The aetiopathogenesis, cardiovascular and metabolic complications, and pharmacogenomics of Addison's disease in South Africa

Includes abstract.Includes bibliographical references.This thesis aimed to address a number of unanswered research questions in Addison's Disease: investigate whether autoimmunity is the predominant cause of Addison's disease in South Africa and if a human leukocyte (HLA) DQ antigen association exists; the extent to which lipids, lipoproteins and biochemical markers of cardiovascular disease are abnormal; the degree to which replacement doses of hydrocortisone are supra-physiological; the impact of glucocorticoid receptor (GCR) polymorphisms on risk factors, markers of cardiovascular disease and replacement doses of hydrocortisone

Hyperthyroidism: What the generalist should know

Thyrotoxicosis is one of the more common endocrine disorders and most cases result from hyperactivity of the thyroid gland (hyperthyroidism) (Table I). Younger patients with thyrotoxicosis of any cause may present with palpitations, anxiety, easy fatigability, psychomotor activity, diarrhoea, excessive sweating, heat intolerance, preference for cold, amenorrhoea, and marked weight loss without appetite loss

Excessive weight gain following therapy for hyperthyroidism - a major problem

One of the most characteristic presenting features of hyperthyroidism is weight loss, despite an increased appetite. This phenomenon is easily understandable, as hyperthyroidism is accompanied by a rise in metabolic rate, energy expenditure and thermogenesis which is clearly not matched by an increased appetite and caloric intake in the vast majority of patients. Consequently a decrease in adipose tissue and muscle results. (Curiously a small proportion of hyperthyroid patients, fewer than 10%, present with weight gain owing to an increased appetite that exceeds the rise in metabolic rate

Amiodarone-induced thyroid dysfunction

Background. Little is known about the frequency of thyroid dysfunction (TD) associated with amiodarone therapy in southern Africa. Objectives. To determine the incidence of TD in a cohort of patients initiated on amiodarone therapy at a cardiac clinic in Cape Town, South Africa, believed to be an iodine-replete area. Patients. Pharmacy records were used to obtain the names of patients who received amiodarone between November 1999 and December 2002. Results. The sample size was 194, but data analysis was limited to the 163 patients for whom there were complete data. The mean age ± standard deviation (SD) was 59.0 ± 15.0 years (range 22 - 89 years). There were 67 female and 96 male patients. The indications for amiodarone therapy were supraventricular tachycardias (N = 102, 62.6%), ventricular tachycardia (N = 55, 33.7%), and prophylaxis against tachycardias (N = 3, 1.8%). The indication was uncertain in 3 patients (1.8%). The median duration of amiodarone treatment was 679.0 days (quartile deviation (QD) 1 172 days, range 3 - 6 425 days) in the whole cohort. The median duration of amiodarone therapy until new TD was 943 days (QD 1 185 days), significantly longer than in patients who remained euthyroid (547 days, QD 1 135 days) (P = 0.05). There were 45 new TD cases (27.6%): 11 patients (6.7%) were thyrotoxic, 1(0.6%) transient thyrotoxicosis, 1 (0.6%) subclinical hyperthyroidism, 13 (8.0%) had subclinical hypothyroidism, 12 (7.4%) hypothyroidism and 7 (4.3%) had minor changes in thyroid function. Conclusions. We found a high incidence of new-onset TD, similar to the highest rates reported internationally. Local factors responsible for this need to be investigated

Cardiovascular risk factors in patients with Addison's disease: a comparative study of South African and Swedish patients

BACKGROUND: Patients with Addison's disease (AD) in Scandinavia have an increased risk for premature death due to cardiovascular disease (CVD). Serum lipids are important risk factors for CVD and vascular mortality. Replacement doses of hydrocortisone have historically been higher in Sweden than South Africa. The primary aim was to study the lipid profiles in a large group of patients with AD with the hypothesis that the lipid profile in patients in Sweden would be worse than in South Africa. METHODS: In a cross-sectional study, 110 patients with AD (55 from South Africa, 55 from Sweden) matched for age, gender, ethnicity and BMI were studied. Anthropometric measures, blood pressure, lipids, highly sensitive C-reactive protein (hs-CRP) and adiponectin were studied. RESULTS: All patients were Caucasian and the majority were women N = 36 (65.5%). Mean (standard deviation; SD) ages of the Swedish and South African patients were 52.9 (13.0) and 52.6 (14.4) years and BMI 25.3 (3.2) and 25.8 (4.1) kg/m 2 , respectively. The mean total daily hydrocortisone dose was greater in the Swedish patients than the South African patients, [33.0 (8.1) versus 24.3 (8.0) mg; p<0.0001]. South African patients had higher median (interquartilerange; IQR) triglycerides (TG) [1.59 (1.1-2.46) versus 0.96 (0.74-1.6) mmol/l; p<0.001], total cholesterol (TC) [6.02(1.50) versus 5.13 (0.87) mmol/l; p<0.001], LDL-C [4.43 (1.44) versus 2.75 (0.80) mmol/l; p<0.001] and median hs-CRP [2.15 (0.93-5.45) versus 0.99 (0.57-2.10) mg/L; p<0.003] and lower HDL-C [0.80 (0.40) versus 1.86 (0.46) mmol/l; p<0.001] than the Swedish patients. Approximately 20% of the patients in both cohorts had hypertension and diabetes mellitus. CONCLUSIONS: South African patients with AD have worse lipid profiles and higher hs-CRP compared to their matched Swedish patients, despite lower doses of hydrocortisone. It is uncertain at this time whether these are due to genetic or environmental factors

Molecular Longitudinal Tracking of Mycobacterium abscessus spp. during Chronic Infection of the Human Lung

<div><p>The <i>Mycobacterium abscessus</i> complex is an emerging cause of chronic pulmonary infection in patients with underlying lung disease. The <i>M. abscessus</i> complex is regarded as an environmental pathogen but its molecular adaptation to the human lung during long-term infection is poorly understood. Here we carried out a longitudinal molecular epidemiological analysis of 178 <i>M. abscessus</i> spp. isolates obtained from 10 cystic fibrosis (CF) and 2 non CF patients over a 13 year period. Multi-locus sequence and molecular typing analysis revealed that 11 of 12 patients were persistently colonized with the same genotype during the course of the infection while replacement of a <i>M. abscessus sensu stricto</i> strain with a <i>Mycobacterium massiliense</i> strain was observed for a single patient. Of note, several patients including a pair of siblings were colonized with closely-related strains consistent with intra-familial transmission or a common infection reservoir. In general, a switch from smooth to rough colony morphology was observed during the course of long-term infection, which in some cases correlated with an increasing severity of clinical symptoms. To examine evolution during long-term infection of the CF lung we compared the genome sequences of 6 sequential isolates of <i>Mycobacterium bolletii</i> obtained from a single patient over an 11 year period, revealing a heterogeneous clonal infecting population with mutations in regulators controlling the expression of virulence factors and complex lipids. Taken together, these data provide new insights into the epidemiology of <i>M. abscessus</i> spp. during long-term infection of the CF lung, and the molecular transition from saprophytic organism to human pathogen.</p></div

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts