Patrizia Cardelli

Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss

BACKGROUND AND AIMS We investigated the effect of different exercise modalities on high sensitivity-C reactive protein (hs-CRP) and other inflammatory markers in patients with type 2 diabetes and the metabolic syndrome. METHODS AND RESULTS Eighty-two patients were randomized into 4 groups: sedentary control (A); receiving counseling to perform low-intensity physical activity (B); performing prescribed and supervised high-intensity aerobic (C) or aerobic+resistance (D) exercise (with the same caloric expenditure) for 12 months. Evaluation of leisure-time physical activity and assessment of physical fitness, cardiovascular risk factors and inflammatory biomarkers was performed at baseline and every 3 months. Volume of physical activity increased and HbA(1c) decreased in Groups B-D. VO(2max), HOMA-IR index, HDL-cholesterol, waist circumference and albuminuria improved in Groups C and D, whereas strength and flexibility improved only in Group D. Levels of hs-CRP decreased in all three exercising groups, but the reduction was significant only in Groups C and D, and particularly in Group D. Changes in VO(2max) and the exercise modalities were strong predictors of hs-CRP reduction, independent of body weight. Leptin, resistin and interleukin-6 decreased, whereas adiponectin increased in Groups C and D. Interleukin-1β, tumor necrosis factor-α and interferon-γ decreased, whereas anti-inflammatory interleukin-4 and 10 increased only in Group D. CONCLUSION Physical exercise in type 2 diabetic patients with the metabolic syndrome is associated with a significant reduction of hs-CRP and other inflammatory and insulin resistance biomarkers, independent of weight loss. Long-term high-intensity (preferably mixed) training, in addition to daytime physical activity, is required to obtain a significant anti-inflammatory effect.

Effect of an Intensive Exercise Intervention Strategy on Modifiable Cardiovascular Risk Factors in Subjects With Type 2 Diabetes Mellitus A Randomized Controlled Trial: The Italian Diabetes and Exercise Study (IDES)

BACKGROUND This study aimed to assess the efficacy of an intensive exercise intervention strategy in promoting physical activity (PA) and improving hemoglobin A(1c)(HbA(1c)) level and other modifiable cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). METHODS Of 691 eligible sedentary patients with T2DM and the metabolic syndrome, 606 were enrolled in 22 outpatient diabetes clinics across Italy and randomized by center, age, and diabetes treatment to twice-a-week supervised aerobic and resistance training plus structured exercise counseling (exercise group) vs counseling alone (control group) for 12 months. End points included HbA(1c) level (primary) and other cardiovascular risk factors and coronary heart disease risk scores (secondary). RESULTS The mean (SD) volume of PA (metabolic equivalent hours per week) was significantly higher (P < .001) in the exercise (total PA [nonsupervised conditioning PA + supervised PA], 20.0 [0.9], and nonsupervised, 12.4 [7.4]) vs control (10.0 [8.7]) group. Compared with the control group, supervised exercise produced significant improvements (mean difference [95% confidence interval]) in physical fitness; HbA(1c) level (-0.30% [-0.49% to -0.10%]; P < .001); systolic (-4.2 mm Hg [-6.9 to -1.6 mm Hg]; P = .002) and diastolic (-1.7 mm Hg [-3.3 to -1.1 mm Hg]; P = .03) blood pressure; high-density lipoprotein (3.7 mg/dL [2.2 to 5.3 mg/dL]; P < .001) and low-density lipoprotein (-9.6 mg/dL [-15.9 to -3.3 mg/dL]; P = .003) cholesterol level; waist circumference (-3.6 cm [-4.4 to -2.9 cm]; P < .001); body mass index; insulin resistance; inflammation; and risk scores. These parameters improved only marginally in controls. CONCLUSIONS This exercise intervention strategy was effective in promoting PA and improving HbA(1c) and cardiovascular risk profile. Conversely, counseling alone, though successful in achieving the currently recommended amount of activity, was of limited efficacy on cardiovascular risk factors, suggesting the need for a larger volume of PA in these high-risk subjects. Trial Registration isrctn.org Identifier: ISRCTN04252749.

Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma

The prognostic value of absolute lymphocytic count (ALC), has been a recent matter of debate in non-Hodgkin-lymphoma (NHL). We assessed prospectively the value of ALC at diagnosis and also after the completion of immuno-chemotherapy in 101 diffuse-large-B-cell-lymphoma (DLBCL). Analysis of prognostic factors with respect to overall survival (OS), event free survival (EFS) and progression free survival (PFS) was done by two-tailed log-rank test. The ALC cut-off value was calculated as <0.84 × 109/L at diagnosis: this was a strong negative prognostic factor for OS (p = 0.0004), EFS (p < 0.00001) and PFS (p < 0.00001) and in multivariate analysis was independent from the revised-international-prognostic-index (R-IPI). ALC after chemo-immunotherapy was not of prognostic value. As R-IPI and ALC < 0.84 × 109/L, were the factors better discriminating poor prognosis, a new trichotomous score (ALC/R-IPI) was built up: (1) low risk: R-IPI = very good or good and ALC < 0.84 × 109/L; (2) intermediate risk: patients with at least one risk factor (R-IPI = poor or ALC < 0.84 × 109/L). (3) high risk: patients with both risk factors. This new prognostic score was highly significant in univariate analysis for OS (p = 0.0002), EFS (p < 0.00001) and PFS (p < 0.00001). In multivariate analysis ALC/R-IPI was the most predictive factor for OS (OR = 2.954; p = 0.002) and EFS (OR = 2.381; p < 0.00001) and the only predictive factor for PFS (OR = 4.018; p < 0.00001).Our data, show that ALC at diagnosis has a strong prognostic relevance and is independent from the R-IPI. The new score including both values proved the most powerful predictor at multivariate analysis.

Effect of high- versus low-intensity supervised aerobic and resistance training on modifiable cardiovascular risk factors in type 2 diabetes; the Italian Diabetes and Exercise Study (IDES).

Background While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes. Objective To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors. Design Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005–2006). Setting Twenty-two outpatient diabetes clinics across Italy. Patients Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303). Interventions Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume. Main Outcome Measure(s) Hemoglobin (Hb) A1c and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores. Results Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA1c (mean difference −0.17% [95% confidence interval −0.44,0.10], P = 0.03), triglycerides (−0.12 mmol/l [−0.34,0.10], P = 0.02) and total cholesterol (−0.24 mmol/l [−0.46, −0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects. Conclusions Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors. Trial Registration www.ISRCTN.org ISRCTN-04252749.

Changes in physical fitness predict improvements in modifiable cardiovascular risk factors independently of body weight loss in subjects with type 2 diabetes participating in the Italian Diabetes and Exercise Study (IDES).

OBJECTIVE Physical fitness is inversely related to mortality in the general population and in subjects with type 2 diabetes. Here, we present data concerning the relationship between changes in physical fitness and modifiable cardiovascular risk factors in subjects with type 2 diabetes from the Italian Diabetes and Exercise Study. RESEARCH DESIGN AND METHODS Sedentary patients with type 2 diabetes (n = 606) were enrolled in 22 outpatient diabetes clinics and randomized to twice-a-week supervised aerobic and resistance training plus exercise counseling versus counseling alone for 12 months. Baseline to end-of-study changes in cardiorespiratory fitness, strength, and flexibility, as assessed by Vo2max estimation, a 5–8 maximal repetition test, and a hip/trunk flexibility test, respectively, were calculated in the whole cohort, and multiple regression analyses were applied to assess the relationship with cardiovascular risk factors. RESULTS Changes in Vo2max, upper and lower body strength, and flexibility were significantly associated with the variation in the volume of physical activity, HbA1c, BMI, waist circumference, high-sensitivity C-reactive protein (hs-CRP), coronary heart disease (CHD) risk score, and inversely, HDL cholesterol. Changes in fitness predicted improvements in HbA1c, waist circumference, HDL cholesterol, hs-CRP, and CHD risk score, independent of study arm, BMI, and in case of strength, also waist circumference. CONCLUSIONS Physical activity/exercise-induced increases in fitness, particularly muscular, predict improvements in cardiovascular risk factors in subjects with type 2 diabetes independently of weight loss, thus indicating the need for targeting fitness in these individuals, particularly in subjects who struggle to lose weight.

Evaluation of Neutrophil CD64 Expression and Procalcitonin as Useful Markers in Early Diagnosis of Sepsis

Quantitation of neutrophil CD64 expression and procalcitonin (PCT) levels in blood samples have been recently proposed as useful tools for early detection of sepsis. To determine the usefulness of these tests, we analyzed blood samples of 112 patients, admitted to an intensive care unit (ICU), presenting clinical symptoms of sepsis, as well as of 50 healthy controls. At the end of the study, a retrospective analysis showed that only 52 of the 112 ICU-patients presented a real sepsis (positive blood culture). The results obtained indicated that of the 52 patients with sepsis, 50 and 49 presented levels of neutrophil CD64 expression ≥ 2398 molecules per cell (cut-off determined by receiver operator characteristic analysis) and PCT levels > 0.5 ng/ml (cut-off suggested by the manufacturer), respectively. However, the neutrophil CD64 test showed higher specificity in detecting sepsis since 5 out of the 60 ICU-patients without sepsis (negative blood culture), presented CD64 expression levels ≥ 2398 molecules per cell, PCT levels ≥ 0.5 ng/ml were shown in 27 patients. Moreover, while none of the 50 healthy controls presented a neutrophil CD64 level higher than the cut-off value, 5 patients presented PCT levels ≥ 0.5 ng/ml. In conclusion, our data seem to indicate that the quantitation of CD64 expression could be taken into consideration as a sensitive and specific test for early diagnosis of sepsis.

HPLC–mass spectrometry method for quantitative detection of neuroendocrine tumor markers: Vanillylmandelic acid, homovanillic acid and 5-hydroxyindoleacetic acid

BACKGROUND The urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) can be increased in the presence of neuroblastic and carcinoid tumors. The former is characterized by defective catecholamine metabolism which results in high urinary levels of VMA and HVA. The latter shows an altered metabolism of tryptophan and an increased synthesis of serotonin, producing high 5-HIAA urinary concentrations. METHODS We describe an HPLC-tandem mass spectrometric method for the simultaneous quantification of VMA, HVA and 5-HIAA in human urine. The chromatographic separation is performed on a reversed-phase C18 column. Instrumental analysis is performed on a Q-Trap 2000 triple quadrupole/ion trap mass spectrometer. RESULTS The method is fast and does not require sample pre-treatment. Multiple calibration curve exhibited consistent linearity and reproducibility. Linear responses were observed in the concentration range 0-50 mg/l for each analyte. Limits of detection were 0.001 mg/l for VMA, 0.015 mg/l for 5-HIAA and 0.050 mg/l for HVA with a signal-to-noise ratio of 3. Limits of quantification were 0.005 mg/l for VMA, 0.050 mg/l for 5-HIAA and 0.1 mg/l for HVA with a signal-to-noise ratio of 10. CONCLUSIONS This method can be proposed as a tool for neuroendocrine tumor markers detection.

Inflammation and immune response in acute aortic dissection.

Abstract Objective. The aim of our study was to evaluate the lymphocyte subpopulations and the cytokines in the peripheral blood of patients with type-A Stanford acute aortic dissection (AAD group) and to determine whether inflammatory cells are present at the site of aortic dissection. Methods. Thirty-five consecutive patients with type-A Stanford dissection were evaluated for haemochrome and lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD4+CD25+, CD16+CD56+, CD4+CD28−, CD8+CD28−) by flow cytometry. C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFN-γ), and monocyte chemoattractant protein (MCP)-1 were measured by ELISA. In addition, immunohistochemical staining with cell type-specific antibodies was performed to study the inflammatory cells detected inside the aortic wall. Results. In the AAD group, a significant increase in natural killer (NK) (P = 0.032), B cells (P = 0.022), and CD8+CD28− (P = 0.045) subpopulations was observed, whereas there was a significant decrease in total T lymphocytes (P = 0.004) and T helper fractions (P = 0.005). Moreover, a significant increase in CRP (P < 0.0001), IL-6 (P < 0.0001), IL-8 (P < 0.0001), IL-10 (P < 0.0001), TNF-α (P < 0.0001), and MCP-1 (P < 0.001) was observed; macrophages represented the main population detected inside the media. Conclusions. Our results strongly support the hypothesis of a pivotal role of innate immunity in type-A Stanford AAD.

Expression of receptors for native and chemically modified low-density lipoproteins in brain microvessels

Despite the importance of cholesterol metabolism in the central nervous system, only relatively few studies have dealt with the cerebral uptake and transport of lipids into the brain compartment. These functions are mediated by the endothelium of brain microvessels, which forms the anatomical basis of the blood‐brain barrier. By a reverse transcriptase PCR study of messenger RNA expression we could show, in bovine brain microvessels, the presence of transcripts of native low‐density lipoprotein receptor and of both type I and II scavenger receptors. Brain microvessels therefore appear to play an active role in the uptake of native and modified low‐density lipoproteins.

Utility of Procalcitonin (PCT) and Mid regional pro-Adrenomedullin (MR-proADM) in risk stratification of critically ill febrile patients in Emergency Department (ED). A comparison with APACHE II score

BackgroundThe aim of our study was to evaluate the prognostic value of MR-proADM and PCT levels in febrile patients in the ED in comparison with a disease severity index score, the APACHE II score. We also evaluated the ability of MR-proADM and PCT to predict hospitalization.MethodsThis was an observational, multicentric study. We enrolled 128 patients referred to the ED with high fever and a suspicion of severe infection such as sepsis, lower respiratory tract infections, urinary tract infections, gastrointestinal infections, soft tissue infections, central nervous system infections, or osteomyelitis. The APACHE II score was calculated for each patient.ResultsMR-proADM median values in controls were 0.5 nmol/l as compared with 0.85 nmol/l in patients (P < 0.0001), while PCT values in controls were 0.06 ng/ml versus 0.56 ng/ml in patients (P < 0.0001). In all patients there was a statistically significant stepwise increase in MR-proADM levels in accordance with PCT values (P < 0.0001). MR-proADM and PCT levels were significantly increased in accordance with the Apache II quartiles (P < 0.0001 and P = 0.0012 respectively).In the respiratory infections, urinary infections, and sepsis-septic shock groups we found a correlation between the Apache II and MR-proADM respectively and MR-proADM and PCT respectively. We evaluated the ability of MR-proADM and PCT to predict hospitalization in patients admitted to our emergency departments complaining of fever. MR-proADM alone had an AUC of 0.694, while PCT alone had an AUC of 0.763. The combined use of PCT and MR-proADM instead showed an AUC of 0.79.ConclusionsThe present study highlights the way in which MR-proADM and PCT may be helpful to the febrile patient’s care in the ED. Our data support the prognostic role of MR-proADM and PCT in that setting, as demonstrated by the correlation with the APACHE II score. The combined use of the two biomarkers can predict a subsequent hospitalization of febrile patients. The rational use of these two molecules could lead to several advantages, such as faster diagnosis, more accurate risk stratification, and optimization of the treatment, with consequent benefit to the patient and considerably reduced costs.