Thesis (M.D.)--Boston University

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Thesis (MSc)--University of Stellenbosch, 2008. / ENGLISH ABSTRACT: Iron metabolism disorders comprise the most common disorders in humans. Hereditary haemochromatosis (HH) is a common condition resulting from inappropriate iron absorption. The most common form of the disease (Type 1) is associated with mutations in the HFE gene. The C282Y homozygous genotype accounts for approximately 80% of all reported cases of HH within the Caucasian population. A second HFE mutation, H63D, is associated with less severe disease expression. The C282Y mutation is extremely rare in Asian and African populations. The H63D mutation is more prevalent and has been observed in almost all populations. Iron overload resulting from haemochromatosis is predicted to be rare in Asian Indian populations and is not associated with common HFE mutations that are responsible for HH in the Caucasian population. The aberrant genes associated with HH in India have not yet been identified. The present study attempted to identify variants in six iron regulatory genes that were resulting in the Type 1 HH phenotype observed in two Asian Indian probands from a highly consanguineous family. The promoter and coding regions of the HMOX1, HFE, HAMP, SLC40A1, CYBRD1 and HJV genes were subjected to mutation analysis. Gene fragments were amplified employing the polymerase chain reaction (PCR) and subsequently subjected to heteroduplex single-strand conformational polymorphism (HEX-SSCP) analysis. Samples displaying aberrations were then analysed using bi-directional semi-automated DNA sequencing analysis to identify any known or novel variants within the six genes. Variants disrupting restriction enzyme recognition sites were genotyped employing restriction fragment length polymorphism (RFLP) analysis. Mutation analysis of the six genes revealed 24 previously identified variants, five novel variants (HFE: 5’UTR-840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR- 1272T→C; HJV: 5’UTR-534G→T, 5’UTR-530G→T), one previously described microsatellite and two novel repeats. Variants identified within the SLC40A1, CYBRD1 and HJV genes do not seem to be associated with the iron overload phenotype. A previously described HAMP variant (5’UTR-335G→T) was observed in the homozygous state in both probands. This variant seems to be the genetic aberration responsible for iron overload in this Indian family. The severe juvenile haemochromatosis phenotype usually associated with HAMP mutations, was not exhibited by the two Indian probands. Their symptoms resembled those observed in classic Type 1 HH. It is suggested that variants identified in the HMOX1 and HFE genes are modifying the effect of the HAMP variant and resulting in the less severe disease phenotype. Although this variant has only been identified in one Indian family, it could shed some light in the hunt for the iron-loading gene in India. / AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is ‘n algemene siektetoestand wat ontstaan as gevolg van oneffektiewe opname van yster in die liggaam. Die mees algemene vorm van die siekte (Tipe 1) word geassosieer met mutasies in die HFE-geen. Die C282Y homosigotiese genotipe is verantwoordelik vir ongeveer 80% van alle gerapporteerde gevalle van OH binne die Kaukasiese bevolking. ‘n Tweede HFE mutasie, H63D, word geassosieer met minder ernstige siekte simptome. Die C282Y mutasie is besonder skaars in Asiese en Afrika bevolkings. Daar word bespiegel dat oorerflike ysteroorlading as gevolg van hemochromatose skaars is in Asiese Indiër bevolkings en word nie geassosieer met algemene HFE mutasies wat verantwoordelik is vir OH in Kaukasiese bevolkings nie. Die abnormale gene wat wél geassosieer word met OH in Indië is tot dusver nog nie identifiseer nie. Die doel van hierdie studie was om die variante in ses yster-regulerende gene te identifiseer wat die Tipe 1 OH fenotipe in hierdie familie veroorsaak. Hierdie fenotipe is waargeneem in twee Asies Indiese familielede afkomstig van ‘n bloedverwante familie. Die promotor en koderingsareas van die HMOX1, HFE, HAMP, SLC40A1, CYBRD1 en HJV gene is gesif vir mutasies. Geen fragmente is geamplifiseer met behulp van die polimerase kettingsreaksie (PKR) en daarna aan heterodupleks enkelstring konformasie polimorfisme (HEX-SSCP) analise blootgestel. PKR produkte wat variasies getoon het, is daarna geanaliseer deur tweerigting semi-geoutomatiseerde DNS volgorde-bepalingsanalise om enige bekende of nuwe variante binne die ses gene te identifiseer. Variante waar restriksie ensiem herkenningsetels teenwoordig is, is verder analiseer met behulp van die restriksie fragment lengte polimorfisme (RFLP) analise sisteem. Mutasie analise van die ses gene het 24 bekende variante, vyf nuwe variante (HFE: 5’UTR- 840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR-1272T→C, HJV: 5’UTR-534G→T, 5’UTR-530G→T), een bekende herhaling en twee nuwe herhalings gewys. Variante wat binne die SLC4041, CYBRD1 en HJV gene geïdentifiseer is, blyk nie om by te dra tot die ysteroorladings-fenotipe nie. Die bekende HAMP variant (5’UTR-335G→T) is waargeneem in die homosigotiese toestand in beide van die aangetaste individue. Hierdie variant blyk om die genetiese fout te wees wat verantwoordelik is vir die ysteroorlading in die betrokke Indiese familie. Die erge juvenielehemochromatose fenotipe wat meestal geassosieer word met HAMP-mutasies, is nie waargeneem in hierdie familie nie. Hul simptome kom ooreen met die simptome van die klassieke Tipe 1 OH. Dit blyk moontlik te wees dat die variante identifiseer in die HMOX1 en HFE gene die impak van die HAMP variant modifiseer en die matiger siekte-fenotipe tot gevolg het. Alhoewel hierdie variant slegs in een Indiese familie geïdentifiseer is, kan dit lig werp op die soektog na die veroorsakende ysterladingsgeen in Indië.

M.Sc. / Sub-Saharan Africa accounts for a large fraction of the world’s infectious diseases, particularly AIDS (Acquired Immunodeficiency Syndrome) and Tuberculosis (TB) and at the same time, iron (Fe) overload is common to several of its regions. Excess Fe aids in the replication of both Human Immunodeficiency Virus (HIV) and Mycobacterium tuberculosis (M.tuberculosis, Lounis, 2001; Georgiou, 2000) and also causes a malfunction of the host’s defense system and may ultimately lead to cell death. Not only does iron assist in pathogen survival but the pathogens themselves have a synergistic relationship where infection of one supports the replication of the other (Toosi, 2001; Bonecini-Almeida et al., 1998). Controlling the replication of these pathogens as well as the iron overload simultaneously becomes a huge task as many pathogenic and host factors needs to be considered at once. Desferrioxamine (DFO), a chelator commonly used to treat clinical conditions of iron overload has been reported to inhibit the multiplication of pathogens and at the same time extract the excess iron.

Thesis (Ph. D.)--University of Chicago, Committee of Genetics, 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.). / Written for the Dept. of Medicine, Division of Experimental Medicine. Title from title page of PDF (viewed 2008/05/08). Includes bibliographical references.

Thesis (M.S.)--University of Missouri-Columbia, 2008. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 14, 2009) Includes bibliographical references.

Thesis (M.Med.Sc.) - University of Queensland, 2003. / Includes bibliography.

Thesis (M.P.H.) - University of Queensland, 2003. / Includes bibliography.

A 72 year-old-patient without known past medical history presented to the hospital with worsening cough, dyspnea on exertion, decreased appetite, weight loss for two months. Prior to admission, he was treated with a 10- day course of levofloxacin and prednisone as a case of bronchitis with minimal improvement. Then he started to develop red urine with marked changes in mental status. On physical examination, the patient had notifiable scleral icterus, confusion and abdominal tenderness in the right upper quadrant. On admission his labs were significant for alkaline phosphatase 541, aspartate transaminase 557, alanine transaminase 94, total bilirubin 8.6, lactate 11.7. CT scan of abdomen showed hepatosplenomegaly, mild ascites and trace bilateral pleural effusion. Work up with Viral hepatitis serology, cryptococcal antigen, histoplasma antigen, respiratory virus panel, Epstein Barr virus tests were negative. Anti-nuclear antibodies (ANA) and anti-mitochondrial antibody were also negative. Blood level of amylase, lipase, acetaminophen and alcohol were negative at admission too. The patient was started initially on broad spectrum antibiotics, N-acetyl cysteine empirically and aggressive intravenous fluid hydration. Patient condition rapidly worsened and he developed profound shock requiring mechanical ventilation and started on stress dose steroid and pressor support. Upon further investigation, patient was noted to take terbinafine for toe onychomycosis (day 112). Ferritin level was elevated to 1596 with 93% iron saturation. Ceruloplasmin level was normal. Patient was not a transplant candidate due to multiple organ failure. As per family request, patient was palliatively extubated and died. Terbinafine is a fungicidal drug with activity against dermatophytes including Epidermophyton flccosum and trichophyton rubrum. It works by inhibition of squalene epoxidase with a resultant accumulation of squalene in the fungal cell and killing it as a result. Commonly used orally to treat onychomycosis and other fingernails and toenails infections. Shortly after its introduction to the market, DILI had been reported with elevation with serum aminotransferases elevation that was usually self-limited. Usually presents within first 6 weeks of therapy with either hepatocellular or cholestatic initially with sings of hypersensitivity. Mechanism of injury entails hypersensitivity reaction, though the full pathogenesis was not elucidated yet, but genetic polymorphism is implicated in the variable presentation especially among HLA-A 33:01 allele carriers. Terbinafine DILI resolves usually within 6 months of stopping the medication but can lead to death or need liver transplantation in some cases.