RESUMO
AIMS: The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial assessed the long-term efficacy of an initial strategy of radiofrequency ablation (RFA) vs. antiarrhythmic drug therapy (AAD) as first-line treatment for patients with PAF. In this substudy, we evaluated the effect of these treatment modalities on the Health-Related Quality of Life (HRQoL) and symptom burden of patients at 12 and 24 months. METHODS AND RESULTS: During the study period, 294 patients were enrolled in the MANTRA-PAF trial and randomized to receive AAD (N = 148) or RFA (N = 146). Two generic questionnaires were used to assess the HRQoL [Short Form-36 (SF-36) and EuroQol-five dimensions (EQ-5D)], and the Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA) was used to evaluate the symptoms appearing during the trial. All comparisons were made on an intention-to-treat basis. Both randomization groups showed significant improvements in assessments with both SF-36 and EQ-5D, at 24 months. Patients randomized to RFA showed significantly greater improvement in four physically related scales of the SF-36. The three most frequently reported symptoms were breathlessness during activity, pronounced tiredness, and worry/anxiety. In both groups, there was a significant reduction in ASTA symptom index and in the severity of seven of the eight symptoms over time. CONCLUSION: Both AAD and RFA as first-line treatment resulted in substantial improvement of HRQoL and symptom burden in patients with PAF. Patients randomized to RFA showed greater improvement in physical scales (SF-36) and the EQ-visual analogue scale. CLINICAL TRIAL REGISTRATION: URL http://www.clinicaltrials.gov. Unique identifier: NCT00133211.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/terapia , Ablação por Cateter , Nível de Saúde , Qualidade de Vida , Adulto , Idoso , Efeitos Psicossociais da Doença , Feminino , Flecainida/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Propafenona/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Fractional Flow Reserve (FFR) is a proven technology for guiding percutaneous coronary intervention (PCI), but is not reimbursed despite the fact that it is frequently used to defer PCI. METHODS: Costs incurred with use of FFR were compared in both the public and private sectors with the costs that would have been incurred if the technology was not available using consecutive cases over a two year period in a public teaching hospital and its co-located private hospital. RESULTS: FFR was performed on 143 lesions in 120 patients. FFR was < 0.80 in 37 lesions in 34 patients and 25 underwent PCI while 11 had CABG. It was estimated that without FFR 78 lesions in 70 patients would have had PCI with 17 patients having CABG with 35 additional functional tests. Despite a cost of $A1200 per wire, FFR actually saved money. Mean savings in the public sector were $1200 per patient while in the private sector the savings were $5000 per patient. CONCLUSIONS: FFR use saves money for the Federal Government in the public sector and for the Private Health Funds in the private sector. These financial benefits are seen in addition to the improved outcomes seen with this technology.
Assuntos
Estenose Coronária/economia , Estenose Coronária/fisiopatologia , Técnicas de Diagnóstico Cardiovascular/economia , Reserva Fracionada de Fluxo Miocárdico , Custos de Cuidados de Saúde , Idoso , Austrália , Ponte de Artéria Coronária/economia , Estenose Coronária/cirurgia , Análise Custo-Benefício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/economia , Setor Privado/economia , Setor Público/economiaRESUMO
We identified the alpha-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between -2.5 and -6.0. Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC). ACTC is the first sarcomeric gene described in which mutations are responsible for 2 different cardiomyopathies. We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC.
Assuntos
Actinas/genética , Cardiomiopatia Hipertrófica/genética , Actinas/química , Actinas/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Primers do DNA/genética , Éxons , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Contração Miocárdica/genética , Linhagem , Mutação Puntual , Conformação ProteicaRESUMO
BACKGROUND: Tako-tsubo cardiomyopathy (TTC) is an acute reversible cause of segmental myocardial dysfunction that is poorly understood. We have noted a variant of this condition where a tiny segment at the apex retains some contractile function. This paper delineates the frequency of this variant relative to the classical form and the clinical differences between patients suffering from the two forms. METHODS: All cases of TTC (n = 35) were identified from our infarct angiography database and separated on the basis of apical sparing (n = 14) or no apical sparing (n = 21). RESULTS: Compared with the classical form, those with apical sparing were significantly younger (63 +/- 12 vs 72 +/- 13 years) and were more likely premenopausal (5/14 vs 0/21) and had higher ejection fractions (35 +/- 6% vs 32 +/- 4%). There was a trend towards higher recurrence (4/21 vs 0/14). There were no differences in time or season of presentation, precipitant stressor, premorbid drug therapy, haemodynamics at catheterization or acute outcomes. CONCLUSION: The apical sparing variant of TTC is common, accounting for 40% of cases. While the patients are younger and more likely premenopausal, there are no other distinguishing features between the classical and the variant form.
Assuntos
Cardiomiopatias/classificação , Cardiomiopatias/diagnóstico , Coração/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Menopausa , Volume Sistólico , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
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
BACKGROUND: The effects of cigarette smoking on the thyroid gland have been studied for years. However, the effect of smoking on thyroid function and size is still controversial. OBJECTIVE: To determine the impact of cigarette smoking on the development of clinically overt thyroid disease. METHODS: Matched case-control study of 132 same-sex twin pairs (264 individuals) discordant for clinically overt thyroid disease, ascertained from a population-based nationwide twin register. Information on thyroid disease and smoking habits was gathered by questionnaire, and the patients' endocrinologist or general practitioner verified the diagnosis. RESULTS: Overall, smoking was associated with an increased risk of developing clinically overt thyroid disease (odds ratio, 3.0; 95% confidence interval, 1.4-6.6; P = .003). This association remained statistically significant in monozygotic and dizygotic disease-discordant pairs. The effect of smoking was more pronounced in monozygotic vs dizygotic pairs (odds ratio, 5.0 vs 2.5; P= .04 for both). Essentially similar results were obtained after subdividing the twin pairs into groups discordant for clinically overt autoimmune (49 pairs) and nonautoimmune (83 pairs) thyroid disease. Among twin pairs concordant for smoking, probands with clinically overt autoimmune thyroid disease smoked significantly more than did their healthy co-twins (17 pairs; P= .03), whereas no difference was found between probands with nonautoimmune thyroid disease and their healthy co-twins (34 pairs; P= .20). CONCLUSIONS: Smoking is associated with an increased risk of developing clinically overt thyroid disease. Furthermore, our data suggest that cumulative cigarette consumption is a risk factor, most pronounced in autoimmune thyroid disease.
Assuntos
Fumar/efeitos adversos , Doenças da Glândula Tireoide/etiologia , Autoimunidade , Estudos de Casos e Controles , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Razão de Chances , Fenótipo , Risco , Inquéritos e Questionários , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/imunologiaRESUMO
OBJECTIVES: HMG CoA reductase inhibitors reduce cellular availability of mevalonate, a precursor in cholesterol synthesis. Since the cholesterol content of cell membranes is an important determinant of Na(+)-K(+) pump function we speculated that treatment with HMG CoA reductase inhibitors affects Na(+)-K(+) pump activity. METHODS: We treated rabbits and rats for 2 weeks with the HMG CoA reductase inhibitor lovastatin and measured Na(+)-K(+) pump current (I(p)) in isolated rabbit cardiac myocytes using the whole cell patch-clamp technique, K-dependent p-nitrophenyl phosphatase (p-NPPase) activity in crude myocardial and skeletal muscle homogenates, and vanadate-facilitated 3H-ouabain binding in intact skeletal muscle samples from rats. RESULTS: Treatment with lovastatin caused statistically significant reductions in I(p), myocardial and skeletal muscle K-dependent p-NPPase activity and 3H-ouabain binding in the myocardium and skeletal muscle. The lovastatin-induced decrease in I(p) was eliminated by parenteral co-administration of mevalonate. However, this was not related to cardiac cholesterol content. CONCLUSIONS: Treatment with lovastatin reduces Na(+)-K(+) pump activity and abundance in rabbit and rat sarcolemma.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Sarcolema/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , 4-Nitrofenilfosfatase/metabolismo , Animais , Membrana Celular/metabolismo , Colesterol/administração & dosagem , Colesterol/sangue , Feminino , Metabolismo dos Lipídeos , Masculino , Ácido Mevalônico/farmacologia , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Ouabaína/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , Coelhos , Ratos , Ratos Wistar , Sarcolema/efeitos dos fármacos , Sódio/metabolismoRESUMO
Mutations in the gene for the low density lipoprotein (LDL) receptor cause the autosomal dominant disease familial hypercholesterolemia (FH), the prevalence of which is about 0.2% in most populations. By PCR-SSCP analysis and direct sequencing, we identified the receptor-negative Trp23-Stop LDL receptor mutation (FH Cincinnati-5) in 10 of 63 FH probands and the receptor-defective Trp66-Gly LDL receptor mutation (FH French Canadian-4) in another 10 of the 63 FH probands. These two mutations thus account for 30% of diagnosed FH families in Denmark. Comparison of the mean lipid concentrations (unadjusted and adjusted for age), including serum total cholesterol and LDL-cholesterol, showed no significant differences between the two groups of FH heterozygote probands (cholesterol: 10.7 mmol/l vs. 10.7 mmol/l) and between the probands and 16 and 22 non-proband family members with the Trp23-stop (cholesterol: 10.1 mmol/l) ad Trp66-Gly (cholesterol: 10.7 mmol/l) mutations, respectively.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Mutação Puntual , Receptores de LDL/genética , Adulto , Idoso , Sequência de Bases , Canadá/epidemiologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Códon/genética , Análise Mutacional de DNA , Dinamarca/epidemiologia , Feminino , França/etnologia , Frequência do Gene , Genes , Haplótipos/genética , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Prevalência , Triglicerídeos/sangueRESUMO
Heterozygous familial hypercholesterolemia (FH) is one of the most common potentially fatal single-gene diseases leading to premature coronary artery disease, but the majority of heterozygous FH patients have not been diagnosed. FH is due to mutations in the gene coding for the low-density lipoprotein (LDL) receptor, and molecular genetic diagnosis may facilitate identification of more FH subjects. The Danish spectrum of 29 different mutations, five of which account for almost half of heterozygous FH, is intermediate between that of countries such as South Africa, where three mutations cause 95% of heterozygous FH in the Afrikaners, and Germany or England, where there are many more mutations. In clinical practice, a strategy for the genetic diagnosis of heterozygous FH, tailored to the mutational spectrum of patients likely to be seen at the particular hospital/region of the country, will be more efficient than screening of the whole LDL receptor gene by techniques such as single-strand conformation polymorphism (SSCP) analysis in every heterozygous FH candidate. In Aarhus, Denmark, we have chosen to examine all heterozygous FH candidates for the five most common LDL receptor gene mutations (W23X, W66G, W556S, 313 + 1G --> A, 1846 - 1G --> A) and the apoB-3500 mutation by rapid restriction fragment analysis. Negative samples are examined for other mutations by SSCP analysis followed by DNA sequencing of the exon indicated by SSCP to contain a mutation. If no point mutation or small insertion/deletion is detected, Southern blot or Long PCR analysis is performed to look for the presence of large gene rearrangements. In conclusion, our data suggest that an efficient molecular diagnostic strategy depends on the composition of common and rare mutations in a population.
Assuntos
DNA/análise , Heterozigoto , Hiperlipoproteinemia Tipo II/diagnóstico , Mutação , Receptores de LDL/genética , Adolescente , Adulto , Southern Blotting , Primers do DNA/química , Dinamarca , Éxons , Feminino , Rearranjo Gênico , Marcadores Genéticos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , RNA Mensageiro/análise , Receptores de LDL/sangueRESUMO
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
In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation, a G to C transition at cDNA position 1730 in exon 12, causing a tryptophan to serine substitution in amino acid position 556 (W556S). In the Danish patients, the W556S mutation was present in 12% of 65 possible mutant alleles. The pathogenicity of the W556S mutation, which is located in one of the five conserved motifs Tyr-Trp-Thr-Asp in the epidermal growth factor homology region, was studied in transfected COS-7 cells expressing normal and mutant LDL receptor cDNAs. Results obtained by immunofluorescence flow cytometry and confocal microscopy, as well as by immunoprecipitation, were compatible with complete retention of the mutant protein in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Mutação Puntual , Receptores de LDL/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Células COS , Sequência Conservada , Dinamarca , Éxons , Citometria de Fluxo , Imunofluorescência , Humanos , Microscopia Confocal , Sequências Repetitivas de Ácido Nucleico , Serina , Transfecção , TriptofanoRESUMO
A 10-year retrospective survey was undertaken of patients with pyogenic hepatic abscesses (PHA). Fifty-two patients fulfilled the criteria of PHA, equivalent to a mean annual incidence of 11/1,000,000. The main symptom was fever. Laboratory tests were compatible with infection, slightly elevated alkaline phosphatase being the only test pointing towards the liver as the focus of infection. Forty-one patients (79%, 95% CL, 68-90%) had positive cultures from aspirated pus, with a total of 79 isolates. Enteric Gram-negative rods accounted for 45% and anaerobic bacteria for 31% of PHA isolates. Gram-positive cocci, predominantly non-haemolytic streptococci, were the third largest group (19%), but were rare among blood isolates. Positive blood cultures were found in 21 patients (40%, 95% CL, 27-54%), with a total of 28 isolates. Percutaneous drainage was performed in 26, percutaneous needle aspiration in 10, combinations thereof in 5, and abdominal surgery in 5. Forty-nine patients received systemic antibiotic therapy, four of whom were treated with antibiotics only. Seven recurrences occurred and the overall case fatality rate was 6% (95%, CL 0-12%), which might reflect a low rate of underlying malignant diseases in our study material.
Assuntos
Abscesso Hepático/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bactérias/isolamento & purificação , Criança , Feminino , Seguimentos , Humanos , Abscesso Hepático/diagnóstico , Abscesso Hepático/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Chronic Helicobacter pylori infection is associated with mucosal inflammation. The aim of the present study was to assess human neutrophil and monocyte activation induced by H. pylori strains with different virulence genotypes. Bacterial sonicates from 12 strains were used to induce phagocyte up-regulation of adherence molecule CD11b, assessed by fluorescence flow cytometry, and oxidative burst responses, assessed by chemiluminescence. A dose-dependent induction of the expression of CD11b was observed with sonicate from all H. pylori strains on both neutrophils and monocytes. Strains negative for cagA and picB genes had the same inducing activity of upregulation of CD11b as strains positive for these genes. A vacA-S2 type strain had the same activity as vacA-S1 type strains. The induction of toxic oxygen radicals by H. pylori-activated neutrophils gave higher median values for the cagA-positive strains than for the cagA-negative strains. For the monocyte chemiluminescence response, cagA-negative strains gave higher median values compared to cagA-positive strains. We conclude that upregulation of the neutrophil and monocyte adherence molecule CD11b induced by H. pylori sonicates is not associated with the presence of cagA, picB or mosaic pattern of vacA, and that cagA, picB-negative strains and vacA-S2 strains retain their inflammatory capacity.
Assuntos
Antígenos de Bactérias , Infecções por Helicobacter/etiologia , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Inflamação/etiologia , Monócitos/fisiologia , Neutrófilos/fisiologia , Adulto , Proteínas de Bactérias/genética , Sequência de Bases , Primers do DNA/genética , Gastrite/etiologia , Genes Bacterianos , Genótipo , Humanos , Técnicas In Vitro , Antígeno de Macrófago 1/metabolismo , Explosão Respiratória , Virulência/genéticaRESUMO
The effect of recombinant human growth hormone (rHGH) on cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol, triglycerides (TG), apolipoprotein (apo) B, apo A-I, and lipoprotein(a) [Lp(a)] was studied in 40 postmenopausal women treated with 0.05, 0.1, or 0.2 IU/kg/d rHGH or placebo for 7 days. Cholesterol, LDL cholesterol, and HDL cholesterol decreased in a dose-dependent manner (P = .001, P = .001, and P = .003, respectively), whereas apo B decreased insignificantly (P = .15). Apo A-I decreased significantly only among women treated with rHGH at a dose of 0.1 IU/kg/d (P = .03). When all rHGH-treated women were grouped together, Lp(a) increased (P = .001). We also studied 20 young men treated with either 0.2 IU/kg/d rHGH or placebo. As in women, cholesterol and apo B decreased P = .005 and P = .02, respectively), whereas Lp(a) increased (P = .05). There was no detectable effect of rHGH on TG concentrations in men. As in women, there was no significant effect of 0.2 IU/kg/d rHGH on apo A-I concentrations. All lipid and lipoprotein measures reached pretreatment levels during the first week after treatment was stopped, except Lp(a), which remained elevated 2 weeks after rHGH cessation.
Assuntos
Hormônio do Crescimento/farmacologia , Lipídeos/sangue , Lipoproteínas/sangue , Caracteres Sexuais , Idoso , Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Hormônio do Crescimento/sangue , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Valores de Referência , Fatores de Tempo , Triglicerídeos/sangueRESUMO
Helicobacter pylori is a human pathogen, whereas the natural hosts for 'Gastrospirillum hominis' and Helicobacter felis are animals. 'G. hominis' is occasionally found to cause infection in humans, whereas H. felis only rarely infects humans. The pathogenesis of H. pylori infection is not completely understood and in order to reveal differences in immune response to the three Helicobacter species, the upregulation of adherence molecule CD11b/CD18, chemotactic activity and oxidative burst response of neutrophils after stimulation with H. pylori, 'G. hominis' and H. felis sonicates, were compared. Like H. pylori, 'G. hominis' and H. felis induced upregulation of CD11b/CD18 and chemotaxis of neutrophils. 'G. hominis' demonstrated a more pronounced upregulation of CD11b/CD18, whereas H. felis was the strongest stimulant of neutrophil chemotaxis. H. felis was unable to stimulate neutrophils to oxidative burst response, whereas 'G. hominis' activated neutrophils in a dose-dependent way similar to H. pylori. 'G. hominis' and H. felis were both able to prime neutrophils for oxidative burst response similar to H. pylori. In conclusion, we observed clear differences in neutrophil responses to different Helicobacter species, which indicates that bacterial virulence factors may be important for the diversity in the pathogenetic outcome of Helicobacter infections.
Assuntos
Helicobacter heilmannii/imunologia , Helicobacter pylori/imunologia , Neutrófilos/microbiologia , Explosão Respiratória , Proteínas de Bactérias/imunologia , Antígenos CD11/análise , Antígenos CD18/análise , Células Cultivadas , Quimiotaxia de Leucócito/imunologia , Relação Dose-Resposta Imunológica , Humanos , Medições Luminescentes , Neutrófilos/imunologiaRESUMO
Apolipoprotein E (apo E) genotypes have been determined in 460 Danish men, with the use of the polymerase chain reaction (PCR) to amplify a 244 base pair fragment spanning the first-base polymorphic sites in the codons of amino acids 112 and 158 followed by restriction endonuclease cleavage. The results were compared with the apo E phenotypes previously determined by isoelectric focusing (IEF) of delipidated plasma, not pretreated with neuraminidase, followed by apo E specific immunoblotting. Conflicting results were found in only 9 cases (2.0%) and in each case only with respect to one allele. Five of the discrepancies can be explained, post hoc, by technical difficulties with the IEF method ('faint bands'). A possible cause of the other 4 discrepancies is the presence of rare mutations. Our findings in this large study are reassuring, since, if appreciable and systematic misclassification of genotypes do occur by using IEF, as has been reported from some laboratories, it may influence the validity of genetic epidemiological studies.
Assuntos
Apolipoproteínas E/genética , Polimorfismo Genético/genética , Adulto , Aminoácidos/análise , Apolipoproteínas E/análise , Dinamarca , Métodos Epidemiológicos , Genótipo , Humanos , Focalização Isoelétrica , Masculino , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
A total of 5000 consecutively samples newborn screening cards were anonymously selected for screening for the apolipoprotein B-3500 (apo B-3500) mutation, which causes familial defective apolipoprotein B-100 (FDB). The mutation was found in 5 of 5000 Danish children, of whom 2 were twins. This indicates a lower prevalence of this mutation in Danes than that reported in the UK, Germany, USA, Austria, Canada and especially Switzerland. Haplotype studies suggest that Caucasian subjects with the apo B-3500 mutation have a common founder. The apparently lower prevalence in Denmark than in Switzerland and Central Europe may indicate that the mutation was brought from these areas to Denmark after the initial settling of Denmark. In 101 unrelated Danish subjects with familial hypercholesterolemia, diagnosed on clinical and biochemical criteria including tendon xanthomata, 2 were heterozygous for the apo B-3500 mutation (2%).
Assuntos
Apolipoproteínas B/genética , Hipercolesterolemia/genética , Mutação , Análise Mutacional de DNA , Dinamarca/epidemiologia , Heterozigoto , Humanos , Hipercolesterolemia/epidemiologia , Recém-Nascido , Triagem Neonatal , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: The number of malaria cases imported to Denmark has been increasing for some years. To analyze the background for this we assessed the use of protective measures in Danish travelers visiting malarious areas. METHOD: Post-travel questionnaires were given during hospitalization to malaria patients, and sent by mail to their traveling companions. RESULTS: In total, 142 persons participated. Only 32% of the travelers used chemoprophylaxis correctly, according to Danish recommendations. Twelve percent of the travelers did not use chemoprophylaxis. Average compliance was 52%. Insufficient drug dosage was reported by 13%, and use of nonrecommended drugs by 7% of the travelers. Thirty-seven percent used insufficient antimosquito precautions, a problem which often coincided with irregular use of chemoprophylaxis. Malaria patients, sole travelers, and travelers with other ethnical background than Danish, were subgroups using insufficient malaria prophylaxis more frequently than healthy traveling companions. CONCLUSION: Insufficient use of the available antimalaria precautions by Danish travelers contributes greatly to maintaining a high incidence of imported malaria. Increased attention from physicians in educating travelers is important for optimizing malaria prophylaxis.