bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Tumor-Released Microvesicles Promote the Differentiation of Myeloid Cells with Transforming Growth Factor-β–Mediated Suppressive Activity on T Lymphocytes
Authors: Valenti Roberta , Huber Veronica , Filipazzi Paola , Pilla Lorenzo , Sovena Gloria , Villa Antonello , Corbelli Alessandro , Fais Stefano , Parmiani Giorgio , Rivoltini Licia
Published: September 2006

Human tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR−/low cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-α, and transforming growth factor-β (TGF-β), and a dose-dependent suppressive activity on activated T-cell–proliferation and cytolytic functions, which could be reversed by anti-TGF-β–neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14+ monocytes, skewing their differentiation toward CD14+HLA-DR−/low cells with TGF-β–mediated suppressive activity on T-cell–functions. Interestingly, a subset of TGF-β–secreting CD14+HLA-DR− cells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell–mediated control of tumor growth in cancer patients. (Cancer Res 2006; 66(18): 9290-8)
Interplay between Notch Signaling and Epigenetic Silencers in Cancer
Authors: Dominguez Maria
Published: September 2006

Given its role in the development and self-renewal of many tissues, it is not surprising that a prominent role has recently been proposed for the Notch signal transduction pathway in tumor development. However, exactly how Notch hyperactivation promotes oncogenesis is poorly understood. Recent findings in Drosophila melanogaster have linked the Notch pathway to epigenetic silencing and the tumor suppressor gene Rb during tumorigenesis. Because aberrant epigenetic gene silencing contributes to the pathogenesis of most human cancers, these findings may provide a new focal point to understand how Notch is associated with cancers, and to help develop better selective cancer therapies. (Cancer Res 2006; 66(18): 8931-4)
A Human Cell-Based Assay to Evaluate the Effects of Alterations in the MLH1 Mismatch Repair Gene
Authors: Blasi Monica Francesca , Ventura Ilenia , Aquilina Gabriele , Degan Paolo , Bertario Lucio , Bassi Chiara , Radice Paolo , Bignami Margherita
Published: September 2006

We describe a new approach to investigate alterations in the human MLH1 mismatch repair (MMR) gene. This is based on complementation of the phenotype of a MLH1-defective subclone of the ovarian carcinoma A2780 cells by transfection of vectors encoding altered MLH1 proteins. Measurements of resistance (tolerance) to methylating agents, mutation rate at HPRT, microsatellite instability (MSI), and steady-state levels of DNA 8-oxoguanine were used to define the MMR status of transfected clones. The approach was validated by transfecting cDNA of wild-type (WT) MLH1, cDNAs bearing two previously identified polymorphisms (I219V and I219L) and two with confirmed hereditary nonpolyposis colorectal cancer (HNPCC) syndrome mutations (G224D and G67R). A low-level expression of two MLH1 polymorphisms partially reversed methylation tolerance and the mutator phenotype, including MSI. Higher levels of I219V resulted in full restoration of these properties to WT. Increased expression of I129L did not fully complement the MLH1 defect, because there was a simultaneous escalation in the level of oxidative DNA damage. The findings confirmed the important relationship between deficient MMR and increased levels of oxidative DNA damage. Mutations from Italian HNPCC families (G224D, G67R, N635S, and K618A) were all ineffective at reversing the phenotype of the MLH1-defective A2780 cells. One (K618A) was identified as a low penetrance mutation based on clinical and genetic observations. (Cancer Res 2006; 66(18): 9036-44)
The Corepressor Silencing Mediator for Retinoid and Thyroid Hormone Receptor Facilitates Cellular Recovery from DNA Double-Strand Breaks
Authors: Yu Jiujiu , Palmer Christine , Alenghat Theresa , Li Yun , Kao Gary , Lazar Mitchell A.
Published: September 2006

Cells are frequently challenged by DNA double-strand breaks (DSB) that threaten their normal function and survival. In mammalian cells, the repair of DSBs is predominantly mediated by the DNA-dependent protein kinase (DNA-PK) complex. We unexpectedly found that the corepressor silencing mediator for retinoid and thyroid hormone receptor (SMRT) associates with the DNA-PK repair complex. The SMRT/histone deacetylase 3 complex is required for the transcriptional repressive property of the Ku70 subunit of the repair complex. Moreover, SMRT, but not the related Nuclear Receptor Corepressor, is required for cellular recovery from DNA DSBs induced by ionizing radiation or DNA damage–inducing drugs. Thus, the corepressor SMRT plays a novel and critical role in the cellular response to DSBs. (Cancer Res 2006; 66(18): 9316-22)
Alteration of the Methylation Status of Tumor-Promoting Genes Decreases Prostate Cancer Cell Invasiveness and Tumorigenesis In vitro and In vivo
Authors: Shukeir Nicholas , Pakneshan Pouya , Chen Gaoping , Szyf Moshe , Rabbani Shafaat A.
Published: September 2006

We tested the hypothesis that cell invasiveness and tumorigenesis are driven by hypomethylation of genes involved in tumor progression. Highly invasive human prostate cancer cells PC-3 were treated with either the methyl donor S-adenosylmethionine (SAM) or methyl DNA-binding domain protein 2 antisense oligonucleotide (MBD2-AS). Both treatments resulted in a dose- and time-dependent inhibition of key genes, such as urokinase-type plasminogen activator (uPA), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor expression to decrease tumor cell invasion in vitro. No change in the levels of expression of genes already known to be methylated in late-stage prostate cancer cells, such as glutathione S-transferase P1 and androgen receptor, was seen. Inoculation of PC-3 cells pretreated with SAM and MBD2-AS into the flank of male BALB/c nu/nu mice resulted in the development of tumors of significantly smaller volume compared with animals inoculated with PC-3 cells treated with vehicle alone or MBD2 scrambled oligonucleotide. Immunohistochemical analysis of tumors showed the ability of SAM and MBD2-AS to significantly decrease tumoral uPA and MMP-2 expression along with levels of angiogenesis and survival pathway signaling molecules. Bisulfite sequencing analysis of tumoral genomic DNA showed that inhibition of both uPA and MMP-2 expression was due to methylation of their 5′ regulatory region. These studies support the hypothesis that DNA hypomethylation controls the activation of multiple tumor-promoting genes and provide valuable insight into developing novel therapeutic strategies against this common disease, which target the demethylation machinery. (Cancer Res 2006; 66(18): 9202-10)
Array Comparative Genomic Hybridization Reveals Distinct DNA Copy Number Differences between Gastrointestinal Stromal Tumors and Leiomyosarcomas
Authors: Meza-Zepeda Leonardo A. , Kresse Stine H. , Barragan-Polania Ana H. , Bjerkehagen Bodil , Ohnstad Hege O. , Namløs Heidi M. , Wang Junbai , Kristiansen Bjørn E. , Myklebost Ola
Published: September 2006

Leiomyosarcomas are spindle cell tumors showing smooth muscle differentiation. Until recently, most gastrointestinal stromal tumors (GIST) were also classified as smooth muscle tumors, but now GISTs are recognized as a separate entity, defined as spindle cell and/or epithelioid tumors localized in the gastrointestinal tract. Using microarray-based comparative genomic hybridization (array CGH), we have created a detailed map of DNA copy number changes for 7 GISTs and 12 leiomyosarcomas. Considerable gains and losses of chromosomal segments were observed in both tumor types. The most frequent aberration observed in GISTs was loss of chromosomes 14 and 22, with minimal recurrent regions in 14q11.2-q32.33 (71% of the tumors) and 22q12.2-q13.31 (100%). In leiomyosarcomas, frequent loss of chromosome 10 and 13q was observed, with minimal recurrent regions in 10q21.3 (75%) and 13q14.2-q14.3 (75%). Recurrent high-level amplification of 17p13.1-p11.2 was detected in leiomyosarcomas. Expression profiling using cDNA microarrays revealed four candidate genes in this region with high expression (AURKB, SREBF1, MFAP4, and FLJ10847). Altered expression of AURKB and SREBF1 has been observed previously in other malignancies. Hierarchical clustering of all samples separated GISTs and leiomyosarcomas into two distinct clusters. Statistical analysis identified six chromosomal regions, 1p36.11-p13.1, 9q21.11-9q34.3, 14q11.2-q23.2, 14q31.3-q32.33, 15q24.3-q26.3, and 22q11.21-q13.31, which were significantly different in copy number between GISTs and leiomyosarcomas. Our results show the potential of using array comparative genomic hybridization to classify histologically similar tumors such as GISTs and leiomyosarcomas. (Cancer Res 2006;66(18):8984-93)
Rare Germ Line CHEK2 Variants Identified in Breast Cancer Families Encode Proteins That Show Impaired Activation
Authors: Sodha Nayanta , Mantoni Tine S. , Tavtigian Sean V. , Eeles Rosalind , Garrett Michelle D.
Published: September 2006

Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutations indicate that two of these, delE161 (483-485delAGA) and R117G, are likely to be deleterious. We show that the proteins encoded by 1100delC and delE161 are both unstable and inefficiently phosphorylated at Thr68 in response to DNA damage, a step necessary for the oligomerization of Chk2. Oligomerization is in turn necessary for additional phosphorylation and full activation of the protein. A second rare mutation, R117G, is phosphorylated at Thr68 but fails to show a mobility shift on DNA damage, suggesting that it fails to become further phosphorylated and hence fully activated. Our results indicate that delE161 and R117G encode nonfunctional proteins and are therefore likely to be pathogenic. The findings from the biochemical analysis correlate well with predictions made by bioinformatics analysis. In addition, the results imply that these mutations, as well as 1100delC, cannot act in a dominant-negative manner to cause cancer, and tumorigenesis in association with these mutations may be due to haploinsufficiency. (Cancer Res 2006; 66(18): 8966-70)
Implications of Gene-Environment Interaction in Studies of Gene Variants in Breast Cancer: An Example of Dietary Isoflavones and the D356N Polymorphism in the Sex Hormone-Binding Globulin Gene
Authors: Low Yen-Ling , Dunning Alison M. , Dowsett Mitch , Luben Robert N. , Khaw Kay-Tee , Wareham Nick J. , Bingham Sheila A.
Published: September 2006

Studies to identify common genetic variants contributing to breast cancer risk often yield inconsistent results. Breast cancer is a complex disease involving both genetic and environmental determinants. Dietary isoflavones are thought to reduce breast cancer risk by stimulating circulating sex hormone-binding globulin (SHBG) levels. The SHBG gene contains a D356N polymorphism and the N variant is associated with reduced SHBG clearance compared with the D variant. In this study, we show a significant gene-environment interaction between SHBG D356N polymorphism and dietary isoflavone exposure on circulating SHBG levels in 1,988 postmenopausal women. SHBG levels were positively associated with isoflavones in women carrying the N variant (ηp2 = 1.9%; P = 0.006) but not in women carrying only the D variant (ηp2 = 0.0%; P = 0.999; Pinteraction = 0.019). This finding shows that the subtle effects of some genetic variants may be magnified and only become detectable in the presence of certain exposures. This gene-environment interaction might explain heterogeneity in studies associating SHBG gene variants and soy consumption with breast cancer risk in Far East population exposed to high isoflavone levels compared with populations with lower levels. (Cancer Res 2006; 66(18): 8980-3)
Small Molecules, Big Players: the National Cancer Institute's Initiative for Chemical Genetics
Authors: Tolliday Nicola , Clemons Paul A. , Ferraiolo Paul , Koehler Angela N. , Lewis Timothy A. , Li Xiaohua , Schreiber Stuart L. , Gerhard Daniela S. , Eliasof Scott
Published: September 2006

In 2002, the National Cancer Institute created the Initiative for Chemical Genetics (ICG), to enable public research using small molecules to accelerate the discovery of cancer-relevant small-molecule probes. The ICG is a public-access research facility consisting of a tightly integrated team of synthetic and analytical chemists, assay developers, high-throughput screening and automation engineers, computational scientists, and software developers. The ICG seeks to facilitate the cross-fertilization of synthetic chemistry and cancer biology by creating a research environment in which new scientific collaborations are possible. To date, the ICG has interacted with 76 biology laboratories from 39 institutions and more than a dozen organic synthetic chemistry laboratories around the country and in Canada. All chemistry and screening data are deposited into the ChemBank web site (http://chembank.broad.harvard.edu/) and are available to the entire research community within a year of generation. ChemBank is both a data repository and a data analysis environment, facilitating the exploration of chemical and biological information across many different assays and small molecules. This report outlines how the ICG functions, how researchers can take advantage of its screening, chemistry and informatic capabilities, and provides a brief summary of some of the many important research findings. (Cancer Res 2006; 66(18): 8935-42)
Body Mass Index and Mortality in Elderly Men and Women from General Population
Authors: Mazza Alberto , Zamboni Sergio , Tikhonoff Valérie , Schiavon Laura , Pessina Achille C. , Casiglia Edoardo
Published: September 2006

Background: The role of body mass index (BMI) as a factor influencing longevity of the elderly subject is still under debate. Objective: To evaluate at a population level whether or not BMI is a risk factor of mortality in the elderly, highlighting possible gender-related differences. Methods: 3,282 subjects aged 65–95 years, were recruited from an Italian general population and 12-year events were recorded. Blood tests and anthropometric measurements were performed. BMI as a continuous item was divided into quintiles and, for each quintile, adjusted hazard ratio (HR) with 95% confidence intervals for mortality was derived by classes of age and gender from Cox analysis. Results: BMI inversely predicted overall and cancer mortality in men only. Overall mortality rate was 64.7% (HR = 1.63 [1.23–2.71]) in the 1st quintile of BMI, 54.9% (1.21 [0.92–1.73]) in the 2nd, 54.1% (1.20 [0.85–1.67]) in the 3rd, 53.3% (1.04 [0.82–1.32]) in the 4th and 52.5% in the 5th; cancer mortality rate was 23.1% (HR = 2.35 [1.31–4.23]), 14.2% (HR = 1.19 [0.65–1.80]), 15.8% (HR = 1.49 [0.93–2.39]), 15.8% (HR = 1.36 [0.84–2.16]) and 13.4%, respectively. The relationship between BMI and mortality remained significant only in men aged 76 years or less. No relationship was found between BMI and coronary or cerebrovascular mortality. Conclusions: BMI <22.7 kg/m2 does not improve survival in the elderly, while it is an independent predictor of cancer mortality in men aged ≤76 years. No prediction based on BMI is possible in women.
Effects of Beta-Adrenoceptors Overexpression on Cell Survival Are Mediated by Bax/Bcl-2 Pathway in Rat Cardiac Myocytes
Authors: Sun Hong , Zhou Feng , Wang Ying , Zhang Yang , Chang Aimin , Chen Qi
Published: September 2006

Background: Chronic activation of β-adrenoceptors (β-ARs) results in cardiac myocyte injury, even death, and diminishes the number of β-ARs. Objectives: To investigate the effects of overexpression of β1- or β2-AR on cardiomyocytes injured by isoprenaline (ISO). Methods: We have used an adenoviral vector carrying the sequence for human β1- or β2-AR (Adv.β1, Adv.β2) to increase the content of β1 or β2-AR in isolated adult rat ventricular myocytes, and we have examined the cell survival and the expression of Bax and Bcl-2. Results: With use of adenoviral vectors, the β1- and β2-AR contents of myocytes were increased 2.98- and 2.87-fold, respectively. Overexpression of β1-AR sharpened the cellular injury of ISO. If β2-AR activity was further blocked by addition of selective β2-AR antagonist ICI118,551, the cells were more sensitive to the impairment of Adv.β1 + ISO. Overexpression of Adv.β2 partially inversed the cytotoxicity of ISO stimulation. The beneficial effects were strengthened by addition of CGP20712A, a β1-AR-blocking agent. Western blot analysis demonstrated that both increasing β1-AR and inhibition of β2-AR increased the ratio of Bax/Bcl-2. Whereas, increasing β2-AR and inhibition of β1-AR decreased the ratio of Bax/ Bcl-2. Control adenovirus CGP had no effect on cell survival. Conclusions: Overexpression of Adv.β2 and/or inhibition of β1-AR have protective effect on adult rat ventricular myocytes chronically stimulated by ISO. Overexpression of Adv.β1 and/or inhibition of β2-AR are deleterious in the same state. The effects of β-ARs on cell survival might be mediated by the Bax/Bcl-2 signal pathway.
Behavioural and Psychological Symptoms of Alzheimer Type Dementia Are Not Correlated with Plasma Homocysteine Concentration
Authors: Tabet N. , Rafi H. , Weaving G. , Lyons B. , Iversen S.A.
Published: September 2006

Background/Aims: Vitamin B12 and folate deficiencies have been associated with cognitive impairment and various psychiatric symptoms but not specifically with behavioural and psychological symptoms of dementia (BPSD). A limitation of previous studies in dementia was lack of concurrent homocysteine measurement especially as it may provide a better indicator of tissue activities of these vitamins. This study was designed to clarify whether a relationship exists between plasma homocysteine concentration and BPSD. Methods: Plasma homocysteine, serum vitamin B12 and folate were measured in23Alzheimer’s disease (AD) patients with BPSD and 27 AD patients without BPSD as determined through the use of the Neuropsychiatric Inventory (NPI). Blood levels of measured substances were also correlated with individual NPI scores and with cumulative NPI scores for different cluster of symptoms. Results: There was no significant difference (p = 0.956) in the mean plasma homocysteine levels between AD patients with BPSD (17.48 µmol/l) and AD patients without BPSD (17.34 µmol/l). Similarly, there was no significant difference between the two groups in the mean serum B12 (382.61 and 391.60 pg/ml, respectively) and folate (7.95 and 10.02 ng/ml, respectively). Mean levels for both vitamins were well within the laboratory reference range. Neither individual nor cluster NPI scores correlated significantly with plasma homocysteine. Conclusion: This study shows for the first time that BPSD are not associated with hyperhomocysteinaemia in Alzheimer dementia. Although previous studies have identified homocysteine as an independent risk factor in AD, the results reported here do not lend weight to an aetiological role for homocysteine specifically in BPSD.
Association of Insulin-Like Growth Factor-1 Receptor Polymorphism in Dementia
Authors: Garcia J. , Ahmadi A. , Wonnacott A. , Sutcliffe W. , Nägga K. , Söderkvist P. , Marcusson J.
Published: September 2006

There is an increasing interest in how oxidative stress can cause cells to go into apoptosis in both normal ageing and in neurodegenerative disorders. Previous research has implicated insulin-like growth factor-1 (IGF-1) as being involved in the pathogenesis in Alzheimer’s disease (AD) by protecting the neurons through reducing neuronal susceptibility to oxidative stress. IGF-1 receptor (IGF-1R) polymorphisms alter cerebral and systemic levels of IGF-1 and may alter the function of the receptor. We genotyped the IGF-1R gene by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) to assess whether this gene polymorphism can be linked to dementia. We used leukocyte DNA from 72 patients with AD, 75 patients with vascular dementia (VaD), 14 patients with mixed dementia (AD+VaD), and a control group consisting of 209 individuals without a history of progressive neurological disorders. Analysis of gene frequency for gender revealed a significant difference between female VaD patients and female controls carrying at least one A allele (OR = 1.8, CI 95% 1.1–2.9, p = 0.02), but not for male patients. In addition, we found a strong tendency to a difference between all cases of female dementia patients and controls carrying the A allele (OR = 1.5, CI 95% 0.99–2.2, p = 0.054). Our results suggest that the A allele of IGF-1R may be involved in the pathogenesis of VaD in females.
An Exploratory Open-Label Trial of Ziprasidone for the Treatment of Behavioral and Psychological Symptoms of Dementia
Authors: Rocha Fábio Lopes , Hara Cláudia , Ramos Melissa Guarieiro , Kascher Gustavo Guimarães , Santos Milena Antunes , de Oliveira Lança Gleida , Magalhães Scoralick Francisca
Published: September 2006

Objective: To evaluate the efficacy and tolerability of ziprasidone in behavioral and psychological symptoms of dementia. Method: A 7-week open-label trial of ziprasidone. Results: Of the 25 patients who participated, 15 completed the study. The main reason for discontinuation was adverse events. The mean total Neuropsychiatric Inventory (NPI) score fell significantly from 47.1 ± 17.1 (baseline) to 25.8 ± 17.9 (day 49) (p < 0.01). The NPI caregiver burden showed a significant improvement from 22.6 ± 8.3 at baseline to 11.8 ± 7.3. The most frequent adverse events were somnolence, gastrointestinal symptoms and parkinsonism. Conclusions: Ziprasidone was able to significantly improve distressing non-cognitive symptoms of dementia although adverse effects occurred. Additional large-scale, double-blind, well-controlled studies are necessary to evaluate the use of ziprasidone in this indication.
Audiometric Patterns in Ototoxicity of Intra-Arterial Cisplatin Chemoradiation in Patients with Locally Advanced Head and Neck Cancer
Authors: Zuur C.L. , Simis Y.J.W. , Lansdaal P.E.M. , Rasch C.R.N. , Tange R.A. , Balm A.J.M. , Dreschler W.A.
Published: September 2006

This study describes audiometric patterns of ototoxicity in a consecutive series of patients uniformly treated with intra-arterial high-dose cisplatin chemoirradiation for advanced cancer of the head and neck. Air conduction thresholds were measured from 0.125 to 16 kHz and bone conduction thresholds were measured from 0.5 to 4 kHz. The overall audiometric pattern was characterized by maximum threshold shifts after the 2nd cisplatin infusion and a maximum total threshold shift at 8 kHz, irrespective of gender, age, pretreatment sensorineural hearing loss (SNHL) or subjective complaints during therapy. A hearing deterioration gradient was observed from (ultra-) high to low frequencies, worse with increasing pre-existent SNHL and with increasing cumulative dose of cisplatin chemoradiation. Cisplatin chemoradiation-induced hearing loss seemed to reach a plateau at higher levels (75–80 dB HL) for frequencies above 8 kHz compared to frequencies up to 8 kHz (45–60 dB HL). Recovery of SNHL was found after therapy in 27 ears characterized by extensive hearing loss at frequencies 1, 2 and 4 kHz.
Distortion Product Otoacoustic Emissions as a Prognostic Factor for Idiopathic Sudden Sensorineural Hearing Loss
Authors: Chao Ting-Kuang , Chen Tony Hsiu-Hsi
Published: September 2006

We investigated distortion product otoacoustic emissions (DPOAE) as a prognostic factor in idiopathic sudden sensorineural hearing loss (ISSHL) patients with the time-dependent Cox proportional-hazards model. We also compared the importance of the prognostic factors that are reported in the literature. 108 patients with ISSHL were included. Both DPOAE and pure tone audiometry were performed everyday for a maximum of 7 days during admission and followed every other week or monthly after discharge. All DPOAE amplitudes were analyzed at 2f1-f2 – namely 1093, 1375, 1750, 2187, 2781, 3500, 4375, and 5500 Hz. The average of two series of DPOAE intensity corrected for the noise level in eight frequencies was coded as dichotomous at ≧6 or <6 dB. We selected the most updated DPOAE at 3 days or more before the assessment of recovery into the analysis. The potential confounders including age, sex, history of vertigo at onset, history of hypertension, diabetes, coronary arterial disease, and stroke, configuration and severity of initial pure tone audiometry, the duration from onset to treatment, auditory brainstem response (ABR), vestibular evoked myogenic potential (VEMP), and plasma triglyceride and cholesterol levels, hemoglobin level, and erythrocyte sedimentation rate were collected for evaluation. The results showed that a better DPOAE amplitude was a significantly good prognostic indicator both in univariate analysis (recovery rate ratio = 3.626, 95% CI = 2.119–6.205, p < 0.0001) and multivariate analysis (recovery rate ratio = 2.94, 95% CI = 1.537–5.624, p = 0.0011). The Kaplan-Meier estimates showed that the younger age group (≤40 years) with better initial pure tone audiometry (<65 dB) represented a better prognosis that was compatible with previous literature (log-rank test, p = 0.0297 and p = 0.0019 respectively). In the univariate analysis, normal ABR and VEMP waveforms were associated with a better prognosis (ABR: recovery rate ratio = 2.984, 95% CI = 1.742–5.112, p < 0.0001; VEMP: recovery rate ratio = 1.978, 95% CI = 1.183–3.305, p = 0.0093). The configuration of initial audiometry was also a significant prognostic factor that patients with scale-out type (recovery rate ratio = 0.228, 95% CI = 0.089–0.584, p = 0.002) and tent type (recovery rate ratio = 0.081, 95% CI = 0.008–0.778, p = 0.0295) were associated with a poorer prognosis than those with the flat type in the multivariate analysis. In this study, the time-dependent Cox proportional-hazards model established the prognostic value of DPOAE for ISSHL patients. This model can also be used for comparison of different treatment protocols. In addition, the further development of a predictive model based on this method is worthy of being investigated.
Succession Planning in SMEs
Authors: Motwani Jaideep , Levenburg Nancy M. , Schwarz Thomas V. , Blankson Charles
Published: September 2006

This study reports the results from a survey of 368 family-owned small to medium size enterprises (SMEs) with regard to the importance, nature, and extent of succession planning. By categorizing SMEs according to their annual revenues, total number of employees, and number of family members employed within the firm, significant differences were found between larger and smaller firms. Consistent with extant literature, the findings reveal that most family members join the firm for altruistic reasons. Issues related to family relationships were rated as significantly more important in firms in which more family members were employed within the firm. Moreover, for firms with less than US$1m in revenues, a high priority is placed on selecting a successor who possesses strong sales and marketing skills. The findings show that regardless of their size, it is important for family-owned businesses to develop a formal plan for succession, communicate the identity of the successor, and provide training/mentoring to the incumbent CEO.
Owner-managers and Business Planning in the Small Firm
Authors: Richbell Suzanne M. , Watts H. Doug , Wardle Perry
Published: September 2006

This article explores the ways in which the characteristics of the owner-managers of small firms influence whether or not those firms have a business plan. The focus is primarily on antecedent influences on owner-managers such as education and prior experience. Data are drawn from a survey of the owner-managers of small metalworking firms in Sheffield, UK. Around half the sample of owner-managers possess a business plan. Antecedent influences on owner-managers showing a significant association with the possession of a business plan include an above average level of education, previous work experience in a large firm immediately before setting up their firm and running firms in sectors outside their previous experience. Not surprisingly, possession of a business plan showed a positive association with those owner-managers with a growth orientation. It is concluded that owner-manager characteristics can be important in explaining the presence/absence of a business plan within the small firm.
A Multiparadigmatic Perspective of Strategy
Authors: Bhalla Ajay , Henderson Steven , Watkins David
Published: September 2006

Research into family businesses has a long history of lacking theoretical underpinnings, especially with respect to strategy. Moreover, the family of the firms in question has frequently been assumed to be Anglo-Saxon, unless the family business of an ethnic minority has been the specific subject of the research. This article broadens the prevailing discourse by studying the strategic affinities of an ethnic family firm in the context of Whittington’s (1993) framework, which proposed four approaches to the study of business strategy. The subject of this study, GOF, is a medium-sized family firm controlled by a South Asian family specializing in the wholesale distribution of ethnic foods and drinks in the UK. The management of this firm believes that its successful firm (of 35 years standing) has never had a strategy. However, a multiparadigmatic examination of the narrative of this family business reveals that there are several ways in which to gain an understanding of business strategy in medium-sized family firms.
On Joy-Sorrow: A Paradoxical Pattern of Human Becoming
Authors: Pilkington F. Beryl
Published: September 2006

The idea of paradox is central to Parse’s human becoming theory. Joy-sorrow is an example of a paradoxical pattern of human becoming which was earlier investigated by Parse, using her research method. Here, the concept is revisited and further explored in light of selected literature, including a classic work on grief and other writings on aesthetic experience. Connections are also drawn between joy-sorrow and the Japanese concept of wabi-sabi.
Teaching the Abyss: Living the Art-Science of Nursing
Authors: Ramey Sandra L. , Bunkers Sandra Schmidt
Published: September 2006

This column addresses how nurse educators can provide the teaching-learning experiences for novice nurses to develop the leadership competence to effectively practice nursing in an extremely demanding healthcare environment. The authors delve into Mitchell and Bunkers’ use of the metaphor of an abyss to explore the lived experience of risking being with others in extremely intense interpersonal situations. Using reflection, students’ journal narratives affirm connections made among past experiences and the new knowledge gleaned from exploring and naming the phenomenon of the abyss. Several teaching-learning strategies are offered as ways for addressing the leadership issues related to dealing with intense relational experiences in nursing practice, including exploring nurse theorist Rosemarie Rizzo Parse’s essentials of leadership.
A Process Model of Healing and Personal Transformation in Persons With Chronic Skin Wounds
Authors: Rosa Katherine C.
Published: September 2006

Utilizing Newman’s research as praxis process, this research examined the patterns of those living with chronic skin wounds. Ten men and 8 women, primarily of retirement age and living with chronic skin wounds for a year or more, reflected upon important relationships and life events during two in-depth interviews and a self-expressive drawing. Emerging from each participant’s pattern was the link among human development, expanding consciousness, and processing a serious physical threat. Considering data across participants, five themes emerged from the data with evolution of a process model of wholistic healing that has implications for advanced nursing practice.
Health Promotion in Adolescents: A Review of Pender’s Health Promotion Model
Authors: Srof Brenda J. , Velsor-Friedrich Barbara
Published: September 2006

Adolescents have unique health considerations as they transition from parent-managed healthcare to personal responsibility for health behavior. One question to consider is the goodness-of-fit of available theoretical models for explaining and predicting adolescent health-promoting behavior. This integrative review explored Pender’s health promotion model in relation to adolescent health. Specifically, this review summarizes the components of Pender’s model and the supporting theoretical underpinnings based in the social cognitive theory. Research literature related to the health promotion model and various aspects of teen health is explored. Recommendations for further research and theory development are discussed.
Instantaneous polarization attributes based on an adaptive approximate covariance method
Authors: Diallo Mamadou Sanou , Kulesh Michail , Holschneider Matthias , Kurennaya Kristina , Scherbaum Frank
Published: September 2006

We introduce a method for computing instantaneous-polarization attributes from multicomponent signals. This is an improvement on the standard covariance method (SCM) because it does not depend on the window size used to compute the standard covariance matrix. We overcome the window-size problem by deriving an approximate analytical formula for the cross-energy matrix in which we automatically and adaptively determine the time window. The proposed method uses polarization analysis as applied to multicomponent seismic by waveform separation and filtering.
3D common-reflection-point-based seismic migration velocity analysis
Authors: Fei Weihong , McMechan George A.
Published: September 2006

Three-dimensional prestack depth migration and depth residual picking in common-image gathers (CIGs) are the most time-consuming parts of 3D migration velocity analysis. Most migration-based velocity analysis algorithms need spatial coordinates of reflection points and CIG depth residuals at different offsets (or angles) to provide updated velocity information. We propose a new algorithm that can analyze 3D velocity quickly and accurately. Spatial coordinates and orientations of reflection points are provided by a 3D prestack parsimonious depth migration; the migration involves only the time samples picked from the salient reflection events on one 3D common-offset volume. Ray tracing from the reflection points to the surface provides a common-reflection-point (CRP) gather for each reflection point. Predicted (nonhyperbolic) moveouts for local velocity perturbations, based on maximizing the stacked amplitude, give the estimated velocity updates for each CRP gather. Then the velocity update for each voxel in the velocity model is obtained by averaging over all predicted velocity updates for that voxel. Prior model constraints may be used to stabilize velocity updating. Compared with other migration velocity analyses, the traveltime picking is limited to only one common-offset volume (and needs to be done only once); there is no need for intensive 3D prestack depth migration. Hence, the computation time is orders of magnitude less than other migration-based velocity analyses. A 3D synthetic data test shows the algorithm works effectively and efficiently.
A multiscale study of the mechanisms controlling shear velocity anisotropy in the San Andreas Fault Observatory at Depth
Authors: Boness Naomi L. , Zoback Mark D.
Published: September 2006

We present an analysis of shear velocity anisotropy using data in and near the San Andreas Fault Observatory at Depth (SAFOD) to investigate the physical mechanisms controlling velocity anisotropy and the effects of frequency and scale. We analyze data from borehole dipole sonic logs and present the results from a shear-wave-splitting analysis performed on waveforms from microearthquakes recorded on a downhole seismic array. We show how seismic anisotropy is linked either to structures such as sedimentary bedding planes or to the state of stress, depending on the physical properties of the formation. For an arbitrarily oriented wellbore, we model the apparent fast direction that is measured with dipole sonic logs if the shear waves are polarized by arbitrarily dipping transversely isotropic (TI) structural planes (bedding/fractures). Our results indicate that the contemporary state of stress is the dominant mechanism governing shear velocity anisotropy in both highly fractured granitic rocks and well-bedded arkosic sandstones. In contrast, within the finely laminated shales, anisotropy is a result of the structural alignment of clays along the sedimentary bedding planes. By analyzing shear velocity anisotropy at sonic wavelengths over scales of meters and at seismic frequencies over scales of several kilometers, we show that the polarization of the shear waves and the amount of anisotropy recorded are strongly dependent on the frequency and scale of investigation. The shear anisotropy data provide constraints on the orientation of the maximum horizontal compressive stress [Formula: see text] and suggest that, at a distance of only [Formula: see text] from the San Andreas fault (SAF), [Formula: see text] is at an angle of approximately 70° to the strike of the fault. This observation is consistent with the hypothesis that the SAF is a weak fault slipping at low levels of shear stress.
Fractured reservoirs: An analysis of coupled elastodynamic and permeability changes from pore-pressure variation
Authors: Daley T. M. , Schoenberg M. A. , Rutqvist J. , Nihei K. T.
Published: September 2006

Equivalent-medium theories can describe the elastic compliance and fluid-permeability tensors of a layer containing closely spaced parallel fractures embedded in an isotropic background. We propose a relationship between effective stress (background or lithostatic stress minus pore pressure) and both permeability and elastic constants. This relationship uses an exponential-decay function that captures the expected asymptotic behavior, i.e., low effective stress gives high elastic compliance and high fluid permeability, while high effective stress gives low elastic compliance and low fluid permeability. The exponential-decay constants are estimated for physically realistic conditions. With relationships coupling pore pressure to permeability and elastic constants, we are able to couple hydromechanical and elastodynamic modeling codes. A specific coupled simulation is demonstrated where fluid injection in a fractured reservoir causes spatially and temporally varying changes in pore pressure, permeability, and elastic constants. These elastic constants are used in a 3D finite-difference code to demonstrate time-lapse seismic monitoring with different acquisition geometries. Changes in amplitude and traveltime are seen in surface seismic P-to-S reflections as a function of offset and azimuth, as well as in vertical seismic profile P-to-S reflections and in crosswell converted S-waves. These observed changes in the seismic response demonstrate seismic monitoring of fluid injection in the fractured reservoir.
A new iterative solver for the time-harmonic wave equation
Authors: Riyanti C. D. , Erlangga Y. A. , Plessix R.-E. , Mulder W. A. , Vuik C. , Oosterlee C.
Published: September 2006

The time-harmonic wave equation, also known as the Helmholtz equation, is obtained if the constant-density acoustic wave equation is transformed from the time domain to the frequency domain. Its discretization results in a large, sparse, linear system of equations. In two dimensions, this system can be solved efficiently by a direct method. In three dimensions, direct methods cannot be used for problems of practical sizes because the computational time and the amount of memory required become too large. Iterative methods are an alternative. These methods are often based on a conjugate gradient iterative scheme with a preconditioner that accelerates its convergence. The iterative solution of the time-harmonic wave equation has long been a notoriously difficult problem in numerical analysis. Recently, a new preconditioner based on a strongly damped wave equation has heralded a breakthrough. The solution of the linear system associated with the preconditioner is approximated by another iterative method, the multigrid method. The multigrid method fails for the original wave equation but performs well on the damped version. The performance of the new iterative solver is investigated on a number of 2D test problems. The results suggest that the number of required iterations increases linearly with frequency, even for a strongly heterogeneous model where earlier iterative schemes fail to converge. Complexity analysis shows that the new iterative solver is still slower than a time-domain solver to generate a full time series. We compare the time-domain numeric results obtained using the new iterative solver with those using the direct solver and conclude that they agree very well quantitatively. The new iterative solver can be applied straightforwardly to 3D problems.
Enhanced interpretation of magnetic survey data from archaeological sites using artificial neural networks
Authors: Bescoby David. J. , Cawley Gavin C. , Chroston P. Neil
Published: September 2006

The use of magnetic surveys for archaeological prospecting is a well-established and versatile technique, and a wide range of data processing routines are often applied to further enhance acquired data or derive source parameters. Of particular interest in this respect is the application of artificial neural networks (ANNs) to predict source parameters such as the burial depths of detected features of interest. Within this study, ANNs based upon a multilayer perceptron architecture are used to perform the nonlinear mapping between buried wall features detected within the magnetic data and their corresponding burial depth for surveys in the ancient city of Butrint in southern Albania, achieving a greater level of information from the survey data.

Suitable network training examples and test data were generated using forward models based upon ground-truth observations. The training procedure adopts a supervised learning routine that is optimized using a conjugate gradient method, while the learning algorithm also prunes network elements to prevent overregularization by reducing model complexity. Data processing was further enhanced by introducing rotational invariance using Zernike moments and by utilizing the combined output of a number, or committee, of networks. When applied to a section of survey data from Butrint, the ANN routine successfully predicted the burial depth of a number of detected wall features, with an rms error on the order of [Formula: see text], and provided a coherent map of the buried building foundations. The neural network approach offered advantages in terms of efficiency and flexibility over more conventional data-inversion techniques within the context of the study, giving fast solutions for large, complex data sets while having high noise tolerance.
Regularization and datuming of seismic data by weighted, damped least squares
Authors: Ferguson Robert J.
Published: September 2006

The possibility of improving regularization/datuming of seismic data is investigated by treating wavefield extrapolation as an inversion problem. Weighted, damped least squares is then used to produce the regularized/datumed wavefield. Regularization/datuming is extremely costly because of computing the Hessian, so an efficient approximation is introduced. Approximation is achieved by computing a limited number of diagonals in the operators involved. Real and synthetic data examples demonstrate the utility of this approach. For synthetic data, regularization/datuming is demonstrated for large extrapolation distances using a highly irregular recording array. Without approximation, regularization/datuming returns a regularized wavefield with reduced operator artifacts when compared to a nonregularizing method such as generalized phase shift plus interpolation (PSPI). Approximate regularization/datuming returns a regularized wavefield for approximately two orders of magnitude less in cost; but it is dip limited, though in a controllable way, compared to the full method. The Foothills structural data set, a freely available data set from the Rocky Mountains of Canada, demonstrates application to real data. The data have highly irregular sampling along the shot coordinate, and they suffer from significant near-surface effects. Approximate regularization/datuming returns common receiver data that are superior in appearance compared to conventional datuming.