Publications

Chronic Obstructive Pulmonary Disease (COPD) is a debilitating inflammatory respiratory condition that presents with worsening breathing difficulties and it is assumed to be progressive and incurable. As an inflammatory disease, COPD is associated with recruitment of immune cells to lung tissue and increased levels of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and GM-CSF. Low-carbohydrate ketogenic diets have anti-inflammatory properties that could, in theory, improve COPD symptoms and progression. Herein, we report on a 54-year-old patient (C.A.) with COPD who adopted a ketogenic diet (70% calories from fat). Subsequently, C.A. experienced a reduction in inflammatory markers in association with a meaningful improvement in lung function. His inflammatory markers decreased into the normal range and his forced expiratory volume increased by 37.5% relative to its pre-ketogenic diet value. Future research should explore nutritional ketosis and ketogenic diets as possible therapeutic options for individuals with COPD.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.

We presenta robust, long-range optical autofocus system for microscopy utilizing machine learning. This can be useful for experiments with long image data acquisition times that may be impacted by defocusing resulting from drift of components, for example due to changes in temperature or mechanical drift. It is also useful for automated slide scanning or multiwell plate imaging where the sample(s) to be imaged may not be in the same horizontal plane throughout the image data acquisition. To address the impact of (thermal or mechanical) fluctuations over time in the optical autofocus system itself, we utilize a convolutional neural network (CNN) that is trained over multiple days to account for such fluctuations. To address the trade-off between axial precision and range of the autofocus, we implement orthogonal optical readouts with separate CNN training data, thereby achieving an accuracy well within the 600 nm depth of field of our 1.3 numerical aperture objective lens over a defocus range of up to approximately +/-100 μm. We characterize the performance of this autofocus system and demonstrate its application to automated multiwell plate single molecule localization microscopy.

Wall shear stress (WSS) is the (tangential) drag force acting on the luminal wall, induced by blood flow, normalized to wall area. As WSS is defined as force/area, its dimension equals that of pressure, i.e., N/m2 or Pa. An older, frequently used unit for shear stress, i.e., dyne/cm2 relates to Pa according to 1 Pa = 10 dyne/cm2. WSS on the endothelium (Fig. 1) can be calculated from the local shear rate (s−1) times blood viscosity (μ) (Pa/s). Shear rate is the spatial blood velocity gradient ([m/s]/m). Especially near the vessel wall, generally large velocity gradients between adjacent fluid layers exist and the shear stress is at its highest value. In a simple straight tube the Hagen-Poiseuille formula (WSS = 4μQ/πR3, with μ viscosity, R tube radius and Q flow) can be applied for steady laminar viscous flow. A normal WSS range of 0.68 ± 0.2 Pa was derived from Doppler based velocity measurements in angiographically normal coronary

"Driven steel H-piles are extensively adopted in engineering practice due to their convenience and efficiency in both economic and construction. The post-driving residual stress, a compressive axial stress distributed along the pile induced by the pile installation, might significantly deteriorate the pile bearing capacity. Thus, a large enough factor of safety is adopted in the traditional analysis to cover the influence caused by the post-driving residual stress. However, it sometimes leads to a large waste in costs and materials. Thus, the present study adopted the second-order analysis, a modern simulationbased design method, for the design of the driven steel H-pile. A robust and efficient finite element formula is necessary to conduct the second-order design method in practice. Hence, a new Line-Finite Element (LFE) formula is proposed in this paper. The developed LFE directly captures all the crucial factors in the analysis of the driven steel H pile, including the nonlinear Soil-Structure Interaction (SSI) and the post-driving residual stress. A validation example is presented at the end of this paper, which illustrates the accuracy and the computational efficiency of the proposed LFE formula."

Platelet-activating factor (PAF) has been implicated in the pathogenesis of several inflammatory pulmonary diseases, and specific binding sites have been demonstrated in human and guinea pig lung membranes by radioligand binding experiments. Both human and guinea pig PAF receptors (PAFR) have recently been cloned. We have used molecular probes to study the gene expression of PAFR in human and animal lung and in situ hybridization to determine the distribution of PAFR mRNA in peripheral lung. Northern blot analysis of total lung RNA from human lung parenchyma, using a 1.1-kb SmaI-EcoRI fragment of human PAFR cDNA or a 0.9-kb SmaI-SmaI fragment of guinea pig PAFR cDNA, demonstrated the expression of PAFR mRNA in human lung, with a single transcript of 4 kb. There was a significant increase in PAFR mRNA in the lungs of asthmatic patients and a significant decrease in PAFR mRNA in the lungs of cigarette smokers compared with normal patients. Similarly, the expression of PAFR mRNA on guinea pig and rat lung was detected as a single transcript of 3 kb, using both guinea pig and human PAFR cDNA probes. A full-length 1.8-kb human leukocyte PAFR cDNA probe was used as the DNA template for producing 35S-labeled antisense and sense cRNA probes for use in in situ hybridization studies of human peripheral lung. These studies revealed high levels of PAFR mRNA hybridization in blood vessels, moderate levels of hybridization in alveolar walls and peripheral airway smooth muscle, but no specific signal in airway epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives. This study was designed to compare the long-term clinical and angiographic effects of successful directional atherectomy and stent implantation and to examine whether restenosis is related to the mechanism of lumen improvement as well as the extent of lumen gain. Background. Directional atherectomy and coronary stent implantation have been shown to achieve a more optimal immediate result that may lead to a more favorable long-term angiographic outcome and fewer target vessel revascularizations than does angioplasty. However, it remains to be determined whether one of the devices used in these interventions provides consistently better results than the other. Methods. To allow meaningful comparisons, a prospectively collected series of 117 patients successfully treated with atherectomy were individually matched with a prospectively collected series of 117 patients successfully treated with stent implantation. Matching for baseline characteristics identified patients with identical lesion location and lesion severity, and immediate and late angiographic and clinical outcome were compared. To evaluate the possibility of a procedure effect on restenosis, patients were further matched for both immediate angiographic outcome and baseline characteristics, providing 150 matched patients for comparison. As confirmatory analysis, multivariate models were constructed to predict late lumen diameter. Results. Matching resulted in two comparable groups with equivalent baseline clinical and stenosis characteristics (n = 117 pairs). Atherectomy led to a smaller immediate gain than stenting and, because late loss was similar in both groups, stenting resulted in a larger late lumen (1.96 ± 0.51 vs.1.66 ± 0.55 mm, p < 0.0001). When patients were matched for immediate gain and baseline characteristics (n = 75 pairs), lumen loss was more pronounced after atherectomy, and thus the minimal lumen diameter at follow-up differed significantly between the two groups (1.66 ± 0.53 vs 1.90 ± 0.47 mm, p = 0.004). This beneficial angiographic effect of stenting was accompanied by a reduced need for repeat interventions. Multivariate analysis confirmed the independent effect of the interventional device used, whereby less loss and greater lumen diameter at follow-up were predicted for stent implantation than for atherectomy. Conclusions. Successful stent implantation provided a more favorable long-term angiographic outcome and lower rates of restenosis and need for target lesion revascularization than did atherectomy. This favorable effect of stenting not only is related to a larger immediate gain, but also seems to attenuate late lumen loss.