bluuebunny/crossref_metadata_2025 huggingface dataset:
Statins and the Risk of Colorectal Cancer: A Meta-Analysis of 18 Studies Involving More Than 1.5 Million Patients
Authors: Bonovas Stefanos , Filioussi Kalitsa , Flordellis Christodoulos S. , Sitaras Nikolaos M.
Published: August 2007

Purpose

Statins have been suggested to prevent colorectal cancer. Several epidemiologic studies have evaluated this association, whereas randomized controlled trials (RCTs) on cardiovascular outcomes provide relevant data as a secondary end point. Our aim was to examine the strength of this association through a detailed meta-analysis of the studies published on the subject in peer-reviewed literature.

Methods

A comprehensive search for studies published up to December 2006 was performed, reviews of each study were conducted, and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates with 95% CIs were calculated using the fixed- and random-effects models.

Results

Eighteen studies involving more than 1.5 million participants contributed to the analysis. They were grouped on the basis of study design, and separate meta-analyses were conducted. There was no evidence of an association between statin use and risk of colorectal cancer either among RCTs (RR = 0.95; 95% CI, 0.80 to 1.13; n = 6) or among cohort studies (RR = 0.96; 95% CI, 0.84 to 1.11; n = 3). However, statin use was associated with a modest reduction in the risk of colorectal cancer among case-control studies (RR = 0.91; 95% CI, 0.87 to 0.96; n = 9). Low evidence of publication bias or heterogeneity was found.

Conclusion

Our meta-analysis results do not support the hypothesis that statins strongly reduce the risk of colorectal cancer, when taken for management of hypercholesterolemia. However, we cannot rule out a modest reduction in risk or an effect associated with higher doses of statins.
Irinotecan Fluorouracil Plus Leucovorin Is Not Superior to Fluorouracil Plus Leucovorin Alone As Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803
Authors: Saltz Leonard B. , Niedzwiecki Donna , Hollis Donna , Goldberg Richard M. , Hantel Alexander , Thomas James P. , Fields Anthony L.A. , Mayer Robert J.
Published: August 2007

Purpose

Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer.

Methods

A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS).

Results

Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm.

Conclusion

The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.
Statistical Power of Negative Randomized Controlled Trials Presented at American Society for Clinical Oncology Annual Meetings
Authors: Bedard Philippe L. , Krzyzanowska Monika K. , Pintilie Melania , Tannock Ian F.
Published: August 2007

Purpose

To investigate the prevalence of underpowered randomized controlled trials (RCTs) presented at American Society of Clinical Oncology (ASCO) annual meetings.

Methods

We surveyed all two-arm phase III RCTs presented at ASCO annual meetings from 1995 to 2003 for which negative results were obtained. Post hoc calculations were performed using a power of 80% and an α level of .05 (two sided) to determine sample sizes required to detect small, medium, and large effect sizes. For studies reporting a proportion or time-to-event as primary end point, effect size was expressed as an odds ratio (OR) or hazard ratio (HR), respectively, with a small effect size defined as OR/HR ≥ 1.3, medium effect size defined as OR/HR ≥ 1.5, and large effect size defined as OR/HR ≥ 2.0. Logistic regression was used to identify factors associated with lack of statistical power.

Results

Of 423 negative RCTs for which post hoc sample size calculations could be performed, 45 (10.6%), 138 (32.6%), and 233 (55.1%) had adequate sample size to detect small, medium, and large effect sizes, respectively. Only 35 negative RCTs (7.1%) reported a reason for inadequate sample size. In a multivariable model, studies that were presented at oral sessions (P = .0038), multicenter studies supported by a cooperative group (P < .0001), and studies with time to event as primary outcome (P < .0001) were more likely to have adequate sample size.

Conclusion

More than half of negative RCTs presented at ASCO annual meetings do not have an adequate sample to detect a medium-size treatment effect.
Attitudes Toward Research Participation and Investigator Conflicts of Interest Among Advanced Cancer Patients Participating in Early Phase Clinical Trials
Authors: Gray Stacy W. , Hlubocky Fay J. , Ratain Mark J. , Daugherty Christopher K.
Published: August 2007

Purpose

Although both financial and intrinsic conflicts of interest can exist throughout the drug development process, little is known about how advanced cancer patients enrolled onto early phase clinical trials perceive investigator conflicts of interests.

Patients and Methods

We interviewed 102 advanced cancer patients enrolled onto phase I clinical trials using a standardized survey that addressed multiple issues related to conflicts of interest and research participation.

Results

Fifty-five percent of patients would not be concerned if physicians involved in running a clinical trial had financial conflicts of interest, whereas 65% of patients would be concerned if physicians involved in running a trial had intrinsic conflicts of interest. Most patients reported that potential conflicts of interest should be disclosed to patients on research trials (52% for financial conflicts of interest and 61% for more intrinsic conflicts of interest). Most patients would be willing to participate in trials after learning conflict of interest information (63%). Younger patients expressed more concern regarding financial conflict of interest than older patients (odds ratio, 6.22; 95% CI, 1.41 to 27.24).

Conclusion

Patients with advanced cancer are equally, if not more, concerned about traditional intrinsic conflicts of interest as compared with financial conflicts of interest. Patients generally believed that conflict of interest information should be disclosed to research participants. The fact that younger patients expressed more concern about financial conflicts of interest may have the potential to influence clinical trial participation rates. The actual impact of conflict of interest disclosure to research subjects needs to be evaluated more carefully.
Tetraspanin CD81 is required for the αvβ5-integrin-dependent particle-binding step of RPE phagocytosis
Authors: Chang Yongen , Finnemann Silvia C.
Published: August 2007

Retinal pigment epithelial (RPE) cells are among the most active phagocytes in the body. Every morning, circadian shedding of outer segment fragments by photoreceptor cells activates a synchronized phagocytic response by RPE cells that is critical for vision. RPE cells require αvβ5 integrin receptors for particle binding that triggers engulfment. Here, we show that tetraspanins CD81 and CD9 reside in a complex specifically with αvβ5 integrin but not the engulfment receptors Mer tyrosine kinase and CD36 at the apical, phagocytic surface of RPE cells. Function blocking and RNA silencing of CD81 but not of CD9 specifically diminish particle binding. CD81 but not CD9 overexpression is sufficient to increase particle binding and surface levels of αvβ5 integrin. Wild-type and mutant RPE cells defective in particle engulfment equally reduce and increase particle binding in response to CD81 inhibition and CD81 overexpression, respectively. By striking contrast, neither CD81 inhibition nor CD81 overexpression has any effect on particle binding by RPE lacking αvβ5 integrin. These results identify a novel and important role for CD81 in phagocytosis. CD81 does not function as a binding receptor by itself but promotes outer segment particle binding through functional interaction specifically with αvβ5 integrin.
Targeted gene disruption of dynein heavy chain 7 ofTetrahymena thermophilaresults in altered ciliary waveform and reduced swim speed
Authors: Wood Christopher R. , Hard Robert , Hennessey Todd M.
Published: August 2007

Tetrahymena thermophila swims by the coordinated beating of hundreds of cilia that cover its body. It has been proposed that the outer arm dyneins of the ciliary axoneme control beat frequency, whereas the inner arm dyneins control waveform. To test the role of one of these inner arms, dynein heavy chain 7 protein (Dyh7p), a knockout mutant was generated by targeted biolistic transformation of the vegetative macronucleus. Disruption of DYH7, the gene which encodes Dyh7p, was confirmed by PCR examination of both genomic and cDNA templates. Both intact and detergent extracted, reactivated cell model preparations of these mutants, which we call DYH7neo3, displayed swim speeds that were almost half that of wild-type cells. Although the DYH7neo3 mutants were slower than wild type, they were able to modulate their swim speed and show ciliary reversal in response to depolarizing stimuli. High-speed video microscopy of intact, free-swimming DYH7neo3 mutants revealed an irregular pattern of ciliary beat and waveform. The mutant cilia appeared to be engaging in less coordinated, swiveling movements in which the typical shape, periodicity and coordination seen in wild-type cilia were absent or disturbed. We propose that the axonemal inner arm dynein heavy chain 7 proteins contribute to the formation of normal ciliary waveform, which in turn governs the forward swimming velocity of these cells.
Impact on physician workload and revenue following the creation of a specialty vein clinic within an academic vascular practice
Authors: Passman M A , Dattilo J B , Guzman R J , Naslund T C
Published: August 2007

Objective: To evaluate the impact of creating a new specialty vein clinic within an academic-based vascular practice on clinical volume, physician workload and financial parameters.

Methods: All patients evaluated and treated for varicose vein related problems within an academic vascular surgery practice were identified from institutional billing databases. Data were stratified according to the time period prior to establishing a vein clinic (PRE-VC) (1999–2001) and after creation of a vein clinic (POST-VC) (2002–2004). Clinical volume, physician workload and financial parameters were evaluated. Comparisons were made between vein (VEIN) and overall vascular (VASC) practice trends.

Results: Comparison of clinical volume, physician workload and financial parameters in both the clinic and operative settings showed larger and more rapid expansion of the VEIN practice than VASC practice between PRE-VC and POST-VC time periods (VEIN vs. VASC growth, respectively: new patient clinic volume +162 vs. +18%; clinic relative value units (RVUs) +131 vs. +1%, clinic revenue +201 vs. +44%; procedure volume +348 vs. +19%; procedure RVUs +129 vs. +11%; procedure revenue +93 vs. +10%). Comparing the beginning of PRE-VC to the end of POST-VC time periods, an increasing trend was also present for the percentage of VEIN practice accounting for the total VASC practice (%VEIN PRE-VC to POST-VC, respectively: new patient clinic volume 11.6–30.2%; clinic RVUs 3.2–48.2%; clinic revenue 17.6–31.2%; procedure volume 3.1–14.3%; procedure RVUs 2.8–9.8%; procedure revenue 3.3–11.7%).

Conclusion: Establishing a specialty vein clinic within an academic vascular practice can lead to a rapid expansion of clinical volume with associated increase in physician workload and reimbursement at a rate greater than that for the overall vascular practice.
Is failure to provide venous thromboprophylaxis negligent?
Authors: Scurr J R H , Scurr J H
Published: August 2007

Objectives: To report the outcome of 100 consecutive medicolegal claims referred to one of the authors (1990–2003) following the development of venous thromboembolism (VTE) in surgical patients.

Methods: A retrospective analysis of the experience of a vascular surgeon acting as an expert witness in the United Kingdom.

Results: Prophylaxis had been provided to 43 claimants with risk factors, who, unfortunately, still developed a VTE and alleged negligence. Twenty-nine claims involved patients who had not received prophylaxis because they were at low risk. In 25/28 claims where no prophylaxis was provided, despite identifiable VTE risk factors, the claim was successful. Claimants who developed a VTE that had been managed incorrectly were successful whether they had received prophylaxis or not. Settlement amounts, where disclosed, are reported.

Conclusions: Failure to perform a risk assessment and to provide appropriate venous thromboprophylaxis in surgical patients is considered negligent. Clinicians looking after all hospitalized patients who are not assessing their patients' risk for VTE and/or not providing appropriate prophylaxis are at risk of being accused of negligence.
The small saphenous vein and other 'neglected' veins of the popliteal fossa: a review
Authors: O'Donnell T F , Iafrati M D
Published: August 2007

The small saphenous vein (SSV) and other veins in the popliteal fossa merit little discussion in the literature or in didactic programmes regarding their role in chronic venous insufficiency (CVI) and, in this sense, they are neglected. The purpose of this review is to present both duplex ultrasound findings and the associated clinical characteristics of patients with SSV reflux, from several large series. Both the anatomic variations and the epidemiology of the SSV, as well as other veins of the popliteal fossa, the gastrocnemius veins, Gocamini vein, popliteal area veins and popliteal vein, will be discussed. Findings from our review of the current available literature will demonstrate the important role that these veins play in association with CVI. The implications for open and endovenous surgery will be underlined.
Programme for detecting chronic venous insufficiency in Belgium
Authors: Schoevaerdts J-C , Staelens I
Published: August 2007

Objective: Epidemiological study related to the detection of chronic venous disease (CVD) in a Belgian population and gathering of a maximum amount of epidemiological data on CVD.

Method: Survey based on a questionnaire completed by a general practitioner during consultation.

Results: In total 3813 files of patients with CVD were completed and analysed. Of these patients suffering from CVD, 70% were women with a mean body mass index of 26.2 and a clinical, aetiological, anatomical and pathological elements classification as follows: C0 = 14; 10%; C1 = 14; 19%; C2 = 14; 29%; C3 = 14; 19%; C4 = 14; 16%; C5 = 14; 4%; C6 = 14; 3%. Risk factors, clinical signs, complications and therapeutic approach are analysed and described.

Conclusion: High level of statistically analysable data could be obtained within a reasonable period. The study confirms the socioeconomic importance of CVD. For example, an industrial disablement of an average duration of 23.6 days is found in 6% of patients.
Nuclear factors are involved in hepatitis C virus RNA replication
Authors: Isken Olaf , Baroth Martina , Grassmann Claus W. , Weinlich Susan , Ostareck Dirk H. , Ostareck-Lederer Antje , Behrens Sven-Erik
Published: August 2007

Unraveling the molecular basis of the life cycle of hepatitis C virus (HCV), a prevalent agent of human liver disease, entails the identification of cell-encoded factors that participate in the replication of the viral RNA genome. This study provides evidence that the so-called NF/NFAR proteins, namely, NF90/NFAR-1, NF110/NFAR-2, NF45, and RNA helicase A (RHA), which mostly belong to the dsRBM protein family, are involved in the HCV RNA replication process. NF/NFAR proteins were shown to specifically bind to replication signals in the HCV genomic 5′ and 3′ termini and to promote the formation of a looplike structure of the viral RNA. In cells containing replicating HCV RNA, the generally nuclear NF/NFAR proteins accumulate in the cytoplasmic viral replication complexes, and the prototype NFAR protein, NF90/NFAR-1, stably interacts with a viral protein. HCV replication was inhibited in cells where RNAi depleted RHA from the cytoplasm. Likewise, HCV replication was hindered in cells that contained another NF/NFAR protein recruiting virus. The recruitment of NF/NFAR proteins by HCV is assumed to serve two major purposes: to support 5′–3′ interactions of the viral RNA for the coordination of viral protein and RNA synthesis and to weaken host–defense mechanisms.
Polyadenylation site choice in yeast is affected by competition between Npl3 and polyadenylation factor CFI
Authors: Bucheli Miriam E. , He Xiaoyuan , Kaplan Craig D. , Moore Claire L. , Buratowski Stephen
Published: August 2007

Multiple steps in mRNA processing and transcription are coupled. Notably, the processing of mRNA 3′ ends is linked to transcription termination by RNA polymerase II. Previously, we found that the yeast hnRNP protein Npl3 can negatively regulate 3′ end mRNA formation and termination at the GAL1 gene. Here we show that overexpression of the Hrp1 or Rna14 subunits of the CF IA polyadenylation factor increases recognition of a weakened polyadenylation site. Genetic interactions of mutant alleles of NPL3 or HRP1 with RNA15 also indicate antagonism between these factors. Npl3 competes with Rna15 for binding to a polyadenylation precursor and inhibits cleavage and polyadenylation in vitro. These results suggest that an important function of hnRNP proteins is to ensure the fidelity of mRNA processing. Our results support a model in which balanced competition of Npl3 with mRNA processing factors may promote recognition of proper polyadenylation sites while suppressing cryptic sites.
Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications
Authors: Aartsma-Rus Annemieke , van Ommen Gert-Jan B.
Published: August 2007

Antisense-mediated modulation of splicing is one of the few fields where antisense oligonucleotides (AONs) have been able to live up to their expectations. In this approach, AONs are implemented to restore cryptic splicing, to change levels of alternatively spliced genes, or, in case of Duchenne muscular dystrophy (DMD), to skip an exon in order to restore a disrupted reading frame. The latter allows the generation of internally deleted, but largely functional, dystrophin proteins and would convert a severe DMD into a milder Becker muscular dystrophy phenotype. In fact, exon skipping is currently one of the most promising therapeutic tools for DMD, and a successful first-in-man trial has recently been completed. In this review the applicability of exon skipping for DMD and other diseases is described. For DMD AONs have been designed for numerous exons, which has given us insight into their mode of action, splicing in general, and splicing of theDMDgene in particular. In addition, retrospective analysis resulted in guidelines for AON design forDMDand most likely other genes as well. This knowledge allows us to optimize therapeutic exon skipping, but also opens up a range of other applications for the exon skipping approach.
Thromboembolic Events During Continuous Vasopressin Infusions: A Retrospective Evaluation
Authors: Doepker Bruce A , Lucarelli Maria R , Lehman Amy , Shirk Mary Beth
Published: August 2007

Background:

Published guidelines suggest that vasopressin has a role in shock treatment, although its safety has not been adequately evaluated in a clinical setting. Vasopressin causes platelet aggregation and has been associated with the release of factor VIII coagulant and von Willebrand factor.

Objective:

To compare the incidence of venous thromboembolism (VTE) in patients with a diagnosis of shock who received vasopressin with those who did not receive vasopressin for hemodynamic support.

Methods:

A retrospective, single-center, cohort study was conducted at an academic, tertiary care center with 350 patients with a diagnosis of shock. Patients from the intensive care unit were randomly selected and separated into 2 groups for comparison of those receiving only catecholamines with those receiving vasopressin with or without catecholamines for hypotension. Patients with diabetes insipidus or variceal hemorrhage and those with any documented history of VTE were excluded. The primary outcome, VTE occurrence, was defined as a positive Doppler ultrasound, spiral computed tomography, or documented diagnosis in the discharge records. Frequency and type of risk factors for VTE were compared between the 2 study arms. A risk factor modeling approach was performed, using logistic regression to identify potential confounders and effect modifiers in the relationship between vasopressin and VTE.

Results:

There were 175 patients in each arm of the study. The crude incidence of VTE was 7.4% and 8% in the vasopressin and catecholamine groups, respectively (p = 0.84). No significant difference in the incidence of deep venous thrombosis (vasopressin 5.1%, control 7.4%; p = 0.51) or pulmonary embolism (vasopressin 2.3%, control 0.6%; p = 0.37) was found between groups. After adjusting for covariates, there was no statistically significant difference in the incidence of VTE between the 2 arms (p = 0.72).

Conclusions:

This investigation provides initial evidence that vasopressin infusions do not increase the risk of VTE in patients with shock.
The effects of explanatory conversations on children's emotion understanding
Authors: Tenenbaum Harriet R. , Alfieri Louis , Brooks Patricia J. , Dunne Guler
Published: August 2007

Ninety‐three children ranging in age from 5 to 8 years (M= 82.46 months,SD= 13.20) participated in a training study designed to improve their emotion understanding. Children either explained (self‐explanation condition) or listened to an experimenter who explained (experimenter‐explanation condition) the causes of protagonists' hidden and ambivalent emotional reactions in nine different vignettes. Compared to a control group who listened to the vignettes and answered questions unrelated to emotions, children assigned to the self‐explanation and experimenter‐explanation conditions increased from pre‐ to post‐test in their emotion understanding. The educational implications of explanatory conversations in facilitating children's emotion understanding and general learning are discussed.
Synthesis of light-colored rosin glycerol ester
Authors: Wang Shifa
Published: August 2007

A light-colored rosin glycerol ester was synthesized from gum rosin and glycerol in the presence of a highly effective decolorizing agent. The effects of the type and dosage of the decolorizing agent and the reaction temperature and time on the yield, softening point, color, and acid number of the rosin glycerol ester were investigated. Experimental results showed that 4,4′-thio-bis(6-tert-butyl-3-methyl phenol) was the best decolorizing agent. It promoted esterification at an optimal dosage of 0.5% (based on the weight percentage of starting material rosin). Suitable conditions for esterification of rosin and glycerol were: reaction temperature, 260–270°C; reaction time, 6–8 h; and rosin/glycerol molar ratio, 2.5:1 (mol mol-1). The characteristics of the rosin glycerol ester obtained under these conditions were as follows: softening point, 90–94°C (ball and ring method); color, 1–2 (Gardner value); acid number, 7–8; and yield, >88% (based on the total weight of rosin and glycerol). The selected additive has a multifunctional effect involving bleaching, disproportionation, and catalysis.
Study of the phenolic compounds formed during pretreatment of sugarcane bagasse by wet oxidation and steam explosion
Authors: Martín Carlos , Klinke Helene B. , Marcet Marcelo , García Luis , Hernández Ena , Thomsen Anne Belinda
Published: August 2007

The formation of phenolic compounds during pretreatment of sugarcane bagasse was investigated. Bagasse was pretreated by wet oxidation (WO) at 195°C during 15 min under either alkaline or acidic conditions and by steam explosion (STEX) at 205°C during 10 min. The total content of phenolic compounds in the prehydrolysates was determined spectrophotometrically. Under acidic and alkaline WO conditions, 3.8% (w/w) and 3% phenols were found, respectively. STEX gave rise to 1.9% phenols. Individual phenols were identified by GC-MS. Phenylpropanoid derivatives, such as p-coumaric and ferulic acids, accounted for more than 50% of the phenols identified in STEX prehydrolysates. In WO prehydrolysates, on the other hand, phenols lacking the propanoid side chain were predominant. Of the latter, p-hydroxybenzaldehyde was the most abundant phenol, with concentrations of 0.27% (acidic conditions) and 0.15% (alkaline conditions). As expected, high concentrations of oxidised compounds were generally observed in WO prehydrolysates, such as carboxylic acids, aldehydes and ketones. This is a true reflection of the oxidative conditions during WO pretreatment.
Including a Model of Visual Processing With a Cognitive Architecture to Model a Simple Teleoperation Task
Authors: Ritter Frank E. , Kukreja Urmila , Amant Robert St.
Published: August 2007

This article describes progress in providing user models with sufficient visual information and motor control to perform teleoperation with an unmodified, physically realized robot. User models that are built by extending cognitive models to interact directly with interfaces can provide a theoretical basis for predicting user behavior. These models can help in summarizing and explaining usability issues in domains for which conventional user testing is too time consuming, too demanding of other resources, or too dynamic for static models. The user model consists of an ACT-R cognitive model and the SegMan image-processing and interpretation system. ACT-R supports directing simple rover navigation and response-time predictions. SegMan supports interpreting many aspects of HCI interfaces and can now interpret simple aspects of video used in simple navigation tasks and can generate key presses and mouse actions directly. Processing limited amounts of an image as a human fovea helped make this system work in real time. A study in robot teleoperation provides evidence that the cognitive and perceptual-motor model approximates human behavior (based on comparison of task time, learning behavior, and mouse actions) in a simple navigation task. This work demonstrates how user modeling techniques are maturing to the extent that they can be used for assessing interfaces for dynamic tasks by predicting performance during teleoperation, a common human-robot interaction task.
Reality and Fiction Cues in Medical Patient Simulation: An Interview Study with Anesthesiologists
Authors: Dieckmann Peter , Manser Tanja , Wehner Theo , Rall Marcus
Published: August 2007

Following the framework of ecological validity, and taking into account the social character of simulation, we investigated how six anesthesiologists each experienced three patient simulation scenarios. Using content analysis, we describe factors mentioned in the 18 half-structured interviews that were relevant for the perceived realism of the scenarios: overall impression and medical plausibility, participants' own actions, role play of the simulator team, workload, technical aspects, group dynamics, and anticipations. Further, we describe the circumstances under which these relevant elements were experienced as fiction cues (emphasizing differences between scenarios and clinical cases) or as reality cues (emphasizing similarities between scenarios and clinical cases). The experience of the scenarios among the anesthesiologists was dynamic over time and differed among participants. Considering the described elements and their character as either fiction or reality cues improves the understanding of the still-unanswered question of why simulators and simulations “work.” Simulators and simulations help in designing, optimizing, conducting, and analyzing patient simulation scenarios in a goal-oriented fashion.
Contextual Control Modes During an Airline Rescheduling Task
Authors: Feigh Karen M. , Pritchett Amy R. , Denq Tina W. , Jacko Julie A.
Published: August 2007

Tasks in complex, dynamic environments typically require many activities, including information seeking, communicating, coordinating, judging, decision making, and implementing decisions. In this paper, we examine how humans choose and organize these activities using a range of contextual control modes (CCMs) as described by Hollnagel: strategic, tactical, opportunistic, and scrambled. These CCMs are viewed as responses to contextual features, such as time limits and task demand. We specifically examine contextual control modes during an airline schedule adherence task and evaluate potential measures of these tasks in a controlled experiment using student participants. In the first portion of the experiment, we varied the time limits and in the second, we introduced a sudden increase in task demand. Information-seeking behaviors and participant solutions were recorded. NASA TLX workload ratings and participant self-assessments of contextual control mode were assessed. Participants reported operating in and transitioning between different contextual control modes in response to time limits and task changes. CCMs did not correlate with TLX ratings of demand and effort but did correlate with TLX-frustration and TLX-performance ratings and with time limits. The results suggest that high performance may be achieved in different contextual control modes and that the design of support systems should aim to support multiple modes.
Intuition and Emotion in Bank Loan Officers' Credit Decisions
Authors: Lipshitz Raanan , Shulimovitz Nurit
Published: August 2007

Within the framework of judgment and decision making (JDM), considerable progress has been made in research on how intuitions and emotions affect decision making. Much of this research has been conducted in experimental settings. The present paper reports findings from a naturalistic decision making (NDM) study of how loan officers' so-called gut feelings (emotionally laden intuitions) affect their credit decisions. In-depth interviews with 14 loan officers in a large commercial bank in Israel revealed that they construed credit applications as both a financial transaction and an interpersonal interaction. As a consequence, they integrated “hard” financial data regarding the soundness of the application with “soft” impressions and gut feelings regarding the credibility of the loan applicant. In the reasoning of loan officers, gut feelings were regarded as more valid indicators of the worthiness of the application than were the relevant financial data. Although loan officers regarded their gut feelings as semiarticulate, ill-understood intuitions, these can be traced to observable specifiable cues from clients' behavior.
Fibroblast Growth Factor Receptors Cooperate to Regulate Neural Progenitor Properties in the Developing Midbrain and Hindbrain
Authors: Saarimäki-Vire Jonna , Peltopuro Paula , Lahti Laura , Naserke Thorsten , Blak Alexandra A. , Vogt Weisenhorn Daniela M. , Yu Kai , Ornitz David M. , Wurst Wolfgang , Partanen Juha
Published: August 2007

Fibroblast growth factors (FGFs) secreted from the midbrain–rhombomere 1 (r1) boundary instruct cell behavior in the surrounding neuroectoderm. For example, a combination of FGF and sonic hedgehog (SHH) can induce the development of the midbrain dopaminergic neurons, but the mechanisms behind the action and integration of these signals are unclear. We studied how FGF receptors (FGFRs) regulate cellular responses by analyzing midbrain–r1 development in mouse embryos, which carry different combinations of mutantFgfr1,Fgfr2, andFgfr3alleles. Our results show that the FGFRs act redundantly to support cell survival in the dorsal neuroectoderm, promote r1 tissue identity, and regulate the production of ventral neuronal populations, including midbrain dopaminergic neurons. The compoundFgfrmutants have apparently normal WNT/SHH signaling and neurogenic gene expression in the ventral midbrain, but the number of proliferative neural progenitors is reduced as a result of precocious neuronal differentiation. Our results suggest aSoxB1family member,Sox3, as a potential FGF-induced transcription factor promoting progenitor renewal. We propose a model for regulation of progenitor cell self-renewal and neuronal differentiation by combinatorial intercellular signals in the ventral midbrain.
DrosophilaOverexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities
Authors: Wang Cheng , Lu Ruifeng , Ouyang Xuezhi , Ho Michelle W. L. , Chia William , Yu Fengwei , Lim Kah-Leong
Published: August 2007

Mutations in the parkin gene are a predominant cause of familial parkinsonism. Although initially described as a recessive disorder, emerging evidence suggest that single parkin mutations alone may confer increased susceptibility to Parkinson's disease. To better understand the effects of parkin mutationsin vivo, we generated transgenicDrosophilaoverexpressing two human parkin missense mutants, R275W and G328E. Transgenic flies that overexpress R275W, but not wild-type or G328E, human parkin display an age-dependent degeneration of specific dopaminergic neuronal clusters and concomitant locomotor deficits that accelerate with age or in response to rotenone treatment. Furthermore, R275W mutant flies also exhibit prominent mitochondrial abnormalities in their flight muscles. Interestingly, these defects caused by the expression of human R275W parkin are highly similar to those triggered by the loss of endogenous parkin inparkinnull flies. Together, our results provide the firstin vivoevidence demonstrating that parkin R275W mutant expression mediates pathogenic outcomes and suggest the interesting possibility that select parkin mutations may directly exert neurotoxicityin vivo.
An Integrated Microcircuit Model of Attentional Processing in the Neocortex
Authors: Ardid Salva , Wang Xiao-Jing , Compte Albert
Published: August 2007

Selective attention is a fundamental cognitive function that uses top-down signals to orient and prioritize information processing in the brain. Single-cell recordings from behaving monkeys have revealed a number of attention-induced effects on sensory neurons, and have given rise to contrasting viewpoints about the neural underpinning of attentive processing. Moreover, there is evidence that attentional signals originate from the prefrontoparietal working memory network, but precisely how a source area of attention interacts with a sensory system remains unclear. To address these questions, we investigated a biophysically based network model of spiking neurons composed of a reciprocally connected loop of two (sensory and working memory) networks. We found that a wide variety of physiological phenomena induced by selective attention arise naturally in such a system. In particular, our work demonstrates a neural circuit that instantiates the “feature-similarity gain modulation principle,” according to which the attentional gain effect on sensory neuronal responses is a graded function of the difference between the attended feature and the preferred feature of the neuron, independent of the stimulus. Furthermore, our model identifies key circuit mechanisms that underlie feature-similarity gain modulation, multiplicative scaling of tuning curve, and biased competition, and provide specific testable predictions. These results offer a synthetic account of the diverse attentional effects, suggesting a canonical neural circuit for feature-based attentional processing in the cortex.
Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents
Authors: Khorkova Olga , Golowasch Jorge
Published: August 2007

Electrical activity in identical neurons across individuals is often remarkably similar and stable over long periods. However, the ionic currents that determine the electrical activity of these neurons show wide animal-to-animal amplitude variability. This seemingly random variability of individual current amplitudes may obscure mechanisms that globally reduce variability and that contribute to the generation of similar neuronal output. One such mechanism could be the coordinated regulation of ionic current expression. Studying identified neurons of theCancer borealispyloric network, we discovered that the removal of neuromodulatory input to this network (decentralization) was accompanied by the loss of the coordinated regulation of ionic current levels. Additionally, decentralization induced large changes in the levels of several ionic currents. The loss of coregulation and the changes in current levels were prevented by continuous exogenous application of proctolin, an endogenous neuromodulatory peptide, to the pyloric network. This peptide does not exert fast regulatory actions on any of the currents affected by decentralization. We conclude that neuromodulatory inputs to the pyloric network have a novel role in the regulation of ionic current expression. They can control, over the long term, the coordinated expression of multiple voltage-gated ionic currents that they do not acutely modulate. Our results suggest that current coregulation places constraints on neuronal intrinsic plasticity and the ability of a network to respond to perturbations. The loss of conductance coregulation may be a mechanism to facilitate the recovery of function.
Functional Properties of Neurons Derived fromIn VitroReprogrammed Postnatal Astroglia
Authors: Berninger Benedikt , Costa Marcos R. , Koch Ursula , Schroeder Timm , Sutor Bernd , Grothe Benedikt , Götz Magdalena
Published: August 2007

With the exception of astroglia-like cells in the neurogenic niches of the telencephalic subependymal or hippocampal subgranular zone, astroglia in all other regions of the adult mouse brain do not normally generate neurons. Previous studies have shown, however, that early postnatal cortical astroglia in culture can be reprogrammed to adopt a neuronal fate after forced expression of Pax6, a transcription factor (TF) required for proper neuronal specification during embryonic corticogenesis. Here we show that also the proneural genes neurogenin-2 and Mash1 (mammalian achaete schute homolog 1) possess the ability to reprogram astroglial cells from early postnatal cerebral cortex. By means of time-lapse imaging of green fluorescent astroglia, we provide direct evidence that it is indeed cells with astroglial characteristics that give rise to neurons. Using patch-clamp recordings in culture, we show that astroglia-derived neurons acquire active conductances and are capable of firing action potentials, thus displaying hallmarks of true neurons. However, independent of the TF used for reprogramming, astroglia-derived neurons appear to mature more slowly compared with embryonic-born neurons and fail to generate a functional presynaptic output within the culturing period. However, when cocultured with embryonic cortical neurons, astroglia-derived neurons receive synaptic input, demonstrating that they are competent of establishing a functional postsynaptic compartment. Our data demonstrate that single TFs are capable of inducing a remarkable functional reprogramming of astroglia toward a truly neuronal identity.
Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity
Authors: Griffin Robert S. , Costigan Michael , Brenner Gary J. , Him Eddie Ma Chi , Scholz Joachim , Moss Andrew , Allchorne Andrew J. , Stahl Gregory L. , Woolf Clifford J.
Published: August 2007

Microarray expression profiles reveal substantial changes in gene expression in the ipsilateral dorsal horn of the spinal cord in response to three peripheral nerve injury models of neuropathic pain. However, only 54 of the 612 regulated genes are commonly expressed across all the neuropathic pain models. Many of the commonly regulated transcripts are immune related and include the complement components C1q, C3, and C4, which we find are expressed only by microglia. C1q and C4 are, moreover, the most strongly regulated of all 612 regulated genes. In addition, we find that the terminal complement component C5 and the C5a receptor (C5aR) are upregulated in spinal microglia after peripheral nerve injury. Mice null for C5 had reduced neuropathic pain sensitivity, excluding C3a as a pain effector. C6-deficient rats, which cannot form the membrane attack complex, have a normal neuropathic pain phenotype. However, C5a applied intrathecally produces a dose-dependent, slow-onset cold pain in naive animals. Furthermore, a C5aR peptide antagonist reduces cold allodynia in neuropathic pain models. We conclude that induction of the complement cascade in spinal cord microglia after peripheral nerve injury contributes to neuropathic pain through the release and action of the C5a anaphylatoxin peptide.
Pallidal Neuron Activity Increases during Sensory Relay through Thalamus in a Songbird Circuit Essential for Learning
Authors: Person Abigail L. , Perkel David J.
Published: August 2007

Disinhibition of the thalamus remains the primary model of information transfer between the basal ganglia and the cortex. Yet in apparent conflict with this model, the globus pallidus, a GABAergic basal ganglia output structure, often exhibits marked increases in firing rate during movement. To investigate the translation of pallidal activity and its relay through the thalamus, we explored a basal ganglia–thalamic pathway essential for song learning in songbirds. We found that single units in the thalamic nucleus DLM of urethane-anesthetized adult male zebra finches responded selectively to playback of the bird's own song, like neurons in its upstream and downstream nuclei. Because the pallidal input to these neurons forms giant calyx-like synapses, we were able to record extracellular signals from these presynaptic terminals as well. Pallidal units were distinctly excited by song playback, suggesting an increase in GABAergic transmission in the thalamus during sensory processing. However, this overall increased firing rate was phasic, punctuated by rapid decelerations in firing rate. In several cases, we were able to record presynaptic and postsynaptic units simultaneously. Correlating the presynaptic and postsynaptic activity, we found that disinhibition of thalamus may entail pallidal firing rate decelerations rather than simple long pauses in spontaneous activity, as has long been assumed.
From Numerosity to Ordinal Rank: A Gain-Field Model of Serial Order Representation in Cortical Working Memory
Authors: Botvinick Matthew , Watanabe Takamitsu
Published: August 2007

Encoding the serial order of events is an essential function of working memory, but one whose neural basis is not yet well understood. In the present work, we advance a new model of how serial order is represented in working memory. Our approach is predicated on three key findings from neurophysiological research: (1) prefrontal neurons that code conjunctively for item and order, (2) parietal neurons that represent count information through a graded and compressive code, and (3) multiplicative gain modulation as a mechanism for information integration. We used an artificial neural network, integrating across these three findings, to simulate human immediate serial recall performance. The model reproduced a core set of benchmark empirical findings, including primacy and recency effects, transposition gradients, effects of interitem similarity, and developmental effects. The model moves beyond previous accounts by bridging between neuroscientific findings and detailed behavioral data, and gives rise to several testable predictions.
Disease Gene Candidates Revealed by Expression Profiling of Retinal Ganglion Cell Development
Authors: Wang Jack T. , Kunzevitzky Noelia J. , Dugas Jason C. , Cameron Meghan , Barres Ben A. , Goldberg Jeffrey L.
Published: August 2007

To what extent do postmitotic neurons regulate gene expression during development or after injury? We took advantage of our ability to highly purify retinal ganglion cells (RGCs) to profile their pattern of gene expression at 13 ages from embryonic day 17 through postnatal day 21. We found that a large proportion of RGC genes are regulated dramatically throughout their postmitotic development, although the genes regulated through developmentin vivogenerally are not regulated similarly by RGCs allowed to agein vitro. Interestingly, we found that genes regulated by developing RGCs are not generally correlated with genes regulated in RGCs stimulated to regenerate their axons. We unexpectedly found three genes associated with glaucoma, optineurin, cochlin, and CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), previously thought to be primarily expressed in the trabecular meshwork, which are highly expressed by RGCs and regulated through their development. We also identified several other RGC genes that are encoded by loci linked to glaucoma. The expression of glaucoma-linked genes by RGCs suggests that, at least in some cases, RGCs may be directly involved in glaucoma pathogenesis rather than indirectly involved in response to increased intraocular pressure. Consistent with this hypothesis, we found that CYP1B1 overexpression potentiates RGC survival.
Local and Global Effects ofIhDistribution in Dendrites of Mammalian Neurons
Authors: Angelo Kamilla , London Michael , Christensen Soren R. , Häusser Michael
Published: August 2007

The hyperpolarization-activated cation currentIhexhibits a steep gradient of channel density in dendrites of pyramidal neurons, which is associated with location independence of temporal summation of EPSPs at the soma. In striking contrast, here we show by using dendritic patch-clamp recordings that in cerebellar Purkinje cells, the principal neurons of the cerebellar cortex,Ihexhibits a uniform dendritic density, while location independence of EPSP summation is observed. Using compartmental modeling in realistic and simplified dendritic geometries, we demonstrate that the dendritic distribution ofIhonly weakly affects the degree of temporal summation at the soma, while having an impact at the dendritic input location. We further analyze the effect ofIhon temporal summation using cable theory and derive bounds for temporal summation for any spatial distribution ofIh. We show that the total number ofIhchannels, not their distribution, governs the degree of temporal summation of EPSPs. Our findings explain the effect ofIhon EPSP shape and temporal summation, and suggest that neurons are provided with two independent degrees of freedom for different functions: the total amount ofIh(controlling the degree of temporal summation of dendritic inputs at the soma) and the dendritic spatial distribution ofIh(regulating local dendritic processing).