Impact of stent overlap on angiographic and long-term clinical outcome in patients undergoing drug-eluting stent implantation

Objectives We compared the angiographic and long-term clinical outcomes of patients with and without overlap of drug-eluting stents (DES). Background DES overlap has been associated with delayed healing and increased inflammation in experimental studies, but its impact on clinical outcome is not well established. Methods We analyzed the angiographic and clinical outcomes of 1,012 patients treated with DES in the SIRTAX (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization) trial according to the presence or absence of stent overlap and the number of stents per vessel: 134 (13.2%) patients with multiple DES in a vessel with overlap, 199 (19.7%) patients with multiple DES in a vessel without overlap, and 679 (67.1%) patients with 1 DES per vessel. Results Angiographic follow-up at 8 months showed an increased late loss in DES overlap patients (0.33 ± 0.61 mm) compared with the other groups (0.18 ± 0.43 mm and 0.15 ± 0.38 mm, p < 0.01). The smallest minimal lumen diameter was located at the zone of stent overlap in 17 (68%) of 25 patients with stent overlap who underwent target lesion revascularization. Major adverse cardiac events were more common in patients with DES overlap (34 events, 25.4%) than in the other groups (42 events, 21.1% and 95 events, 14.0%) at 3 years (p < 0.01). Both the risk of target lesion revascularization (20.2% vs. 16.1% vs. 9.7%, p < 0.01) and the composite of death or myocardial infarction (17.2% vs. 14.1% vs. 9.1%, p = 0.01) were increased in patients with DES overlap compared with the other groups. Conclusions DES overlap occurs in >10% of patients undergoing percutaneous coronary intervention in routine clinical practice and is associated with impaired angiographic and long-term clinical outcome, including death or myocardial infarction. (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization; NCT00297661).

Frontal areas contribute to reduced global coordination of resting-state gamma activities in drug-naïve patients with schizophrenia

Schizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attracted a great deal of interest as they appear to represent a pathophysiological process of cortical dysfunction in schizophrenia. Gamma band oscillations reflect local cortical activities, and the synchronization of these activities among spatially distributed cortical areas has been suggested to play a central role in the formation of networks. To assess global coordination across spatially distributed brain regions, Omega complexity (OC) in multichannel EEG was proposed. Using OC, we investigated global coordination of resting-state EEG activities in both gamma (30–50 Hz) and below-gamma (1.5–30 Hz) bands in drug-naïve patients with schizophrenia and investigated the effects of neuroleptic treatment. We found that gamma band OC was significantly higher in drug-naïve patients with schizophrenia compared to control subjects and that a right frontal electrode (F3) contributed significantly to the higher OC. After neuroleptic treatment, reductions in the contribution of frontal electrodes to global OC in both bands correlated with the improvement of schizophrenia symptomatology. The present study suggests that frontal brain processes in schizophrenia were less coordinated with activity in the remaining brain. In addition, beneficial effects of neuroleptic treatment were accompanied by improvement of brain coordination predominantly due to changes in frontal regions. Our study provides new evidence of improper intrinsic brain integration in schizophrenia by investigating the resting-state gamma band activity.

Coronary collateral function long after drug-eluting stent implantation

OBJECTIVES: This study was designed to compare coronary collateral function in patients after bare-metal stent (BMS) or drug-eluting stent (DES) implantation. BACKGROUND: Drug-eluting stents have an inhibitory effect on the production of cytokines, chemotactic proteins, and growth factors, and may therefore negatively affect coronary collateral growth. METHODS: A total of 120 patients with long-term stable coronary artery disease (CAD) after stent implantation were included. Both the BMS group and the DES group comprised 60 patients matched for in-stent stenosis severity of the vessel undergoing collateral flow index (CFI) measurement at follow-up and for the duration of follow-up. The primary end point of the investigation was invasively determined coronary collateral function 6 months after stent implantation. Collateral function was assessed by simultaneous aortic, coronary wedge, and central venous pressure measurements (yielding CFI) and by intracoronary electrocardiogram during balloon occlusion. RESULTS: There were no differences between the groups regarding age, gender, body mass index, frequency of cardiovascular risk factors, use of cardiovascular drugs, severity of CAD, or site of coronary artery stenoses. Despite equal in-stent stenosis severity (46 +/- 34% and 45 +/- 36%) and equal follow-up duration (6.2 +/- 10 months and 6.5 +/- 5.4 months), CFI was diminished in the DES versus BMS group (0.154 +/- 0.097 vs. 0.224 +/- 0.142; p = 0.0049), and the rate of collaterals insufficient to prevent ischemia during occlusion (intracoronary electrocardiographic ST-segment elevation > or =0.1 mV) was higher with 50 of 60 patients in the DES group and 33 of 60 patients in the BMS group (p = 0.001). CONCLUSIONS: Collateral function long after coronary stenting is impaired with DES (sirolimus and paclitaxel) when compared with BMS. Considering the protective nature of collateral vessels, this could lead to more serious cardiac events in the presence of an abrupt coronary occlusion.

Neospora caninum: functional inhibition of protein disulfide isomerase by the broad-spectrum anti-parasitic drug nitazoxanide and other thiazolides

Nitazoxanide (NTZ) and several NTZ-derivatives (thiazolides) have been shown to exhibit considerable anti-Neospora caninum tachyzoite activity in vitro. We coupled tizoxanide (TIZ), the deacetylated metabolite, to epoxy-agarose-resin and performed affinity chromatography with N. caninum tachyzoite extracts. Two main protein bands of 52 and 43kDa were isolated. The 52kDa protein was readily recognized by antibodies directed against NcPDI, and mass spectrometry confirmed its identity. Poly-histidine-tagged NcPDI-cDNA was expressed in Escherichia coli and recombinant NcPDI (recNcPDI) was purified by Co2+-affinity chromatography. By applying an enzyme assay based on the measurement of insulin crosslinking activity, recNcPDI exhibited properties reminiscent for PDIs, and its activity was impaired upon the addition of classical PDI inhibitors such as bacitracin (1-2mM), para-chloromercuribenzoic acid (0.1-1mM) and tocinoic acid (0.1-1mM). RecNcPDI-mediated insulin crosslinking was inhibited by NTZ (5-100 microM) in a dose-dependent manner. In addition, the enzymatic activity of recNcPDI was inhibited by those thiazolides that also affected parasite proliferation. Thus, thiazolides readily interfere with NcPDI, and possibly also with PDIs from other microorganisms susceptible to thiazolides.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Vision and night driving abilities of elderly drivers

OBJECTIVE: In this article, we review the impact of vision on older people's night driving abilities. Driving is the preferred and primary mode of transport for older people. It is a complex activity where intact vision is seminal for road safety. Night driving requires mesopic rather than scotopic vision, because there is always some light available when driving at night. Scotopic refers to night vision, photopic refers to vision under well-lit conditions, and mesopic vision is a combination of photopic and scotopic vision in low but not quite dark lighting situations. With increasing age, mesopic vision decreases and glare sensitivity increases, even in the absence of ocular diseases. Because of the increasing number of elderly drivers, more drivers are affected by night vision difficulties. Vision tests, which accurately predict night driving ability, are therefore of great interest. METHODS: We reviewed existing literature on age-related influences on vision and vision tests that correlate or predict night driving ability. RESULTS: We identified several studies that investigated the relationship between vision tests and night driving. These studies found correlations between impaired mesopic vision or increased glare sensitivity and impaired night driving, but no correlation was found among other tests; for example, useful field of view or visual field. The correlation between photopic visual acuity, the most commonly used test when assessing elderly drivers, and night driving ability has not yet been fully clarified. CONCLUSIONS: Photopic visual acuity alone is not a good predictor of night driving ability. Mesopic visual acuity and glare sensitivity seem relevant for night driving. Due to the small number of studies evaluating predictors for night driving ability, further research is needed.

Impact of stent overlap on long-term clinical outcomes in patients treated with newer-generation drug-eluting stents

Aims: Early-generation drug-eluting stent (DES) overlap (OL) is associated with impaired long-term clinical outcomes whereas the impact of OL with newer-generation DES is unknown. Our aim was to assess the impact of OL on long-term clinical outcomes among patients treated with newer-generation DES. Methods and results: We analysed the three-year clinical outcomes of 3,133 patients included in a prospective DES registry according to stent type (sirolimus-eluting stents [SES; N=1,532] versus everolimus-eluting stents [EES; N=1,601]), and the presence or absence of OL. The primary outcome was a composite of death, myocardial infarction (MI), and target vessel revascularisation (TVR). The primary endpoint was more common in patients with OL (25.1%) than in those with multiple DES without OL (20.8%, adj HR=1.46, 95% CI: 1.03-2.09) and patients with a single DES (18.8%, adj HR=1.74, 95% CI: 1.34-2.25, p<0.001) at three years. A stratified analysis by stent type showed a higher risk of the primary outcome in SES with OL (28.7%) compared to other SES groups (without OL: 22.6%, p=0.04; single DES: 17.6%, p<0.001), but not between EES with OL (22.3%) and other EES groups (without OL: 18.5%, p=0.30; single DES: 20.4%, p=0.20). Conclusions: DES overlap is associated with impaired clinical outcomes during long-term follow-up. Compared with SES, EES provide similar clinical outcomes irrespective of DES overlap status.

Can a novel web-based computer test predict poor simulated driving performance? A pilot study with healthy and cognitive-impaired participants

BACKGROUND Driving a car is a complex instrumental activity of daily living and driving performance is very sensitive to cognitive impairment. The assessment of driving-relevant cognition in older drivers is challenging and requires reliable and valid tests with good sensitivity and specificity to predict safe driving. Driving simulators can be used to test fitness to drive. Several studies have found strong correlation between driving simulator performance and on-the-road driving. However, access to driving simulators is restricted to specialists and simulators are too expensive, large, and complex to allow easy access to older drivers or physicians advising them. An easily accessible, Web-based, cognitive screening test could offer a solution to this problem. The World Wide Web allows easy dissemination of the test software and implementation of the scoring algorithm on a central server, allowing generation of a dynamically growing database with normative values and ensures that all users have access to the same up-to-date normative values. OBJECTIVE In this pilot study, we present the novel Web-based Bern Cognitive Screening Test (wBCST) and investigate whether it can predict poor simulated driving performance in healthy and cognitive-impaired participants. METHODS The wBCST performance and simulated driving performance have been analyzed in 26 healthy younger and 44 healthy older participants as well as in 10 older participants with cognitive impairment. Correlations between the two tests were calculated. Also, simulated driving performance was used to group the participants into good performers (n=70) and poor performers (n=10). A receiver-operating characteristic analysis was calculated to determine sensitivity and specificity of the wBCST in predicting simulated driving performance. RESULTS The mean wBCST score of the participants with poor simulated driving performance was reduced by 52%, compared to participants with good simulated driving performance (P<.001). The area under the receiver-operating characteristic curve was 0.80 with a 95% confidence interval 0.68-0.92. CONCLUSIONS When selecting a 75% test score as the cutoff, the novel test has 83% sensitivity, 70% specificity, and 81% efficiency, which are good values for a screening test. Overall, in this pilot study, the novel Web-based computer test appears to be a promising tool for supporting clinicians in fitness-to-drive assessments of older drivers. The Web-based distribution and scoring on a central computer will facilitate further evaluation of the novel test setup. We expect that in the near future, Web-based computer tests will become a valid and reliable tool for clinicians, for example, when assessing fitness to drive in older drivers.

Effects of anticancer drug docetaxel on the structure and function of the rabbit olfactory mucosa

Docetaxel (DCT) is an anticancer drug which acts by disrupting microtubule dynamics in the highly mitotic cancer cells. Thus, this drug has a potential to affect function and organization of tissues exhibiting high cellular turnover. We investigated, in the rabbit, the effects of a single human equivalent dose (6.26mg/kg, i.v.) of DCT on the olfactory mucosa (OM) through light and electron microscopy, morphometry, Ki-67 immunostaining, TUNEL assay and the buried food test for olfactory sensitivity. On post-exposure days (PED) 5 and 10, there was disarrangement of the normal cell layering in the olfactory epithelium (OE), apoptotic death of cells of the OE, Bowman's glands and axon bundles, and the presence (including on PED 3) of blood vessels in the bundle cores. A decrease in bundle diameters, olfactory cell densities and cilia numbers, which was most significant on PED 10 (49.3%, 63.4% and 50%, respectively), was also evident. Surprisingly by PED 15, the OM regained normal morphology. Furthermore, olfactory sensitivity decreased progressively until PED 10 when olfaction was markedly impaired, and with recovery from the impairment by PED 15. These observations show that DCT transiently alters the structure and function of the OM suggesting a high regenerative potential for this tissue.

The Impact of Renal Impairment on Long-Term Safety and Effectiveness of Drug-Eluting Stents

BACKGROUND Renal impairment (RI) is associated with impaired prognosis in patients with coronary artery disease. Clinical and angiographic outcomes of patients undergoing percutaneous coronary intervention (PCI) with the use of drug-eluting stents (DES) in this patient population are not well established. METHODS We pooled individual data for 5,011 patients from 3 trials with the exclusive and unrestricted use of DES (SIRTAX - N = 1,012, LEADERS - N = 1,707, RESOLUTE AC - N = 2,292). Angiographic follow-up was available for 1,544 lesions. Outcomes through 2 years were stratified according to glomerular filtration rate (normal renal function: GFR≥90 ml/min; mild RI: 90impaired among patients with moderate/severe RI.

Stent thrombosis in early-generation drug-eluting stents versus newer-generation everolimus-eluting stent assorted by LVEF.

OBJECTIVE Everolimus drug-eluting stents (EES) are superior to early-generation drug-eluting stents (DES), releasing sirolimus (SES) or paclitaxel (PES) in preventing stent thrombosis (ST). Since an impaired LVEF seems to increase the risk of ST, we aimed to investigate the difference in outcome of patients with varying LVEF using EES versus early-generation DES. METHODS In a prospective cohort study, we compared the risk of ST in patients in three LVEF subgroups: normal (LVEF >50%), mildly impaired (LVEF >40% and ≤50%) and moderate-severely impaired (LVEF ≤40%). Within these various LVEF groups, we compared EES with SES and PES after adjustment for baseline differences. RESULTS We assessed a cohort of 5363 patients, with follow-up of up to 4 years and available LVEF. Overall definite ST occurred in 123 (2.3%) patients. ST rates were higher in the LVEF moderate-severely impaired group compared with the normal LVEF group (2.8% vs 2.1%; HR 1.82; CI 1.10 to 3.00). Especially early ST (EST) was more frequent in the moderate-severely impaired LVEF group (HR 2.20; CI 1.06 to 4.53). Overall rates of definite ST were lower in patients using EES compared with patients using SES or PES in all LVEF groups. Interaction terms were not statistically significant. ST rates were higher in the moderate-severely impaired LVEF group compared with the normal LVEF group when using SES or PES, but not significantly different when using EES. CONCLUSIONS EES was associated with a lower risk of definite ST compared with early-generation DES. This lower risk was independent of LVEF, even though ST rates were higher in patients with a moderate-severely impaired LVEF. TRIAL REGISTRATION NO MEC-2013-262.

Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial.

BACKGROUND Drug-eluting balloons (DEB) may reduce infrapopliteal restenosis and reintervention rates versus percutaneous transluminal angioplasty (PTA) and improve wound healing/limb preservation. OBJECTIVES The goal of this clinical trial was to assess the efficacy and safety of IN.PACT Amphirion drug-eluting balloons (IA-DEB) compared to PTA for infrapopliteal arterial revascularization in patients with critical limb ischemia (CLI). METHODS Within a prospective, multicenter, randomized, controlled trial with independent clinical event adjudication and angiographic and wound core laboratories 358 CLI patients were randomized 2:1 to IA-DEB or PTA. The 2 coprimary efficacy endpoints through 12 months were clinically driven target lesion revascularization (CD-TLR) and late lumen loss (LLL). The primary safety endpoint through 6 months was a composite of all-cause mortality, major amputation, and CD-TLR. RESULTS Clinical characteristics were similar between the 2 groups. Significant baseline differences between the IA-DEB and PTA arms included mean lesion length (10.2 cm vs. 12.9 cm; p = 0.002), impaired inflow (40.7% vs. 28.8%; p = 0.035), and previous target limb revascularization (32.2% vs. 21.8%; p = 0.047). Primary efficacy results of IA-DEB versus PTA were CD-TLR of 9.2% versus 13.1% (p = 0.291) and LLL of 0.61 ± 0.78 mm versus 0.62 ± 0.78 mm (p = 0.950). Primary safety endpoints were 17.7% versus 15.8% (p = 0.021) and met the noninferiority hypothesis. A safety signal driven by major amputations through 12 months was observed in the IA-DEB arm versus the PTA arm (8.8% vs. 3.6%; p = 0.080). CONCLUSIONS In patients with CLI, IA-DEB had comparable efficacy to PTA. While primary safety was met, there was a trend towards an increased major amputation rate through 12 months compared to PTA. (Study of IN.PACT Amphirion™ Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia [INPACT-DEEP]; NCT00941733).

Linking altered central pain processing and genetic polymorphism to drug efficacy in chronic low back pain.

BACKGROUND Inability to predict the therapeutic effect of a drug in individual pain patients prolongs the process of drug and dose finding until satisfactory pharmacotherapy can be achieved. Many chronic pain conditions are associated with hypersensitivity of the nervous system or impaired endogenous pain modulation. Pharmacotherapy often aims at influencing these disturbed nociceptive processes. Its effect might therefore depend on the extent to which they are altered. Quantitative sensory testing (QST) can evaluate various aspects of pain processing and might therefore be able to predict the analgesic efficacy of a given drug. In the present study three drugs commonly used in the pharmacological management of chronic low back pain are investigated. The primary objective is to examine the ability of QST to predict pain reduction. As a secondary objective, the analgesic effects of these drugs and their effect on QST are evaluated. METHODS/DESIGN In this randomized, double blinded, placebo controlled cross-over study, patients with chronic low back pain are randomly assigned to imipramine, oxycodone or clobazam versus active placebo. QST is assessed at baseline, 1 and 2 h after drug administration. Pain intensity, side effects and patients' global impression of change are assessed in intervals of 30 min up to two hours after drug intake. Baseline QST is used as explanatory variable to predict drug effect. The change in QST over time is analyzed to describe the pharmacodynamic effects of each drug on experimental pain modalities. Genetic polymorphisms are analyzed as co-variables. DISCUSSION Pharmacotherapy is a mainstay in chronic pain treatment. Antidepressants, anticonvulsants and opioids are frequently prescribed in a "trial and error" fashion, without knowledge however, which drug suits best which patient. The present study addresses the important need to translate recent advances in pain research to clinical practice. Assessing the predictive value of central hypersensitivity and endogenous pain modulation could allow for the implementation of a mechanism-based treatment strategy in individual patients. TRIAL REGISTRATION Clinicaltrials.gov, NCT01179828.

Effect of Chronic Kidney Disease in Women Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents: A Patient-Level Pooled Analysis of Randomized Controlled Trials.

OBJECTIVES This study sought to evaluate: 1) the effect of impaired renal function on long-term clinical outcomes in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES); and 2) the safety and efficacy of new-generation compared with early-generation DES in women with chronic kidney disease (CKD). BACKGROUND The prevalence and effect of CKD in women undergoing PCI with DES is unclear. METHODS We pooled patient-level data for women enrolled in 26 randomized trials. The study population was categorized by creatinine clearance (CrCl) <45 ml/min, 45 to 59 ml/min, and ≥60 ml/min. The primary endpoint was the 3-year rate of major adverse cardiovascular events (MACE). Participants for whom baseline creatinine was missing were excluded from the analysis. RESULTS Of 4,217 women included in the pooled cohort treated with DES and for whom serum creatinine was available, 603 (14%) had a CrCl <45 ml/min, 811 (19%) had a CrCl 45 to 59 ml/min, and 2,803 (66%) had a CrCl ≥60 ml/min. A significant stepwise gradient in risk for MACE was observed with worsening renal function (26.6% vs. 15.8% vs. 12.9%; p < 0.01). Following multivariable adjustment, CrCl <45 ml/min was independently associated with a higher risk of MACE (adjusted hazard ratio: 1.56; 95% confidence interval: 1.23 to 1.98) and all-cause mortality (adjusted hazard ratio: 2.67; 95% confidence interval: 1.85 to 3.85). Compared with older-generation DES, the use of newer-generation DES was associated with a reduction in the risk of cardiac death, myocardial infarction, or stent thrombosis in women with CKD. The effect of new-generation DES on outcomes was uniform, between women with or without CKD, without evidence of interaction. CONCLUSIONS Among women undergoing PCI with DES, CKD is a common comorbidity associated with a strong and independent risk for MACE that is durable over 3 years. The benefits of newer-generation DES are uniform in women with or without CKD.