published_or_final_version / abstract / toc / Pharmacology / Master / Master of Philosophy

BACKGROUND: In the US 47.2% of adults have periodontitis. Alcohol affects the host response, impairs immune function, has toxic effects on the liver and affects with protein metabolism, and therefore may increase the risk of periodontitis. Alcohol may also interfere with homocysteine (Hcy) metabolism and result in hyperhomocysteinemia (HHcy), a risk factor for inflammatory diseases such as cardiovascular disease and possibly periodontal disease. Understanding the exact relationship between alcohol consumption, HHcy and periodontitis is incomplete. OBJECTIVES: To add to our understanding of the alcohol-periodontitis, periodontitis-Hcy and alcohol-Hcy associations longitudinally by addressing methodological issues that confound past research. Methods: The study used existing data from 562 male participants in the VA Dental Longitudinal Study (DLS) who answered food frequency questionnaires (FFQ), underwent periodontal examinations and had plasma . Hcy measurements (N=469). Periodontitis was defined using the CDC case definition (Eke et al., 2009) and categorized into none/mild/moderate or severe disease. HHcy was defined as Hcy ≥10.2 umol/L based on Spence et al., 2001. Alcohol intake was categorized as none, ≤ 1 drink/day, >1 but <2 drinks/day, or ≥ 2 drinks/day. RESULTS: In longitudinal analyses, the risk of developing severe periodontitis among alcohol consumers was 10-17% higher over a period of 19-years compared to non-drinkers after controlling for age, smoking, diabetes, education, and number of teeth present. These estimates were higher still among men with lower than average vitamin B6 or B12 intakes. However, these results were not statistically significant The analyses suggested that men with mild, moderate or severe periodontitis had greater hazards of developing HHcy compared to disease-free participants after adjusting for covariates, but these results were not statistically significant. Consuming more than 2 drinks of alcohol per day significantly increased the risk of developing HHcy by 76% (p= 0.037). SUMMARY: Our findings suggest that alcohol consumption may increase the hazards of developing severe periodontal disease especially if vitamin B complex intakes are low. These results also suggest that periodontal disease and alcohol consumption each increases the hazards of hyperhomocysteinemia. We believe this is the first prospective cohort study to examine associations among periodontitis, homocysteine and alcohol consumption.

Elevated levels of homocysteine (HCy) are a known risk factor in several disease states (1). HCy has several other metabolites, homocysteine thiolactone (HCy-T) and homocysteic acid (HCA). Whilst HCy-mediated neurotoxicity has been extensively studied, the underlying mechanisms of HCy-T and HCA mediated neuronal damage remain largely unknown. This thesis aims to explore the underlying mechanisms, triggered by HCy and metabolites which result in neuronal cell death, and may be appropriate targets for future research on disease-modifying interventions in neurodegenerative disorders. As ageing is the greatest risk factor for neurodegeneration, a novel model of human neuronal ageing was established, permitting investigation of the pathways triggered by HCy in ageing. Using SH-SY5Y cells, a novel differentiation protocol was established and categorised, once fully differentiated, these cells were shown to be fully functional neurons and could be maintained for a month in culture. Using a range of concentrations of HCy and HCy-T, the concentration cell death occurs at was determined using crystal violet and lactate dehydrogenase assays. Mechanisms of toxicity were determined using pharmacological intervention at the NMDA receptor, nitric oxide scavengers and antioxidants. Using a combination of immunocytochemistry, live cell imaging and ELISA, alterations in markers of cell damage could be examined. The results showed HCy and HCy-T have distinct mechanisms of toxicity. Whilst both are neurotoxic, HCy directly acts via the NMDA receptor, however HCy-T appears to be less potent. Additionally, HCy-T caused a greater increase in reactive oxygen species generation than HCy, and each metabolite also displayed distinct mitochondrial network abnormalities. Finally, using the long-term culture methods, the chronic effects of HCy, HCy-T and HCA were examined. However, extensive cell death was apparent at low doses in all metabolites therefore no definitive mechanisms could be determined. This culture method was deemed not appropriate for toxicity experiments.

Thesis (M.S.)--University of Delaware, 2006. / Principal faculty advisor: Diane S. Herson, Dept. of Biological Sciences. Includes bibliographical references.

none

Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 53-67).

In this study we determined the effect of nitrous oxide (N2O) on homocysteine concentrations in children and whether blood levels of folate, vitamin B12, B6, methylmalonic acid (MMA) and methylenetetrahydrofolate reductase C6777T genotype affected this relationship. Homocysteine was measured before and after N2O. Vitamin levels, MMA and genotype were determined preoperatively. Median age of the 32 participants was 11 months (3-126 months). All children had folate and B6 levels above deficiency values (7.4, 20nmol/L respectively). Five children had MMA levels indicating deficiency (≥0.21µmol/L). Post-exposure homocysteine concentrations increased by 25% (P= <0.001). Duration of exposure and initial homocysteine concentrations were predictors of the increase (r2= 0.821, P= <0.001). Vitamin B12 and initial homocysteine concentrations were inversely associated (r2 = 0.277, P= 0.004). Folate, vitamin B6 and genotype showed no effect. In conclusion, N2O exposure leads to increased homocysteine in children. Studies investigating benefit of pre-surgical vitamin B12 supplementation may prove worthwhile.

In this study we determined the effect of nitrous oxide (N2O) on homocysteine concentrations in children and whether blood levels of folate, vitamin B12, B6, methylmalonic acid (MMA) and methylenetetrahydrofolate reductase C6777T genotype affected this relationship. Homocysteine was measured before and after N2O. Vitamin levels, MMA and genotype were determined preoperatively. Median age of the 32 participants was 11 months (3-126 months). All children had folate and B6 levels above deficiency values (7.4, 20nmol/L respectively). Five children had MMA levels indicating deficiency (≥0.21µmol/L). Post-exposure homocysteine concentrations increased by 25% (P= <0.001). Duration of exposure and initial homocysteine concentrations were predictors of the increase (r2= 0.821, P= <0.001). Vitamin B12 and initial homocysteine concentrations were inversely associated (r2 = 0.277, P= 0.004). Folate, vitamin B6 and genotype showed no effect. In conclusion, N2O exposure leads to increased homocysteine in children. Studies investigating benefit of pre-surgical vitamin B12 supplementation may prove worthwhile.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Chemistry. Title from thesis description page. Includes bibliographical references.

Thesis (M.Med.Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 53-67). Also available in print.