bluuebunny/crossref_metadata_2025 huggingface dataset:
The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon
Authors: Prades C. , Arnould I. , Annilo T. , Shulenin S. , Chen Z.Q. , Orosco L. , Triunfol M. , Devaud C. , Maintoux-Larois C. , Lafargue C. , Lemoine C. , Denèfle P. , Rosier M. , Dean M.
Published: April 2003

The ABCA subfamily of ATP-binding cassette (ABC) transporters includes eleven members to date. In this study, we describe a new, unusually large gene on chromosome 7p12.3, ABCA13. This gene spans over 450 kb and is split into 62 exons. The predicted ABCA13 protein consists of 5,058 ami- no acid residues making it the largest ABC protein described to date. Like the other ABCA subfamily members, ABCA13 contains a hydrophobic, predicted transmembrane segment at the N-terminus, followed by a large hydrophilic region. In the case of ABCA13, the hydrophilic region is unexpectedly large, more than 3,500 amino acids, encoded by 30 exons, two of which are 4.8 and 1.7 kb in length. These two large exons are adjacent to each other and are conserved in the mouse Abca13 gene. Tissue profiling of the major transcript reveals the highest expression in human trachea, testis, and bone marrow. The expression of the gene was also determined in 60 tumor cell lines and the highest expression was detected in the SR leukemia, SNB-19 CNS tumor and DU-145 prostate tumor cell lines. ABCA13 has high similarity with other ABCA subfamily genes which are associated with human inherited diseases: ABCA1 with the cholesterol transport disorders Tangier disease and familial hypoalphalipoproteinemia, and ABCA4 with several retinal degeneration disorders. The ABCA13 gene maps to chromosome 7p12.3, a region that contains an inherited disorder affecting the pancreas (Shwachman-Diamond syndrome) as well as a locus involved in T-cell tumor invasion and metastasis (INM7), and therefore is a positional candidate for these pathologies.
Signal Transduction Pathways Mediated by PECAM-1
Authors: Newman Peter J. , Newman Debra K.
Published: April 2003

Recent studies of platelet endothelial cell adhesion molecule-1 (PECAM-1 [CD31])-deficient mice have revealed that this molecule plays an important role in controlling the activation and survival of cells on which it is expressed. In this review, we focus on the complex cytoplasmic domain of PECAM-1 and describe what is presently known about its structure, posttranslational modifications, and binding partners. In addition, we summarize findings that implicate PECAM-1 as an inhibitor of cellular activation via protein tyrosine kinase–dependent signaling pathways, an activator of integrins, and a suppressor of cell death via pathways that depend on damage to the mitochondria. The challenge of future research will be to bridge our understanding of the functional and biochemical properties of PECAM-1 by establishing mechanistic links between signals transduced by the PECAM-1 cytoplasmic domain and discrete cellular responses.
Isolation, Characterization, and Functional Assessment of Oxidatively Modified Subfractions of Circulating Low-Density Lipoproteins
Authors: Yang Chao-yuh , Raya Joe L. , Chen Hsin-Hung , Chen Chu-Huang , Abe Yasunori , Pownall Henry J. , Taylor Addison A. , Smith Charles V.
Published: April 2003

Objective—Current evidence suggests that oxidatively modified human plasma low-density lipoproteins (ox-LDLs) are proatherogenic and cytotoxic to endothelial and vascular smooth muscle cells. The present study describes a method using ion-exchange chromatography that is capable of large-scale subfractionation of LDL for adequate analyses of composition or bioactivities.

Methods and Results—LDLs from normolipidemic (N-LDL) and homozygous familial hypercholesterolemic (FH-LDL) subjects were separated into 5 subfractions (L1 through L5) by high-capacity ion-exchange chromatography. The most strongly retained fraction from FH subjects, FH-L5, suppressed DNA synthesis in cultured bovine aortic endothelial cells and stimulated mononuclear cell adhesion to cultured endothelial cells under flow conditions in vitro. L5, which represented 1.1±0.2% and 3.7±1.7% of the LDL from N-LDL and FH-LDL, respectively, was more triglyceride-rich (17% versus 5%) and cholesteryl ester-poor (23% versus 33%) than were L1 through L4. Electrophoretic mobilities on agarose gels increased from L1 to L5. According to SDS-PAGE, apolipoprotein B-100 in N-LDL fractions L1 through L5 appeared as a single ≈500-kDa band. In contrast, the fractions isolated from FH-LDL showed substantial fragmentation of the apolipoprotein B-100, including bands between 200 and 116 kDa. Competitive ELISA analyses using a malondialdehyde-specific monoclonal antibody against Cu2+ox-LDL suggest that FH-L5 is malondialdehyde-modified.

Conclusions—Relative to N-LDL, FH-LDL contains higher concentrations of a fraction, L5, that exhibits distinctive physicochemical properties and biological activities that may contribute to initiation and progression of atherogenesis in vivo.
Differential Regulation of Early Growth Response Gene-1 Expression by Insulin and Glucose in Vascular Endothelial Cells
Authors: Hasan Rukhsana N. , Phukan Sharbani , Harada Shuko
Published: April 2003

Objective—

Early growth response gene (Egr)-1 is a key transcription factor involved in vascular pathophysiology. Its role in diabetic vascular complications, however, remains unclear. Because hyperinsulinemia and hyperglycemia are major risk factors leading to diabetic vascular complications, we examined the effect of insulin and glucose on Egr-1 expression in murine glomerular vascular endothelial cells.

Methods and Results—

Insulin or glucose, when added separately, increased
egr-1
mRNA levels and promoter activity, as well as Egr-1 protein levels in nuclear extracts. When insulin was added to cells preincubated with glucose, the two had an additive effect on Egr-1 expression. Furthermore, vascular endothelial growth factor receptor-1 (
flt-1
) and plasminogen activator inhibitor-1, two known Egr-1-responsive genes, were also upregulated in the presence of insulin or glucose. An investigation into the underlying molecular mechanisms demonstrated that insulin, but not glucose, increased Egr-1 expression through extracellular signal-regulated kinase 1/2 activation, which is consistent with our previous reports. In contrast, inhibition of protein kinase C by phorbol ester or by the specific protein kinase C inhibitor chelerythrine chloride downregulated glucose-induced, but not insulin-induced, Egr-1 expression.

Conclusions—

Differential regulation of Egr-1 expression by insulin and glucose in vascular cells may be one of the initial key events that plays a crucial role in the development of diabetic vascular complications.
Statins Are Associated With a Reduced Incidence of Perioperative Mortality in Patients Undergoing Major Noncardiac Vascular Surgery
Authors: Poldermans Don , Bax Jeroen J. , Kertai Miklos D. , Krenning Boudewijn , Westerhout Cynthia M. , Schinkel Arend F.L. , Thomson Ian R. , Lansberg Peter J. , Fleisher Lee A. , Klein Jan , van Urk Hero , Roelandt Jos R.T.C. , Boersma Eric
Published: April 2003

Background—

Patients undergoing major vascular surgery are at increased risk of perioperative mortality due to underlying coronary artery disease. Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (statins) may reduce perioperative mortality through the improvement of lipid profile, but also through the stabilization of coronary plaques on the vascular wall.

Methods and Results—

To evaluate the association between statin use and perioperative mortality, we performed a case-controlled study among the 2816 patients who underwent major vascular surgery from 1991 to 2000 at the Erasmus Medical Center. Case subjects were all 160 (5.8%) patients who died during the hospital stay after surgery. From the remaining patients, 2 controls were selected for each case and were stratified according to calendar year and type of surgery. For cases and controls, information was obtained regarding statin use before surgery, the presence of cardiac risk factors, and the use of other cardiovascular medication. A vascular complication during the perioperative phase was the primary cause of death in 104 (65%) case subjects. Statin therapy was significantly less common in cases than in controls (8% versus 25%;
P
<0.001). The adjusted odds ratio for perioperative mortality among statin users as compared with nonusers was 0.22 (95% confidence interval 0.10 to 0.47). Similar results were obtained in subgroups of patients according to the use of cardiovascular therapy and the presence of cardiac risk factors.

Conclusion—

This case-controlled study provides evidence that statin use reduces perioperative mortality in patients undergoing major vascular surgery.
Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia
Authors: Mackus Wendelina J. M. , Frakking Florine N. J. , Grummels Annette , Gamadia Laila E. , de Bree Godelieve J. , Hamann Dörte , van Lier René A. W. , van Oers Marinus H. J.
Published: April 2003

In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n = 12; Rai I-II, n = 10; Rai III-IV, n = 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3+ cells was observed. Whereas the number of CD4+ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8+ cells, which exhibited a CD45RA+CD27- cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)–peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramer-binding CMV-specific CD8+ T cells. The rise in the total number of CD8+ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8+ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell–depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; α-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8+ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.
Soluble receptor activator of nuclear factor κB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index
Authors: Terpos Evangelos , Szydlo Richard , Apperley Jane F. , Hatjiharissi Evdoxia , Politou Marianna , Meletis John , Viniou Nora , Yataganas Xenophon , Goldman John M. , Rahemtulla Amin
Published: April 2003

Interaction between receptor activator of nuclear factor κB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and β2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
When is the best time to fix fractures?
Authors: Revell MP , Porter KM
Published: April 2003

The best time to operate on a fracture is governed in part by the nature of the fracture itself. It is also influenced by the premorbid condition of the patient and by the degree that associated injuries have disrupted normal processes. It is likely that some patients have a period of increased physiological risk for intervention, during which a second insult will result in further harm. The picture is not yet fully clear but relates to variations in the inflammatory response to trauma. One consistent lesson appears to resonate throughout the published literature. The most predictable risk factor for iatrogenic physiological disturbance is transfer to the operating theatre before adequate resuscitation of the patient has taken place.
Apoptotic-Regulatory and Complement-Protecting Protein Expression in Chronic Lymphocytic Leukemia: Relationship to In Vivo Rituximab Resistance
Authors: Bannerji Rajat , Kitada Shinichi , Flinn Ian W. , Pearson Michael , Young Donn , Reed John C. , Byrd John C.
Published: April 2003

Purpose: Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy.

Patients and Methods: Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome.

Results: Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 ± 0.28 v 0.39 ± 0.29, P < .016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P = .02).

Conclusion: These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted.
Early Change in Patient-Reported Health During Lung Cancer Chemotherapy Predicts Clinical Outcomes Beyond Those Predicted by Baseline Report: Results From Eastern Cooperative Oncology Group Study 5592
Authors: Eton David T. , Fairclough Diane L. , Cella David , Yount Susan E. , Bonomi Philip , Johnson David H.
Published: April 2003

Purpose: To determine the ability of longitudinal patient-reported health (PRH) scores to enhance prediction of clinical outcomes beyond baseline scores.

Patients and Methods: In 573 advanced non–small-cell lung cancer patients enrolled in a phase III clinical trial, we used baseline and 6-week follow-up PRH scores to predict best response to treatment, disease progression, and survival. Using regression analyses, we tested the predictive ability of the five subscales of the Functional Assessment of Cancer Therapy–Lung (physical, functional, social/family, emotional well-being, and the lung cancer subscale) as well as the trial outcome index (TOI) aggregate score.

Results: After clinical factors were controlled for, baseline physical well-being (PWB) and TOI scores predicted all three clinical outcomes. A higher baseline PWB score was associated with a better response to treatment (odds ratio, 1.09; P < .001) and lower risk of death (risk ratio, 0.95; P < .001). Higher baseline TOI score was associated with a lower risk of disease progression (risk ratio, 0.98; P < .001). These two baseline predictors (PWB and TOI) were then used along with 6-week change scores to classify patients into four groups: low baseline-declined, low baseline-improved, high baseline-declined, and high baseline-improved. Patients with low baseline-declined PWB scores showed the worst responses to treatment and survived the shortest duration. Patients with low baseline-declined TOI scores had the shortest time to progression.

Conclusion: The physical aspects of baseline PRH and PRH change during chemotherapy are significant predictors of clinical outcomes in lung cancer. This has implications for patient stratification in clinical trials and may aid decision-making in clinical practice.
Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741
Authors: Citron Marc L. , Berry Donald A. , Cirrincione Constance , Hudis Clifford , Winer Eric P. , Gradishar William J. , Davidson Nancy E. , Martino Silvana , Livingston Robert , Ingle James N. , Perez Edith A. , Carpenter John , Hurd David , Holland James F. , Smith Barbara L. , Sartor Carolyn I. , Leung Eleanor H. , Abrams Jeffrey , Schilsky Richard L. , Muss Hyman B. , Norton Larry
Published: April 2003

Purpose: Using a 2 × 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node–positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities.

Patients and Methods: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A × 4 (doses) → T × 4 → C × 4 with doses every 3 weeks, (II) sequential A × 4 → T × 4 → C × 4 every 2 weeks with filgrastim, (III) concurrent AC × 4 → T × 4 every 3 weeks, or (IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim.

Results: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P = .010), and OS (RR = 0.69; P = .013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens.

Conclusion: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.
Phase III Study Comparing Three Cycles of Infusional Carmustine and Cisplatin Followed by Radiation Therapy With Radiation Therapy and Concurrent Carmustine in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme: Eastern Cooperative Oncology Group Trial 2394
Authors: Grossman Stuart A. , O’Neill Anne , Grunnet Margaret , Mehta Minesh , Pearlman James L. , Wagner Henry , Gilbert Mark , Newton Herbert B. , Hellman Richard
Published: April 2003

Purpose: This phase III Eastern Cooperative Oncology Group-Southwest Oncology Group intergroup study was conducted to determine whether three 72-hour infusions of carmustine (BiCNU) and cisplatin administered monthly before external-beam radiotherapy would improve the survival of patients with newly diagnosed glioblastoma multiforme. The control arm consisted of radiation with standard adjuvant BiCNU.

Patients and Methods: A total of 223 patients were accrued from 1996 to 1999. Of these, 219 patients were eligible; 109 were randomly assigned to the experimental arm, and 110 were randomly assigned to the control arm. Randomization was stratified by age, performance status, and extent of resection.

Results: The median age of the patients was 55 years; 55% were male, 93% were white, 26% had a biopsy only, and 84% were ambulatory. Treatment arms were well balanced with respect to baseline characteristics. Median follow-up time of the 15 patients still alive at the time of analysis was 3.3 years (range, 2 to 5 years). Median survival times for the standard and experimental arms were 11.2 and 11.0 months (P = .33, two-sided log-rank test), and survival at 1 year was 45% versus 44%, respectively. Fifty-six percent of patients received all three cycles of BiCNU/cisplatin, 12% received two cycles, and 31% received only one cycle. Toxicity was primarily hematologic and was more common in the experimental arm (P < .01).

Conclusion: This study demonstrates that 72-hour infusions of BiCNU and cisplatin followed by radiation do not improve median survival, survival at 1 year, or time to progression. Furthermore, this treatment requires more time in the hospital and is associated with more serious toxicities than standard therapy.
Continued Cigarette Smoking by Patients Receiving Concurrent Chemoradiotherapy for Limited-Stage Small-Cell Lung Cancer Is Associated With Decreased Survival
Authors: Videtic Gregory M.M. , Stitt Larry W. , Dar A. Rashid , Kocha Walter I. , Tomiak Anna T. , Truong Pauline T. , Vincent Mark D. , Yu Edward W.
Published: April 2003

Purpose: To determine the impact of continued smoking by patients receiving chemotherapy (CHT) and radiotherapy (RT) for limited-stage small-cell lung cancer (LSCLC) on toxicity and survival.

Patients and Methods: A retrospective review was carried out on 215 patients with LSCLC treated between 1989 and 1999. Treatment consisted of six cycles of alternating cyclophosphamide, doxorubicin, vincristine and etoposide, cisplatin (EP). Thoracic RT was concurrent with EP (cycle 2 or 3) only. Patients were known smokers, with their smoking status recorded at the start of chemoradiotherapy (CHT/RT). RT interruption during concurrent CHT/RT was used as the marker for treatment toxicity.

Results: Of 215 patients, smoking status was recorded for 186 patients (86.5%), with 79 (42%) continuing to smoke and 107 (58%) abstaining during CHT/RT. RT interruptions were recorded in 38 patients (20.5%), with a median duration of 5 days (range, 1 to 18 days). Median survival for former smokers was greater than for continuing smokers (18 v 13.6 months), with 5-year actuarial overall survival of 8.9% versus 4%, respectively (log-rank P = .0017). Proportion of noncancer deaths was comparable between the two cohorts. Continuing smokers did not have a greater incidence of toxicity-related treatment breaks (P = .49), but those who continued to smoke and also experienced a treatment break had the poorest overall survival (median, 13.4 months; log-rank P = .0014).

Conclusion: LSCLC patients who continue to smoke during CHT/RT have poorer survival rates than those who do not. Smoking did not have an impact on the rate of treatment interruptions attributed to toxicity.
Steroidogenic Factor-1 Controls the Aldose Reductase akr1b7 Gene Promoter in Transgenic Mice through an Atypical Binding Site
Authors: Martinez Antoine , Val Pierre , Sahut-Barnola Isabelle , Aigueperse Christelle , Veyssière Georges , Lefrançois-Martinez Anne-Marie
Published: April 2003

Aldo-keto-reductase 1B7/mouse vas deferens protein (AKR1B7/MVDP) is expressed in rodent steroidogenic glands and in the mouse vas deferens. In steroidogenic organs, AKR1B7/MVDP scavenges isocaproaldehyde produced from the cholesterol side-chain cleavage reaction. Akr1b7/mvdp is responsive to ACTH in adrenals and to androgens in vas deferens. Using transgenic mice, we previously delimited the regulatory DNA sequences necessary for expression in both organs and identified by cell transfections, a cryptic steroidogenic factor-1 (SF-1) response element (SFRE) at −102 that overlaps a proximal androgen-responsive element. To address its in vivo functions in adrenals, we devised a transgenic mouse study using wild-type and mutant akr1b7 promoters driving the chloramphenol acetyltransferase reporter gene. Adrenal expression in adults was impaired in all lines mutant for −102 SFRE. This effect is linked to impaired SF-1 binding and not to impaired androgen receptor binding, because akr1b7 expression is not affected in adrenals of androgen receptor-defective Tfm mice. Triphasic developmental patterns of both AKR1B7 and wild-type transgene expression paralleled changes in SF-1 levels/binding activity; expression was maximal in late embryos, minimal in 6- to 15-d-old neonates, and thereafter progressively restored. Differences in developmental expression between wild-type and mutant transgenes revealed that requirement for the −102 SFRE appears stage specific, as its integrity is an absolute prerequisite for reinduction of gene expression after postnatal d 15. Further, mutation of this site did not affect transgene responsiveness to ACTH. These findings demonstrate a new function for SFRE in vivo, via influencing promoter sensibility to postnatal changes of SF-1 contents, in controlling promoter strength in adults without affecting adrenal targeting, hormonal control, or early gene expression.
Activation of p38 Mitogen-Activated Protein Kinase Is Required for Osteoblast Differentiation
Authors: Hu Yuanyu , Chan Emily , Wang Sherry X. , Li Baojie
Published: April 2003

p38 MAPK is a conserved subfamily of MAPKs involved in inflammatory response, stress response, cell growth and survival, as well as differentiation of a variety of cell types. In this report we demonstrated that p38 MAPK played an important role in osteoblast differentiation using primary calvarial osteoblast, bone marrow osteoprecursor culture, and a murine cell line, MC3T3-E1. We found that p38 MAPK was activated as calvarial osteoblast differentiates along with extracellular signal-regulated kinases (ERKs). When p38 MAPK is inhibited with a specific inhibitor, the expression of differentiation markers, such as alkaline phosphatase and mineral deposition, were significantly reduced. MC3T3-E1 cells expressing dominant negative p38 MAPK also displayed signs of delay in ALP and mineral deposition. Differentiation of the bone marrow osteoprecursors was also impeded by the p38 MAPK inhibitor, justified by the same markers. Yet the inhibitory effects observed in calvarial osteoblasts and bone marrow osteoprogenitor cells could be partially prevailed by bone morphogenetic protein-2. Inhibition of ERKs with a specific drug did not significantly affect osteoblast differentiation even though ERK1/2 were also activated during osteoblast differentiation. These results taken together indicate that p38 MAPK, but not ERKs, is necessary for osteoblast differentiation.
New Bone Formation with Teriparatide [Human Parathyroid Hormone-(1–34)] Is Not Retarded by Long-Term Pretreatment with Alendronate, Estrogen, or Raloxifene in Ovariectomized Rats
Authors: Ma Yanfei L. , Bryant Henry U. , Zeng Qingqiang , Schmidt Allen , Hoover Jennifer , Cole Harlan W. , Yao Wei , Jee Webster S. S. , Sato Masahiko
Published: April 2003

With the ready availability of several osteoporosis therapies, teriparatide [human PTH-(1–34)] is likely to be prescribed to postmenopausal women with prior exposure to agents that prevent bone loss, such as bisphosphonates, estrogen, or selective estrogen receptor modulators. Therefore, we evaluated the ability of once daily teriparatide to induce bone formation in ovariectomized (Ovx) rats with extended prior exposure to various antiresorptive agents, such as alendronate (ABP), 17α-ethinyl estradiol (EE), or raloxifene (Ral). Sprague Dawley rats were Ovx and treated with ABP (28 μg/kg, twice weekly), EE (0.1 mg/kg·d), or Ral (1 mg/kg·d) for 10 months before switching to teriparatide 30 μg/kg·d for another 2 months. Analysis of the proximal tibial metaphysis showed that all three antiresorptive agents prevented ovariectomy-induced bone loss after 10 months, but were mechanistically distinct, as shown by histomorphometry. Before teriparatide treatment, ABP strongly suppressed activation frequency and bone formation rate to below levels in other treatment groups, whereas these parameters were not different from sham values for EE or Ral. Trabecular area for ABP, EE, and Ral were greater than that in Ovx controls. However, the trabecular bone effects of ABP were attributed not only to effects on the secondary spongiosa, but also to the preservation of primary spongiosa, which was prevented from remodeling. After 2 months of teriparatide treatment, lumbar vertebra showed relative bone mineral density increases of 18%, 7%, 11%, and 10% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Histomorphometry showed that trabecular area was increased by 105%, 113%, 36%, and 48% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Teriparatide enhanced mineralizing surface, mineral apposition rate, and bone formation rate in all groups. Compression testing of vertebra showed that teriparatide improved strength (peak load) and toughness in all groups to a proportionately similar extent compared with 10 month levels. These data showed a surprising ability of the rat skeleton to respond to teriparatide despite extensive pretreatment with ABP, EE, or Ral. Therefore, the mature skeleton of Ovx rats remains highly responsive to the appositional effects of teriparatide regardless of pretreatment status in terms of cancellous bone area or rate of bone turnover.
Immunolocalization of Estrogen Receptor β in the Mouse Brain: Comparison with Estrogen Receptor α
Authors: Mitra Sudha Warrier , Hoskin Elena , Yudkovitz Joel , Pear Lisset , Wilkinson Hilary A. , Hayashi Shinji , Pfaff Donald W. , Ogawa Sonoko , Rohrer Susan P. , Schaeffer James M. , McEwen Bruce S. , Alves Stephen E.
Published: April 2003

Estrogen receptor α (ERα) and ERβ are members of the steroid nuclear receptor family that modulate gene transcription in an estrogen-dependent manner. ER mRNA and protein have been detected both peripherally and in the central nervous system, with most data having come from the rat. Here we report the development of an ERβ-selective antibody that cross-reacts with mouse, rat, and human ERβ protein and its use to determine the distribution of ERβ in the murine brain. Further, a previously characterized polyclonal antibody to ERα was used to compare the distribution of the two receptors in the first comprehensive description of ER distribution specifically in the mouse brain. ERβ immunoreactivity (ir) was primarily localized to cell nuclei within select regions of the brain, including the olfactory bulb, cerebral cortex, septum, preoptic area, bed nucleus of the stria terminalis, amygdala, paraventricular hypothalamic nucleus, thalamus, ventral tegmental area, substantia nigra, dorsal raphe, locus coeruleus, and cerebellum. Extranuclear-ir was detected in several areas, including fibers of the olfactory bulb, CA3 stratum lucidum, and CA1 stratum radiatum of the hippocampus and cerebellum. Although both receptors were generally expressed in a similar distribution through the brain, nuclear ERα-ir was the predominant subtype in the hippocampus, preoptic area, and most of the hypothalamus, whereas it was sparse or absent from the cerebral cortex and cerebellum. Collectively, these findings demonstrate the region-selective expression of ERβ and ERα in the adult ovariectomized mouse brain. These data provide an anatomical framework for understanding the mechanisms by which estrogen regulates specific neural systems in the mouse.
Evaluation of energy-saving driving styles for bus drivers
Authors: Vangi D , Virga A
Published: April 2003

A procedure is presented for evaluating the performance in terms of driving style of public transport bus drivers, within the context of a programme for energy savings in urban public transportation. The purpose of this evaluation is that of providing suitable tools for training of personnel with the objective of attaining more energy-efficient driving styles and improving driving quality. Quality can be defined as the combination of an energy saving driving style with a behaviour that is respectful of the environment (noise, pollution and safety) and of the vehicle and is comfortable for the passengers as well. Economical driving provides direct savings in fuel of up to 25 per cent as well as indirect savings deriving from general improvements in quality; a more controlled driving style can also be accompanied by reductions in air pollution and noise emission.

The procedure utilizes a fuzzy logic approach and can be implemented aboard vehicles in an automatic monitoring system, the sole requirement being that of measuring the instantaneous road speed of the vehicle and its current load.

The procedure has been developed and validated on the basis of data coming from a test campaign carried out on vehicles equipped with automatic and manual transmission, operating over both urban and intercity itineraries in three different cities, and adopting different driving styles with different drivers. By analysing the results, in relation to the itinerary and conditions of traffic, stops, load, etc., it can be determined which conditions, for each driver, lead to either good or poor performance. Such specific information, together with assessment of the overall driving style, provides useful indications for training drivers, both through training programmes with specific itineraries and trials, and through self-learning processes with the procedure implemented using an on-board monitoring system.
Experimental investigation of the role of soot volatile organic fraction in the regeneration of diesel filters
Authors: Stratakis G A , Konstantas G S , Stamatelos A M
Published: April 2003

This paper involves an experimental investigation of the role of the volatile organic fraction (VOF) adsorbed on the diesel particulate, in the initiation of regeneration of a SiC diesel filters installed on a modern diesel engine, run on catalytic additive-doped fuel. VOF adsorption-desorption and oxidation behaviour is mainly determined by performing a thermogravimetric analysis (TGA) of samples collected directly from a SiC filters installed on the engine running under low- and medium-speed and low- and medium-load conditions, as more representative of city driving. Based on the TGA analysis results, the percentage VOF content in soot was calculated and mapped as a function of engine speed and load in the range of investigation. The effect of adsorbed hydrocarbons on the regeneration behaviour was assessed by comparing regeneration experiments with the stepwise load increase for a filter loaded with soot at different VOF concentration levels. The appearance of a number of incidents of stochastic regeneration behaviour during loading at low exhaust temperatures with a relative high VOF content was observed and discussed. An effort was made to correlate regeneration rate with the VOF content in soot and the prevailing engine operation point during loading. This work aims at better understanding of diesel filter behaviour with modern diesel engines and also aims to support improved modelling of fuel-additive assisted regeneration by use of fuel additives at low temperatures (150-400 °C).
The impact of low levels of carbon dioxide on rats
Authors: Krohn Thomas C. , Hansen Axel Kornerup , Dragsted Nils
Published: April 2003

The widespread use of individually ventilated cage (IVC) systems today has made the impact of CO2 on rodents a highly important matter. Leaving cages from these systems without ventilation increases CO2 concentrations inside the cages, as CO2 generated from the animals is no longer removed actively. In modern IVC systems the CO2 levels may reach 3-5% within a very short time, as the cages are very tightly sealed. The aim of the present study was to investigate the effects of 1%, 3%, and 5% CO2 by studying the preferences of the animals as well as changes in the heart rate and systolic blood pressure as measured by telemetry. The rats avoided the cages, which contained 3% CO2. In the telemetric study an anaesthetic effect on the rats were seen at 3% as a drop in the heart rate, and at 5% CO2 a drop in the systolic blood pressure was also seen. The results from the present study could indicate that CO2 levels of up to 3% do not affect the animals, or at least only to a minor extent, but that if the animals are exposed to CO2 levels of higher than 3% they are affected directly as seen by changes in physiological parameters and preferences.
Blood vessels of the rat tail: a histological re-examination with respect to blood vessel puncture methods
Authors: Staszyk Carsten , Bohnet Willa , Gasse Hagen , Hackbarth Hansjoachim
Published: April 2003

The rat tail vascularization is histologically re-examined especially with respect to blood sampling and vascular-injection methods. The terminal third of the tail is recommended for blood vessel puncturing. In this segment, the arteries and veins are most prominent, since the structures of the musculo-skeletal system diminish towards the tip of the tail. In addition to the commonly-known blood vessels (one ventral artery, two lateral veins), there is a dorsal vein in the rat tail that is well suited for puncture and cannulation.
Faecal corticosterone and immunoglobulin A in young adult rats
Authors: Pihl Liselotte , Hau Jann
Published: April 2003

Quantitative analyses of relevant molecules in faeces may have potential as future non-invasive measures of stress. This study examined levels of faecal corticosterone and immunoglobulin A (IgA) in young adult rats and how these levels varied according to age, gender and time of day. Faecal samples were collected from 40 young adult rats (7 weeks old, n = 20 and 10 weeks old, n = 20) of both sexes from two time windows: day and night. The concentrations of corticosterone and IgA were measured by ELISAs following organic solvent extraction and aqueous extraction, respectively, of the molecules from faecal pellets. The production of faeces per time unit was higher in males than in females, and linear correlations were found between the faecal concentrations of corticosterone and IgA and total amounts of the respective molecules excreted in faeces per kg body weight per hour. In all further analyses the levels of the two molecules were calculated as amounts secreted per kg of body weight per hour. There was no gender difference between females and males in the production of corticosterone and IgA, but 7-week-old animals excreted significantly higher amounts of both molecules than did 10-week-old rats. The levels of IgA excreted by female rats were higher in the evening than in the morning, and male rats excreted higher concentrations of corticosterone in the morning than in the evening.
Competing with New Product Technologies: A Process Model of Strategy
Authors: Das Shobha S. , Van de Ven Andrew H.
Published: April 2003

This paper draws upon research in the economics of technical change and in the social construction of technology to develop and test a process model of strategy. We conducted a longitudinal study of leading firms that were sponsoring new and competing product technologies in two industries: the videoplayer industry and the medical diagnostic imaging industry. We built original datasets on the actions of these firms, and then empirically examined the strategy process. Our findings indicate that the nature of the product technology, whether novel or evolved, and the market, whether concentrated or dispersed, influences when firms use technical or institutional strategies to get their new product technology accepted by the market.
A Time-Oriented Branch-and-Bound Algorithm for Resource-Constrained Project Scheduling with Generalised Precedence Constraints
Authors: Dorndorf Ulrich , Pesch Erwin , Phan-Huy Toàn
Published: April 2003

Resource-constrained project scheduling with generalised precedence constraints is a very general scheduling model with applications in areas such as make-to-order production planning. We describe a time-oriented branch-and-bound algorithm that uses constraint-propagation techniques which actively exploit the temporal and resource constraints of the problem in order to reduce the search space. Extensive computational experiments with systematically generated test problems show that the algorithm solves more problems to optimality than other exact solution procedures which have recently been proposed, and that the truncated version of the algorithm is also a very good heuristic.
Centralization vs. Decentralization in a Multi-Unit Organization: A Computational Model of a Retail Chain as a Multi-Agent Adaptive System
Authors: Chang Myong-Hun , Harrington Joseph E.
Published: April 2003

A computational model of a retail chain is developed in which store managers continually search for better practices. Search takes place over a rugged landscape defined over the space of store practices. The main objective of this research is to determine how the amount of discretion given to store managers as to how they run their stores influences the rate of innovation at the store level. We find that greater decentralization enhances firm performance when stores' markets are sufficiently different, the horizon is sufficiently long, and markets are sufficiently stable.
A Parameter-Free Elicitation of the Probability Weighting Function in Medical Decision Analysis
Authors: Bleichrodt Han , Pinto Jose Luis
Published: April 2003

An important reason why people violate expected utility theory is probability weighting. Previous studies on the probability weighting function typically assume a specific parametric form, exclude heterogeneity in individual preferences, and exclusively consider monetary decision making. This study presents a method to elicit the probability weighting function in rank-dependent expected utility theory that makes no prior assumptions about the functional form of the probability weighting function. We use both aggregate and individual subject data, thereby allowing for heterogeneity of individual preferences, and we examine probability weighting in a new domain, medical decision making. There is significant evidence of probability weighting both at the aggregate and at the individual subject level. The modal probability weighting function is inverse S-shaped, displaying both lower subadditivity and upper subadditivity. Probability weighting is in particular relevant at the boundaries of the unit interval. Compared to studies involving monetary outcomes, we generally find more elevation of the probability weighting function. The robustness of the empirical findings on probability weighting indicates its importance. Ignoring probability weighting in modeling decision under risk and in utility measurement is likely to lead to descriptively invalid theories and distorted elicitations.
Coordination of Pricing and Multiple-Period Production Across Multiple Constant Priced Goods
Authors: Gilbert Stephen M.
Published: April 2003

This paper addresses the problem of jointly determining prices and production schedules for a set of items that are produced on the same production equipment. Under the assumptions that the production setup costs are negligible and that demand is seasonal but price dependent, we exploit the special structure of the problem to develop a solution procedure. Through a set of numerical examples, we demonstrate how a product's contribution to aggregate seasonality can increase its optimal price. Our examples also demonstrate that, among products that experience demand peaks during the firm's busy season, those that peak early in the busy season should be priced more aggressively than those that peak later.
Third Degree Stochastic Dominance and Mean-Risk Analysis
Authors: Gotoh Jun-ya , Konno Hiroshi
Published: April 2003

In their recent article, Ogryczak and Ruszczyński (1999) proved that those portfolios associated with the efficient frontiers generated by mean-lower semi-standard deviation model and mean- (lower semi-)absolute deviation model are efficient in the sense of second degree stochastic dominance. This rather surprising result reveals the importance of lower partial risk models in portfolio analysis.

In this paper, we extend the results of Ogryczak and Ruszczyński for second degree stochastic dominance to third degree stochastic dominance. We show that portfolios on a significant portion of the efficient frontier generated by mean-lower semi-skewness model are efficient in the sense of third degree stochastic dominance. Also, we prove that the portfolios generated by mean-variance-skewness model are semi-efficient in the sense of third degree stochastic dominance.
The Effects of Coefficient Correlation Structure in Two-Dimensional Knapsack Problems on Solution Procedure Performance
Authors: Hill Raymond R. , Reilly Charles H.
Published: April 2003

This paper presents the results of an empirical study of the effects of coefficient correlation structure and constraint slackness settings on the performance of solution procedures on synthetic two-dimensional knapsack problems (2KP). The population correlation structure among 2KP coefficients, the level of constraint slackness, and the type of correlation (product moment or rank) are varied in this study. Representative branch-and-bound and heuristic solution procedures are used to investigate the influence of these problem parameters on solution procedure performance. Population correlation structure, and in particular the interconstraint component of the correlation structure, is found to be a significant factor influencing the performance of both the algorithm and the heuristic. In addition, the interaction between constraint slackness and population correlation structure is found to influence solution procedure performance.
Optimal Control of Drug Epidemics: Prevent and Treat—But Not at the Same Time?
Authors: Behrens Doris A. , Caulkins Jonathan P. , Tragler Gernot , Feichtinger Gustav
Published: April 2003

Drug use and related problems change substantially over time, so it seems plausible that drug interventions should vary too. To investigate this possibility, we set up a continuous time version of the first-order difference equation model of cocaine use introduced by Everingham and Rydell (1994), extended to make initiation an endogenous function of prevalence. We then formulate and solve drug treatment and prevention spending decisions in the framework of dynamic optimal control under different assumptions about how freely drug control budgets can be manipulated. Insights include: (1) The effectiveness of prevention and treatment depend critically on the stage in the epidemic in which they are employed. Prevention is most appropriate when there are relatively few heavy users, e.g. in the beginning of an epidemic. Treatment is more effective later. (2) Hence, the optimal mix of interventions varies over time. (3) The transition period when it is optimal to use extensively both prevention and treatment is brief. (4) Total social costs increase dramatically if control is delayed.