RESUMO
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system driven by autoreactive lymphocytes. Due to its close contact with the gut-associated lymphoid tissue, the intestinal microbiota and/or their metabolites may be one of the factors that influence the activation of autoreactive lymphocytes. This article summarizes and discusses the current research efforts to characterize the microbiome of MS patients using human material. In addition, we present research studies that utilized classical or humanized animal models to determine the influence of certain microbiota species or compositions of microbiota on the immune system and disease progression and to define possible causal associations.
Assuntos
Encefalomielite Autoimune Experimental , Microbioma Gastrointestinal , Microbiota , Esclerose Múltipla , Animais , Sistema Nervoso Central , HumanosRESUMO
This study consisted of two experiments with the following objectives: to evaluate the effects of tannins from the tropical legume macrotiloma (Macrotyloma axillare) on total gas and methane (CH4 ) production, as well as on ruminal fermentation parameters by performing an in vitro bioassay, with samples incubated with and without polyethylene glycol (PEG) in a semi-automatic system; and secondly in a 17 day in vivo experiment, to determine apparent total tract digestibility (ATTD) of dietary nutrients and ruminal fermentation parameters of 12 intact 8- to 9-month-old Santa Inês (averaging 24.95 ± 1.8 kg body weight) ewes fed tropical grass hay supplemented with macrotiloma hay. The ewes were divided into two treatment groups depending on their diet: chopped aruana grass hay (Panicum maximum cv. Aruana) (control-CON); and aruana grass hay supplemented with chopped macrotiloma hay (macrotiloma-MAC). The animals were kept for 5 consecutive days in metabolic cages for the ATTD assay, and at the end of this period, samples of rumen fluid were collected from each ewe to determine ammoniacal nitrogen (NH3 -N) and short-chain fatty acid (SCFA) production, and protozoa count. For the in vitro assay, a decrease in total gas and CH4 production was observed for samples incubated without PEG (p < .05). No differences were observed for the other parameters evaluated (p > .05). In the in vivo experiment, increased intake and ATTD of crude protein were observed for the animals fed MAC when compared to CON (p < .05). For rumen fermentation parameters, increased NH3 -N, total SCFA and isobutyrate concentrations, as well as reduced protozoa count were observed for MAC when compared to CON (p < .05). The results observed here indicated the potential of macrotiloma for use as a ruminant feed, and antimethanogenic potential of this plant was noted.
Assuntos
Ração Animal/análise , Dieta/veterinária , Fabaceae , Ovinos/fisiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Feminino , Valor NutritivoRESUMO
BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.
Assuntos
Apolipoproteínas E/genética , Encefalomielite Autoimune Experimental/genética , Esclerose Múltipla/genética , Animais , Apolipoproteínas E/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Imunofluorescência , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Fatores SexuaisRESUMO
BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. OBJECTIVE: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. METHODS: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R RESULTS: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q (n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS (p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. CONCLUSION: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.
Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Avaliação da Deficiência , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Alemanha , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/imunologia , Fenótipo , Estudos Prospectivos , Pirina , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: We used meta-analysis to test hypotheses concerning whether adult celiac disease is reliably linked with anxiety and/or depression. METHOD: We examined published reports on anxiety and depression in adult celiac disease. RESULTS: Eighteen studies on depression and eleven studies on anxiety in adult celiac disease met selection criteria. They show that depression is reliably more common and/or more severe in adults with celiac disease than in healthy adults (overall meta-analysis effect size: 0.97). The fail-safe margin of unpublished reports that would be required to negate the finding exceeds 8000. Adults with celiac disease do not, however, differ reliably in terms of depression from adults with other physical illnesses, nor do they differ reliably from healthy adults or adults with other physical illnesses in terms of anxiety. CONCLUSION: Depression is common in adult celiac disease and resembles the condition in other physical illnesses. We view the findings as support for the notion that non-specific mechanisms mediate emotional disorders in adult celiac disease.
Assuntos
Ansiedade/complicações , Doença Celíaca/complicações , Depressão/complicações , Adulto , Doença Crônica/psicologia , HumanosRESUMO
As most COVID-19 patients only receive thoracic CT scans, but body composition, which is relevant to detect sarcopenia, is determined in abdominal scans, this study aimed to investigate the relationship between thoracic and abdominal CT body composition parameters in a cohort of COVID-19 patients. This retrospective study included n = 46 SARS-CoV-2-positive patients who received CT scans of the thorax and abdomen due to severe disease progression. The subcutaneous fat area (SF), the skeletal muscle area (SMA), and the muscle radiodensity attenuation (MRA) were measured at the level of the twelfth thoracic (T12) and the third lumbar (L3) vertebra. Necessity of invasive mechanical ventilation (IMV), length of stay, or time to death (TTD) were noted. For statistics correlation, multivariable linear, logistic, and Cox regression analyses were employed. Correlation was excellent for the SF (r = 0.96) between T12 and L3, and good for the respective SMA (r = 0.80) and MRA (r = 0.82) values. With adjustment (adj.) for sex, age, and body-mass-index the variability of SF (adj. r2 = 0.93; adj. mean difference = 1.24 [95% confidence interval (95% CI) 1.02-1.45]), of the SMA (adj. r2 = 0.76; 2.59 [95% CI 1.92-3.26]), and of the MRA (adj. r2 = 0.67; 0.67 [95% CI 0.45-0.88]) at L3 was well explained by the respective values at T12. There was no relevant influence of the SF, MRA, or SMA on the clinical outcome. If only thoracic CT scans are available, CT body composition values at T12 can be used to predict abdominal fat and muscle parameters, by which sarcopenia and obesity can be assessed.
Assuntos
COVID-19 , Sarcopenia , Abdome , Composição Corporal , COVID-19/diagnóstico , COVID-19/diagnóstico por imagem , Humanos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Estudos Retrospectivos , SARS-CoV-2 , Sarcopenia/diagnóstico por imagem , Sarcopenia/patologia , Tomografia Computadorizada por Raios XRESUMO
We report a 55-year-old male patient with secondary progressive multiple sclerosis who developed an acute febrile syndrome with fever, neutrophilia and tender erythematous plaques and papules on his upper extremities after his fifth mitoxantrone infusion. Infectious, haematological and rheumatological diseases were ruled out, but skin biopsy showed neutrophilic infiltrations in the dermis consistent with Sweet's syndrome. Treatment with oral corticosteroids led to prompt improvement of systemic and cutaneous symptoms. To our knowledge, this is the first report of a patient with Sweet's syndrome after mitoxantrone therapy. Clinicians should be aware of Sweet's syndrome in patients with otherwise unexplained acute febrile illness and erythematous skin rash in association with mitoxantrone therapy. Skin biopsy helped to exclude other diseases and confirmed Sweet's syndrome.
Assuntos
Mitoxantrona/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Síndrome de Sweet/induzido quimicamente , Glucocorticoides/uso terapêutico , Humanos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Síndrome de Sweet/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Carriers of the epsilon4 allele of the apolipoprotein E gene are at a higher risk of coronary heart disease than individuals with other genotypes. We examined whether the risk of death or a major coronary event in survivors of myocardial infarction depended on apolipoprotein E genotype and whether the benefits of treatment with simvastatin differed between genotypes. METHODS AND RESULTS: Cox proportional hazards models were used to analyze 5.5 years of follow-up data from 966 Danish and Finnish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study. A total of 16% of the 166 epsilon4 carriers in the placebo group died compared with 9% of the 312 patients without the allele, which corresponds to a mortality risk ratio of 1.8 (95% confidence interval, 1.1 to 3.1). The risk ratio was unaffected by considerations of sex, age, concurrent angina, diabetes, smoking, and serum lipids in multivariate analyses. Simvastatin treatment reduced the mortality risk to 0.33 (95% confidence interval, 0.16 to 0.69) in epsilon4 carriers and to 0.66 (95% confidence interval, 0. 35 to 1.24) in other patients (P=0.23 for treatment by genotype interaction). Apolipoprotein E genotype did not predict the risk of a major coronary event. Baseline serum levels of lipoprotein(a) also predicted mortality risk and could be combined with epsilon4-carrier status to define 3 groups of patients with different prognoses and benefits from treatment. CONCLUSIONS: Myocardial infarction survivors with the epsilon4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin.
Assuntos
Apolipoproteínas E/genética , Hipolipemiantes/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Sinvastatina/uso terapêutico , Adulto , Idoso , Alelos , Apolipoproteína E4 , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P = 0.05). Lp(a) was highest in the apoE genotypes epsilon 2 epsilon 3 and epsilon 3 epsilon 3 and lowest in genotype epsilon 3 epsilon 4, and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P = 0.04) in apoE genotype epsilon 2 epsilon 3 than in genotype epsilon 3 epsilon 3. Lp(a) concentrations did not differ among the XbaI (P = 0.65) or SP 24/27 (P = 0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P < 0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors.
Assuntos
Apolipoproteínas A/química , Apolipoproteínas E/genética , Doença das Coronárias/epidemiologia , Lipoproteína(a)/metabolismo , Polimorfismo Genético/genética , Apolipoproteínas A/genética , Peso Corporal , Colesterol/sangue , Colesterol/metabolismo , Doença das Coronárias/fisiopatologia , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Peso Molecular , Fenótipo , Ativadores de Plasminogênio/metabolismo , Polimorfismo de Fragmento de Restrição , Análise de Regressão , Fatores de Risco , Triglicerídeos/sangue , Triglicerídeos/metabolismo , População BrancaRESUMO
Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apoB) is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated. High plasma levels of Lp(a) are associated with atherosclerotic diseases. It is therefore of interest to study whether factors other than the apo(a) gene locus are involved in the regulation of Lp(a) concentrations. We measured plasma concentrations of Lp(a) and other lipoproteins and determined apo(a) phenotypes in 31 patients with hyperthyroidism, before and after the patients had become euthyroid by treatment. The mean concentration of LDL cholesterol rose from 2.67 to 3.88 mmol/l (P < 0.01), apoB rose from 0.79 to 1.03 g/l (P < 0.01), and the median Lp(a) concentration increased from 9.74 to 18.97 mg/dl (P < 0.01) on treatment. Lp(a) concentrations were inversely associated to the size of the apo(a) molecule both before (P < 0.01) and after treatment (P < 0.01). The increase in Lp(a) was significant in patients with high molecular weight apo(a) phenotypes (n = 9; P < 0.01) and in patients with low molecular weight apo(a) phenotypes (n = 16; P < 0.01), but not in those with apo(a) "null types" (n = 6; P = 0.5). The low levels LDL cholesterol and apoB in untreated hyperthyroidism may result from increased LDL receptor activity. The increase in Lp(a) levels were not correlated with the increase in LDL cholesterol or apoB.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Apolipoproteínas/genética , Hipertireoidismo/genética , Lipoproteína(a)/sangue , Apolipoproteínas/sangue , Apolipoproteínas B/sangue , Apoproteína(a) , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Tireotropina/sangue , Tiroxina/sangue , Triglicerídeos/sangue , Tri-Iodotironina/sangueRESUMO
OBJECTIVE: To examine glucose metabolism, blood pressure, physical fitness, and lipid metabolism in adult untreated women with Turner's syndrome compared with a group of normal women and to examine the effects of female sex hormone substitution on these factors. RESEARCH DESIGN AND METHODS: A total of 26 patients with Turner's syndrome were examined before and during sex hormone replacement with 17 beta-estradiol and norethisterone, and an age-matched control group (n = 24) was examined once. A frequently sampled intravenous glucose tolerance test was applied with minimal model assessment. We also performed an oral glucose tolerance test, measurement of 24-h ambulatory blood pressure, and assessment of physical fitness and lipid metabolism. RESULTS: Insulin sensitivity (SI) and glucose effectiveness (SG) were similar in Turner's syndrome patients and control subjects, whereas the acute insulin response (P = 0.03) was lower in Turner's syndrome patients, and no change was seen during sex hormone treatment. Abnormal glucose tolerance was found in 50% of Turner's syndrome patients before and 78% during treatment with sex hormones. Fat-free mass (FFM; P = 0.0005) and physical fitness (P = 0.002) were lower in Turner's syndrome subjects compared with control subjects. During treatment, an increase in FFM (P = 0.001) and physical fitness (P = 0.02) was seen in Turner's syndrome patients. Blood pressure was increased in Turner's syndrome, and a decrease was seen in diastolic blood pressure during treatment with sex hormones. CONCLUSIONS: Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.
Assuntos
Glucose/farmacocinética , Lipídeos/sangue , Síndrome de Turner/sangue , Administração Oral , Adulto , Área Sob a Curva , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Monitorização Ambulatorial da Pressão Arterial , Composição Corporal/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Injeções Intravenosas , Insulina/sangue , Resistência à Insulina , Metabolismo dos Lipídeos , Modelos Biológicos , Consumo de Oxigênio/efeitos dos fármacos , Fatores de Risco , Síndrome de Turner/complicações , Síndrome de Turner/tratamento farmacológicoRESUMO
We studied 479 perimenopausal Danish women aged 45-58 years to examine differences between APOE genotypes with respect to (1) baseline total body bone mineral density (BMD) and densities measured in five different regions (ultradistal forearm, proximal forearm, lumbar spine, femoral neck, and total hip region); (2) serum levels of alkaline phosphatase, bone isoenzyme alkaline phosphatase, osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D, and urine hydroxyproline/creatinine excretion ratio; and (3) changes in bone mineral during 5 years of follow-up. Baseline BMDs were identical, whereas serum levels of alkaline phosphatase and its bone isoenzyme were higher in women with APOE 2-2 and APOE 2-3 than in women with APOE 3-3 and APOE 3-4 and lower in women with APOE 4-4. Among women not receiving hormonal-replacement therapy (HRT; n = 262), those with APOE 2-2 and APOE 2-3 had 30-40% lower rates of femoral neck and total hip bone mineral loss than women with APOE 3-3 and APOE 3-4, whereas the rates of mineral loss in other skeletal regions did not differ between these APOE genotypes. Women with APOE 4-4 appeared to have lower rates of bone mineral loss in all regions. Women treated with hormones throughout the follow-up period (n = 113) gained bone mineral, and women with APOE 3-4 and APOE 4-4 gained relatively more mineral than other women. A comparison of untreated and treated women with APOE 2-3, APOE 3-3, and APOE 3-4 suggests a possible modification of the effect of APOE genotype by HRT. In conclusion, the common APOE polymorphism has a complex effect on bone metabolism in perimenopausal Danish women including possible modification by hormone use: (1) among women not receiving HRT, those with APOE*2 have lower bone mineral losses in the femoral neck and hip region than other women, and (2) among women receiving HRT, those with APOE*4 gain more bone mineral than other women.
Assuntos
Apolipoproteínas E/fisiologia , Osso e Ossos/metabolismo , Climatério/sangue , Vitamina D/análogos & derivados , Fosfatase Alcalina/sangue , Apolipoproteína E2 , Apolipoproteína E3 , Apolipoproteína E4 , Biomarcadores/sangue , Densidade Óssea , Climatério/metabolismo , Dinamarca , Feminino , Seguimentos , Genótipo , Terapia de Reposição Hormonal , Humanos , Hidroxiprolina/urina , Pessoa de Meia-Idade , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Monoéster Fosfórico Hidrolases/sangue , Vitamina D/sangueRESUMO
The aim of the present study was to search for genetic determinants of combined hyperlipidemia and hypertriglyceridemia, and to evaluate whether such determinants might be associated with predisposition to atherosclerosis. Four DNA polymorphisms in the apo AI-CIII-AIV gene cluster (G to A mutation at position -75 basepairs in the apo AI promoter, XmnI, PstI and SstI) were studied in relation to combined hyperlipidemia, hypertriglyceridemia, lipoprotein levels, atherosclerosis and age in 221 Danish men. The frequency of the rare allele of the XmnI polymorphism, the X+ allele, was higher in individuals below 55 years of age with combined hyperlipidemia than in individuals with normal lipid levels (0.31 vs. 0.14; P = 0.05). The rare allele of the SstI polymorphism, the S+ allele, was more frequent in hypertriglyceridemic individuals compared with normotriglyceridemic individuals (0.16 vs. 0.09; P < 0.05) and on analysis of variance the combined S-S+ and S+S+ genotypes were also associated with the highest triglyceride levels. Furthermore, the frequency of the S+ allele decreased significantly as a function of age in nonatherosclerotic subjects (from 0.15 to 0.10 to 0.02 in 48-, 63- and 85-year-olds, respectively; 48- versus 85-year-olds, P = 0.03). These results suggest that genetic variation in the apo AI-CIII-AIV gene complex is associated with combined hyperlipidemia and hypertriglyceridemia and may have an impact on longevity and/or predisposition to atherosclerosis.
Assuntos
Apolipoproteína A-I/genética , Apolipoproteínas A/genética , Apolipoproteínas C/genética , Arteriosclerose/genética , Hiperlipidemia Familiar Combinada/genética , Hipertrigliceridemia/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteína C-III , Doença das Coronárias/genética , Suscetibilidade a Doenças , Feminino , Marcadores Genéticos , Humanos , Lipídeos/sangue , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Família Multigênica , Infarto do Miocárdio/genética , Polimorfismo Genético , Polimorfismo de Fragmento de RestriçãoRESUMO
Three DNA polymorphisms (XbaI, EcoRI, MspI) in the 3'-end of the apolipoprotein B gene were studied in relation to atherosclerosis, lipoprotein levels and age in three groups of atherosclerotic individuals and in nonatherosclerotic controls. The atherosclerotic groups comprised a postmyocardial infarction group with a mean age of 48 years, a group of individuals operated on for carotid stenosis with a mean age of 62 years, and a group of 85-year-olds with clinical coronary artery disease, peripheral arterial disease, or both. All 311 individuals were unrelated Caucasians of Danish ancestry. For the XbaI polymorphism, the X- allele was an independent predictor for myocardial infarction on multivariate analysis, but did not distinguish between patients and controls on univariate analysis. Additionally, this polymorphism was associated with variation in lipoprotein levels, but there was no clear evidence of a gene dosage effect. For the EcoRI polymorphism, the E- allele was associated with elevated levels of VLDL cholesterol, plasma triglycerides and VLDL triglycerides. Similar, but weaker associations were found for the MspI polymorphism. There were no significant differences in allele frequencies as a function of age for any of the DNA polymorphisms. In conclusion, while variation associated with the EcoRI polymorphism appears to be involved in the regulation of VLDL metabolism, variation associated with the XbaI polymorphism may determine susceptibility to coronary artery disease independent of other conventional risk factors, but it also appears to affect variation in lipoprotein levels.
Assuntos
Apolipoproteínas B/genética , Lipoproteínas/sangue , Infarto do Miocárdio/genética , Adulto , Idoso , Alelos , Arteriosclerose/sangue , Arteriosclerose/genética , Estenose das Carótidas/sangue , Estenose das Carótidas/genética , DNA/genética , Dinamarca , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Polimorfismo de Fragmento de Restrição , Fatores de RiscoRESUMO
The objective of the present study was to examine the possible associations between low molecular weight (LMW) apolipoprotein(a) (apo(a)) isoforms (F,B,S1,S2) and coronary heart disease (CHD). We conducted a nested case-control (prospective) study of five cohorts of white men: The 1936 cohort (baseline 1976, n = 548) and four cohorts from MONICA I born in 1923 (n = 463), 1933 (n = 491), 1943 (n = 504) and 1953 (n = 448) studied at baseline in 1983. At follow up in 1991, 52 subjects had developed a first myocardial infarction and 22 had been hospitalized with angina pectoris. Plasma samples obtained at baseline were stored frozen until 1993-94, when case samples (n = 74) were analyzed together with samples from matched (disease free) controls (n = 190). In a statistical model (conditional logistic regression) including all age groups, cholesterol (or apo B) level (P < 0.01), systolic blood pressure (P = 0.05) and smoking (P = 0.02) predicted CHD. In the statistical model Lp(a) interacted significantly with age (OR = 5.7; 95% CI: 1.4-23.6; P = 0.016), and high Lp(a) (over 45 mg/dl) was associated with significantly increased risk in subjects under 60 years (OR = 3.82; 95% CI: 1.47-9.96), but not in older men (OR = 0.67; 95% CI: 0.235-1.89). Therefore, we studied the impact of Lp(a)/apo(a) and other variables in subjects who had been under 60 years when they became cases. Among the younger subjects the presence of LMW apo(a) isoforms significantly predicted the development of CHD (OR = 3.83; 95% CI: 1.18-12.4). The increased risk pertained to high Lp(a) (above versus below 45 mg/dl: OR = 3.68; 95% CI: 1.03-13.10), and to Lp(a) concentrations when entered into the model as a continuous variable (P = 0.04). Cholesterol or apo B (P < 0.01), smoking (P = 0.02), systolic blood pressure (P = 0.05) and low alcohol consumption (under nine drinks/week) (P = 0.04) were also significant predictors of CHD. We conclude that LMW apo(a) isoforms are significantly associated with increased risk of CHD in men under 60 years.
Assuntos
Apolipoproteínas/sangue , Doença das Coronárias/sangue , Adulto , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Apolipoproteínas/química , Apolipoproteínas/genética , Apoproteína(a) , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Dinamarca/epidemiologia , Suscetibilidade a Doenças , Humanos , Hipertensão/epidemiologia , Lipídeos/sangue , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Peso Molecular , Polimorfismo Genético , Estudos Prospectivos , Fatores de Risco , Fumar/epidemiologiaRESUMO
About 40% of patients with non-insulin-dependent diabetes (NIDDM) have hypertension, which in turn may contribute to their enhanced risk for cardiovascular diseases. However, a number of antihypertensive agents tend to cause a deterioration in the control of diabetes. The present study was designed to elucidate whether treatment with perindopril (a new angiotensin-converting enzyme [ACE] inhibitor) affects plasma lipid metabolism, glucose homeostasis, and insulin sensitivity. Ten patients with NIDDM and moderate hypertension were studied in a double-blind, placebo-controlled, crossover study encompassing 6 weeks of placebo treatment and 6 weeks of perindopril treatment given in random order. Mean systolic/diastolic blood pressure was 162/94 +/- 6/3 mm Hg during placebo treatment versus 157/91 +/- 5/2 mm Hg during perindopril therapy. Plasma levels of free fatty acids, triglycerides, high density lipoprotein (HDL) cholesterol, and total cholesterol were similar during placebo and perindopril treatment. Oral glucose tolerance tests showed similar responses of plasma glucose, serum insulin, and serum C peptide following placebo and perindopril treatment. Insulin sensitivity estimated with an intravenous insulin tolerance test (IVITT) was unchanged by perindopril therapy (KIVITT: 0.014 +/- 0.001 min-1 [placebo] versus 0.015 +/- 0.003 min-1 [perindopril], difference not significant. In conclusion, treatment with perindopril in NIDDM patients had no adverse effects on plasma lipids, glucose tolerance, or insulin sensitivity.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Hipertensão/tratamento farmacológico , Indóis/uso terapêutico , Insulina/sangue , Lipídeos/sangue , Idoso , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Humanos , Hipertensão/sangue , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , PerindoprilRESUMO
As part of the Danish WHO MONICA study, a register of patients with myocardial infarction was established in 1982, covering 11 municipalities in the western part of Copenhagen County, Denmark. During the period 1982-91, all cases of myocardial infarction among citizens aged 25-74 years were registered and validated according to the criteria set up for the WHO MONICA project. Short-term (28 days) and long-term (up to 15 years) survival in three periods were compared. The rate of mortality after a non-fatal myocardial infarction was compared with that of the general population, and causes of death were analyzed. Short-term survival did not change during the study period, whereas long-term survival improved for men but did not change for women. The excess mortality rate among female patients over that of the general population was due to ischemic heart disease, other cardiovascular diseases, cancer and other diseases. The excess mortality among male patients was due only to cardiovascular diseases.
Assuntos
Infarto do Miocárdio/mortalidade , Adulto , Idoso , Causas de Morte/tendências , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Sistema de Registros , Análise de SobrevidaRESUMO
Data from 6695 men and women of ages 30, 40, 50, and 60 years, examined in the Danish WHO MONICA surveys in 1982-84, in 1986-87, and in 1991-92, were analyzed to estimate secular trends in body height and weight, blood pressure, and serum total, HDL-, and LDL-cholesterol, and triglyceride. Body height increased 0.1% per year, and body mass index increased 0.4% per year in women. Diastolic blood pressure increased 0.4% per year in women and 0.6% per year in 60-year-old men. HDL cholesterol declined 0.4% per year. Body mass indices in men, diastolic blood pressures in men <60 years of age, systolic blood pressures, total- and LDL cholesterol and triglyceride did not change. The levels of biological risk factors in the Danish WHO MONICA study population did not show trends during the 1980s that help explain the declining incidence of myocardial infarction in the population.
Assuntos
Doenças Cardiovasculares/epidemiologia , Adulto , Distribuição por Idade , Antropometria , Pressão Sanguínea , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/fisiopatologia , Dinamarca/epidemiologia , Feminino , Humanos , Modelos Lineares , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Fatores de Risco , Distribuição por Sexo , Organização Mundial da SaúdeRESUMO
The antihypertensive effect of captopril, metoprolol, and hydrochlorothiazide was compared in 23 non-insulin-dependent (NIDDM) diabetic patients less than or equal to 75 years of age, with borderline to moderate primary hypertension. In a double blind, placebo-controlled cross-over trial the patients were treated with 25 to 50 mg captopril, 50 to 100 mg metoprolol, 12.5 to 25 mg hydrochlorothiazide, and placebo, each given twice daily for 8 weeks. Antidiabetic treatment remained unchanged during the study. After receiving placebo for a 4 week run-in period, arterial blood pressure was 168/101 +/- 93/10 (mean +/- SEM) mm Hg. Diastolic blood pressure was lowered significantly during all active treatment periods compared to the placebo value of 97 +/- 2 mm Hg: captopril, 92 +/- 1 mm Hg; metoprolol, 90 +/- 1 mm Hg; hydrochlorothiazide, 91 +/- 1 mm Hg. Metabolic variables were not significantly altered by captopril and metoprolol, while hydrochlorothiazide treatment increased hemoglobin A1c from 7.5 +/- 0.3 to 8.2 +/- 0.4% (P less than .001), decreased high-density lipoprotein-cholesterol from 1.19 +/- 0.08 to 1.10 +/- 0.06 mmol/L (P less than .05). Glomerular filtration rate, urinary albumin excretion, orthostatic blood pressure response, and digital systolic blood pressure in the lower limb remained unchanged during the active treatment periods. The frequency of subjective adverse effects was acceptable during active treatment and not significantly different compared to placebo. We conclude that antihypertensive treatment for 8 weeks with captopril or metoprolol in NIDDM patients is well-tolerated and causes no deterioration in metabolic control and kidney function, while hydrochlorothiazide causes a slight deterioration in glycemic control and lipid profile.
Assuntos
Captopril/uso terapêutico , Diabetes Mellitus Tipo 2/fisiopatologia , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Metoprolol/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hidroclorotiazida/efeitos adversos , Hipertensão/fisiopatologia , Hipoglicemiantes/antagonistas & inibidores , Lipídeos/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apo B) is attached to a large plasminogen-like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated. LDL and apo B levels are often elevated in untreated hypothyroidism and lowered by thyroxine (T4) treatment, probably due to an increase in LDL receptors. We measured plasma concentrations of LDL, apo B, and Lp(a) in 13 patients with symptomatic primary hypothyroidism before and during T4 therapy. The mean concentration of LDL decreased significantly (P = .006) from 6.05 mmol/L to 4.07 mmol/L, and the mean concentration of apo B decreased significantly (P = .005) from 1.42 g/L to 1.12 g/L. Median Lp(a) concentrations remained unchanged (P = .77); they were 17.05 mg/dL before and 16.59 mg/dL during T4 treatment. In both the untreated condition and during substitution therapy, Lp(a) levels were higher in patients than in healthy controls, probably due to a relatively high frequency of the small Lp(a) phenotypes in our patients. Since Lp(a) contains apo B, which is a ligand for the LDL receptor, it is surprising that Lp(a) is not reduced along with LDL and apo B. These findings suggest that the catabolism of LDL and Lp(a) differ in some respect, and that thyroid hormones have little, if any, effect on Lp(a).