Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men

BACKGROUND: We investigated whether chromosome 9p21.3 single-nucleotide polymorphisms (SNPs), identified in coronary heart disease (CHD) genome-wide association scans, added significantly to the predictive utility for CHD of conventional risk factors (CRF) in the Framingham risk score (FRS) algorithm. METHODS: In the Northwick Park Heart Study II of 2742 men (270 CHD events occurring during a 15-year prospective study), rs10757274 A>G [mean frequency G = 0.48 (95% CI 0.47-0.50)] was genotyped. Using the area under the ROC curve (A(ROC)) and the likelihood ratio (LR) statistic, we assessed the discriminatory performance of the FRS based on CRFs with and without genotype. RESULTS: rs10757274 A>G was associated with incident CHD, with an effect size as reported previously [hazard ratio in GG vs AA men of 1.60 (95% CI 1.12-2.28)], independent of CRFs and family history of CHD. Although the A(ROC) for CRFs alone [0.62 (95% CI 0.58-0.66)] did not increase significantly (P = 0.14) when rs10757274 A>G genotype was added [0.64 (95% CI 0.60-0.68)], including genotype gave better fit (LR P = 0.01) and including rs10757274 moved 369 men (13.5% of the total) into more accurate risk categories. To model polygenic effects, 10 hypothetical, randomly assigned gene variants, with similar effect size and frequencies were added. Two variants made significant A(ROC) improvements to the FRS prediction (P = 0.01), whereas further variants had smaller incremental effects (final A(ROC) = 0.71, P <0.001 vs CRFs; LR vs CRFs P <0.0001). CONCLUSIONS: Although overall, rs10757274 did not add substantially to the usefulness of the FRS for predicting future events, it did improve reclassification of CHD risk, and thus may have clinical utility.     

Subintimal angioplasty

While the technique of subintimal dissection was described almost 2 decades ago, initial adoption of the technique was quite slow. Recently, a growing number of centers have embraced the technique as a valuable adjunct to standard endovascular and open revascularizations. During our experience with over 100 duplex guidance subintimal angioplasties (SIA) and over 100 flouroscopically guided SIA, we have encountered that persistence can be greatest ally. Fortunately, this is a trait that is common among vascular surgeons. Herein, we will describe the technique with focus on its limitations and advantages.     

Carotid Artery Stump Pressure (CASP) in 1135 consecutive endarterectomies under general anesthesia: an old method that survived the test of times

AIM: Intraoperative electroencephalography, somato-sensory evoked potentials and transcranial Doppler have been proposed to replace carotid artery stump pressure measurement (CASP) as the test of choice in the evaluation of cerebral tolerance during temporary carotid occlusion. CASP is a simple, inexpensive test that does not require an additional specialist in the operating room. Herein, we attempt to demonstrate that CASP is a reliable test that does not need to be replaced by more sophisticated and expensive techniques. METHODS: Over the last 6 years, 1 135 consecutive carotid endarterectomies (CEA) were performed under general anesthesia at our institution. There were 592 males and 429 female patients with an age range of 39 to 95 years (mean 72 +/- 9 years). Hypertension, diabetes, smoking, coronary artery disease and chronic renal insufficiency were present in 71%, 39%, 36%, 32% and 26%, respectively. Internal carotid artery (ICA) stenosis ? 70% was confirmed by duplex scanning in 92% of the cases. The remaining 8% of cases had 50% to 69% ICA stenosis in neurologically symptomatic patients. Asymptomatic patients accounted for 75% of the cases. Contralateral ICA occlusion was observed in 57 cases (5%). Indwelling shunts were used when CASP was < 45 mmHg. Carotid patches were used in 233 cases. Completion duplex scanning was performed in all cases. CASP was measured by inserting a 23-gauge needle into the common carotid artery (CCA) after clamping the ICA to avert possible embolization during needle insertion. Once the tip of the needle was confirmed intraluminally by pressure measurement and triphasic waveform tracing, the CCA and the external carotid artery were clamped. After a flat line tracing was depicted on the monitor, ICA clamp was released and CASP was recorded. RESULTS: CASP was < 45 mmHg in 233 cases (21%) (Group I) and > or = 45 mmHg in 902 cases (79%) (Group II). The mean CASP in presence of contralateral ICA occlusions was 40 +/- 15 mmHg while it was 65 +/- 27 mmHg for patent contralateral ICAs (P < 0.0001). The overall 30-day stroke rate was 1% (1 135 cases). It was 3% (7/233) for group I and 0.5% (4/902) for group II (P < 0.01). In patients with postoperative strokes CASP ranged from 23 to 44 mmHg (mean 33 +/- 8) in group I (shunted) and it varied from 59 to 116 mmHg (mean 99 +/- 28) in group II (non-shunted) with P < 0.001. The causes of stroke in group I were hyperperfusion (2), partial ICA thrombosis (2), embolization (2) and worsening of acute stroke (1). In group II there were 2 cases of embolization and 2 of ICA thrombosis. No patient had a stroke caused by decreased intraoperative global cerebral perfusion. The overall 30-day mortality rate was 0.5%. The overall combined stroke/death rate was 1.5%. CONCLUSION: CASP > or = 45 mmHg was a reliable predictor of adequate cerebral perfusion during 1,135 consecutive CEAs performed under general anesthesia. The percentage of indwelling shunts utilized in this series was not significantly different from the ones using more expensive and sophisticated techniques.     

Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer

Recent advances in our understanding of the biology of cancer have provided enormous opportunities for the development of novel therapies against specific molecular targets. It is likely that most of these targeted therapies will have only modest single agent activities but may have the potential to accentuate the therapeutic effects of ionising radiation. In this introductory review, the 5Rs of classical radiobiology are interpreted in terms of their relationship to the hallmarks of cancer. Future articles will focus on the specific hallmarks of cancer and will highlight the opportunities that exist for designing new combination treatment regimens.     

Rapid assessment of in vitro expanded human regulatory T cell function

Human regulatory T cells (Treg) are able to actively suppress autoreactive immune responses. Phenotypically, they are broadly characterized as CD4+, CD25+, CD127(lo/?) and FoxP3+. CD45RA can be used to further differentiate the population into na?ve (CD45RA(+)) and induced (CD45RA?) Treg. The functional potential of Treg is routinely determined by assessing their ability to suppress T cell function in 3-5day proliferation assays. Since Treg are being explored for therapeutic use, a short-term functional assay could serve as a valuable tool for evaluating the potency of Treg. Therefore, an assay designed to measure Treg suppression of activation marker expression by responder T cells in 7 to 20h has been examined in this report. Using flow cytometry, expression of CD69 and CD154 on T cells, in response to stimulation with CD3/CD28 beads, was used as a measure of activation in the assay. Treg from healthy volunteers were sorted as CD4+CD25+CD127(lo/?)CD45RA+ cells with a BD FACSAria? II. The highly purified Treg were then expanded in vitro and their function was assessed in short term activation marker suppression assays using autologous PBMC as responder cells. The data suggest that this short term suppression assay could be a reliable surrogate for assessing Treg functional potential.