bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein Kinase C Inhibition by Tamoxifen Antagonizes Manic-Like Behavior in Rats: Implications for the Development of Novel Therapeutics for Bipolar Disorder
Authors: Einat Haim , Yuan Peixiong , Szabo Steven T. , Dogra Samriti , Manji Husseini K.
Published: July 2007

Rationale: In the context of bipolar disorder (BPD) research it was demonstrated that administration of the structurally dissimilar mood stabilizers lithium and valproate produced a striking reduction in protein kinase C (PKC) in rat brain. In a small clinical study, tamoxifen (a PKC inhibitor) had antimanic efficacy. However, both lithium and valproate exert many biochemical changes and attribution of therapeutic relevance to any molecular findings needs to be based on linking them to behavioral effects. Objectives: The present study was designed to explore such relationship by studying the effects of PKC inhibition in amphetamine-induced behavioral animal models of mania and changes in GAP-43. Methods: The effects of two daily tamoxifen (1 mg/kg) i.p. injections on acute or chronic (7 injections) amphetamine (0.5 mg/kg) -induced behaviors and GAP-43 phosphorylation were tested. Results: The study demonstrates that tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity levels and normalized amphetamine-induced increase in visits to the center of an open field (representing risk-taking behavior). Tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43, a result that is consistent with the behavioral findings. Conclusions: These results support the possibility that PKC signaling may play an important role in the pathophysiology and treatment of BPD. These findings may have direct clinical implications as they offer a new avenue for attempts to develop more specific drugs for the disorder.
Effect of Low-Frequency rTMS on Electromagnetic Tomography (LORETA) and Regional Brain Metabolism (PET) in Schizophrenia Patients with Auditory Hallucinations
Authors: Horacek Jiri , Brunovsky Martin , Novak Tomas , Skrdlantova Lucie , Klirova Monika , Bubenikova-Valesova Vera , Krajca Vladimir , Tislerova Barbora , Kopecek Milan , Spaniel Filip , Mohr Pavel , Höschl Cyril
Published: July 2007

Background: Auditory hallucinations are characteristic symptoms of schizophrenia with high clinical importance. It was repeatedly reported that low frequency (≤1Hz) repetitive transcranial magnetic stimulation (rTMS) diminishes treatment-resistant auditory hallucinations. A neuroimaging study elucidating the effect of rTMS in auditory hallucinations has yet to be published. Objective: To evaluate the distribution of neuronal electrical activity and the brain metabolism changes after low-frequency rTMS in patients with auditory hallucinations. Methods: Low-frequency rTMS (0.9 Hz, 100% of motor threshold, 20 min) applied to the left temporoparietal cortex was used for 10 days in the treatment of medication-resistant auditory hallucinations in schizophrenia (n = 12). The effect of rTMS on the low-resolution brain electromagnetic tomography (LORETA) and brain metabolism (18FDG PET) was measured before and after 2 weeks of treatment. Results: We found a significant improvement in the total and positive symptoms (PANSS), and on the hallucination scales (HCS, AHRS). The rTMS decreased the brain metabolism in the left superior temporal gyrus and in interconnected regions, and effected increases in the contralateral cortex and in the frontal lobes. We detected a decrease in current densities (LORETA) for the beta-1 and beta-3 bands in the left temporal lobe whereas an increase was found for beta-2 band contralaterally. Conclusion: Our findings implicate that the effect is connected with decreased metabolism in the cortex underlying the rTMS site, while facilitation of metabolism is propagated by transcallosal and intrahemispheric connections. The LORETA indicates that the neuroplastic changes affect the functional laterality and provide the substrate for a metabolic effect.
A Multicenter Phase II Study of Docetaxel in Combination with Gefitinib in Gemcitabine-Pretreated Patients with Advanced/Metastatic Pancreatic Cancer
Authors: Ignatiadis Michail , Polyzos Aris , Stathopoulos George P. , Tselepatiotis Evangelos , Christophylakis Charalambos , Kalbakis Kostas , Vamvakas Lambros , Kotsakis Athanasios , Potamianou Anna , Georgoulias Vassilis
Published: July 2007

Purpose: To evaluate the efficacy and tolerance of the docetaxel/gefitinib combination as second-line treatment in patients with advanced pancreatic cancer. Patients and Methods: Twenty-six patients pretreated with gemcitabine-based chemotherapy were enrolled in the study. Docetaxel (75 mg/m2, i.v.) was administered every 3 weeks for a maximum of 6 cycles and gefitinib (250 mg/day, p.o.) was given continuously. Results: Five (19.2%) patients achieved stable disease. The median duration of disease control was 4.8 months (range 1–13.2), the median time to disease progression 2.1 months (range 1–7.3) and the median survival time 2.9 months (range 1–13.9). Grade 3/4 neutropenia was recorded in 9 (34.6%) patients, although only 1 (3.8%) developed grade 2 febrile neutropenia. One (3.8%) patient experienced grade 3 fatigue and 2 (7.7%) grade 3 diarrhea. Grade 1/2 rash was observed in 13 (50%) patients. There were no treatment-related deaths. Conclusion: The docetaxel/gefitinib combination, although safe, has no activity as salvage treatment for advanced pancreatic cancer after failure of gemcitabine-based chemotherapy.
Herpes Infections in Breast Cancer Patients Treated with Adjuvant Chemotherapy
Authors: Masci Giovanna , Magagnoli Massimo , Gullo Giuseppe , Morenghi Emanuela , Garassino Isabella , Simonelli Matteo , Santoro Armando
Published: July 2007

Objective: There is little information on Herpes zoster infection in breast cancer patients as a complication during adjuvant chemotherapy. The aim of this study is to evaluate the incidence of Herpes zoster and simplex infections in this patients setting. Methods: We analyzed 623 early-stage breast cancer patients in our Institute over a period of 7 years (1998–2005). Four-hundred and sixty-onepatients were treated with anthracycline-based chemotherapy, 116 with CMF and 46 with taxane-containing regimens. Results: Twelve (1.9%) developed herpes zoster; 9 patients, receiving anthracycline-based chemotherapy, two taxane-containing regimens, and one CMF regimen. Herpes zoster infection required treatment delay in 6 patients. Adjuvant chemotherapy was delayed for 1 week in 2 patients, while in 4 patients with more severe symptoms chemotherapy was delayed for 2 weeks. One patient, despite i.v. acyclovir, had severe postherpetic motor neuropathy with a permanent ambulation impairment, and chemotherapy was stopped. In our study, herpes zoster occurred in 55/1,000 cases/year. The reported incidence in the general population varies between 2.2 and 4.1 per 1,000 patients/year; therefore, the risk of developing herpes zoster in these patients may be 13- to 25-fold higher compared to the incidence in the general population. In addition, 13 of 623 patients developed herpes simplex. Conclusion: Our findings suggest that adjuvant chemotherapy can facilitate reactivation of herpes infection.
Blood Flow Indices by Doppler Ultrasonography Vary with Neoadjuvant Chemotherapy but Are Not Related to Plasma VEGF Levels in Locally Advanced Breast Cancer
Authors: Öksüzoğlu Berna , Vural Murat , Abalı Hüseyin , Yılmaz Mesude , Yıldırım Nuriye , Zengin Nurullah
Published: July 2007

Objective: The aim of our study was to assess the quantity of blood flow to malignant tissue by color Doppler ultrasonography, its correlation with plasma vascular endothelial growth factor (VEGF) levels and response to neoadjuvant chemotherapy of patients with locally advanced and inflammatory breast carcinoma. Methods: We measured blood velocity at peak systole (PSV), end-diastolic velocity and resistivity index [RI = (PSV – end-diastolic velocity)/PSV] by Doppler ultrasonography in primary tumors and/or axillary lymph nodes of patients before and after 2–4 cycles of anthracycline-containing neoadjuvant chemotherapy and basal plasma VEGF levels. Results: Of 21 patients with a median age of 42 years (range 26–68), 16 (76.2%) were premenopausal. Median basal RI was 0.70 (interquartile range 0.68–0.78) and PSV was 24.2 cm/s (interquartile range 18.7–56.6). The median measured VEGF level was 231.5 pg/ml (interquartile range 187.5–345.5). After 2–4 cycles of chemotherapy, 13 patients (61.9%) had partial remission and 8 (38.1%) were stable. Median basal RI (0.70, interquartile range 0.68–0.78) significantly decreased to 0.66 (interquartile range 0.59–073) after chemotherapy (p = 0.043). There was a trend that the greater the shrinkage of the tumor with chemotherapy, the lower the RI (r = 0.70, p = 0.078). Conclusion: The decrease in RI with chemotherapy, which means increased blood flow at diastole of the cardiac cycle into the tumoral tissue, may be related to decreased intratumoral pressure secondary to tumor shrinkage and may reflect a new type of response, that is vascular response.
A Dose Escalation Study of Gemcitabine plus Pemetrexed Administered Biweekly in Patients with Solid Tumors
Authors: Kalykaki A. , Vamvakas L. , Agelaki S. , Kalbakis K. , Vardakis N. , Sfakiotaki G. , Ignatiadis M. , Saridaki Z. , Karampeazis A. , Mavroudis D. , Georgoulias V.
Published: July 2007

Purpose: The study aimed to determine the maximum tolerated doses (MTDs) and identify the dose-limiting toxicities of the biweekly administration of pemetrexed plus gemcitabine in patients with solid tumors. Patients and Methods: Patients with advanced malignancies were treated with escalated doses of gemcitabine and pemetrexed (starting doses 1,250 and 300 mg/m2, respectively) both given on days 1 and 15 in cycles of 4 weeks. Results: Forty-one patients were treated at 7 dose levels. The MTD was reached at the dose of 1,750 mg/m2 for gemcitabine and 450 mg/m2 for pemetrexed. Dose-limiting events were grade IV neutropenia, febrile neutropenia and treatment delay due to grade III hematological toxicities. One partial response in a pretreated patient with ovarian cancer was observed, while 4 other patients experienced stable disease. Conclusions: The biweekly administration of gemcitabine plus pemetrexed at the recommended MTDs is safe, well tolerated and demonstrates antitumor activity which merits further evaluation in phase II studies.
Association between Expression of Vascular Endothelial Growth Factor C, Chemokine Receptor CXCR4 and Lymph Node Metastasis in Colorectal Cancer
Authors: Fukunaga S. , Maeda K. , Noda E. , Inoue T. , Wada K. , Hirakawa K.
Published: July 2007

Objectives: Lymph node metastasis is one of the determining factors of a poor prognosis for colorectal cancer. Recent studies have reported that cancer cells can promote lymphangiogenesis and that chemokine receptors expressed by cancer cells might play a role in metastasis. In this study, we examined the correlation between the expression of vascular endothelial growth factor (VEGF) C, the chemokine receptor CXCR4 and lymph node metastasis in colorectal cancer. Methods: One hundred and sixty-one consecutive patients who underwent resection at our department were studied. Lymph node metastasis was observed in 69 cases (43%) and lymphatic involvement was present in 105 cases (65%). Immunohistochemical staining was performed using antibodies for VEGF-C and CXCR4. Moreover, lymphatic vessel density (LVD) was evaluated within the tumor by immunostaining with a D2-40 antibody. Results: VEGF-C expression was found in 81 cases (50%) and CXCR4 expression in 87 cases (54%). Regarding the correlation between nodal metastasis and the expression of CXCR4 and VEGF-C, the incidence of nodal metastasis was significantly (p < 0.01) higher in patients with CXCR4-positive tumors than in those with CXCR4-negative tumors. In addition, a significant correlation was observed between CXCR4 and VEGF-C expression and lymphatic invasion (p < 0.01). LVD was significantly higher in VEGF-C-positive tumors compared with VEGF-C-negative tumors. However, there was no significant correlation between LVD and CXCR4 expression. Using multivariate analysis, VEGF-C, CXCR4, lymphatic invasion and wall invasion were found to be independent risk factors for lymph node metastasis. Conclusions: This study suggests that although the mechanism that promoted lymph node metastasis was different between VEGF-C and CXCR4, both VEGF-C and CXCR4 contributed to lymphatic involvement and nodal metastasis in colorectal cancer.
Two Cases of Acneiform Eruption Induced by Inhibitor of Epidermal Growth Factor Receptor
Authors: Gencoglan G. , Ceylan C.
Published: July 2007

Background: Cetuximab is a member of a new family of antineoplastic agents that inhibit the epidermal growth factor receptor (EGF-R), and which are increasingly being used in the treatment of solid tumors. Methods: We have observed new secondary side effects. We present here 2 patients with acneiform eruption secondary to the administration of cetuximab (IMC-C225, Erbitux). The diagnoses of these patients were adenocarcinoma. Results: Histologically, a superficial purulent folliculitis and disordered differentiation with focal parakeratosis were observed. The follicular eruption responded favorably to treatment with 5% benzoyl peroxide and 4% erythromycin gel. These lesions healed within a few days after treatment. Conclusion: The cutaneous adverse effects of cetuximab are similar to other EGF-R-targeted agents and result from direct interference with the functions of EGF-R signaling in the skin.
Rapid Responses to Steroid Hormones in the Kidney
Authors: Thomas Warren , McEneaney Victoria , Harvey Brian J.
Published: July 2007

Rapid signalling responses stimulated by steroid hormones have been detected in various tissues including the nephron. The significance of these responses in modulating the physiological effects elicited by mineralocorticoids, glucocorticoids and the reproductive hormones in the kidney is now becoming more evident. This review outlines how rapid signalling responses stimulated by these hormones are coupled to the regulation of membrane transport targets that impact upon the reabsorptive and excretory functions of the kidney.
Reliability of Measuring Anomalous Experience: The Bonn Scale for the Assessment of Basic Symptoms
Authors: Vollmer-Larsen Anne , Handest Peter , Parnas Josef
Published: July 2007

Background: Studying subjective experience, apart from preformed self-rating questionnaires, has nearly vanished in psychiatry, partly due to reliability concerns. Recent research in early detection of schizophrenia has entailed an increasing interest in the subtle experiential anomalies that may assist in identifying the patients at risk of psychosis. Some of these anomalies are described in the Bonn Scale for the Assessment of Basic Symptoms (BSABS). We examined the reliability of this instrument. Sampling and Method: 18 hospitalised patients accepted to participate in a psychopathological interview assessing BSABS items, affective and psychotic symptoms. Results: Out of the total 79 BSABSitems examined,we found an interrater reliability kappa >0.60 in 68 items (86%). Conclusion: Good reliability can be achieved using BSABS.
Klinefelter’s Syndrome and Prader-Willi Syndrome: A Rare Combination
Authors: Verhoeven W.M.A. , de Vries B.B.A. , Duffels S.J.H. , Egger J.I.M. , Noordam C. , Tuinier S.
Published: July 2007

In this paper a review is presented of the rare combination of Klinefelter’s syndrome and Prader-Willi syndrome (PWS) and a second case of this combination with a uniparental disomy (UPD) etiology of PWS is described. Patients outlined in all other 8 reports and the present case have a PWS phenotype. Virtually no information is available on the behavioral and psychopathological phenotype in this combination. The latter may be explained by the observation that psychiatric syndromes are especially prevalent in PWS patients with a UPD. It is concluded that instability in mood and behavior in this and other syndromes should be preferentially treated with mood stabilizing agents.
The GSTP1 Gene Is a Susceptibility Gene for Childhood Asthma and the GSTM1 Gene Is a Modifier of the GSTP1 Gene
Authors: Kamada Fumiaki , Mashimo Yoichi , Inoue Hiroki , Shao Chenchen , Hirota Tomomitsu , Doi Satoru , Kameda Makoto , Fujiwara Hiroshi , Fujita Kimie , Enomoto Tadao , Sasaki Sei , Endo Hiroko , Takayanagi Reiko , Nakazawa Chifuyu , Morikawa Toshio , Morikawa Miki , Miyabayashi Shigeaki , Chiba Yasushi , Tamura Gen , Shirakawa Taro , Matsubara Yoichi , Hata Akira , Tamari Mayumi , Suzuki Yoichi
Published: July 2007

Background: Bronchial asthma is a chronic airway disorder characterized by bronchial inflammation. Oxidative stress is a key component of inflammation. Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays a key role in cellular protection against oxidative stress. Several studies have shown that the GSTP1 geneis involved in the pathogenesis of asthma and a gene-gene interaction may occur within the GST gene superfamily. Methods: We screened single-nucleotide polymorphisms (SNPs) at the GSTP1 locus and performed an association study in the Japanese population using two independent case-control groups (group 1: 391 pediatric patients with asthma, 462 adult patients with asthma, and 639 controls, and group 2: 115 pediatric patients with asthma and 184 controls). The effect of GSTM1 null/present genotype on the association between GSTP1 Ile105Val and asthma was also investigated. Results: We identified 20 SNPs at this locus and found this region consisted of one linkage disequilibrium block represented by four SNPs (tag SNPs). The association between the Ile105Val polymorphism in the GSTP1 gene and childhood asthma was significant in both groups (p = 0.047 in group 1, and p = 0.021 in group 2). This association was only significant in patients with GSTM1-positive genotype in both groups (group 1: GSTM1 present p = 0.013 and GSTM1 null p = 0.925, and group 2: GSTM1 present p = 0.015 and GSTM1 null p = 0.362). Conclusions: These findings suggest that the GSTP1 gene is a childhood asthma susceptible gene, and the GSTM1 gene is a modifier gene of GSTP1 for the risk of childhood asthma in the Japanese population.
Involvement of Local Orphanin FQ in the Tolerance Induced by Repeated Microinjections of Morphine into Ventrolateral Periaqueductal Gray in Rats
Authors: Ge Zhi Jun , Zhang Li Cai , Zeng Yin Ming , Dai Ti Jun , Chang Li , Wang Jun Ke , Cui Guo Xin , Tan Yong Fei , Zhao Yan Ping , Liu Guo Jun
Published: July 2007

The present study evaluated the role of ventrolateral periaqueductal gray (vlPAG)-located orphanin-FQ (OFQ) in the opioid tolerance induced by repeated microinjections of morphine (MOR) into vlPAG. Microinjection of MOR (5 µg/0.5 µl) into vlPAG caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days (tolerance). However, if MOR microinjection was preceded by the OFQ receptor antagonist nocistatin (NST; 1 ng/0.5 µl), the microinjections of MOR did not induce tolerance. If NST microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single NST microinjection into vlPAG was enough to restore the antinociceptive effect of MOR. Furthermore, if OFQ (1 ng/0.5 µl) was microinjected into vlPAG, then a MOR microinjection administered 15 min later into vlPAG did not elicit antinociception. Finally, opioid tolerance induced by repeated systemic MOR injections (5 mg/kg, i.p.) was reversed by a single microinjection of NST into vlPAG. This emphasizes the central importance of vlPAG-located OFQ in the MOR tolerance.
Genital Anomalies in Klinefelter’s Syndrome
Authors: Lee Yung Seng , Cheng Anna Wai Fun , Ahmed Syed Faisal , Shaw Nick J. , Hughes Ieuan A.
Published: July 2007

Background/Aims: Klinefelter’s syndrome is characterized by progressive testicular failure causing aspermatogenesis and androgen deficiency. Klinefelter patients classically have complete male sex differentiation, and genital anomalies are generally not recognized as associated features of the syndrome. Methods: We reviewed the cases of Klinefelter’s syndrome with genitalia abnormalities from the Cambridge Disorders of Sex Development Database, and also reviewed previous case reports of genital anomalies associated with Klinefelter’s syndrome and its variants. Results: We present seven Klinefelter patients with abnormalities of the genitalia, ranging from mild anomalies (chordee) to moderate undervirilisation (bifid scrotum and perineal hypospadias). Two cases were true hermaphrodites with karyotypes 47,XXY and 47,XXY/46,XX respectively. Though androgen insensitivity has been postulated previously as a possible pathogenic mechanism, we demonstrated normal androgen binding in 3 cases in which this was studied. Review of other case reports revealed a range of mild-to-severe abnormalities as well as cases reported as sex reversal, testicular feminization, and true hermaphroditism. Conclusion: Genital anomalies are not commonly observed in Klinefelter’s syndrome. However, it is important to acknowledge the association, and recognize Klinefelter’s syndrome as one of the causes of abnormal genitalia at birth.
Nitric Oxide and Exhaled Breath Nitrite/Nitrates in Chronic Obstructive Pulmonary Disease Patients
Authors: Liu Jia , Sandrini Alessandra , Thurston Michelle C. , Yates Deborah H. , Thomas Paul S.
Published: July 2007

Background: Measurement of nitric oxide (NO) and nitrite/nitrates (NOx) levels in exhaled breath condensate (EBC) are non-invasive techniques, which can be used to monitor airway inflammatory diseases. Production of NO is often increased in inflammatory diseases of the airways, including exacerbations of chronic obstructive pulmonary disease (COPD). COPD-associated airway inflammation may be affected by multiple factors, including cigarette smoking and glucocorticosteroid (GCS) treatment. Objectives: To test the hypothesis that total NOx levels in EBC and exhaled NO levels would be affected by cigarette smoking or the presence of COPD. Methods: Exhaled NO levels and NOx levels in EBC were measured in 96 COPD patients and in 80 normal subjects. Results: Exhaled NO levels in COPD patients were significantly higher than those of normal subjects when comparing either the total groups (9.8 ± 0.7 vs. 5.5 ± 0.4 ppb, p < 0.0005) or 2 appropriate subgroups, ex-smokers (10.3 ± 1.0 vs. 5.4 ± 0.6 ppb, p < 0.0005) and smokers (9.2 ± 1.2 vs. 5.7 ± 0.5 ppb, p = 0.002). There was no significant difference in NOx levels in EBC, however, between COPD patients and healthy subjects when analysed either together or as subgroups. No significant difference was found in either exhaled NO levels or NOx levels in EBC between GCS-naïve subjects and those on GCS treatment in the ex-smoking or smoking COPD subgroups. Conclusions: COPD patients have higher exhaled NO levels than control subjects when either combined or analysed as non-smoking, ex-smoking and smoking subgroups. GCS treatment did not appear to affect these non-invasive markers of airway inflammation in COPD.
Detection of Active Fraction of Glycogen Synthase Kinase 3β in Cancer Cells by Nonradioisotopic in vitro Kinase Assay
Authors: Mai Wei , Miyashita Katsuyoshi , Shakoori Abbas , Zhang Bin , Yu Zhi Wei , Takahashi Yutaka , Motoo Yoshiharu , Kawakami Kazuyuki , Minamoto Toshinari
Published: July 2007

Glycogen synthase kinase 3β (GSK3β) is a well-known marker and potential therapeutic target in non-insulin-dependent diabetes mellitus and Alzheimer’s disease. Our recent demonstration that GSK3β has a previously unrecognized role in colorectal cancer facilitates the development of a nonradioisotopic in vitro kinase assay (NRIKA) for detecting GSK3β activity in gastrointestinal cancer cells. The NRIKA uses a sequential combination of immunoprecipitations to isolate GSK3β in sample cells’ lysates, and an in vitro kinase reaction that uses recombinant β-catenin protein (substrate) and nonradioisotopic ATP, followed by immunoblotting to detect β-catenin phosphorylated in serine 33, 37 and/or threonine 41 residues. The NRIKA detected higher expression of active GSK3β in stomach, colon, pancreas and liver cancer cell lines than in human embryonic kidney cells (HEK293) considered nonneoplastic. Inhibition of cancer cell-derived GSK3β activity by GSK3β inhibitors (SB-216763, AR-A014418) was detected by the NRIKA. GSK3β inhibition attenuated survival and proliferation and induced apoptosis in all types of cancer cells but not in HEK293. These findings supported the idea that the pathologic roles of GSK3β are definite and common in various types of cancer. The NRIKA provides a basis for evolving a high-throughput tool for testing substances for GSK3β inhibition, and for screening and identifying novel GSK3β inhibitors with a view to discovering drugs for treatment of cancer as well as non-insulin-dependent diabetes mellitus and Alzheimer’s disease.
Metabolic Mechanisms in Heart Failure
Authors: Ashrafian Houman , Frenneaux Michael P. , Opie Lionel H.
Published: July 2007

Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure → altered metabolism → heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure.
Judgments About Work
Authors: Johnson Monica Kirkpatrick , Mortimer Jeylan T. , Lee Jennifer C. , Stern Michael J.
Published: July 2007

The authors examine the measurement structure of individuals' orientations toward work rewards, or “judgments about work,” a concept central to the social psychology of work. Despite extensive and sustained interest in the level of importance attached to work rewards by major markers of social location such as birth cohort, social class origins, and gender, prior studies have not examined whether the same classification schema captures the underlying variation in judgments about work across these axes of social location. Drawing on five data sets, the authors examine the fit of models corresponding to the recently revived entrepreneurial–bureaucratic classification schema with those corresponding to the dominant extrinsic–intrinsic classification schema across subgroups of the population using confirmatory factor analysis. Findings offer only limited support for reconceptualizing judgments about work along entrepreneurial–bureaucratic dimensions but call for additional research on the dimensions of judgments about work that emerge under distinct conditions and across different groups.
Staying Underground: Informal Work, Small Firms, and Employment Regulation in the United Kingdom
Authors: Ram Monder , Edwards Paul , Jones Trevor
Published: July 2007

Why does a universal labor law, the National Minimum Wage (NMW) in the United Kingdom, have little effect on firms operating in the informal economy? In explaining this particular empirical puzzle, the authors go beyond dominant accounts of the informal economy—the neo-liberal and the marginalization theses—to develop analysis based on the negotiation of consent within the labor process. Evidence from employers and employees in 17 firms is presented. The informal sector developed social relations of work that operated independently of the NMW, a key aspect being a tacit negotiation of order even under conditions apparently unhelpful to such practices. Informality was deeply embedded in relations of work that continued to reproduce themselves.
Music and Meaning on the Factory Floor
Authors: Korczynski Marek
Published: July 2007

This article examines an unexplored topic within industrial sociology—the terrain of music for meaning making on the factory floor. The article is based on ethnographic research undertaken in a blinds factory. Although contemporary popular music appears to speak only rarely to the arena of work, this article shows that workers reappropriated music to articulate their experience of working in the factory. Many workers independently created meaning systems through music, which displayed both a negative experience of the work and an active resistance and defiance. The way in which this functioned was through the process of avowal in which choruses of songs allowed deeply felt, but usually tacit, feelings to be given direct articulation. Social listening in the factory played a key role in shaping the way in which music was used to create meaning.
Historical Amnesia: New Urbanism and the City of Tomorrow
Authors: Saab A. Joan
Published: July 2007

This article explores the ideology behind the contemporary “New Urbanist” movement alongside two key twentieth-century American utopian urban plans for the city of the future, Democracity and Futurama. Both Democracity and Futurama were displays at the 1939 New York World's Fair, and like many contemporary New Urbanist projects, both were totalizing visions—holistic attempts to remake the entire American landscape and in so doing link art and life in the name of democracy. It is the author's argument that many New Urbanist planners suffer from what she calls historical amnesia rooted in a myopic form of nostalgia, since, as she demonstrates in the article, the plans for Democracity and Futurama contain both the closest precursors and the root of many of the problems that proponents of New Urbanism are attempting to rectify. By exploring these two historical models within the context of contemporary urban community building, the author calls for the eradication of historical amnesia in further planning for the city of the future and the development of a new model of American urbanism that appropriates nostalgia for more radical ends and grounds it in the present and its problems.
Taming the Neighborhood Revolution: Planners, Power Brokers, and the Birth of Neotraditionalism in Portland, Oregon
Authors: Thompson Gregory L.
Published: July 2007

In the early 1970s, neighborhood-based movements arose in Portland, Oregon, against freeways, while networks of individuals championed a revival of rail transit. At decade's end, regional leaders rejected two interstate freeways, repudiated a freeway-based regional transportation plan, and agreed to build the beginning of a regional rail system. In seeming contradiction to their anti-auto actions, they also lobbied Congress to change federal law so that they could spend money from deleted interstate highway projects on noninterstate roads rather than on transit. This article documents how planners and power brokers in Portland negotiated among themselves to channel the energy from what began as a citizen- and neighborhood-based revolution into the beginnings of a new consensus about transit, road, and land use development by the end of the decade, one that implicitly recognized personal preference for mass mobility but that explicitly championed designs of transportation facilities to reflect local objectives.
More Than Sector Theory: Homer Hoyt's Contributions to Planning Knowledge
Authors: Beauregard Robert
Published: July 2007

Known primarily for his sector theory of urban development, Homer Hoyt contributed to planning knowledge in other ways: advancing the concept of economic base, developing procedures for analyzing the location and size of suburban shopping malls, and documenting comparative trends in urbanization. A land economist and real estate consultant and appraiser throughout most of his professional life, Hoyt's career combined practice and scholarship, though of a non-academic variety. This article explores Hoyt's intellectual contributions, his melding of practice and theory, and his relationship to the field of planning.
Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1
Authors: Marteijn Jurgen A. F. , van der Meer Laurens T. , van Emst Liesbeth , van Reijmersdal Simon , Wissink Willemijn , de Witte Theo , Jansen Joop H. , Van der Reijden Bert A.
Published: July 2007

Growth factor independence 1 (Gfi1) is a transcriptional repressor essential for the function and development of many different hematopoietic lineages. The Gfi1 protein expression is regulated by the ubiquitin-proteasome system. In granulocytes, Gfi1 is rapidly degraded by the proteasome, while it is more stable in monocytes. How the ubiquitination and degradation of Gfi1 is regulated is unclear. Here, we show that the ubiquitin ligase Triad1 interacts with the DNA-binding domain of Gfi1. Unexpectedly, we found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life. Down-regulation of endogenous Triad1 by siRNAs resulted in increased Gfi1 ubiquitination. In U937 cells, Triad1 caused an increase in endogenous Gfi1 protein levels and slowed cell proliferation in a similar manner when Gfi1 itself was expressed. A Triad1 mutant that lacks the Gfi1-binding domain did not affect Gfi1 levels and proliferation. Because neither proteasome-ubiquitin nor Triad1 ubiquitin ligase activity was required for the inhibition of Gfi1 ubiquitination, these data suggest that Triad1 competes for Gfi1 binding with as yet to be identified E3 ubiquitin ligases that do mark Gfi1 for proteasomal degradation. The finetuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis.
PKCδ and cofilin activation affects peripheral actin reorganization and cell-cell contact in cells expressing integrin α5 but not its tailless mutant
Authors: Oh Min-A , Kang Eun-Sil , Lee Sin-Ae , Lee Eun-Ok , Kim Yong-Bae , Kim Sung-Hoon , Lee Jung Weon
Published: July 2007

Integrin-mediated cell adhesion transduces signaling activities for actin reorganization, which is crucially involved in cellular function and architectural integrity. In this study, we explored the possibility of whether cell-cell contacts might be regulated via integrin-α5β1-mediated actin reorganization. Ectopic expression of integrin α5 in integrin-α5-null intestinal epithelial cells resulted in facilitated retraction, cell-cell contact loss, and wound healing depending on Src and PI3K (phosphoinositide 3-kinase) activities by a reagent that affects actin organization. However, cytoplasmic tailless integrin α5 (hereafter referred to as α5/1) expression caused no such effects but rather sustained peripheral actin fibers, regardless of Src and PI3K signaling activities. Furthermore, integrin α5 engagement with fibronectin phosphorylated Ser643 of PKCδ, upstream of FAK and Src and at a transmodulatory loop with PI3K/Akt. Pharmacological PKCδ inactivation, dominant-negative PKCδ adenovirus or inactive cofilin phosphatase (SSH1L mutant) retrovirus infection of α5-expressing cells sustained peripheral actin organization and blocked the actin reorganizing-mediated loss of cell-cell contacts. Meanwhile, wild-type PKCδ expression sensitized α5/1-expressing cells to the actin disruptor to induce cell scattering. Altogether, these observations indicate that integrin α5, but not α5/1, mediates PKCδ phosphorylation and cofilin dephosphorylation, which in turn modulate peripheral actin organization presumably leading to an efficient regulation of cell-cell contact and migration.
Activation of multiple DNA repair pathways by sub-nuclear damage induction methods
Authors: Dinant Christoffel , de Jager Martijn , Essers Jeroen , van Cappellen Wiggert A. , Kanaar Roland , Houtsmuller Adriaan B. , Vermeulen Wim
Published: July 2007

Live cell studies of DNA repair mechanisms are greatly enhanced by new developments in real-time visualization of repair factors in living cells. Combined with recent advances in local sub-nuclear DNA damage induction procedures these methods have yielded detailed information on the dynamics of damage recognition and repair. Here we analyze and discuss the various types of DNA damage induced in cells by three different local damage induction methods: pulsed 800 nm laser irradiation, Hoechst 33342 treatment combined with 405 nm laser irradiation and UV-C (266 nm) laser irradiation. A wide variety of damage was detected with the first two methods, including pyrimidine dimers and single- and double-strand breaks. However, many aspects of the cellular response to presensitization by Hoechst 33342 and subsequent 405 nm irradiation were aberrant from those to every other DNA damaging method described here or in the literature. Whereas, application of low-dose 266 nm laser irradiation induced only UV-specific DNA photo-lesions allowing the study of the UV-C-induced DNA damage response in a user-defined area in cultured cells.
Combinatorial effects of splice variants modulate function of Aiolos
Authors: Caballero Rosalia , Setien Fernando , Lopez-Serra Lidia , Boix-Chornet Manuel , Fraga Mario F. , Ropero Santiago , Megias Diego , Alaminos Miguel , Sanchez-Tapia Eva M. , Montoya Maria C. , Esteller Manel , Gonzalez-Sarmiento Rogelio , Ballestar Esteban
Published: July 2007

The transcription factor Aiolos (also known as IKZF3), a member of the Ikaros family of zinc-finger proteins, plays an important role in the control of B lymphocyte differentiation and proliferation. Previously, multiple isoforms of Ikaros family members arising from differential splicing have been described and we now report a number of novel isoforms of Aiolos. It has been demonstrated that full-length Ikaros family isoforms localize to heterochromatin and that they can associate with complexes containing histone deacetylase (HDAC). In this study, for the first time we directly investigate the cellular localization of various Aiolos isoforms, their ability to heterodimerize with Ikaros and associate with HDAC-containing complexes, and the effects on histone modification and binding to putative targets. Our work demonstrates that the cellular activities of Aiolos isoforms are dependent on combinations of various functional domains arising from the differential splicing of mRNA transcripts. These data support the general principle that the function of an individual protein is modulated through alternative splicing, and highlight a number of potential implications for Aiolos in normal and aberrant lymphocyte function.
Numerical study of a rotor-bearing-seal system
Authors: Cheng M , Meng G , Jing J P
Published: July 2007

Seal and bearing characteristic is an important factor affecting the performance of the rotor system. The non-linear dynamic behaviours of a rotor-bearing-seal coupled system are investigated. Dynamic trajectories, Poincaré maps, largest Lyapunov exponents, frequency spectra, and bifurcation diagrams which are applied to analyse the features of the rotor-bearing-seal system in various parameters. Various non-linear phenomena in the rotor-bearing-seal system, such as periodic motion, double-periodic motion, multi-periodic, and quasi-periodic motion are investigated. The results of this study may contribute to a further understanding of the non-linear dynamics of such a rotor-bearing-seal coupled system.
An optimum design procedure for both serial and parallel manipulators
Authors: Carbone G , Ottaviano E , Ceccarelli M
Published: July 2007

Serial and parallel manipulators can be used in different manipulative tasks when their peculiarities in kinematic and dynamic behaviours are properly considered from the design stage. The basic performance in workspace, mobility constraints, and stiffness makes them alternative solutions and not competitive manipulator chains. Thus, it is convenient to deduce a common design procedure that considers common design criteria, but specific numerical evaluations. In this paper, a multi-objective optimization problem has been proposed to formulate a unique design procedure that takes into account the contradicting design optimality criteria in terms of suitable general algorithms for workspace volumes, Jacobian matrices, and compliant displacements. Numerical examples are reported to show not just the feasibility but also the numerical efficiency of the proposed formulations.
Application of exergy method to a two-stage irreversible combined refrigeration system
Authors: Su Y-F , Chen C-K
Published: July 2007

The exergy method, based on the maximum exergetic efficiency criterion, is applied to a two-stage irreversible combined refrigeration system. The exergetic efficiency defined as the ratio of rate of exergy output to rate of exergy input is taken as the objective index to be maximized. The related cycle temperature parameters are first solved. The maximum exergetic efficiency is then obtained analytically. Comparisons between the exergetic efficiency and the coefficient of performance of the combined refrigeration system are performed. The influences of various parameters on the system performances are discussed. It shows that the exergy method is practical and effective when operating or designing the combined refrigeration system.
Numerical analysis of combined influences of inter-asperity cavitation and elastic deformation on flow factors
Authors: Meng F-M , Wang W-Z , Hu Y-Z , Wang H
Published: July 2007

Combined influences of inter-asperity cavitation and elastic deformation of rough surfaces on flow factors were investigated based on an extended Reynolds equation for flow factor analyses. The numerical results reveal that when effect of cross-flow of lubricant is not obvious, the pressure flow factor increases, whereas the shear flow factor decreases, for a small ratio of film thickness to roughness, due to influences of inter-asperity cavitation and the elastic deformation of rough surfaces. When the ratio of film thickness to roughness becomes big, however, the influences become weak and can even be negligible. Moreover, the above influences are sensitive to the orientations of rough surfaces. Therefore, combined effects of inter-asperity cavitation and elastic deformation of rough surfaces should be considered in flow factor analyses.
Dual robot system for upper limb rehabilitation after stroke: The design process
Authors: Jackson A E , Holt R J , Culmer P R , Makower S G , Levesley M C , Richardson R C , Cozens J A , Williams M Mon , Bhakta B B
Published: July 2007

Stroke is the most common cause of severe disability in the UK. Arm impairment is common and recovery is partly dependent on the intensity and frequency of rehabilitation intervention. However, physical therapy resources are often limited, so methods of supplementing traditional physiotherapy are essential. Robot assisted physiotherapy is one way to increase the duration patients spend participating in rehabilitation activities.

A single robot system has been developed at the University of Leeds that actively assists patients undertaking therapeutic movements in a three-dimensional workspace. However, using only a single point of contact at the wrist to assist with therapeutic reaching movements does not allow control or support of the more proximal joints of the upper limb. This could lead to discomfort during assisted exercise. In addition, the design suffers from a restrictive workspace, limiting the range of therapeutic exercise that can be undertaken. To address these limitations, the intelligent Pneumatic Arm Movement system has been developed.

A major aspect of the development process has been the continual involvement of physiotherapists and stroke patients; the end users of the system. Through inclusion of these stakeholders, a system has been developed that satisfies their requirements for workspace, comfort, safety, and ease of use.
Idealized steering for hauling locomotives
Authors: Simson S A , Cole C
Published: July 2007

Most of the passive and active steering developments of traction bogies have been directed towards high speed rail or light rail and commuter rail applications. Previous studies ignored coupler forces and often assumed the wheel rail profiles have ample conicity for the curving task. There is little work directed towards high adhesion rates which is a critical area for freight locomotive performance. In heavy haul train operations ruling grades are often associated with tight curvatures, and steering tasks of hauling locomotives are affected by lateral components of longitudinal train forces. Haul locomotives also have a significant yaw moment from coupler forces making uneven longitudinal creeps useful in balancing these yaw forces. The use of larger diameter wheels on locomotives reduces effective steering conicity such that contact profiles may become insufficient to negotiate tight curves. The large diameter wheels make longitudinal creepage or slip inevitable and Goodall et al. [1] definition of perfect steering unattainable. A new criteria for ideal steering in these conditions is proposed. For hauling locomotives, ideal steering is defined as when the lateral rail creep and contact loads of each axle in one bogie are equal and longitudinal creeps are positive to the applied traction. This definition is applicable to all curving tasks that a hauling locomotive encounters while still applying low wheel rail creep forces. In most of the cases ideal steering can be achieved with zero lateral creep forces.

The paper describes equations for quasi-static curving forces including traction and in-train forces. An analysis of curving forces for locomotives with three axle bogies is made with the equations for various curvatures and with haulage locomotives in different train configurations including pusher configuration.
Kriging-based approximate optimization of high-speed train nose shape for reducing micropressure wave
Authors: Lee J , Kim J
Published: July 2007

Trains travelling at high-speed into a tunnel generate micropressure waves causing an explosive noise at the tunnel exit. This paper deals with the design of high-speed railways nose shape design to minimize the maximum micropressure wave which is known to be mainly affected by train speed, train-to-tunnel area ratio, slenderness and shape of train nose, etc. It is more efficient to develop a proper approximate meta-model for replacing the real analysis code in the context of approximate design optimization. The study has adopted the Kriging meta-model; the central of the paper is to develop and examine Kriging for use in the sequential approximate optimization process. In the sequential approximate optimization process, Owen's random orthogonal arrays and D-optimal design are used to generate training data for building approximate models. The paper describes how Kriging works and how much it is efficient as an approximation model in the context of approximate optimization. Consequently, the present study suggests the new optimal nose shape that is more improved than currently used design in terms of micropressure wave.