Open-Label Phase I Clinical Study to Assess the Safety and Efficacy of Cilostazol in Patients Undergoing Internal Carotid Artery Stent Placement

BACKGROUND: One-month dual antiplatelet treatment, with aspirin and clopidogrel, following internal carotid artery stent placement is the current standard of care to prevent in-stent thrombosis. Cilostazol, an antiplatelet drug, has been demonstrated to have a safety profile comparable to aspirin and clopidogrel. OBJECTIVE: To evaluate the safety and clinical efficacy of cilostazol and aspirin therapy following internal carotid artery stent placement up to 1 month postprocedure. METHODS: A phase I open-label, nonrandomized two-center prospective study was conducted. All subjects received aspirin (325 mg/day) and cilostazol (200 mg/day) 3 days before extracranial stent placement. Two antiplatelet agents were continued for 1 month postprocedure followed by aspirin daily monotherapy. The primary efficacy end point was the 30-day composite occurrence of death, cerebral infarction, transient ischemic attack, and in-stent thrombosis. The primary safety end point was bleeding. RESULTS: Twelve subjects (mean age ± SD, 66 ± 12 years; 9 males) were enrolled and underwent internal carotid artery angioplasty and stent placement. None of the subjects who successfully followed the study protocol experienced any complications at the 1- and 3-month follow-ups. One patient had a protocol deviation due to concurrent use of enoxaparin (1 mg/kg twice daily) in addition to aspirin and cilostazol, resulting in a fatal symptomatic intracerebral hemorrhage following successful stent placement on postprocedure day 1. One patient discontinued cilostazol after the first dose secondary to dizziness. CONCLUSION: The use of cilostazol and aspirin for internal carotid artery stent placement appears to be safe, but protocol compliance needs to be emphasize

It’s all about the money? A qualitative study of healthcare worker motivation in urban China

Background China’s healthcare reform programme continues to receive much attention. Central to these discussions has been how the various financial incentives underpinning reform efforts are negatively impacting on the healthcare workforce. Research continues to document these trends, however, qualitative analysis of how these incentives impact on the motivation of healthcare workers remains underdeveloped. Furthermore, the application of motivational theories to make sense of healthcare worker experiences has yet to be undertaken. Methods The purpose of our paper is to present a comparative case study account of healthcare worker motivation across urban China. It draws on semi structured interviews (n = 89) with a range of staff and organisations across three provinces. In doing so, the paper analyses how healthcare worker motivation is influenced by a variety of financial incentives; how motivation is influenced by the opportunities for career development; and how motivation is influenced by the day to day pressures of meeting patient expectations. Results The experience of healthcare workers in China highlights how a reliance on financial incentives has challenged their ability to maintain the values and ethos of public service. Our findings suggest greater attention needs to be paid to the motivating factors of improved income and career development. Further work is also needed to nurture and develop the motivation of healthcare workers through the building of trust between fellow workers, patients, and the public. Conclusions Through the analysis of healthcare worker motivation, our paper presents a number of ways China can improve its current healthcare reform efforts. It draws on the experience of other countries in calling for policy makers to support alternative approaches to healthcare reform that build on multiple channels of motivation to support healthcare workers

Breast tumor copy number aberration phenotypes and genomic instability

BACKGROUND: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. METHODS: We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability. RESULTS: We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability. CONCLUSION: Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome

p53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions

Most normal somatic cells enter a state called replicative senescence after a certain number of divisions, characterized by irreversible growth arrest. Moreover, they express a pronounced inflammatory phenotype that could contribute to the aging process and the development of age-related pathologies. Among the molecules involved in the inflammatory response that are overexpressed in senescent cells and aged tissues is intercellular adhesion molecule-1 (ICAM-1). Furthermore, ICAM-1 is overexpressed in atherosclerosis, an age-related, chronic inflammatory disease. We have recently reported that the transcriptional activator p53 can trigger ICAM-1 expression in an nuclear factor-kappa B (NF-kappa B)-independent manner (Gorgoulis et al, EMBO J. 2003; 22: 1567 - 1578). As p53 exhibits an increased transcriptional activity in senescent cells, we investigated whether p53 activation is responsible for the senescence-associated ICAM-1 overexpression. To this end, we used two model systems of cellular senescence: ( a) human fibroblasts and (b) conditionally immortalized human vascular smooth muscle cells. Here, we present evidence from both cell systems to support a p53-mediated ICAM-1 overexpression in senescent cells that is independent of NF-kappa B. We also demonstrate in atherosclerotic lesions the presence of cells coexpressing activated p53, ICAM-1, and stained with the senescence-associated beta-galactosidase, a biomarker of replicative senescence. Collectively, our data suggest a direct functional link between p53 and ICAM-1 in senescence and age-related disorders

Antioxidant agent nimesulid and beta-blocker metoprolol do not exert protective effects against rat mitochondrial DNA alterations in adriamycin-induced cardiotoxicity

Possible protective effects of two therapeutical agents (nimesulid and metoprolol) in adriamycin-induced cardiotoxicity were examined in rat cardiomyocytes at the mitochondrial DNA (mt DNA) level. Analysis by PCR revealed the presence of multiple deletions in a large region of the long are of mt DNA which codes for several important genes involved in oxidative phosphorylation, in all animals under drug administration. No differences were found in the frequency of defective mt DNA between the animals that received only adriamycin (83%, 10/12), nimesulid and adriamycin (92%, 13/14), or metoprolol and adriamycin (80, 12/15) (p = 0.004). (C) 1999 Academic Press

Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas - Synergistic effect with mutant p53 on tumor growth and chromosomal instability - Evidence of E2F-1 transcriptional control over hCdt1

Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy. This is the first study of these fundamental licensing elements in primary human lung carcinomas. We herein demonstrate elevated levels (more than fourfold) of hCdt1 and hCdc6 in 43% and 50% of neoplasms, respectively, whereas aberrant expression of hGeminin was observed in 49% of cases (underexpression, 12%; overexpression, 37%). hCdt1 expression positively correlated with hCdc6 and E2F-1 levels (P = 0.001 and P = 0.048, respectively). Supportive of the observed link between E2F-1 and hCdt1, we provide evidence that E2F-1 up-regulates the hCdt1 promoter in cultured mammalian cells. Interestingly, hGeminin overexpression was statistically related to increased hCdt1 levels (P = 0.025). Regarding the kinetic and ploidy status of hCdt1- and/or hCdc6-overexpressing tumors, p53-mutant cases exhibited significantly increased tumor growth values (Growth index; GI) and aneuploidy/CIN compared to those bearing intact p53 (P = 0.008 for GI, P = 0.001 for CIN). The significance of these results was underscored by the fact that the latter parameters were independent of p53 within the hCdt1-hCdc6 normally expressing cases. Cumulatively, the above suggest a synergistic effect between hCdt1-hCdc6 overexpression and mutant-P53 over tumor growth and CIN in non-small-cell. lung carcinomas