Lack of quantitative adsorption data makes it difficult for a physician to determine the actual amount of insulin received by a patient against the amount added to the intravenous infusion system. This project was therefore initiated to determine quantitatively the extent of adsorption that would occur in a clinical setting. In order to achieve the above aim, varying amounts of carrier insulin containing I-labeled insulin were added to the intravenous infusion delivery system. Using the most commonly utilized mode of delivery and flow rate the tagged insulin solution was allowed to flow through the intravenous delivery system. Both the amount of activity delivered and the amount of activity remaining in the system were measured.

In the present study lanolin alcohol films were investigated as potential drug delivery systems for the controlled release of salicylic acid. A series of experiments were conducted in vitro to study the release of salicylic acid from these films. The effect of changes in film composition and stirrer speed on drug release were examined. Seven film compositions with varying proportions of lanolin alcohol and ethyl cellulose were prepared over the ethyl cellulose concentrations of 0-30% w/w, while keeping the drug concentration at 2.5% w/w. The release data obtained in this study were examined by the Q vs 1/2 relationship and the first-order relationship. This was done to probe deeper into the underlying mechanism of drug release. Upon examination of the release data by the Q vs 1/2 treatment, it was observed that the correlation coefficients were quite high and lag times were only slightly negative in agreement with the observed initial release data. In contrast, the first-order treatment of data showed somewhat lower correlation coefficients and very high negative lag times. These data strongly suggest that the unidirectional release of salicylic acid from the lanolin alcoholethyl cellulose films follows Higuchi's diffusion-controlled granular matrix model. The release rate constant showed an initial increase with inclusion of ethyl cellulose followed by a sharp decline as the ethyl cellulose concentration was further increased reaching a minimum value at about 15-20 percent of ethyl cellulose. Further increases in the concentration of ethyl cellulose increased the rate of drug release with a tendency to level off at about 30 percent ethyl cellulose concentration. The effect of stirring rate on the release rate constant showed that the rates of release of salicylic acid increased with increases in the stirring rate.

Bakgrund: Ländryggssmärta är en av de vanligaste typerna av muskuloskeletal smärta och den ledande formen av nedsatt funktion världen över. Styrketräning (ST) är en av de vanligaste formerna av konservativ behandling vid kronisk ospecifik ländryggssmärta (CNSLBP). Det saknas rekommendationer för dosering av ST och effekten av olika doseringar är oklar. Syfte: Syftet med denna systematiska litteraturstudie var att kartlägga rapporterade träningsdoseringar vid CNSLBP samt att jämföra effekten av olika doseringar. Metod: En systematisk granskning av randomiserade kontrollerade studier publicerade de fem senaste åren genomfördes efter sökningar i databaserna MEDLINE, CINAHL och PEDro. En kvalitetsbedömning av studierna genomfördes och träningsdosering av styrketräning som behandling vid CNSLBP kartlades och kategoriserades. I inkluderade studier där liknande träningsupplägg med olika dosering jämförts, utvärderades doseringarnas effekt avseende smärtintensitet och funktion. Resultat: Totalt inkluderades sex artiklar. Risken för systematiska fel bedömdes som genomgående låg till medelhög. Träningsdoseringarna kategoriserades som moderata till medelhöga. Enbart en av de sex inkluderade studierna jämförde olika träningsdosering där komponenten intensitet varierats i två grupper. Högintensiv styrketräning uppvisade signifikanta förbättringar avseende funktion och små ickesignifikanta förbättringar avseende smärtintensitet jämfört med den medelintensiva träningsgruppen. Slutsats: Den här litteraturstudien visade att få studier anger träningsdosering av styrketräning som behandling för patienter med CNSLBP. De kartlagda träningsdoseringarna var moderata till medelhöga och liknar doseringarna som rekommenderas för motionärer. Inga slutsatser kunde dras avseende doseringarnas effekt. Framtida kliniska studier med träning som intervention bör definiera styrketräningsdosering vilket anses relevant för såväl forskare som fysioterapeuter i praktiken. / Background: Low back pain is one of the most common musculoskeletal disorders and the leading cause of disability worldwide. Resistance training (RT) is an effective therapeutic modality for the treatment of patients with chronic non-specific low back pain (CNSLBP). However, recommendations of RT dosages is lacking and the effects of different dosages remains unclear. Objective: The objective of this review was to map and evaluate the effectiveness of reported RT dosages for the treatment of CNSLBP. Method: A systematic search for literature was conducted in the databases MEDLINE, CINAHL and PEDro. Dosages were mapped and categorized. Effect sizes of pain intensity and disability were extracted from articles with comparisons between dosages. The risk of bias was judged for the articles, respectively. Results: A total of six articles were included. The dosages were categorized as moderate to medium high. Comparison between dosages was made in one of the included articles. Significant improvements in pain intensity and non-significant improvements in disability in favour of a high intensity group compared to a low intensity training group was found. The risk of bias was consistently judged as low or moderate. Conclusion: This study showed a lack of correctly reported RT dosages. The mapped dosages where corresponding to the recommendations for a healthy population. No conclusions could be drawn upon the effect of different dosages. A clear definition of the RT dosage in future trials is of importance to further investigate the effect of RT as an intervention for the treatment of CNSLBP.

The International Commission on Radiological Protection (ICRP) determines the policy regarding radiation safety internationally. To the ICRP, hereditary changes as a result of either high or low doses, are of a major concern. The SA Forum for Radiation Protection recommended that a research project to determine the genetically-significant dose (GSD) for the South African population should be done as such a project has never been undertaken to date. This term was at first defined by UNSCEAR in 1958. The National Radiological Protection Board derived a formula from this definition as shown in the NRPB Report, NRPB-R106 (1980). This formula was implemented in the project. It combines the frequency of radiological examinations obtained during the country-wide survey and estimates of gonadal doses for different examination types, together with population and child expectancy data. New procedures, techniques and data processing that were relevant to this project had to be developed because the available information and conditions are unique to South Africa. The task was set to find a model in order to draw the best representative sample of the population and it was determined in a unique way, namely the so-called Dollar Unit Sampling method. A sample of 27 institutions out of a possible 292 (9%) was drawn in comparison, e.g., with the 8% of France and 8% in Great Britain. It was necessary to rely mainly on the calculation of gonad doses due to a shortage of manpower, contrary to other countries that were able to physically measure doses. Information obtained in the survey was used in this regard. The "RADCOMP Entrance Skin Exposure Software Program " of Nuclear Associates was used to produce parametric Free Air Exposure tables based on doses from Table B.3, NCRP Report No. 102. After the skin entrance doses were calculated, it was possible to calculate the gonad doses. A computer program was obtained from the Food and Drug Administration in the USA for this purpose. Data analysis was performed by means of the software package Microsoft Excel version 4.0. The above-mentioned formula was used in order to obtain the final results. The GSD for the total SA-population was calculated as 94.6 μGy. The breakdown of the GSD for the various South African race groups was Asian - 229.0 μGy, Black - 66.5 μGy, Coloured - 112.2 μGy and White - 463.4 μGy.

Orientador: Antonio de Queiroz Neto / Banca: Guilherme de Camargo Ferraz / Banca: Antonio Raphael Teixeira Neto / Resumo: O estudo objetivou avaliar a segurança da administração oral da dose terapêutica do firocoxib por 14 dias em equinos saudáveis. Foram utilizados 9 equinos, 4 machos e 5 fêmeas, com peso médio de 405±31 Kg e idade média 11±3 anos que receberam uma vez ao dia, 0,1mg/kg de firocoxib. Hemograma, avaliação dos parâmetros de coagulação e bioquímicos séricos e urinálise foram realizados antes do início do tratamento (D1), após 7 e 14 dias de tratamento (D7 e D14) e 7 dias após o final do tratamento (D21). Foi realizado exame gastroscópico 1 dia antes do início do tratamento (D0) e dois dias após a última coleta de dados. O número de leucócitos diminuiu na avaliação do D14 em relação ao D1, voltando aos valores basais no D21- 7 dias após o final do tratamento. A concentração de hemoglobina aumentou nos momentos D14 e D21 em relação ao do D1. A concentração plasmática de fibrinogênio aumentou no momento D21 em relação a D7 e D14. O tempo de tromboplastina parcial ativada e o tempo de protrombina aumentaram em D7 e D14 e D21 quando comparadas as médias em relação à média do D1. A contagem de plaquetas diminuiu nas avaliações em D7, D14 e D21 em relação ao momento D1. A atividade sérica da aspartato aminotranferase aumentou no D14 em relação ao D1. A atividade sérica da fosfatase alcalina aumentou nos momentos D7 e D14 em relação ao D1. A concentração de ureia diminuiu no D14 em relação ao D1. A creatinina se manteve estável no período de tratamento porém, no D21 apresentou diminuição em relação a D1, D7 e D14. A atividade sérica da gama glutamiltranferase diminuiu no D21 quando comparada ao D14, mas não houve diminuição em relação ao D1 e ao D7. Não foram observadas alterações na urinálise e no exame gastroscópico. Conclui-se que a administração do firocoxib em equinos é segura uma vez... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The study aimed to evaluate the safety of oral administration of the therapeutic dose of firocoxib for 14 days in healthy horses. Were used 9 horses, 4 males and 5 females, with a mean weight of 405 ± 31 kg and an average age 11 ± 3 years who received once a day orally 0.1 mg/kg firocoxib. CBC, evaluation of coagulation parameters and serum biochemical and urinalysis were performed before the initiation of treatment (D1) after 7 and 14 days of treatment (D7 and D14) and 7 days after end of treatment (D21). Gastroscopic examination was conducted 1 day prior to initiation of treatment (D0) and two days after the last data collection. The number of leukocytes decreased in evaluating the relative D14 to D1, returning to baseline at D21-7 days after end of treatment. The hemoglobin concentration increased during times D14 and D21 in relation to the D1. The plasma concentration of fibrinogen increased when compared to D7 D21 and D14. The activated partial thromboplastin time and prothrombin time increased at D7 and D14 and D21 compared the averages from the average of D1. Platelet count decreased in assessments in D7, D14 and D21 compared to D0 moment. Serum activity of aspartate aminotranferase increased in D14 compared to D1. The serum alkaline phosphatase activity increased in times D7 and D14 compared to D1. The concentration of urea has decreased compared to the D14 D1. Creatinine remained stable during treatment but showed a decrease in D21 compared to D1, D7 and D14. Serum activity of gamma glutamyltranferase decreased when compared to the D21 D14, but no decrease from D1 and D7. No changes were observed in the gastroscopic examination and urinalysis. It is concluded that administration of firocoxib is safe in horses since it was not able to promote the appearance of adverse effects, allowing... (Complete abstract click electronic access below) / Mestre

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections and is part of a broader class of antibiotics called carbapenems. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. Previously, a physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose in normal height, normal weight males. Due to the absorption properties of ertapenem, the amount of fat in the body can influence how the drug binds, how quickly the drug passes through the body, and thus how effective the drug might be. Thus, we have revised the model so that it is applicable to males and females of differing body mass index (BMI). Simulations were performed to consider the distribution of the antibiotic in males and females with varying body mass indexes. These results could help to determine if there is a need for altered dosing regimens in the future.

Klinefelter Syndrome (KS) is a multisystemic disorder associated with a plethora of phenotypic features including mental retardation, cardiac abnormalities, osteoporosis, infertility, gynecomastia, type two diabetes and increased cancer risk. KS is the most common aneuploidy in humans (with a prevalence of 1:500 to 1:1000 born males) and is characterized by one or more supernumerary X-chromosomes (47-XXY, 48-XXXY, and 49-XXXXY karyotypes). While X-chromosome inactivation (XCI) represses extra Xs, few genes called “escape genes” elude the XCI mechanism and are actively transcribed from X inactive. The overdosage of escape genes has been considered the molecular landscape that underlies KS clinical features. In this project, we exploit an integration-free reprogramming method to generate the largest described cohort of iPSCs from seven patients with KS and healthy donor fibroblasts from two relatives. The unicity of this cohort relies on the derivation of 47-XXY iPSCs and their isogenic 46-XY healthy counterparts, along with multiple rare 48-XXXY and 49-XXXXY iPSC lines. Through X chromosome inactivation (XCI) assessment, we show consistent retention of n-1 XCI in all derived KS-iPSCs. We identify the genes within the PAR1 region as the most susceptible to dosage-dependent transcriptional dysregulation and therefore putatively responsible for the progressively worsening phenotype in higher grade X aneuploidies. Moreover, we explore the transcriptional impact of X overdosage on autosomes and identify that the X-dosage-sensitive autosomal transcription factor NRF1 is a master regulator of the X-linked escape gene ZFX. Finally, we dissect the potential pathological impact of the escape gene KDM6A on low- and high-grade supernumerary X iPSCs and differentiated derivatives. We highlight a considerable proportion of KDM6A targets that could be responsible for paradigmatic clinical manifestations of KS.

Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: Regenerative endodontic therapy in immature teeth with necrotic pulps triggers continued root development, thereby improving the prognosis of these teeth. Disinfection of the canal is accomplished with an intracanal medicament, such as triple antibiotic paste (TAP) composed of metronidazole, ciprofloxacin, and minocycline. A modified triple antibiotic paste (MTAP) that replaces minocycline with clindamycin has recently been suggested to avoid the tooth discoloration and potential demineralization from minocycline. The effect these pastes have on radicular dentin is unknown. Objectives: The aim of this study was to investigate the effects of two intracanal medicaments used during endodontic regeneration, TAP and MTAP, at concentrations of 1 g/mL and 1 mg/mL, on the microhardness and chemical structure of radicular dentin. Materials and Methods: Roots from extracted, unrestored, non-carious human premolar teeth were sectioned. An antibiotic paste (MTAP or TAP) or sterile water (control) was applied to treatment groups and stored for four weeks in 80-percent humidity at 37 °C. The effect of each paste on the microhardness of radicular dentin was measured using a Vickers Microhardness Tester (n = 17) to take three pretreatment and post-treatment measurements at both 500 µm and 1000 µm from the pulp-dentin interface. The chemical structure was assessed from dentin specimens treated with the same medicaments or sterile water for four weeks. After treatment, three measurements were taken on each specimen using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy to measure the phosphate/amide I ratios of dentin (n = 7). Results: The 1 g/mL of TAP or MTAP and the 1 mg/mL methylcellulose-based TAP caused significant reduction in microhardness of roots compared with untreated control roots at 500 µm and 1000 µm from the pulp-dentin interface. Furthermore, the methylcellulose-based 1 mg/mL TAP and MTAP caused significantly less reduction in microhardness compared with 1 g/mL TAP and MTAP. The 1 g/mL of TAP and DAP caused significantly lower phosphate/amide I ratios compared with other groups. Conclusion: The use of methylcellulose based 1 mg/mL of TAP and MTAP may minimize the reduction in microhardness of roots compared with the currently used 1 g/mL concentration of these antibiotics.

Due to their underlying genetic complexity, chromosomal disorders such as Down syndrome (DS), which is caused by trisomy 21, have long been understudied and continue to lack effective treatments. With over 200 genes on the extra chromosome, even the specific cell pathologies and pathways impacted in DS are not known, and it has not been considered a viable target for the burgeoning field of gene therapy. Recently, our lab demonstrated that the natural mechanism of dosage compensation can be harnessed to silence the trisomic chromosome in pluripotent cells. Using an inducible XIST transgene allows us to study the effects of trisomy in a tightly controlled system by comparing the same cells with either two or three active copies of chromosome 21. In addition, it raises the prospect that insertion of a single gene into a trisomic chromosome could potentially be developed in the future for “chromosome therapy”. This thesis aims to utilize this inducible system for dosage compensation to study the neurodevelopmental effects of trisomy 21 in vitro, and to answer basic epigenetic questions critical to the viability of chromosome silencing as a therapeutic approach. Foremost, for XIST to have any prospect as a therapeutic, and to strengthen its experimental utility, it must be able to initiate chromosome silencing beyond its natural context of pluripotency. Here I demonstrate that, contrary to the current literature, XIST is capable of initiating chromosome silencing in differentiated cells and producing fully dosage compensated DS neurons. Additionally, I show that silencing of the trisomic chromosome in neural stem cells enhances their terminal differentiation to neurons, and transcriptome analysis provides evidence of a specific pathway involved. Separate experiments utilize novel three-dimensional organoid technology and transcriptome analysis to model DS neurodevelopment in relation to isogenic euploid cells. Overall, this work demonstrates that dosage compensation provides a powerful experimental tool to examine early DS neurodevelopment, and establishes that XIST function does not require pluripotency, thereby overcoming a perceived obstacle to the potential of XIST as a therapeutic strategy for trisomy.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21256号 / 医博第4374号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 小川 修, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM