No description available.

No description available.

The etiology of obesity is heterogeneous as are the cardio-metabolic complications, associated with it. The cardio-metabolic profile of obese individuals places them at risk of a range of chronic metabolic diseases including diabetes. Paradoxically, a subset of the population classified as obese based on established methods present with few metabolic abnormalities, whereas a subset classified as non-obese present with a wide range of abnormalities. The observed heterogeneity suggests not only that excess adiposity is likely one of many determinant of metabolic complications, but also that our methods of measuring obesity might not be fully capturing the underlying biological mechanisms at play. The heterogeneity by which obesity presents itself in the general population is becoming more pertinent to the field of infectious diseases as findings increasingly implicate obesity in impaired host defenses and increased susceptibility to a range of different infectious organisms, one of which is Staphylococcus aureus. S. aureus is an opportunistic pathogen with significant infectious burdens in clinical, community as well as incarcerated settings. The organism also asymptomatically colonizes human mucosal surfaces, particularly the anterior nares. The anterior nares of approximately 25-30% of US adults are colonized at any given time, and prior colonization serves as a strong predictor of subsequent infection. Obese females have been consistently shown to be at elevated risk of S. aureus colonization, however, findings amongst obese males have been inconsistent. The mechanism by which obesity increases risk of colonization remain unclear, however, many cite the underlying metabolic dysfunction that frequently accompanies obesity. Given the global burden of obesity and increasing evidence that it impairs host defenses, understanding how obesity increases host colonization with S. aureus is imperative. The overall objective of this dissertation was therefore to evaluate the influence of obesity and metabolic abnormalities on S. aureus colonization among New York State Maximum-Security prison inmates. The objective of the dissertation was met using three aims. First a systematic review was conducted to assess the different definitions used to define persistent S. aureus colonization in community dwelling adults, as well as the reported prevalence estimates associated with those definitions. The study demonstrated that a considerable amount of variation existed in the way persistent colonization was defined in the extant literature. Despite the variation however, the prevalence of persistent S. aureus carriage remained relatively consistent after categorizing the different definitions into four general groups. The review also demonstrated that two groups of persistent carriers might exist. Therefore, differentiating strain persistence carriers from species persistence carriers may reconcile some of the inconsistencies with regard to length of strain carriage reported in the literature. Second, the influence of metabolic heath (a measure incorporating both body mass index (BMI) and metabolic abnormalities) was assessed. A significantly higher probability of S. aureus colonization of the anterior nares and/or oropharynx was observed among metabolically abnormal normal weight (BMI < 25 kg/m²) as well metabolically abnormal obese (BMI ≥ 30 kg/m²) females when compared to metabolically healthy females. No significant association was observed between the categories of metabolic health and the prevalence of S. aureus colonization among males. We did, however observe a significant decline in exclusive oropharyngeal colonization among obese male inmates with metabolic abnormalities. Lastly, factors associated with persistent S. aureus carriage were evaluated in the third aim. Approximately 27% of the population was persistent carriers at the species level and 17% were persistent carriers at the strain level. Obesity was independently associated with species persistent carriage but not strain persistent carriage. Correspondence analysis evaluating strain compositional differences between exclusive persistent anterior nares carriers, exclusive persistent oropharynx carriers, exclusive persistent carriers at both the anterior nares and oropharynx and intermittent carriers suggested compositional differences existed between the different groups. More specifically, the relative abundance of certain S. aureus strains appeared more prominent among exclusive nasal carriers as compared to all other carriage/mucosal site types (exclusive oropharynx, both nasal and oropharynx.

This thesis describes biochemical and molecular methods diagnostic for a spectrum of steroid metabolic diseases. Deficiency of any enzyme in the steroid hormone biosynthetic pathways leads to disorders including congenital adrenal hyperplasia, while some cause disorders of sex development (DSD). A gas chromatography mass spectrometry-based analytical technique called urinary steroid profiling (USP) has been shown to be a useful diagnostic test for these diseases and for steroid-secreting adrenocortical tumours. To test the hypothesis that this approach would be effective in our local population, we interpreted 482 USP results using reference intervals set up from 371 local healthy subjects. Characteristic steroid metabolite excretion patterns were found in 39 patients, including 21 patients with 21-hydroxylase deficiency (21OHD) where there were grossly increased 17-hydroxyprogesterone metabolites, 12 patients with 5α-reductase 2 deficiency (5ARD) with extremely low 5α- to 5β-reduced steroid metabolite ratios, and five patients with adrenocortical carcinoma with markedly raised tetrahydro-11-deoxycortisol and 3,16,20-pregnenetriols levels. / The genetic basis of 21OHD in various populations is mainly due to conversion between the CYP21A2 and the CYP21A1P genes but this has not yet been explored in our population. By using DNA sequencing and multiplex ligation-dependent probe amplification, 74 mutations were found in 35 patients with 21OHD. Gross deletion/conversion of the CYP21A2 gene accounted for 27%. c.290-13A/C>G was the most common point mutation (27%), followed by p.Ile172Asn (17.6%). One novel mutation c.1367delA was also detected. Their prevalence in our patients differs from those in other populations. / The most common cause of 46,XY DSD in Western populations is androgen insensitivity syndrome (AIS) but this has not been verified locally. A prospective study was conducted where 64 patients were recruited for comprehensive hormonal profiling and targeted molecular analysis. In this study, a genetic diagnosis was established in 22 patients, with 5ARD being the most common disease, followed by AIS. Traditionally the diagnosis of 5ARD relies on measuring dihydrotestosterone. However, with our experience in diagnosing this condition based on USP and mutational analysis of the SRD5A2 gene, two new diagnostic algorithms for 46,XY DSD were proposed where dihydrotestosterone is not required. / In vitro study is the preferred method for characterising the function of novel genetic variants. However, clinical laboratories rarely have the facilities and resources for it. In silico prediction programmes appear to be practical alternatives but their performance on testing non-synonymous variants in genes related to steroid metabolism has not been verified. Three web-based in silico prediction programmes, namely Sorting Intolerant From Tolerant, PolyPhen-2 and Pathogenic-Or-Not-Pipeline, were tested by analysing 797 published non-synonymous genetic variants in 12 genes related to steroid metabolism. The results of in vitro functional study and/or clinical phenotype were used as gold standards. The performance of these three programmes were: sensitivity (76.6%, 84.1%, 70.0%), specificity (56.6%, 56.3%, 89.4%) and accuracy (70.1%, 75.2%, 76.8%), respectively. / In conclusion, USP is a valuable biochemical phenotyping technique that helps to select patients for subsequent genetic confirmation. Since the mutation spectrum of 21OHD and the aetiological basis of 46,XY DSD in our population differ from the others, laboratory diagnostic algorithms and molecular analytical strategies must be adjusted accordingly. / Chan, On Kei Angel. / Thesis (M.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 250-269). / Appendixes includes Chinese.

Addenda slip inserted in back. Includes bibliographical references (leaves 178-231). To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts

Bibliography: leaves 94-106. / v, 106, [33] leaves, [2] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Assessment of myocardial metabolism with radiolabelled substrates and positron emission tomography provides a potentially sensitive technique to investigate physiological and pathological cardiac states "in vitro". Prior studies have indicated that overall metabolic activity cannot be estimated from rates of utilization of any one particular substrate. It was hypothesized that acetate labelled with carbon-11 would provide an index of oxidative metabolism, based on fundamental biochemical principles. The hypothesis is confirmed in studies using isolated perfused rabbit hearts and closed chest canine studies. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1995

Bibliography: p. 252-281. / xiii, 281, [110] p., [11] leaves of plates : ill. ; 35 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Identifies and analyses the two 4S mutant alleles in selected patients, in order to test the hypothesis that the mutant genotype could be correlated with the clinical and biochemical phenotype. / Thesis (Ph.D.)--University of Adelaide, Faculty of Medicine, 1995?

Addenda slip inserted in back. / Includes bibliographical references (leaves 178-231). / xiv, 234, [19] leaves, [56] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2001

<p>Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases.</p><p>In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated.</p><p>In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium.</p><p>In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.</p>

Primary hyperparathyroidism (pHPT), characterized by elevated serum levels of calcium and parathyroid hormone (PTH), is associated with a number of metabolic derangements causing secondary manifestations. These include osteoporosis and increased risk of fractures, but also risk factors for cardiovascular morbidity and mortality. These risk factors include impaired glucose tolerance (IGT), dyslipidemia, increased body mass index and hypertension. While the skeletal abnormalities are mainly due to elevated PTH, the latter disturbances are still unexplained. Non-insulin dependent diabetes mellitus (NIDDM), IGT, dyslipidemia and hypertension are all included in the metabolic syndrome, also associated with morbidity and mortality in cardiovascular diseases. In this thesis, decreased bone mineral density (BMD) and variables of the metabolic syndrome are explored in patients with mild and normocalcemic pHPT before and after parathyroidectomy. To further investigate the relationship between insulin sensitivity and calcium, a community-based cohort was investigated. In two different patient cohorts of pHPT, lipoprotein alterations with decreased levels of HDL-cholesterol and elevated triglycerides were found in association with a high frequency of IGT, NIDDM and decreased insulin sensitivity. Parathyroidectomy had effects on the dyslipidemia and in part on the glucose metabolism. The disturbed glucose metabolism in pHPT was substantiated by results from the general population by a negative association between insulin sensitivity, measured by hyperinsulinemic clamp, and serum calcium. In conclusion, normocalcemic, mild and overt pHPT are associated with a range of risk factors for cardiovascular diseases, development of NIDDM and decreased BMD in cortical as well as trabecular bone. These findings explain, at least in part, the elevated morbidity and mortality from cardiovascular disease as well as fractures, reported in pHPT patients. Moreover, in the general population, serum calcium is associated with decreased insulin sensitivity. Parathyroidectomy has positive effects on several, but not all, of the investigated metabolic parameters.