bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Prostate-Specific Antigen a Valid Surrogate End Point for Survival in Hormonally Treated Patients With Metastatic Prostate Cancer? Joint Research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals
Authors: Collette Laurence , Burzykowski Tomasz , Carroll Kevin J. , Newling Don , Morris Tom , Schröder Fritz H.
Published: August 2005

Purpose

The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa.

Patients and Methods

Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered.

Results

The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69).

Conclusion

It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).
Outcomes From the Moving Beyond Cancer Psychoeducational, Randomized, Controlled Trial With Breast Cancer Patients
Authors: Stanton Annette L. , Ganz Patricia A. , Kwan Lorna , Meyerowitz Beth E. , Bower Julienne E. , Krupnick Janice L. , Rowland Julia H. , Leedham Beth , Belin Thomas R.
Published: August 2005

Purpose

Evidence suggests that the re-entry phase (ie, early period after medical treatment completion) presents distinct challenges for cancer patients. To facilitate the transition to recovery, we conducted the Moving Beyond Cancer (MBC) trial, a multisite, randomized, controlled trial of psychoeducational interventions for breast cancer patients.

Methods

Breast cancer patients were registered within 6 weeks after surgery. After medical treatment, they completed baseline measures and were randomly assigned to standard National Cancer Institute print material (CTL); standard print material and peer-modeling videotape (VID); or standard print material, videotape, two sessions with a trained cancer educator, and informational workbook (EDU). Two primary end points were examined: energy/fatigue and cancer-specific distress. Secondary end points were depressive symptoms and post-traumatic growth. Perceived preparedness for re-entry was analyzed as a moderator of effects.

Results

Of 558 women randomly assigned to treatment, 418 completed the 6-month assessment and 399 completed the 12-month assessment. In analyses controlling for study site and baseline depressive symptoms, VID produced significant improvement in energy/fatigue at 6 months relative to CTL, particularly among women who felt less prepared for re-entry at baseline. No significant main effect of the interventions emerged on cancer-specific distress, but EDU prompted greater reduction in this outcome relative to CTL at 6 months for patients who felt more prepared for re-entry. Between-group differences in the primary outcomes were not significant at 12 months, and no significant effects emerged on the secondary end points.

Conclusion

A peer-modeling videotape can accelerate the recovery of energy during the re-entry phase in women treated for breast cancer, particularly among those who feel less prepared for re-entry.
Randomized Study on the Efficacy of Cognitive-Behavioral Therapy for Insomnia Secondary to Breast Cancer, Part I: Sleep and Psychological Effects
Authors: Savard Josée , Simard Sébastien , Ivers Hans , Morin Charles M.
Published: August 2005

Purpose

Chronic insomnia is highly prevalent in cancer patients. Cognitive-behavioral therapy (CBT) is considered the treatment of choice for chronic primary insomnia. However, no randomized controlled study has been conducted on its efficacy for insomnia secondary to cancer. Using a randomized controlled design, this study conducted among breast cancer survivors evaluated the effect of CBT on sleep, assessed both subjectively and objectively, and on hypnotic medication use, psychological distress, and quality of life.

Patients and Methods

Fifty-seven women with insomnia caused or aggravated by breast cancer were randomly assigned to CBT (n = 27) or a waiting-list control condition (n = 30). The treatment consisted of eight weekly sessions administered in a group and combined the use of stimulus control, sleep restriction, cognitive therapy, sleep hygiene, and fatigue management. Follow-up evaluations were carried out 3, 6, and 12 months after the treatment.

Results

Participants who received the insomnia treatment had significantly better subjective sleep indices (daily sleep diary, Insomnia Severity Index), a lower frequency of medicated nights, lower levels of depression and anxiety, and greater global quality of life at post-treatment compared with participants of the control group after their waiting period. Results were more equivocal on polysomnographic indices. Therapeutic effects were well maintained up to 12 months after the intervention and generally were clinically significant.

Conclusion

This study supports the efficacy of CBT for insomnia secondary to breast cancer.
Phase I and Pharmacokinetic Study of Gefitinib in Children With Refractory Solid Tumors: A Children’s Oncology Group Study
Authors: Daw Najat C. , Furman Wayne L. , Stewart Clinton F. , Iacono Lisa C. , Krailo Mark , Bernstein Mark L. , Dancey Janet E. , Speights Rose Anne , Blaney Susan M. , Croop James M. , Reaman Gregory H. , Adamson Peter C.
Published: August 2005

Purpose

Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors.

Patients and Methods

Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28).

Results

Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non–dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing’s sarcoma had a partial response. Disease stabilized for 8 to ≥ 60 weeks in two patients with Wilms’ tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2(range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults.

Conclusion

Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.
Randomized Phase II Trial of Three Schedules of Pemetrexed and Gemcitabine As Front-Line Therapy for Advanced Non–Small-Cell Lung Cancer
Authors: Ma Cynthia X. , Nair Suresh , Thomas Sachdev , Mandrekar Sumithra J. , Nikcevich Daniel A. , Rowland Kendrith M. , Fitch Tom R. , Windschitl Harold E. , Hillman Shauna L. , Schild Steven E. , Jett James R. , Obasaju Coleman , Adjei Alex A.
Published: August 2005

Purpose

A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-naïve patients with non–small-cell lung cancer.

Patients and Methods

Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8.

Results

One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms.

Conclusion

Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.
Deletions Affecting Codons 557-558 of the c-KIT Gene Indicate a Poor Prognosis in Patients With Completely Resected Gastrointestinal Stromal Tumors: A Study by the Spanish Group for Sarcoma Research (GEIS)
Authors: Martín Javier , Poveda Andrés , Llombart-Bosch Antonio , Ramos Rafael , López-Guerrero José A. , del Muro Javier García , Maurel Joan , Calabuig Silvia , Gutierrez Antonio , de Sande José L. González , Martínez Javier , De Juan Ana , Laínez Nuria , Losa Ferrán , Alija Valentín , Escudero Pilar , Casado Antonio , García Pilar , Blanco Remei , Buesa José M.
Published: August 2005

Purpose

To explore the prognostic value of mutations in c-KIT and PDGFR-α genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST.

Methods

For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT–positive immunostaining; and no other primary tumors.

Results

The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-α. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients.

Conclusion

Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
Population-Based Assessment of Surgical Treatment Trends for Patients With Melanoma in the Era of Sentinel Lymph Node Biopsy
Authors: Cormier Janice N. , Xing Yan , Ding Meichun , Lee Jeffrey E. , Mansfield Paul F. , Gershenwald Jeffrey E. , Ross Merrick I. , Du Xianglin L.
Published: August 2005

Purpose

The surgical staging of melanoma dramatically changed with the introduction of sentinel lymph node (SLN) biopsy. In this study, Surveillance, Epidemiology, and End Results (SEER) data were examined to determine how surgical treatment is being carried out and whether SLN biopsy is being performed in melanoma patients in conformance with National Comprehensive Cancer Network (NCCN) guidelines.

Patients and Methods

The SEER database (1998 to 2001) was searched for all patients with invasive melanoma. NCCN guidelines were used to define optimal stage-specific surgical treatment. Treatment trends in patients with stages I to III disease were summarized, and multivariate analyses were performed to identify factors associated with nonadherence with treatment guidelines.

Results

A total of 21,867 melanoma patients were identified; 18,499 of these patients met the inclusion criteria. The number of patients diagnosed with stage III melanoma increased by 55.7% over the study period, and this corresponded to a 53% increase in the number of SLN biopsies performed annually. The odds ratios for nonadherence were 2.32, 2.27, and 1.54 for stages IB, II, and III disease, respectively, compared with stage IA melanoma. Multivariate analyses revealed that age more than 65 years, marital status, minority populations, and primary tumor location were associated with nonadherence with guidelines. Treatment patterns among tumor registries also varied significantly.

Conclusion

Stage migration is evident in the SEER registries in consort with increasing use of SLN biopsy. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head/neck melanomas, and also in some geographic regions of the United States.
Bioinformatic identification of candidate cis-regulatory elements involved in human mRNA polyadenylation
Authors: HU JUN , LUTZ CAROL S. , WILUSZ JEFFREY , TIAN BIN
Published: August 2005

Polyadenylation is an essential step for the maturation of almost all cellular mRNAs in eukaryotes. In human cells, most poly(A) sites are flanked by the upstream AAUAAA hexamer or a close variant, and downstream U/GU-rich elements. In yeast and plants, additional cis elements have been found to be located upstream of the poly(A) site, including UGUA, UAUA, and U-rich elements. In this study, we have developed a computer program named PROBE (Polyadenylation-Related Oligonucleotide Bidimensional Enrichment) to identify cis elements that may play regulatory roles in mRNA polyadenylation. By comparing human genomic sequences surrounding frequently used poly(A) sites with those surrounding less frequently used ones, we found that cis elements occurring in yeast and plants also exist in human poly(A) regions, including the upstream U-rich elements, and UAUA and UGUA elements. In addition, several novel elements were found to be associated with human poly(A) sites, including several G-rich elements. Thus, we suggest that many cis elements are evolutionarily conserved among eukaryotes, and human poly(A) sites have an additional set of cis elements that may be involved in the regulation of mRNA polyadenylation.
Direct selection of trans-acting ligase ribozymes by in vitro compartmentalization
Authors: LEVY MATTHEW , GRISWOLD KARL E. , ELLINGTON ANDREW D.
Published: August 2005

We have used a compartmentalized in vitro selection method to directly select for ligase ribozymes that are capable of acting on and turning over separable oligonucleotide substrates. Starting from a degenerate pool, we selected a trans-acting variant of the Bartel class I ligase which statistically may have been the only active variant in the starting pool. The isolation of this sequence from the population suggests that this selection method is extremely robust at selecting optimal ribozymes and should, therefore, prove useful for the selection and optimization of other trans-acting nucleic acid catalysts capable of multiple turnover catalysis.
The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro
Authors: WESTMAN BELINDA , BEEREN LISA , GRUDZIEN EWA , STEPINSKI JANUSZ , WORCH REMIGIUSZ , ZUBEREK JOANNA , JEMIELITY JACEK , STOLARSKI RYSZARD , DARZYNKIEWICZ EDWARD , RHOADS ROBERT E. , PREISS THOMAS
Published: August 2005

The eukaryotic initiation factor eIF4E binds the mRNA 5′ cap structure and has a central role during translational initiation. eIF4E and the mechanisms to control its activity have oncogenic properties and thus have become targets for anticancer drug development. A recent study (Kentsis et al. 2004) presented evidence that the antiviral nucleoside ribavirin and its phosphorylated derivatives were structural mimics of the mRNA cap, high-affinity ligands for eIF4E, and potent repressors of eIF4E-mediated cell transformation and tumor growth. Based on these findings, we tested ribavirin, ribavirin triphosphate (RTP), and the dinucleotide RpppG for their ability to inhibit translation in vitro. Surprisingly, the ribavirin-based compounds did not affect translation at concentrations where canonical cap analogs efficiently block cap-dependent translation. Using a set of reporter mRNAs that are translated via either cap-dependent or viral internal ribosome entry sites (IRES)-dependent initiation, we found that these ribavirin-containing compounds did inhibit translation at high (millimolar) concentrations, but there was no correlation of this inhibition with an eIF4E requirement for translation. The addition of a ribavirin-containing cap to mRNA did not stimulate translation. Fluorescence titration experiments with eIF4E and the nuclear cap-binding complex CBC indicated affinities for RTP and RpppG that were two to four orders of magnitude lower than those of m7GTP and m7GpppG. We conclude that, at least with respect to translation, ribavirin does not act in vitro as a functional mimic of the mRNA cap.
Rat1p and Rai1p function with the nuclear exosome in the processing and degradation of rRNA precursors
Authors: FANG FENG , PHILLIPS SEASSON , BUTLER J. SCOTT
Published: August 2005

Exoribonucleases function in the processing and degradation of a variety of RNAs in all organisms. These enzymes play a particularly important role in the maturation of rRNAs and in a quality-control pathway that degrades rRNA precursors upon inhibition of ribosome biogenesis. Strains with defects in 3′–5′ exoribonucleolytic components of the RNA processing exosome accumulate polyadenylated precursor rRNAs that also arise in strains with ribosome biogenesis defects. These findings suggested that polyadenylation might target pre-rRNAs for degradation by the exosome. Here we report experiments that indicate a role for the 5′–3′ exoribonuclease Rat1p and its associated protein Rai1p in the degradation of poly(A)+ pre-rRNAs. Depletion of Rat1p enhances the amount of poly(A)+ pre-rRNA that accumulates in strains deleted for the exosome subunit Rrp6p and decreases their 5′ heterogeneity. Deletion of RAI1 results in the accumulation of poly(A)+ pre-rRNAs, and inhibits Rat1p-dependent 5′-end processing and Rrp6p-dependent 3′-end processing of 5.8S rRNA. RAT1 and RAI1 mutations cause synergistic growth defects in the presence of rrp6-Δ, consistent with the interdependence of 5′-end and 3′-end processing pathways. These findings suggest that Rai1p may coordinate the 5′-end and 3′-end processing and degradation activities of Rat1p and the nuclear exosome.
Rhabdomyolysis After Correction of Hyponatremia in Psychogenic Polydipsia Possibly Complicated by Ziprasidone
Authors: Zaidi Ali N
Published: August 2005

OBJECTIVE:

To report a case of rhabdomyolysis related to correction of hyponatremia secondary to psychogenic polydipsia, possibly complicated by the use of ziprasidone.

CASE SUMMARY:

A 50-year-old white man treated for 3 weeks with ziprasidone 40 mg twice daily for chronic paranoid schizophrenia was admitted to the intensive care unit after a witnessed generalized seizure. Marked hypotonic hyponatremia was present secondary to psychogenic polydipsia. After correction of hyponatremia with intravenous NaCl 0.9%, he developed a substantial elevation in the creatine kinase level without any evidence of muscle trauma, stiffness, or swelling or any signs of neuroleptic malignant syndrome. Renal failure or compartment syndrome did not complicate the clinical picture.

DISCUSSION:

It is well known that severe hyponatremia can cause neurologic complications such as stupor, seizures, and even coma. Hyponatremia from water intoxication (n = 28) and its correction with intravenous fluids (n = 2) may cause non-neurologic complications such as rhabdomyolysis. An explanation may lie within the calcium–sodium exchange mechanism across the skeletal myocyte or the failure of cell volume regulation secondary to extracellular hypo-osmolality. Neuroleptic medications have been linked to the development of rhabdomyolysis, with antipsychotics being the primary offenders. As of August 2005, there has been only one reported case of rhabdomyolysis related to correction of hyponatremia complicated by an atypical antipsychotic (clozapine). It is possible that ziprasidone, like clozapine, may enhance muscle cell permeability leading to rhabdomyolysis under similar conditions.

CONCLUSIONS:

Psychiatric patients treated with atypical antipsychotic medications should be closely monitored for rhabdomyolysis during correction of hyponatremia, thus permitting prompt therapy to limit its complications.
Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia Requiring Renal Replacement Therapy
Authors: Reddy Bharathi V , Grossman Eric J , Trevino Sharon A , Hursting Marcie J , Murray Patrick T
Published: August 2005

BACKGROUND:

Argatroban, a direct thrombin inhibitor, is used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). The recommended initial dose is 2 μg/kg/min (0.5 μg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) values 1.5–3.0 times baseline. However, few argatroban-treated patients with HIT and renal failure requiring renal replacement therapy (RRT) have been described.

OBJECTIVE:

To evaluate the safety and efficacy of argatroban anticoagulation during RRT in patients with HIT.

METHODS:

We retrospectively reviewed records from 47 patients with HIT and renal failure requiring RRT who underwent 50 treatment courses with argatroban. Patients with HIT had received argatroban during prospective, multicenter studies. Outcomes, safety, and dosing information were summarized.

RESULTS:

In the multicenter experience, no patient died due to thrombosis and 2 (4%) patients developed new thrombosis while on argatroban. No adverse outcomes occurred during argatroban reexposure. Starting doses were typically 2 μg/kg/min in patients without hepatic impairment and <1.5 μg/kg/min in those with hepatic impairment. Median (range) infusion doses were 1.7 (0.2–2.8) and 0.7 (0.1–1.7) μg/kg/min, respectively, with associated median (range) aPTT ratios, relative to baseline, of 2.2 (1.6–3.6) and 2.0 (1.4–4.1), respectively. Major bleeding occurred in 3 (6%) of 50 treatment courses.

CONCLUSIONS:

Argatroban provides effective anticoagulation upon initial and repeated administration in patients with HIT and renal impairment requiring RRT, with an acceptably low bleeding risk. Current dosing recommendations are adequate for these patients.
Treating Pregnancy-Related Nausea and Vomiting with Ginger
Authors: Boone Sarah A , Shields Kelly M
Published: August 2005

OBJECTIVE:

To review literature assessing the safety and efficacy of the use of ginger to treat nausea and vomiting in pregnancy.

DATA SOURCES:

Iowa Drug Information Service (1966–September 2004), International Pharmaceutical Abstracts (1971–September 2004), MEDLINE (1966–September 2004), and EMBASE (1966–September 2004) were searched. Key terms included ginger, nausea, vomiting, emesis, and pregnancy.

DATA SYNTHESIS:

Studies evaluating the safety and efficacy of ginger in the management of nausea and vomiting in pregnancy were reviewed. Various doses and forms of ginger were used to treat women during their first and second trimesters of pregnancy. Ginger has been shown to improve the symptoms of nausea and vomiting compared with placebo in pregnant women.

CONCLUSIONS:

While data are insufficient to recommend ginger universally and there are concerns with product quality due to limited regulation of dietary supplements, ginger appears to be a fairly low-risk and effective treatment for nausea and vomiting associated with pregnancy. In low doses, this may be appropriate for patients not responding to traditional first-line therapies.
Eszopiclone for Insomnia
Authors: Melton Sarah T , Wood Jill M , Kirkwood Cynthia K
Published: August 2005

Objective:

To review the pharmacology, pharmacokinetics, efficacy data, and adverse effects of eszopiclone in the treatment of transient and chronic insomnia in adult and geriatric patients.

Data Sources:

A MEDLINE literature search (1966–May 2005) was conducted to retrieve articles and abstracts involving eszopiclone. The manufacturer of the drug provided a general summary of clinical data and abstracts of unpublished Phase III clinical trials.

Study Selection and Data Extraction:

All articles identified from the data sources were reviewed, and information deemed relevant was included for this review.

Data Synthesis:

Food and Drug Administration approval of eszopiclone was based on 6 double-blind, placebo-controlled trials. Five trials published in abstract or study form were reviewed. The sixth trial was not available for evaluation. An open-label continuation trial was also reviewed. All studies showed statistically significant improvements in sleep parameters in adult and elderly patients treated for insomnia with eszopiclone.

CONCLUSIONS:

The results of the 5 available double-blind, placebo-controlled studies (and 1 open-label, 6-month extension) showed that eszopiclone was safe and effective in the treatment of transient and chronic insomnia in adult and geriatric patients. Tolerance with long-term exposure (6 mo) and rebound insomnia were not observed. The results of the 6-month, open-label extension trial demonstrated that improvements in sleep parameters were sustained. Future studies comparing eszopiclone with other non benzodiazepine sedative–hypnotics (eg, zolpidem, zaleplon) are needed with cost data to clearly define the role of eszopiclone in the pharmacotherapy of chronic insomnia.
Psychological Aspects of the Transfer of Expert Systems Into Application
Authors: Chang I-Chiu , Chen Edward T , Chiang Ming-Shien , Jiang James J
Published: August 2005

To gain the full value of expert systems (ES), transfer from design to application must not only ensure use of the technology but also that users are heeding the decision advice of the system. We report on a study that investigates variables relating to an intention to use an ES and acceptance of ES advice. A technology acceptance model is applied to test that perception of usefulness and whether ease of use has a strong link to the user's intent to use ES technology. A separate model of persuasion relates measures of confidence to the acceptance of the advice provided by an ES. A laboratory study of 205 student subjects utilizing a computer-selection ES served to test the two models. The study data confirmed the two models and also indicated that intent to use an ES and acceptance of the advice provided by the systems relate to different sets of variables. Organizations employing ES for crucial decisions must be alert to design an ES to build user acceptance along both psychological considerations.
Technology Transfer and Innovation: Reexamining and Broadening the Perspective of the Transfer of Discoveries Resulting From Government-Sponsored Research
Authors: Faley Timothy L , Sharer Michael
Published: August 2005

The Bayh–Dole Act transferred to universities and government laboratories the responsibility for operationalizing the vision of Vannevar Bush's doctrine Science, the Endless Frontier (1945). Twenty-four years later, these organizations seemingly continue to struggle with incorporating this federally mandated function of "technology transfer" as an integral component of their operations. This paper examines the decision process involved in formulating and assessing an institution's technology transfer function. Several important conclusions follow from this analysis. The first is that technology transfer is a subset of the knowledge dissemination mission of research institutions, and is therefore an important part of their core mission. Another conclusion is that there are different types of new knowledge generated at research institutions that require different dissemination strategies. The five most important functions of an institutional technology transfer office are identified, three of which fall within the auspices of intellectual asset management. Finally, for institutions to maximize the public benefit of their research, they must optimize their technology transfer process. To accomplish this, each institution must embrace a clear and specific objective for their technology transfer function, and then implement technology transfer operating tactics consistent with the chosen objective.
The Route to the Techno-Industrial World Economy and the Transfer of German Organic Chemistry to America Before, During, and Immediately After World War I
Authors: Hugill Peter J , Bachmann Veit
Published: August 2005

This paper deals with one component of one of the major aspects of hegemonic competition, technological change achieved largely through technology transfer, in this case in the chemical industry. It deals with how the new technology of organic chemistry was created and encouraged in the late 1800s by the global textile industry's need for dyestuffs; how that technology, though invented in Britain, was developed in Germany; and how that technology was finally successfully transferred to America once its central importance to the production of explosives became obvious in World War I. It follows the argument developed by Hugill (1988, 1993) that a switch began in the late 1800s from one form of capitalist world economy to another: from one in which agro-industrial supremacy was what mattered—the argument of Wallerstein (1984)—to one in which techno-industrial supremacy became the main route to the efficiencies demanded by hegemony. It also follows Hugill's argument that software innovations in the way work is done are often more important for success in the world economy than the hardware innovations of what is actually produced (Hugill, 1993). What made the switch from the agro- to the techno-industrial world economy possible was innovation and technology transfer across a wide range of activities, although some technologies turned out to be much more critical than others.
The Temple of Zeus at Olympia, Heroes, and Athletes
Authors: Barringer Judith M.
Published: August 2005

The two pediments and twelve metopes adorning the Temple of Zeus at Olympia of ca. 470–456 B.C. have been the subject of scholarly inquiry since their discovery in the 19th century. These inquiries tend to treat the sculptural elements separately from each other, or largely detached from their Olympic context, and to interpret the sculptures as negative admonitions about hubris and consequent justice, or about dike and arete, or as political allegories. The present study examines the sculptures as a programmatic unity intimately connected with Olympia and the activities that occurred there and argues that, contrary to previous interpretations, the sculptures were created to serve as positive models to inspire and exhort Olympic athletes to deeds of honor and glory.
Trading Civil Liberties for National Security: Warnings from a World War II Internment Program
Authors: Friedman Max Paul
Published: August 2005

A recurring theme in American political discourse is how to strike the appropriate balance between protecting the nation against threats to its security without eroding the liberty that is at the heart of its democratic character. Civil liberties versus national security is a choice apparently to be made in every crisis and every war, whether hot or cold. We can trace the debate from the Alien and Sedition Acts of 1798 through Abraham Lincoln's suspension of habeas corpus, to the Red Scares that followed both world wars. The classic case of going too far, and the most widely repudiated example, is the illegal mass internment of more than 110,000 Japanese Americans, most of them U.S. citizens, without charge, during World War II. Today, in what is commonly called the war on terrorism, hawks and doves take up their customary positions on opposing sides of the old argument as they debate the U.S.A Patriot Act, the imprisonment of foreigners at Camp Delta on Guantánamo Bay, and the indefinite detention of American citizens by presidential order.
Clutching to “Christian” America: Aimee Semple McPherson, the Great Depression, and the Origins of Pentecostal Political Activism
Authors: Sutton Matthew A.
Published: August 2005

In 1934 pentecostal evangelist Aimee Semple McPherson went on a national preaching tour to promote her political sermon “America Awake!” Praising “those staunch souls” who were “lifting up hand and voice” to turn the nation “back to the Faith of Our Fathers,” she challenged what she perceived as the nation's secularizing trends. More than two million people—one in every fifty Americans—attended her meetings in addition to even larger audiences that listened in by radio. While she was traveling through Washington, D.C., her publicist, Guido Orlando, introduced the charismatic preacher to Louisiana Senator Huey Long. According to Orlando, “The Kingfish and the Angel clicked so well that, before I could get Aimee out of there, they had decided to run for President and Vice President on the same independent ticket.” Long's assassination the following year foiled the potential plan, leaving no way to confirm Orlando's account. What can be confirmed from abundant new sources is that McPherson was far more politically active and her influence far greater than historians have realized.
Imagining the Administrative State: Legal Pragmatism, Securities Regulation, and New Deal Liberalism
Authors: Wang Jessica
Published: August 2005

After more than two decades of “bringing the state back in,” law persists as a neglected stepchild in the history of American state-building. Legal historians have identified a profound transformation in jurisprudence that took place during the late nineteenth and early twentieth centuries, but they have said relatively little about how radically new conceptions of law influenced public policy during the 1930s.1 Conversely, historians of public policy have written extensively about American political development, the nature of bureaucratic autonomy, and the uses of economic knowledge in upholding the administrative state, but the role of law and jurisprudence in recasting state power has remained elusive.2 Moreover, as William J. Novak has observed, both groups of scholars remain hamstrung by the inherited wisdom of Progressive historiography, and they continue to subscribe to a familiar litany of cases fromLochnertoSchechterthat undergirds a grand narrative about law's sole function as an impediment to state-building. As a corrective, Novak has urged historians to consider more carefully the “massive amount of everyday lawmaking” and “structural sociolegal changes” rendered invisible by the court battles of the first third of the twentieth century. Although largely unacknowledged in public discussion and debate, such developments ultimately provided critical support for the consolidation and legitimation of the modern American state.3
Structural Determinants of Benzodiazepine Allosteric Regulation of GABAAReceptor Currents
Authors: Jones-Davis Dorothy M. , Song Luyan , Gallagher Martin J. , Macdonald Robert L.
Published: August 2005

Benzodiazepine enhancement of GABAAreceptor current requires a γ subunit, and replacement of the γ subunit by the δ subunit abolishes benzodiazepine enhancement. Although it has been demonstrated that benzodiazepines bind to GABAAreceptors at the junction between α and γ subunits, the structural basis for the coupling of benzodiazepine binding to allosteric enhancement of the GABAAreceptor current is unclear. To determine the structural basis for this coupling, the present study used a chimera strategy, using γ2L-δ GABAAreceptor subunit chimeras coexpressed withα1 andβ3 subunits in human embryonic kidney 293T cells. Different domains of the γ2L subunit were replaced by δ subunit sequence, and diazepam sensitivity was determined. Chimeric subunits revealed two areas of interest: domain 1 in transmembrane domain 1 (M1) and domain 2 in the C-terminal portion of transmembrane domain 2 (M2) and the M2–M3 extracellular loop. In those domains, site-directed mutagenesis demonstrated that the following two groups of residues were involved in benzodiazepine transduction of current enhancement: residues Y235, F236, T237 in M1; and S280, T281, I282 in M2 as well as the entire M2–M3 loop. These results suggest that a pocket of residues may transduce benzodiazepine binding to increased gating. Benzodiazepine transduction involves a group of residues that connects the N terminus and M1, and another group of residues that may facilitate an interaction between the N terminus and the M2 and M2–M3 loop domains.
MONaKA, a Novel Modulator of the Plasma Membrane Na,K-ATPase
Authors: Mao Hua , Ferguson Tanya S. , Cibulsky Susan M. , Holmqvist Mats , Ding Chunming , Fei Hong , Levitan Irwin B.
Published: August 2005

We have cloned and characterized mouse and human variants of MONaKA, a novel protein that interacts with and modulates the plasma membrane Na,K-ATPase. MONaKA was cloned based on its sequence homology to theDrosophilaSlowpoke channel-binding protein dSlob, but mouse and human MONaKA do not bind to mammalian Slowpoke channels. At least two splice variants of MONaKA exist; the splicing is conserved perfectly between mouse and human, suggesting that it serves some important function. Both splice variants of MONaKA are expressed widely throughout the CNS and peripheral nervous system, with different splice variant expression ratios in neurons and glia. A yeast two-hybrid screen with MONaKA as bait revealed that it binds tightly to the β1 and β3 subunits of the Na,K-ATPase. The association between MONaKA and Na,K-ATPase β subunits was confirmed further by coimmunoprecipitation from transfected cells, mouse brain, and cultured mouse astrocytes. A glutathioneS-transferase-MONaKA fusion protein inhibits Na,K-ATPase activity from whole brain or cultured astrocytes. Furthermore, transfection of MONaKA inhibits86Rb+uptake via the Na,K-ATPase in intact cells. These results are consistent with the hypothesis that MONaKA modulates brain Na,K-ATPase and may thereby participate in the regulation of electrical excitability and synaptic transmission.
Self-Motion and the Hippocampal Spatial Metric
Authors: Terrazas Alejandro , Krause Michael , Lipa Peter , Gothard Katalin M. , Barnes Carol A. , McNaughton Bruce L.
Published: August 2005

Self-motion signals are sufficient for animal navigation (“path integration”) and for updating hippocampal location-specific firing. The contributions of ambulatory, vestibular, and optic self-motion signals to CA1 unit activity and EEG were studied while rats either walked or drove a car between locations on a circular track (referred to as WALK and CAR, respectively) or experienced pseudomotion, in which the animal was stationary and the environment was rotated (WORLD). Fewer pyramidal cells expressed place fields during CAR and those that did exhibited substantially larger place fields. The number of theta cycles required to traverse a place field increased, whereas the slope of the theta phase of firing versus position function was reduced. The presence and/or location of place fields were not well correlated between conditions. These effects were even more accentuated during WORLD. These results are not explainable by a simple “smearing out” of place fields but, in terms of size of place fields relative to the track size, are comparable with what would be observed if the track circumference was reduced and the animal moved around it at a correspondingly slower speed. Theta (and its 14–18 Hz harmonic) power were dependent on velocity, but the gain of this function was substantially reduced during CAR and WORLD, again as if the rat were moving more slowly. The spatial scale over which the hippocampal population vector is updated appears to be derived primarily from the gain of a self-motion velocity signal with approximately equal components derived from ambulation, vestibular, and optic-flow signals.
Involvement of Cholecystokininergic Systems in Anxiety-Induced Hyperalgesia in Male Rats: Behavioral and Biochemical Studies
Authors: Andre Judith , Zeau Brigitte , Pohl Michel , Cesselin, François , Benoliel, Jean-Jacques , Becker Chrystel
Published: August 2005

Keeping in mind the increased pain complaints reported in anxious or depressive patients, our goal was to investigate in rats the consequences of an experimentally provoked state of anxiety/depression on pain behavior and on its underlying mechanisms. We therefore used a model of social defeat consisting of a 30 min protected confrontation followed by a 15 min physical confrontation, repeated during 4 d, that elicited symptoms close to those observed in humans with anxiety or depression. Indeed, 5 d later, animals subjected to social-defeat confrontation were characterized by a decrease of sweet-water consumption and of body weight, and a hyperactivity of the hypothalamic–pituitary–adrenal axis, suggesting that the social-defeat procedure induced a prolonged state of anxiety.

Rats subjected to the social-defeat procedure showed an enhanced nociceptive behavior to the subcutaneous administration of formalin, 5 d after the last confrontation session. Because chronic treatment with the established anxiolytic chlordiazepoxide (10 mg · kg–1· d–1) prevented hyperalgesia, this strongly suggested that this experimental procedure might be a suitable animal model of “anxiety-induced hyperalgesia.” Hyperalgesia associated with anxiety not only was related to a significant increase of CCKLM [cholecystokinin (CCK)-like material] in frontal cortex microdialysates but also was prevented by a CCK-B receptor antagonist [4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[(tricyclo[3.3[12,17]dec-2-yloxy)-carbonyl]amino]-propyl]amino]-1-phenyethyl]amino]-4-oxo-[R-(R*,R*)]-butanoateN-methyl-d-glucamine (CI-988)] (2 mg/kg), strongly supporting the involvement of central CCKergic systems in these phenomena. Finally, combined treatments with CI-988 and morphine completely suppressed pain-related behavior, supporting the idea that the association of both compounds might represent a new therapeutic approach to reduce the increase of pain complaints highly prevalent among anxious or depressive patients.
Posthearing Developmental Refinement of Temporal Processing in Principal Neurons of the Medial Superior Olive
Authors: Scott Luisa L. , Mathews Paul J. , Golding Nace L.
Published: August 2005

In mammals, principal neurons of the medial superior olive (MSO) exhibit biophysical specializations that enable them to detect sound localization cues with microsecond precision. In the present study, we used whole-cell patch recordings to examine the development of the intrinsic electrical properties of these neurons in brainstem slices from postnatal day 14 (P14) to P38 gerbils. In the week after hearing onset (P14–P21), we observed dramatic reductions in somatic EPSP duration, input resistance, and membrane time constant. Surprisingly, somatically recorded action potentials also dramatically declined in amplitude over a similar period (38 ± 3 to 17 ± 2 mV; τ = 5.2 d). Simultaneous somatic and dendritic patch recordings revealed that these action potentials were initiated in the axon, which primarily emerged from the soma. In older gerbils, the rapid speed of membrane voltage changes and the attenuation of action potential amplitudes were mediated extensively by low voltage-activated potassium channels containing the Kv1.1 subunit. In addition, whole-cell voltage-clamp recordings revealed that these potassium channels increase nearly fourfold from P14 to P23 and are thus a major component of developmental changes in excitability. Finally, the electrophysiological features of principal neurons of the medial nucleus of the trapezoid body did not change after P14, indicating that posthearing regulation of intrinsic membrane properties is not a general feature of all time-coding auditory neurons. We suggest that the striking electrical segregation of the axon from the soma and dendrites of MSO principal neurons minimizes spike-induced distortion of synaptic potentials and thus preserves the accuracy of binaural comparisons.
Enhanced Synchrony in Epileptiform Activity? Local versus Distant Phase Synchronization in Generalized Seizures
Authors: Dominguez, Luis Garcia , Wennberg Richard A. , Gaetz William , Cheyne Douglas , Snead O. Carter , Velazquez Jose Luis Perez
Published: August 2005

Synchronization is a fundamental characteristic of complex systems and a basic mechanism of self-organization. A traditional, accepted perspective on epileptiform activity holds that hypersynchrony covering large brain regions is a hallmark of generalized seizures. However, a few recent reports have described substantial fluctuations in synchrony before and during ictal events, thus raising questions as to the widespread synchronization notion. In this study, we used magnetoencephalographic recordings from epileptic patients with generalized seizures and normal control subjects to address the extent of the phase synchronization (phase locking) in local (neighboring) and distant cortical areas and to explore the ongoing temporal dynamics for particular ranges of frequencies at which synchrony occurs, during interictal and ictal activity. Synchronization patterns were found to differ somewhat depending on the epileptic syndrome, with primary generalized absence seizures displaying more long-range synchrony in all frequency bands studied (3–55 Hz) than generalized tonic motor seizures of secondary (symptomatic) generalized epilepsy or frontal lobe epilepsy. However, all seizures were characterized by enhanced local synchrony compared with distant synchrony. There were fluctuations in the synchrony between specific cortical areas that varied from seizure to seizure in the same patient, but in most of the seizures studied, regardless of semiology, there was a constant pattern in the dynamics of synchronization, indicating that seizures proceed by a recruitment of neighboring neuronal networks. Together, these data indicate that the concept of widespread “hypersynchronous” activity during generalized seizures may be misleading and valid only for very specific neuronal ensembles and circumstances.