Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance.

We evaluated the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing elective coronary stenting. Patients (n = 150) treated with aspirin but not clopidogrel had blood samples drawn at baseline and 24 h after clopidogrel loading. Depending on the definition used, 9% to 15% were resistant to aspirin and 24% to clopidogrel. About half of the aspirin-resistant patients were also resistant to clopidogrel. As a group, aspirin-resistant patients had lower response to clopidogrel (assessed by platelet aggregation and activation markers) than aspirin-sensitive patients. Both aspirin- and clopidogrel-resistant patients had higher incidence of creatine kinase-MB elevation than the respective sensitive patients. OBJECTIVES: We sought to evaluate the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Wide variability has been reported in response to aspirin and clopidogrel. There are limited data on the simultaneous responses to both drugs. METHODS: Elective PCI patients (n = 150) who received aspirin for > or = 1 week but not clopidogrel were included. All patients received bivalirudin during PCI. Blood samples were drawn at baseline and 20 to 24 h after a 300-mg clopidogrel dose. Aspirin resistance was defined by > or = 2 of 3 criteria: rapid platelet function analyzer-ASA score > or = 550, 5 micromol/l adenosine diphosphate (ADP)-induced aggregation > or = 70%, and 0.5 mg/ml arachidonic acid-induced aggregation > or = 20%. Clopidogrel resistance was defined as baseline minus post-treatment aggregation < or = 10% in response to 5 and 20 micromol/l ADP. RESULTS: Nineteen (12.7%) patients were resistant to aspirin and 36 (24%) to clopidogrel. Nine (47.4%) of the aspirin-resistant patients were also clopidogrel resistant. Aspirin-resistant patients were more likely to be women and have diabetes than were aspirin-sensitive patients. They also had lower response to clopidogrel, assessed by platelet aggregation and activation markers (flow cytometry-determined PAC-1 binding and P-selectin expression). Elevation of creatine kinase-myocardial band after stenting occurred more frequently in aspirin-resistant versus aspirin-sensitive patients (38.9% vs. 18.3%; p = 0.04) and in clopidogrel-resistant versus clopidogrel-sensitive patients (32.4% vs. 17.3%; p = 0.06). CONCLUSIONS: Aspirin-resistant patients as a group have reduced response to clopidogrel. Furthermore, we have identified a unique group of dual drug-resistant patients who may be at increased risk for thrombotic complications after PCI.     

Differential surface marker expression in patients with CD-16+ lymphoproliferative disorders: in vivo model for NK differentiation

In this study, we report on three patients, each with a CD-16+ lymphoproliferative disorder. Peripheral blood lymphocyte from all three patients were evaluated for lymphocyte morphology, natural killer (NK) function, and surface marker expression. In addition, two-color flow cytometric analysis was performed to determine the phenotype of the CD-16+ cells. Our findings indicate that the presence of increased numbers of CD-16+ cells alone is not a good predictor of NK activity. However, we observed a differential expression of the HLA class II molecules DR and DQ on the CD-16+ cells obtained from these patients that was associated with NK function. Hence, a CD-16+, Leu-7-, Leu-19+ (NKH-1A) and HLA class II+ phenotype did correlate with NK function in contrast to a CD-16+, Leu-7+, Leu-19- (NKH-1A) and HLA class II- phenotype. Of importance was the fact that the CD-16+, HLA class II+ cells did not express CD-25 or TFR, nor did they mediate cytotoxicity against solid tumor targets, suggesting that these CD-16+ cells are not activated. Thus, in contrast to previous studies of NK ontogeny that utilized in vitro activated NK cells, studies of patients with CD-16+ lymphoproliferative disorders may provide an alternative approach for examining NK differentiation.     

Occult abdominal wall peristomal abscess following percutaneous endoscopic gastrostomy

This case report describes the complication of peristomal abscess formation associated with the insertion of a percutaneous endoscopic gastrostomy (PEG). The formation of a peristomal anterior abdominal wall abscess in this patient was associated with the failure to give prophylactic antibiotics. The development of this potentially fatal complication may be avoided by strict observance of insertion protocols. This case was treated by removal of the gastrostomy tube after diagnosis which allowed drainage of the abscess. In similar cases of occult abscess formation, where symptoms are present but signs are absent, ultrasonography may be useful in diagnosis.     

Promoter hyper-methylation of calcium binding proteins S100A6 and S100A2 in human prostate cancer

BACKGROUND: S100A6 and S100A2 are members of the S100 family of calcium binding proteins, which are down regulated in prostate cancer, however the molecular mechanism(s) underlying their loss of expression is unknown. METHODS: The promoter and exon 1 region of the S100A6 and S100A2 genes was sequenced in bisulfite modified DNA from non-malignant, benign prostatic hyperplasia (BPH), malignant and metastatic prostate tissues and in cell lines. Immunohistochemistry was performed to correlate S100A2 expression with methylation status. RESULTS: S100A6 methylation was absent or occurred at isolated sites in 14/14 cases of non-malignant epithelium and 5/5 cases of BPH tissues, whereas methylation was seen in 14/27 (52%) cases of prostatic cancer (P<0.0001), 2/2 cases of metastatic cancer and in the CWR22 prostatic cancer xenograft. Critical CpG sites within the S100A2 promoter were methylated in LNCaP, LNCaP-LN3, and CWR22 cells but not in Du145, PC3 or BPH45 cells. In tissues, S100A2 methylation was seen in 32/34 (94%) cases of adenocarcinoma and 5/5 cases of metastatic cancer. However, S100A2 methylation was also seen in 9/12 (75%) cases of non-malignant tissues and in 5/5 cases of BPH. Immunostaining, showed absent S100A2 expression all 41 cases of prostatic cancer, whereas staining was seen in the basal cells of non-malignant epithelium. CONCLUSIONS: Loss of S100A6 and S100A2 proteins is frequent in human prostatic cancer. A major mechanism underlying the loss of S100A6 expression appears to involve promoter hyper-methylation. However, mechanisms other than methylation of the known promoter are involved in silencing S100A2 in the prostate.     

The Warm Homes for Health project: exploring the cost-effectiveness of improving population health through better housing

Housing has a major effect on the health and wellbeing of individuals. There are an estimated 40 000 more deaths in the UK during the coldest months of the year (December to March) than during the rest of the year. Two-thirds of these excess deaths are related to dangerously cold homes. An estimated 20% of the National Health Service clinical budget is spent on avoidable illness (such as cardiovascular and respiratory disease) caused or exacerbated by issues such as poor housing. Housing modifications to improve warmth and damp can help to improve population health. At present there are no data on the cost-effectiveness of improving the warmth of homes through housing modification. The Warm Homes for Health project is a collaboration between public health economists at Bangor University and UK housing providers Gentoo Green and Nottingham City Homes. The project will measure the effect of housing improvements on the health, quality of life, and wellbeing of residents in some of the most socioeconomically disadvantaged areas of the UK.Data will be collected from occupants of retrofitted homes. We will collect data at baseline before housing modification installation and then 6 and 12 months after installation. Outcome measures will include the EQ-5D (for health related quality of life) and the Short Warwick-Edinburgh Mental Well-being Scale. We will also collect individual health and social service use data. We will explore how a cost per quality-adjusted life year (QALY) for housing modification can be calculated for the purpose of comparing relative cost-effectiveness with medical interventions and the National Institute for Health and Care Excellence threshold of £20 000 to £30 000 per QALY. We will produce an incremental cost-effectiveness ratio to examine the incremental cost and quality of life effects of housing improvements. We will use independent t tests between individuals to test the hypothesis that different housing improvements have different effects on quality of life. If we require additional analysis of subgroups we will use one-way repeated measures and between-groups ANOVAs with ad-hoc comparisons. Sensitivity analyses will be used to test uncertainty.We aim to establish whether housing improvements are a cost-effective approach to improving population health. The project is currently ongoing, so there are no results to report.FundingThe Warm Homes for Health project is jointly funded by Gentoo Green and Nottingham City Homes. The funders are also represented on the research team and have provided input into the design of the study, recruitment, data collection, and follow-up.