bluuebunny/crossref_metadata_2025 huggingface dataset:
Which diagnostic tests are most useful in a chest pain unit protocol?
Authors: Goodacre Steve , Locker Thomas , Arnold Jane , Angelini Karen , Morris Francis
Published: August 2005

Background

The chest pain unit (CPU) provides rapid diagnostic assessment for patients with acute, undifferentiated chest pain, using a combination of electrocardiographic (ECG) recording, biochemical markers and provocative cardiac testing. We aimed to identify which elements of a CPU protocol were most diagnostically and prognostically useful.

Methods

The Northern General Hospital CPU uses 2–6 hours of serial ECG / ST segment monitoring, CK-MB(mass) on arrival and at least two hours later, troponin T at least six hours after worst pain and exercise treadmill testing. Data were prospectively collected over an eighteen-month period from patients managed on the CPU. Patients discharged after CPU assessment were invited to attend a follow-up appointment 72 hours later for ECG and troponin T measurement. Hospital records of all patients were reviewed to identify adverse cardiac events over the subsequent six months. Diagnostic accuracy of each test was estimated by calculating sensitivity and specificity for: 1) acute coronary syndrome (ACS) with clinical myocardial infarction and 2) ACS with myocyte necrosis. Prognostic value was estimated by calculating the relative risk of an adverse cardiac event following a positive result.

Results

Of the 706 patients, 30 (4.2%) were diagnosed as ACS with myocardial infarction, 30 (4.2%) as ACS with myocyte necrosis, and 32 (4.5%) suffered an adverse cardiac event. Sensitivities for ACS with myocardial infarction and myocyte necrosis respectively were: serial ECG / ST segment monitoring 33% and 23%; CK-MB(mass) 96% and 63%; troponin T (using 0.03 ng/ml threshold) 96% and 90%. The only test that added useful prognostic information was exercise treadmill testing (relative risk 6 for cardiac death, non-fatal myocardial infarction or arrhythmia over six months).

Conclusion

Serial ECG / ST monitoring, as used in our protocol, adds little diagnostic or prognostic value in patients with a normal or non-diagnostic initial ECG. CK-MB(mass) can rule out ACS with clinical myocardial infarction but not myocyte necrosis(defined as a troponin elevation without myocardial infarction). Using a low threshold for positivity for troponin T improves sensitivity of this test for myocardial infarction and myocardial necrosis. Exercise treadmill testing predicts subsequent adverse cardiac events.
Pharmacological challenge with a serotonin 1D agonist in alcohol dependence
Authors: Vythilingum Bavanisha , Hugo Charmaine J , Maritz J Stefan , Pienaar Willie , Stein Dan J
Published: August 2005

Background

Both animal and clinical studies have implicated serotonergic dysfunction in the pathogenesis of alcohol abuse and dependence. However the exact mechanisms involved remain unknown. Theoretically, low serotonin promotes alcohol seeking behavior. Sumatriptan is a serotonin1D agonist. It is postulated that sumatriptan's agonism at this terminal autoreceptor increases negative feedback, creating a net effect of decreased serotonergic neurotransmission. Administration of sumatriptan should therefore produce a craving for alcohol and the desire to drink.

Methods

Fifteen patients with alcohol dependence who had undergone detoxification were recruited. Sumatriptan (100 mg) and placebo was administered in cross-over fashion on 2 separate days 72 hours apart. Both patients and raters were blind to all treatments.

Patients were assessed on the following scales at -30, 0, 30, 90, 150 and 210 minutes: A 6-item scale designed to rate the patient's intention to drink; The Sensation Scale; a 13-item affect analog scale designed to rate the pattern and extent of emotional changes; and an 8-item scale designed to rate the patient's craving for alcohol

Results

No significant differences were found between the placebo and sumatriptan groups and no significant cross over effects were found.

Conclusion

The general lack of efficacy of sumatriptan in producing alcohol-like symptoms or a desire to drink alcohol may suggest that the 5HT1D receptor plays little role in the pathophysiology of alcoholism.
The characteristics of suicides within a week of discharge after psychiatric hospitalisation – a nationwide register study
Authors: Pirkola Sami , Sohlman Britta , Wahlbeck Kristian
Published: August 2005

Background

The characteristics of victims of immediate post-discharge suicides are not well known. We explored these characteristics for the purposes of better recognition and preventive efforts of potential immediate post-discharge suicides.

Methods

Suicides from a Finnish nationwide register were linked with preceding periods of psychiatric inpatient treatment. Characteristics of suicides within a week of discharge were compared to those occurring later after discharge.

Results

Compared to other previously hospitalised suicide victims, those committing suicide within a week of discharge were more often female, unmarried, had a higher grade of education and a diagnosis of schizophrenia spectrum or affective disorder, tended to use more drowning and jumping from heights as the methods for suicide and had gained a smaller improvement in psychological functioning during hospitalization.

Conclusion

These characteristics indicate a more severe psychopathology, relatively poorer level of functioning, less global response to hospitalisation, and a more frequent choice of lethal and easily available method for suicide. Potentially suicidal psychiatric patients should be better recognized and an immediate follow-up arranged if it is decided they be discharged.
Heart failure guidelines and prescribing in primary care across Europe
Authors: Sturm Heidrun B , van Gilst Wiek H , Swedberg Karl , Hobbs FD Richard , Haaijer-Ruskamp Flora M
Published: August 2005

Background

Major international differences in heart failure treatment have been repeatedly described, but the reasons for these differences remain unclear. National guideline recommendations might be a relevant factor. This study, therefore, explored variation of heart failure guideline recommendations in Europe.

Methods

Treatment recommendations of 14 national guidelines published after 1994 were analyzed in relation to the heart failure treatment guideline of the European Society of Cardiology. To test potential relations between recommendations and prescribing, national prescribing patterns as obtained by a European study in primary care (IMPROVEMENT-HF) were related to selected recommendations in those countries.

Results

Besides the 14 national guidelines used by primary care physicians in the countries contacted, the European guideline was used in four countries, and separate guidelines for specialists and primary care were available in another four countries. Two countries indicated that no guideline was used up to 2000. Comprehensiveness of the guidelines varied with respect to length, literature included and evidence ratings. Relevant differences in treatment recommendations were seen only in drug classes where evidence had changed recently (β-blockers and spironolactone). The relation between recommendation and prescribing for selected recommendations was inconsistent among countries.

Conclusion

Differences in guideline recommendations are not sufficient to explain variation of prescribing among countries, thus other factors must be considered.
Implementations of translational medicine
Authors: Sonntag Kai-Christian
Published: August 2005

New developments in science are rapidly influencing and shaping basic and clinical research and medicine. This has led to the emergence of multiple opportunities and challenges on many levels in the bio-medical and other associated fields. To face these opportunities and challenges, new concepts and strategies are needed. These can be provided by translational research/medicine as an integrative concept based on a multidirectional understanding of research and medicine embedded in a socio-economical environment. Although the implementation of translational research/medicine faces many obstacles, some of its goals have already been part of new programs in local institutions and in medical or scientific societies. These implementations are important in creating a unified national and international system of translational research/medicine.
Adenomatoid odontogenic tumor of the mandible: review of the literature and report of a rare case
Authors: Handschel Jörg GK , Depprich Rita A , Zimmermann André C , Braunstein Stefan , Kübler Norbert R
Published: August 2005

Adenomatoid odontogenic tumor (AOT) is a rare odontogenic tumor which is often misdiagnosed as odontogenic cyst. To acquire additional information about AOT, all reports regarding AOT and cited in "pubmed" since 1990 onward were reviewed. AOT accounts for about 1% until 9% of all odontogenic tumors. It is predominantly found in young and female patients, located more often in the maxilla in most cases associated with an uneruppted permanent tooth. For radiological diagnose the intraoral periapical radiograph seems to be more useful than panoramic. However, AOT frequently resemble other odontogenic lesions such as dentigerous cysts or ameloblastoma. Immunohistochemically AOT is characterized by positive reactions with certain cytokeratins. Treatment is conservative and the prognosis is excellent. For illustration a rare case of an AOT in the mandible is presented.
Vascular basis of mucosal color
Authors: Kleinheinz Johannes , Büchter André , Fillies Thomas , Joos Ulrich
Published: August 2005

Background

Besides the color of the teeth the color of the alveolar gingiva plays a crucial role in esthetic rehabilitation in dento-alveolar treatment. Whereas nowadays the color of the teeth can be determined exactly and individually, the specific influence of the red color of the gingiva on treatment has not been assessed yet. The aim of this study was to evaluate the vascularization as the basis for gingival esthetics.

Methods

Standardized photographs of defined areas of the alveolar gingiva in operated and non-operated patients were taken and assigned to groups with same characteristics after color comparisons. In addition, histologic and immunohistologic analyses of gingival specimens were performed for qualitative and quantitative assessment of vessels and vascularization. Finally, colors and number of vessels were correlated.

Results

Our results demonstrated three different constellations of colors of the alveolar gingiva in healthy patients. The operated patients could not be grouped because of disparate depiction. There was a clear correlation between color and vessel number in the alveolar gingiva.

Conclusion

Our investigations revealed the connections between vascularization and gingival color. Recommendations for specific change or even selection of colors based on the results cannot be given, but the importance of vascularly based incision lines was demonstrated.
Pro-inflammatory properties of stromal cell-derived factor-1 (CXCL12) in collagen-induced arthritis
Authors: De Klerck Bert , Geboes Lies , Hatse Sigrid , Kelchtermans Hilde , Meyvis Yves , Vermeire Kurt , Bridger Gary , Billiau Alfons , Schols Dominique , Matthys Patrick
Published: August 2005

CXCL12 (stromal cell-derived factor 1) is a unique biological ligand for the chemokine receptor CXCR4. We previously reported that treatment with a specific CXCR4 antagonist, AMD3100, exerts a beneficial effect on the development of collagen-induced arthritis (CIA) in the highly susceptible IFN-γ receptor-deficient (IFN-γR KO) mouse. We concluded that CXCL12 plays a central role in the pathogenesis of CIA in IFN-γR KO mice by promoting delayed type hypersensitivity against the auto-antigen and by interfering with chemotaxis of CXCR4+ cells to the inflamed joints. Here, we investigated whether AMD3100 can likewise inhibit CIA in wild-type mice and analysed the underlying mechanism. Parenteral treatment with the drug at the time of onset of arthritis reduced disease incidence and modestly inhibited severity in affected mice. This beneficial effect was associated with reduced serum concentrations of IL-6. AMD3100 did not affect anti-collagen type II antibodies and, in contrast with its action in IFN-γR KO mice, did not inhibit the delayed type hypersensitivity response against collagen type II, suggesting that the beneficial effect cannot be explained by inhibition of humoral or cellular autoimmune responses. AMD3100 inhibited the in vitro chemotactic effect of CXCL12 on splenocytes, as well as in vivo leukocyte infiltration in CXCL12-containing subcutaneous air pouches. We also demonstrate that, in addition to its effect on cell infiltration, CXCL12 potentiates receptor activator of NF-κB ligand-induced osteoclast differentiation from splenocytes and increases the calcium phosphate-resorbing capacity of these osteoclasts, both processes being potently counteracted by AMD3100. Our observations indicate that CXCL12 acts as a pro-inflammatory factor in the pathogenesis of autoimmune arthritis by attracting inflammatory cells to joints and by stimulating the differentiation and activation of osteoclasts.
Percentage density, Wolfe's and Tabár's mammographic patterns: agreement and association with risk factors for breast cancer
Authors: Gram Inger T , Bremnes Yngve , Ursin Giske , Maskarinec Gertraud , Bjurstam Nils , Lund Eiliv
Published: August 2005

Introduction

The purpose of this report was to classify mammograms according to four methods and to examine their agreement and their relationship to selected risk factors for breast cancer.

Method

Mammograms and epidemiological data were collected from 987 women, aged 55 to 71 years, attending the Norwegian Breast Cancer Screening Program. Two readers each classified the mammograms according to a quantitative method (Cumulus or Madena software) and one reader according to two qualitative methods (Wolfe and Tabár patterns). Mammograms classified in the reader-specific upper quartile of percentage density, Wolfe's P2 and DY patterns, or Tabár's IV and V patterns, were categorized as high-risk density patterns and the remaining mammograms as low-risk density patterns. We calculated intra-reader and inter-reader agreement and estimated prevalence odds ratios of having high-risk mammographic density patterns according to selected risk factors for breast cancer.

Results

The Pearson correlation coefficient was 0.86 for the two quantitative density measurements. There was moderate agreement between the Wolfe and Tabár classifications (Kappa = 0.51; 95% confidence interval 0.46 to 0.56). Age at screening, number of children and body mass index (BMI) showed a statistically significant inverse relationship with high-risk density patterns for all four methods (all P < 0.05). After adjustment for percentage density, the Wolfe classification was not associated with any of the risk factors for breast cancer, whereas the association with number of children and BMI remained statistically significant for the Tabár classification. Adjustment for Wolfe or Tabár patterns did not alter the associations between these risk factors and percentage mammographic density.

Conclusion

The four assessments methods seem to capture the same overall associations with risk factors for breast cancer. Our results indicate that the quantitative methods convey additional information over the qualitative methods.
Induction of surface CCR4 and its functionality in mouse Th2 cells is regulated differently during Th2 development
Authors: Morimoto Yasunari , Bian Yang , Gao Ping , Yashiro-Ohtani Yumi , Zhou Xu-Yu , Ono Shiro , Nakahara Hirokazu , Kogo Mikihiko , Hamaoka Toshiyuki , Fujiwara Hiromi
Published: August 2005

T helper cell type 1 (Th1) and Th2 cells express distinct sets of chemokine receptors. In contrast to Th1 chemokine receptors, it is largely unknown how Th2 chemokine receptors such as CC chemokine receptor 4 (CCR4) are induced during Th2 differentiation. Here, we investigated the induction of CCR4 surface expression and ligand responsiveness evaluated by functional assays such as chemokine binding and chemotaxis. This was done in comparison with those of a Th1 chemokine receptor, CXC chemokine receptor 3 (CXCR3). Resting T cells expressed neither CXCR3 nor CCR4. CXCR3 expression and ligand responsiveness were observed when resting T cells were stimulated with anti-CD3 plus anti-CD28 in the presence of [interleukin (IL)-12+anti-IL-4] and then recultured without T cell receptor (TCR) stimulation. Unlike CXCR3, CCR4 was induced immediately after anti-CD3/anti-CD28 stimulation in the presence of (IL-4+anti-interferon-γ+anti-IL-12). However, these CCR4-positive cells failed to exhibit chemokine binding and chemotaxis. Although the levels of surface CCR4 expression were not increased after the subsequent reculture in the absence of TCR stimulation, CCR4 responsiveness was induced in this stage of Th2 cells. The induction of CCR4 expression and the acquisition of CCR4 responsiveness did not occur in IL-4-deficient (IL-4–/–) and signal transducer and activator of transcription (STAT)6–/– T cells. CCR4 expression and functionality were regained in IL-4–/– but not in STAT6–/– T cells by the addition of recombinant IL-4. Although surface expression and functionality of CCR4 are induced depending on the IL-4/STAT6 signaling pathway, the present results indicate that the functionality of CCR4 does not correlate with CCR4 expression but emerges at later stages of Th2 differentiation.
Loss of Heterozygosity for Chromosomes 1p and 16q Is an Adverse Prognostic Factor in Favorable-Histology Wilms Tumor: A Report From the National Wilms Tumor Study Group
Authors: Grundy Paul E. , Breslow Norman E. , Li Sierra , Perlman Elizabeth , Beckwith J. Bruce , Ritchey Michael L. , Shamberger Robert C. , Haase Gerald M. , D'Angio Giulio J. , Donaldson Milton , Coppes Max J. , Malogolowkin Marcio , Shearer Patricia , Thomas Patrick R.M. , Macklis Roger , Tomlinson Gail , Huff Vicki , Green Daniel M.
Published: August 2005

Purpose

To determine if tumor-specific loss of heterozygosity (LOH) for chromosomes 1p or 16q is associated with a poorer prognosis for children with favorable-histology (FH) Wilms tumor entered on the fifth National Wilms Tumor Study (NWTS-5).

Patients and Methods

Between August 1995 and June 2002, 2,021 previously untreated children with FH or anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK) or malignant rhabdoid tumor of the kidney (RTK), were treated with stage- and histology-specific therapy. Their tumors were assayed for LOH for polymorphic DNA markers on chromosomes 1p and 16q.

Results

LOH for 1p or 16q was rarely observed in CCSK (n = 90) or RTK (n = 22). The relative risk (RR) of relapse for patients with FH stage I to IV tumors with LOH, stratified by stage, was 1.56 for LOH 1p (P = .01) and 1.49 for LOH 16q (P = .01), whereas the RR of death was 1.84 (P = .03) and 1.44 (P = .15), respectively. When the effects of LOH for both regions were considered jointly among patients with stage I to II FH disease, the risks of relapse and death were increased for LOH 1p only (RR = 2.2, P = .02 for relapse; RR = 4.0, P = .02 for death), for LOH 16q only (RR = 1.9, P = .01 and RR = 1.4, P = .60) and for LOH for both regions (RR = 2.9, P = .001 and RR = 4.3, P = .01) in comparison with patients with LOH at neither locus. The risks of relapse and death for patients with stage III to IV FH tumors were increased only with LOH for both regions (RR = 2.4, P = .01 and RR = 2.7, P = .04).

Conclusion

Tumor-specific LOH for both chromosomes 1p and 16q identifies a subset of FH Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.
Breast Cancer Prognosis Determined by Gene Expression Profiling: A Quantitative Reverse Transcriptase Polymerase Chain Reaction Study
Authors: Espinosa E. , Vara J.A. Fresno , Redondo A. , Sánchez J.J. , Hardisson D. , Zamora P. , Pastrana F. Gómez , Cejas P. , Martínez B. , Suárez A. , Calero F. , Barón M. González
Published: August 2005

Purpose

We sought to reproduce with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) the results obtained with a 70-gene expression profile that has been described previously in breast cancer.

Patients and Methods

Frozen breast cancer samples from patients who were operated on were used to isolate tumor RNA. Ninety-six patients with stage I to II disease were included. Median age was 57 years (range, 27 to 80 years). Forty-eight patients had lymph node–negative and 48 lymph node–positive disease. qRT-PCR amplifications were performed and the results were correlated with clinical data.

Results

After a minimum follow-up of 5 years, 25 patients had a relapse. The gene profile divided patients into two groups with poor and good prognosis. Significant differences with regard to grade of differentiation, size and hormone receptors were seen between the two groups. The gene profile was significantly associated with relapse-free survival and overall survival in the whole group of 96 patients. Multivariate analysis showed that only lymph node status and gene profile were significantly correlated to overall survival.

Conclusion

qRT-PCR reproduced the results obtained with microarrays for a prognostic gene profile in women with early-stage breast cancer.
Impact of Five Prophylactic Filgrastim Schedules on Hematologic Toxicity in Early Breast Cancer Patients Treated With Epirubicin and Cyclophosphamide
Authors: Papaldo Paola , Lopez Massimo , Marolla Paolo , Cortesi Enrico , Antimi Mauro , Terzoli Edmondo , Vici Patrizia , Barone Carlo , Ferretti Gianluigi , Di Cosimo Serena , Carlini Paolo , Nisticò Cecilia , Conti Francesca , Di Lauro Luigi , Botti Claudio , Di Filippo Franco , Fabi Alessandra , Giannarelli Diana , Calabresi Federico
Published: August 2005

Purpose

To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC).

Patients and Methods

From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 × 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles ± lonidamine ± G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 μg/d subcutaneously days 8 to 14; (2) 480 μg/d days 8, 10, 12, and 14; (3) 300 μg/d days 8 to 14; (4) 300 μg/d days 8, 10, 12, and 14; and (5) 300 μg/d days 8 and 12.

Results

All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non–G-CSF arms.

Conclusion

In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.
Clinical Outcomes in t(4;14) Multiple Myeloma: A Chemotherapy-Sensitive Disease Characterized by Rapid Relapse and Alkylating Agent Resistance
Authors: Jaksic Wilfrid , Trudel Suzanne , Chang Hong , Trieu Young , Qi Xi , Mikhael Joseph , Reece Donna , Chen Christine , Stewart A. Keith
Published: August 2005

Purpose

To determine whether primary drug resistance or rapid relapse explains the poor prognosis seen in t(4;14)-positive multiple myeloma (MM).

Patients and Methods

A total of 131 patients treated with high-dose therapy (HDT) were assessed, of whom 19 were t(4;14) positive. We examined the presentation features, chemotherapy responsiveness at presentation and to salvage therapies at relapse, and overall survival outcomes.

Results

t(4;14)-positive patients had a predominance of the immunoglobulin A isotype (52.6%) but otherwise baseline characteristics were indistinguishable. After treatment with vincristine, doxorubicin, and dexamethasone or dexamethasone alone, 17 (89.7%) of the 19 patients achieved a partial response and 11 patients (57.9%) demonstrated an additional 50% reduction in paraprotein after HDT. Thus, t(4;14)-positive patients are chemotherapy sensitive; however, early progression was common, with 26% of patients progressing before HDT and a median progression-free survival after HDT of only 14.1 months. At relapse, a resistance to alkylating agents was evident, with no responses (zero of 11 patients) seen with conventional-dose alkylating agents. Salvage regimens using thalidomide and/or dexamethasone achieved at least minimal response in 59% of patients. The duration of response was short, however, with a median of only 4.7 months. The median overall survival after HDT was 24.2 months.

Conclusion

We conclude that t(4;14)-positive MM is chemotherapy sensitive but rapid relapse occurs. Resistance to alkylating agents is evident at relapse. The development of novel therapeutic agents is required, including the early clinical study of targeted fibroblast growth factor receptor 3 tyrosine kinase inhibitors, which have shown promise in preclinical studies.
Medroxyprogesterone Acetate Induces Cell Proliferation through Up-Regulation of Cyclin D1 Expression via Phosphatidylinositol 3-Kinase/Akt/Nuclear Factor-κB Cascade in Human Breast Cancer Cells
Authors: Saitoh Maki , Ohmichi Masahide , Takahashi Kazuhiro , Kawagoe Jun , Ohta Tsuyoshi , Doshida Masakazu , Takahashi Toshifumi , Igarashi Hideki , Mori-Abe Akiko , Du Botao , Tsutsumi Seiji , Kurachi Hirohisa
Published: August 2005

The mechanism of medroxyprogesterone acetate (MPA)-induced cell proliferation in human breast cancer cells remains elusive. We examined the mechanism by which MPA affects the cyclin D1 expression in progesterone receptor (PR)-positive T47D human breast cancer cells. MPA (10 nm) treatment for 48 h induced proliferation of the cells (1.6-fold induction). MPA induced cyclin D1 expression (3.3-fold induction), and RU486, a selective PR antagonist, blocked the MPA-induced cell proliferation and cyclin D1 expression (23% inhibition). MPA increased both the protein level (2.2-fold induction) and promoter activity (2.7-fold induction) of cyclin D1 in MCF-7 cells transfected with PRB but not with PRA. Although MPA transcriptionally activated cyclin D1 expression, cyclin D1 promoter does not have progesterone-responsive element-related sequence. We further examined the mechanism for the regulation of the cyclin D1 expression. Because the cyclin D1 promoter contains three putative nuclear factor-κB (NFκB)-binding motifs and NFκB is a substrate of Akt, we investigated the effect of the phosphatidylinositol 3-kinase (PI3K)/Akt/NFκB cascade on the responses of cyclin D1 to MPA. MPA induced the transient phosphorylation of Akt (2.7-fold induction at 5 min), and treatment with PI3K inhibitor (wortmannin) attenuated the MPA-induced up-regulation of cyclin D1 expression (40% inhibition) and cell proliferation (40% inhibition). MPA also induced phosphorylation of inhibitor of NFκBα (IκBα) (2.3-fold induction), and treatment with wortmannin attenuated the MPA-induced IκBα phosphorylation (60% inhibition). Treatment with an IκBα phosphorylation inhibitor (BAY 11-7085) or a specific NFκB nuclear translocation inhibitor (SN-50) attenuated the MPA-induced up-regulation of both cyclin D1 expression (80 and 50% inhibition, respectively) and cell proliferation (55 and 34% inhibition, respectively). Because MPA induced a transient phosphorylation of Akt and the cyclin D1 promoter contains no progesterone-responsive element-related sequence, the MPA-induced cell proliferation through PRB by up-regulation of cyclin D1 expression via the PI3K/Akt/NFκB cascade may be a nongenomic mechanism.
Tau Is Hyperphosphorylated in the Insulin-Like Growth Factor-I Null Brain
Authors: Cheng Clara M. , Tseng Victor , Wang Jie , Wang Daniel , Matyakhina Ludmila , Bondy Carolyn A.
Published: August 2005

IGF action has been implicated in the promotion of oxidative stress and aging in invertebrate and murine models. However, some in vitro models suggest that IGF-I specifically prevents neuronal oxidative damage. To investigate whether IGF-I promotes or retards brain aging, we evaluated signs of oxidative stress and neuropathological aging in brains from 400-d-old Igf1−/− and wild-type (WT) mice. Lipofuscin pigment accumulation reflects oxidative stress and aging, but we found no difference in lipofuscin deposition in Igf1−/− and WT brains. Likewise, there was no apparent difference in accumulation of nitrotyrosine residues in Igf1−/− and WT brains, except for layer IV/V of the cerebral cortex, where these proteins were about 20% higher in the Igf1−/− brain (P = 0.03). We found no difference in the levels of oxidative stress-related enzymes, neuronal nitric oxide synthase, inducible nitric oxide synthase, and superoxide dismutase in Igf1−/− and WT brains. Tau is a microtubule-associated protein that causes the formation of neurofibrillary tangles and senile plaques as it becomes hyperphosphorylated in the aging brain. Tau phosphorylation was dramatically increased on two specific residues, Ser-396 and Ser-202, both glycogen synthase kinases target sites implicated in neurodegeneration. These observations indicate that IGF-I has a major role in regulating tau phosphorylation in the aging brain, whereas its role in promoting or preventing oxidative stress remains uncertain.
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) as a Growth Hormone (GH)-Releasing Factor in Grass Carp. I. Functional Coupling of Cyclic Adenosine 3′,5′-Monophosphate and Ca2+/Calmodulin-Dependent Signaling Pathways in PACAP-Induced GH Secretion and GH Gene Expression in Grass Carp Pituitary Cells
Authors: Wong Anderson O. L. , Li Wensheng , Leung Ching Yu , Huo Longfei , Zhou Hong
Published: August 2005

Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the glucagon/secretin peptide family, has been recently proposed to be the ancestral GH-releasing factor. Using grass carp as a model for bony fish, we examined the mechanisms for PACAP regulation of GH synthesis and secretion at the pituitary level. Nerve fibers with PACAP immunoreactivity were identified in the grass carp pituitary overlapping with the distribution of somatotrophs. At the somatotroph level, PACAP was shown to induce cAMP synthesis and Ca2+ entry through voltage-sensitive Ca2+ channels (VSCC). In carp pituitary cells, PACAP but not vasoactive intestinal polypeptide increased GH release, GH content, total GH production, and steady-state GH mRNA levels. PACAP also enhanced GH mRNA stability, GH promoter activity, and nuclear expression of GH primary transcripts. Increasing cAMP levels, induction of Ca2+ entry, and activation of VSCC were all effective in elevating GH secretion and GH mRNA levels. PACAP-induced GH secretion and GH mRNA expression, however, were abolished by inhibiting adenylate cyclase and protein kinase A, removing extracellular Ca2+ or VSCC blockade, or inactivating calmodulin (CaM)-dependent protein kinase II (CaM kinase II). Similar sensitivity to VSCC and CaM kinase II blockade was also observed by activating cAMP production as a trigger for GH release and GH gene expression. These results suggest that PACAP stimulates GH synthesis and secretion in grass carp pituitary cells through PAC1 receptors. These stimulatory actions probably are mediated by the adenylate cyclase/cAMP/protein kinase A pathway coupled to Ca2+ entry via VSCC and subsequent activation of CaM/CaM kinase II cascades.
Acetate and Propionate Short Chain Fatty Acids Stimulate Adipogenesis via GPCR43
Authors: Hong Yeon-Hee , Nishimura Yukihiko , Hishikawa Daisuke , Tsuzuki Hiroaki , Miyahara Hisae , Gotoh Chizu , Choi Ki-Choon , Feng Dan Dan , Chen Chen , Lee Hong-Gu , Katoh Kazuo , Roh Sang-Gun , Sasaki Shinichi
Published: August 2005

It has recently been discovered that G protein-coupled receptors (GPCR) 41 and 43 are characterized by having the short chain fatty acids acetate and propionate as their ligands. The objective of this study was to investigate the involvement of GPCR41, GPCR43, and their ligands in the process of adipogenesis. We measured the levels of GPCR41 and GPCR43 mRNA in both adipose and other tissues of the mouse. GRP43 mRNA expression was higher in four types of adipose tissue than in other tissues, whereas GPCR41 mRNA was not detected in any adipose tissues. A high level of GPCR43 expression was found in isolated adipocytes, but expression level was very low in stromal-vascular cells. Expression of GPCR43 was up-regulated in adipose tissues of mice fed a high-fat diet compared with those fed a normal-fat diet. GPCR43 mRNA could not be detected in confluent and undifferentiated 3T3-L1 adipocytes; however, the levels rose with time after the initiation of differentiation. GPCR41 expression was not detected in confluent and differentiated adipocytes. Acetate and propionate treatments increased lipids present as multiple droplets in 3T3-L1 adipocytes. Propionate significantly elevated the level of GPCR43 expression during adipose differentiation, with up-regulation of PPAR-γ2. Small interfering RNA mediated a reduction of GPCR43 mRNA in 3T3-L1 cells and blocked the process of adipocyte differentiation. In addition, both acetate and propionate inhibited isoproterenol-induced lipolysis in a dose-dependent manner. We conclude that acetate and propionate short chain fatty acids may have important physiological roles in adipogenesis through GPCR43, but not through GPCR41.
Rapid Estrogenic Regulation of Extracellular Signal- Regulated Kinase 1/2 Signaling in Cerebellar Granule Cells Involves a G Protein- and Protein Kinase A-Dependent Mechanism and Intracellular Activation of Protein Phosphatase 2A
Authors: Belcher Scott M. , Le Hoa H. , Spurling Lynda , Wong Jeremy K.
Published: August 2005

In neonatal rat cerebellar neurons, 17β-estradiol (E2) rapidly stimulates ERK1/2 phosphorylation through a membrane-associated receptor. Here the mechanism of rapid E2-induced ERK1/2 signaling in primary cultured granule cells was investigated in more detail. The results of these studies show that E2 and ICI182,780, a steroidal antagonist of estrogen receptor transactivation, rapidly increased ERK signaling with a time course similar to the transient activation induced by epidermal growth factor (EGF). However, EGF receptor (EGFR) autophosphorylation was not increased by E2, and blockade of EGFR tyrosine kinase activity did not abrogate the rapid actions of E2. The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E2 and by blockade of E2-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity. Inhibition of Gαi signaling or protein kinase A (PKA) activity blocked the ability of ICI182,780 to rapidly stimulate ERK signaling. Under those conditions, E2 treatment induced a rapid and transient suppression of basal ERK1/2 phosphorylation. Protein phosphatase 2A (PP2A) activity was rapidly increased by E2 but not by E2 covalently linked to BSA. Rapid E2-induced increases in PP2A activity were insensitive to pertussis toxin. The presented evidence indicates that the rapid effects of estrogens on ERK signaling in cerebellar granule cells are induced through a novel G protein-coupled receptor mechanism that requires PKA and Src-kinase activity to link E2 to the ERK/MAPK signaling module. Along with stimulating ERK signaling, E2 rapidly activates PP2A via an independent signaling mechanism that may serve as a cell-specific regulator of signal duration.
Regulation of Glucagon Secretion at Low Glucose Concentrations: Evidence for Adenosine Triphosphate-Sensitive Potassium Channel Involvement
Authors: Muñoz Alvaro , Hu Min , Hussain Khalid , Bryan Joseph , Aguilar-Bryan Lydia , Rajan Arun S.
Published: August 2005

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic α-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/KIR6.2-type ATP-sensitive K+ (KATP) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type KATP channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca2+ and is inhibited by nifedipine. Consistent with a regulatory interaction between KATP channels and intra-islet zinc-insulin, WT islets exhibit an inverse correlation between β-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of α-cell KATP channels uncouples glucagon release from inhibition by β-cells and reveals a role for KATP channels in the regulation of glucagon release by low glucose.
Prolactin Specifically Activates Signal Transducer and Activator of Transcription 5b in Neuroendocrine Dopaminergic Neurons
Authors: Ma Frank Y. , Anderson Greg M. , Gunn Travis D. , Goffin Vincent , Grattan David R. , Bunn Stephen J.
Published: August 2005

The hypothalamic neuroendocrine dopaminergic (NEDA) neurons are crucial in regulating prolactin secretion from the anterior pituitary. Rising prolactin concentrations stimulate these neurons to secrete dopamine, which acts via the pituitary portal vasculature to inhibit additional prolactin release. Prolactin is known to activate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathways in other cell types, including neurons. The possible role of JAK-STAT signaling in NEDA neurons has therefore been examined in this study using fetal rat mediobasal hypothalamic cell cultures and an adult rat in vivo preparation. Cultured cells expressing the dopamine synthesizing enzyme tyrosine hydroxylase (TH) responded to prolactin with a time-dependent increase in phospho-STAT5, but not phospho-STAT1 or phospho-STAT3, nuclear labeling. This response was inhibited by the prolactin receptor antagonist Δ1–9-G129R-human prolactin and the JAK inhibitor AG490, but was unaffected by selected serine/threonine kinase inhibitors (H89, KN-93, bisindolymaleimide, or PD98059). Antibodies selective for STAT5a or STAT5b indicated that the response was restricted to STAT5b, with the number of TH cells displaying STAT5b nuclear immunoreactivity rising from less than 10% under basal conditions to approximately 70% after prolactin stimulation. STAT5a nuclear labeling remained unchanged at 6–10% of TH-positive cells. STAT5b selectivity was confirmed in vivo, where the injection of prolactin into bromocriptine-treated rats stimulated a time-dependent increase in STAT5b, but not STAT5a, nuclear staining in the TH-expressing neurons in the arcuate nucleus. These results extend our previous findings with STAT5b-deficient mice and strongly suggest that in NEDA neurons, prolactin signaling via the JAK/STAT pathway is mediated exclusively by STAT5b.
Divergent Behavioral Roles of Angiotensin Receptor Intracellular Signaling Cascades
Authors: Daniels Derek , Yee Daniel K. , Faulconbridge Lucy F. , Fluharty Steven J.
Published: August 2005

Central injections of angiotensin II (AngII) increase both water and NaCl intake. These effects of AngII occur largely through stimulation of the AngII type 1 (AT1) receptor. Stimulation of the AT1 receptor leads to a number of intracellular events, including phospholipase C (PLC) activation and the subsequent formation of diacylglycerol and inositol trisphosphate (IP3), which then activate protein kinase C (PKC) and increase intracellular calcium, respectively. In addition, AT1 receptor stimulation leads to the activation of MAPK family members. Recent experiments using mutated AT1 receptor constructs or the AngII analog Sar1,Ile4,Ile8-AngII (SII) revealed that MAPK activation can occur independent of PLC/PKC/IP3 activation. The present experiments used in vitro and in vivo approaches to clarify the cellular and behavioral responses to SII. Specifically, SII mimicked AngII stimulation of MAPK in AT1 receptor-transfected COS-1 cells and rat brain but blocked the effects of AngII in two distinct settings: in vitro stimulation of IP3 and in vivo increases in water intake. Moreover, SII increased intake of 1.5% NaCl, despite the SII blockade of IP3 formation and water intake. Examination of brain tissue showed increases in Fos expression in several AngII-sensitive brain areas after injection of AngII, but not SII. The lack of SII-induced IP3 production, water intake, and Fos expression strongly suggest that the PLC/PKC/IP3 pathway is required for water intake, but not NaCl consumption stimulated by AngII. Collectively, these results support the hypothesis that divergent intracellular signals from a single receptor type can give rise to separable behavioral phenomena.
Cholesterogenic Lanosterol 14α-Demethylase (CYP51) Is an Immediate Early Response Gene
Authors: Fink Martina , Ačimovič Jure , Režen Tadeja , Tanšek Nataša , Rozman Damjana
Published: August 2005

Lanosterol 14α-demethylase (CYP51) responds to cholesterol feedback regulation through sterol regulatory element binding proteins (SREBPs). The proximal promoter of CYP51 contains a conserved region with clustered regulatory elements: GC box, cAMP-response elements (CRE-like), and sterol regulatory element (SRE). In lipid-rich (SREBP-poor) conditions, the CYP51 mRNA drops gradually, the promoter activity is diminished, and no DNA-protein complex is observed at the CYP51-SRE1 site. The majority of cAMP-dependent transactivation is mediated through a single CRE (CYP51-CRE2). Exposure of JEG-3 cells to forskolin, a mediator of the cAMP-dependent signaling pathway, provokes an immediate early response of CYP51, which has not been described before for any cholesterogenic gene. The CYP51 mRNA increases up to 4-fold in 2 h and drops to basal level after 4 h. The inducible cAMP early repressor (ICER) is involved in attenuation of transcription. Overexpressed CRE-binding protein (CREB)/CRE modulator (CREM) transactivates the mouse/human CYP51 promoters containing CYP51-CRE2 independently of SREBPs, and ICER decreases the CREB-induced transcription. Besides the increased CYP51 mRNA, forskolin affects the de novo sterol biosynthesis in JEG-3 cells. An increased consumption of lanosterol, a substrate of CYP51, is observed together with modulation of the postlanosterol cholesterogenesis, indicating that cAMP-dependent stimuli cross-talk with cholesterol feedback regulation. CRE-2 is essential for cAMP-dependent transactivation, whereas SRE seems to be less important. Interestingly, when CREB is not limiting, the increasing amounts of SREBP-1a fail to transactivate the CYP51 promoter above the CREB-only level, suggesting that hormones might have an important role in regulating cholesterogenesis in vivo.
Approximate Prediction Methods For Multiaxial Notch Stresses and Strains Under Elastic-Plastic and Creep Conditions
Authors: Hyde T H , Sabesan R , Leen S. B
Published: August 2005

This paper describes general techniques for predicting multiaxial notch stresses and strains under elastic-plastic and creep conditions. The Neuber method, which is often used in elastic-plastic analysis, has been adapted and extended for predicting creep equivalent notch stresses and strains, based on a time-stepping integration scheme. A linear interpolation method, often used in creep analysis, is adapted and extended for predicting elastic-plastic equivalent stresses and strains. Then notch principal stresses and strains are obtained by applying plasticity theory in combination with assumptions concerning the ratios of the stress or strain components. The accuracy of the predicted equivalent and principal stress and strain values are assessed by comparing predictions based on them with results obtained from finite element analyses.
Analysis of Stress and Strain Distribution in a Vehicle Wheel: Finite Element Analysis Versus the Experimental Method
Authors: Stearns J , Srivatsan T S , Gao X , Prahash A , Lam P. C
Published: August 2005

An extensive finite element analysis of a vehicle wheel subject to the conjoint influence of inflation pressure and radial load (vehicle load) is reported in this paper. The commonly used design considerations in an automotive wheel are presented and discussed. A method for determining the load(s) transmitted from the vehicle to the wheel is detailed and the intrinsic influence of inflation pressure on wheel performance is discussed. The finite element results are compared with experimental measurements of strain obtained using strain gauges. The salient advantage of the finite element analysis as an attractive and cost-effective approach to the design and analysis of vehicle wheels is elaborated.
Dynamical Interactions between Solute and Solvent Studied by Three-Pulse Photon Echo Method
Authors: Ohta Kaoru , Tominaga Keisuke
Published: August 2005

This account summarizes our recent work on measurements of the correlation function of the transition frequency fluctuations by a three-pulse photon echo method. The correlation function of the transition frequency fluctuations is a sensitive measure for the magnitudes and time scales of dynamical interactions between solute and solvent. We describe the results of the solvation dynamics of small ions in protic solvents such as methanol and water obtained by an infrared photon echo method.
2-Methoxy-4-nitrobenzenediazonium Salt as a Practical Diazonium-Transfer Agent for Primary Arylamines via Tautomerism of 1,3-Diaryltriazenes: Deaminative Iodination and Arylation of Arylamines without Direct Diazotization
Authors: Saeki Tomoyuki , Son Eun-Cheol , Tamao Kohei
Published: August 2005

1,3-Diaryltriazenes, prepared from a 2-methoxy-4-nitrobenzenediazonium salt and primary arylamines, exist as “azo-transfer” tautomers in which the 2-methoxy-4-nitrophenyl group is present on the saturated nitrogen atom and forms a hydrogen bond between the 2-methoxy group and the N–H moiety. The synthetic utility of the diazonium salt as a practical diazonium-transfer agent for primary arylamines via tautomerism of the 1,3-diaryltriazenes has been demonstrated by the deaminative iodination and arylation of the arylamines without direct diazotization. The starting 2-methoxy-4-nitrophenylamine can be easily recovered after the reactions.
Synthesis of α-Carbolines by Copper-Catalyzed Radical Cyclization of β-(3-Indolyl) Ketone O-Pentafluorobenzoyloximes
Authors: Tanaka Kenichi , Kitamura Mitsuru , Narasaka Koichi
Published: August 2005

Radical cyclization of β-(3-indolyl) ketone O-pentafluorobenzoyloximes proceeds by the treatment with a catalytic amount of copper powder in 1,2-dichloroethane to generate 3,4-dihydro-α-carbolines, which are oxidized to α-carbolines with chloranil.