Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer’s disease

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.     

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Objective Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. Design and methods We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Results Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Conclusions Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.     

Wavelet-based sparse functional linear model with applications to EEGs seizure detection and epilepsy diagnosis

In epilepsy diagnosis or epileptic seizure detection, much effort has been focused on finding effective combination of feature extraction and classification methods. In this paper, we develop a wavelet-based sparse functional linear model for representation of EEG signals. The aim of this modeling approach is to capture discriminative random components of EEG signals using wavelet variances. To achieve this goal, a forward search algorithm is proposed for determination of an appropriate wavelet decomposition level. Two EEG databases from University of Bonn and University of Freiburg are used for illustration of applicability of the proposed method to both epilepsy diagnosis and epileptic seizure detection problems. For this data considered, we show that wavelet-based sparse functional linear model with a simple classifier such as 1-NN classification method leads to higher classification results than those obtained using other complicated methods such as support vector machine. This approach produces a 100 % classification accuracy for various classification tasks using the EEG database from University of Bonn, and outperforms many other state-of-the-art techniques. The proposed classification scheme leads to 99 % overall classification accuracy for the EEG data from University of Freiburg.     

Peripheral vascular complications after intracoronary stent placement: Prevention by use of a pneumatic vascular compression device

Peripheral vascular complications are a significant source of morbidity after coronary artery stent implantation. The goal of this study was to assess the incidence, risk factors, and management of vascular complications after stent placement. The study population consisted of 101 consecutive patients who underwent stent placement for either elective or bailout indications. All patients received a standardized anticoagulation regimen of aspirin, dipyridamole, low molecular weight dextran, heparin, and warfarin. Peripheral vascular access sites were examined daily until hospital discharge. Vascular complications occurred in 16 of 101 (16%) patients, including femoral artery pseudoaneurysm (n = 11), hematoma requiring transfusion or surgery (n = 4), and arterlovenous fistula (n = 1). Intervention was required in 14 of 16 (88%) patients with complications. These included transfusion (n = 7), ultrasound-guided compression (n = 8), and/or vascular surgery (n = 7). Length of hospital stay was prolonged in patients with complications (14 ± 9 vs. 8 ± 5 d, P < 0.001). The development of peripheral vascular complications did not correlate with clinical or procedural variables such as age, cardiovascular risk factors, arterial sheath size, or elective vs. bailout indication. After the introduction of a pneumatic vascular compression device (FemoStop, C.A. Bard, Billerica, MA), a significant reduction In vascular complications was observed. Complications occurred in only 1 of 41 (2.4%) patients in whom the compression device was used in contrast to 13 of 58 (22.4%) patients compressed manually (P < 0.01). Thus peripheral vascular complications are frequent after coronary artery stent placement and are associated with serious morbidity and prolongation of hospital stay. These complications are significantly reduced by the use of a pneumatic vascular compression device despite intensive systemic anticoagulation. © 1996 Wiley-Liss, Inc.     

Doppler estimation of reduced coronary flow reserve in mice with pressure overload cardiac hypertrophy

Aortic banding produces pressure overload cardiac hypertrophy in mice, leading to decompensated heart failure in four to eight weeks, but the effects on coronary blood flow velocity and reserve are unknown. To determine whether coronary flow reserve (CFR) was reduced, we used noninvasive 20-MHz Doppler ultrasound to measure left main coronary flow velocity at baseline (B) and at hyperemia (H) induced by low (1%) and high (2.5%) concentrations of isoflurane gas anesthesia. Ten mice were studied before (Pre) and at 1 d, 7 d, 14 d and 21 d after constricting the aortic arch to 0.4 mm diameter distal to the innominate artery. We also measured cardiac inflow and outflow velocities at the mitral and aortic valves and velocity at the jet distal to the aortic constriction. The pressure drop as estimated by 4V2 at the jet was 51 +/- 5.1 (mean +/- SE) mm Hg at 1 d, increasing progressively to 74 +/- 5.2 mm Hg at 21 d. Aortic and mitral blood velocities were not significantly different after banding (p = NS), but CFR, as estimated by H/B, dropped progressively from 3.2 +/- 0.3 before banding to 2.2 +/- 0.4, 1.7 +/- 0.3, 1.4 +/- 0.2 and 1.1 +/- 0.1 at 1 d, 7 d, 14 d and 21 d, respectively (all p < 0.01 vs. Pre). There was also a significant and progressive increase the systolic/diastolic velocity ratio (0.17 Pre to 0.92 at 21 d, all p < 0.01 vs. Pre) suggesting a redistribution of perfusion from subendocardium to subepicardium. We show for the first time that CFR, as estimated by the hyperemic response to isoflurane and measured by Doppler ultrasound, can be measured serially in mice and conclude that CFR is virtually eliminated in banded mice after 21 d of remodeling and hypertrophy. These results demonstrate that CFR is reduced in mice as in humans with cardiac disease but before the onset of decompensated heart failure.     

Computer-aided analysis of gait rhythm fluctuations in amyotrophic lateral sclerosis

Deterioration of motor neurons due to amyotrophic lateral sclerosis (ALS) would affect the strides from one gait cycle to the next. Computer-assisted techniques are useful for gait analysis, and also have high potential in quantitatively monitoring the pathological progression. In this paper, we applied the signal turns count method to measure the fluctuations in the swing-interval time series recorded from 16 healthy control subjects and 13 patients with ALS. The swing-interval turns count (SWITC) parameter derived with the threshold of 0.06 s presented a significant difference (p < 0.001) between the healthy control subjects and ALS patients. Besides the SWITC, we also computed the averaged stride interval (ASI), which is usually longer in the patient with ALS (p < 0.0001), to characterize the gait patterns of ALS patients. In the pattern classification experiments, the Fisher’s linear discriminant analysis (FLDA) and the least squares support vector machine (LS-SVM), both input with the SWITC and ASI features, were evaluated using the leave-one-out cross-validation method. The results showed that the LS-SVM with sigmoid kernels was able to provide a classification accurate rate of 89.66% and an area of 0.9629 under the receiver operating characteristic (ROC) curve, which were superior to those obtained with the linear classifier in the form of FLDA.     

Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function.

PURPOSE: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. EXPERIMENTAL DESIGN: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. RESULTS: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). CONCLUSIONS: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.