Polymorphism can influence every aspect of the properties of a solid including the shelf life, dissolution rate, solubility, formulation properties and processing properties of a solid drug. A deeper understanding of polymorphism and related solid state properties would ensure an improved quality of the materials used throughout drug preparation, dosage form formulation and clinical trials. Therefore, determination of the existence of polymorphs and pseudopolymorphs, characterization of different solid state forms and their respective properties, and controlling the existing form in the resulting formulation all form part of a rapidly growing field within pharmaceutical research and industry. Carbamazepine (CBZ) was the model drug used in this study. FT-Raman spectroscopy was chosen as a main investigative technique in this study to evaluate its potential in monitoring (pseudo)polymorphic conversions in aqueous suspensions in the absence or presence of various pharmaceutical excipients. Partial least squares analysis (PLS) was used for quantitative analysis of the spectral data. Earlier it has been found that CBZ converts rapidly to the dihydrate (DH) when exposed to humidity or water, and this has been reported to be the main reason for the sometimes observed greatly decreased bioavailability of marketed CBZ tablets. In this study, the conversion kinetics of CBZ (forms I, II and III) to DH in aqueous suspension were found to be first order kinetics with an unconverted portion (R� [greater than or equal to] 0.95), where the crystal morphology appeared to play a more important role in its conversion kinetics than the polymorphic form. The influence of pharmaceutical excipients on the conversion of CBZ in aqueous suspension was also explored. For excipients such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) which have both a low solubility parameter (< 27.0 MPa[1/2]) and strong hydrogen bonding groups, complete inhibition of the conversion of CBZ was possible even at a very low concentration (0.1 % w/v). Raman spectroscopy showed its high applicability in investigating CBZ conversion kinetics and screening of excipient effects in aqueous environment. It was demonstrated that Raman has a robust nature in quantitative analysis since problems such as different particle size, morphology, and spatial distribution of the two solid state forms of the drug seemed not to have significant influence on Raman scattering. This study has also clarified the relative importance of many contributing factors (type of crystalline form (CBZ or DH), crystal morphology, surface area, and excipient interactions with drug particles) influencing the in vitro dissolution of CBZ. The solid state characterization approach taken in this study will provide a deeper insight into the dissolution performance of drugs and should thus lead to a better understanding of in vitro/in vivo behavior of drugs.

HSCR has been felt to be a polygeneic disease on the basis of an incompletely penetrant sex modified transmission, which may be either autosomal dominant or recessive in different kindred. During the 1990's several of the genes involved in this transmission have come to light. Other genes remain to be discovered.

The ecological factors that maintain defensive chemical variation within and between plant species have intrigued ecologists for decades. While theory posits that polymorphisms may be maintained different forms of balancing selection, relatively few experimental studies have tested whether such balancing selection can maintain defensive chemical trait polymorphisms in nature. Further, evidence demonstrating balancing selection is rare for any trait. Here, I investigated a stereochemical trait polymorphism in Xanthium strumarium. This species is polymorphic with respect to the stereochemistry of the lactone ring junction of a prominent defensive compound class ? the sesquiterpene lactones. Individual plants typically produce only cis-fused or trans-fused lactones across their entire suite of compounds. Sesquiterpene lactones are known to influence feeding behavior and growth rates of various herbivores, but nothing is known about the ecological implications of variation in this stereochemical trait. I first examined whether sesquiterpene lactone stereochemical variation can influence folivore feeding behavior in the laboratory. Using pure sesquiterpene lactones in controlled feeding experiments, I found that laboratory-reared grasshoppers were less deterred by the cis-fused compounds than the trans-fused compounds. I then found that these patterns extended to the field: in common gardens, plants producing cis-fused lactones received more damage than plants producing trans-fused lactones. Additionally, folivore damage was negatively correlated with plant fitness. Taken together, these results indicate that herbivores can impose natural selection on this stereochemical trait polymorphism in nature. Finally, I found evidence that spatially variable selection leads to fitness patterns conducive to the maintenance of this polymorphism. Further, I found that the intensity of folivore damage across spatial scales predicted in which environments each morph outperformed the other, with plants producing cis-fused lactones achieving higher fitness than plants producing trans-fused lactones when herbivore pressure was low (and the reverse being true when herbivore pressure was high). This work demonstrates that relatively minor defensive chemical variation can have far-reaching impacts on the ecology and evolution of plant populations.

<p>Single nucleotide polymorphisms (SNP) in leptin (LEP) and pro-opiomelanocortin (POMC) have been associated with beef carcass quality and yield respectively. Both hormones also play a role in immune performance. Since both of these genes are pleiotrophic, it was important to determine whether selection based on these SNPs would negatively affect immune cell numbers. A SNP in each of these hormones was assessed for effects on immune cell counts and antibody titres in twenty-seven beef cattle herds (n = 556). A commercial rabies vaccine was administered to these animals. Prior to being vaccinated, the types of lymphocytes evaluated included B cells, gamma delta cells, regular and activated CD4 and CD8 cells and numbers of lymphocytes as well as baseline serum antibody titres. On day 21, antibody titres were measured and a booster vaccine was administered. Finally on day 42, antibody titres and lymphocyte types were again counted. Several cell types were significantly associated with the LEP genotype however, no consistent pattern of correlation was observed between LEP genotype (TT, CT or CC) and peripheral blood lymphocyte populations. The number of different lymphocytes significantly associated with LEP genotype increased from two on day 0 to four on day 42. Animals with CT and CC genotypes had significantly higher increased rabies antibody titres in the first 21 days after vaccination than those with TT genotypes. The POMC SNP also did not show a clear pattern of association between lymphocyte subtypes and genotype. There was no difference in response to the rabies vaccination associated with the POMC genotype. Our results suggested that selection at either of the SNPs examined in this research would not detrimentally impact immune function in beef cattle.</p>

The programming language Cforall extends the C language with, among other things, overloading, parametric polymorphism, and functions that can return multiple values from a single call. This thesis presents an outline of the first implementation of the core Cforall language. An effective implementation of Cforall requires complete support for new language constructs while preserving the behaviour and efficiency of existing C programs. Analyzing the meaning of Cforall programs requires significantly more sophisticated techniques than are necessary for C programs; existing techniques for the analysis of overloading and polymorphism are adapted and extended to apply to Cforall. Three strategies for generating code for polymorphic programs are compared, using plain C as an intermediate representation. Finally, a realistic Cforall program is presented and characteristics of the generated C code are examined.

<p>Single nucleotide polymorphisms (SNP) in leptin (LEP) and pro-opiomelanocortin (POMC) have been associated with beef carcass quality and yield respectively. Both hormones also play a role in immune performance. Since both of these genes are pleiotrophic, it was important to determine whether selection based on these SNPs would negatively affect immune cell numbers. A SNP in each of these hormones was assessed for effects on immune cell counts and antibody titres in twenty-seven beef cattle herds (n = 556). A commercial rabies vaccine was administered to these animals. Prior to being vaccinated, the types of lymphocytes evaluated included B cells, gamma delta cells, regular and activated CD4 and CD8 cells and numbers of lymphocytes as well as baseline serum antibody titres. On day 21, antibody titres were measured and a booster vaccine was administered. Finally on day 42, antibody titres and lymphocyte types were again counted. Several cell types were significantly associated with the LEP genotype however, no consistent pattern of correlation was observed between LEP genotype (TT, CT or CC) and peripheral blood lymphocyte populations. The number of different lymphocytes significantly associated with LEP genotype increased from two on day 0 to four on day 42. Animals with CT and CC genotypes had significantly higher increased rabies antibody titres in the first 21 days after vaccination than those with TT genotypes. The POMC SNP also did not show a clear pattern of association between lymphocyte subtypes and genotype. There was no difference in response to the rabies vaccination associated with the POMC genotype. Our results suggested that selection at either of the SNPs examined in this research would not detrimentally impact immune function in beef cattle.</p>

X-ray repair cross complementing Group 1 (XRCC1) protein plays an important role in base excision repair. Single nucleotide polymorphisms (SNPs) in XRCC1 gene may affect DNA repairing ability, genetic susceptibility, and prognosis to oral and pharyngeal squamous cell cancer (OPSCC). This study was carried out to evaluate the association of three XRCC1 SNPs with the risk and prognosis of OPSCC. A total of 509 OPSCC cases and 678 cancer-free controls were recruited to detect the genotypes of XRCC1 by PCR-RFLP. Then, 447 case patients with surgical treatment and safety margins were included in the survival analysis. No association was observed for XRCC1 194 and the risk of OPSCC. As compared with the wild Arg/Arg genotype, the combined genotypes of 280 Arg/His and His/His were with decreased risk (AOR=0.73, 95% CI, 0.52-1.03, p = 0.069) of OPSCC and with a significantly decreased risk (AOR=0.67, 95% CI, 0.47-0.97, p = 0.035) of oral cavity. As compared with the Arg/Arg genotype of XRCC1 399, the Gln/Gln genotype was with the increased risk of OPSCC (AOR=2.06, 95%CI: 1.21-3.51, p = 0.008) and oral cavity cancer (AOR=1.89, 95%CI: 1.08-3.33, p = 0.026). We defined the ¡§putative high risk haplotypes¡¨ as ¡§Arg-Arg-Gln and Trp-Arg-Gln¡¨. The AOR were 1.29 (95% CI, 1.04-1.60, p = 0.020) for the ¡§putative high risk haplotypes¡¨ as compared with other haplotypes for OPSCC. Then, two putative high risk haplotypes were combined into ¡§putative high risk diplotypes¡¨. The AOR for the ¡§high risk diplotypes¡¨ were 1.98 (95% CI, 1.18-3.33, p = 0.010) as compared with other diplotypes for OPSCC. No association between XRCC1 polymorphisms and clinicopathological outcomes, except XRCC1 280. Those carriers of XRCC1 280His allele (combined Arg/His and His/His genotypes) were associated with late onset (≥50 yrs) of oral cavity cancers. No association between genetic variants in XRCC1 and disease-specific survival except XRCC1 399. Patients with 399 Arg/Gln and Gln/Gln genotypes showed a significant better survival as compared to Arg/Arg genotype carriers (AHR 0.41 95% CI: 0.18-0.93), especially for those patients younger than 50 years (p = 0.012), in pathological stage III or IV (p = 0.044), and without postoperative radiotherapy (p = 0.012). In summary, XRCC1 280 Arg/His and His/His genotypes were associated with decreased risk of oral cavity cancer. 399 Gln/Gln genotype was associated with increased risk of OPSCC and oral cavity cancer. The putative ¡§high risk haplotypes and diplotypes¡¨ were with increased risk of OPSCC. However, 399 Arg/Gln and Gln/Gln genotypes were prognostic factors, especially for those with young age, aggressive tumor stage, and without postoperative radiotherapy for oro and hypopharynx patients. These findings suggest that XRCC1 polymorphisms may play a role in the development and prognosis of OPSCC.

To elucidate the correlation between host susceptible genes and the carcinogenesis of gastric cancer and duodenal ulcer, myeloperoxidase (MPO) -463 G/A polymorphism was detected by PCR-RFLP and nucleotide autosequencing, respectively. On the other hand, E-cadherin (CDH1) -160 C/A polymorphism was analyzed by nucleotide autosequencing. No positive correlation among MPO genotype distributions, gastric cancer (p=0.26,

For more than fifty years glucocorticoids (GCs) has been used to treat a wide range of inflammatory diseases, such as allergies, asthma, rheumatoid arthritis, and autoimmune diseases, due to its potentiality on the antiinflammatory and immunomodulatory effects. The anti-inflammation actions of glucocorticoid were mediated by an intracellular receptor, glucocorticoid receptor (GR), a member of the nuclear receptor family of ligand-dependent transcription factor. Upon activation by their ligand, GRs translocated to the nuclear and then bound to glucocorticoid responsive element (GRE) or negative glucocorticoid responsive elemen (nGRE). The administration of GCs depended on the acuity of disease and on the responses of patient clinically. Although some Systemic Lupus Erythematosus (SLE) patients given the maximal steroid doses, the response to the therapy remained poorly, and thus called ¡§glucocorticoid resistance¡¨. Despite the fact that the side effects and complications in SLE patients may result from the restrictions of physic; it has been documented that there were some relationships between the glucocorticoid resistance with the polymorphisms of GR, and the levels of glucocorticoid receptor beta. However, no significant differences in the GR polymorphisns (TthIII, ER22/23EK, N363S, BclI and I559N) between controls and SLE patients were found and there were no significant differences found on the levels of SUMO-2 antibody between patients with active and inactive SLE in this study. Neverthless, a significant association on the the allelic polymorphism of BclI was observed in patients with glucocorticoid resistance. Additionally, the expression of GR£] in patients with SLE was higher than that of controls and the TthIII CT genotype was associated with GR£\ expression.

Thesis (M. Sc.)--University of Alberta, 2009. / Title from pdf file main screen (viewed on Dec. 29, 2009). "A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Animal Science, Department of Agricultural, Food and Nutritional Science, University of Alberta." Includes bibliographical references.