Identification of Two Distinct Immune Subtypes in Hepatitis B Virus (HBV)-Associated Hepatocellular Carcinoma (HCC).

HBV is the most common risk factor for HCC development, accounting for almost 50% of cases worldwide. Despite significant advances in immunotherapy, there is limited information on the HBV-HCC tumor microenvironment (TME), which may influence the response to checkpoint inhibitors. Here, we characterize the TME in a unique series of liver specimens from HBV-HCC patients to identify who might benefit from immunotherapy. By combining an extensive immunohistochemistry analysis with the transcriptomic profile of paired liver samples (tumor vs. nontumorous tissue) from 12 well-characterized Caucasian patients with HBV-HCC, we identified two distinct tumor subtypes that we defined immune-high and immune-low. The immune-high subtype, seen in half of the patients, is characterized by a high number of infiltrating B and T cells in association with stromal activation and a transcriptomic profile featuring inhibition of antigen presentation and CTL activation. All the immune-high tumors expressed high levels of CTLA-4 and low levels of PD-1, while PD-L1 was present only in four of six cases. In contrast, the immune-low subtype shows significantly lower lymphocyte infiltration and stromal activation. By whole exome sequencing, we documented that four out of six individuals with the immune-low subtype had missense mutations in the CTNNB1 gene, while only one patient had mutations in this gene in the immune-high subtype. Outside the tumor, there were no differences between the two subtypes. This study identifies two distinctive immune subtypes in HBV-associated HCC, regardless of the microenvironment observed in the surrounding nontumorous tissue, providing new insights into pathogenesis. These findings may be instrumental in the identification of patients who might benefit from immunotherapy.

Diagnostic role of head-up tilt test in patients with cough syncope.

AIMS: The aim of this study was to describe the head-up tilt (HUT) test and carotid sinus massage (CSM) responses, and the occurrence of syncope with coughing during HUT in a large cohort of patients. METHODS AND RESULTS: A total of 5133 HUT were retrospectively analysed to identify patients with cough syncope. Head-up tilt followed by CSM were performed. Patients were made to cough on two separate occasions in an attempt to reproduce typical clinical symptoms on HUT. Patients with cough syncope were compared with 29 age-matched control patients with syncope unrelated to coughing. A total of 29 patients (26 male, age 49 ± 14 years) with cough syncope were identified. Coughing during HUT reproduced typical prodromal symptoms of syncope in 16 (55%) patients and complete loss of consciousness in 2 (7%) patients, with a mean systolic blood pressure reduction of 45 ± 26 mmHg, and a mean increase in heart rate of 13 ± 8 b.p.m. No syncope or symptoms after coughing were observed in the control group. The HUT result was positive in 13 (48%) patients with the majority of positive HUT responses being vasodepressor (70% of positive HUT). Carotid sinus massage was performed in 18 patients being positive with a vasodepressor response causing mild pre-syncopal symptoms in only 1 patient. CONCLUSION: Syncope during coughing is a result of hypotension, rather than bradycardia. Coughing during HUT is a useful test in patients suspected to have cough syncope but in whom the history is not conclusive.

A long-term follow-up of patients with prolonged asystole of greater than 15s on head-up tilt testing.

BACKGROUND: Head-up tilt (HUT) is used for diagnosis of vasovagal syncope (VVS), and can provoke cardioinhibition. VVS is usually considered benign, however pacemaker insertion may be indicated in some patients. We sought to characterize the long-term outcomes of patients with prolonged asystole (>15s) on HUT. METHODS: We conducted a retrospective study on patients with asystole >15s on HUT identified from 5133 patients who were investigated between 1998 and 2012 at our institution. Patients were mailed questionnaires or telephoned to ascertain outcomes. Where contact was not possible, the patients' general practitioners were contacted to request up-to-date information. RESULTS: A total of 26 patients with a mean age of 45 ± 18 years and a mean duration of asystole on HUT of 26 ± 7s were successfully followed up from a total of 77 patients identified. The follow-up duration was 99 ± 39 months. Six patients had undergone pacemaker (PPM) implantation. Of the patients without PPM, 16 reported spontaneously improved symptoms. Ten patients sustained injury prior to HUT compared with one after HUT, when a clear diagnosis was made and management advice was given. There were no major injuries or deaths after HUT. The 6 patients with PPMs had a mean age of 60 ± 16 (67% male) at HUT. Four patients had no further syncope after PPM and two demonstrated improvement but still experienced recurrent syncope. CONCLUSIONS: Prolonged asystole (>15s) on tilt does not necessarily predict adverse outcomes with most patients improving spontaneously over the long-term. Pacemaker insertion in selected patients may reduce syncope recurrence but does not always abolish it.

Trained breathing-induced oxygenation acutely reverses cardiovascular autonomic dysfunction in patients with type 2 diabetes and renal disease.

AIMS: Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment. METHODS: Twenty-six patients with type 2 diabetes (aged 61.0 ± 0.8 years, mean ± SEM; duration of diabetes 10.5 ± 2 years, BMI 29.9 ± 0.7 kg/m(2), GFR 68.1 ± 5.6 ml/min) and 24 healthy controls (aged 58.5 ± 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen). RESULTS: During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 ± 1.2 vs. 12.6 ± 2.0 ms/mmHg, p < 0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 ± 1.8 and 15.4 ± 2.4 ms/mmHg, respectively, p < 0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p < 0.025 vs. spontaneous breathing during normoxia). CONCLUSIONS: Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.

Diagnostic algorithm for syncope.

Syncope is a common symptom with many causes. Affecting a large proportion of the population, both young and old, it represents a significant healthcare burden. The diagnostic approach to syncope should be focused on the initial evaluation, which includes a detailed clinical history, physical examination and 12-lead electrocardiogram. Following the initial evaluation, patients should be risk-stratified into high or low-risk groups in order to guide further investigations and management. Patients with high-risk features should be investigated further to exclude significant structural heart disease or arrhythmia. The ideal currently-available investigation should allow ECG recording during a spontaneous episode of syncope, and when this is not possible, an implantable loop recorder may be considered. In the emergency room setting, acute causes of syncope must also be considered including severe cardiovascular compromise due to pulmonary, cardiac or vascular pathology. While not all patients will receive a conclusive diagnosis, risk-stratification in patients to guide appropriate investigations in the context of a diagnostic algorithm should allow a benign prognosis to be maintained.

Heart rate/blood pressure ratio as predictor of neuromediated syncope.

BACKGROUND: Predicting the occurrence of syncope in advance during tilt test could be useful to prepare the medical staff in preventing complications connected with this procedure, particularly in patients with no pre-syncopal symptoms. Our objective was to develop a simple algorithm able to predict the onset of neuromediated syncope during the tilt test. METHODS: We analysed the trend in RR interval, blood pressures, the ratio of these two variables and their derivative, as possible predictors of neuromediated syncope during tilt test. We studied 145 patients: 72 tilt test positive (age 7-82 years, 23 male, 49 female) and 73 tilt test negative (age 8-82 years, 36 male, 37 female), coming at our attention for suspected syncope. We evaluated time of prediction, sensitivity, specificity and receiver-operating curves (ROC) of the trends in RR interval, blood pressure, their ratio and the derivative of their ratio, in predicting syncope. RESULTS: The derivative of the ratio between RR interval and systolic blood pressure (dRR/SBP) was able to predict syncope 44.1 ± 6.6s in advance with a sensitivity of 86.2% and a specificity of 89.1%. Area under the curve of ROC was 0.877 (p<0.001). The method was able to predict syncope in all three forms of neuromediated syncope: cardioinhibitory, mixed and vasodepressor. Similar results were found using the pulse pressure (dRR/PP). CONCLUSIONS: Using dRR/SBP or dRR/PP it is possible to predict the occurrence of syncope in advance during tilt test.

High meat consumption is associated with type 1 diabetes mellitus in a Sardinian case-control study.

The large worldwide variation in type 1 diabetes incidence and increasing incidence over time points toward important environmental risk factors. Among them, nutrition plays an important role. The objective was to investigate the relationship between type 1 diabetes and nutritional factors in pregnancy and early in life. We carried out, using semi-quantitative food frequency questionnaires, a retrospective case-control study in 298 children of 0-15 years old, 145 of which were affected by type 1 diabetes. The diet of all children and of their mothers during pregnancy and lactation was assessed. In children, a statistically significant dose-response association between type 1 diabetes and the amount of meat consumption was found while no other nutritional factors were associated with the disease. High meat consumption seems to be an important early in life cofactor for type 1 diabetes development, although these findings need to be confirmed in wider prospective follow-up studies.

Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients.

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA(1c), fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone. Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.

Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients.

OBJECTIVE: To evaluate the effects of one year of treatment with sibutramine plus L-carnitine compared to sibutramine on body weight, glycemic control, and insulin resistance state in type 2 diabetic patients. METHODS: Two hundred and fifty-four patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) >8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP). RESULTS: There was a decrease in body weight, BMI, HbA(1c), FPI, HOMA-IR, and RBP-4 in both groups, even when the values obtained with sibutramine plus L-carnitine were lower than the values obtained in sibutramine group. There was a faster decrease of FPG, PPG, TC, LDL-C, resistin and Hs-CRP with sibutramine plus L-carnitine even when no differences between the two groups were obtained. Furthermore, only sibutramine plus L-carnitine improved Tg, and visfatin. CONCLUSION: Sibutramine plus L-carnitine gave a faster improvement of lipid profile, insulin resistance parameters, glycemic control, and body weight compared to sibutramine.

Comparison of orlistat treatment and placebo in obese type 2 diabetic patients.

AIM: To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients. MATERIALS AND METHODS: Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR). RESULTS: Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-alpha, and a faster decrease of leptin and HS-CRP in the orlistat group compared with the control group. We also recorded a significant reduction of body weight and BMI with orlistat, but not with placebo. A faster improvement of glycemic profile and FPI was obtained with orlistat compared with the controls. Also, there was a significant reduction of lipid profile with orlistat, not reached with placebo. CONCLUSIONS: Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha, and anthropometric parameters.

Differential effects of candesartan and olmesartan on adipose tissue activity biomarkers in type II diabetic hypertensive patients.

The aim of this study is to compare the effects of candesartan and olmesartan on insulin sensitivity-related parameters, before and after antihypertensive therapy. After a 4-week washout placebo period, 194 hypertensive (diastolic blood pressure (DBP) > or =80 mm Hg and systolic blood pressure (SBP) > or =130 mm Hg) patients with well-controlled type II diabetes were randomized to receive either 8 mg of candesartan once a day (o.d.) or 10 mg olmesartan o.d. and titrated after 1 month to 16 mg candesartan o.d. or 20 mg olmesartan o.d., respectively; the treatment period had a 1-year duration. We evaluated body weight, body mass index, SBP, DBP, glycated hemoglobin, fasting plasma glucose, M value, adiponectin (ADN), resistin (r), retinol-binding protein 4, visfatin, vaspin and high-sensitivity C-reactive protein (Hs-CRP) at their baseline values and after 6 and 12 months of treatment. We observed no variation in body weight or glycemic profile for either treatment. SBP and DBP were significantly reduced by both treatments (from 144+/-8/88+/-6 to 126+/-5/77+/-4 mm Hg by candesartan (P<0.001) and from 145+/-9/89+/-7 to 128+/-7/79+/-5 mm Hg by olmesartan (P<0.001)) without any difference between them. Retinol binding protein-4, r, and the vaspin value decreased in the candesartan group but not in olmesartan group. The M value, visfatin and ADN increased with candesartan, whereas no significant variations were observed with olmesartan. Both treatments resulted in a similar reduction in Hs-CRP. Although both therapies resulted in similar reductions in blood pressure, candesartan therapy was more effective than olmesartan therapy in improving insulin sensitivity.

Effects of a standardized oral fat load on vascular remodelling markers in healthy subjects.

The most adequate way to experimentally reproduce the post-prandial lipemia condition appears to be the administration of a standardized oral fat load (OFL) to fasting patients. We studied the effects of a standardized OFL on markers of vascular remodelling in healthy subjects. We enrolled 286 Caucasians aged >or= 18 of either sex. The OFL was given after a 12-h fast. Blood samples were drawn before and 3, 6, 9 and 12h after the fat load. The following parameters were evaluated: body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, nitrites and nitrates, adiponectin (ADP), metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). High density lipoprotein-cholesterol (HDL-C) decrease was present in subjects after 6h. Triglycerides (Tg) change was observed after 6h. Nitrites/nitrates variation was observed after 6 and 9h during OFL. Adiponectin level was decreased after 6 and 9h during OFL. Both MMP-2 and MMP-9 levels were higher after 6h during OFL. We observed that nitrites/nitrates and ADP significantly decreased and MMP-2 and MMP-9 significantly increased after a standardized OFL. Other studies need to confirm the direct acute effects of post-prandial lipemia on vascular damage.

Modification of vascular and inflammation biomarkers after OGTT in overweight healthy and diabetic subjects.

We evaluated the effect of an oral glucose tolerance test (OGTT) on the level of biomarkers of vascular remodelling. We enrolled 256 Caucasian overweight healthy subjects (H) and 274 overweight type 2 diabetic patients (D). All patients underwent basal measurements of blood glucose (BG), nitrites/nitrates, adiponectin (ADP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) before and after OGTT. Nitrites/nitrates decrease was present after 60, 90, 120, and 180 min in both groups. Nitrite/nitrate levels were decreased at baseline, after 30 and 60 min in D group compared to H group. ADP decrease was present after 90, 120, and 180 min, in both groups. ADP levels were lower in D group than in H group during OGTT. MMP-2 increase was present after 60, 90, and 120 min in H group, while MMP-2 increase was observed after 90, 120, and 180 min in D group. MMP-2 levels were higher in D group than in H group during OGTT. MMP-9 increase was present in H group after 60, 90, 120, and 180 min, while MMP-9 increase was observed after 90, 120, and 180 min in D group. MMP-9 levels were higher in D group than in H group during OGTT. Postprandial glycemia induces an acute increase in biomarkers of vascular remodelling.

Candesartan effect on inflammation in hypertension.

The aim of this study was to evaluate the effect of candesartan on inflammatory biomarkers in hypertensive patients with and without type 2 diabetes mellitus after a standardized oral fat load (OFL). A total of 219 patients were enrolled: 106 patients were assigned to the non-diabetic hypertensive (NH) group, and 113 to the diabetic hypertensive (DH) group. All patients received candesartan therapy for 6 months and underwent a standardized OFL at baseline and after 6 months of therapy. We evaluated systolic blood pressure (SBP) and diastolic blood pressure (DBP), blood glucose (BG), triglycerides (Tg), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6) and high-sensitivity C reactive protein (Hs-CRP). At baseline, glycated hemoglobin, homeostasis model assessment insulin resistance index, BG, fasting plasma insulin, Tg, sICAM-1, IL-6 and Hs-CRP in the DH group were significantly higher, whereas high-density lipoprotein-cholesterol value was significantly lower compared to NH group. After 6 months of candesartan therapy, sICAM-1, IL-6 and Hs-CRP were significantly lower compared to baseline in both groups; furthermore, there was a significant decrease of SBP and DBP values in both groups. After the OFL administered at baseline, there was an increase of Tg, sICAM-1, IL-6 and Hs-CRP in both groups. After the OFL administered after 6 months of therapy, instead, there was no significant variation of BG, Tg or sICAM-1 value in both groups, whereas there was an increase of IL-6 and Hs-CRP compared to time 0. We observed that candesartan treatment attenuated the inflammatory answer in both groups of patients, even if more efficiently in nondiabetic ones.

Modulation of adipokines and vascular remodelling markers during OGTT with acarbose or pioglitazone treatment.

Adipose tissue secretes biologically active mediators as adipokines. We evaluate the effect of pioglitazone and acarbose on adipokines and vascular remodelling markers during an oral glucose tolerance test (OGTT). Height and body weight, BMI, glycemic and lipid profile, blood pressure, Nitrites/nitrates, ADP, resistin, MMP-2, and MMP-9 were evaluated at titration beginning, after 3, 6 months, and at the study end in 473 type 2 diabetic patients. BMI and weight increased after full treatment with pioglitazone respect to acarbose. HbA(1c) decreased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone compared to the end of titration period and to acarbose. FPG decreased after full treatment with pioglitazone compared to the end of titration period. PPG decreased with acarbose after titration period respect to baseline and after full treatment respect to the end of titration period. FPI and Homa index decreased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone respect to the end of titration period and to acarbose. ADP increased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone compared to the end of titration period and to acarbose. Resistin decreased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone respect to acarbose. Pioglitazone improves glucose metabolism and insulin-resistance compared to acarbose in type 2 diabetic patients already treated with metformin and sulphonilureas.

Risk factors for cardiovascular disease in Sardinia from 1978 to 2001: a comparative study with Italian mainland.

BACKGROUND: This study is a survey of cardiovascular risk factors in Sardinia in the years 1999-2001 and allows us to update previously observed trends of such factors and to compare them with those in the Italian mainland. METHODS: Random samples of free living population of the Mediterranean island of Sardinia, Italy, were collected. Overall, 6818 subjects, 50% of each sex, and aged 20-80+ years constituted the sample. Personal and family data were collected using a semiquantitative questionnaire of frequencies. Blood biochemical variables related to risk for atherosclerosis were measured. In particular, serum total cholesterol, HDL-cholesterol, triglycerides, Apo A-1, Apo B, Lp(a), uric acid, blood glucose and plasma homocysteine were analyzed in each subject enrolled. RESULTS: In the age classes 20-59 years, during a 30 year period, prevalence of smoking among males continued to decrease from 58 to 24% (p for trend <0.001), and, for the first time, prevalence of smoking among females decreased as well: from 31% in 1995 to 20% in 2001 (p for trend <0.001). In contrast, a steady increase in TC (mg/dl) (189, 206, 215, 216, p for trend <0.05 in males and 184 197, 212, 217, p for trend <0.05 in females), and LDL-C (136, 143, 138, 144, p for tend <0.05 in males and 127, 139, 136, 135, p for trend <0.05 in females) was observed. HDL-C showed a steady increase (p for trend <0.01 in males and females). Lp(a) values were high in both sexes, a finding linked to the ethnic influence on them. Systolic and diastolic blood pressure values (mm Hg) increased with age. In the present survey (population aged 20-80+ years, current smokers were 17.5% among males and 13.8% among females. Total and HDL-cholesterol were higher than in other parts of Italy (209 vs 205 in males, and 211 vs 204 in females), while systolic and diastolic blood pressure were lower. CONCLUSION: Overall, total- and LDL-cholesterol showed an increasing trend, while blood pressure and smoking habits had a decreasing tendency. The increase in blood cholesterol follows the trend in other areas of the world, mainly due to changing dietary habits. Therefore, a campaign of eating information and education (population strategy) could favourably modify cardiovascular risk, as occurred in Sardinia during the past decade with the Regional ATS-Sardegna Campaign.

Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients.

OBJECTIVE: To evaluate the efficacy of fenofibrate, simvastatin or their combination in type 2 diabetic patients with combined dyslipidaemia. RESEARCH DESIGN AND METHODS: 241 patients, who had never previously taken lipid-lowering medications, received fenofibrate 145 mg/day, or simvastatin 40 mg/day, or fenofibrate 145 mg/day + simvastatin 40 mg/day combination for 12 months. We evaluated lipids, glycaemic, haemostatic, and inflammatory variables at baseline, and after 6 and 12 months. RESULTS: After 12 months total cholesterol (TC), LDL cholesterol (LDL-C) and triglycerides (Tg) decreased while HDL cholesterol (HDL-C) increased in all groups, even if the values obtained with fenofibrate + simvastatin were the best. At the end of the study apolipoprotein A-1 (Apo A-1) increased with fenofibrate + simvastatin, while apolipoprotein B (Apo B) decreased in all groups compared to baseline. Plasminogen activator inhibitor-1 (PAI-1) and high-sensitivity C reactive protein (hs-CRP) decreased after 12 months compared to baseline with simvastatin, and with fenofibrate + simvastatin even if the value obtained with fenofibrate-simvastatin was the lowest. After 12 months, fibrinogen (Fg) decreased compared to baseline with fenofibrate + simvastatin. LIMITATIONS: This study has some limitations. The first one is the relatively small sample of studied patients. The second one is the lack of an advanced lipid proteins evaluation, such as lipoprotein subfraction changes in the different treatment regimen. Finally, we have not selected patients that could show the best response to fibrate (i.e.: hypertriglyceridemics) or statins (i.e.: hypercholesterolemics) monotherapy, so the effect of these drugs administered alone may have been partly attenuated. CONCLUSIONS: Fenofibrate + simvastatin association improved lipid parameters, prothrombotic and inflammatory factors, and appeared to have a good tolerability profile over 12 months of therapy.

Oral fat load effects on inflammation and endothelial stress markers in healthy subjects.

The aim was to study the effect of a standardized oral fat load (OFL) on different inflammatory parameters in a large sample of adult healthy subjects (n = 286) of both sexes. The fat load was given between 08:00 and 09:00 h after a 12-h fast. Blood samples were drawn before and 3, 6, 9, and 12 h after the OFL. All patients underwent a measurement of body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and tumor necrosis factor-alpha (TNF-alpha). Fasting plasma glucose (FPG) increase was +3.26% at 3 h, +4.35% at 6 h, +1.09% at 9 h while FPG decrease was -1.09% at 12 h. High-density lipoprotein cholesterol increase was +2.08% at 3 h, and at 12 h during OFL study; a significant HDL-C decrease was present in subjects after 6 h (-4.17%; P < 0.05 vs 0). A significant Tg change was observed after 6 h (+70.37%; P < 0.01 vs 0) and 9 h (+58.33%; P < 0.05 vs 0) respectively, and the increase was +22.22% at 3 h and +18.52% at 12 h. Total cholesterol increase was +0.52% after 3 h, +1.04% after 6 h, while after 12 h the decrease was -0.52%. Low-density lipoprotein cholesterol increase was +1.64% after 6 h with a decrease of -0.82% at 9 and 12 h. A significant sICAM-1, hsCRP, and sE-selectin variation was observed after 6 and 9 h, while a significant sVCAM-1 change occurred after 3, 6, and 9 h. Soluble ICAM-1 increase was +20.58% at 3 h, +34.10% at 6 h (P < 0.05 vs 0) +25.94% at 9 h (P < 0.01 vs 0), and +19.14% at 12 h; sVCAM-1 increase was +13.97% (P < 0.05 vs 0) at 3 h, +18.55% at 6 h (P < 0.01 vs 0), +12.02% at 9 h (P < 0.05 vs 0), and +8.70% at 12 h. High-sensitivity CRP increase was +36.36% at 3 h, +90.91% at 6 h (P < 0.01 vs 0), +63.64% at 9 h (P < 0.05 vs 0), and +36.36% at 12 h. Soluble E-selectin increase was +27.11% at 3 h, +51.90% at 6 h (P < 0.05 vs 0), +45.19% at 9 h (P < 0.01 vs 0), and +20.12% at 12 h. Interleukin-6 increase was +61.11% at 3 h (P < 0.05 vs 0), +83.33% at 6 h (P < 0.001 vs 0), +55.56% at 9 h (P < 0.01 vs 0), and +22.22% at 12 h. Tumor necrosis factor-alpha increase was +42.86% at 3 h (P < 0.05 vs 0), +71.43% at 6 h (P < 0.01 vs 0), (+50.00% at 9 h (P < 0.05 vs 0), and +28.57% at 12 h. We observed that the OFL induces a complex and massive systemic inflammatory response that includes IL-6, TNF-alpha, hsCRP, and cell adhesion molecules, even before Tg significantly rises.