bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial
Authors: Gatzemeier Ulrich , Pluzanska Anna , Szczesna Aleksandra , Kaukel Eckhard , Roubec Jaromir , De Rosa Flavio , Milanowski Janusz , Karnicka-Mlodkowski Hanna , Pesek Milos , Serwatowski Piotr , Ramlau Rodryg , Janaskova Terezie , Vansteenkiste Johan , Strausz Janos , Manikhas Georgy Moiseevich , Von Pawel Joachim
Published: April 2007

Purpose

Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2on days 1 and 8 and cisplatin 80 mg/m2on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL).

Results

A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild).

Conclusion

Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.
Correlation Between O6-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide
Authors: Chinot Olivier L. , Barrié Maryline , Fuentes Stephane , Eudes Nathalie , Lancelot Sophie , Metellus Philippe , Muracciole Xavier , Braguer Diane , Ouafik L'Houcine , Martin Pierre-Marie , Dufour Henry , Figarella-Branger Dominique
Published: April 2007

Purpose

This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma.

Patients and Methods

Patients received temozolomide (150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase (MGMT) expression.

Results

Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%).

Conclusion

This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.
Pretreatment Levels of Peripheral Neutrophils and Leukocytes As Independent Predictors of Overall Survival in Patients With American Joint Committee on Cancer Stage IV Melanoma: Results of the EORTC 18951 Biochemotherapy Trial
Authors: Schmidt Henrik , Suciu Stefan , Punt Cornelis J.A. , Gore Martin , Kruit Wim , Patel Poulam , Lienard Danielle , von der Maase Hans , Eggermont Alexander M.M. , Keilholz Ulrich
Published: April 2007

Purpose

An elevated count of blood neutrophils and monocytes recently was shown independently to predict short survival in patients with stage IV melanoma undergoing interleukin-2–based immunotherapy. In this study, we aimed to validate this finding in a large cohort of stage IV melanoma patients.

Patients and Methods

For this retrospective prognostic study, the data from the European Organisation for the Research and Treatment of Cancer 18951 study were used. Patients were randomly assigned between treatment with dacarbazine, cisplatin, and interferon alfa with or without interleukin-2. Counts of neutrophils and leukocytes were analyzed together with other known prognostic factors: serum lactate dehydrogenase, performance status, metastatic site, and sex. Two multivariate prognostic factor analyses were carried out in the model: one with leukocyte counts and one with neutrophil counts.

Results

A total of 363 patients were randomly assigned and baseline blood neutrophil and leukocyte counts were available from 316 and 350 patients, respectively. A high neutrophil count (> 7.5 × 109/L) was an independent prognostic factor for short overall survival (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = 0.02), and a high leukocyte count (> 10 × 109/L) was an independent prognostic factor of both short overall survival (HR, 1.7; 95% CI, 1.3 to 2.4; P = 0.0005) and short progression-free survival (HR, 1.5; 95% CI, 1.1 to 2.1; P = 0.008).

Conclusion

A high pretreatment count of neutrophils in blood was confirmed as an independent prognostic factor for short overall survival in stage IV melanoma patients undergoing interleukin-2–based immunotherapy. Furthermore, a high count of leukocytes was an independent prognostic factor for short overall survival and progression-free survival. Both parameters should be useful as stratification factors in clinical trials.
Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group
Authors: Malempati Suman , Nicholson H. Stacy , Reid Joel M. , Blaney Susan M. , Ingle Ashish M. , Krailo Mark , Stork Linda C. , Melemed Allen S. , McGovern Renee , Safgren Stephanie , Ames Matthew M. , Adamson Peter C.
Published: April 2007

Purpose

We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children.

Patients and Methods

Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment.

Results

Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively.

Conclusion

Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2administered every 21 days with dexamethasone, folic acid, and vitamin B12supplementation.
Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National Cancer Institute of Canada and Intergroup Study JBR.10
Authors: Pepe Carmela , Hasan Baktiar , Winton Timothy L. , Seymour Lesley , Graham Barbara , Livingston Robert B. , Johnson David H. , Rigas James R. , Ding Keyue , Shepherd Frances A.
Published: April 2007

Purpose

Recent trials have shown significant survival benefit from adjuvant chemotherapy for non–small-cell lung cancer (NSCLC). Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, adjuvant chemotherapy delivery, and toxicity in National Cancer Institute of Canada (NCIC) Clinical Trials Group study JBR.10.

Patients and Methods

Pretreatment characteristics and survival were compared for 327 young (≤ 65 years) and 155 elderly (> 65 years) patients. Chemotherapy delivery and toxicity were compared for 213 treated patients (63 elderly, 150 young).

Results

Baseline demographics by age were similar with the exception of histology (adenocarcinoma: 58% young, 43% elderly; squamous: 32% young, 49% elderly; P = .001) and performance status (PS; PS 0: 53% young, 41% elderly; P = .01). Chemotherapy significantly prolonged overall survival for elderly patients (hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .04). This benefit is similar to the effect for all patients in JBR.10. Mean dose-intensities of vinorelbine and cisplatin were 13.2 and 18.0 mg/m2/wk in young, respectively, and 9.9 and 14.1 mg/m2/wk in elderly patients (vinorelbine, P = .0004; cisplatin, P = .001), respectively. The elderly received significantly fewer doses of vinorelbine (P = .014) and cisplatin (P = .006). Fewer elderly patients completed treatment and more refused treatment (P = .03). There were no significant differences in toxicities, hospitalization, or treatment-related death by age group. Fifteen (11.9%) of 126 deaths in the young resulted from nonmalignant causes, and 15 (21.1%) of 71 in the elderly (P = .13).

Conclusion

Despite elderly patients’ receiving less chemotherapy, adjuvant vinorelbine and cisplatin improves survival in patients older than 65 years with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients.
Etiology of Early-Onset Type 2 Diabetes in Indians: Islet Autoimmunity and Mutations in Hepatocyte Nuclear Factor 1α and Mitochondrial Gene
Authors: Sahu Ravi P. , Aggarwal Ajay , Zaidi Ghazala , Shah Ajay , Modi Kirti , Kongara Srikanth , Aggarwal Suraksha , Talwar Sudha , Chu Su , Bhatia Vijayalakshmi , Bhatia Eesh
Published: April 2007

Context: Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available.

Objective: The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1α (HNF1α) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology.

Design: This was an observational cohort study.

Setting: The setting was an outpatient diabetes clinic in a teaching hospital.

Patients: Ninety-six consecutive young patients with T2DM (onset, ≤30 yr) were included in the study.

Interventions: Glutamic acid decarboxylase and insulinoma antigen 2 antibodies, mitochondrial A3243G mutation, and the common HNF1α mutation P291fsinsC were measured in all patients. The entire HNF1α gene was studied for mutations in 32 subjects with onset less than 25 yr or with normal weight. The common HNF1α A98V polymorphism was studied in 91 patients.

Results: The patients were clinically heterogeneous, with 42% having a normal body mass index. Glutamic acid decarboxylase antibodies were present in three (3%) subjects and mitochondrial A3243G mutation in one (1%) subject. The P291fsinsC mutation was not detected in any patient. A MODY3 mutation (R200W) was detected in one patient (3%). In this family, diabetes cosegregated with the R200W mutation in the proband and his youngest brother but not in three paternal uncles. The Val 98 allele was associated with T2DM (allele frequency, 0.14 vs. 0.03 in controls; odds ratio, 5.2; P < 0.001).

Conclusions: Despite a significant proportion of young Indian patients with T2DM having normal weight, islet autoimmunity, A3243G mitochondrial, and HNF1α gene mutations were infrequent.
Peptide Products of the Neurotrophin-Inducible Gene vgf Are Produced in Human Neuroendocrine Cells from Early Development and Increase in Hyperplasia and Neoplasia
Authors: Rindi Guido , Licini Lisa , Necchi Vittorio , Bottarelli Lorena , Campanini Nicoletta , Azzoni Cinzia , Favret Maurizio , Giordano Giovanna , D’Amato Filomena , Brancia Carla , Solcia Enrico , Ferri Gian-Luca
Published: April 2007

Background: Although the neurotrophin-inducible gene vgf is expressed in mammalian neurons and endocrine cells, limited data is available in man.

Aim: The objective of the study was to map proVGF peptides in human endocrine cells during development, adulthood, hyperplasia, and tumors.

Methods: Antisera were generated against peptides related to internal cleavage or cleavage-amidation sites (rat proVGF422–430 and human proVGF298–306-NH2) and the proVGF C-terminal ending (human proVGF607–615). Developing and normal adult endocrine cells, hyperplastic endocrine lesions (thyroid, parathyroid, lung, and stomach), and 120 tumors (102 endocrine) were studied. Immunogold electron microscopy was performed on normal adult pancreas and gut, and Western blotting was performed on extracts of control tissues and endocrine tumors.

Results: proVGF fragments were revealed in developing pituitary, gut, pancreas, and adrenal medulla from 10 gestational weeks, in normal adult pituitary and adrenal medulla, pancreatic glucagon, and insulin cells and gut serotonin cells, in hyperplastic thyroid calcitonin cells, lung P cells, gastric enterochromaffin-like cells, and gastrin cells, and in 88 of 102 endocrine tumors. At electron microscopy proVGF immunoreactivity was restricted to electron-dense granules. Western blotting revealed large molecular weight forms and cleavage fragments in both control tissues and tumor extracts.

Conclusions: proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.
Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress
Authors: Kino Tomoshige , Ichijo Takamasa , Amin Niranjana D. , Kesavapany Sashi , Wang Yonghong , Kim Nancy , Rao Sandesh , Player Audrey , Zheng Ya-Li , Garabedian Michael J. , Kawasaki Ernest , Pant Harish C. , Chrousos George P.
Published: April 2007

Glucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system and influence diverse functions of neuronal cells. We found that cyclin-dependent kinase 5 (CDK5), which plays important roles in the morphogenesis and functions of the nervous system and whose aberrant activation is associated with development of neurodegenerative disorders, interacted with the ligand-binding domain of the glucocorticoid receptor (GR) through its activator p35 or its active proteolytic fragment p25. CDK5 phosphorylated GR at multiple serines, including Ser203 and Ser211 of its N-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to DNA. In microarray analyses using rat cortical neuronal cells, the CDK5 inhibitor roscovitine differentially regulated the transcriptional activity of the GR on more than 90% of the endogenous glucocorticoid-responsive genes tested. Thus, CDK5 exerts some of its biological activities in neuronal cells through the GR, dynamically modulating GR transcriptional activity in a target promoter-dependent fashion.
Congenital Hypothyroidism, Dwarfism, and Hearing Impairment Caused by a Missense Mutation in the Mouse Dual Oxidase 2 Gene, Duox2
Authors: Johnson Kenneth R. , Marden Coleen C. , Ward-Bailey Patricia , Gagnon Leona H. , Bronson Roderick T. , Donahue Leah Rae
Published: April 2007

Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T>G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named “thyroid dyshormonogenesis” (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T4 in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50–60 decibels (dB) above those of controls.
Efficiency and dynamic performance of Digital Displacement™ hydraulic transmission in tidal current energy converters
Authors: Payne G. S. , Kiprakis A. E. , Ehsan M , Rampen W. H S. , Chick J. P. , Wallace A. R.
Published: April 2007

Tidal current turbines extract kinetic energy from tidal current in much the same way as wind turbines do with wind. Tidal current velocities are by nature slow and variable, whereas electricity generation typically requires fast and steady rotary motion. This article investigates the performance of a hydraulic transmission system based on Digital Displacement™ technology, which allows variable speed of the tidal current turbine rotor while maintaining constant generator shaft speed. The case study of a generic horizontal axis tidal turbine is considered. Control strategies based on rotor variable speed are derived to optimize yearly power generation and to cope with short-term variations in stream velocity.
Impact of alternative electricity generation technologies on the Scottish economy: An illustrative input—output analysis
Authors: Allan G , McGregor P. G. , Swales J. K. , Turner K
Published: April 2007

UK energy policy is at a critical juncture, with major changes in the electricity generation mix in prospect. In Scotland, significant reductions in electricity-generating capacity are expected as coal- and nuclear-powered stations close, and renewable technologies provide a growing share of total electricity. Despite these radical changes, there has as yet been no assessment of the likely implications for the Scottish economy. This paper explores the likely systemwide impact of these changes on aggregate and sectoral outputs and employment levels using an input-output analysis that separately identifies eight generating technologies. The results suggest the need for careful disaggregation of the electricity generation sector and emphasize the economic distinctiveness of individual generation technologies.
Direct electric energy conversion system for energy conversion from marine currents
Authors: Leijon M , Nilsson K
Published: April 2007

Direct electric energy conversion without input power regulating system or gearboxes may offer a simpler and thus low cost way of converting the energy of moving water. The proposed electrical system consists of a permanent magnetized direct drive generator, a rectification step, transmission, an inverter, a transformer, and a grid connection. This paper focuses on the generator, and simulations of a 5 kW permanent magnetized direct drive generator have been performed. Operation of the generator at both part load and overloads are calculated and presented. It is found that this direct drive permanent magnetized generator provides a relatively high efficiency for both part load and overload conditions.
Marine current turbines: Pioneering the development of marine kinetic energy converters
Authors: Fraenkel P. L.
Published: April 2007

This paper gives the rationale and background to an already advanced research and development (R&D) programme aimed at developing technology for the commercial exploitation of kinetic energy from marine currents. This is followed by a brief overview of the characteristics of the tidal stream resource, the technical principles by which it may be exploited, and the key technical challenges that need to be overcome.

The paper includes a description of the pioneering ‘Seaflow’ Project involving the installation and testing, since May 2003, of a prototype 300 kW tidal turbine 3 km off Lynmouth. The next stage of Marine Current Turbines Ltd's R&D programme is then described: this involves the development of a 1 MW twin axial-flow rotor system, called ‘Seagen’ which is planned for installation early in 2007. The installation and testing of ‘Seagen’ will mark a landmark stage in the R&D programme because it will form the basis for the commercial technology to follow. A brief outline of future plans beyond ‘Seagen’ is also given.
Investigation into wave—current interactions in marine current turbines
Authors: Barltrop N , Varyani K. S. , Grant A , Clelland D , Pham X. P.
Published: April 2007

The paper looks at the use of blade element-momentum theory for predicting the torque and thrust on a marine current turbine and the results of wave tank tests using a 400 mm-diameter rotor model. To include the effects of waves, linear wave theory particle velocities and accelerations were integrated into the mathematical model. Comparison with test data shows a good agreement which implies that the theory can be effective in analysing the wave-current interactions in marine current turbines. The paper also carried out parametric studies into related parameters, which include wave height, wave frequency, and tip-speed ratio. The interaction of waves with the current may increase or decrease the torque and hence power output of the turbine. The paper also explains the selection and manufacture of the rotor and the experimental setup.
Tidal energy resource assessment for tidal stream generators
Authors: Blunden L. S. , Bahaj A. S.
Published: April 2007

This article is a review of the current understanding of tidal energy resources in the context of the emerging technology of tidal stream power generation. The geographical focus is on the north-west European continental shelf, the scope of a number of published reports on exploitable tidal stream energy resources. These estimates are reviewed as are some analytical models of energy extraction by tidal stream generators.
Tidal current energy assessment for Johnstone Strait, Vancouver Island
Authors: Sutherland G , Foreman M , Garrett C
Published: April 2007

The maximum tidal power potential of Johnstone Strait, BC, Canada is evaluated using a two-dimensional finite element model (TIDE2D) with turbines simulated in certain regions by increasing the drag. Initially, side channels are closed off so that the flow is forced through one channel to test the validity of a general analytic theory [1] with numerical results. In this case, the modelled power potential of 886 MW agrees reasonably well with the analytic estimate of 826 MW. In reality, two main channels, Discovery Passage and Cordero Channel, connect the Pacific Ocean to the Strait of Georgia. Turbines are simulated in Johnstone Strait, northwest of the two main channels, and separately for Discovery Passage and Cordero Channel. Northwestern Johnstone Strait is similar to the one channel case as the flow must go through this channel, but Discovery Passage and Cordero Channel are different as the flow can be diverted away from the channel with the turbines and into the other channel. The maximum extractable power in northwestern Johnstone Strait is found to be 1335 MW, which agrees well with the theoretical estimate of 1320 MW. In Discovery Passage and Cordero Channel, the maximum extractable power is modelled to be 401 and 277 MW, respectively, due to the flow being partly diverted into the other channel. In all cases, the current is reduced to between 57 and 58 per cent of the undisturbed flow, close to the 56 per cent predicted by the analytic theory. All power calculations are for the M2 constituent alone, as this is the largest current in the region. The total power from the eight major constituents (M2, S2, N2, K2, K1, 01, P1, and Q1) can be obtained by multiplying the power estimates for M2 by 1.12.
R-weighting provides better estimation for rat hearing sensitivity
Authors: Böjrk E. , Nevalainen T. , Hakumäki M. , Voipio H.-M.
Published: April 2007

Since sounds may induce physiological and behavioural changes in animals, it is necessary to assess and define the acoustic environment in laboratory animal facilities. Sound studies usually express sound levels as unweighted linear sound pressure levels. However, because a linear scale does not take account of hearing sensitivity-which may differ widely both between and within species at various frequencies-the results may be spurious. In this study a novel sound pressure level weighting for rats, R-weighting, was calculated according to a rat's hearing sensitivity. The sound level of a white noise signal was assessed using R-weighting, with H-weighting tailored for humans, A-weighting and linear sound pressure level combined with the response curves of two different loudspeakers. The sound signal resulted in different sound levels depending on the weighting and the type of loudspeaker. With a tweeter speaker reproducing sounds at high frequencies audible to a rat, R- and A-weightings gave similar results, but the H-weighted sound levels were lower. With a middle-range loudspeaker, unable to reproduce high frequencies, R-weighted sound showed the lowest sound levels. In conclusion, without a correct weighting system and proper equipment, the final sound level of an exposure stimulus can differ by several decibels from that intended. To achieve reliable and comparable results, standardization of sound experiments and assessment of the environment in animal facilities is a necessity. Hence, the use of appropriate species-specific sound pressure level weighting is essential. R-weighting for rats in sound studies is recommended.
Coronary artery anomalies and aortic valve morphology in the Syrian hamster
Authors: Fernández M. C. , Durán A. C. , Real R. , López D. , Fernández B. , de Andrés A. V. , Arqué M. , Gallego A. , Sans-Coma V.
Published: April 2007

In the Syrian hamster, anomalies in the origin of the left coronary artery are significantly associated with the bicuspid condition of the aortic valve. In this species, bicuspid aortic valves are expressions of a trait, the variation of which takes the form of a phenotypic continuum, ranging from a tricuspid aortic valve with no commissural fusion to a bicuspid aortic valve with the aortic sinuses located in ventrodorsal orientation and devoid of any raphe. The intermediate stages of the continuum are represented by tricuspid aortic valves with a more or less extensive fusion of the ventral commissure and bicuspid aortic valves with a more or less developed raphe located in the ventral aortic sinus. The present study was designed to decide whether there is a gap between tricuspid and bicuspid aortic valves regarding the incidence of coronary artery anomalies, or whether this incidence varies according to the different tricuspid and bicuspid morpho types of the continuum. The study was carried out in Syrian hamsters belonging to a single inbred family with a high incidence of tricuspid aortic valves with fusion of the ventral commissure, bicuspid aortic valves, and anomalies in the origin of the left coronary artery, i.e. single right coronary artery ostium in aorta, anomalous origin of the left coronary artery from the pulmonary artery, and anomalous origin of the left coronary artery from the dorsal aortic sinus. The specimens were examined by means of a stereomicroscope and, in several cases; scanning electron microscopy was also used. The relationships between anomalous coronary artery patterns and aortic valve morphologies were tested using a logistic regression model. The results obtained indicate that there is no discontinuity between tricuspid and bicuspid aortic valves regarding the incidence of coronary artery anomalies. The probability of occurrence of anomalous coronary artery patterns increases continuously according to the deviation degree of the aortic valve from its normal (tricuspid) design. The present findings suggest that in the Syrian hamster, the morphogenetic mechanisms involved in the formation of congenital anomalous aortic valves and anomalies in the origin of the left coronary artery, respectively, are strongly related from an aetiological viewpoint.
Dietary fats influence consumption and metabolic measures in male and female laboratory mice
Authors: Brain Paul F. , Maimanee Tahia A. , Andrade Maria
Published: April 2007

Juvenile and adult male and female Swiss mice in metabolism cages were fed one of four specially-formulated, pelleted diets containing respectively 8% saturated vegetable fat, 8% soya oil, 8% olive oil and 2% soya oil. The identities of the diets were hidden from the experimenter. Subjects were individually housed in metabolism cages and their consumption of food, growth and eliminative activities were measured. Clearly, these non-isocaloric diets differed in palatability, producing complex effects on growth as well as metabolic measures. Many indices were influenced by age, sex, and the duration of dietary exposure. Interactions between factors were common. Dietary fats appear to have subtle effects on the physiology and behaviour of rodents and may account for some differences between studies.
Guidelines for reporting the results of experiments on fish
Authors: Brattelid Trond , Smith Adrian J.
Published: April 2007

A detailed account of experimental design, including an accurate description of the animals used, is an essential part of good research practice. Without these details, the reader will be unable not only to form an opinion on the significance of the findings but also to repeat the experiment in another laboratory. This paper presents suggested guidelines for reporting experimental studies using fish.
Animal definition: a necessity for the validity of animal experiments?
Authors: Örink K. J. , Rehbinder C.
Published: April 2007

In most scientific journals, experimental animals are described poorly. Whether this is scientifically justified is discussed in this article. It was concluded that when laboratory animals are used in scientific experiments, which almost always are of a quantitative nature, a detailed animal definition is imperative.
Fighting in NIH/S male mice: consequences for behaviour in resident-intruder tests and physiological parameters
Authors: Kaliste-Korhonen E. , Eskola S.
Published: April 2007

Fighting is known to occur frequently in male mouse groups. In this study with outbred NIH/S mice, the possible impact of individual aggressiveness on fighting in groups and on the social status of animals was studied. Male mice were pre-tested in a resident-intruder (RI) test and rated as initially aggressive or non-aggressive according to their attack behaviour against an intruder. Thereafter they were randomly allocated to new social groups, with four mice per cage. Fighting in groups was increased when several initially aggressive animals were included in the group. Within the groups, animals were rated as dominants and subordinates according to their behaviour toward a strange intruder introduced into their home-cage (Group Intruder, GI) test and the occurrence of wounds. Additionally, subordinates were divided into aggressive and non-aggressive categories according to their behaviour in the second RI test, which was performed 3 weeks after grouping. The behaviour in the RI test prior to group-housing did not predict the individual social status or possibility of being wounded in the new social environment. On the other hand, the social relationships in the new group affected the behaviour in a subsequent RI test. All dominants showed aggressive behaviour during the second RI test. Those subordinates which behaved aggressively during this test received the most numerous and serious wounds, suggesting that in the new groups their interactions with the other group members were mostly aggressive. The reduced weight of epididymal adipose tissue in dominant and aggressive subordinates may indicate that they had fought continuously. Social status or levels of fighting in a group did not affect individual weight gain or the other physiological parameters measured. The wounded animals had enlarged spleens and reduced weights of epididymal adipose tissue, which were probably the results of increased activity of the immune system and reduced welfare, respectively. In conclusion, individual aggressiveness seems to be greatly affected by the demands of the social environment. Fighting in mouse groups leading to wounded animals may have effects on physiological research parameters.
Decision Making with Multiattribute Performance Targets: The Impact of Changes in Performance and Target Distributions
Authors: Tsetlin Ilia , Winkler Robert L.
Published: April 2007

In many situations, performance on several attributes is important. Moreover, a decision maker’s utility may depend not on the absolute level of performance on each attribute, but rather on whether that level of performance meets a target, in which case the decision maker is said to be target oriented. For example, typical attributes in new product development include cost, quality, and features, and the corresponding targets might be the best performance on these attributes by competing products. Targets and performance levels typically are uncertain and often are dependent. We develop a model that allows for uncertain dependent targets and uncertain dependent performance levels, and we study implications for decision making in this general multiattribute target-oriented setting. We consider the impact on expected utility of modifying key characteristics of performance (or target) distributions: location, spread, and degree of dependence. In particular, we show that explicit consideration of dependence is important, and we establish when increasing or decreasing dependence is beneficial. We illustrate the results numerically with a normal model and discuss some extensions and implications.
Optimizing Service Parts Inventory in a Multiechelon, Multi-Item Supply Chain with Time-Based Customer Service-Level Agreements
Authors: Caggiano Kathryn E. , Jackson Peter L. , Muckstadt John A. , Rappold James A.
Published: April 2007

In the realm of service parts management, customer relationships are often established through service agreements that extend over months or years. These agreements typically apply to a piece of equipment that the customer has purchased, and they specify the type and timing of service that will be provided. If a customer operates in multiple locations, service agreements may cover several pieces of equipment at several locations. In this paper, we describe a continuous-review inventory model for a multi-item, multiechelon service parts distribution system in which time-based service-level requirements exist. Our goal is to determine base-stock levels for all items at all locations so that the service-level requirements are met at minimum investment. We derive exact time-based fill-rate expressions for each item within its distribution channel, as well as approximate expressions for the gradients of these fill-rate functions. Using these results, we develop an intelligent greedy algorithm that can be used to find near-optimal solutions to large-scale problems quickly, as well as a Lagrangian-based approach that provides both near-optimal solutions and good lower bounds with increased computational effort. We demonstrate the effectiveness and scalability of these algorithms on three example problems.
The Cost Allocation Problem for the First Order Interaction Joint Replenishment Model
Authors: Anily Shoshana , Haviv Moshe
Published: April 2007

We consider an infinite-horizon deterministic joint replenishment problem with first order interaction. Under this model, the setup transportation/reorder cost associated with a group of retailers placing an order at the same time equals some group-independent major setup cost plus retailer-dependent minor setup costs. In addition, each retailer is associated with a retailer-dependent holding-cost rate. The structure of optimal replenishment policies is not known, thus research has focused on optimal power-of-two (POT) policies. Following this convention, we consider the cost allocation problem of an optimal POT policy among the various retailers. For this sake, we define a characteristic function that assigns to any subset of retailers the average-time total cost of an optimal POT policy for replenishing the retailers in the subset, under the assumption that these are the only existing retailers. We show that the resulting transferable utility cooperative game with this characteristic function is concave. In particular, it is a totally balanced game, namely, this game and any of its subgames have nonempty core sets. Finally, we give an example for a core allocation and prove that there are infinitely many core allocations.
Sensitivity Analysis of a Dynamic Fleet Management Model Using Approximate Dynamic Programming
Authors: Topaloglu Huseyin , Powell Warren B.
Published: April 2007

We present tractable algorithms to assess the sensitivity of a stochastic dynamic fleet management model to fleet size and load availability. In particular, we show how to compute the change in the objective function value in response to an additional vehicle or an additional load introduced into the system. The novel aspect of our approach is that it does not require multiple simulations with different values of the model parameters, and in this respect it differs from trial-and-error-based “what-if” analyses. Numerical experiments show that the proposed methods are accurate and computationally attractive.
Note: Generalized Notions of Concavity with an Application to Capacity Management
Authors: Semple John
Published: April 2007

We introduce a generalization of K-concavity termed weak (K1, K2)-concavity and show how it can be used to analyze certain dynamic systems arising in capacity management. We show that weak (K1, K2)-concavity has two fundamental properties that are relevant for the analysis of such systems: First, it is preserved for linear interpolations; second, it is preserved for certain types of linear extensions. In capacity management problems where both buying and selling capacity involve a fixed cost plus a proportional cost/revenue term, interpolations and extensions are fundamental building blocks of the optimality analysis. In the context of the capacity management problem studied by Ye and Duenyas (2007), we show that weak (K1, K2)-concavity is sufficient to prove the general structure of the optimal policy established in that paper.
Classification and Regression via Integer Optimization
Authors: Bertsimas Dimitris , Shioda Romy
Published: April 2007

Motivated by the significant advances in integer optimization in the past decade, we introduce mixed-integer optimization methods to the classical statistical problems of classification and regression and construct a software package called CRIO (classification and regression via integer optimization). CRIO separates data points into different polyhedral regions. In classification each region is assigned a class, while in regression each region has its own distinct regression coefficients. Computational experimentations with generated and real data sets show that CRIO is comparable to and often outperforms the current leading methods in classification and regression. We hope that these results illustrate the potential for significant impact of integer optimization methods on computational statistics and data mining.
Fast, Fair, and Efficient Flows in Networks
Authors: Correa José R. , Schulz Andreas S. , Stier-Moses Nicolás E.
Published: April 2007

We study the problem of minimizing the maximum latency of flows in networks with congestion. We show that this problem is NP-hard, even when all arc latency functions are linear and there is a single source and sink. Still, an optimal flow and an equilibrium flow share a desirable property in this situation: All flow-carrying paths have the same length, i.e., these solutions are “fair,” which is in general not true for optimal flows in networks with nonlinear latency functions. In addition, the maximum latency of the Nash equilibrium, which can be computed efficiently, is within a constant factor of that of an optimal solution. That is, the so-called price of anarchy is bounded. In contrast, we present a family of instances with multiple sources and a single sink for which the price of anarchy is unbounded, even in networks with linear latencies. Furthermore, we show that an s-t-flow that is optimal with respect to the average latency objective is near-optimal for the maximum latency objective, and it is close to being fair. Conversely, the average latency of a flow minimizing the maximum latency is also within a constant factor of that of a flow minimizing the average latency.
Relative Entropy, Exponential Utility, and Robust Dynamic Pricing
Authors: Lim Andrew E. B. , Shanthikumar J. George
Published: April 2007

In the area of dynamic revenue management, optimal pricing policies are typically computed on the basis of an underlying demand rate model. From the perspective of applications, this approach implicitly assumes that the model is an accurate representation of the real-world demand process and that the parameters characterizing this model can be accurately calibrated using data. In many situations, neither of these conditions are satisfied. Indeed, models are usually simplified for the purpose of tractability and may be difficult to calibrate because of a lack of data. Moreover, pricing policies that are computed under the assumption that the model is correct may perform badly when this is not the case. This paper presents an approach to single-product dynamic revenue management that accounts for errors in the underlying model at the optimization stage. Uncertainty in the demand rate model is represented using the notion of relative entropy, and a tractable reformulation of the “robust pricing problem” is obtained using results concerning the change of probability measure for point processes. The optimal pricing policy is obtained through a version of the so-called Isaacs’ equation for stochastic differential games, and the structural properties of the optimal solution are obtained through an analysis of this equation. In particular, (i) closed-form solutions for the special case of an exponential nominal demand rate model, (ii) general conditions for the exchange of the “max” and the “min” in the differential game, and (iii) the equivalence between the robust pricing problem and that of single-product revenue management with an exponential utility function without model uncertainty, are established through the analysis of this equation.
Argatroban Anticoagulation in Critically III Patients
Authors: Beiderlinden Martin , Treschan Tanja A , Görlinger Klaus , Peters Jürgen
Published: April 2007

Background:

Despite long-term use of argatroban in clinical practice, no dosing recommendations exist for critically ill patients with multiple organ dysfunction (MODS) and suspected or proven heparin-induced thrombocytopenia (HIT).

Objective:

To determine the suitability of argatroban use in critically ill patients with MODS and HIT.

Methods:

We conducted prospective observation of 24 consecutive patients with suspected HIT who were being anticoagulated with argatroban (target activated partial thromboplastin time [aPTT] 1.5–2 times normal or 50–60 sec) using 2 μg/kg/min in the first 5 patients and 0.2 μg/kg/min in the subsequent 19 patients.

Results:

Infusion of argatroban 2 μg/kg/min over 4 hours caused bleeding complications in 3 patients as aPTT increased from 51 ± 18 to 86 ± 34 seconds (p = 0.02), prothrombin time (PT) decreased from 76 ± 27% to 33 ± 12% of normal reference values, and international normalized ratio (INR) increased from 1.4 ± 0.4 to 2.5 ± 0.9 (p = 0.007). Infusion of argatroban 0.2 μg/kg/min over 4 hours provided sufficient anticoagulation without bleeding complications. The aPTT in this population increased from 44 ± 9 to 59 ± 13 seconds (p < 0.001), and PT and INR remained unchanged (76 ± 22% and 69 ± 23% of normal reference values, 1.3 ± 0.3 and after 1.3 ± 0.3, respectively [p = 0.4]). Coagulation variables (aPTT, PT, INR) were significantly different between both dosing regimens after 4 hours of infusion (p = 0.042 and p = 0.003, respectively). The maintenance dose for target aPTT averaged 0.22 ± 0.15 μg/kg/min in both groups.

Conclusions:

In critically ill patients with MODS, argatroban 2 μg/kg/min, as recommended by the manufacturer, resulted in extensive anticoagulation. A tenfold lower starting dose is sufficient and safe for effective anticoagulation in this specific patient population.