Stefano Necozione

Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH). Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH. After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43.7±7.8 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period, patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment. The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values. Ambulatory BP decreased after DC (24-hour systolic BP −11.9±7.7 mm Hg, P<0.0001; 24-hour diastolic BP −8.5±5.0 mm Hg, P<0.0001) but not WC. DC but not WC decreased HOMA-IR (P<0.0001), but it improved QUICKI, ISI, and FMD. DC also decreased serum LDL cholesterol (from 3.4±0.5 to 3.0±0.6 mmol/L; P<0.05). In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives. These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH.

Is Theory of Mind in Schizophrenia More Strongly Associated with Clinical and Social Functioning than with Neurocognitive Deficits

This paper examines the correlations between ‘Theory of Mind’ (ToM) and neurocognitive performance, together with clinical and social functioning, in out-patients with schizophrenic disorders. It was hypothesised that, since the ability to make inferences about the environment and about other peoples’ mental states is a key ingredient of social competence, the assessment of ToM would correlate more strongly with current social functioning than with more traditional neurocognitive measures. ‘Independent raters’ assessed Theory of Mind, neurocognitive and clinical variables as well as community functioning in 44 subjects with schizophrenia. The neuropsychological measures were more closely associated with community functioning than with psychiatric symptoms. These associations remained evident when the effects of intelligence were controlled. Patients with a higher level of competence in making social inferences had better overall community functioning than those who showed less ability in this aspect of social cognition. In a regression model, the capacity to comprehend other people’s mental states (ToM-2) was among the best predictors of global social functioning, together with recent onset of illness, good verbal fluency and low levels of negative and positive symptoms. These results are consistent with other recent findings. ToM measures of social cognition may be a useful addition to neuropsychological assessment when developing programmes for reducing clinical impairments and improving the community functioning of subjects with schizophrenic disorders. Further studies are needed to verify the value of these measures as predictors of the successful application of specific psychosocial rehabilitation strategies.

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment The Cocoa, Cognition, and Aging (CoCoA) Study

Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P=0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P<0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P<0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r2=0.4013; P<0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study—a randomized controlled trial

Background: Recent evidence has indicated that flavanol consumption may have many health benefits in humans, including improved cognitive activities. Objective: The aim was to evaluate the effect of flavanol consumption on cognitive performance in cognitively intact elderly subjects. Design: This was a double-blind, controlled, parallel-arm study conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 wk a drink containing 993 mg [high flavanol (HF)], 520 mg [intermediate flavanol (IF)], or 48 mg [low flavanol (LF)] cocoa flavanols (CFs). Cognitive function was assessed at baseline and after 8 wk by using the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT) A and B, and the Verbal Fluency Test (VFT). Results: The changes in MMSE score in response to the 3 different treatments were not different. In contrast, there was a positive impact of the intervention on specific aspects of cognitive function. Mean changes (±SEs) in the time required to complete the TMT A and B after consumption of the HF (−8.6 ± 0.4 and −16.5 ± 0.8 s, respectively) and IF (−6.7 ± 0.5 and −14.2 ± 0.5 s, respectively) drinks significantly (P < 0.0001) differed from that after consumption of the LF drinks (−0.8 ± 1.6 and −1.1 ± 0.7 s, respectively). Similarly, VFT scores significantly improved among all treatment groups, but the magnitude of improvement in the VFT score was significantly (P < 0.0001) greater in the HF group (7.7 ± 1.1 words/60 s) than in the IF (3.6 ± 1.2 words/60 s) and LF (1.3 ± 0.5 words/60 s) groups. Significantly different improvements in insulin resistance (P < 0.0001), blood pressure (P < 0.0001), and lipid peroxidation (P = 0.001) were also observed for the HF and IF groups in comparison with the LF group. Changes in insulin resistance explained ∼17% of changes in composite z score (partial r2 = 0.1703, P < 0.0001). Conclusions: This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age. This trial was registered at www.controlled-trials.com as ISRCTN68970511.

Protective Effects of Flavanol-Rich Dark Chocolate on Endothelial Function and Wave Reflection During Acute Hyperglycemia

Nitric oxide plays a pivotal role in regulating vascular tone. Different studies show endothelial function is impaired during hyperglycemia. Dark chocolate increases flow-mediated dilation in healthy and hypertensive subjects with and without glucose intolerance; however, the effect of pretreatment with dark chocolate on endothelial function and other vascular responses to hyperglycemia has not been examined. Therefore, we aimed to investigate the effects of flavanol-rich dark chocolate administration on (1) flow-mediated dilation and wave reflections; (2) blood pressure, endothelin-1 and oxidative stress, before and after oral glucose tolerance test (OGTT). Twelve healthy volunteers (5 males, 28.2±2.7 years) randomly received either 100 g/d dark chocolate or flavanol-free white chocolate for 3 days. After 7 days washout period, volunteers were switched to the other treatment. Flow-mediated dilation, stiffness index, reflection index, peak-to–peak time, blood pressure, endothelin-1 and 8-iso-PGF2&agr; were evaluated after each treatment phase and OGTT. Compared with white chocolate, dark chocolate ingestion improved flow-mediated dilation (P=0.03), wave reflections, endothelin-1 and 8-iso-PGF2&agr; (P<0.05). After white chocolate ingestion, flow-mediated dilation was reduced after OGTT from 7.88±0.68 to 6.07±0.76 (P=0.027), 6.74±0.51 (P=0.046) at 1 and 2 h after the glucose load, respectively. Similarly, after white chocolate but not after dark chocolate, wave reflections, blood pressure, and endothelin-1 and 8-iso-PGF2&agr; increased after OGTT. OGTT causes acute, transient impairment of endothelial function and oxidative stress, which is attenuated by flavanol-rich dark chocolate. These results suggest cocoa flavanols may contribute to vascular health by reducing the postprandial impairment of arterial function associated with the pathogenesis of atherosclerosis.

Cocoa consumption dose-dependently improves flow-mediated dilation and arterial stiffness decreasing blood pressure in healthy individuals.

Background: Cocoa flavonoids exert beneficial vascular effects and reduce the risk of cardiovascular morbidity and mortality. Nevertheless, the involved mechanisms have not been clarified and no study has yet focused on the dose–response effects. Objectives: We aimed to investigate the effects of different doses of cocoa flavonoids on flow-mediated dilation (FMD), endothelin-1 (ET-1), pulse wave velocity (PWV), and SBP and DBP. Design: According to a randomized, double-blind, controlled, cross-over design, 20 healthy volunteers (1.5% improvement in FMD in 20 individuals: 0.99 at alpha = 0.05) were assigned to receive either five treatments with daily intake of 10 g cocoa (0, 80, 200, 500 and 800 mg cocoa flavonoids/day) in five periods lasting 1 week each. Results: Cocoa dose-dependently increased FMD from 6.2% (control) to 7.3, 7.6, 8.1 and 8.2% after the different flavonoid doses, respectively (P < 0.0001). Compared with the control, even 80 mg cocoa flavonoids per day increased FMD (P < 0.0001). Cocoa dose-dependently decreased PWV (P < 0.0001). Cocoa intake decreased office blood pressure (BP) (SBP: −4.8 ± 1.03 mmHg, P < 0.0001; DBP: −3.03 ± 1.07 mmHg, P = 0.0011). With respect to control, cocoa ingestion decreased 24-h (P = 0.05) and daytime (P = 0.038) SBP, and 24-h (P = 0.0064), daytime (P = 0.0088) and night-time (P = 0.0352) pulse pressure. Compared with the control, cocoa dose-dependently decreased ET-1 levels [from 17.1 (control) to 15.2, 14.5, 14.2 and 14.1 pg/ml, after the different flavonoid doses, respectively (P for treatment <0.05)]. Compared with the control, significant changes were observed for all doses of flavonoids (ET-1; P < 0.05). Conclusion: Our study showed for the first time that cocoa dose-dependently improved FMD and decreased PWV and ET-1 also by ameliorating office and monitored BP. Our findings are clinically relevant, suggesting cocoa, with very low calorie intake, might be reasonably incorporated into a dietary approach, representing a consistent tool in cardiovascular prevention.

Preoperative APACHE II and ASA Scores in Patients Having Major General Surgical Operations: Prognostic Value and Potential Clinical Applications

OBJECTIVE To assess the prognostic value of the APACHE II score and the American Society of Anesthesiologists (ASA) classification system in preoperative evaluation of patients. DESIGN Prospective study. SETTING University hospital, Italy. SUBJECTS 187 consecutive patients undergoing elective or emergency major general surgical operations. INTERVENTIONS Patients were evaluated preoperatively using both indices. MAIN OUTCOME MEASURES Morbidity and mortality within 30 days. RESULTS Logistic regression and ROC curve analyses showed that the APACHE II score predicted morbidity and mortality well; it was superior to the ASA system in predicting outcome (area under the curve 0.894 for the APACHE II index, 0.777 for the ASA system; p < 0.001). The APACHE II score without its age points (area 0.888) had the same prognostic value as the complete score (area 0.894; p = 0.55). CONCLUSIONS The APACHE II score may help clinicians to evaluate preoperatively the risk of postoperative morbidity and death after major general surgical operations. Age does not seem to have a specific weight.

Low birth weight and later development of insulin resistance and biochemical/clinical features of polycystic ovary syndrome

Reduced insulin sensitivity in adult life has been reported in subjects born at term small for gestational age (SGA) and in those born prematurely with very low birth weight (LBW) (<1,500 g). We assessed whether LBW (<2,500 g) young women, irrespective of whether they were born SGA or adequate for gestational age (premature AGA), exhibited a reduction in insulin sensitivity through a prospective historical design. The risk of developing biochemical and clinical features of polycystic ovary syndrome was also investigated. The study population included 35 LBW women (19 SGA [BW range, 1,000-2,400 g] and 16 premature AGA [BW range, 1,700-2,440 g]) aged 21.8 +/- 1.8 years and 35 term AGA controls, of similar age, recruited from a neonatal registry. All women underwent clinical, ultrasonographic, hormonal, and metabolic evaluations, including the composite insulin sensitivity index. Women under hormonal contraception (21.4%) were excluded from hormonal and metabolic analyses. Composite insulin sensitivity index was significantly lower in LBW women even when the 2 LBW subgroups, SGA and premature AGA, were analyzed separately (4.4 +/- 2.2 and 4.0 +/- 1.7, respectively) than in controls (6.9 +/- 4.4). The LBW women showed a significantly higher incidence proportion of irregular menses (14/35 [40%] vs 2/35 [5.7%]) and a significantly higher free androgen index (5.8 +/- 3.5 vs 3.9 +/- 3.2). They also showed a nonsignificantly higher proportion of hirsutism, acne, and polycystic ovaries. In conclusion, LBW (<2,500 g) young women, irrespective of whether they were SGA and premature AGA, exhibited a reduction in insulin sensitivity as compared with born at term AGA women. Furthermore, they exhibited an increased risk of developing clinical and biochemical features of polycystic ovary syndrome.

The Italian version of the lower extremity functional scale was reliable, valid, and responsive.

OBJECTIVE To determine the measurement properties of an Italian Version of the Lower Extremity Functional Scale (LEFS) in patients with lower extremity musculoskeletal dysfunction. STUDY DESIGN AND SETTING This is a prospective methodological study of repeated measures with a sample of 250 consecutive patients. Reliability, validity, and responsiveness were evaluated. RESULTS The Italian version of the LEFS showed a high degree of internal consistency with a Cronbach alpha of 0.94 (95% confidence interval [CI]: 0.91, 0.96). The test-retest reliability was high for both intra-interviewer and inter-interviewer measures with an ICC((2,1 and 2,k)) of 0.91 (95% CI: 0.86, 0.93) and 0.89 (95% CI: 0.83, 0.91), respectively. The LEFS showed a better correlation with the 36-Item Short-Form Health Survey (SF-36) physical component summary score rather than with the SF-36 mental component summary score both at the initial assessment (r=0.61 and 0.26, respectively) and at the discharge (r=0.72 and 0.22, respectively). Receiver operating characteristic curve analysis revealed a large responsiveness for the LEFS (area under the curve [AUC]=0.97) and a moderate responsiveness for the SF-36 (AUC=0.68). CONCLUSION The Italian version of the LEFS is a valid, reliable, and responsive tool that can be used to measure function in Italian patients with lower extremity musculoskeletal dysfunction.

Enhanced soluble CD40 ligand and Alzheimer's disease: Evidence of a possible pathogenetic role

It has been suggested that cerebrovascular factors contribute to Alzheimers disease. Soluble CD40 ligand (sCD40L) is directly involved in the development of vascular damage. We tested the hypothesis that sCD40L may be enhanced in Alzheimers disease and predictive of its clinical course. Plasma sCD40L levels were evaluated in three groups of 40 consecutive patients each referring for mild or moderate or severe Alzheimers disease, as assessed by the Clinical Dementia Rating (CDR), and in 40 healthy subjects. Seventy-seven patients with mild or moderate disease were re-evaluated after 2 years. Cross-sectional comparisons revealed higher plasma sCD40L levels in Alzheimers disease patients than in controls (9.3+/-4.7 ng/mL versus 3.4+/-1.3 ng/mL, p<0.0001). Circulating sCD40L levels significantly increased through the three CDR stages (p=0.0011 or less) and were correlated with MMSE (r=-0.574, p<0.0001) and ADAS-cog subscale (r=0.538, p<0.0001) scores. Longitudinal evaluation identified sCD40L as an independent predictor of MMSE (beta=-0.157, t=-3.650, p=0.0005) and ADAS-cog subscale (beta=0.484, t=3.890, p=0.0002) score changes after 2 years. Patients with plasma sCD40L level>or=6.0 ng/mL, identified by ROC curve analysis as the best discriminating value for disease progression, had a three-fold increase in the risk of progression toward a worse CDR stage (odd ratio: 3.0, C.I. 95% 1.2-8.1). In conclusion, circulating sCD40L is enhanced in patients with Alzheimers disease and independently associated with the severity and progression of the disease. These data might suggest a pathogenetic role for sCD40L in Alzheimers disease.