bluuebunny/crossref_metadata_2025 huggingface dataset:
Fine-tuning of immune responses by SLAM-related receptors
Authors: Bhat Rauf , Eissmann Philipp , Endt Johanna , Hoffmann Sabrina , Watzl Carsten
Published: December 2005

The modulation of antigen receptor signals is important for a productive immune response. The main function of the recently identified members of the signaling lymphocyte activating molecule (SLAM)-related receptors (SRR) is the fine-tuning of immune cell activation. Disruption of SRR function is the cause for severe immune disorders such as X-linked lymphoproliferative syndrome (XLP), where XLP patients carry a mutation in SLAM-associated protein (SAP) (SH2D1A), an important adaptor molecule for the signal transduction of SRR. Recent data also suggest that SRR may play a role in autoimmune diseases and the function of hematopoietic stem and progenitor cells. Here, we review the current understanding of SRR function in different immune cells.
Application of the TIMI Risk Score for Unstable Angina and Non‐ST Elevation Acute Coronary Syndrome to an Unselected Emergency Department Chest Pain Population
Authors: Pollack Charles V. , Sites Frank D. , Shofer Frances S. , Sease Keara L. , Hollander Judd E.
Published: December 2005

Objectives:
Patients presenting with chest pain or related symptoms suggestive of myocardial ischemia, without ST‐segment elevation (NSTE) on their presenting electrocardiograms, often present a diagnostic challenge in the emergency department (ED). Prompt and accurate risk stratification to identify those patients with NSTE chest pain who are at highest risk for adverse events is essential, however, to optimal management. Although validated and used frequently in patients already enrolled in acute coronary syndrome trials, the Thrombolysis in Myocardial Infarction (TIMI) risk score never has been examined for its value in risk stratification in an all‐comers, non–trial‐based ED chest pain population.

Methods:
An analysis of an ED‐based prospective observational cohort study was conducted in 3,929 adult patients presenting with chest pain syndrome and warranting evaluation with an electrocardiogram. These patients had TIMI risk scores determined at ED presentation. The main outcome was the composite of death, acute myocardial infarction (MI), and revascularization within 30 days.

Results:
The TIMI risk score at ED presentation successfully risk‐stratified this unselected cohort of chest pain patients with respect to 30‐day adverse outcome, with a range from 2.1%, with a score of 0, to 100%, with a score of 7. The highest correlation of an individual TIMI risk indicator to adverse outcome was for elevated cardiac biomarker at admission. Overall, the score had similar performance characteristics to that seen when applied to other databases of patients enrolled in clinical trials and registries using a 14‐day end point.

Conclusions:
The TIMI risk score may be a useful tool for risk stratification of ED patients with chest pain syndrome.
Out‐of‐hospital Auricular Acupressure in Elder Patients with Hip Fracture: A Randomized Double‐Blinded Trial
Authors: Barker Renate , Kober Alexander , Hoerauf Klaus , Latzke Daniela , Adel Sharam , Kain Zeev N. , Wang Shu‐Ming
Published: December 2005

Objectives: Auricular acupressure is known to decrease the level of anxiety in patients during ambulance transport. The purpose of this randomized, double‐blind, sham control study was to determine whether auricular acupressure can decrease not only the level of anxiety but also the level of pain in a group of elder patients with acute hip fracture.

Methods: With the assistance of the Vienna Red Cross, 38 patients with acute hip fracture were enrolled into this study. Patients were randomized into two study groups: the true intervention group and the sham control group. Subjects in the true intervention group (n= 18) received bilateral auricular acupressure at three auricular acupressure points for hip pain. Patients in the sham group (n= 20) received bilateral auricular acupressure at sham points. Baseline demographic information, anxiety level, pain level, blood pressure, and heart rate were obtained before the administration of the appropriate acupressure intervention. The level of anxiety, level of pain, hemodynamic profiles, and level of satisfaction were reassessed once the patients arrived at the hospital.

Results: Patients in the true intervention groups had less pain (F = 28, p = 0.0001) and anxiety (F = 4.3, p = 0.018) and lower heart rate (F = 18, p = 0.0001) on arrival at the hospital than did patients in the sham control group. As a result, the patients in the true intervention group reported higher satisfaction in the care they received during the ride to the hospital.

Conclusions: The authors encourage physicians, health care providers, and emergency rescuers to learn this easy, noninvasive, and inexpensive technique for its effects in decreasing anxiety and pain during emergency transportation.
Lazaroid U‐83836E Improves Tolerance to Hemorrhagic Shock and Limb Ischemia and Reperfusion in Rats and Increases Cardiac Heat Shock Protein 72
Authors: Labruto Fausto , Song Xiaoliang , Valen Guro , Vaage Jarle
Published: December 2005

Objectives:Aminosteroids of the lazaroid type protect organs from ischemia–reperfusion damage. The authors hypothesized that lazaroid U‐83836E may be beneficial in a shock model with hemorrhage combined with limb ischemia. Furthermore, the authors hypothesized that lazaroids induce expression of heat shock proteins (HSPs) of the 72‐kDa family.Methods:Rats were divided into two groups (lazaroid and control groups,n= 8 each) and pretreated with the lazaroid U‐83836E (5 mg/kg) or with vehicle intraperitoneally at 12 and 24 hours before experiments. At the time of the experiment, rats were anesthetized, and the femoral artery of each rat was cannulated. After 20 minutes of stabilization, blood was shed from each rat to bring its mean arterial pressure to 24–28 mmHg for 2 hours. Bilateral tourniquets were tightened proximally on the rat thighs during those 2 hours and then released. Shed blood plus equal amounts of Ringer acetate then were infused to restore normal blood pressure, followed by a continuous infusion of Ringer acetate, the rate of which was regulated to maintain blood pressure, until 30 minutes after start of resuscitation. Fluid resuscitation was stopped, and rats were observed for another 3.5 hours. At the end of the observation period, the rats' hearts were collected for immunoblot analysis of HSP72. Additional hearts were collected from similarly pretreated rats not undergoing the episode of hemorrhagic shock and fluid resuscitation.Results:Pretreatment with U‐83836E improved mean arterial blood pressure after hemorrhagic shock and fluid resuscitation (p = 0.02), combined with improvements in acid–base balance (improved base excess and standard bicarbonate; p = 0.02 and p = 0.01, respectively). Western blot of cardiac protein extracts demonstrated that lazaroid pretreatment increased expression of HSP72.Conclusions:Pretreatment with the lazaroid U‐83836E improved outcome markers in this hemorrhagic shock model. The observed protection may be caused by increased expression of HSP72.
Description and Evaluation of a Pilot Physician‐directed Emergency Medical Services Diversion Control Program
Authors: Shah Manish N. , Fairbanks Rollin J. , Maddow Charles L. , Lerner E. Brooke , Syrett James I. , Davis Eric A. , Schneider Sandra M.
Published: December 2005

Objectives:

To describe the characteristics and feasibility of a physician‐directed ambulance destination‐control program to reduce emergency department (ED) overcrowding, as measured by hospital ambulance diversion hours.

Methods:

This controlled trial took place in Rochester, New York and included a university hospital and a university‐affiliated community hospital. During July 2003, emergency medical services (EMS) providers were asked to call an EMS destination‐control physician for patients requesting transport to either hospital. The destination‐control physician determined the optimal patient destination by using patient and system variables as well as EMS providers' and patients' input. Program process measures were evaluated to characterize the program. Administrative data were reviewed to compare system characteristics between the intervention program month and a control month.

Results:

During the intervention month, 2,708 patients were transported to the participating hospitals. EMS providers contacted the destination‐control physician for 1,866 (69%) patients. The original destination was changed for 253 (14%) patients. Reasons for redirecting patients included system needs, patient needs, physician affiliation, recent ED or hospital care, patient wishes, and primary care physician wishes. During the intervention month, EMS diversion decreased 190 (41%) hours at the university hospital and 62 (61%) hours at the community hospital, as compared with the control month.

Conclusions:

A voluntary, physician‐directed destination‐control program that directs EMS units to the ED most able to provide appropriate and timely care is feasible. Patients were redirected to maximize continuity of care and optimally use available emergency health care resources. This type of program may be effective in reducing overcrowding.
Influence of Electromagnetic Fields on Function of Automated External Defibrillators
Authors: Fleischhackl Roman , Singer Florian , Nitsche Wolfgang , Gamperl Guenther , Roessler Bernhard , Arrich Jasmin , Fleischhackl Sabine , Losert Heidrun , Sterz Fritz , Mittlboeck Martina , Hoerauf Klaus
Published: December 2005

Objectives:
In this study, the authors tested whether electromagnetic interference (EMI) is able to impair correct electrocardiogram analysis and produce false‐positive shock advice from automated external defibrillators (AEDs) when the true rhythm is sinus.

Methods:
Nineteen healthy subjects were used to test five AEDs available on the Austrian market in a prospective, open, and sequence‐randomized study. The primary outcome variable was the absolute number of shocks advised in the presence of EMI. The secondary outcome was the number of impaired analyses caused by incorrectly detected patient movements or electrode failure.

Results:
Of 760 tests run, 18 (2.37%) cases of false‐positive results occurred, and two of five AEDs recommended shocks in the presence of sinus rhythm. Of 760 tests run, no electrode failures occurred. There were 27 occurrences (3.55%) of motion detected by an AED in the presence of strong electromagnetic fields.

Conclusions:
AED models differ in their response to EMI; it may be useful to consider specific safety requirements for areas with such fields present. Working personnel and emergency medical services staff should be informed about potential risks and the possible need for patient evacuation before AEDs are attached and shock recommendations are followed.
Accuracy of Mild Traumatic Brain Injury Case Ascertainment Using ICD‐9 Codes
Authors: Bazarian Jeffrey J. , Veazie Peter , Mookerjee Sohug , Lerner E. Brooke
Published: December 2005

Objectives:

To determine the accuracy of mild traumatic brain injury (TBI) case ascertainment using International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐CM) codes proposed by the Centers for Disease Control and Prevention (CDC) in a 2003 Report to Congress.

Methods:

This was a prospective cohort study of all patients presenting to an urban academic emergency department (ED) over six months in 2003. A real‐time clinical assessment of mild TBI was compared with the ICD‐9 codes assigned after ED or hospital discharge for a determination of sensitivity and specificity.

Results:

Of the 35,096 patients presenting to the ED, 516 had clinically defined mild TBI and 1,000 were assigned one or more of the mild TBI ICD‐9 codes proposed by the CDC. The sensitivity of these codes was 45.9% (95% confidence interval [95% CI] = 41.3% to 50.2%) with a specificity of 97.8% (95% CI = 97.6% to 97.9%).

Conclusions:

The identification of mild TBI patients using retrospectively assigned ICD‐9 codes appears to be inaccurate. These codes are associated with a significant number of false‐positive and false‐negative code assignments. Mild TBI incidence and prevalence estimates using these codes should be interpreted with caution. ICD‐9 codes should not replace a clinical assessment for mild TBI when accurate case ascertainment is required.
A Test to Detect Chest Tube Kinking
Authors: Adame Norberto , Horwood Bruce T. , Caruso Daniel , Wallace Ted , Velasco Louis
Published: December 2005

Objectives:
To determine whether the Mac‐technique test can detect kinking of the chest tube upon thoracostomy tube placement.

Methods:
This was a prospective observational study that was conducted October 2000 through October 2001 in an urban Level 1 trauma center. There were 103 consecutive nonrandomized adult trauma patients who required immediate tube thoracostomy during their initial resuscitation who were entered into the study. The Mac‐technique test was performed during standard tube thoracostomy insertion to the appropriate depth. The test involved grasping the external portion of the thoracostomy tube, turning it clockwise 180°, and then releasing the tube. If the tube spontaneously spun back to its original position, the test was considered positive, and the tube was considered kinked. If the tube did not spontaneously spin back and stayed in position upon release, the test was considered negative. Regardless of the results of this test, the tube was secured, and a postprocedure chest radiograph was obtained. The criterion standard for determining a kinked chest tube was its appearance on this chest radiograph.

Results:
A total of 103 chest tubes were placed by using the Mac‐technique test. The test was positive in eight placements; four tubes were kinked on chest radiograph. The Mac‐technique test was negative in 95 placements; four tubes were kinked on chest radiograph. The Mac technique had a sensitivity of 50% (95% confidence interval [CI] = 15.7% to 84.3%), a specificity of 95.8% (95% CI = 89.6% to 98.8%), a positive likelihood ratio of 11.9, a negative likelihood ratio of 0.52, and an odds ratio using Yates correction of 20.3 (95% CI = 4.1 to 102.1).

Conclusions:
On the basis of this study, a positive Mac‐technique test is useful to detect chest tubes that are likely to be kinked after insertion and before securing.
Prehospital 12‐lead Electrocardiography Impact on Acute Myocardial Infarction Treatment Times and Mortality: A Systematic Review
Authors: Morrison Laurie J. , Brooks Steven , Sawadsky Bruce , McDonald Andrew , Verbeek P. Richard
Published: December 2005

Objectives:
Prehospital 12‐lead electrocardiogram (PHECG) interpretation and advance emergency department (ED) notification may improve time‐to‐treatment intervals for a variety of treatment strategies to improve outcome in acute myocardial infarction. Despite consensus guidelines recommending this intervention, few emergency medical services (EMS) employ this. The authors systematically reviewed the literature to report whether mortality or treatment time intervals improved when compared with standard care.

Methods:
The authors used the Cochrane strategy to search MEDLINE, EMBASE, Current Contents, Dissertation Abstracts, Cochrane Library, and Index of Scientific and Technical Proceedings. Bibliographies and grant‐agency Websites were reviewed, and primary investigators and industry were contacted for published and unpublished studies. Inclusion criteria included PHECG and advance ED notification versus standard EMS care; controlled trials; English only; and evaluation of treatment time intervals, all‐cause mortality, or both. Study selection was hierarchical, blinded, and independent. Agreement at each level of review was evaluated by using a kappa statistic. Study quality was measured with a validated scale and was interpreted by two independent reviewers.

Results:
A total of 1,283 citations were identified, and five studies met the inclusion criteria. The weighted kappa for selection was 0.61 (standard error [SE], 0.045) for titles, 0.63 (SE, 0.051) for abstracts, and 0.79 (SE, 0.146) for full articles. Mean study quality measures by two independent reviewers were 6.0/15 and 5.5/15 (correlation coefficient, 0.85; p = 0.06). PHECG and advance ED notification increased the weighted mean on‐scene time by 1.2 minutes (95% confidence interval [95% CI] =−0.84 to 3.2). The weighted mean door‐to‐needle interval was shortened by 36.1 minutes (95% CI = 9.3 to 63.0: range of means, 22–48 minutes vs. 50–97 minutes). One study reported all‐cause mortality, with a statistically nonsignificant reduction from 15.6% to 8.4%.

Conclusions:
For patients with AMI, the literature would suggest that PHECG and advanced ED notification reduces in hospital time to fibrinolysis. One controlled trial found no difference in mortality with this out‐of‐hospital intervention.
Simulation‐based Morbidity and Mortality Conference: New Technologies Augmenting Traditional Case‐based Presentations
Authors: Vozenilek John , Wang Ernest , Kharasch Morris , Anderson Britney , Kalaria Amit
Published: December 2005

The authors describe the use of a high‐fidelity simulation laboratory to re‐create a patient encounter for the purposes of enhancing a morbidity and mortality conference. The use of two separate technologies were enlisted: a METI high‐fidelity patient simulator to re‐create the case in a more lifelike fashion, and an audience response system to collect clinical impressions throughout the case presentation and survey data at the end of the presentation. The re‐creation of the patient encounter with all relevant physical findings displayed in high fidelity, with relevant laboratory data, nursing notes, and imaging as it occurred in the actual case, provides a more engaging format for the resident–learner. This technological enhancement was deployed at a morbidity and mortality conference, and the authors report the impressions collected via the audience response system. Guidelines for those who wish to re‐create this type of educational experience are presented in the discussion.
Impact of Vascular Endothelial Growth Factor-A Expression, Thrombospondin-2 Expression, and Microvessel Density on the Treatment Effect of Bevacizumab in Metastatic Colorectal Cancer
Authors: Jubb Adrian M. , Hurwitz Herbert I. , Bai Wei , Holmgren Eric B. , Tobin Patti , Guerrero A. Steven , Kabbinavar Fairooz , Holden Scott N. , Novotny William F. , Frantz Gretchen D. , Hillan Kenneth J. , Koeppen Hartmut
Published: December 2005

Purpose

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab.

Patients and Methods

In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizumab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. MVD was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses.

Results

In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22. VEGF or THBS-2 expression and MVD were not significant prognostic factors.

Conclusion

These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD.
Postoperative Surveillance in Patients With Colorectal Cancer Who Have Undergone Curative Resection: A Prospective, Multicenter, Randomized, Controlled Trial
Authors: Rodríguez-Moranta Francisco , Saló Joan , Arcusa Àngels , Boadas Jaume , Piñol Virgínia , Bessa Xavier , Batiste-Alentorn Eduard , Lacy Antonio M. , Delgado Salvadora , Maurel Joan , Piqué Josep M. , Castells Antoni
Published: December 2005

Purpose

Although systematic postoperative surveillance of patients with colorectal cancer has been demonstrated to improve survival, it remains unknown whether a more intensive strategy provides any significant advantage. This prospective, multicenter, randomized, controlled trial was aimed at comparing the efficacy of two different surveillance strategies in terms of both survival and recurrence resectability.

Patients and Methods

Patients with stage II or III colorectal cancer were allocated randomly to either a simple surveillance strategy including clinical evaluation and serum carcinoembryonic antigen monitoring, or an intensive strategy in which abdominal computed tomography or ultrasonography, chest radiograph, and colonoscopy were added.

Results

A total of 259 patients were included: 132 were observed according to the simple strategy and 127 were observed according to the intensive strategy. Both groups were similar with respect to baseline characteristics and rate and type of tumor recurrence. After a median follow-up of 48 months, there was no difference in the probability of overall survival in the whole series (hazard ratio [HR] = 0.87; 95% CI, 0.49 to 1.54; P = .62). However, the intensive strategy was associated with higher overall survival in patients with stage II tumors (HR = 0.34; 95% CI, 0.12 to 0.98; P = .045) and in those with rectal lesions (HR = 0.09; 95% CI, 0.01 to 0.81; P = .03), mainly due to higher rate of resectability for recurrent tumors. Colonoscopy was responsible for the detection of the highest proportion (44%) of resectable tumor recurrence in the intensive arm.

Conclusion

A more intensive surveillance strategy improves the prognosis of patients with stage II colorectal cancer or those with rectal tumors. Inclusion of regular performance of colonoscopy seems justified up to the fifth year of follow-up, at least.
Similar Outcomes Between African American and Non–African American Patients With Extensive-Stage Small-Cell Lung Carcinoma: Report From the Cancer and Leukemia Group B
Authors: Blackstock A. William , Herndon James E. , Paskett Electra D. , Miller Antonius A. , Lathan Christopher , Niell Harvey B. , Socinski Mark A. , Vokes Everett E. , Green Mark R.
Published: December 2005

Purpose

Among patients with small-cell lung carcinoma, African Americans have lower survival rates than non–African Americans. We investigated whether the disparity in survival would persist when patients were treated with similar therapies (ie, phase II/III Cancer and Leukemia Group B [CALGB] trials).

Patients and Methods

We assessed 995 patients (928 non–African American and 67 African American) receiving chemotherapy in CALGB studies for extensive-stage small-cell lung cancer (ES-SCLC). Clinical and demographic characteristics, treatment received, and survival data were obtained from the CALGB database. The Cox proportional hazards model was used to assess the effect of race/ethnicity on survival after adjustment for other known prognostic factors. All statistical tests were two sided.

Results

The unadjusted survival distribution of African American patients was not significantly different from that of non–African American patients; median survival was 11.5 months (95% CI, 9.4 to 13.4 months) for African American patients versus 9.9 months (95% CI, 9.6 to 10.3 months) for non–African American patients. Multivariable adjustment for the effect of treatment arm, histology, and metastatic site at presentation did not alter the outcome for African American patients. Survival was similar even though African American patients were more likely to have a poorer performance status, present with significant weight loss, and be Medicaid recipients (20% v 6%), which is an indicator of lower socioeconomic status.

Conclusion

African American patients tended to present with prognostic features associated with a worse survival. However, when offered equivalent therapy, the outcome for African American patients was the same as that observed for non–African American patients.
The Effect of Race on Invasive Staging and Surgery in Non–Small-Cell Lung Cancer
Authors: Lathan Christopher S. , Neville Bridget A. , Earle Craig C.
Published: December 2005

Purpose

Black patients with early-stage non–small-cell lung cancer (NSCLC) have worse overall survival than white patients. Decreased likelihood of resection has been implicated. To isolate the effect of decision making from access to care, we used receipt of surgical staging as a proxy for access and willingness to undergo invasive procedures, and examined treatments and outcomes by race.

Patients and Methods

We examined registry and claims data of Medicare-eligible patients with nonmetastatic NSCLC in areas monitored by the Surveillance, Epidemiology, and End Results program from 1991 to 2001. Patients who obtained invasive staging, defined as bronchoscopy, mediastinoscopy, or thoracoscopy, were included. Logistic regression and Cox modeling calculated the odds of having staging and surgery, and survival outcomes.

Results

A total of 14,224 patients underwent staging, and 6,972 had surgery for lung cancer. Black patients were less likely to undergo staging (odds ratio [OR] = 0.75; 95% CI, 0.67 to 0.83), and once staged, were still less likely to have surgery than whites (OR = 0.55; 95% CI, 0.47 to 0.64). Survival for blacks and whites was equivalent after resection (hazard ratio = 1.02; P = .06). Staged black patients were less likely to receive a recommendation for surgery when it was not clearly contraindicated (67.0% v 71.4%; P < .05), and were more likely to decline surgery (3.4% v 2.0%; P < .05).

Conclusion

Black patients obtain surgery for lung cancer less often than whites, even after access to care has been demonstrated. They are more likely not to have surgery recommended, and more likely to refuse surgery. Additional research should focus on the physician-patient encounter as a potential source of racial disparities.
Tumor Necrosis Factor-α–Induced Protein 3 As a Putative Regulator of Nuclear Factor-κB–Mediated Resistance to O6-Alkylating Agents in Human Glioblastomas
Authors: Bredel Markus , Bredel Claudia , Juric Dejan , Duran George E. , Yu Ron X. , Harsh Griffith R. , Vogel Hannes , Recht Lawrence D. , Scheck Adrienne C. , Sikic Branimir I.
Published: December 2005

Purpose

Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas.

Methods

We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells.

Results

We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-κB (NF-κB), which included the persistent alterations of various NF-κB pathway elements. Tumor necrosis factor-α–induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-κB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-κB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022).

Conclusion

Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-κB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.
Centrosome destined to decay in starfish oocytes
Authors: Shirato Yukako , Tamura Miwa , Yoneda Mitsuki , Nemoto Shin-ichi
Published: December 2005

In contrast to the somatic cell cycle, duplication of the centrioles does not occur in the second meiotic cycle. Previous studies have revealed that in starfish each of the two centrosomes in fully-grown immature oocytes consists of two centrioles with different destinies: one survives and retains its reproductive capacity, and the other is lost after completion of meiosis. In this study, we investigated whether this heterogeneity of the meiotic centrioles is already determined before the re-initiation of meiosis. We prepared a small fragment of immature oocyte containing the four centrioles and fused it electrically with a mature egg in order to transfer two sets of the premeiotic centrioles into the mature cytoplasm. Two asters were present in this conjugate, and in each of them only a single centriole was detected by electron microscopy. In the first mitosis of the conjugate artificially activated without sperm, two division poles formed, each of which doubled in each subsequent round of mitosis. These results indicate that only two of the four premeiotic centrioles survived in the mature cytoplasm and that they retained their reproductive capacity, which suggests that the heterogeneity of the maternal centrioles is determined well before re-initiation of meiosis,and that some factor in the mature cytoplasm is responsible for suppressing the reproductive capacity of the centrioles destined to decay.
Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling
Authors: Ribes Vanessa , Wang Zengxin , Dollé Pascal , Niederreither Karen
Published: December 2005

Although retinoic acid (RA) has been implicated as one of the diffusible signals regulating forebrain development, patterning of the forebrain has not been analyzed in detail in knockout mouse mutants deficient in embryonic RA synthesis. We show that the retinaldehyde dehydrogenase 2 (RALDH2) enzyme is responsible for RA synthesis in the mouse craniofacial region and forebrain between the 8- and 15-somite stages. Raldh2-/- knockout embryos exhibit defective morphogenesis of various forebrain derivatives,including the ventral diencephalon, the optic and telencephalic vesicles. These defects are preceded by regionally decreased cell proliferation in the neuroepithelium, correlating with abnormally low D-cyclin gene expression. Increases in cell death also contribute to the morphological deficiencies at later stages. Molecular analyses reveal abnormally low levels of FGF signaling in the craniofacial region, and impaired sonic hedgehog signaling in the ventral diencephalon. Expression levels of several regulators of diencephalic,telencephalic and optic development therefore cannot be maintained. These results unveil crucial roles of RA during early mouse forebrain development,which may involve the regulation of the expansion of neural progenitor cells through a crosstalk with FGF and sonic hedgehog signaling pathways.
Hormonal regulation ofmummyis needed for apical extracellular matrix formation and epithelial morphogenesis inDrosophila
Authors: Tonning Anna , Helms Sigrun , Schwarz Heinz , Uv Anne E. , Moussian Bernard
Published: December 2005

Many epithelia produce apical extracellular matrices (aECM) that are crucial for organ morphogenesis or physiology. Apical ECM formation relies on coordinated synthesis and modification of constituting components, to enable their subcellular targeting and extracellular assembly into functional matrices. The exoskeleton of Drosophila, the cuticle, is a stratified aECM containing ordered chitin polysaccharide lamellae and proteinaceous layers, and is suited for studies of molecular functions needed for aECM assembly. Here, we show that Drosophila mummy (mmy) mutants display defects in epithelial organisation in conjunction with aberrant deposition of the cuticle and an apical matrix needed for tracheal tubulogenesis. We find that mmy encodes the UDP-N-acetylglucosamine pyrophosphorylase, which catalyses the production of UDP-N-acetylglucosamine,an obligate substrate for chitin synthases as well as for protein glycosylation and GPI-anchor formation. Consequently, in mmy mutants GlcNAc-groups including chitin are severely reduced and modification and subcellular localisation of proteins designated for extracellular space is defective. Moreover, mmy expression is selectively upregulated in epithelia at the time they actively deposit aECM, and is altered by the moulting hormone 20-Hydroxyecdysone, suggesting that mmy is part of a developmental genetic programme to promote aECM formation.
Shaping BMP morphogen gradients in theDrosophilaembryo and pupal wing
Authors: O'Connor Michael B. , Umulis David , Othmer Hans G. , Blair Seth S.
Published: December 2005

In the early Drosophila embryo, BMP-type ligands act as morphogens to suppress neural induction and to specify the formation of dorsal ectoderm and amnioserosa. Likewise, during pupal wing development, BMPs help to specify vein versus intervein cell fate. Here, we review recent data suggesting that these two processes use a related set of extracellular factors, positive feedback, and BMP heterodimer formation to achieve peak levels of signaling in spatially restricted patterns. Because these signaling pathway components are all conserved, these observations should shed light on how BMP signaling is modulated in vertebrate development.
Skewness Preference, Risk Aversion, and the Precedence Relations on Stochastic Changes
Authors: Chiu W. Henry
Published: December 2005

This paper provides a general choice-theoretic characterization of the trade-off between risk and skewness, whose importance in understanding risk-taking behavior is well documented in empirical studies. The condition under which the prudence measure (Kimball 1990) characterizes the strength of an individual’s downside-risk aversion against his own risk aversion is identified and interpreted in a unifying framework based on the concept of one stochastic dominant change preceding another and that of the desirability of a stochastic change. The framework is also shown to be useful for a better understanding of the Arrow-Pratt measure, the stronger Ross measure, and the coincidence of the characterizations of downside-risk aversion and prudence, as well as the relationship between stochastic dominances of different degrees.
Simple Models for Multiattribute Choice with Many Alternatives: When It Does and Does Not Pay to Face Trade-offs with Binary Attributes
Authors: Hogarth Robin M. , Karelaia Natalia
Published: December 2005

Given the difficulties people experience in making trade-offs, what are the consequences of using simple models that avoid trade-offs? We examine choices by such models in environments where “true” preferences are linear and attributes are characterized by binary attributes. A deterministic elimination-by-aspects (DEBA) model is highly effective over a range of conditions. When preferences are quite compensatory, however, a modified equal weighting (EW) model that uses DEBA to resolve ties is more effective. We explore the sensitivity of results to errors in using DEBA, to different distributions of alternatives, and to error in “true” preferences. Under the conditions examined here, the outcomes of these “boundedly rational” models are highly consistent with “rational” models that explicitly confront trade-offs. We emphasize the importance of binary attributes in reaching these conclusions.
Management Control for Market Transactions: The Relation Between Transaction Characteristics, Incomplete Contract Design, and Subsequent Performance
Authors: Anderson Shannon W. , Dekker Henri C.
Published: December 2005

Using an unusually comprehensive database on 858 transactions for information technology products and accompanying services, we study how close partners who are exposed to opportunistic hazards structure and control a significant transaction. We analyze data on the terms of contracting to determine whether transaction and supplier characteristics that generate opportunistic hazards are related to the formal management control structure. We also examine whether misalignment between transaction and supplier characteristics and the control structure is associated with ex post performance problems. Characteristics associated with hazards are found to be positively related to contract extensiveness. Factor analysis of the use of 24 contract terms reveals four groups of contract terms that are commonly used in combination. We interpret these factors as “dimensions of management control” and label them: assignment of rights, product and price, after-sales service, and legal recourse. Characteristics associated with hazards are positively related to the use of all four dimensions of management control, with different hazards associated with different controls. We then examine the relation between transaction characteristics and ex post transaction problems, demonstrating that even in the presence of mutually agreeable contracts, hazards remain. We conclude that costs of contracting are associated with increased use of contract terms on assignment of rights, after-sales service, and legal recourse. Finally, we present evidence that management control structures that are better aligned with transaction hazards mitigate subsequent performance problems, though at a nontrivial cost of contracting.
Sampling Bias of Hook-and-Line Gear Used to Capture Rainbow Trout in Gertrude Creek, Alaska
Authors: Hetrick Nicholas J. , Bromaghin Jeffrey F.
Published: December 2005

Hook-and-line gear is commonly used for monitoring the size and abundance of resident fish populations in southwest Alaska. The selectivity of the gear, however, may contribute to bias in the catch, making it difficult to detect changes in population structure over time. This study assessed the potential bias in sampling a population of rainbow trout Oncorhynchus mykiss with angling gear. A bidirectional weir was operated on Gertrude Creek from 1997 to 1999 to intercept the annual upstream spring migration of rainbow trout into the stream. Captured fish were measured and tagged to establish a population of marked individuals with a known length distribution above the weir. The marked population was then sampled with angling gear on three occasions during each of three summers. A variety of terminal tackle was used, and types were selected to maximize the catch of rainbow trout. Size selectivity was evaluated by use of an exact Kolmogorov–Smirnov (KS) test of the hypothesis that the length distribution of all marked fish was equivalent to that of the subset of marked fish recaptured by anglers during a single recapture event. Test results were not significant for any of the recapture events, providing strong evidence that length selectivity did not exist for fish within the size range of the marked population. An exact KS test was also used to test length distribution equality between the marked population and all fish captured during an angling event. All of these KS tests were significant, suggesting that the marked group was a size-biased subset of the rainbow trout population in the drainage. The results of this study support the use of angling gear as a potentially viable sampling method for monitoring the size composition of rainbow trout in small southwest Alaskan streams.
Pacific Rim Population Structure of Sockeye Salmon as Determined from Microsatellite Analysis
Authors: Beacham Terry D. , McIntosh Brenda , MacConnachie Cathy , Miller Kristina M. , Withler Ruth E. , Varnavskaya Natalia
Published: December 2005

The Pacific Rim population structure of sockeye salmon Oncorhynchus nerka was examined with a survey of microsatellite variation. Variation at 14 microsatellite loci was surveyed for over 48,000 sockeye salmon sampled from 299 localities ranging from the Columbia River to Japan. The value of the genetic differentiation index FST over all populations and loci was 0.097; individual locus values ranged from 0.038 to 0.154. Sockeye salmon from the Queen Charlotte Islands and the Columbia River displayed the least number of alleles relative to sockeye salmon from other regions in the Pacific Rim distribution of the species. Conversely, sockeye salmon displaying the greatest allelic diversity were observed in Southeast Alaska and the central coast of British Columbia. Sockeye salmon from these two regions displayed approximately 30% more alleles than did sockeye salmon from the Queen Charlotte Islands and the Columbia River. Sockeye salmon from Russia and western Alaska were, on average, less diverse than sockeye salmon from Southeast Alaska and more southerly locations in North America. A regional structuring of populations was generally observed among the sockeye salmon populations sampled, and populations were clustered within lakes and river drainages. At the Pacific Rim scale of population structure, there were two major groups of populations. The first group included populations from Russia, Bristol Bay, Kodiak Island, the Alsek River, and the Queen Charlotte Islands. The second group generally included populations from Southeast Alaska, British Columbia, and Washington. The distribution of microsatellite variation of sockeye salmon on a Pacific Rim basis reflected the origins of sockeye salmon radiating from refuges after the last glaciation period.
Optimizing First-Line Treatment Options for Patients with Advanced NSCLC
Authors: Wakelee Heather , Belani Chandra P.
Published: December 2005

Learning Objectives

After completing this course, the reader will be able to: Explain the clinical implications of large randomized trials evaluating chemotherapy combinations for patients with advanced NSCLC.Summarize the activity and toxicity of current chemotherapy regimens for the first-line treatment of advanced NSCLC.Describe regimens that have quality-of-life benefits in the treatment of NSCLC.Identify potential future standards of care for advanced disease based on recent research findings evaluating novel targeted agents.

Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane–platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane–gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.
Paradigm Shift in the Treatment of Head and Neck Cancer: The Role of Neoadjuvant Chemotherapy
Authors: Posner Marshall R.
Published: December 2005

Learning Objectives

After completing this course, the reader will be able to: Explain the need for chemotherapeutic treatment for patients with squamous cell carcinoma of the head and neck.Identify the role of neoadjuvant chemotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.Discuss results of randomized trials evaluating taxane-based neoadjuvant chemotherapy for patients with unresectable locally advanced squamous cell carcinoma of the head and neck.

Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com

Chemotherapy is an integral component of the management of patients with locally advanced head and neck cancer, though the optimal use of chemotherapy remains to be defined. The combination of a platinum agent and 5-fluorouracil has been used as the standard neoadjuvant treatment and has been shown to permit organ preservation in operable patients and improve long-term survival outcomes in operable and inoperable patients. Recently, the addition of a taxane, docetaxel or paclitaxel, to standard platinum plus 5-fluorouracil induction chemotherapy has been shown to further improve response rates and survival outcomes. Phase III data are emerging to support combinations of docetaxel or paclitaxel with a platinum plus 5-fluorouracil as a new, more effective and less toxic standard for neoadjuvant chemotherapy. Sequential treatment regimens, incorporating a combination of induction chemotherapy and chemoradiation, are also under study in efforts to further improve long-term survival outcomes. Induction regimens incorporating docetaxel or paclitaxel with a platinum plus 5-fluorouracil are under evaluation in this setting. Randomized trials comparing a sequential treatment approach with standard therapies are also being undertaken and will likely define a new treatment paradigm for patients with locally advanced head and neck cancer.
S
amuel's Checkers Player
Authors: Schaeffer Jonathan
Published: December 2005

Arthur Samuel's checkers‐playing program of the 1960s was a milestone in the history of computer science and artificial intelligence.
Perceptron
Authors: Haykin Simon
Published: December 2005

The perceptron is a neural network designed to simulate the ability of the brain to recognize and discriminate.
Computation, Formal Models of
Authors: Jagota Arun
Published: December 2005

This is the study of abstract machines that compute, and of what they compute. This is also a study that characterizes what problems can be computed in principle, and which of the computable problems can be computed in practice.
Real‐Valued Computation and Complexity
Authors: Cucker Felipe , Smale Steve
Published: December 2005

The theory of real‐valued computation and complexity deals with foundational aspects of scientific computation. Here the basic unit of information is the floating‐point number and a computational model whose basic unity of information is a real number reasonably captures this feature.
Dynamical Systems: Mathematics
Authors: Busemeyer Jerome R
Published: December 2005

Dynamical systems are mathematical models for describing how the state of a biological or an artificial system changes over time.