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1.
Artigo em Inglês | MEDLINE | ID: mdl-32053090

RESUMO

BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. OBJECTIVE: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. METHODS: We performed a narrative review of the PCSK9 inhibitor class of drugs Results: Current data indicates that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. CONCLUSION: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Post-marketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

2.
S Afr Med J ; 108(11b): 973-1000, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30421699

RESUMO

South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: <3 mmol/L in low- and moderate risk cases; <2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and <1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV-positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group.


Assuntos
Doenças Cardiovasculares , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Programas de Rastreamento/métodos , Administração dos Cuidados ao Paciente , Comportamento de Redução do Risco , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/psicologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Consenso , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/terapia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/normas , Medição de Risco/métodos , Fatores de Risco , África do Sul
3.
Horm Metab Res ; 48(12): 814-821, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27813051

RESUMO

Salivary cortisol has been used to monitor hydrocortisone replacement in patients with Addison's disease (AD). Since salivary cortisol is metabolised to salivary cortisone, it may be an adjunctive analyte to assess adequacy of hydrocortisone replacement in patients with AD. We aimed to characterise the exposure of salivary cortisol and cortisone in patients and healthy controls. We measured salivary cortisol and cortisone by liquid chromatography-tandem mass spectrometry and constructed a day curve (08:00 until 24:00 h) with 16 time points in 25 AD patients taking their usual hydrocortisone dose and in 26 healthy controls. The median (interquartile range) area under the curve (AUC) for cortisol was not different for patients, compared with controls [55.63 (32.91-151.07) nmol*min*l-1 vs. 37.49 (27.41-52.00) nmol*min*l-1; p=0.098, respectively], whereas the peak cortisol Cmax was higher in patients [32.61 (5.75-146.19) nmol/l vs. 8.96 (6.96-12.23) nmol/l; p=0.013], compared with controls. The AUC for cortisone [23.65 (6.10-54.76) nmol*min*l-1 vs. 227.73 (200.10-280.52) nmol*min*l-1; p≤ 0.001, respectively], and peak cortisone Cmax was lower in patients than in controls [11.11 (2.91-35.85) nmol/l vs. 33.12 (25.97-39.95) nmol/l; p=0.002]. The AUC for salivary cortisol and salivary cortisone were not correlated with any measures of hydrocortisone dose. The time-course and AUC of salivary cortisol were similar between Addison's patients and healthy controls. Patients had substantially lower salivary cortisone AUC, compared to healthy controls. Salivary cortisol AUC and pharmacokinetics were not related to hydrocortisone dose and thus are not likely useful markers for the adequacy of hydrocortisone replacement.


Assuntos
Doença de Addison/tratamento farmacológico , Cortisona/metabolismo , Terapia de Reposição Hormonal , Hidrocortisona/metabolismo , Hidrocortisona/uso terapêutico , Saliva/metabolismo , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Cortisona/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
4.
Atherosclerosis ; 240(2): 408-14, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25897792

RESUMO

OBJECTIVE: Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide. METHODS: Existing lipid-lowering therapy, including apheresis, was to remain stable from Week -6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5 mg to 60 mg a day (maximum). The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the impact of apheresis on LDL-C reductions in patients receiving lomitapide. RESULTS: Of the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week 26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (-48%) and not treated (-55%) with apheresis (p = 0.545). Changes in Lp(a) levels were modest and not different between groups (p = 0.436). CONCLUSION: The LDL-C lowering efficacy of lomitapide is unaffected by lipoprotein apheresis.


Assuntos
Anticolesterolemiantes/administração & dosagem , Benzimidazóis/administração & dosagem , Remoção de Componentes Sanguíneos/métodos , LDL-Colesterol/sangue , Homozigoto , Hiperlipoproteinemia Tipo II/terapia , Adulto , Anticolesterolemiantes/efeitos adversos , Benzimidazóis/efeitos adversos , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/efeitos adversos , Terapia Combinada , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Lipoproteína(a)/sangue , Masculino , Fenótipo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
Horm Metab Res ; 46(10): 691-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24799025

RESUMO

Hypogonadism may complicate Addison's disease (primary hypoadrenalism), but prevalence and metabolic sequelae of hypogonadism in Addison's disease are poorly described. We recruited patients from the South African Addison's disease national registry who received stable replacement doses of hydrocortisone and had no acute illness. Male biochemical testosterone deficiency was defined as an early morning basal testosterone<9.9 nmol/l and premature ovarian failure (POF) when menopause occurred before 40 years of age. Cardiometabolic risk variables were measured in males only. Male hypogonadism prevalence was 33% (14/42), and 10 patients had newly diagnosed hypogonadism. Two untreated patients had elevated FSH or LH (>10 or 12 IU/l). Testosterone deficiency did not correlate with age, disease duration or hydrocortisone dose. Untreated male hypogonadal subjects had a higher (mean ± standard deviation) BMI compared to eugonadal subjects 29.2 ± 4.9 kg/m(2) vs. 24.7 ± 3.4 kg/m(2) (p=0.01) and a higher median (interquartile range) high-sensitive-CRP 6.4 (2.5-14.0) mg/l vs. 1.45 (0.6-2.8) mg/l (p=0.002). There were no differences between the 2 groups in lipids, lipoproteins and fasting glucose. The median (interquartile range) DHEAS was lower in the hypogonadal 0.31 (0.27-0.37) µmol/l, compared with the eugonadal group 0.75 (0.50-1.51) µmol/l (p=0.005). POF was documented in 11% of female patients. Male testosterone deficiency was highly prevalent in this cohort and was primarily due to secondary hypogonadism. Only BMI and hs-CRP were increased in untreated male hypogonadal subjects. Male and female hypogonadism appears to be a common complication of Addison's disease and may contribute to its morbidity.


Assuntos
Doença de Addison/complicações , Hipogonadismo/epidemiologia , Hipogonadismo/etiologia , Doença de Addison/sangue , Adulto , Idoso , Proteína C-Reativa/metabolismo , Estudos de Coortes , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hipogonadismo/sangue , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , África do Sul/epidemiologia , Testosterona/sangue
6.
Crit Rev Clin Lab Sci ; 51(1): 46-62, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24405372

RESUMO

Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low-density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia.


Assuntos
Apolipoproteínas E/genética , Hiperlipoproteinemia Tipo III , Humanos , Mutação
7.
Eur J Endocrinol ; 168(3): 403-12, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23239757

RESUMO

BACKGROUND: Uncertainty exists whether glucocorticoid receptor (GCR) polymorphisms play a role in steroid-related side effects in Addison's disease (AD) patients on hydrocortisone. The polymorphisms Bcll and N363S appear to increase sensitivity to cortisol, while the ER22/23EK polymorphism has been associated with resistance to cortisol. METHOD: One hundred and forty seven AD patients, and gender, and ethnicity-matched controls were recruited in South Africa. Three polymorphisms in the GCR were studied, using PCR followed by restriction fragment length analysis. Associations with BMI, lipids, glucose and inflammatory markers were investigated. RESULTS: In both patients and controls, the Bcll polymorphism occurred more frequently in whites than in other ethnic groups studied but was not associated with any of the metabolic parameters tested. The ER22/23EK polymorphism was associated with an increased BMI in both patients (29.4 vs 24.7  kg/m²) and control subjects (26.3 vs 24.2  kg/m²). The ER22/23EK polymorphism was also associated with lower LDL cholesterol in control subjects (3.46 vs 3.93  mmol/l) and in patients (3.52 vs 4.10  mmol/l). N363S was associated with increased BMI in controls 29.9  kg/m² vs wild type 24.8  kg/m². Median hydrocortisone doses were greater in patients heterozygous for either ER22/23EK 30.0  mg or N363S 25.0  mg polymorphisms than in wild type patients 20.0  mg (both comparisons). CONCLUSION: Alterations in lipids, BMI and hydrocortisone dose were associated with two polymorphisms. Further larger studies are warranted to corroborate these findings.


Assuntos
Doença de Addison/genética , Doença de Addison/fisiopatologia , Resistência a Medicamentos , Hiperlipidemias/etiologia , Sobrepeso/complicações , Polimorfismo Genético , Receptores de Glucocorticoides/genética , Doença de Addison/complicações , Doença de Addison/tratamento farmacológico , Adulto , Índice de Massa Corporal , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Estudos de Associação Genética , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/efeitos adversos , Hidrocortisona/uso terapêutico , Hiperlipidemias/epidemiologia , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/metabolismo , Fatores de Risco , África do Sul/epidemiologia
8.
S Afr Med J ; 98(2): 105-8, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18350203

RESUMO

Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia, and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective. We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and Red Cross Children's War Memorial Hospital in Cape Town. Criteria for inclusion were an initial plasma triglyceride concentration of >15 mmol/l and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years, but ranged from 0 to 43 years. The modes of presentation differed: pancreatitis (N=16), eruptive xanthomata (N=2), coincidental detection of hypertriglyceridaemia (N=2), screening relatives (N=7), and after death from pancreatitis (N=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction, and some patients sustained good control of the hyperlipidaemia. The onset of pancreatitis was earlier in patients of Indian ancestry, suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages, and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis.


Assuntos
Hiperlipoproteinemia Tipo I/complicações , Hiperlipoproteinemia Tipo I/epidemiologia , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Grupos de Populações Continentais , Dieta com Restrição de Gorduras , Feminino , Efeito Fundador , Humanos , Hipertrigliceridemia/terapia , Achados Incidentais , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento , Mutação , Pancreatite/epidemiologia , Pancreatite/etiologia , África do Sul/epidemiologia , Xantomatose/epidemiologia , Xantomatose/etiologia
9.
Curr Atheroscler Rep ; 4(1): 19-25, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11772418

RESUMO

Homozygous familial hypercholesterolemia is a rare disorder resulting in severe premature atherosclerosis. Drug therapy was previously viewed as inadequate for control of the dyslipidemia, so portacaval shunting, plasmapheresis, and liver transplantation were undertaken to treat this condition. Despite these drastic measures, additional cholesterol-lowering treatment may still be required. Furthermore, there is a need for pharmacologic control until additional measures can be undertaken. The statins, an evolving class of cholesterol-modifying drugs, represent a significant development in the treatment of homozygous familial hypercholesterolemia. The experience with statins in this condition is limited, but some insight into their utility has been gained from studies reviewed in this article. It is recommended that high doses of statins be used in combination with other lipid-modifying strategies for the best control of the dyslipidemia of homozygous familial hypercholesterolemia.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Ensaios Clínicos como Assunto , Homozigoto , Humanos , Resultado do Tratamento
10.
S Afr Med J ; 92(11): 892-7, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12506591

RESUMO

OBJECTIVES: Dysbetalipoproteinaemia (type III hyperlipidaemia, broad-beta disease) is a highly atherogenic genetic disorder of lipoprotein metabolism. It presents with a severe mixed hyperlipidaemia in which the ratio of total cholesterol to triglycerides is typically 2:1. There is a high incidence of atherosclerotic complications and severe hypertriglyceridaemia may cause pancreatitis. Highly effective therapy is available and affected families also benefit from genetic counselling. We present a review of our experience with dysbetalipoproteinaemia at the lipid clinic of Groote Schuur Hospital to enhance awareness of this serious condition, for which the index of suspicion should be raised. DESIGN: Retrospective review of case records, 1969-2001. SETTING: Lipid clinic of Groote Schuur Hospital, Cape Town. SUBJECTS: Patients with dysbetalipoproteinaemia diagnosed by the presence of cholesterol-enriched very-low-density lipoproteins (VLDL) and/or dyslipidaemia associated with homozygosity for apolipoprotein E2 or carriers of the apoE2 (Arg145-->Cys) mutation. RESULTS: One hundred and five patients were identified, 55 of whom were male and 50 female. The age at presentation was 48.8 +/- 11.1 years (mean, standard deviation). Total cholesterol was 12.0 +/- 5.5 mmol/l and plasma triglycerides 8.3 +/- 9.8 mmol/l. The ratio (by mass) of cholesterol to triglycerides within VLDL was 0.52 +/- 0.17, while VLDL cholesterol to plasma triglycerides was 0.33 +/- 0.09. Fifty patients were epsilon 2 homozygotes while 22 carried the apoE2 (Arg145-->Cys) mutation. Palmar crease xanthomas occurred in 20% of patients, cutaneous xanthomas in 18%, and tendon xanthomas in 13%. Coronary artery disease was found in 47% of patients and peripheral vascular disease in 20%. Fibrates were the most commonly used hypolipidaemic agents (48%), while 31% of patients received combination therapy with a fibrate and statin. Statin monotherapy was used in 11% of patients and a few patients were treated with niacin or required no drug therapy. The treated cholesterol was 5.7 +/- 2.4 mmol/l, with plasma triglycerides of 2.7 +/- 1.9 mmol/l. CONCLUSIONS: Dysbetalipoproteinaemia is a highly atherogenic disorder and is extremely responsive to therapy. A significant proportion of dysbetalipoproteinaemia locally is caused by the apoE2 (Arg145-->Cys) mutation and is therefore dominantly inherited. This mutation is particularly prevalent in the black community where dysbetalipoproteinaemia may be undiagnosed in many patients. Patients with severe mixed hyperlipidaemia or clinical stigmata of dyslipidaemia should be assessed at a lipid clinic for a specific diagnosis and initiation of therapy.


Assuntos
Hiperlipoproteinemia Tipo III/sangue , Hiperlipoproteinemia Tipo III/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E2 , Apolipoproteínas E/genética , Criança , VLDL-Colesterol/sangue , VLDL-Colesterol/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo III/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Ned Tijdschr Geneeskd ; 145(17): 834-9, 2001 Apr 28.
Artigo em Holandês | MEDLINE | ID: mdl-11370431

RESUMO

In two young patients with an elevated temperature, a girl aged 6 months and a boy aged 10 months, purpura and oedema were noticed on the face, ears, arms and legs. On one occasion the boy lost blood anally. A histopathological examination revealed leucocytoclastic vasculitis with fibrin deposits. The diagnosis was 'acute haemorrhagic oedema of infancy' (AHOI), a relatively unknown variant of palpable purpura due to leucocytoclastic vasculitis affecting infants and young children (up to two years of age). AHOI is characterised clinically by marked oedema and fever as well as large palpable purpuric and ecchymotic skin lesions in a target-like pattern mainly on the face, ears and extremities. The skin lesions heal spontaneously within one to three weeks and internal organs are rarely affected. This is in contrast to Henoch-Schönlein purpura, which was observed in a 5-year old boy suffering from similar skin lesions on the legs as well as painful joints, in whom IgA deposits were found in the vasculitis. Henoch-Schönlein purpura is clinically characterised by palpable purpura on the extensor surfaces of the legs and on the buttocks, whereas in AHOI larger purpura and ecchymoses are found on the face, ankles and wrists, with far more extensive oedema. There are also histological differences: in AHOI there is more extensive vasculitis with fibrin deposits and IgA deposits are seen in a minority of cases. Awareness of this relatively unknown form of leucocytoclastic vasculitis will assist in making an early diagnosis possible, thereby avoiding unnecessary treatment and concern.


Assuntos
Púrpura de Schoenlein-Henoch/diagnóstico , Pele/patologia , Vasculite Leucocitoclástica Cutânea/diagnóstico , Doença Aguda , Pré-Escolar , Diagnóstico Diferencial , Equimose/etiologia , Edema/etiologia , Feminino , Febre/etiologia , Fibrina/análise , Humanos , Imunoglobulina A/análise , Lactente , Masculino , Púrpura/etiologia , Síndrome , Vasculite Leucocitoclástica Cutânea/complicações , Vasculite Leucocitoclástica Cutânea/patologia
12.
Melanoma Res ; 9(3): 297-302, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10465586

RESUMO

Transpupillary thermotherapy (TTT) is a new treatment modality for uveal melanoma. We studied whether application of TTT influences the immunogenicity of the tumour cells in vivo or the expression of molecules related to apoptosis. Immunohistochemistry using monoclonal antibodies directed against HLA molecules, HMB45, P53, Fas ligand (FasL), Fas, Bcl-2 and tumour-infiltrating cells was applied to sections of an enucleated eye containing a uveal melanoma that received TTT 1 week before enucleation. The innermost part of the tumour which had been exposed directly to the laser treatment showed no staining for HLA antigens, nor for Fas or FasL epitopes. The intermediate part of the tumour showed a wet necrosis and HLA expression similar to the expression in the peripheral tumour. A large number of macrophages were observed in the necrotic as well as the intact tumour tissue, especially bordering the wet necrotic area. FasL and Bcl-2 were only expressed in the viable, outer part of the tumour. This immunological evaluation of one case of uveal melanoma treated with TTT revealed that TTT may not only have a direct destructive effect on the primary tumour, but may also influence the immunogenicity of uveal melanoma cells, induce infiltration of macrophages into the tumour, and induce apoptosis. The presence of many macrophages suggests that they play a role in the removal of the TTT-treated tumour tissue by phagocytosis.


Assuntos
Apoptose , Neoplasias da Coroide/imunologia , Neoplasias da Coroide/terapia , Hipertermia Induzida , Melanoma/imunologia , Melanoma/terapia , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Neoplasias da Coroide/patologia , Proteína Ligante Fas , Feminino , Antígeno HLA-A2/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imuno-Histoquímica , Células Matadoras Naturais/metabolismo , Melanoma/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor fas/metabolismo
13.
J Interferon Cytokine Res ; 17(11): 695-700, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9402107

RESUMO

Tumor cells are protected from antibody-dependent complement-mediated lysis by membrane-bound regulators of complement activation (m-RCA). m-RCA are expressed on uveal melanoma cells. We determined whether cytokine treatment affects expression of m-RCA on these cells in vitro. m-RCA expression on uveal melanoma cell lines was studied by flow cytometry, using monoclonal antibodies directed against CD46, CD55, and CD59. Cytokines studied were interferon-alpha (IFN-alpha), IFN-gamma, interleukin-1B (IL-1B), IL-12, and tumor necrosis factor-alpha (TNF-alpha). All three m-RCA were expressed on the uveal melanoma cell lines (CD59>>CD46>CD55), although in variable amounts. With a few exceptions, the cytokines had no effect on m-RCA expression. CD55 expression was not influenced by any of the cytokines. IFN-gamma downregulated expression of CD46 on one cell line (p < 0.01). TNF-alpha upregulated CD59 expression on two of the five cell lines (p < 0.012 and p < 0.001, respectively), which effect was dose dependent. IFN-alpha, IFN-gamma, IL1-beta, IL12, and TNF-alpha had limited effects on m-RCA expression on uveal melanoma cells in vitro.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Citocinas/uso terapêutico , Melanoma/tratamento farmacológico , Proteínas de Membrana/metabolismo , Neoplasias Uveais/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interferons/uso terapêutico , Interleucinas/uso terapêutico , Melanoma/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/uso terapêutico , Neoplasias Uveais/metabolismo
14.
Invest Ophthalmol Vis Sci ; 38(12): 2523-30, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9375571

RESUMO

PURPOSE: Metastatic uveal melanoma is strongly resistant to chemotherapy, and multidrug resistance (MDR) may be involved. To investigate the role of MDR, the presence of the MDR-associated proteins P-glycoprotein (Pgp), MRP, and lung resistance protein (LRP) was determined on primary choroidal melanomas and cell lines. METHODS: A panel of primary choroidal melanomas was examined for the presence of MDR-associated proteins by immunohistochemical analysis. In cell lines established from four primary choroidal melanomas and one metastatic choroidal melanoma, the expression of MDR-associated proteins was determined with monoclonal antibodies in cytospin preparations and flow cytometry. In addition, the functional capacities of transporter proteins Pgp and MRP as adenosine triphosphate-driven efflux pumps were determined by measuring the cellular accumulation and efflux of the fluorescent dyes rhodamine 123 and calcein-AM, with and without the presence of specific pump inhibitors PSC833 and probenecid. RESULTS: Low levels of Pgp and MRP were detected in most primary tumors and in some cell lines. Measurable transporter function of Pgp could be determined in cell line OCM-1. Lung-resistance protein was present in all primary tumors and cell lines and showed high expression levels. CONCLUSIONS: This study revealed the involvement of LRP and at least a minor role of Pgp and MRP in chemoresistance of choroidal melanoma. Compared with cutaneous melanomas, uveal melanomas appear to express slightly higher levels of Pgp. These findings provide insights into the drug-resistant phenotype of this disease and can aid in the design of therapeutic protocols.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Coroide/metabolismo , Resistência a Múltiplos Medicamentos , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Partículas de Ribonucleoproteínas em Forma de Abóbada , Anticorpos Monoclonais , Antineoplásicos/farmacologia , Neoplasias da Coroide/tratamento farmacológico , Neoplasias da Coroide/patologia , Citometria de Fluxo , Fluoresceínas/metabolismo , Corantes Fluorescentes/metabolismo , Humanos , Técnicas Imunoenzimáticas , Melanoma/tratamento farmacológico , Melanoma/patologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Rodamina 123 , Rodaminas/metabolismo , Células Tumorais Cultivadas
15.
Invest Ophthalmol Vis Sci ; 38(9): 1865-72, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9286277

RESUMO

PURPOSE: Because the expression of human leukocyte antigen (HLA) antigens is important for immunologic recognition of tumor cells, we determined expression of locus-specific HLA class I antigens in uveal melanoma and tested whether the level of HLA expression was related to prognosis or associated with known prognostic parameters. METHODS: Expression of HLA-A and -B antigens was determined on 30 formalin-fixed and paraffin-embedded sections of uveal melanoma by immunohistochemistry with locus-specific monoclonal antibodies and scored semiquantitatively. RESULTS: The level of expression of HLA-A and -B varied between uveal melanomas. Expression levels of HLA-A and -B were significantly correlated (P = 0.02). High HLA-B expression was significantly correlated with the presence of epithelioid cells (P = 0.04) in the tumor. Expression levels of HLA-A as well as of HLA-B, cell type, mitotic rate, Mib-1 score, and largest tumor diameter were significant predictive factors for survival. High expression of HLA-A and -B was associated with a decreased survival. Multiple Cox regression analysis with stepwise selection of covariates showed that the contribution of HLA-A expression to survival (P = 0.0003) exceeded that of tumor diameter (P = 0.02) and Mib-1 score (P = 0.04). CONCLUSIONS: Lack of expression of HLA-A as well as of HLA-B antigens on uveal melanoma is correlated with a better patient survival. Our data suggest that shedding of uveal melanoma micrometastases with a low expression of HLA class I into the systemic circulation may facilitate their removal and prevent the development of metastases. These findings support a protective role for natural killer cells in the development of metastatic disease in uveal melanoma.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígenos HLA-A/metabolismo , Antígenos HLA-B/metabolismo , Melanoma/metabolismo , Neoplasias Uveais/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia
16.
Melanoma Res ; 7(2): 103-9, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9167175

RESUMO

Hyperthermia is used as a new treatment modality for ocular melanoma. We wondered whether this treatment would affect the antigenicity of melanoma cells and studied the effect of hyperthermia on the expression of histocompatibility antigens (HLA), beta 2-microglobulin, as well as heat-shock proteins (HSP-60 and HSP-70) on choroidal melanoma cells. Uveal melanoma cell lines were exposed to different temperatures (39-45 degrees C) in a waterbath. Antigen expression was determined with fluorescence-activated cell sorting analysis, using monoclonal antibodies against HLA and HSP. In a 51Cr-release cytotoxicity assay we studied the effect of heat on natural killer (NK) cell susceptibility. Exposure to 45 degrees C for 30 min reduced expression of HLA class I antigens and beta 2-microglobulin. A greater reduction was observed after longer exposure times. Expression of HSP-70 was increased after exposure to 45 degrees C at all time intervals, while expression of HSP-60 was not induced by heat treatment. We did not find a significant difference in the NK cell susceptibility between heated and unheated cells. Hyperthermia has a time- and temperature-dependent effect on expression of HLA class I and HSP-70 molecules on the cell surface of uveal melanoma cells. Hyperthermia did not alter the susceptibility to NK cell lysis.


Assuntos
Chaperonina 60/biossíntese , Neoplasias Oculares/metabolismo , Proteínas de Choque Térmico HSP70/biossíntese , Antígenos de Histocompatibilidade Classe I/biossíntese , Células Matadoras Naturais/imunologia , Melanoma/metabolismo , Células Cultivadas , Neoplasias da Coroide/imunologia , Neoplasias da Coroide/metabolismo , Citotoxicidade Imunológica , Neoplasias Oculares/imunologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Temperatura Alta , Humanos , Hipertermia Induzida , Melanoma/imunologia , Fatores de Tempo , Células Tumorais Cultivadas , Neoplasias Uveais/imunologia , Neoplasias Uveais/metabolismo , Microglobulina beta-2/biossíntese
17.
Cancer Lett ; 112(2): 239-43, 1997 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-9066734

RESUMO

Our objective was to investigate whether photodynamic therapy (PDT) influences the expression of HLA Class I and beta 2-microglobulin molecules on cultured uveal melanoma cells. Uveal melanoma cells were incubated with hematoporphyrin esters (HPE) and illuminated using red light. HLA expression on cells was determined by flowcytometry. PDT treatment induced an immediate reduction in expression of HLA Class I and beta 2-microglobulin, followed by a transient increase in expression after 2 h. Normalization occurred after 6 h. Treatment of ocular melanoma cells with PDT temporally alters the expression of HLA Class I and beta 2-microglobulin, which may affect anti-tumor-immune responses.


Assuntos
Antígenos de Neoplasias/biossíntese , Antígenos de Histocompatibilidade Classe I/biossíntese , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Fotoquimioterapia , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/metabolismo , Citometria de Fluxo , Hematoporfirinas/farmacologia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Células Tumorais Cultivadas , Microglobulina beta-2/biossíntese
18.
J Pathol ; 181(1): 75-9, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9072006

RESUMO

HLA class I is expressed in 75-85 per cent of uveal melanoma and cytoplasmic c-myc expression has been reported in 78 per cent of uveal melanoma. In skin melanoma, an inverse relationship has been observed between HLA class I expression and c-myc. The purpose of this study was to determine whether a similar correlation occurred between high expression of c-myc and low expression of HLA class I in uveal melanoma. The expression of c-myc, HLA-A, and HLA-B was determined by immunohistochemistry on formalin-fixed and paraffin-embedded sections of 30 uveal melanomas. Cell cultures from four primary uveal melanomas (lines 92-1, MEL 202, OCM-1, and EOM-3) and one uveal melanoma metastasis (line OMM-1) were tested for mRNA levels of c-myc and HLA-A and HLA-B in Northern blot assays. The high level of expression of cytoplasmic c-myc was significantly correlated with low expression of HLA-B (P = 0.03) and vice versa. High expression of HLA-B was significantly correlated with the presence of epithelioid cells (P = 0.004). The inverse correlation observed between c-myc and HLA-B expression is similar to previous observations in cutaneous melanoma. By downregulating HLA-B expression, c-myc may influence the immune response in uveal melanoma. Tumours containing epithelioid cells showed a significantly higher expression of HLA-B than tumours of the spindle cell type.


Assuntos
Antígenos HLA-B/metabolismo , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Uveais/metabolismo , Adolescente , Adulto , Idoso , Northern Blotting , Regulação para Baixo , Feminino , Antígenos HLA-A/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Células Tumorais Cultivadas
19.
Br J Ophthalmol ; 81(11): 989-93, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9505825

RESUMO

BACKGROUND: The level of HLA expression on a tumour may influence the immunological response against this tumour, and vice versa. HLA expression was determined in a primary uveal melanoma, its metastases, and on a cell line derived from this melanoma, and the presence and type of infiltrate in tissue sections were also studied. METHODS: Immunohistochemistry with monoclonal antibodies (MAbs) against HLA class I and II, T cells, NK cells, and macrophages. RESULTS: Primary and metastatic lesions, as well as the cell line showed high levels of expression of the monomorphic determinants of HLA class I. Expression of the polymorphic HLA-A2 and HLA-A3 antigens was decreased on metastases to the skin and liver. HLA-Bw4 expression was low on all lesions, as well as expression of HLA class II. Tumour infiltrating cells consisted mainly of CD3, CD4, and CD8 positive cells. Expression on the cell line corresponded to expression on the primary tumour. CONCLUSION: The primary uveal melanoma as well as the cell line showed a high expression of monomorphic and polymorphic HLA-A antigens, while metastases showed a high expression of monomorphic and a lower expression of polymorphic antigens. This variation in expression may support tumour cell escape from NK cells as well as CTL mediated lysis.


Assuntos
Antígenos de Neoplasias/análise , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe I/análise , Melanoma/imunologia , Neoplasias Uveais/imunologia , Idoso , Antígenos de Neoplasias/genética , Feminino , Expressão Gênica , Neoplasias Cardíacas/imunologia , Neoplasias Cardíacas/patologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Melanoma/secundário , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas , Neoplasias Uveais/patologia
20.
Invest Ophthalmol Vis Sci ; 37(9): 1884-91, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8759358

RESUMO

PURPOSE: To identify the presence of membrane-bound regulators of complement activation (m-RCA) on uveal melanomas and uveal melanoma cell lines and to examine their role in the inhibition of complement-mediated lysis in vitro. METHODS: Immunohistochemistry and flow cytometric analysis with monoclonal antibodies directed against m-RCA CD46, CD55, and CD59 were applied to tissue sections of 10 uveal melanomas, three primary uveal melanoma cell lines, and one uveal melanoma metastatic cell line. A microcytotoxicity test was used for measuring antibody-dependent complement-mediated lysis. RESULTS: The tissue sections and all four uveal melanoma cell lines expressed CD46, CD55, and CD59. Complement-mediated lysis in the presence of human complement was increased after partial removal of the m-RCA CD55 and CD59 with phosphatidylinositol-specific phospholipase C from the uveal melanoma cell line 92-1. CONCLUSIONS: These results demonstrate that CD46, CD55, and CD59 are expressed in uveal melanomas and that CD55 or CD59, or both, plays a role in resistance to complement-mediated cytotoxicity. The finding that m-RCA are expressed in uveal melanomas may have implications for the effectiveness of the anti-tumor response and in the therapeutic application of monoclonal antibodies directed against tumor-associated antigens.


Assuntos
Antígenos CD/análise , Antígenos CD55/análise , Antígenos CD59/análise , Ativação do Complemento , Proteínas Inativadoras do Complemento/análise , Melanoma/imunologia , Glicoproteínas de Membrana/análise , Neoplasias Uveais/imunologia , Idoso , Anticorpos Monoclonais , Citotoxicidade Celular Dependente de Anticorpos , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/patologia , Neoplasias da Coroide/imunologia , Neoplasias da Coroide/patologia , Feminino , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/análise , Humanos , Imuno-Histoquímica , Linfócitos/imunologia , Masculino , Melanoma/patologia , Proteína Cofatora de Membrana , Pessoa de Meia-Idade , Neoplasias Uveais/patologia
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