RESUMO
The extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH). We hypothesized that the variability of the FH phenotype might be partly explained by variation in proprotein convertase subtilisin kexin type 9 (PCSK9) activity. Individuals between 18 and 53 years of age who had been tested for a pathogenic LDLR or APOB mutation were eligible. Mutation carriers with a LDL-C level below the 75(th) percentile (called "FH low") were selected, as well as those with LDL-C above the 90(th) percentile (called "FH high"). Relatives who tested negative for the mutation were the "controls." PCSK9 plasma levels were assessed in 267 individuals who did not receive cholesterol-lowering treatment at the time of the study. Mean PCSK9 plasma levels (95% CI) were lower in the FH-low group compared with the FH-high group [152 (137-167) ng/ml vs. 186 (165-207) ng/ml, P = 0.010] and the control group [177 (164-190) ng/ml, P = 0.013]. Mean PCSK9 levels did not statistically differ between the FH-high and control groups (P = 0.50). Plasma PCSK9 levels are positively associated with LDL-C levels in FH patients and might contribute to the phenotypic severity in this disorder. Therefore, the results of pharmaceutical inhibition of PCSK9 in FH patients are eagerly awaited.
Assuntos
Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Fenótipo , Pró-Proteína Convertases/sangue , Serina Endopeptidases/sangue , Adolescente , Adulto , Espessura Intima-Media Carotídea , LDL-Colesterol/sangue , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Adulto JovemRESUMO
Two unrelated individuals were referred to Lipid Clinics in The Netherlands and Chile with extreme xanthomatosis and hypercholesterolemia. Both were diagnosed with heterozygous familial hypercholesterolemia (heFH) after molecular genetic analysis of the low-density lipoprotein (LDL) receptor gene. Since heFH by itself could not account for the massive xanthomas, the presence of an additional hereditary lipid or lipoprotein disorder was suspected. Further genetic analysis revealed homozygozity for mutations in the sterol 27-hydroxylase gene, confirming the diagnosis of cerebrotendinous xanthomatosis (CTX). Markedly, the typical neurological manifestations of CTX were absent, suggestive of a protective role of LDL-receptor deficiency against the severe neurological consequences of CTX.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Xantomatose Cerebrotendinosa/genética , Tendão do Calcâneo/patologia , Adulto , Colestanotriol 26-Mono-Oxigenase/genética , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/patologia , Masculino , Mutação , Receptores de LDL/genética , Xantomatose Cerebrotendinosa/complicações , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/patologia , Adulto JovemRESUMO
BACKGROUND: In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. METHODS: Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified FH patients in each postal code area was calculated and visualised in different maps. RESULTS: A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. CONCLUSIONS: Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherlands.
RESUMO
To step up from current day fusion experiments to power producing fusion reactors, it is necessary to control long pulse, burning plasmas. Stability and confinement properties of tokamak fusion reactors are determined by the current or q profile. In order to control the q profile, it is necessary to measure it in real-time. A real-time motional Stark effect diagnostic is being developed at Korean Superconducting Tokamak for Advanced Research for this purpose. This paper focuses on 3 topics important for real-time measurements: minimize the use of ad hoc parameters, minimize external influences and a robust and fast analysis algorithm. Specifically, we have looked into extracting the retardance of the photo-elastic modulators from the signal itself, minimizing the influence of overlapping beam spectra by optimizing the optical filter design and a multi-channel, multiharmonic phase locking algorithm.
RESUMO
BACKGROUND: Hemophilia A patients have a lower cardiovascular mortality rate than the general population. Whether this protection is caused by hypocoagulability or decreased atherogenesis is unclear. OBJECTIVES: To evaluate atherosclerosis and endothelial function in hemophilia A patients with and without obesity as well as in matched, unaffected controls. METHODS: Fifty-one obese (body mass index [BMI] ≥ 30 kg m(-2)) and 47 non-obese (BMI ≤ 25 kg m(-2)) hemophilia A patients, and 42 obese and 50 matched non-obese male controls were included. Carotid and femoral intimamedia thickness [IMT] and brachial flow-mediated dilatation (FMD) were measured as markers of atherogenesis and endothelial function. RESULTS: The overall population age was 50 ± 13 years. Carotid IMT was increased in obese subjects (0.77 ± 0.22 mm) as compared with non-obese subjects (0.69 ± 0.16 mm) [mean difference 0.07 mm (95% confidence interval [CI] 0.020.13, P = 0.008)]. No differences in mean carotid and femoral IMT between obese hemophilic patients and obese controls were found (mean difference of 0.02 mm [95% CI ) 0.070.11, P = 0.67], and mean difference of 0.06 mm [95% CI ) 0.130.25, P = 0.55], respectively). Thirty-five per cent of the obese hemophilic patients and 29% of the obese controls had an atherosclerotic plaque (P = 0.49), irrespective of the severity of hemophilia. Brachial FMD was comparable between obese hemophilic patients and obese controls (4.84% ± 3.24% and 5.32% ± 2.37%, P = 0.45). CONCLUSION: Hemophilia A patients with obesity develop atherosclerosis to a similar extent as the general male population. Detection and treatment of cardiovascular risk factors in hemophilic patients is equally necessary.
Assuntos
Aterosclerose/etiologia , Hemofilia A/complicações , Adulto , Aterosclerose/diagnóstico , Índice de Massa Corporal , Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Endotélio Vascular/fisiopatologia , Hemofilia A/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade , Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present study we evaluated the treatment of heFH patients in The Netherlands. METHODS: A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals. RESULTS: The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum therapy despite an LDL-c >or=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c >or=2.5mmol/l and not using maximum therapy. CONCLUSION: Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels.
Assuntos
Azetidinas/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Estudos Transversais , Monitoramento de Medicamentos , Ezetimiba , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Masculino , Pessoa de Meia-Idade , Países BaixosRESUMO
BACKGROUND: A frequent complication of orthopaedic procedures is venous thromboembolism (VTE ). Hyperglycaemia has been shown to activate the coagulation system and is associated with postoperative morbidity and mortality. Therefore, we hypothesised that glucose levels increase during orthopaedic surgery and are associated with an activation of the coagulation system. METHODS: Nine adult patients undergoing elective hip replacement were included. Venous blood samples were taken before, during and after surgery. Plasma glucose levels, factor VIII clotting activity (fVIII:c), von Willebrand ristocetin cofactor activity, von Willebrand factor antigen and prothrombin fragment 1+2 were measured. RESULTS: Immediately after induction of anaesthesia, plasma glucose levels started to increase until the second day postoperatively (peak 8.0 mmol/l). After seven weeks glucose values had returned to baseline (6.1 mmol/l), p<0.001 with ANOVA. All coagulation parameters increased during surgery, subsequent to the rise in glucose. The change in mean FVIII:c and von Willebrand ristocetin cofactor activity was significantly correlated with mean glucose values. CONCLUSIONS: These observations indicate that total hip replacement surgery causes an increase in glucose levels that precedes the proportional rise of the measured coagulation parameters. This suggests a possible role of glucose in the activation of the coagulation system during hip surgery.
Assuntos
Artroplastia de Quadril/efeitos adversos , Transtornos da Coagulação Sanguínea/etiologia , Quadril/cirurgia , Hiperglicemia/etiologia , Estresse Fisiológico , Estresse Psicológico/complicações , Tromboembolia Venosa/etiologia , Análise de Variância , Glicemia , Intervalos de Confiança , Fator VIII , Humanos , Procedimentos Ortopédicos/efeitos adversos , Fatores de Risco , Estatística como Assunto , Fatores de Tempo , Fator de von Willebrand/imunologiaRESUMO
BACKGROUND: Patients with (undiagnosed) diabetes mellitus, impaired glucose tolerance or stress-induced hyperglycemia may be at greater risk for venous thrombosis and present with relative hyperglycemia during the thrombotic event. OBJECTIVES: To assess whether venous thrombosis is associated with hyperglycemia at diagnosis. PATIENTS/METHODS: We performed a case-control study, derived from a cohort of consecutive patients referred for suspected deep vein thrombosis. Cases were patients with confirmed symptomatic venous thrombosis of the lower extremity. Controls were randomly selected in a 1 : 2 ratio from individuals in whom this diagnosis was excluded. We measured plasma glucose levels upon presentation to the hospital. RESULTS: In total, 188 patients with thrombosis and 370 controls were studied. The glucose cut-off levels for the first to fourth quartiles were as follows: first quartile, < 5.3 mmol L(-1); second quartile, 5.3-5.7 mmol L(-1); third quartile, 5.7-6.6 mmol L(-1); and fourth quartile, >or= 6.6 mmol L(-1). When adjusted for body mass index, a known history of diabetes mellitus, age, sex, ethnicity and whether known risk factors for deep vein thrombosis were present, the odds ratios for deep vein thrombosis in the second, third and fourth quartiles of glucose levels as compared with the first quartile were 1.59 [95% confidence interval (CI) 0.89-2.85], 2.04 (95% CI 1.15-3.62) and 2.21 (95% CI 1.20-4.05), respectively; P for trend = 0.001. CONCLUSIONS: Increased glucose levels measured at presentation were associated with venous thrombosis. Experimental evidence supports a potential causal role for hyperglycemia in this process. As this is the first report on the association between (stress) hyperglycemia and venous thrombosis, confirmation in other studies is required.