Non-linear models for black carbon exposure modelling using air pollution datasets.

Black carbon (BC) is a product of incomplete combustion, present in urban aerosols and sourcing mainly from road traffic. Epidemiological evidence reports positive associations between BC and cardiovascular and respiratory disease. Despite this, BC is currently not regulated by the EU Air Quality Directive, and as a result BC data are not available in urban areas from reference air quality monitoring networks in many countries. To fill this gap, a machine learning approach is proposed to develop a BC proxy using air pollution datasets as an input. The proposed BC proxy is based on two machine learning models, support vector regression (SVR) and random forest (RF), using observations of particle mass and number concentrations (N), gaseous pollutants and meteorological variables as the input. Experimental data were collected from a reference station in Barcelona (Spain) over a 2-year period (2018-2019). Two months of additional data were available from a second urban site in Barcelona, for model validation. BC concentrations estimated by SVR showed a high degree of correlation with the measured BC concentrations (R2 = 0.828) with a relatively low error (RMSE = 0.48 µg/m3). Model performance was dependent on seasonality and time of the day, due to the influence of new particle formation events. When validated at the second station, performance indicators decreased (R2 = 0.633; RMSE = 1.19 µg/m3) due to the lack of N data and PM2.5 and the smaller size of the dataset (2 months). New particle formation events critically impacted model performance, suggesting that its application would be optimal in environments where traffic is the main source of ultrafine particles. Due to its flexibility, it is concluded that the model can act as a BC proxy, even based on EU-regulatory air quality parameters only, to complement experimental measurements for exposure assessment in urban areas.

Calcium dependent plasticity applied to repetitive transcranial magnetic stimulation with a neural field model.

The calcium dependent plasticity (CaDP) approach to the modeling of synaptic weight change is applied using a neural field approach to realistic repetitive transcranial magnetic stimulation (rTMS) protocols. A spatially-symmetric nonlinear neural field model consisting of populations of excitatory and inhibitory neurons is used. The plasticity between excitatory cell populations is then evaluated using a CaDP approach that incorporates metaplasticity. The direction and size of the plasticity (potentiation or depression) depends on both the amplitude of stimulation and duration of the protocol. The breaks in the inhibitory theta-burst stimulation protocol are crucial to ensuring that the stimulation bursts are potentiating in nature. Tuning the parameters of a spike-timing dependent plasticity (STDP) window with a Monte Carlo approach to maximize agreement between STDP predictions and the CaDP results reproduces a realistically-shaped window with two regions of depression in agreement with the existing literature. Developing understanding of how TMS interacts with cells at a network level may be important for future investigation.

Pharmacogenetics of Bisphosphonate-associated Osteonecrosis of the Jaw.

Osteonecrosis of the jaws (ONJ) is a potentially severe disorder that develops in a subgroup of individuals who have used bisphosphonate (BP) medications. Several clinical risk factors have been associated with the risk of ONJ development, but evidence is limited and in most instances ONJ remains an unpredictable adverse drug reaction. Interindividual genetic variability can contribute to explaining ONJ development in a subset of BP users and the discovery of relevant associated gene variants could lead to the identification of individuals at higher risk. No genetic variant has been found to be robustly associated with susceptibility to ONJ.

Neural field theory of synaptic metaplasticity with applications to theta burst stimulation.

Transcranial magnetic stimulation (TMS) is characterized by strong nonlinear plasticity effects. Experimental results that highlight such nonlinearity include continuous and intermittent theta-burst stimulations (cTBS and iTBS, respectively), where depression is induced in the continuous case, but insertion of an off period of around 8s for every 2s of stimulation changes the induced plasticity to potentiation in the intermittent case. Another nonlinearity is that cTBS and iTBS exhibit dosage dependency, where doubling of the stimulation duration changes the direction of induced plasticity. Guided by previous experimental results, this study postulates on the characteristics of metaplasticity and formulates a physiological system-level plasticity theory to predict TMS experiments. In this theory, plasticity signaling induces plasticity in NMDA receptors to modulate further plasticity signals, and is followed by a signal transduction delayed plasticity expression. Since this plasticity in NMDA receptor affects subsequent plasticity induction, it is a form of metaplasticity. Incorporating this metaplasticity into a recent neural field theory of calcium dependent plasticity gives a physiological basis for the theory of Bienenstock, Cooper, Munro (1982), where postsynaptic intracellular calcium level becomes the measure of temporal averaged postsynaptic activity, and converges to the plasticity threshold to give homeostatic effects. Simulations of TMS protocol responses show that intracellular calcium oscillations around the threshold predicts the aforementioned nonlinearities in TMS-induced plasticity, as well as the interpersonal TBS response polarity found experimentally, where the same protocol may induce opposite plasticity effect for different subjects. Thereby, recommendations for future experiments and TMS protocol optimizations are made. Input selectivity via spatially extended, mean field neural dynamics is also explored.

Long-term effectiveness of intralesional triamcinolone acetonide therapy in orofacial granulomatosis: an observational cohort study.

BACKGROUND: It has been suggested that intralesional triamcinolone injections represent a safe and effective therapeutic strategy in controlling the permanent disfiguring swelling of orofacial granulomatosis (OFG). However, robust supporting evidence is lacking, due to the variable and inconsistent design of available studies. OBJECTIVES: To investigate whether a standardized regimen of intralesional triamcinolone has beneficial long-term effects on orofacial swelling of OFG. We also studied potential associations with a number of prognostic factors. METHODS: We designed a retrospective observational study of a homogeneous cohort of 22 well-phenotyped patients with OFG. The primary outcome was defined as a statistically significant decrease in post-treatment disease severity. Statistically significant association with prognostic factors was the secondary outcome. Statistical analysis included Wilcoxon signed-rank tests and logistic regression. RESULTS: Compared with pretreatment, there were statistically significant decreases in disease severity scores at all time points until 48 months post-treatment (P < 0·01). Logistic regression analysis showed there was no independent prognostic variable of statistical significance (P > 0·05). The majority of patients (14/22, 63·6%) received one course of intralesional triamcinolone and did not experience disease recurrence. The mean disease-free period after the first course of intralesional therapy was 28·9 ± 18 months (95% confidence interval 28·7-29·1). No adverse effects were reported. CONCLUSIONS: This is the first study to have employed robust cohort methodology and sound statistics to demonstrate long-term effectiveness of intralesional triamcinolone in controlling the disfiguring swelling of OFG. Because of limitations inherent in observational studies, further research in the form of randomized case-control trials is needed to confirm the present findings.

Neural field theory of calcium dependent plasticity with applications to transcranial magnetic stimulation.

Calcium dependent plasticity (CaDP), a physiologically realistic plasticity mechanism in the microscopic regime, is incorporated into a neural field theory to explore system-level plasticity. This system-level plasticity model is capable of reproducing the characteristic plasticity window of spike-timing dependent plasticity (STDP) in paired associative stimulation (PAS), where a peripheral electric pulse stimulation is paired to transcranial magnetic stimulation (TMS) in the cortex, and rTMS frequency dependent plasticity, where low and high frequency rTMS trains induce depression and potentiation, respectively. These thus reproduce experimental results for system-level plasticity for the first time. This also bridges the gap between microscopic plasticity theory and system-level plasticity observed experimentally, and addresses long standing problems of stability and adaptability by predicting stable plasticity, a possible seizure state where neurons fire at a high rate, and spike-rate adaptation.

Neural field theory of plasticity in the cerebral cortex.

A generalized timing-dependent plasticity rule is incorporated into a recent neural field theory to explore synaptic plasticity in the cerebral cortex, with both excitatory and inhibitory populations included. Analysis in the time and frequency domains reveals that cortical network behavior gives rise to a saddle-node bifurcation and resonant frequencies, including a gamma-band resonance. These system resonances constrain cortical synaptic dynamics and divide it into four classes, which depend on the type of synaptic plasticity window. Depending on the dynamical class, synaptic strengths can either have a stable fixed point, or can diverge in the absence of a separate saturation mechanism. Parameter exploration shows that time-asymmetric plasticity windows, which are signatures of spike-timing dependent plasticity, enable the richest variety of synaptic dynamics to occur. In particular, we predict a zone in parameter space which may allow brains to attain the marginal stability phenomena observed experimentally, although additional regulatory mechanisms may be required to maintain these parameters.

Cyclic guanosine monophosphate dependent pathway contributes to human mast cell inhibitory actions of the nitric oxide donor, diethylamine NONOate.

We have previously demonstrated that exogenous nitric oxide (NO) inhibited anti-IgE-mediated histamine release from human cultured mast cells. In the current study, we further investigated if syntheses of eicosanoids and cytokines were also suppressed by NO donors and evaluated if activation of soluble guanylyl cyclase (sGC) was an underlying mechanism. The effects of the NO donor diethylamine NONOate (DEA/NO) on IgE-dependent syntheses of eicosanoids (prostaglandin D(2) and cysteinyl leukotrienes) and cytokines (tumor necrosis factor-alpha and interleukin-8) from buffy coat derived human cultured mast cells were examined. The effects of sGC related agents on human mast cell activation were studied by measuring histamine release. DEA/NO (10(-7)-10(-4)M) dose-dependently inhibited anti-IgE induced release of histamine, eicosanoids and cytokines. It could also significantly increase intracellular cyclic guanosine monophosphate (cGMP) but reduce anti-IgE induced activation of ERK1/2, JNK1/2 and NF-kappaB. The inhibition of anti-IgE induced histamine release by DEA/NO was reversed by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10(-7)M) and the cGMP-dependent protein kinase (PKG) inhibitor, Rp-8-(4-Chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS, 10(-5)M). The current study confirmed the inhibitory action of exogenous NO on immunological activation of human mast cells. We also provided evidence for the first time that the activation of the sGC-cGMP-PKG pathways together with the suppression of phosphorylation of MAPKs and NF-kappaB contributed to the mast cell modulating action of NO in human.

Acute gastroenteritis in Hong Kong: a population-based telephone survey.

A population-based telephone survey of acute gastroenteritis (AG) was conducted in Hong Kong from August 2006 to July 2007. Study subjects were recruited through random digit-dialing with recruitments evenly distributed weekly over the 1-year period. In total, 3743 completed questionnaires were obtained. An AG episode is defined as diarrhoea >or=3 times or any vomiting in a 24-h period during the 4 weeks prior to interview, in the absence of known non-infectious causes. The prevalence of AG reporting was 7%. An overall rate of 0.91 (95% CI 0.81-1.01) episodes per person-year was observed with women having a slightly higher rate (0.94, 95% CI 0.79-1.08) than men (0.88, 95% CI 0.73-1.04). The mean duration of illness was 3.6 days (S.D.=5.52). Thirty-nine percent consulted a physician, 1.9% submitted a stool sample for testing, and 2.6% were admitted to hospital. Of the subjects aged >or=15 years, significantly more of those with AG reported eating raw oysters (OR 2.4, 95% CI 1.3-4.4), buffet meals (OR 1.8, 95% CI 1.3-2.5), and partially cooked beef (OR 1.8, 95% CI 1.2-2.7) in the previous 4 weeks compared to the subjects who did not report AG. AG subjects were also more likely to have had hot pot, salad, partially cooked or raw egg or fish, sushi, sashimi, and 'snacks bought at roadside' in the previous 4 weeks. This first population-based study on the disease burden of AG in Asia showed that the prevalence of AG in Hong Kong is comparable to that experienced in the West. The study also revealed some 'risky' eating practices that are more prevalent in those affected with AG.

A homogeneous cell-based assay to measure nuclear translocation using beta-galactosidase enzyme fragment complementation.

Positional complementation describes the use of homogeneous assays using beta- galactosidase (beta gal) enzyme fragment complementation to detect cellular protein translocation. This phenomenon occurs when the protein of interest, recombinantly expressed as a fusion protein with a modified alpha fragment of beta gal, translocates to a cellular compartment expressing an enzyme acceptor fragment of the enzyme. When these fragments interact, high-affinity complementation occurs, and a signal is generated that is then detected upon cell lysis. In the present paper the use of positional complementation is exemplified by measuring nuclear translocation of the glucocorticoid receptor in Chinese hamster ovary-K1 cells. The approach thus provides for homogeneous protocols, in an endpoint microtiter plate assay format, without the use of either imaging or reporter gene techniques. Consequently, these characteristics suggest that the technique is suitable for automated instrumentation protocols used in high throughput screening campaigns designed to identify activators or inhibitors of nuclear translocation.

Recent advances in the treatment of colon cancer.

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Although surgical resection is still the only treatment capable of curing colon cancer, adjuvant therapy continues to play an important role in preventing recurrence and metastasis. In recent years remarkable progress has been made in the treatment of colon cancer. This review discusses recent advances in adjuvant therapy for colon cancer, including chemotherapy, immunotherapy, antiangiogenic therapy and apoptosis induction. In the meantime, molecular therapy is also elucidated in the above methods. All these new advances will provide new promises for patients of colon cancer.

Automatic correction of artifact from single-trial event-related potentials by blind source separation using second order statistics only.

Event-related potentials (ERP) are in general masked by various kinds of artifacts. To attenuate the effects of artifacts, various schemes have been introduced, such as epoch rejection, electro-oculogram (EOG) regression and independent component analysis (ICA). However, none of the existing techniques can automatically remove various kinds of artifacts from a single ERP epoch. EOG regression cannot handle artifacts other than ocular ones. ICA incorporating higher order statistics (HOS) normally requires data with large number of time samples in order that the solution is robust. In this paper we blindly separate the multi-channel ERP into source components by estimating the correlation matrices of the data. Since only second order statistics (SOS) is involved, the process performs well at the single epoch level. Automatic artifact identification is performed in the source domain by introducing objective criteria for various artifacts. Criteria are based on time domain signal amplitude for blink and spurious peak artifact, scalp distribution of signal power for eye movement artifact and power distribution of frequency components for muscle artifact. The correction procedure can be completed by removing the identified artifactual sources from the raw multi-channel ERP.

Gene selection for brain cancer classification.

With the introduction of microarray, cancer classification, diagnosis and prediction are made more accurate and effective. However, the final outcome of the data analyses very much depend on the huge number of genes with relatively small number of samples present in each experiment. It is thus crucial to select relevant genes to be used for future specific cancer markers. Many feature selection methods have been proposed but none is able to classify all kinds of microarray data accurately, especially on those multi-class datasets. We propose a one-versus-one comparison method for selecting discriminatory features instead of performing the statistical test in a one-versus-all manner. Brain cancer is chosen as an example. Here, 3 types of statistics are used: signal-to-noise ratio (SNR), t-statistics and Pearson correlation coefficient. Results are verified by performing hierarchical and k-means clustering. Using our one-versus-one comparisons, best performance accuracies of 90.48% and 97.62% can be obtained by hierarchical and k-means clustering respectively. However best performance accuracies of 88.10% and 80.95% can be obtained respectively when using one-versus-all comparison. This shows that one-versus-one comparison is superior.

An Improved Method for Discriminating ECG Signals using Typical Nonlinear Dynamic Parameters and Recurrence Quantification Analysis in Cardiac Disease Therapy.

The discrimination of ECG signals using nonlinear dynamic parameters is of crucial importance in the cardiac disease therapy and chaos control for arrhythmia defibrillation in the cardiac system. However, the discrimination results of previous studies using features such as maximal Lyapunov exponent (λmax) and correlation dimension (D2) alone are somewhat limited in recognition rate. In this paper, improved methods for computing λmaxand D2are purposed. Another parameter from recurrence quantification analysis is incorporated to the new multi-feature Bayesian classifier with λmaxand D2so as to improve the discrimination power. Experimental results have verified the prediction using Fisher discriminant that the maximal vertical line length (Vmax) from recurrence quantification analysis is the best to distinguish different ECG classes. Experimental results using the MIT-BIH Arrhythmia Database show improved and excellent overall accuracy (96.3%), average sensitivity (96.3%) and average specificity (98.15%) for discriminating sinus, premature ventricular contraction and ventricular flutter signals.

Catalase and peroxiredoxin 5 protect Xenopus embryos against alcohol-induced ocular anomalies.

PURPOSE: To study the molecular mechanisms underlying alcohol-induced ocular anomalies in Xenopus embryos. METHODS: Xenopus embryos were exposed to various concentrations (0.1%-0.5%) of alcohol, and the subsequent effects in eye development and in eye marker gene expression were determined. To investigate the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in fetal alcohol syndrome (FAS)-associated ocular injury, two antioxidant enzymes, catalase and peroxiredoxin 5, were overexpressed in the two blastomeres of the two-cell stage Xenopus embryos. RESULTS: Exposure of Xenopus embryos to alcohol during eye development produced marked gross ocular anomalies, including microphthalmia, incomplete closure of the choroid fissure, and malformation of the retina in 40% of the eyes examined. In parallel, alcohol (0.1%-0.5%) dose dependently and significantly reduced the expression of several eye marker genes, of which TBX5, VAX2, and Pax6 were the most vulnerable. Overexpression of catalase and of cytosolic and mitochondrial peroxiredoxin 5 restored the expression of these alcohol-sensitive eye markers and significantly decreased the frequency of ocular malformation from 39% to 21%, 19%, and 13% respectively. All these enzymes reduced alcohol-induced ROS production, but only peroxiredoxin 5 inhibited RNS formation in the alcohol-treated embryos. CONCLUSIONS: The results suggest that oxidative and nitrosative stresses both contribute to alcohol-induced fetal ocular injury.

Free radical EPR spectroscopy analysis using blind source separation.

In this paper, we propose a novel approach for electron paramagnetic resonance (EPR) mixture spectra analysis based on blind source separation (BSS) technique. EPR spectrum of a free radical is often superimposed by overlapping spectra of other species. It is important and challenging to accurately identify and quantify the 'pure' spectra from such mixtures. In this study, an automated BSS method implementing independent component analysis is used to extract the components from mixed EPR spectra that contain overlapping components of different paramagnetic centers. To apply this method, there is no requirement to know the component spectra or the number of components in advance. The method is applied to analyze free radical EPR spectra which are collected from standard chemical system, cultured cell suspense, and ex vivo rat kidneys by spin trapping EPR technique. Results show that the BSS method proposed here is capable of identifying the component EPR spectra from mixtures with unknown compositions. The BSS technique can offer powerful aids in resolving spectral overlapping problems in general EPR spectroscopy analysis.

Interstitial lung disease in systemic sclerosis.

PURPOSE: To evaluate high-resolution CT (HRCT) parameters of inflammation and fibrosis in systemic sclerosis (SSc), for correlation with lung function, skin scores and exercise tolerance. MATERIAL AND METHODS: 45 SSc patients (40 women, 48.5+/-13.4 years), underwent thoracic HRCT, lung function assessment, and modified Rodnan skin scores. Exercise tolerance was also graded. HRCT were scored for extent of 4 HRCT patterns of interstitial lung disease (ILD): ground glass opacification (GGO), reticular, mixed and honeycomb pattern in each lobe. Total HRCT score, inflammation index (GGO and mixed score) and fibrosis index (reticular and honeycomb scores) were correlated with lung function and clinical parameters. RESULTS: ILD was present in 39/45 (86.7%) patients. Abnormal (<80% predicted) forced vital capacity (FVC), total lung capacity (TLC) and carbon monoxide diffusion factor (DLco) were detected in 30%, 22% and 46% of patients. Total HRCT score correlated with FVC (r=-0.43, p=0.008), FEV1 (forced expiratory volume) (r=-0.37, p=0.03), TLC (r=-0.47, p=0.003), and DLCO (r=-0.43, p=0.008); inflammatory index with DLCO (r=-0.43, p=0.008) and exercise tolerance (r=-0.39, p < 0.05); and fibrosis index with FVC (r=-0.31, p=0.05) and TLC (r=-0.38, p=0.02). Higher total HRCT score, and inflammation and fibrosis indices were found in patients with abnormal lung function. CONCLUSION: Qualitative HRCT is able to evaluate inflammation and fibrosis, showing important relationships with diffusion capacity and lung volume, respectively.

Melatonin reduces nitric oxide level during ischemia but not blood-brain barrier breakdown during reperfusion in a rat middle cerebral artery occlusion stroke model.

Melatonin is a potent antioxidant and free radical scavenger. Previously, we showed that a single injection of melatonin before ischemia significantly reduced the infarct volume in both permanent and 3-hr middle cerebral artery occlusion (MCAO) rat stroke models. Nitric oxide (NO) and other free radicals play an important role in the pathogenesis of cerebral ischemia, and they have been postulated to mediate the breakdown of the blood-brain barrier (BBB) during ischemia. In this study, we evaluated the influence of melatonin, given at 30 min before MCAO, on brain NO concentration and BBB breakdown. Brain NO concentration was measured at 15 min of MCAO using electron paramagnetic resonance spectroscopy. BBB breakdown at 3 hr of reperfusion following 3 hr of MCAO was assessed using Evans blue extravasation. The relative brain NO concentration was increased to 141.69 +/- 9.71% (mean +/- S.E.M.; n = 9) at 15 min of MCAO. Treatment with melatonin at 1.5, 5, or 50 mg/kg significantly reduced the brain NO concentration to 104.20 +/- 11.20% (n = 8), 55.67 +/- 5.58% (n = 11), and 104.86 +/- 12.56% (n = 9), respectively. Melatonin at 5 mg/kg did not affect Evans blue extravasation. Our results suggest that a single injection of melatonin protects against focal cerebral ischemia partly via inhibition of ischemia-induced NO production and that this regimen does not prevent BBB breakdown following ischemia-reperfusion.