Ice (i.e., methamphetamine) use. Participants in our study reported high levels of illicit drug use, including the injection of both illicit and licit drugs. In bivariate analyses, no association between increased police presence and drug use behaviors was observed. These findings demonstrate high ongoing rates of drug injecting in Thailand despite reports of increased levels of strict enforcement and enforcement-related violence, and raise questions regarding the merits of this approach.
Experimental models for the study of neurodegeneration in amyotrophic lateral sclerosis
Authors: Tovar-y-Romo Luis B , Santa-Cruz Luz Diana , Tapia Ricardo 
Published: July 2009

Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown cause, characterized by the selective and progressive death of both upper and lower motoneurons, leading to a progressive paralysis. Experimental animal models of the disease may provide knowledge of the pathophysiological mechanisms and allow the design and testing of therapeutic strategies, provided that they mimic as close as possible the symptoms and temporal progression of the human disease. The principal hypotheses proposed to explain the mechanisms of motoneuron degeneration have been studied mostly in models in vitro, such as primary cultures of fetal motoneurons, organotypic cultures of spinal cord sections from postnatal rodents and the motoneuron-like hybridoma cell line NSC-34. However, these models are flawed in the sense that they do not allow a direct correlation between motoneuron death and its physical consequences like paralysis. In vivo, the most widely used model is the transgenic mouse that bears a human mutant superoxide dismutase 1, the only known cause of ALS. The major disadvantage of this model is that it represents about 2%–3% of human ALS. In addition, there is a growing concern on the accuracy of these transgenic models and the extrapolations of the findings made in these animals to the clinics. Models of spontaneous motoneuron disease, like the wobbler and pmn mice, have been used aiming to understand the basic cellular mechanisms of motoneuron diseases, but these abnormalities are probably different from those occurring in ALS. Therefore, the design and testing of in vivo models of sporadic ALS, which accounts for >90% of the disease, is necessary. The main models of this type are based on the excitotoxic death of spinal motoneurons and might be useful even when there is no definitive demonstration that excitotoxicity is a cause of human ALS. Despite their difficulties, these models offer the best possibility to establish valid correlations between cellular alterations and motor behavior, although improvements are still necessary in order to produce a reliable and integrative model that accurately reproduces the cellular mechanisms of motoneuron degeneration in ALS.
Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status
Authors: Abboud Imad , Lerolle Nicolas , Urien Saik , Tadié Jean-Marc , Leviel Françoise , Fagon Jean-Yves , Faisy Christophe 
Published: July 2009

AbstractIntroductionIn septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock.MethodsThirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM.ResultsPlasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 μg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 × (BW/70)0.60× (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 – 56.7) at C0vs. 4.5 (0.3 – 38.9) nmol/L at C1,P< 0.001).ConclusionsEpinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients.
Generation of a Concise Gene Panel for Outcome Prediction in Urinary Bladder Cancer
Authors: Mitra Anirban P. , Pagliarulo Vincenzo , Yang Dongyun , Waldman Frederic M. , Datar Ram H. , Skinner Donald G. , Groshen Susan , Cote Richard J. 
Published: July 2009

Purpose This study sought to determine if alterations in molecular pathways could supplement TNM staging to more accurately predict clinical outcome in patients with urothelial carcinoma (UC). Patients and Methods Expressions of 69 genes involved in known cancer pathways were quantified on bladder specimens from 58 patients with UC (stages Ta-T4) and five normal urothelium controls. All tumor transcript values beyond two standard deviations from the normal mean expression were designated as over- or underexpressed. Univariate and multivariable analyses were conducted to obtain a predictive expression signature. A published external data set was used to confirm the potential of the prognostic gene panels. Results In univariate analysis, six genes were significantly associated with time to recurrence, and 10 with overall survival. Recursive partitioning identified three genes as significant determinants for recurrence, and three for overall survival. Of all genes identified by either univariate or partitioning analysis, four were found to significantly predict both recurrence and survival (JUN, MAP2K6, STAT3, and ICAM1); overexpression was associated with worse outcome. Comparing the favorable (low or normal) expression of ≥ three of four versus ≤ two of four of these oncogenes showed 5-year recurrence probability of 41% versus 88%, respectively (P < .001), and 5-year overall survival probability of 61% versus 5%, respectively (P < .001). The prognostic potential of this four-gene panel was confirmed in a large independent external cohort (disease-specific survival, P = .039). Conclusion We have documented the generation of a concise, biologically relevant four-gene panel that significantly predicts recurrence and survival and may also identify potential therapeutic targets for UC.
Individualizing Quality-of-Life Outcomes Reporting: How Localized Prostate Cancer Treatments Affect Patients With Different Levels of Baseline Urinary, Bowel, and Sexual Function
Authors: Chen Ronald C. , Clark Jack A. , Talcott James A. 
Published: July 2009

Purpose Although it is the most powerful predictor of early prostate cancer treatment-related complications and quality-of-life (QOL) outcomes, most studies do not stratify results by baseline function. Further, reporting functional outcomes as averaged numerical results may obscure informatively disparate courses. Using levels of treatment-related dysfunction, we address these problems and present the final QOL outcomes of our prospective cohort study of patients with early prostate cancer. Methods We created categories for sexual, bowel, and urinary function, measured using numerical scores of the validated Prostate Cancer Symptom Indices and stratified into “normal,” “intermediate” and “poor” levels of function by incorporating patient-reported symptom and distress information. We present QOL outcomes for 409 patients 36 months after radical prostatectomy, external-beam radiation therapy, and brachytherapy. Results Different levels of baseline sexual, bowel, and urinary function produced distinctive treatment-related changes from baseline to 36 months. In general, the average scale increases in dysfunction were greatest among patients with normal baseline function, although patients with normal and intermediate baseline function had similar increases in sexual dysfunction. For patients whose baseline urinary obstruction/irritation was poor, both average scale scores and most patients' level of function improved after treatment, particularly after surgery. Conclusion The use of functional levels to stratify treatment-related outcomes by pretreatment functional status and to display the proportions of patients with improved, stable, or worsened function after treatment provides information that more specifically conveys the expected impact of treatment to patients choosing among localized prostate cancer treatments.
Outcome of Patients With Early-Stage Breast Cancer Treated With Doxorubicin-Based Adjuvant Chemotherapy As a Function of HER2 and TOP2A Status
Authors: Tubbs Raymond , Barlow William E. , Budd G. Thomas , Swain Eric , Porter Peggy , Gown Allen , Yeh I-Ten , Sledge George , Shapiro Charles , Ingle James , Haskell Charles , Albain Kathy S. , Livingston Robert , Hayes Daniel F. 
Published: July 2009

Purpose Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C). Patients and Methods TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533). Results An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio ≥ 4.0). Survival was not associated with low-level HER2 amplification (ratio ≥ 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio ≥ 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size. Conclusion In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.
Allogeneic Stem Cell Transplantation Is Able to Induce Long-Term Remissions in Angioimmunoblastic T-Cell Lymphoma: A Retrospective Study From the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation
Authors: Kyriakou Charalampia , Canals Carmen , Finke Jürgen , Kobbe Guido , Harousseau Jean-Luc , Kolb Hans-Jochem , Novitzky Nicolas , Goldstone Anthony H. , Sureda Anna , Schmitz Norbert 
Published: July 2009

Purpose To analyze the long-term outcome in terms of nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS) in patients with angioimmunoblastic T-cell lymphoma (AITL) treated with allogeneic stem-cell transplantation (alloSCT). Patients and Methods Forty-five patients with AITL who had undergone an alloSCT between January 1998 and December 2005 and were registered in the European Group for Blood and Marrow Transplantation database were analyzed. Median age was 48 years (range, 23 to 68 years), 34 patients had received ≥ two lines of chemotherapy before alloSCT, and 11 patients had experienced treatment failure with a prior autologous stem-cell transplantation. Twenty-five patients underwent a myeloablative alloSCT, and 20 underwent a reduced-intensity alloSCT. Donors were HLA-identical siblings in 26 patients. Twenty-seven patients were allografted in chemotherapy-sensitive disease, and 18 were allografted in refractory disease. Results The cumulative incidence of NRM was 18%, 22%, and 25% at 3, 6, and 12 months, respectively. Patients with poor performance status had a significantly higher NRM (P = .01). RR was estimated as 16% and 20% at 2 and 3 years, respectively, and was lower in patients developing chronic graft-versus-host disease (cGVHD). PFS and OS rates were 62% and 53% and 66% and 64% at 1 and 3 years, respectively, and were significantly better in chemotherapy-sensitive patients. Conclusion AlloSCT represents a valid therapeutic option for patients with AITL. Both the lower RR after transplantation as well as the decreased RR in patients developing cGVHD after the alloSCT suggests the existence of a clinically relevant graft-versus-lymphoma effect.
Detecting BRCA2 Protein Truncation in Tissue Biopsies to Identify Breast Cancers That Arise in BRCA2 Gene Mutation Carriers
Authors: Watson Patrice , Lieberman Rita , Snyder Carrie , Clark Vanessa J. , Lynch Henry T. , Holt Jeffrey T. 
Published: July 2009

Purpose Mutations in the BRCA2 gene are dominantly inherited but cause cancers when the wild-type allele has loss of heterozygosity (LOH) within the cancer. Because most disease-associated BRCA2 mutations are protein-truncating mutations, a test for truncated BRCA2 proteins should identify most BRCA2 hereditary cancers. Methods We have developed a tissue truncation test to identify truncated BRCA2 proteins in breast cancer tissue biopsies in vivo that does not use amplification or genetic manipulations. N-terminal and C-terminal antibodies are used to visualize protein truncation by demonstrating that the beginning of the protein is present but the end (ie, terminus) is absent. Results A quantitative C-terminal immunostaining score or a C-terminal to N-terminal truncation ratio correctly classified 20 of 21 breast cancers arising in BRCA2 mutation carriers and 57 of 58 cancers arising outside the context of a multiple-case breast cancer family. This represents a sensitivity of 95% and a specificity of 98%. Because of the presence of C-terminal BRCA2 protein and atypical clinical features of the misclassified cancer in a BRCA2 mutation carrier, we performed polymerase chain reaction and sequence analyses on this cancer. The results showed continued presence of the BRCA2 wild-type allele in the cancer, which indicated that intact BRCA2 protein was present in this cancer. Conclusion This immunohistochemistry-based test (which takes only 4 hours) appears to identify BRCA2 hereditary cancer with high accuracy. The test also appears to diagnose the biochemical loss of BRCA2 protein in cancers (ie, BRCA2-mutant genotype), which will usually but not always agree with the presence of a germline BRCA2 mutation found by susceptibility testing by DNA sequencing of blood samples.
Sex Steroid, Gonadotropin, Cortisol, and Prolactin Levels in Healthy, Massively Obese Women: Correlation with Abdominal Fat Cell Size and Effect of Weight Reduction*
Authors: GRENMAN S. , RÖNNEMAA T. , IRJALA K. , KAIHOLA H. L. , GRÖNROOS M. 
Published: July 2009

Abstract
To examine hormonal status in obese, gynecologically normal women we studied 25 regularly menstruating, massively obese (mean weight, 120 kg) women participating in a weight reduction program and 25 age-matched normal weight (mean weight, 60 kg) women. Serum 17β-estradiol (E2), estrone (E1), androstenedione (A), dehydroepiandrosterone sulfate, testosterone, LH, FSH, PRL, and cortisol concentrations were measured during the follicular phase of the menstrual cycle. Waist to hip ratio and abdominal fat cell size were measured at the beginning of the study. The serum levels of E2 (P &lt; 0.04) as well as those of A, SHBG, and LH (P &lt; 0.002) were lower in the obese group. Consequently, the testosterone to SHBG ratio and the E1 to A ratio were higher and the LH to FSH ratio was lower in this group. Waist to hip ratio did not correlate with the levels of circulating hormones or SHBG, but an inverse correlation was found between abdominal fat cell size and A as well as the LH to FSH ratio in the nonhirsute women of the obese group. Subsequent to moderate weight reduction (13.2 kg), serum A and Ei levels (P &lt; 0.01) increased, and serum cortisol levels decreased (P &lt; 0.001). Thus, massive obesity is associated with abnormalities in hormonal balance in gynecologically symptomless women, there being an association between E1, E2, A, LH, cortisol, and relative weight and/or abdominal fat cell size.
Ein XML-basiertes Datenbanksystem für digitale Wörterbücher — Ein Werkstattbericht aus dem Institut für Deutsche SpracheAn XML-Based Database System for Online Dictionaries — A Report on Lexicographic Work at the Institute for German Language
Authors: Müller-Spitzer Carolin , Schneider Roman 
Published: July 2009

Zusammenfassung
Das Online-Wortschatz-Informationssystem Deutsch (OWID) ist ein digitales Wörterbuchportal des Instituts für Deutsche Sprache. Alle darin zusammengeführten lexikografischen Daten sind auf XML-Basis feingranular strukturiert. Speicherung, Verwaltung und Retrieval dieser Daten übernimmt das Oracle-basierte Electronic Dictionary Administration System (EDAS). Der vorliegende Beitrag erläutert die XML-basierte Modellierung der Daten, XML-spezifische Fragen der Speicherung, sowie das Retrieval mit XPath und SQL/XML.
The Genetic Basis of Transgressive Ovary Size in Honeybee Workers
Authors: Linksvayer Timothy A , Rueppell Olav , Siegel Adam , Kaftanoglu Osman , Page Robert E , Amdam Gro V 
Published: July 2009

Abstract
Ovarioles are the functional unit of the female insect reproductive organs and the number of ovarioles per ovary strongly influences egg-laying rate and fecundity. Social evolution in the honeybee (Apis mellifera) has resulted in queens with 200–360 total ovarioles and workers with usually 20 or less. In addition, variation in ovariole number among workers relates to worker sensory tuning, foraging behavior, and the ability to lay unfertilized male-destined eggs. To study the genetic architecture of worker ovariole number, we performed a series of crosses between Africanized and European bees that differ in worker ovariole number. Unexpectedly, these crosses produced transgressive worker phenotypes with extreme ovariole numbers that were sensitive to the social environment. We used a new selective pooled DNA interval mapping approach with two Africanized backcrosses to identify quantitative trait loci (QTL) underlying the transgressive ovary phenotype. We identified one QTL on chromosome 11 and found some evidence for another QTL on chromosome 2. Both QTL regions contain plausible functional candidate genes. The ovariole number of foragers was correlated with the sugar concentration of collected nectar, supporting previous studies showing a link between worker physiology and foraging behavior. We discuss how the phenotype of extreme worker ovariole numbers and the underlying genetic factors we identified could be linked to the development of queen traits.