Search

AIMS: Increased fasting and postprandial triglyceridemia is one of the cardiovascular risk factors for patients with insulin resistance. Since triglyceride (TG) metabolism largely depends on gender, we have investigated diurnal TG changes in patients with and without overweight, focusing on gender differences. METHODS: Twenty-two males and 22 females with overweight (mean body mass index (BMI) 28.0 ± 2.3 kg/m²) measured capillary TG concentrations at six fixed time points on three different days. Diurnal TG profiles were calculated as area under the capillary TG curves (TGc-AUCs). The control group consisted of 24 males and 21 females who were not overweight (mean BMI 22.4 ± 1.5 kg/m²). Biochemical and anthropometric parameters associated with insulin resistance were measured. RESULTS: Lean males and lean females had comparable fasting insulin levels (6.9 ± 2.6 and 8.1 ± 4.7 mU/l, respectively), but females had a more favorable fasting lipoprotein profile when compared to males. Diurnal TG profiles were lower in lean females than in lean males (16.9 ±4.3 vs 20.3 ±5.7mMh, respectively, P<0.05). Overweight males and females had comparable fasting insulin levels (10.3 ± 3.4 and 12.1 ± 4.9 mU/l, respectively), which were higher than in lean subjects. Overweight females also had a more favorable fasting lipoprotein profile compared to overweight males. Diurnal TG profiles were similar in overweight females and overweight males (31.1 ± 15.6 and 32.9 ± 13.2 mMh, respectively). Stepwise multiple regression analysis showed that in both males and females, waist circumference was the strongest determinant of diurnal TG profiles when fasting TG concentrations were excluded from the model (R² = 0.49 for males and R² = 0.33 for females). These results suggest that overweight resulted in a 'male diurnal TG profile' in females due to abdominal fat accumulation. CONCLUSION: Insulin... [ABSTRACT FROM AUTHOR]

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group B) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.). [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV)-specific T-cells are crucial to prevent CMV disease. CMV seropositive recipients transplanted with stem cells from a CMV seronegative allogeneic donor (R + D - ) may be at risk for CMV disease due to absence of donor CMV-specific memory T-cells in the graft., Methods: We analyzed the duration of CMV reactivations and the incidence of CMV disease in R + D - and R + D + patients after alemtuzumab-based T-cell depleted allogeneic stem cell transplantation (TCD alloSCT). To determine the presence of donor-derived primary CMV-specific T-cell responses we analyzed the origin of CMV-specific T-cells in R + D - patients., Results: The duration of CMV reactivations (54 versus 38 days, respectively, p = 0.048) and the incidence of CMV disease (0.14 versus 0.02, p = 0.003 at 1 year after alloSCT) were higher in R + D - patients compared to R + D + patients. In R + D - patients, CMV-specific CD4 + and CD8 + T-cells were mainly of recipient origin. However, in 53% of R + D - patients donor-derived CMV-specific T-cells were detected within the first year., Conclusions: In R + D - patients, immunity against CMV was predominantly mediated by recipient T-cells. Nevertheless, donor CMV serostatus significantly influenced the clinical severity of CMV reactivations indicating the role of CMV-specific memory T-cells transferred with the graft, despite the ultimate formation of primary donor-derived CMV-specific T-cell responses in R + D - patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intensive chemotherapy followed by allogeneic stem cell transplantation (alloSCT) can cure AML. Most studies on alloSCT in elderly AML report results of highly selected patient cohorts. Hardly any data exist on the effectiveness of prospective strategies intended to bring as many patients as possible to transplant. Between 2006 and 2011 we implemented a treatment algorithm for all newly diagnosed AML patients aged 61-75 years, consisting of intensive chemotherapy cycles to induce complete remission, followed by alloSCT. 44 of 60 (73%) newly diagnosed elderly AML patients started with chemotherapy. By meticulously following our algorithm in almost all patients, we could induce complete remission (CR) in 66% of patients starting with chemotherapy, and transplant 32% of these patients in continuous CR. Main reasons for failure were early relapse (16%), early death (14%), primary refractory disease (9%), and patient or physician decision to stop treatment (16%). Patients in continuous CR after first induction benefit most with 36% long-term survival. Patients not in CR after first induction benefit less; although additional chemotherapy induces CR in 45% of these patients, only 23% are transplanted and no long-term survival is observed, mainly due to relapse. Long-term survival in the group of 44 patients is 9% (median 4.5 years after alloSCT). Considering that 27% of patients do not start with chemotherapy and 64% of patients starting with chemotherapy do not reach alloSCT, the reasons for failure presented here should be used as a guide to develop new treatment algorithms to improve long-term survival in elderly AML patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Three patients were analysed for an extreme leucocytosis (>50x10(9)/l) because leukaemia was suspected. In all three patients the leucocytosis proved to be caused by a leukaemoid reaction. This reaction was associated with a hepatic angiosarcoma in the first patient, with a Salmonella infection in the second patient and with a necrotic leg abscess in the third patient. Retrospectively, 25 patients with a leukaemoid reaction were identified in our hospital during a four-year period. Besides leukaemia, a leukaemoid reaction, which often has a dismal prognosis, should be considered in patients with an extreme leucocytosis.

Aims: Despite agreement on the need for screening for the presence of cardiovascular risk factors in first-degree family members of patients with premature coronary artery disease (CAD), this is not routinely carried out in relatives of normocholesterolaemic patients. We evaluated cardiovascular risk factors in family members of normocholesterolaemic patients with premature CAD., Methods: Eligible index subjects were patients with premature CAD (<55 years in men and <65 years in women), who had undergone percutaneous transluminal coronary angioplasty. Patients with fasting total cholesterol levels >6.5 mmol/l were excluded. Sixteen index subjects were included with a mean age of 49±8 years and total cholesterol levels of 5.5±0.8 mmol/l. Sixty-four first-degree relatives from these 16 pedigrees were screened, namely 18 children, 42 siblings and four parents. National Cholesterol Education Program III guidelines were used to identify candidates for lipid-lowering treatment. Furthermore, the presence of four additional metabolic disorders was investigated: the metabolic syndrome, increased levels of lipoprotein(a) (Lp(a)), hyperhomocysteinaemia and postprandial hyperlipidaemia., Results: Of 64 relatives free of CAD, 34 subjects (53%) fulfilled the criteria to receive therapeutic advice, 20 of whom (31% of the relatives) were candidates for drug therapy. Sixty-one relatives were available for a full assessment of metabolic disorders and in 37 relatives (61%) at least one metabolic abnormality was present. Twelve subjects had hyper-Lp(a), seven subjects had postprandial hyperlipidaemia and two had the metabolic syndrome. Furthermore, 16 subjects had a combination of at least two out of four metabolic disorders., Conclusion: Careful evaluation of coronary risk factors and metabolic variables in first-degree relatives of normocholesterolaemic CAD patients identifies a significant number of subjects at increased coronary risk in whom primary prevention measures should be initiated.

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.

Postprandial hyperlipidemia is associated with premature coronary sclerosis in fasting normolipidemic subjects. Self-determined daytime capillary triglyceride (cTG) profiles were compared between 26 fasting normotriglyceridemic patients with premature coronary artery disease (CAD) and 26 controls matched for gender, age and BMI. Daytime triglyceridemia was calculated as total area under the cTG-curve (cTG-AUC). Total and LDL cholesterol were not different between CAD patients (5.4+/-0.8 mmol/l and 3.6+/-0.7 mmol/l, respectively) and controls (5.0+/-0.9 mmol/l and 3.3+/-0.8 mmol/l, respectively). Patients with CAD were characterized by a 44% higher cTG-AUC than matched controls (P<0.01). Using logistic regression analysis, cTG-AUC was the strongest predictor of the presence of CAD (P<0.001). Adding apo AI to the model improved the predictive power from 71 to 77%. Sixteen patients were studied after increasing doses of simvastatin up to 80 mg/day. Although the target for LDL cholesterol was reached by simvastatin 20mg/day, significant effects on cTG-AUC were found only by higher doses of simvastatin. Simvastatin 40 mg/day decreased cTG-AUC by 28% (P<0.05 versus baseline), reaching comparable values as in controls, without further improvement with simvastatin 80 mg/day (26% reduction versus baseline; P<0.05). Daytime triglyceridemia is linked to premature coronary sclerosis in fasting normotriglyceridemic patients. A higher dose of simvastatin was needed to normalize daytime triglyceridemia than was required to "normalize" LDL cholesterol.

Objective: An increased hepatic flow of free fatty acids (FFAs) is associated with impaired peripheral FFA trapping by malfunctioning of the complement component 3 (C3)/acylation-stimulating protein system and overproduction of VLDL in familial combined hyperlipidemia (FCHL). Postprandial ketone bodies reflect FFA oxidation in the liver, but the postprandial changes in male and female patients separately have not been determined yet. Gender differences in postprandial ketone bodies and C3 changes were investigated in normolipidemic patients and patients with untreated FCHL., Methods and Results: Thirty-two normolipidemic patients (16 female and 16 male) and 19 patients with untreated normolipidemia (9 female and 10 male) underwent an oral fat-loading test. Total and incremental areas under the curves (AUC and dAUC, respectively) after the oral fat load were calculated. Triglyceride AUC was similar between genders in each group. Normolipidemic female subjects showed a higher levels of dAUC-hydroxybutyric acid than male subjects (1.37+/-0.49 and 0.98+/-0.43 mmol x h/L). In FCHL, a similar trend was observed in female (1.92+/-0.38) compared with male (1.55+/-0.87) subjects. In contrast to normolipidemia, FCHL did not show a postprandial increase in C3, although C3 was higher in FCHL., Conclusions: Women have higher postprandial ketone bodies than men, probably reflecting enhanced postprandial hepatic FFA oxidation. In FCHL, both genders have higher postprandial ketone bodies and therefore higher hepatic FFA delivery. The higher fasting and postprandial C3 levels in FCHL may reflect resistance of the C3/acylation-stimulating protein system to promote peripheral fatty acid trapping.

Postprandial hypertriglyceridemia associated with insulin resistance is one of the cardiovascular risk factors in obesity and type 2 diabetes. It is not known whether diabetics have a more pronounced postprandial hypertriglyceridemia than obese subjects. Daylong triglyceridemia, representing postprandial lipemia, was determined in obese subjects with and without type 2 diabetes and in lean subjects. Nineteen type 2 diabetics (F/M: 7/12, body mass index [BMI]: 30.6 +/- 5.4 kg/m(2)), 45 obese nondiabetics (F/M: 16/29, BMI: 29.5 +/- 2.6 kg/m(2)) and 78 lean subjects (F/M: 28/50, BMI: 23.7 +/- 2.2 kg/m(2)) measured capillary triglycerides (TGc) during 3 days on 6 fixed time-points each day in an out-of-hospital situation. Daylong TGc profiles were calculated as mean integrated area under the TGc-curve (TGc-AUC). Fasting plasma TG were higher in diabetics and obese nondiabetics (1.81 +/- 0.79 and 1.77 +/- 0.80 mmol/L) compared with lean subjects (1.23 +/- 0.67 mmol/L, P <.001). TGc-AUC was similarly increased in both diabetics and obese nondiabetics (35.0 +/- 12.1 and 35.2 +/- 10.6 mmol.1 h/L) compared with lean controls (25.5 +/- 12.0 mmol.1 h/L, P <.001). Self-reported energy intake was not significantly different between the groups. Fasting TGc (r =.87, P <.001) and waist circumference (r =.51, P <.001) were the parameters best associated with TGc-AUC. Using stepwise multiple regression analysis, fasting TGc, BMI, total cholesterol, and high-density lipoprotein (HDL) cholesterol were the best predictors of TGc-AUC, explaining 77% of the variation. The cut-off level for "normal" TGc-AUC, calculated as the 75th percentile of TGc-AUC in lean subjects, was 30.7 mmol.1 h/L and corresponded with a fasting TGc of 1.8 mmol/L (eg, 1.6 mmol/L in plasma), calculated using univariate regression analysis. In conclusion, daylong triglyceridemia is similarly increased in diabetics and obese nondiabetics compared with lean subjects. Fasting TG and central obesity largely determine daylong triglyceridemia, independent of the presence of type 2 diabetes. Decreasing fasting plasma TG below 1.6 mmol/L could lead to a normalization of postprandial lipemia in obese subjects with and without diabetes.