Estudos anteriores (Zayas, 1990) tem sugerido a existência de uma melhor transportabilidade por cílio do muco respiratório de pacientes fumantes que não apresentam câncer de pulmão em comparação com pacientes fumantes com câncer de pulmão e semelhante carga tabágica. Nosso principal objetivo foi verificar esta hipótese. Nós estudamos 16 tabagistas com câncer de pulmão (média carga tabágica = 58,78), 16 tabagistas com câncer extra-pulmonar (média carga tabágica = 53,87) e 11 não Tabagistas com Metástase Pulmonar com indicação de broncoscopia diagnóstica. O muco respiratório foi coletado durante a broncoscopia, usando um pequeno cateter através do canal de aspiração do broncoscopio. A transportabilidade por cílio no palato de rã, ângulo de contato (wetabilidade), transportabilidade pela tosse e viscosidade (cone-plate) e análise morfológica do epitélio respiratório foi realizado. Não foi encontrada diferença estatística entre os pacientes Tabagistas (Câncer de pulmão e Câncer extra-Pulmonar) para os parâmetros de muco estudos. Da mesma forma não foi encontrada diferença estatística nas análises do muco coletado de um lado do tumor comparado com o lado contralateral. Entretanto, encontramos diferença estatística entre os grupos não tabagistas com Metástase Pulmonar e Tabagistas com câncer Pulmonar e Extra-Pulmonar para os parâmetros de Transportabilidade pela Tosse (p = 0,018), Viscosidade 10 rpm (p= 0,021), FEV 1 (L) (p= 0,028) e FEV 1 (%) (p= 0,042) e diferença estatística nos Tabagistas para Correlação entre carga tabágica e idade (p=0,038) e Viscosidade (p= 0,029). Na análise histologica observamos 10 Tabagistas (60% alteração, sendo, 30% metaplasia escamosa; 20% hyperplasia e 10% epitélio com ausência de cílios) e 15 não Tabagistas (40% com alteração histológica sendo 20% destes com metaplasia escamosa e em pacientes com Câncer pulmonar ou Câncer extra-pulmonar). Não teve diferença na composição das mucinas entre os tabagistas. Concluímos que não há diferença entre as propriedades físicas do muco respiratório de Tabagistas com Câncer de Pulmão e Câncer Extra-Pulmonar com similar carga tabágica e que essas alterações das propriedades físicas do muco respiratório e alterações morfológicas, devem-se mais à exposição dose-tempo da fumaça do cigarro ao epitélio respiratório / Previous study (Zayas 1990) has suggested the existence of a better transportability by cilia in respiratory mucus of smoking patients who did not present lung cancer in comparison to lung cancer patients smoking similar packages/year. Our aim was to verify this hypothesis. We studied 16 smoking patients with lung cancer (mean packages/year = 58,78), 16 smoking patients with extra pulmonary cancer (esophagus and head and neck), (mean packages/year = 53,87), and 11 non-smoking patients (metastasis) that underwent diagnostic bronchoscopy. Respiratory mucus was collected during bronchoscopy, using a small catheter passed through the aspiration channel of the bronchoscope. Mucus transportability in frog palate, contact angle (wettability), transportability by cough and viscosity (cone-plate) as well as morphological analysis the respiratory epithelium were performed. No statistical differences were found between smoking patients (lung and extra pulmonary cancer) in the mucus parameters studied. In the same way, no difference was found in the analysis of mucus samples collected from the tumor side compared to contra lateral samples. Nevertheless, statistical difference between Smoking (Lung Cancer and Extra-Pulmonary Cancer) and non Smoking (metastasis Pulmononary) for valous Clearance by cough (p = 0,018), viscosity 10rpm (p=0,021) FEV 1 (L) (p= 0,028) and FEV1 (%) (p=0,042) and statistical difference for correlation between smoking history and age (p=0,038) and viscosity 10 rpm (p= 0,029). The analysis histological of the 10 smoking, observed 60% of cases with alteration histological (30% with squamous metaplasia; 20% with hyperplasia and 10% with epithelium with cilia absence) and 15 non smoking presented 40% of cases with alteration histological (205 with squamous metaplasia in patients with lung cancer or exra-pulmonary cancer. We conclude that there is no difference between the physical properties of the respiratory mucus of smokers with lung cancer and extra-pulmonary cancer with similar packages/year and that changes in physical properties of respiratory mucus and morphological changes, due to more exposure to the dose-time of cigarette smoke in the respiratory epithelium

Conventional ‘well-stirred’ extrapolation methodology using intrinsic metabolic clearance data from rat liver microsomes poorly predicts in vivo clearance for approximately half of drug discovery compounds. The aim of this present study was to gain a more detailed understanding of the hepatobiliary disposition pathways which influence drug clearance. A set of 77 new chemical entities (NCEs), demonstrating a range of physicochemical properties and in vitro-in vivo clearance correlations (IVIVC), were employed to explore relationships between hepatobiliary disposition pathways in rat and physicochemical, structural and molecular properties of the NCEs. Primary rat hepatocytes with >80% cell viability were successfully isolated from male Han Wistar rats and used to establish in vitro models of drug uptake and biliary efflux. Preliminary studies with cultured primary rat hepatocytes indicated that uptake of d8-taurocholic acid and pitavastatin was time, concentration and temperature dependent. Initial studies with sandwich cultured primary rat hepatocytes demonstrated that cellular accumulation and biliary efflux of [3H]-Taurocholic acid was time and concentration dependent. These in vitro rat hepatocyte models were then used to investigate drug uptake and biliary efflux for all NCEs. In general, NCEs with high (passive) permeability showed better IVIVC and a lower incidence of active uptake and biliary efflux compared to NCEs with lower permeability, suggesting permeability is a key property influencing hepatobiliary drug disposition in rat. Preliminary in silico models analysing structural and molecular descriptors of substrates of active transport in rat hepatocytes were developed and indicated modest potential to highlight clearance pathways beyond hepatic metabolism but further follow up work with larger, more diverse compound sets is warranted to gain confidence in these models. Extended clearance models were investigated to estimate the effect of hepatic transporters on clearance and to predict the overall hepatic clearance of the NCEs. None of these models resulted in a 1 to 1 correlation but in general, improvements in clearance predictions were made when drug transport processes were accounted for. In vivo excretion studies using bile duct cannulated rats demonstrated that NCEs with high permeability and good IVIVC were not directly eliminated in bile or urine as unchanged drug, whereas NCEs with lower permeability and poor IVIVC (> 3-fold under predicted) were all directly eliminated unchanged indicating key drivers of clearance beyond metabolism. In conclusion these investigations confirmed a role for hepatic transporters in clearance but the complex nature of active transport mechanisms and a lack of robust in vitro tools create challenges in the quantitative prediction of hepatobiliary clearance. However, one of the key findings from this research, which is highly applicable in early drug discovery, was to identify the existence of disposition permeability relationships. These can be anticipated by observing physicochemical parameters of NCEs in conjunction with conventional IVIVC, since NCEs that are not highly permeable, possess some hydrophobic characteristics, and which are poor substrates of cytochrome P450 enzymes are more likely to be good substrates of transporters and be directly eliminated in bile and/or urine. The present study focused on exploring hepatobiliary disposition pathways using rat as the investigative species. Whilst there is no guarantee that pathways relevant to rat will be similar to other preclinical species or even humans, an early diagnosis of dominant clearance pathways can guide a more efficient use of the ADME-PK toolbox.

Os efeitos da suplementação de creatina sobre a função renal são debatidos intensamente na literatura científica. Os poucos trabalhos sobre o tema envolvendo humanos têm sido severamente criticados por apresentarem ausência de randomização, dosagens não uniformes de creatina, baixo poder estatístico e, sobretudo, ausência de marcadores padrão-ouro de função renal. Além disso, embora tenhamos mostrado recentemente que a suplementação de creatina não prejudica a função renal em sujeitos submetidos a treinamento aeróbio, a natureza desse tipo de atividade, bem como o habitual consumo de proteína dessa amostra, não permite que generalizemos nossos achados à população que mais utiliza creatina: praticantes de treinamento de força sob dietas ricas em proteína. Desta forma, foi conduzido um ensaio randomizado, duplo-cego, controlado por placebo, com o objetivo de investigar os efeitos da suplementação de creatina e sua possível interação com o alto consumo de proteínas sobre a função renal, em praticantes de treinamento de força. Os sujeitos foram divididos aleatoriamente em 2 grupos: a) suplementação de creatina (20g/dia durante cinco dias e 5g/dia até o término do estudo) e b) placebo (dextrose). No período basal e após 12 e 24 semanas, os sujeitos tiveram acompanhamento do consumo alimentar, e foram analisados o clearance de 51Cr-EDTA, creatinina sérica, sódio e potássio séricos e urinários e microalbuminúria. Não foram encontradas diferenças significativas nas variáveis analisadas após 12 e 24 semanas. Demonstrando assim, a ausência de alteração da função renal decorrente da suplementação de creatina, em praticantes de treinamento de força recreacionais com consumo proteico >=1,2g/kg peso/dia / The effects of creatine supplementation on renal function are discussed extensively in the literature. Few studies on the topic involving humans have been severely criticized because of the absence of randomization, non-uniform doses of creatine, low statistical power and, above all, the absence of a gold standard markers of renal function. Furthermore, although we have recently shown that creatine supplementation does not impair renal function in subjects undergoing aerobic training, the nature of this type of activity, as well as the usual protein intake in this sample does not allow generalization of our findings to the population who consume creatine: practitioners of strength training with a high protein intake. Thus, we conducted a randomized, double-blind, placebo-controlled study, in order to investigate the effects of creatine supplementation and its possible interaction with high protein intake on renal function in practicioners of strength training. The subjects were randomly assigned to 2 groups: a) creatine supplementation (20g/day during five days and 5g/day until the end of the study) and b) placebo (dextrose). At baseline and after 12 and 24 weeks, food intake, 51Cr-EDTA clearance, serum creatinine, sodium and potassium serum and urinary microalbuminuria was assessed. No significant differences were observed throughout the trial. Demonstrating that creatine supplementation on practitioners of strength training with high protein intake does not harm renal function

PURPOSE. To determine the effects of blurring vision on whole-body center-of-mass (CM) dynamics and foot-clearance parameters in elderly individuals performing a single step up to a new level. METHODS. Twelve healthy subjects (mean age, 72.3 ±4.17 years) performed a single step up to a new level (heights of 73 and 146 mm). Trials were undertaken with vision optimally corrected and with vision diffusively blurred by light-scattering lenses (cataract simulation). CM and foot-clearance parameter data were assessed by analyzing data collected by a five-camera, three-dimensional (3-D) motion analysis system. RESULTS. When vision was blurred, subjects took 11% longer to execute the stepping task (P < 0.05), mediolateral displacement of the point of application of the ground reaction force vector (i.e., weighted average of all pressures over the area in contact with the ground; the so called center of pressure, CP) decreased from 37.6% of stance width to 28.3% (P < 0.01), maximum distance between the mediolateral position of the CM and CP decreased by 9.8 mm (P < 0.01), and toe clearance (distance between tip of shoe and edge of step) increased in both the horizontal (28%) and vertical (19%) direction (P < 0.05). CONCLUSIONS. These findings suggest that when vision was blurred, subjects used a twofold safety-driven adaptation: First, to increase dynamic stability they ensured that the horizontal position of their CM was kept close to the center of the base of support and second, they increased horizontal and vertical toe clearance while swinging their lead limb forward to reduce the risk of tripping.

Clinical research in cystic fibrosis (CF) requires study endpoints that are sensitive to airways disease, repeatable and non-invasive. Despite significant advances in the treatment of CF, lung function assessments continue to rely on the forced expiratory volume in 1 second (FEV1). Although simple to perform, it lacks sensitivity, is difficult for younger subjects, and changes over time. An alternative method of assessing lung physiology is to derive measures of ventilation heterogeneity from inert gas washout tests. In early lung disease, measures of gas mixing appear to be more sensitive than spirometry. In addition, since only tidal breathing is required, they are more physiological and are more straightforward for younger subjects. Widespread use has been impaired by the lack of a robust and cost effective gas analyser technology. The work presented in this thesis concerns the adaptation, validation and then use of a novel gas analyser (Innocor) in a clinical system for the performance of multiple breath washouts. Lung clearance index (LCI), a simple measure of ventilation heterogeneity, has been calculated from washouts in 52 adults with CF and 50 healthy controls. LCI was more sensitive to disease than FEV1 in CF, being elevated in 11 of the 12 CF patients with normal spirometry. In healthy subjects, LCI has been shown to be repeatable and reproducible, with a narrow range of normal that is stable over a wide age range. In a separate study of 19 patients, LCI has also been shown to improve with treatment of an exacerbation in CF. Correlation with changes in other biochemical (serum CRP, peripheral blood white cell count, sputum IL-8, sputum neutrophil) clinical (symptom score) or structural (computed tomography) markers was poor. Short term change in LCI has also been demonstrated in CF patients in response to chest physiotherapy, although there was considerable heterogeneity of response in terms of both LCI and volume of lung ventilated by tidal breathing (as measured by washout functional residual capacity). In addition to LCI, multiple breath phase III slope analysis has been performed on washouts of CF patients and healthy controls, and this has been compared to other measures of lung physiology. Proposed measures of convective and diffusive gas mixing have been shown to be unreliable in CF. These studies have also been the first to demonstrate multi-centre use of washout tests as endpoints. The technology described here offers the possibility of a simple and reliable system for performing multiple breath washouts, though at present it is not available commercially. The studies have added to the understanding of the utility and reliability of washout tests, as well as some of their limitations. It is hoped that in future LCI will be an important clinical endpoint in therapeutic intervention studies in CF, and that it will also offer new ways to follow changes in lung physiology in other diseases.

International Telemetering Conference Proceedings / October 23-26, 2000 / Town & Country Hotel and Conference Center, San Diego, California / Automatic spectrum management and monitoring systems are very useful to manage frequencies at test ranges and assure interference-free transmission of telemetry signals. Spectrum management systems assign telemetry frequencies using database information on available and occupied channels and analysis tools which can determine whether a data link will support telemetry. Modern, DSP-based spectrum monitoring systems, in fixed or mobile configurations, automate the process of performing spectrum occupancy to verify clear channels and identify and locate sources of interference; they are integrated with and utilize the management system database. Such systems are important to assure reliable communications channels for telemetry.

This report to RCP Ltd and University of Canterbury summarises the findings of a 5 month secondment to the CERA Port Hills Land Clearance Team. Improvement strategies were initiated and observed. The Port Hills Land Clearance Programme is the undertaking of the demolition of all built structures from the Crown’s compulsory acquired 714 residential red zoned properties. These properties are zoned red due to an elevated life risk as a result of geotechnical land uncertainty following the 2011 Canterbury Earthquakes.

Background. Allometric scaling (AS) is widely used in predicting human clearance (CL) based on animal data. Substantial prediction errors have been commonly observed and various modifications to AS have not provided a broad reliable improvement. In this study, an extensive data set was assembled including animal and human systemic CL and physiochemical properties. The allometric exponents were calculated based on multiple species AS and single-species AS methods. The correlations between the allometic exponents and physiochemical properties were evaluated in an attempt to find covariates that may explain the inter-compound variability in the allometric exponents. Lastly, the statistical approaches in analyzing the allometric function were evaluated with the collected data. Methods. 1- A nonlinear mixed effect modeling (MEM) approach was performed to investigate the central tendency and distribution of AS exponents as well as to identify whether there are any correlations between the allometric exponent, and coefficient, with the physicochemical and drug metabolism and pharmacokinetics (DMPK) properties of the compounds. 2- Single-species AS was performed to estimate the single-species AS exponent distributions and their corresponding central tendencies. The correlation between the estimated single-species AS exponents and the physicochemical and DMPK properties of the compounds were also examined. 3- The methodologies of log-log transformation followed by linear regression (LL-LR) and direct nonlinear regression methods (NLS) with different weighting schemes on the AS power function were investigated. The central tendency and distribution of the allometric exponents were evaluated and compared across methods. Furthermore, the human CL prediction performance was evaluated among methods. Results. The estimated central tendency and distribution of AS exponents from the nonlinear MEM as well as the single-species AS approaches were consistent with literature reports. There were no significant correlations identified between the estimated AS exponents and the physicochemical or DMPK properties. The methods of LL-LR and the NLS with 1/w2 weighting (variance weighted by CL2 during the variance minimization process) results in the most similar allometric exponent with central tendency around 0.668 and provided the best human CL prediction among methods investigated. Conclusion. The knowledge gained in this work by extensive modeling and simulations contributed to a better understanding of the variability in AS exponents and better practice in performing AS in human CL prediction

Aujourd’hui, les pathologies respiratoires chroniques constituent un fardeau sanitaire mondial. Beaucoup sont associées à une modification rhéologique du mucus. Le rôle de clairance du mucus tapissant les voies respiratoires est de capturer des particules étrangères afin qu’enzymes et anticorps le nettoient, puis d’être transporté vers le pharynx pour être digéré ou expectoré. Dans des conditions pathologiques (e.g. mucoviscidose), les propriétés physiques assurant cette fonction vitale sont entravées par des modifications de la composition du mucus. L’objectif ici est de caractériser en profondeur les propriétés mécaniques du mucus vis-à-vis du développement d’appareils d’aide à la clairance. Ceci est réalisé par des moyens expérimentaux et de la modélisation depuis la base de données qui en découle. Le mucus réel implique de sérieuses problématiques de collecte, c’est pourquoi le choix a été fait de préparer des simulants à partir de glycoprotéines à différentes concentrations reproduisant la variété naturelle du mucus. Cela a permis de tester chacune des variétés vastement, palliant ainsi les problèmes de cohérence intrinsèque. La microscopie optique et la MEB ont donné un aperçu visuel du réseau 3D des simulants et confirmé sa similarité avec des mucus réels. La tension de surface, liée à la mouillabilité et l’adhésivité du mucus sur la surface épithéliale a été mesurée. Cela a montré une bonne concordance avec des mucus pathologiques, en particulier les concentrations élevées, en cohérence avec les observations cliniques. Le mucus est sujet aux changements de température in-vivo et peut varier de 20°C près de la bouche à 40°C en cas d... / Today, chronic respiratory pathologies constitute a worldwide health burden. Most of them are associated to a modification of the mucus rheology. The clearance role of mucus is first to trap foreign particles, so that enzymes and antibodies can start the cleaning and then to transport them towards the pharynx, to be digested or expectorated. Under disease conditions (e.g. Cystic Fibrosis), the physical properties ensuring this vital function are hindered by modifications of the mucus composition. The purpose of this thesis is then to characterize thoroughly the physical (essentially rheological) properties of mucus to improve the development of clearance helping devices using both experiments and modeling based on the subsequent database. Real mucus implies strong issues related to sample collection, hence the choice made in this work was to use mucus simulants prepared from glycoproteins at various concentrations to mimic the real mucus variety. It allowed to widely test each unique sample thus palliating the issue of intrinsic consistency. Optical microscopy and SEM were used to give a complementary insight into the 3D network of samples and confirmed the similarity with former observations made on real mucus. The surface tension (closely related to the wettability and adhesiveness of the bronchial mucus on the epithelium surface) was also measured for each concentration. It showed a good agreement with pathological mucus, especially for the high polymer concentrations. Mucus is prone to temperature variations in-vivo 20°C close to the mouth to 40°C under fever conditions. Hence thermal diffusivity, conductivity, and heat capacity were measured in this tem...

Low prices in textile fabrics are a phenomenon that can be traced back for centuries. In 2011 a new record was set when 37.7 percent of all items in the fashion commerce were sold at a discounted price. Retailers today on the Swedish market have taught the consumers a new consumption behavior due to the constant flow of new products. It has become difficult to increase a price of a product due to globalization and the hard competition it brings. Economies of scale have made it possible for retail chains to offer products with low prices. Because of the fluctuated demand among consumers today clearance sales have become a natural part of a company’s business strategy.The purpose of the thesis is to define if companies use clearance sales as a strategy in today’s volatile business world and to compare retailers’ approaches with consumers’ attitudes towards clearance sales. This study questions whether clearance sales are necessary today. The purpose is also to clarify if clearance sales can be limited by several factors and how companies will manage clearance sales in the future.The methodology used in this thesis is an inductive approach together with a qualitative and a quantitative research strategy. A case study including interviews with seven different retailers and a survey with 100 participating consumers have been accomplished.The authors of this thesis could not discover a strategy how clearance sales are managed among the participating retailers. They claimed that clearance sales are necessary and that it is a result of faulty forecasting and a decreased willingness to buy among consumers due to the volatile business world. A speeded up system with more collections each year stresses and forces retailers to purchase more products that cannot be sold at regular prices, which in the end lead to even more clearance sales. Clearance sales affect the companies differently depending on their retail construction.The authors have noticed a shift in the society where consumers’ willingness to buy has decreased due to a rise in environmental thinking. Meanwhile, companies are still using clearance sales as a tool with the purpose to attract consumer to low prices. However the authors claim that clearance sales have lost its function. Companies are realizing that they need to understand their consumers and their market so that their forecasts are more correct and thereby they will have less unsold products that will end up at clearance sales. / Program: Master programme in Applied Textile Management