bluuebunny/crossref_metadata_2025 huggingface dataset:
Gap Effect in Reflexive and Intentional Prosaccades
Authors: Crevits Luc , Vandierendonck André
Published: December 2004

The analysis of saccadic eye movements has assumed an important role as a pathophysiological approach in neuropsychiatric diseases. However, before abnormal cognitive saccade behavior can be fully understood, some basic psychophysiological aspects have to be further investigated. Previous studies have demonstrated a shortening of saccade latency when the fixation stimulus was removed prior to the appearance of a peripheral visual target. This gap effect is smaller for antisaccades (AS; away from the target) than for reflexive saccades (RS; towards the target). Apart from the generation of an intentional eye movement, AS rely on different processes including reflex inhibition and spatial reversal of the saccade direction. We wondered whether intentional prosaccades (IpS) that do not rely on these additional processes also show a reduced gap effect. Therefore, we compared the gap effect in a saccade paradigm for RS and IpS in healthy subjects. We found a smaller gap effect in IpS than in RS and suggest that this reduction reflects endogenous strategic processes. Our findings further imply that reflex inhibition is not the unique cause for the smaller gap effect in AS than in RS and suggest that an endogenous component may be involved. We hypothesize that frontal control on the superior colliculus fixation cell activity may continue even after the fixation stimulus has disappeared, thus inhibiting a fixation offset and reducing the gap effect.
Effect of Age and Global Function Score on Schizophrenic P300 Characteristics
Authors: Yu Younger W.-Y. , Chen Tai-Jui , Chen Ming-Chao , Tsai Shih-Jen , Lee Tien-Wen
Published: December 2004

The relationship between function level and P300 has long been ignored and awaits clarification. Further, previous Western studies have discussed the trait/state markers of schizophrenic P300; this has not been assessed for an analogous Chinese population. P300 was recorded and compared in 153 schizophrenic patients and 101 normal controls. Reduced and delayed P300 was demonstrated for the schizophrenic group. Regression analysis was performed to determine the factors contributing to P300 amplitude and latency variation. Global Assessment of Functioning score and age had a significant influence on P300 latency prolongation. Amplitude decrement was not affected by age, duration of illness, education, psychotic status, antipsychotic dosage, or function level. Our results were grossly concordant with analogous Western reports and provided evidence that function level is an important variable contributing to P300 latency change in Chinese schizophrenics. Besides, the effect of gender on P300 amplitude was noted in normal population.
Relationship between DRD4 Polymorphism and Lipid Metabolism: What Is the Role of Novelty Seeking?
Authors: Elovainio Marko , Puttonen Sampsa , Heponiemi Tarja , Reuter Martin , Kivimäki Mika , Viikari Jorma , Keltikangas-Järvinen Liisa
Published: December 2004

Objective: This study examined the association of the dopamine receptor D4 (DRD4) gene polymorphism with the temperament dimension of novelty seeking (NS) on cardiovascular heart disease risk factors [the levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides]. Method: From the ongoing population-based study of ‘Cardiovascular Risk in Young Finns’, 125 participants were DRD4 genotyped in 1997 and responded to the NS scale of the Temperament and Character Inventory in 2001. Their cholesterol and triglyceride concentrations were assessed in 2001. Results: Having a 2- or 5-allele DRD4 polymorphism was related to high HDL cholesterol levels in men, but to low HDL cholesterol levels in women. NS was related to triglycerides in men and to LDL in women, but this was mediated by behavioral, age, and weight factors, and NS was not the underlying factor for the association between the polymorphism and lipids. Conclusion: Our preliminary findings suggest that there is a link between the dopaminergic receptor gene DRD4 and lipid metabolism, but this link is dependent on gender.
Rapid and Sustained Relief from the Symptoms of Carcinoid Syndrome: Results from an Open 6-Month Study of the 28-Day Prolonged-Release Formulation of Lanreotide
Authors: Ruszniewski Philippe , Ish-Shalom Sofia , Wymenga Machteld , O’Toole Dermot , Arnold Rudolf , Tomassetti Paola , Bax Nigel , Caplin Martyn , Eriksson Barbro , Glaser Benjamin , Ducreux Michel , Lombard-Bohas Catherine , de Herder Wouter W. , Delle Fave Gianfranco , Reed Nick , Seitz Jean François , van Cutsem Eric , Grossman Ashley , Rougier Philippe , Schmidt Wolfgang , Wiedenmann Bertram
Published: December 2004

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with ≧3 stools/day and/or ≧1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p ≤ 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved ≧50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.
Management of Pelvic Lymphocysts by Ultrasound-Guided Aspiration and Minocycline Sclerotherapy
Authors: Liu Fu-Shing , Hung Man-Jung , Hwang Sheau-Feng , Lu Chien-Hsing , Ke Yu-Min , Ho Esther Shih-Chu
Published: December 2004

Objective: The purpose of this study was to describe our experience with ultrasound-guided aspiration of postoperative pelvic lymphocysts followed by intracavitary minocycline injection as sclerotherapy. Patients and Methods: From 1997 to 2003, patients who developed either symptomatic or persistent lymphocyst after pelvic lymphadenectomy for gynecological malignancy were recruited in this study. All of the lymphocysts were palpable and were further examined by ultrasonography. Percutaneous ultrasound-guided needle aspiration of the lymphocyst was performed and then immediately followed by a single-dose injection of minocycline into the collapsed cavity. Follow-up was conducted every 4 weeks with pelvic examination and ultrasonography. Results: Nineteen patients with a total of 21 pelvic lymphocysts underwent this procedure. The median size of the lymphocysts was 6 cm in diameter (range, 4–9 cm). Fifteen patients received 1 treatment, 3 received 2, and 1 patient with bilateral lymphocysts received 3 treatments. Complete resolution occurred in 14 patients (74%), and the other 5 patients (26%) had partial resolution with the volume of the lymphocyst decreasing at least 50%. For the 14 patients with complete resolution, the median time from treatment to disappearance of the lymphocyst was 3 months (range, 1–10 months), and none of them developed recurrence during the average follow-up period of 40 months (range, 2–62 months). No significant complication occurred with this procedure except for transient mild to moderate pelvic pain. Discussion: Minocycline sclerotherapy seems to be a simple and safe method with a satisfactory success rate in treating lymphocysts which develop after pelvic lymphadenectomy. It can be performed in an outpatient setting and can be repeated if necessary. This procedure may be considered as the initial treatment modality for patients suffering from symptomatic or persistent lymphocysts after radical gynecological surgery.
Diagnostic Criteria for Irritable Bowel Syndrome: Utility and Applicability in Clinical Practice
Authors: Lea R. , Hopkins V. , Hastleton J. , Houghton L.A. , Whorwell P.J.
Published: December 2004

Background/Aims: Symptom-based criteria have been introduced to aid the diagnosis of irritable bowel syndrome (IBS). Although they have been widely adopted and have proved useful for research purposes by ensuring homogeneity of study populations, there is little information about their utility in routine clinical practice. It was the aim of this study to assess the applicability of the Manning, Rome I and Rome II criteria in the clinical setting and to ascertain how often hospital specialists and general practitioners (GPs) use them. Methods: Hundred secondary-care IBS patients were assessed for their conformity to these criteria. Forty-eight hospital specialists and 68 GPs were asked about their knowledge and utilization of these criteria. Results: Seventy-three percent of IBS patients met Rome II diagnostic criteria with 82 and 94% meeting Rome I and Manning, respectively. Approximately 80% of GPs had no knowledge of any of the specific criteria, and only 4% had ever used them. The majority of specialists had knowledge of the criteria, with 70% having used them. Conclusion: The Rome II criteria are remarkably insensitive and if rigidly applied in the clinical situation would lead to much diagnostic uncertainty. The current lack of interest in them, especially amongst GPs, is unlikely to change unless they can be considerably improved.
Quality or quantity? the role of donor condition in the production of chemical alarm cues in juvenile convict cichlids
Authors: Mirza Reehan , Brown Grant , Roh Ellie
Published: December 2004

Much study has been devoted to the function of chemical alarm cues in predator-prey relationships in aquatic environments, but little is known about the production of these valuable sources of chemosensory information. Recent studies have demonstrated that donor (cue sender) condition may play an important role in the production of chemical alarm cues in juvenile convict cichlids (Archocentrus nigrofasciatus). In laboratory experiments, we conducted trials to test for the effect of donor body condition on the minimum behavioural response threshold and/or intensity of antipredator response to conspecific chemical alarm cues. Chemical alarm cue donors were sampled from high or low condition populations. Pairs of juvenile cichlids were exposed to the skin extracts of high condition versus low condition donors, across a range of relative concentrations (200, 100, 50, 25, and 12.5%), and a distilled water control. We found that cichlids exhibited overt antipredator behaviour beginning at a concentration of 25% for the high condition cue, while a minimum response threshold concentration of 50% was seen for low condition cue. The intensity of antipredator response was greater following exposure to the alarm cues of high condition stimulus versus low condition donors. Taken together, these findings suggest that the damage-released chemical alarm cues from high condition donors are qualitatively and quantitatively greater than those of low condition donors.
Changes in male mate choice in a sexually cannibalistic orb-web spider (Araneae: Araneidae)
Authors: Elgar Mark , Gaskett Anne , Downes Barbara , Herberstein Marie
Published: December 2004

In theory, male mate choice should occur when the costs of copulation, in terms of future mating opportunities, are high. The criteria males use to choose mates may change depending upon male mating history and the potential for future matings. We examine male mate choice in the St. Andrew's Cross Spider (Argiope keyserlingi Araneae: Araneidae). Laboratory experiments revealed that death and injury caused by female sexual cannibalism limits males to a maximum of two copulations. We assessed the mate choices of virgin and mated males for females of different reproductive status. We used field and laboratory choice bioassays involving airborne and web-based pheromones. In field experiments, wild males were strongly attracted to webs built by laboratory-raised virgin females. Webs from mated females did not attract males. Male mate choice was affected by male reproductive status: while virgin males strongly preferred penultimate and virgin females to mated females, mated males were apparently indifferent to females of different mating status. Such post-copulatory changes in male mate choice have not been previously documented, and may reflect a decreased potential for future mating.
Innate predator recognition in newly-hatched Atlantic salmon
Authors: Hawkins  , Magurran  , Armstrong
Published: December 2004

It is well established that fish can learn to associate odours from potential predators with risk and alter their behaviour accordingly. However, newly-hatched individuals have few opportunities for acquired predator recognition and may depend on unlearnt (innate) responses. We therefore considered whether newly hatched Atlantic salmon fry (alevins) exhibit innate predator recognition and whether this recognition could be improved by prior exposure to combined conspecific and predator (pike) odours. Our investigation showed that the response to pike odour was not affected by previous exposure to pike odour and conspecific tissue extract but was consistent with innate recognition of pike as predators. Trials conducted using odour from a non-piscivorous species confirmed that the fish were not simply reacting to a novel stimulus.
Agonism and interference competition in freshwater decapods
Authors: Cioni Astra , Gherardi Francesca
Published: December 2004

We tested the hypothesis that agonistic behavior and interference competition induce species replacements in freshwater decapods. Our model organisms were two crayfish (the indigenous Austropotamobius italicus and the non-indigenous and invasive Procambarus clarkii) and the indigenous river crab Potamon fluviatile. A first experiment was aimed at analyzing the agonistic behavior of similarly-sized males in pairs of the three species combinations. Records were taken for an hour per day during five consecutive days of combats. Results showed that P. fluviatile was dominant over the two crayfish species and P. clarkii over A. italicus, as confirmed by their field distribution. In nature, the non-indigenous species might even reach higher levels of dominance over A. italicus. In fact, both the larger body size and the 'stronger' chelae of P. clarkii can induce asymmetries in fighting ability. Pairs composed of the non-indigenous crayfish and either A. italicus or P. fluviatile did not form stable hierarchies, possibly due to the failure of status recognition. In a second set of experiments, the agonistic behavior of the three species combinations was studied in the presence of either food (earthworms) or an artificial shelter (a 10 cm-long piece of a PVC pipe). As expected, resources influenced fighting and dominance translated into a differential capability to compete. In a third experiment, in which we measured shelter use by each species in a non-competitive context, shelters were more extensively occupied by A. italicus (which is dependent on natural crevices as hiding places) than by the other two species (which usually dig burrows). We expected that Potamon and Procambarus would gain less from occupying the offered shelter than Austropotamobius, and therefore their defense should be less vigorous. To the contrary, the presence of a rival strengthened the attraction to the shelter of these two species, in particular when river crabs were opposed to A. italicus.
Muscles versus bones: catfishes as a case study for a discussion on the relative contribution of myological and osteological features in phylogenetic reconstructions
Authors: Diogo Rui
Published: December 2004

The levels of homoplasy and phylogenetic reliability of different types of data sets have since long intrigued evolutionary scientists. This paper provides, to the author's knowledge, the first assessment of the relative contribution of a large set of myological and osteological characters in simultaneous phylogenetic analyses. The biological taxon used as a case study for this comparison was the highly diverse and cosmopolitan teleost Siluriformes (catfishes) which, with 34 families, about 437 genera and more than 2700 species, represents about one third of all freshwater fishes and one of the most diverse vertebrate groups. Such a direct comparison of the relative contribution of these two types of data sets has the advantage that the homoplasy levels and the phylogenetic trees being compared refer to the same group and, more importantly, to the very same terminal taxa. The overall analysis of the results presented in this work seems to indicate that: (1) osteological structures display a greater morphological variation than myological ones; (2) this difference (which is very likely overenhanced by the fact that the phylogenetic variation of osteological structures has historically been the subject of many more studies and descriptions than myological ones) is particularly notable in small taxa, such as genera or species; (3) myological characters provide, however, a high proportion of informative characters for disclosing the relationships between larger taxa, and, thus, for disclosing the phylogeny of the higher clades in which these taxa are included. These results raise some puzzling, general questions. For instance, what are the reasons for the seemingly greater morphological variation of osteological structures? And why is this greater morphological variation of osteological structures in relation to myological structures particularly pronounced in low ranking taxa? Does natural selection eventually act, in certain cases, more on bones than on muscles? Is the development of myological structures eventually more constrained than that of osteological features? What explains the apparently high reliability of muscular characters to disclose the higher-level phylogeny of higher taxa? More direct comparisons, either of other major groups of teleosts or of vertebrates in general, are clearly needed to infer if the patterns found in the direct comparison of this work correspond to a more general phylogenetic pattern, or instead refer to a particular situation found in the order Siluriformes.
Local Item Dependence for Items Across Tests Connected by Common Stimuli
Authors: Wang Wen-Chung , Cheng Ying-Yao , Wilson Mark
Published: December 2004

A parallel design, in which items across different scales within an instrument share common stimuli and subjects respond to the common stimulus for each scale, is sometimes used in questionnaires or inventories. Because the items across scales share the same stimuli, the assumption of local item independence may not hold, thereby violating the assumption of local item independence under standard psychometric models. In this study, the authors describe a multidimensional item response model to detect specific forms of local item dependence. Three real data sets were analyzed to illustrate implications and applications of the proposed method.
Why Is There So Much Conflict in the Middle East?
Authors: Sørli Mirjam E. , Gleditsch Nils Petter , Strand Håvard
Published: December 2004

The Middle East is one of the most conflict-prone regions—butwhy? The Collier-Hoeffler model of civil war provides the starting point for our analysis. In an application to Africa, Collier and Hoeffler found poverty to be the most significant predictor of conflict. For conflict in the Middle East, a more complex picture emerges. Consistent with Collier and Hoeffler, the authors find that economic development and economic growth, in addition to longer periods of peace, generally decrease the likelihood of conflict. They also find that ethnic dominance is significant, while social fractionalization is not. Contrary to Collier and Hoeffler, they find that regime type matters. Variables for the Middle East region, Islamic countries, and oil dependence are not significant. Conflict in the Middle East is quite well explained by a general theory of civilwar, and there is no need to invoke a pattern of “Middle Eastern exceptionalism.”
Offense-Defense Theory
Authors: Gortzak Yoav , Haftel Yoram Z. , Sweeney Kevin
Published: December 2004

Proponents of offense-defense theory (ODT) contend that the offense-defense balance (ODB) forms the “master key” to understanding the question of peace and war. Time-series event count models of war and militarized interstate disputes at the systemic level are used to test the theory’s claims that shifts in the ODB have an important effect on the likelihood of internationalwar and militarized disputes and thatODToffers a more powerful explanation for conflict than other explanations in the international relations (IR) literature. Results cast doubt on the empirical validity of the ODT and indicate that other IR theories have important explanatory power.
Understanding Covert Repressive Action
Authors: Davenport Christian
Published: December 2004

Although overt repression has been studied extensively (e.g., mass arrests), there have been no rigorous investigations of covert repressive action (CRA; e.g., electronic and physical surveillance). To better understand the latter behavior, the author uses newdata about U.S. domestic intelligence activity directed against a Black Nationalist organization in Detroit, Michigan, during the late 1960s and early 1970s ( N= 3,136, by neighborhood-month). In line with existing research, evidence reveals that CRA responds to dissent, lagged repression, and the level of economic development within a neighborhood. Differing from existing literature, however, results also disclose thatCRAresponds to where dissidents live and, most important, in accordance to the racial characteristics of the neighborhood within which potential targets are located. Wiretaps and tails are thus prompted by numerous factors, but the identity of challengers (i.e., political “profiling”) proves to be an essential part of the explanation.
Liberty: One or Two Concepts Liberty
Authors: Nelson Eric
Published: December 2004

Isaiah Berlin’s distinction between “negative” and “positive” concepts of liberty has recently been defended on newand interesting grounds. Proponents of this dichotomy used to equate positive liberty with “self-mastery”—the rule of our rational nature over our passions and impulses. However, Berlin’s critics have made the case that this account does not employ a separate “ concept” of liberty: although the constraints it envisions are internal, rather than external, forces, the freedom in question remains “negative” (freedom is still seen as the absence of such impediments). Responding to this development, Berlin’s defenders have increasingly tended to identify positive liberty with “self-realization.” The argument is that such an account of freedom is genuinely “nonnegative,” in that it does not refer to the absence of constraints on action. This essay argues that the claims made on behalf of “freedom as self-realization” cannot withstand scrutiny, and that they fail to isolate a coherent viewof liberty that is distinguishable fromthe absence of constraint.
Learning To Be Cruel?: Exploring the Onset and Frequency of Animal Cruelty
Authors: Hensley Christopher , Tallichet Suzanne E.
Published: December 2004

Few studies have examined how animal cruelty is learned within a specific social context among incarcerated individuals. Using data from 261 inmates, this study specifically addressed how demographic characteristics and childhood experiences with animal abuse may have affected the recurrence and onset of childhood and adolescent cruelty as a learned behavior. Multiple regression analyses revealed that inmates who experienced animal cruelty at a younger age were more likely to demonstrate recurrent animal cruelty themselves. In addition, respondents who observed a friend abuse animals were more likely to hurt or kill animals more frequently. Finally, inmates who were younger when they first witnessed animal cruelty also hurt or killed animals at a younger age.
Relationship Between Time Interval From Primary Surgery to the Start of Taxane- Plus Platinum-Based Chemotherapy and Clinical Outcome of Patients With Advanced Epithelial Ovarian Cancer: Results of a Multicenter Retrospective Italian Study
Authors: Gadducci Angiolo , Sartori Enrico , Landoni Fabio , Zola Paolo , Maggino Tiziano , Maggioni Angelo , Cosio Stefania , Frassi Eleonora , LaPresa Maria Teresa , Fuso Luca , Cristofani Renza
Published: December 2004

Purpose

To assess whether the interval from primary surgery to the start of taxane- plus platinum-based chemotherapy has any impact on the clinical outcome of advanced ovarian cancer patients.

Patients and Methods

The study was conducted on 313 patients who underwent surgery followed by taxane- plus platinum-based chemotherapy. The median follow-up of survivors was 30.7 months (range, 6 to 109 months).

Results

The 25%, 50%, and 75% quantiles of intervals from surgery to the start of chemotherapy were 11, 21, and 31 days, respectively. After the sixth cycle, 102 patients achieved a pathologic complete response at second-look surgery and 98 obtained a clinical complete response but were not submitted to second-look surgery. Taking into consideration the best assessed response, a complete (either clinical or pathologic) response was found in 200 patients. Residual disease (≤ 1 v > 1 cm; P < .0001) and ascites (absent v present; P = .003) were independent predictive factors for achieving a complete response, whereas residual disease (P = .001) and stage (IIc to III v IV; P = .04) were independent prognostic variables for survival. Conversely, statistical analyses failed to detect significant differences in complete response rates and survival among patients with an interval from surgery to chemotherapy shorter than 11 days, 12 to 21 days, 22 to 31 days, and longer than 31 days.

Conclusion

The interval from surgery to the start of taxane- plus platinum-based chemotherapy seems to have neither a predictive value for response to treatment nor a prognostic relevance for survival of advanced ovarian cancer patients.
Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors
Authors: Strumberg Dirk , Richly Heike , Hilger Ralf A. , Schleucher Norbert , Korfee Sonke , Tewes Mitra , Faghih Markus , Brendel Erich , Voliotis Dimitris , Haase Claus G. , Schwartz Brian , Awada Ahmad , Voigtmann Rudolf , Scheulen Max E. , Seeber Siegfried
Published: December 2004

Purpose

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors.

Patients and Methods

BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate–stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry.

Results

Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate–stimulated ERK phosphorylation (P < .01) were identified at doses ≥ 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient.

Conclusion

Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.
Phase I Study of Sequential Vaccinations With Fowlpox-CEA(6D)-TRICOM Alone and Sequentially With Vaccinia-CEA(6D)-TRICOM, With and Without Granulocyte-Macrophage Colony-Stimulating Factor, in Patients With Carcinoembryonic Antigen–Expressing Carcinomas
Authors: Marshall John L. , Gulley James L. , Arlen Philip M. , Beetham Patricia K. , Tsang Kwong-Yok , Slack Rebecca , Hodge James W. , Doren Sandra , Grosenbach Douglas W. , Hwang Jimmy , Fox Evelyn , Odogwu Lauretta , Park Susie , Panicali Dennis , Schlom Jeffrey
Published: December 2004

Purpose

Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene).

Patients and Methods

Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule.

Results

In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested.

Conclusion

We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.
TheDrosophilaBub3 protein is required for the mitotic checkpoint and for normal accumulation of cyclins during G2 and early stages of mitosis
Authors: Lopes Carla S. , Sampaio Paula , Williams Byron , Goldberg Michael , Sunkel Claudio E.
Published: December 2004

During mitosis, a checkpoint mechanism delays metaphase-anaphase transition in the presence of unattached and/or unaligned chromosomes. This delay is achieved through inhibition of the anaphase promoting complex/cyclosome (APC/C) preventing sister chromatid separation and cyclin degradation. In the present study, we show that Bub3 is an essential protein required during normal mitotic progression to prevent premature sister chromatid separation, missegreation and aneuploidy. We also found that Bub3 is required during G2 and early stages of mitosis to promote normal mitotic entry. We show that loss of Bub3 function by mutation or RNAi depletion causes cells to progress slowly through prophase, a delay that appears to result from a failure to accumulate mitotic cyclins A and B. Defective accumulation of mitotic cyclins results from inappropriate APC/C activity, as mutations in the gene encoding the APC/C subunit cdc27 partially rescue this phenotype. Furthermore, analysis of mitotic progression in cells carrying mutations for cdc27 and bub3 suggest the existence of differentially activated APC/C complexes. Altogether, our data support the hypothesis that the mitotic checkpoint protein Bub3 is also required to regulate entry and progression through early stages of mitosis.
PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli
Authors: Meder Véronique S. , Boeglin Marcel , de Murcia Gilbert , Schreiber Valérie
Published: December 2004

The DNA damage-dependent poly(ADP-ribose) polymerases-1 and -2 (PARP-1 and PARP-2) are survival factors that share overlapping functions in the detection, signaling and repair of DNA strand breaks resulting from genotoxic lesions in mammalian cells. Here we show that PARP-1 and PARP-2 subnuclear distributions partially overlap, with both proteins accumulating within the nucleolus independently of each other. PARP-2 is enriched within the whole nucleolus and partially colocalizes with the nucleolar factor nucleophosmin/B23. We have identified a nuclear localization signal and a nucleolar localization signal within the N-terminal domain of PARP-2. PARP-2, like PARP-1, interacts with B23 through its N-terminal DNA binding domain. This association is constitutive and does not depend on either PARP activity or ribosomal transcription, but is prevented by mutation of the nucleolar localization signal of PARP-2. PARP-1 and PARP-2, together with B23, are delocalized from the nucleolus upon RNA polymerase I inhibition whereas the nucleolar accumulation of all three proteins is only moderately affected upon oxidative or alkylated DNA damage. Finally, we show that murine fibroblasts deficient in PARP-1 or PARP-2 are not affected in the transcription of ribosomal RNAs. Taken together, these results suggest that the biological role of PARP-1 and PARP-2 within the nucleolus relies on functional nucleolar transcription, without any obvious implication of either PARP on this major nucleolar process.
A synthetic glycosaminoglycan mimetic (RGTA) modifies natural glycosaminoglycan species during myogenesis
Authors: Barbosa Isabelle , Morin Christophe , Garcia Stephanie , Duchesnay Arlette , Oudghir Mustapha , Jenniskens Guido , Miao Hua-Quan , Guimond Scott , Carpentier Gilles , Cebrian José , Caruelle Jean-Pierre , van Kuppevelt Toin , Turnbull Jeremy , Martelly Isabelle , Papy-Garcia Dulce
Published: December 2004

Crucial events in myogenesis rely on the highly regulated spatiotemporal distribution of cell surface heparan sulfate proteoglycans to which are associated growth factors, thus creating a specific microenvironment around muscle cells. Most growth factors involved in control of myoblast growth and differentiation are stored in the extracellular matrix through interaction with specific sequences of glycosaminoglycan oligosaccharides, mainly heparan sulfate (HS). Different HS subspecies revealed by specific antibodies, have been shown to provide spatiotemporal regulation during muscle development. We have previously shown that glycosaminoglycan (GAG) mimetics called RGTA (ReGeneraTing Agent), stimulate muscle precursor cell growth and differentiation. These data suggest an important role of GAGs during myogenesis; however, little is yet known about the different species of GAGs synthesized during myogenesis and their metabolic regulation. We therefore quantified GAGs during myogenesis of C2.7 cells and show that the composition of GAG species was modified during myogenic differentiation. In particular, HS levels were increased during this process. In addition, the GAG mimetic RGTA, which stimulated both growth and differentiation of C2.7 cells, increased the total amount of GAG produced by these cells without significantly altering their rate of sulfation. RGTA treatment further enhanced HS levels and changed its sub-species composition. Although mRNA levels of the enzymes involved in HS biosynthesis were almost unchanged during myogenic differentiation, heparanase mRNA levels decreased. RGTA did not markedly alter these levels. Here we show that the effects of RGTA on myoblast growth and differentiation are in part mediated through an alteration of GAG species and provide an important insight into the role of these molecules in normal or pathologic myogenic processes.
Nak1 interacts with Hob1 and Wsp1 to regulate cell growth and polarity inSchizosaccharomyces pombe
Authors: Huang Timothy Y. , Renaud-Young Margaret , Young Dallan
Published: December 2004

We have previously reported that Nak1, a group-II germinal center (GC) kinase, is essential for polarized growth in Schizosaccharomyces pombe. Here, we provide evidence that Nak1 regulates cell growth and polarity, in part, through its interactions with Hob1 (an Rvs167/amphiphysin homolog) and Wsp1 (Wiskott-Aldrich-syndrome-protein homolog). We found that Nak1, Hob1 and Wsp1 interact physically, and that both Hob1/green-fluorescent-protein (Hob1-GFP) and Wsp1-GFP fusion proteins localized to F-actin patches at growing cell ends and medial division sites. Hob1-GFP was dissociated from patches in cells lacking Wsp1. Also, Hob1 overexpression dissociated Wsp1-GFP from foci, inhibited Wsp1-directed F-actin formation in vitro and partially restored polarity defects associated with Wsp1 overexpression or nak1 repression. Furthermore, loss of both Wsp1 and Hob1 resulted in rounded cells, slow growth and multiple septae. Together, these observations suggest that Hob1 and Wsp1 cooperate to mediate cell polarity, growth and division. Repression of nak1 resulted in a random redistribution of Hob1-GFP and Wsp1-GFP foci, and inhibition of Wsp1-directed F-actin formation in vitro. Furthermore, hob1Δ and wsp1Δ mutants exhibited synthetic growth defects in combination with nak1 repression, suggesting that Nak1 has redundant functions with Hob1 and Wsp1. Collectively, our results suggest that Nak1 both regulates and cooperates with Hob1 and Wsp1 to promote F-actin formation and polarized cell growth.
Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration
Authors: El-Remessy Azza B. , Bartoli Manuela , Platt Danial H. , Fulton David , Caldwell Ruth B.
Published: December 2004

In diabetic retinopathy, endothelial cell apoptosis is paradoxically increased despite upregulation of the potent pro-survival factor VEGF. We tested the hypothesis that elevated glucose levels disrupt VEGF's pro-survival function via peroxynitrite-mediated alteration of the Akt-1/p38 MAP kinase signaling pathway by studies of retinal endothelial cells in vitro. High glucose or exogenous peroxynitrite caused significant increases in apoptosis in the presence or absence of VEGF. Treatment with a peroxynitrite decomposition catalyst blocked these effects, implying a causal role of peroxynitrite. Peroxynitrite or high glucose treatment also increased phosphorylation of p38 MAP kinase, whereas phosphorylation of Akt-1 was significantly decreased in basal or VEGF-stimulated conditions. High glucose- or peroxynitrite-treated cells also showed significant increases in tyrosine nitration on the p85 subunit of PI 3-kinase that blocked PI 3-kinase and Akt-1 kinase activity. Inhibiting peroxynitrite formation or blocking tyrosine nitration of p85 restored the activity of PI 3-kinase and Akt-1 kinase, blocked phosphorylation of p38 MAP kinase and normalized pro-survival function. Transfecting the cells with constitutively active Akt-1 or inhibiting activity of p38 MAP kinase completely masked the pro-apoptotic effects of high glucose and exogenous peroxynitrite, suggesting an interaction between the Akt-1 and p38 MAP kinase pathways. In conclusion, high glucose treatment blocks the pro-survival effect of VEGF and causes accelerated endothelial cell apoptosis via the action of peroxynitrite in causing tyrosine nitration of PI 3-kinase, inhibiting activity of Akt-1 kinase and increasing the activity of p38 MAP kinase.
A Novel Route to Octahedral In2O3 Particles Exhibiting Near Band Emission
Authors: Zhang Wu , Huang Zhen , Li Ting , Tang Qun , Ma Dekun , Qian Yitai
Published: December 2004

A novel solvothermal route combined with calcination was successfully established to synthesize octahedral In2O3 particles, which exhibit near band emission. Interesting shape transformation from amorphous sphere to well-shaped octahedron was found.
3D models of yeast RNase P/MRP proteins Rpp1p and Pop3p
Authors: DLAKIĆ MENSUR
Published: December 2004

Sensitive profile searches and fold recognition were used to predict the structures of two yeast RNase P/MRP proteins. Rpp1p, which is one of the subunits common to eukaryotes and archaea, is predicted to adopt the seven-stranded TIM-barrel fold found in PHP phosphoesterases. Pop3p, initially thought to be one of the RNase P/MRP subunits unique to yeast, has been assigned the L7Ae/L30e fold. This RNA-binding fold is also present in human RNase P subunit Rpp38, raising the possibility that Pop3p and Rpp38 are functional homologs.
RNA–protein interactions in the yeast three-hybrid system: Affinity, sensitivity, and enhanced library screening
Authors: HOOK BRAD , BERNSTEIN DAVID , ZHANG BEILIN , WICKENS MARVIN
Published: December 2004

The yeast three-hybrid system has become a useful tool in analyzing RNA–protein interactions. An RNA sequence is tested in combination with an RNA-binding protein linked to a transcription activation domain (AD). A productive RNA–protein interaction activates a reporter gene in vivo. The system has been used to test candidate RNA–protein pairs, to isolate mutations in each interacting partner, and to identify proteins that bind a given RNA sequence. However, the relationship between reporter gene activation and in vitro affinity of an RNA–protein interaction has not been examined systematically. This limits interpretation of the data and complicates the development of new strategies. Here, we analyze several key parameters of the three-hybrid system, using as a model the interaction of a PUF protein, FBF-1, with a range of RNA targets. We compare activation of two reporter genes as a function of the in vitro affinity of the interaction. HIS3 and LacZ expression levels are directly related to affinity over a 10-fold range of Kd. Expression of the reporter genes also is directly related to the abundance of the activation domain fusion protein. We describe a new yeast strain, YBZ1, that simplifies screening of cDNA/AD libraries. This strain possesses a tandem, head-to-tail dimer of a high-affinity variant of MS2 coat protein, fused to a monomer of the LexA DNA-binding protein. We show that the use of this strain in cDNA library screens increases the number of genuine, sequence-specific positives detected, and at the same time reduces the background of false, RNA-independent positives.
Acute Inhalant-Induced Neurotoxicity with Delayed Recovery
Authors: Finch Christopher K , Lobo Bob L
Published: December 2004

OBJECTIVE:

To report a case of neurotoxicity and subsequent hospitalization due to abuse of an ethyl chloride inhalant.

CASE SUMMARY:

A 41-year-old African American male presented to the emergency department due to mental status changes and an inability to walk. After the blood alcohol and urine drug screen returned negative, a family member revealed that the patient frequently abused an inhalant containing the volatile solvent ethyl chloride.

DISCUSSION:

Inhalant abuse is common and is facilitated by the widespread availability of volatile solvents that have legitimate commercial or household uses. Most inhalants are central nervous system depressants and are highly lipophilic. Maximum Impact, which contains ethyl chloride, is sold in stores and is readily available over the Internet. While the product has a legitimate use as a VCR head cleaner, it is often illicitly marketed over the Internet as a means of getting a “rush” or “high” and for enhancing sexual pleasure. Neurologic symptoms have been reported after deliberate inhalational exposure to ethyl chloride, and 2 deaths have been associated with its use. An objective causality assessment using the Naranjo probability scale revealed a probable adverse drug event.

CONCLUSIONS:

Inhalants should be included in the differential diagnosis of patients presenting with acute mental status changes and neurologic impairment that resolve over less than one week.
Immunosuppressant Drug Monitoring: Is the Laboratory Meeting Clinical Expectations?
Authors: Morris Raymond G
Published: December 2004

OBJECTIVE:

To review the literature relating to immunosuppressant drug measurement as performed in therapeutic drug monitoring laboratories associated with transplantation centers and consider whether the assay methods widely used for patient dosage management achieve acceptable quality criteria in the context of other sources of variability with these drugs.

DATA SOURCES:

Articles used were accessed primarily through MEDLINE, as well as references cited in related publications. Searches were restricted to organ transplantation in humans.

STUDY SELECTION AND DATA EXTRACTION:

Emphasis was placed on the literature relating to the quality of immunosuppressant drug assays, their limitations, and evidence of clinical benefit in dosage individualization.

DATA SYNTHESIS:

There is a dilemma evident between the quality of the analytical services offered by some diagnostic immunoassay manufacturers and the ability of a significant number of clinical laboratories globally to select only appropriate assay methods.

CONCLUSIONS:

In many cases, clinical laboratories fail to meet the reasonable clinical expectations required for interpretation of immunosuppressant drug assay results as an adjunct to optimal dosage individualization and patient care.
Eplerenone: A Selective Aldosterone Receptor Antagonist for Patients with Heart Failure
Authors: Barnes Brian J , Howard Patricia A
Published: December 2004

OBJECTIVE:

To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF).

DATA SOURCES:

English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles.

STUDY SELECTION AND DATA EXTRACTION:

Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated.

DATA SYNTHESIS:

Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence.

CONCLUSIONS:

The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone—related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.