Class of 2006 Abstract / Objectives: To develop a new equation to predict creatinine clearance specific for cystic fibrosis patients. Methods: A literature review was performed to capture data on the daily creatinine excretion in CF patients in relation to age, weight, height, and other physiologic variables. Nonlinear mixed effect modeling was then used to develop an equation to estimate creatinine clearance using individual covariates. The performance of the new equation developed was compared to the Cockcroft and Gault method in a CF population (age > 16 years). Results: A database of individual patient data from a previously published study of 19 patients was created. Significant covariates for model development included actual body weight, sex, and serum creatinine. The final candidate model was: 5.62× ABW0.67 CrCl = sCr(mg / dl) × 0.649( female) Conclusions: The results of the mean absolute error and root mean squared error calculations show that the new equation resulted in less bias and better precision than Cockcroft-Gault, Jeliffe I, and Jeliffe II based on the limited data available. However, these conclusions are limited in that the only evaluation data available was the same data that was used for model development.

According to the World Health Organization, nearly 3.2 billion people are at risk of malaria. The most deadliest form of human malaria is caused by the pathogen Plasmodium falciparum, which has claimed over 400,000 lives worldwide in 20151. Even when optimally treated with drug and donor blood therapies, severe malaria has a high mortality rate. The parasites target a patient’s red blood cells and convert them into paramagnetic units before eventually rupturing the host cell, further spreading the infection. Combination drug therapies using quinine and artemisinin derivatives are common but are either expensive or have associated toxicities from mis-dosing. Moreover, antimalarial drugs are becoming increasingly ineffective against the growing number of drug-resistant malaria strains. Combination drug and blood exchange therapies are often implemented to flush out malaria-infected red blood cells (iRBC) but consume a great quantity of donor blood, carry a high risk of transmitting other blood-borne diseases, and have no agreed upon advantage or disadvantage among clinicians. Due to the relative disadvantages of other treatment methods, small scale high gradient magnetic separation (HGMS) devices, used in a variety of biological applications, may be another treatment option to consider. mPharesis (“magnetic apheresis”) is a proposed low-cost, disposable magnetic blood filtration device which continually removes iRBCs from a patient’s whole blood by capitalizing on the iRBC’s unique magnetic properties. The proposed treatment-scale system will provide emergency care with parameters similar to continuous hemofiltration systems in terms of blood flow rates (up to approximately 500 mL min-1), vascular access, and treatment times (up to about 3 hours). A novel medium-scale high gradient magnetic separation device is detailed here. The device consists of a disposable photo-etched embedded wire array and acrylic layered housing on an external permanent magnet set. The magnetic force and flow field design were computationally optimized. In-vitro feasibility experiments were conducted at several flow rates and physiological hematocrits (Hct) using a blood mixture composed of healthy RBCs and a non-pathogenic paramagnetic blood analog called methemoglobin RBCs (metRBCs). The device was able to selectively remove paramagnetic RBCs without excessive loss of healthy RBCs. Simplified experiments were performed with 30% Hct with 20% metRBCs. At steady state, the concentration of metRBCs was reduced by 27.0±2.2% in a single pass at a flow rate of 77 μL min-1 as compared to 1.6±0.7% in control experiments without a magnet present. The experimental paramagnetic RBC removal rate was over 380 times greater than similar published HGMS devices. These successful results were applied to a theoretical transport model. The model was designed to compare the parasite removal and Hct level changes between combination drug and exchange transfusion (ET) therapy versus treatment-scale mPharesis-drug therapy. When the mPharesis flow rate was set to typical continuous dialysis rates, treatment times and donor blood volumes were reduced for all 10 cases. Calculated treatment times were all less than 60% of the reported ET-drug treatments, with times ranging from 47 to 71 minutes. The mPharesis-drug treatment was calculated to need between 4% and 53% less donor blood than the reported ET-drug treatments. Between 775 and 1772 mL of packed donor RBCs (3 to 6 units of whole blood) were estimated for the mPharesis-drug treatments, versus the average 5 to 20 units used during ET2. Treatment reference charts were generated to provide time and donor blood volume estimates for a range of patient sizes and disease severities. Based on the maximum flow rate of 500 mL min-1, a treatment-scale mPharesis system was estimated to be the size of three stacked briefcases, which is a feasible size for deployment in a clinical setting. Finally, the design, fabrication, and microscopic visualization of a simple, benchtop-fabricated continuous HGMS device was detailed. This proof-of-concept microfluidic device was implemented to test the effect of hematocrit and flow rate on the separation of mixtures of metRBCs (heat-treated and un-heated) and transparent ghost RBCs. An automated image processing protocol provided feasible cell concentration profiles for each flow and rheological condition with a 6.5 to 9.7% lower sum than manual counting for three samples. For the no magnet conditions, the average near-magnet concentration of paramagnetic RBCs at the outlet (within 10% of 130 μm channel height adjacent to the wire array) was between 1.3 and 2.4 times greater than the average of the rest of the flow field (degree of separation, DOS). The most effective separation was found to occur at the lowest flow rate 0.4 μL min-1 and with the 0.5% Hct metRBC sample with DOS=26. The addition of 30% ghost RBCs reduced the efficiency for all flow rates, with DOS=7.4 for best flow rate of 0.4 μL min-1. Heat treatment did not significantly affect separation with DOS=7.3, likely due to the low impact of the relatively low concentration of metRBCs (0.5%). The mesoscale fabrication and design process, clearance model, cell counting algorithm, and HGMS fabrication protocol and microscopy study described in this thesis provides a useful framework for future HGMS optimization and the further development of a clinical treatment system for severe malaria patients with often limited treatment options.

As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of xenobiotic biotransformation, accurate prediction of hepatic clearance (CLh) is vital. The use of cellular and subcellular in vitro systems for this purpose is common practice; however, prediction accuracy tends to be poor. The aim of this thesis was to explore potential contributing factors to the underprediction of in vivo clearance, specifically with relation to the in vitro methodology of hepatocyte clearance assays, which is largely unstandardised. Literature data analyses highlighted an overall clearance-dependent trend of underprediction in both human and rat hepatocytes, indicating a fundamental in vitro system bias which is independent of species. During initial investigation of incubation conditions, the format of hepatocyte assays (suspension in microcentrifuge tubes, 96-well plates, 24-well plates and short-term monolayer culture) was demonstrated to influence determined intrinsic clearance (CLint). Differences in midazolam CLint were observed not only between suspended and short-term cultured hepatocytes, but also between suspended hepatocytes in different vessels/plate formats. The applicability of 1 µM as a generic substrate incubation concentration for determination of CLint by substrate depletion was evaluated in rat hepatocytes using nine well-characterised drugs. For seven of the nine drugs, a statistically significantly (p < 0.05) higher CLint was observed in determinations of 0.1 µM substrate as opposed to 1 µM, highlighting the potential for false determinations using current practices. Cofactor depletion in isolated hepatocytes was investigated based on previous speculation as the cause of clearance-dependent underprediction of in vivo clearance. Although moderate increases in CLint were observed with the addition of NADPH to hepatocyte incubations, this was subsequently attributed to the replenishment of NADPH in membrane-damaged hepatocytes. Retained functionality of metabolic enzymes in cells which would generally be considered non-viable by trypan blue exclusion was indicated in comparisons of unpurified and Percoll-purified cryopreserved hepatocytes. This phenomenon was conclusively demonstrated in incubations of permeabilised hepatocytes supplemented with NADPH, revealing a need for re-evaluation of the use of plasma membrane integrity (trypan blue exclusion) as a measure of viability in metabolic studies. ATP content was considered as a potential alternative measure; however no significant correlations were found between ATP content, trypan blue exclusion and the CLint of nine drugs in associated preparations. The effect of shaking on CLint in rat hepatocytes was also examined. For 10 out of 12 drugs, CLint determined at 900 rpm was significantly (p < 0.05) higher than in static incubations. Three potential mechanisms were hypothesised: plasma membrane damage, increased substrate distribution throughout the bulk medium and reduction in the depth of the unstirred water layer (UWL) surrounding cells. Shaking of saponin-permeabilised hepatocytes (supplemented with NADPH to maintain metabolism) also increased the determined CLint of saquinavir, indicating a rate-limitation other than membrane permeation. However, shaking of ultra-sonicated hepatocytes in which the plasma membrane was entirely destroyed (also supplemented with NADPH) did not change the determined CLint of saquinavir, revealing the rate-limitation of UWL permeation in both intact and permeabilised cells. The depth of such an UWL in vitro is likely to be artificially greater than in vivo; therefore reduction of UWL depth through incubation shaking is proposed as a physiologically sound approach by which to increase in vitro CLint. In addition, a framework of experiments and related equations is presented by which intact and permeabilised hepatocytes in static and shaken conditions may be utilised to identify the rate-determining process and contribution of individual processes to the in vitro CLint of a drug. The effects of substrate concentration and shaking were also evaluated in human hepatocytes. Significant increases in determined CLint of drugs with use of 0.1 µM substrate (as opposed to 1 µM) and shaking at 900 rpm were demonstrated, confirming equivalent potential in vitro sources of underprediction between rat and human. These highly significant findings reveal the existing limitations of in vitro assays and potential flaws in current practice in in vitro determinations of CLint. Appropriate consideration of the properties of in vitro systems, including the presence of the UWL, should lead to improved predictions of in vivo clearance.

Abstract: Previous lower limb weighting studies have placed a load on the legs bilaterally and tested different placement locations. It was previously determined that kinematic changes occur with greater masses and at joints proximal to weight placement [1]. Other studies have determined that these changes exist for a short adaptation period before parameters revert to a steady state [2]. Tasks that require voluntary gait modifications such as obstacle clearance have also been performed with lower leg bilateral weight addition [4]. In cases of normal obstacle clearance increased flexion at all three joints in the lower limb is needed to safely traverse the obstacle [3]. The goal of this study was to investigate joint kinematics and kinetics of unilaterally weighted participants using level ground force platform collection techniques, rather than a treadmill. It was hoped that this would allow for new insight into the adaptation periods and strategic motor pattern changes seen at the ankle, knee and hip. Kinematic and force platform data were collected on two groups of 10 healthy male subjects. Group 1 (mean age = 23years, mean weight = 82.181kg, mean height = 1.798m) was a normal walking group and group 2 (mean age = 24.8years, mean weight = 79.901kg, mean height = 1.773m) was an obstacle clearance group. Both groups participated in 20 trials each of three different conditions; normal, weighted and weight off using a 2.27kg limb mass attached just proximal to the right maleoli markers. A repeated-measures two-way ANOVA was carried out on relevant variables in order to determine statistical significance. Weight addition and removal affected the kinematics and kinetics of the normal walking and obstacle clearance groups. This effect was more prominent in the normal walking group. If changes were seen, trials 1 through 3 were the locations showing a quick adaptation followed by a leveling off back to a new steady state in later trials. Participants in the normal walking group chose to utilize the hip joint in order to control for weight addition and removal. Kinematically, changes in the hip joint angle occurred at all instances analyzed throughout the gait cycle with this effect being more prominent in the weight off condition. In conjunction with this, the hip joint energy generation increased during all phases of the gait cycle while the ankle and knee joints either decreased energy generation or increased energy absorption. In the obstacle group, participants also chose to increase flexion at the hip joint. However, the ankle joint also had either decreased plantarflexion or increased dorsiflexion at all the instances analyzed during the gait cycle. However, joint energy generation increases at these joints were only found during stance and at heel contact. The toe obstacle clearance values also showed a marked increase in trial 1 for the weighted condition which demonstrates a voluntary gait modification made by participants to safely traverse the obstacle that was quickly adapted for. Overall, the results found by previous studies using treadmill collection techniques were still seen in overground force platform data but they were not as robust. References: 1.Martin PE et al. J Biomech. 1990; 23(6):529-536. 2.Noble et al. Exp Brain Res. 2006; 169: 482-495. 3.Patla AE et al. Exp Brain Res. 1995; 196: 499-504. 4.Reid MJ et al. Neurosci Res Comm. 2001; 29(2): 79-87.

Abstract: Previous lower limb weighting studies have placed a load on the legs bilaterally and tested different placement locations. It was previously determined that kinematic changes occur with greater masses and at joints proximal to weight placement [1]. Other studies have determined that these changes exist for a short adaptation period before parameters revert to a steady state [2]. Tasks that require voluntary gait modifications such as obstacle clearance have also been performed with lower leg bilateral weight addition [4]. In cases of normal obstacle clearance increased flexion at all three joints in the lower limb is needed to safely traverse the obstacle [3]. The goal of this study was to investigate joint kinematics and kinetics of unilaterally weighted participants using level ground force platform collection techniques, rather than a treadmill. It was hoped that this would allow for new insight into the adaptation periods and strategic motor pattern changes seen at the ankle, knee and hip. Kinematic and force platform data were collected on two groups of 10 healthy male subjects. Group 1 (mean age = 23years, mean weight = 82.181kg, mean height = 1.798m) was a normal walking group and group 2 (mean age = 24.8years, mean weight = 79.901kg, mean height = 1.773m) was an obstacle clearance group. Both groups participated in 20 trials each of three different conditions; normal, weighted and weight off using a 2.27kg limb mass attached just proximal to the right maleoli markers. A repeated-measures two-way ANOVA was carried out on relevant variables in order to determine statistical significance. Weight addition and removal affected the kinematics and kinetics of the normal walking and obstacle clearance groups. This effect was more prominent in the normal walking group. If changes were seen, trials 1 through 3 were the locations showing a quick adaptation followed by a leveling off back to a new steady state in later trials. Participants in the normal walking group chose to utilize the hip joint in order to control for weight addition and removal. Kinematically, changes in the hip joint angle occurred at all instances analyzed throughout the gait cycle with this effect being more prominent in the weight off condition. In conjunction with this, the hip joint energy generation increased during all phases of the gait cycle while the ankle and knee joints either decreased energy generation or increased energy absorption. In the obstacle group, participants also chose to increase flexion at the hip joint. However, the ankle joint also had either decreased plantarflexion or increased dorsiflexion at all the instances analyzed during the gait cycle. However, joint energy generation increases at these joints were only found during stance and at heel contact. The toe obstacle clearance values also showed a marked increase in trial 1 for the weighted condition which demonstrates a voluntary gait modification made by participants to safely traverse the obstacle that was quickly adapted for. Overall, the results found by previous studies using treadmill collection techniques were still seen in overground force platform data but they were not as robust. References: 1.Martin PE et al. J Biomech. 1990; 23(6):529-536. 2.Noble et al. Exp Brain Res. 2006; 169: 482-495. 3.Patla AE et al. Exp Brain Res. 1995; 196: 499-504. 4.Reid MJ et al. Neurosci Res Comm. 2001; 29(2): 79-87.

Economy is an very important factor to the cause of crimes. The unemployment rate play a key role to the economy side of a society. Besides, the probability of being arrested is also been calculated by the offenders. So this paper tries to use the crime rate ,clearance rate , unemployment rate , as variables to discuss their relations. This paper selects 138 data samples from January, 1995 to June, 2006, analyze them by Literature Survey Method¡BUnit Root Test Method¡BJohansen of Maximum Likelihood Estimation Method. The result shows that constantly descend in the other conditions, when the unemployment rate increases by 1%, causing the crime rate to increase by 3.38%, namely the unemployment rate increases the function for the crime rate. When the clearance rate increase by 1%, the crime rate will be reduced by 0.67%, meaning that then clearance rate can reduce the function of the crime rate.

In this study, the seal bushings were designed to allow the lubricant stored in the screw and the nut system. Effect of thread clearance on the life of the screw were investigated. The screw and nut are made of S45C and HBsC3, respectively. Effects of material pairs on friction coefficient were investigated by using the pin on disk tester to simulate the friction condition between the screw and the nut. Result shows that the life of the screw increases with increasing thread clearance. The longest life for the maximum clearance can achieve 6790 cycles. Under the same surface pressure, the friction coefficients of HBsC3 on self-lubricating alloy and HBsC3 on SCM 440 are much smaller than self-lubricating alloy on self-lubricating alloy and self-lubricating alloy on SCM 440 by using nut on screw.

Conventionally the size of the back clearance played a great importance on reducing the axial clearance by utilizing the concept that the decreased axial clearance results in lower axial force acting on the impeller. However, from the previous works on the effect of the back clearance on the hydrodynamic forces upon the semi-open impeller showed the opposite trend: increasing the back clearance results in the reduced axial loading. In this work, the CFD simulation of an entire pump and detailed analysis on the back clearance flow are performed. By utilizing the commercially available software, meshing and CFD simulations are performed. LDA data, unsteady pressure data, and pressure distributions on the housing are used to validate the CFD model. The flow field prediction of the back clearance flow is then compared with other researcher’s works of the gap flow analysis between the rotating and stationary disks. The flow field inside the impeller passage, which is very sensitive to the back clearance size, is also studied. The empirical equation for the leakage loss through the balance holes is produced using the CFD predictions.

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Freie Universiẗat, Diss., 2006--Berlin. / Dateiformat: zip, Dateien im PDF-Format.