CIRCADIAN RHYTHMS AND NUTRITION

The system of Circadian Rhythms is a mechanism that, in the forms of animal life, has evolved in order to synchronize the behavior and physiological responses to environmental periodical stimuli, so as to allow faster response and better adaptation to environmental changes. These stimuli (light, food availability, presence of predators, availability of a partner for reproduction) in turn depend on the rotation of the earth on its axis and around the sun. In mammals, there is a central hypothalamic clock , said Master Clock, directly regulated by light in its periodicity, which therefore plays the role of primary synchronizer, and several peripheral clocks, Slave Clock, synchronized with each other and constantly reset the MC. Between external stimuli food plays a fundamental role, as capable of take the place of the light in certain conditions. In recent years there has emerged a direct correlation between alteration of Circadian Rhythm , variously induced, and the development of multifactorial diseases such as obesity and diabetes. The biological clock is involved in the maintenance of energy homeostasis and thus in search of food and in the regulation of body weight. The recent concept of chrono-nutrition, expressed perfectly the influence of food, through times of intake but also by its specific composition, is able to exert on the expression of regulatory genes of circadian rhythms, and therefore the maintenance or alteration of energy homeostasis of the org

A low resting metabolic rate is associated with metabolic syndrome

Background & aims: The metabolic syndrome is associated with central accumulation of fat. Previous studies showed that some obese subjects are characterized by a sparing energy metabolism. The aim of this study was to investigate whether obese subjects with metabolic syndrome have a lower resting metabolic rate than obese subjects without metabolic syndrome. Methods: Forty obese subjects were divided into three groups according to the presence of metabolic syndrome and type 2 diabetes; 15 non-obese healthy control subjects were also enrolled. Body composition (bio-impedance analysis) and resting metabolic rate (indirect calorimetry) were performed. Results: The group with metabolic syndrome exhibited a significantly lower resting metabolic rate adjusted for fat-free mass with respect to the control group and the obese group without metabolic syndrome (respectively: 10873 vs. 11873, po0.01 and 12373kJ/kg fat-free mass 24h, po0.01; mean7sem). The obese group with metabolic syndrome and type 2 diabetes (T2D) had a not different adjusted resting metabolic rate (11476 kJ/kg fat-free mass 24 h) with respect to other groups. Conclusions: An energy sparing condition seems to characterize non-diabetic obese subjects with metabolic syndrome

Coffee and endothelial function: a battle between caffeine and antioxidants ?

Although coffee is largely consumed by adults in Western countries, controversy exists about its impact on the cardiovascular system. We recently demonstrated that caffeinated and decaffeinated espresso coffee have different acute effects on endothelial function in healthy subjects, measured using flow-mediated dilation (FMD) of the brachial artery. In this study, we measured the anti-oxidant capacity of two coffee substances in terms of free stable radical 2,2-diphenyl-1-picryl-hydrazyl 50% inhibition (I50 DPPH). The caffeinated coffee had a slightly higher anti-oxidant capacity than decaffeinated espresso coffee (I50 DPPH: 1.13±0.02 vs 1.30±0.03 ml; Po0.001). We suggest that the unfavourable effects observed after caffeinated coffee ingestion are due to caffeine and that the antioxidant activity is responsible for the increased FMD observed after decaffeinated coffee ingestion. Further clinical and epidemiological studies are needed to understand the chronic effects of coffee consumption on health

Acute effects of coffee on QT interval in healthy subjects

The coronary endothelial function is recognized to have an important role in the physiology of the diastolic ventricular relaxation, a phase of the heart cycle that influences the electrocardiographic QT interval. Endothelial function is investigated in vivo by flow mediated dilation (FMD) in the brachial artery and has proven to be a strong predictor of both coronary endothelial function and cardiovascular events. It has been reported that coffee acutely induces FMD changes. In particular, the brachial artery FMD seems to decrease after caffeinated coffee (CC) and to increase after decaffeinated coffee (DC) ingestion. Since the cardiovascular effects of coffee are still a debated matter, this study aimed at investigating with a randomized, double-blind crossover design, if the QT interval of adult healthy subjects (19 males and 21 females) changes in the hour following CC or DC ingestion. Both systolic and diastolic blood pressure were higher in the hour following the ingestion of CC; the heart rate significantly increased 30 minutes after CC ingestion. A significant increase of the QT duration was observed one hour after DC ingestion (398.9 ± 3.8 vs 405.3 ± 3.7 msec; P < 0.05), not after CC. The QT interval corrected for heart rate did not significantly change following CC or DC ingestion. In conclusion, despite CC and DC previously demonstrated to influence the FMD they do not seem to induce a significant unfavourable acute change of the left ventricular repolarization. Further investigations are required to elucidate the effects of coffee in subjects with cardiovascular diseases

Intrarenal hemodynamics and carotid intima-media thickness in the metabolic syndrome

Aims: Metabolic syndrome (MetS) is associated with increased cardiovascular risk. We hypothesize that early vascular changes are already present at the time of diagnosis of MetS. The relationship of different measures of early vascular impairment with body fat distribution and the natural progression of MetS was examined in newly diagnosed subjects non-pharmacologically treated. Methods: 246 consecutively enrolled subjects were categorized according to the presence of MetS and type 2 diabetes (T2D). Intra-renal Doppler flow was used to ascertain resistive (RI) and pulsatility (PI) indices as markers of vascular resistance. Carotid intima-media thick- ness (IMT), cutis-rectis (CR) and rectis-aorta (RA) thicknesses were measured by ultrasono- graphy; RA/CR ratio was used as measure of body fat distribution. Pro-inflammatory cytokines, C-reactive protein, oxidative markers insulin and adiponectin blood concentra- tions were also measured. Results: Baseline characteristics demonstrated increasing trends in biochemical, inflam- matory, and oxidative parameters from MetS??, MetS+, to MetS+/T2D (p&lt;0.001). After adjusting for age, the same increasing trends across the groups were observed in both sexes in IMT (p &lt; 0.001), RI (p &lt; 0.001) and PI (p &lt; 0.001). IMT correlated with RI (r = 0.25; p &lt; 0.001), PI (r = 0.26; p &lt; 0.001), and RA/CR ratio (r = 0.43; p &lt; 0.001). Conclusions: Carotid IMT and intra-renal resistances are elevated at an early stage in MetS and are associated with a dysregulated production of fat-derived hormones and cytokines

Short and middle term effects of hypocaloric low carbohydrate diet vs hypocaloric Mediterranean diet on endothelial function in obese subjects

Adequate nutritional treatment is required to address the problem of increasing prevalence of obesity in Western countries. The Mediterranean diet style is now acknowledged to have large scientific evidences in terms of cardiovascular prevention. However, many popular diets are diffusing also as self-prescribed treatments. Among those, the efficacy of low-carbohydrate diets (also known as Atkins’ diet in its most popular variety) has been addressed by some investigations. It is generally concluded that the low-carbohydrate diet is able to induce a greater weight loss, at least in the middle term, and a better serum lipid profile than the conventional diet. In this longitudinal, randomised, open study we compared the effects on endothelial function of a hypocaloric low-carbohydrate diet (according to the Atkins’ diet; AD) versus a similarly hypocaloric Mediterranean diet (MD). Overweight-obese (range of BMI: 27-34.9 Kg/m2; range of age: 30-50 years) otherwise healthy, normal glucose tolerant women were enrolled and randomly assigned to one of the two dietary treatments until reaching the final number of 10 women for each group of treatment. So, twenty-five women were enrolled and five of them (3 in the MD group and 2 in the AD group) were subsequently excluded from the study due to intercurrent diseases (1 subject) or declaration of inadequate compliance (2 subjects) or f voluntary drop out (2 subjects). Measurements were performed before (T0), 5-7 days (T5) and 2 months (T60) after starting the diet treatment. Endothelial function was investigated at each time of the study by measuring the brachial artery flow-mediated dilation (FMD). Serum concentrations of insulin, adiponectin, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and 8-iso-prostaglandin (8-iso-PG) F2α were also assessed at each time of the study. Urinary ketone bodies were observed at T5 only in AD group. Briefly, body weight was not significantly decreased at T5 in both groups; as expected, a higher body weight reduction was observed at T60 in AD group (change in body weight T60 – T0, mean ± sem, MD -4.9 ± 0.6 Kg vs AD -7.6 ± 0.8 Kg, p= 0.014). The FMD was significantly reduced at T5 in the AD group and increased at T60 until reaching the T0 values (T0: 12.2 ± 2.9; T5: 5.2 ± 0.8; T60: 11.0 ± 1.2 %; p< 0.05 T5 vs T0 and T60). On the contrary, the FMD increased significantly at T5 in the MD group and decreased until reaching values comparable to those of T0 at T60 (T0: 10.3 ± 2.3; T5: 14.5 ± 2.8; T60: 10.6 ± 1.9 %; p< 0.05 T5 vs T0 and T60). This trend of FMD change was observed in each subject. Insulin concentrations and HOMA-I decreased significantly at T5 and at T60 in both groups. Adiponectin and TNF-α concentrations remained unchanged in both groups throughout the study. Both IL-6 and 8-iso-PGF2α increased significantly at T5 in the AD group and decreased at T60 to values comparable to T0 (IL-6: T0 57.5 ± 9.0, T5 78.1 ± 10.9, T60 56.6 ± 6.8 pg/ml; T5 vs T0 p< 0,005, T5 vs T60 p< 0,02; 8-iso-PGF2α: T0 171.5 ± 30.6, T5 222.6 ± 35.1, T60 178.7 ± 25.8 pg/ml; T5 vs T0 p< 0,005, T5 vs T60 p< 0,02); no significant change was observed in the MD group. This study suggests that the hypocaloric low-carbohydrate diet induces a significant endothelial dysfunction in the short term (5-7 days) that is reverted in the middle term (2 months) as suggested by both the brachial artery FMD and serum markers of inflammation (IL-6) and oxidative stress (8-iso-PGF2α). On the contrary, the hypocaloric Mediterranean diet is able to improve the endothelial function at least in the short term. These effects are independent of body weight loss. Therefore, this study points out also the potential disadvantages of low-carbohydrate diets when prescribed (or self-prescribed) especially in subjects at high cardiovascular risk

Acute effects of coffee on endothelial function in healthy subjects

Background/Objectives: Coffee is the most widely consumed beverage in the world, but its effect on the cardiovascular system has not been fully understood. Coffee contains caffeine and antioxidants, which may influence endothelial function, both of which have not yet been investigated. The objective of this study was to investigate the acute effects of coffee on endothelial function measured by brachial artery flow-mediated dilation (FMD). Subjects/Methods: A total of 20 (10 males and 10 females) healthy non-obese subjects underwent a double-blind, crossover study. Subjects ingested one cup of caffeinated (CC) and one cup of decaffeinated (DC) Italian espresso coffee in random order at 5- to 7-day intervals. Results: Following CC ingestion, FMD decreased progressively and significantly (mean±s.e.m.: 0min, 7.7±0.6; 30min, 6.3±0.7; 60 min, 6.0±0.8%; ANOVA (analysis of variance), Po0.05), but it did not significantly increase after DC ingestion (0min, 6.9±0.6; 30min, 8.1±0.9; 60min, 8.5±0.9%; P1⁄40.115). Similarly, CC significantly increased both systolic and diastolic blood pressure; this effect was not observed after DC ingestion. Blood glucose concentrations remained unchanged after ingestion of both CC and DC, but insulin (0min, 15.8±0.9; 60min, 15.0±0.8mU/ml; Po0.05) and C-peptide (0min, 1.25±0.09; 60 min, 1.18±0.09 ng/ml; Po0.01) blood concentrations decreased significantly only after CC ingestion. Conclusions: CC acutely induced unfavorable cardiovascular effects, especially on endothelial function. In the fasting state, insulin secretion is also likely reduced after CC ingestion. Future studies will determine whether CC has detrimental clinically relevant effects, especially in unhealthy subjects

Endothelial function and serum concentration of toxic metals in frequent consumers of fish

BACKGROUND:Endothelial dysfunction is involved in the pathogenesis of atherosclerosis. Consumption of fish is associated with reduced cardiovascular risk, but there is paucity of data concerning its effect on endothelial function. Furthermore, investigation of the effects of fish consumption on health must take into account the ingestion of contaminants, including transition metals and some metalloids, which may have unfavorable effects on health, including those on the cardiovascular system. We investigated the association between fish consumption, endothelial function (flow mediated dilation of the brachial artery), and serum concentration of some toxic metals in apparently healthy people. METHODS:Twenty-nine high fish consumers (at least 3 portions a week) were compared with 25 low fish consumers (less than 1 portion a week). All participants were free of diabetes, cardiovascular or other systemic diseases. Serum metal (antimonium, arsenic, mercury, lead, cobalt, copper, zinc, selenium, strontium) concentrations were measured in subgroups of 24 high fish consumers and 19 low fish consumers. RESULTS:Both groups exhibited similar habitual dietary patterns, age and anthropometric characteristics. The high fish consumers had higher flow mediated dilation (9.7 ± 1.8 vs. 7.3 ± 1.9%; P<0.001), but also higher serum concentrations of mercury (5.87 ± 2.69 vs. 1.65 ± 1.10 mcg/L; P<0.001) and arsenic (6.04 ± 3.25 vs. 2.30 ± 1.58 mcg/L; P<0.001). The fasting plasma glucose concentrations were significantly correlated with both mercury (r = 0.39; P = 0.01) and arsenic concentrations (r = 0.55; P<0.001). CONCLUSIONS:Habitual consumption of high amounts of fish is associated with better endothelial function despite higher serum concentrations of mercury and arsenic

SHIP2: A ‘‘NEW’’ Insulin Pathway Target for Aging Research

Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovascular disease, as well as Alzheimer’s disease (AD), all characterized by chronic inflammatory status. On the other hand, extensive abnormalities in insulin and insulin-like growth factor I (IGF-I) and IGF-II signaling mechanisms in brains with AD have been demonstrated, suggesting that AD could be a third form of diabetes. The Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) has an important role in the insulin pathway because its over-expression causes impairment of insulin/IGF-1 signaling. Because some singlenucleotide polymorphisms (SNP) of the gene encoding SHIP2 were significantly associated in T2DM patients with metabolic syndrome and some related conditions, we decided to conduct a case–control study on this gene, analyzing AD and T2DM subjects as cases and young, old, and centenarians as controls. Our results suggest a putative correlation between the the rs144989913 SNP and aging, both successful and unsuccessful, rather than age-related diseases. Because this SNP is an insertion/deletion of 28 bp, it might cause an alteration in SHIP2 expression. It is noteworthy that SHIP2 has been demonstrated to be a potent negative regulator of insulin signaling and insulin sensitivity. Many studies demonstrated the association of the insulin/IGF1 pathway with aging and longevity, so it is tempting to speculate that the found association with SHIP2 and aging might depend on its effect on the insulin/IGF-1 pathwa

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study

: Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p &lt; 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin ) was greater than three times higher than reported; moreover, midostaurin Cmin , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient