Thesis (M.Sc.(Dietetics))--University of Pretoria, 2009. / Abstract in English. Includes bibliographical references.

Lamin A/C is a component of the nuclear lamina that contributes to nuclear integrity, chromatin organisation, gene transcription and DNA replication. Mutation of the LMNA gene, encoding lamin A/C, causes a number of diseases affecting different tissues, but the mechanism(s) by which this widely expressed protein causes tissue-specific disease remains unclear. Hutchinson-Gilford progeria syndrome (HGPS) is an early-onset premature aging disorder. The most common LMNA mutation (G608G) prevents complete posttranslational processing of lamin A, resulting in aberrant retention of a farnesyl group. In this study, a cohort of children with progeroid phenotypes were screened for genetic defects. The G608G mutation was identified in one patient with a classical phenotype. A second patient with mild progeria carried a rare T623S mutation, which also results in aberrant farnesylation of lamin A. In contrast, a severe progeroid phenotype resulted from homozygous mutation of ZMPSTE24, the key enzyme in lamin A processing. Studies of skin fibroblasts showed a correlation between farnesylated lamin A level and disease severity. FRAP studies revealed that retention of the farnsesyl group causes a 50% decrease in mobility of lamin A, irrespective of the exact mutation. Interestingly, one non-farnesylated mutant also had a 50% reduction in mobility, whilst other non-farnesylated mutants had normal mobility. The results of these studies indicate that incomplete processing of lamin A is an important contributor to severity of progeroid disorders but, in agreement with other reports, is not the only disease mechanism involved. Familial partial lipodystrophy (FPLD) is a fat wasting disorder also resulting from LMNA mutations. Preliminary analysis of the adipogenic potential of mesenchymal stem cells isolated from FPLD patients do not produce detectable levels of adipogenesis. Preliminary immunofluorescence and binding studies in FPLD and progeria tend to support existing evidence that mislocalisation of the adipogenic factor SREBP1 may underlie the lipodystrophy phenotype.

Thesis (M.D. with Distinction in Research) -- University of Texas Southwestern Medical Center at Dallas, 2003. / Vita. Bibliography: 64-91.

Lipodystrophic syndromes encompass a wide range of both inherited and acquired conditions whereby adipose tissue is lost or absent. We report a rare case of acquired localized, pressure-induced lipodystrophy whereby continuous elbow pressure to the distal thighs led to marked tissue disfigurement. Pressure-induced lipodystrophy is a condition that likely results from protracted, localized pressure which ultimately decreases blood flow to the surrounding tissues. Overtime, the decreased perfusion is thought to induce adipocyte degeneration and eventual tissue deformation. Our findings resemble those described in the case reports of leg crossers’ dimples and lipoatrophia semicircularis and support current literature suggesting that prolonged pressure can indeed lead to significant adipose tissue loss and local architectural distortion. Our findings are significant because pressure-induced lipodystrophy represents an avoidable condition that can be circumvented if patients and physicians are knowledgeable of the underlying causes. We highlight a rare case report to educate the public as well as physicians about the causes of pressure-induced lipodystrophy and ultimately prevent future cases of unnecessary and unintended disfigurement.

Efeitos colaterais têm sido associados à terapia anti-retroviral em portadores da infecção pelo HIV. Entre esses, destaca-se a a síndrome da lipodistrofia, caracterizada por hiperlipidemia e lipodistrofia. A lipodistrofia é manifestada por alterações na forma do corpo, com aumento progressivo da circunferência abdominal e torácica, aparecimento de gordura dorsocervical com expansão da circunferência do pescoço; e lipoatrofia, com perda de tecido adiposo na face, nas nádegas e nos membros superiores e inferiores. O presente estudo, seccional e descritivo, realizado com 84 pacientes atendidos em um ambulatório de dislipidemias específico para os portadores do HIV, abordou, através da técnica do auto-relato, a ocorrência da lipodistrofia e as principais repercussões relacionadas ao seu aparecimento. Dos 84 pacientes, 40 (47,61%) apresentavam alterações corporais. Para 65,00% deles, as alterações na sua aparência física constituem uma \"marca registrada\", capaz de revelar a soropositividade para infecção pelo HIV, o que acarreta sérias conseqüências para sua saúde afetivo-emocional. Além da lipodistrofia, as alterações metabólicas, que incluem as dislipidemias estão associadas ao risco elevado para o surgimento de doenças coronarianas. Do total de pacientes avaliados, 8 (9,52%) deles eram hipertensos, 1 (1,19%) relatou infarto agudo do miocárdio e 1 (1,19%) acidente vascular cerebral após ter iniciado a terapia anti-retroviral. Os achados deste estudo reforçam a relevância da temática, e ressaltam a necessidade de novos estudos com uma abordagem não somente dos parâmetros biológicos da síndrome da lipodistrofia, mas também do seu impacto psicossocial, fornecendo subsídios para a integralidade e qualidade da assistência de enfermagem prestada a esses pacientes. / Collateral effects have being connected to anti-retroviral therapy in patients with HIV infection. Among them, we observe the lipodystrophy syndrome that is characterized by hyperlipidemia and lipodystrophy. The lipodystrophy is manifested by alterations in the body shape, with the progressive enlargement of abdominal and chest perimeter, the appearing of dorsocervical fat with expansion of the neck perimeter; and the lipoatrophy, with loss of fat tissue on the face, on the buttocks and in the superior and inferior members. This research, sectional and speech, done in 84 patients in an ambulatory specialized for HIV patients, approached through the auto-telling technique, the occurrence of lipodystrophy and its main repercussions related to its appearance. From these 84 patients, 40 (47,61%) show body alterations. For 65,00% of them, the alterations in their physical appearance constitute a \"stigma\", able to reveal the HIV-positive to the HIV infection, that leads serious consequences to their affective-emotional health. Besides the lipodystrophy, the metabolically alterations, that includes the dislipidemias are associated the high risk of coronaries diseases. The total of evaluated patients, 8 (9,52%) of them were hypertense, 1 (1,19%) showed acute infarct of myocardium and 1 (1,19%) had a stroke after had initiated an anti-retroviral therapy. The results found in this research reinforce the relevance of the thematic, and show up the need of new studies with an approach of the biological parameters of the lipodystrophy syndrome, but its psychosocial impact as well, giving support for its integrality and quality of the nursing assistance given to these patients.

Apesar de causar um enorme impacto na história da evolução e prognóstico a partir da infecção pelo HIV, a terapia anti-retroviral altamente potente prolongada apresenta vários efeitos colaterais. Dentre esses, a síndrome da lipodistrofia (SL) caracterizada por alterações metabólicas e morfológicas. Embora tenha sido descrito que a adesão à terapia esteja associada, sua patogenia ainda permanece desconhecida. Um enfoque têm sido dado aos mediadores pró-inflamatórios, como o Fator de Necrose Tumoral (TNF), sugerindo que o aumento nos níveis dessa citocina esteja associado com o desenvolvimento da SL. Como os sítios polimórficos têm sido associados com a magnitude da produção de citocinas, no presente estudo avaliamos a freqüência de alguns sítios polimórficos na região do gene que codifica o TNF em portadores do HIV/aids apresentando ou não a SL. Para avaliar o polimorfismo genético dos microssatélites TNFa-e e da região promotora do TNF (TNF-308 e TNF-238) foram estudados 117 portadores do HIV-1 usando terapia anti-retroviral (67 com SL e 50 sem SL) e 131 controles saudáveis. Os microssatélites e região promotora do TNF foram tipificados usando DNA genômico hibridizado com iniciadores específicos. Os pacientes foram arrolados no Hospital das Clínicas da Universidade de São Paulo (HCFMRP-USP). A analise estatística foi realizada utilizando-se o teste exato de Fisher. Quando consideramos as comparações das freqüências dos alelos dos microssatélites da região do TNF podemos inferir que a presença do alelo TNFa5 pode conferir proteção aos indivíduos portadores do HIV/aids no desenvolvimento da SL. Já as comparações dos alelos da região promotora do TNF nos sugerem que a presença do alelo TNF-308G, assim como seu homozigoto TNF-308GG, podem conferir susceptibilidade para o desenvolvimento da SL. A presença do haplótipo TNFe3 d3 -238G -308A c1 a5 b7 sugere proteção para o desenvolvimento dessa síndrome. Esse é o primeiro estudo associando o polimorfismo dos microssatelites do TNF com a SL e aponta diversas associações entre alelos da região do gene que codifica o TNF com a SL. Embora os mecanismos relacionados com a participação do TNF no desenvolvimento da SL não estejam bem esclarecidos, este estudo sugere que fatores imunogenéticos associados com a magnitude de expressão do TNF e, provavelmente da expressão de outras citocinas pró-inflamatórias, estejam envolvidas no desenvolvimento da SL em portadores do HIV/aids. / Despite causing a significant impact in the history of evolution and prognosis after HIV infection, the highly potent antiretroviral therapy causes various side effects, which include lipodystrophy syndrome (LS), characterized by metabolic and morphologic changes. Although it has been reported that treatment compliance is associated, LS pathogenesis remains unknown. Special attention has been given to proinflammatory mediators, such as the Tumoral Necrosis Factor (TNF), suggesting that the increase in levels of this cytokine is associated with the development of LS. Since polymorphic sites have been associated with the magnitude of cytokine production, in the present study we evaluated the frequency of some polymorphic sites in the gene region that codes TNF in HIV/aids-infected patients presenting LS or not. In order to evaluate the genetic polymorphism of TNFa-e microsatellites and of the TNF promoter region (TNF-308 and TNF-238), 117 HIV-1 infected patients using antiretroviral therapy (67 with LS and 50 without LS) and 131 healthy controls were studied. Microsatellites and the TNF promoter region were typified using hybridized genomic DNA with specific initiators. Patients were selected at the Clinics Hospital of the University of São Paulo (HCFMRP-USP). Statistical analysis was performed using the Fisher\'s exact test. Comparisons of the frequencies of microsatellite alleles of the TNF region suggest that the presence of the TNFa5 allele could provide HIV/aids patients with protection against developing LS. In addition, comparisons of alleles of the TNF promoter region suggest that the presence of TNF-308G allele, as well as of its homozygote TNF-308GG could pose susceptibility to developing LS. The presence of the haplotype, TNFe3 d3 -238G -308A c1 a5 b7, suggests protection against developing that syndrome. The present study is the first to associate TNF microsatellite polymorphism with LS, indicating several associations among alleles of the gene region that codes TNF with LS. Although the mechanisms regarding the participation of TNF in the development of LS are not clear, this study suggests that immunogenetic factors associated with the TNF expression magnitude and probably the expression of other proinflammatory cytokines are involved in the development of LS in HIV/aids infected patients.

Efeitos colaterais têm sido associados à terapia anti-retroviral em portadores da infecção pelo HIV. Entre esses, destaca-se a a síndrome da lipodistrofia, caracterizada por hiperlipidemia e lipodistrofia. A lipodistrofia é manifestada por alterações na forma do corpo, com aumento progressivo da circunferência abdominal e torácica, aparecimento de gordura dorsocervical com expansão da circunferência do pescoço; e lipoatrofia, com perda de tecido adiposo na face, nas nádegas e nos membros superiores e inferiores. O presente estudo, seccional e descritivo, realizado com 84 pacientes atendidos em um ambulatório de dislipidemias específico para os portadores do HIV, abordou, através da técnica do auto-relato, a ocorrência da lipodistrofia e as principais repercussões relacionadas ao seu aparecimento. Dos 84 pacientes, 40 (47,61%) apresentavam alterações corporais. Para 65,00% deles, as alterações na sua aparência física constituem uma \"marca registrada\", capaz de revelar a soropositividade para infecção pelo HIV, o que acarreta sérias conseqüências para sua saúde afetivo-emocional. Além da lipodistrofia, as alterações metabólicas, que incluem as dislipidemias estão associadas ao risco elevado para o surgimento de doenças coronarianas. Do total de pacientes avaliados, 8 (9,52%) deles eram hipertensos, 1 (1,19%) relatou infarto agudo do miocárdio e 1 (1,19%) acidente vascular cerebral após ter iniciado a terapia anti-retroviral. Os achados deste estudo reforçam a relevância da temática, e ressaltam a necessidade de novos estudos com uma abordagem não somente dos parâmetros biológicos da síndrome da lipodistrofia, mas também do seu impacto psicossocial, fornecendo subsídios para a integralidade e qualidade da assistência de enfermagem prestada a esses pacientes. / Collateral effects have being connected to anti-retroviral therapy in patients with HIV infection. Among them, we observe the lipodystrophy syndrome that is characterized by hyperlipidemia and lipodystrophy. The lipodystrophy is manifested by alterations in the body shape, with the progressive enlargement of abdominal and chest perimeter, the appearing of dorsocervical fat with expansion of the neck perimeter; and the lipoatrophy, with loss of fat tissue on the face, on the buttocks and in the superior and inferior members. This research, sectional and speech, done in 84 patients in an ambulatory specialized for HIV patients, approached through the auto-telling technique, the occurrence of lipodystrophy and its main repercussions related to its appearance. From these 84 patients, 40 (47,61%) show body alterations. For 65,00% of them, the alterations in their physical appearance constitute a \"stigma\", able to reveal the HIV-positive to the HIV infection, that leads serious consequences to their affective-emotional health. Besides the lipodystrophy, the metabolically alterations, that includes the dislipidemias are associated the high risk of coronaries diseases. The total of evaluated patients, 8 (9,52%) of them were hypertense, 1 (1,19%) showed acute infarct of myocardium and 1 (1,19%) had a stroke after had initiated an anti-retroviral therapy. The results found in this research reinforce the relevance of the thematic, and show up the need of new studies with an approach of the biological parameters of the lipodystrophy syndrome, but its psychosocial impact as well, giving support for its integrality and quality of the nursing assistance given to these patients.

Apesar de causar um enorme impacto na história da evolução e prognóstico a partir da infecção pelo HIV, a terapia anti-retroviral altamente potente prolongada apresenta vários efeitos colaterais. Dentre esses, a síndrome da lipodistrofia (SL) caracterizada por alterações metabólicas e morfológicas. Embora tenha sido descrito que a adesão à terapia esteja associada, sua patogenia ainda permanece desconhecida. Um enfoque têm sido dado aos mediadores pró-inflamatórios, como o Fator de Necrose Tumoral (TNF), sugerindo que o aumento nos níveis dessa citocina esteja associado com o desenvolvimento da SL. Como os sítios polimórficos têm sido associados com a magnitude da produção de citocinas, no presente estudo avaliamos a freqüência de alguns sítios polimórficos na região do gene que codifica o TNF em portadores do HIV/aids apresentando ou não a SL. Para avaliar o polimorfismo genético dos microssatélites TNFa-e e da região promotora do TNF (TNF-308 e TNF-238) foram estudados 117 portadores do HIV-1 usando terapia anti-retroviral (67 com SL e 50 sem SL) e 131 controles saudáveis. Os microssatélites e região promotora do TNF foram tipificados usando DNA genômico hibridizado com iniciadores específicos. Os pacientes foram arrolados no Hospital das Clínicas da Universidade de São Paulo (HCFMRP-USP). A analise estatística foi realizada utilizando-se o teste exato de Fisher. Quando consideramos as comparações das freqüências dos alelos dos microssatélites da região do TNF podemos inferir que a presença do alelo TNFa5 pode conferir proteção aos indivíduos portadores do HIV/aids no desenvolvimento da SL. Já as comparações dos alelos da região promotora do TNF nos sugerem que a presença do alelo TNF-308G, assim como seu homozigoto TNF-308GG, podem conferir susceptibilidade para o desenvolvimento da SL. A presença do haplótipo TNFe3 d3 -238G -308A c1 a5 b7 sugere proteção para o desenvolvimento dessa síndrome. Esse é o primeiro estudo associando o polimorfismo dos microssatelites do TNF com a SL e aponta diversas associações entre alelos da região do gene que codifica o TNF com a SL. Embora os mecanismos relacionados com a participação do TNF no desenvolvimento da SL não estejam bem esclarecidos, este estudo sugere que fatores imunogenéticos associados com a magnitude de expressão do TNF e, provavelmente da expressão de outras citocinas pró-inflamatórias, estejam envolvidas no desenvolvimento da SL em portadores do HIV/aids. / Despite causing a significant impact in the history of evolution and prognosis after HIV infection, the highly potent antiretroviral therapy causes various side effects, which include lipodystrophy syndrome (LS), characterized by metabolic and morphologic changes. Although it has been reported that treatment compliance is associated, LS pathogenesis remains unknown. Special attention has been given to proinflammatory mediators, such as the Tumoral Necrosis Factor (TNF), suggesting that the increase in levels of this cytokine is associated with the development of LS. Since polymorphic sites have been associated with the magnitude of cytokine production, in the present study we evaluated the frequency of some polymorphic sites in the gene region that codes TNF in HIV/aids-infected patients presenting LS or not. In order to evaluate the genetic polymorphism of TNFa-e microsatellites and of the TNF promoter region (TNF-308 and TNF-238), 117 HIV-1 infected patients using antiretroviral therapy (67 with LS and 50 without LS) and 131 healthy controls were studied. Microsatellites and the TNF promoter region were typified using hybridized genomic DNA with specific initiators. Patients were selected at the Clinics Hospital of the University of São Paulo (HCFMRP-USP). Statistical analysis was performed using the Fisher\'s exact test. Comparisons of the frequencies of microsatellite alleles of the TNF region suggest that the presence of the TNFa5 allele could provide HIV/aids patients with protection against developing LS. In addition, comparisons of alleles of the TNF promoter region suggest that the presence of TNF-308G allele, as well as of its homozygote TNF-308GG could pose susceptibility to developing LS. The presence of the haplotype, TNFe3 d3 -238G -308A c1 a5 b7, suggests protection against developing that syndrome. The present study is the first to associate TNF microsatellite polymorphism with LS, indicating several associations among alleles of the gene region that codes TNF with LS. Although the mechanisms regarding the participation of TNF in the development of LS are not clear, this study suggests that immunogenetic factors associated with the TNF expression magnitude and probably the expression of other proinflammatory cytokines are involved in the development of LS in HIV/aids infected patients.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 111-145).

Introduction: Sclerosing mesenteritis is a rare autoimmune disease that eventually evolves into fibrotic changes affecting the adipose tissue around the mesenteric vessels. It can present through a myriad of gastroenterological as well as constitutional symptoms including but not limited to abdominal pain, diarrhea, fever, nausea or vomiting. Although the exact etiology of the disease is yet to be determined, there are several predisposing factors the most common of which is history of previous abdominal trauma and/or surgery. This is a case report of abdominal mesenteric panniculitis that presented with abdominal pain in a middle-aged male with history of cholecystectomy. Case Presentation: The patient was a 53-year-old male with past medical history of hypertension who presented with a 2-week history of intolerance to food and liquids and abdominal pain, colicky in nature, radiating to both flanks with no alleviating or relieving factors. One year before, the patient had cholecystectomy due to biliary dyskinesia. His hospital stay at that time was complicated by biliary leak treated with biliary stenting. He later also developed multiloculated abscess collection in the gallbladder fossa that was managed with external drainage and IV antibiotics. In the ER his vital signs were as the following: BP between 120-130/70-80, HR 70s, temperature 97, oxygen saturation was more than 95%. On physical examination, he had abdominal tenderness in all four quadrants with no rigidity, rebound tenderness, masses or skin changes. CBC showed WBC of 7K with no shift to the left, hemoglobin of 15.6 and platelets of 107. CMP showed Na of 142, K 4.2, Chl 19, Glu 99, Ca 9.5, AG 18, lactic acid 1, lipase 50, phos 2.7, beta-hydroxybutyrate 0.12 and Mg of 1.9. urine analysis and Troponins were within normal limits. EKG showed sinus rhythm. Urine drug screen was negative. CRP and ESR were within normal limits. Porphyria workup was negative. Alpha-1-antitrypsin was 123. Ceroluplasmin level was 17. Actin antibody was negative as well as mitochondria M2 antibody. CT angiogram of the abdomen showed patent mesenteric vessels. However, fat stranding was noticed especially at the root of the mesenteric vessels. The patient was placed on prednisone 40mg once daily and tamoxifen. His abdominal pain greatly improved after 2 days. He was discharged with a prolonged prednisone taper. He was scheduled for an appointment with his primary care at discharge but didn’t show up and was lost to follow up. Conclusion: Mesenteric panniculitis is a rare cause of abdominal pain. it is divided based on histological features into sclerosing (retractile) mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy. Diagnoses is usually rarely inferred from the clinical presentation and is often suggested by radiological features. Distinctive findings on CT include fat ring sign and pseudotumor capsule. Although radiological characteristics are helpful, histological proof is essential for definitive diagnosis, especially with an atypical clinical and radiological appearance. There is no consensus on the optimal treatment option but prolonged steroid taper has been used with various degrees of success.