Positive Association of High Leptin Level and Abdominal Aortic Calcification in Men　- The Prospective MINOS Study.

BACKGROUND: Severe abdominal aortic calcification (AAC) points to high cardiovascular risk and leptin stimulates arterial calcification; however, clinical data on their association are scarce. We studied the link between serum leptin and AAC severity and progression, and the effect of smoking and lipid levels, on this association in men. Methods and Results: At baseline, 548 community-dwelling men aged 50-85 years underwent blood collection and lateral lumbar spine radiography. In 448 men, X-ray was repeated after 3 and 7.5 years. AAC was assessed using Kauppila's semiquantitative score. In multivariable models, high leptin was associated with higher odds of severe AAC (odds ratio [OR]=1.71 per SD, 95% confidence interval [CI]: 1.22-2.40). The odds of severe AAC were the highest in men who had elevated leptin levels and either were ever-smokers (OR=9.22, 95% CI: 3.43-24.78) or had hypertriglyceridemia (vs. men without these characteristics). Higher leptin was associated with greater AAC progression (OR=1.34 per SD, 95% CI: 1.04-1.74). The risk of AAC progression was the highest in men who had elevated leptin levels and either were current smokers or had high low-density lipoprotein-cholesterol levels (OR=5.91, 95% CI: 2.46-14.16 vs. men without these characteristics). These links remained significant after adjustment for baseline AAC and in subgroups defined according to smoking and low-density lipoprotein-cholesterol levels. CONCLUSIONS: In older men, high leptin levels are associated with greater severity and rapid progression of AAC independent of smoking, low-density lipoprotein-cholesterol or triglycerides.

High serum oxytocin is associated with metabolic syndrome in older men - The MINOS study.

AIM: Oxytocin regulates food intake, carbohydrate and lipid metabolism, and urinary sodium excretion. We assessed the association between serum oxytocin levels and presence of metabolic syndrome (MetS) in older men. METHODS: Cross-sectional study was performed in 540 volunteer men aged 50-85yrs from the MINOS cohort. Oxytocin was measured in fasting serum by radioimmunoassay (Oxytocin RIA, Phoenix Pharmaceuticals). MetS was diagnosed using the harmonized definition. RESULTS: Serum oxytocin was higher in 166 men with MetS vs. controls (p<0.005). After adjustment for confounders including leptin, higher oxytocin was associated with higher odds of MetS (OR=1.38 per SD, 95%CI: 1.10-1.71, p<0.005). Men with serum oxytocin >0.74pg/mL (median) had higher odds of MetS vs. men with oxytocin ⩽0.74pg/mL (OR=2.06, 95%CI: 1.33-3.18, p<0.005). Higher oxytocin levels and low testosterone levels (total or free) were significantly associated with higher odds of MetS jointly and independently of each other. Men having oxytocin >0.74pg/mL and total testosterone <300ng/dL (<10.4nmol/L) had higher odds of MetS vs. men without these characteristics (OR=3.95, 95%CI: 1.65-9.46, p<0.005). Men having 25-hydroxycholecalciferol levels <30ng/mL and oxytocin >0.74pg/mL had higher odds of MetS vs. men without these characteristics (OR=2.86, 95%CI: 1.47-5.58, p<0.01). Men having oxytocin >0.74pg/mL and osteocalcin levels <14.6ng/mL (lowest quartile) had higher odds of MetS vs. men without these characteristics (OR=4.12, 95%CI: 2.07-8.20, p<0.001). CONCLUSION: In older men, higher serum oxytocin levels are associated with higher odds of MetS regardless of potential confounders.

Dramatic increase of central venous catheter-related infections associated with a high turnover of the nursing team.

BACKGROUND & AIMS: This retrospective study evaluated the impact of new organization during the moving to a new university pediatric hospital on the incidence of central catheter-related blood stream infections (CRBSIs) among children on long-term parenteral nutrition. METHODS: The study ran from April 2007 to March 2014, starting a year prior to reorganisation of the department of pediatric Hepato-Gastroenterology and Nutrition associated to moving the children to a new hospital in April 2008, and continuing for 6 years following the move. During this time, data from all children hospitalized in this department who received parenteral nutrition (PN) for more than 15 days were analysed. RESULTS: During this 7-years study, 183 children aged 4.6 ± 0.5 years received prolonged PN. Intestinal diseases were the main aetiologies (89%), primarily short bowel syndrome (18.4%), Hirschsprung disease and CIPO (13.5%) and inflammatory bowel disease (13.8%). The mean durations of hospitalization and of PN during hospitalization were, respectively, 70 ± 2.1 and 55.7 ± 3.6 days. During the study period, 151 CRBSIs occurred in 77 children (42% of all patients), i.e. 14.8 septic episodes/1000 PN days and 12.0 septic episodes/1000 CVC days. No patient died of a central venous catheter-related infection. However, following the move from the older hospital to the newer one, the rate of CRBSIs significantly doubled, from 3.9/1000 to 8.8/1000 CVC days (p = 0.02). During the following 4 years, the incidence of CRBSIs tended to increase between the 2nd and the 5th year after the move: 11.3 (p = NS); 21.4 (p = 0.01); 17.3 (p = NS), 20.3/1000 (p = NS) CVC days. We also observed that after evaluations by the Department of Infection Control, nurse training and stabilization of the nursing team, the incidence decreased significantly from 20.3 to 11.1/1000 CVC days during the 6th year after the move (p = 0.01). CONCLUSION: Our results reveal the deleterious impact of the reorganization during the hospital moving on the CRBSI incidence rate, and the possible implication of inexperienced team of nurses.

Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria

We aimed to study the change in mitochondrial oxidative phosphorylation efficiency occurring at the early stage of septic shock in an experimental model. Thirty-six male Wistar rats were divided into two groups. In the first group, a cecal ligation and puncture (CLP) was carried out to induce septic shock for 5 h. The second group includes sham-operated rats and constitutes the control group. Blood gas analysis, alanine amino transferase, and lactic acid dosages were assayed 5 h after surgery. Liver mitochondria were isolated for in vitro functional characterization, including mitochondrial respiratory parameters, oxidative phosphorylation efficiency, oxi-radical production, membrane potential, and cytochrome c oxidase activity and content. Liver interleukin 1β (IL-1β) and tumor necrosis α mRNA levels were determined. Septic shock induced a severe hypotension occurring 180 min after CLP in association with a metabolic acidosis, an increase in plasma alanine amino transferase, liver IL-1β gene expression, and mitochondrial reactive oxygen species production. The rates of mitochondrial oxygen consumption and the activity and content of cytochrome c oxidase were significantly decreased while no alterations in the oxidative phosphorylation efficiency and inner membrane integrity were found. These results show that contrary to what was expected, liver mitochondria felt to adjust their oxidative phosphorylation efficiency in response to the decrease in the mitochondrial oxidative activity induced by CLP. This loss of mitochondrial bioenergetics plasticity might be related to mitochondrial oxidative stress and liver cytokines production

Lower serum osteocalcin is associated with more severe metabolic syndrome in elderly men from the MINOS cohort.

BACKGROUND: Bone has emerged as an endocrine organ regulating energy metabolism through secretion of osteocalcin. In epidemiological studies, presence of metabolic syndrome (MetS) was associated with lower osteocalcin level. OBJECTIVES: We evaluated whether osteocalcin level was associated with MetS severity in men and whether it was more strongly associated with MetS compared with N-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP), and C-terminal telopeptide of type I collagen (ßCTX). METHODS: We included 798 men aged 51-85 years for total osteocalcin measurement. Number of MetS criteria was used to define severity. We used polytomous logistic regression to assess the relationship between MetS severity and osteocalcin level. RESULTS: Thirty percent of men had MetS. In patients with MetS, the higher the number of MetS traits were present, the lower was the average osteocalcin level (0-2 criteria: 551 men: 19.5±6.7 ng/ml, three criteria: 155 men: 19.3±7.4 ng/ml, four criteria: 72 men: 17.3±5.7 ng/ml, and five criteria: 20 men: 15.0±5.1 ng/ml; P for trend=0.002).In the polytomous logistic regression model, an increase in osteocalcin level of 10 ng/ml was associated with lower prevalence of severe MetS: three criteria (odds ratio (OR)=0.93 (0.70-1.24)), four criteria (OR=0.54 (0.34-0.84)), and five criteria (OR=0.28 (0.10-0.82)) in comparison with no MetS (P for trend=0.008).After adjustment, using stepwise analysis of the polytomous logistic regression model, we observed that osteocalcin, age, and apparent free testosterone entered in the model but not other bone markers (PINP, ßCTX, and BAP). CONCLUSION: In older Caucasian men, total osteocalcin level was associated with MetS severity. Osteocalcin was more strongly associated with MetS severity than other bone turnover markers.

Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria.

We aimed to study the change in mitochondrial oxidative phosphorylation efficiency occurring at the early stage of septic shock in an experimental model. Thirty-six male Wistar rats were divided into two groups. In the first group, a cecal ligation and puncture (CLP) was carried out to induce septic shock for 5 h. The second group includes sham-operated rats and constitutes the control group. Blood gas analysis, alanine amino transferase, and lactic acid dosages were assayed 5 h after surgery. Liver mitochondria were isolated for in vitro functional characterization, including mitochondrial respiratory parameters, oxidative phosphorylation efficiency, oxi-radical production, membrane potential, and cytochrome c oxidase activity and content. Liver interleukin 1ß (IL-1ß) and tumor necrosis α mRNA levels were determined. Septic shock induced a severe hypotension occurring 180 min after CLP in association with a metabolic acidosis, an increase in plasma alanine amino transferase, liver IL-1ß gene expression, and mitochondrial reactive oxygen species production. The rates of mitochondrial oxygen consumption and the activity and content of cytochrome c oxidase were significantly decreased while no alterations in the oxidative phosphorylation efficiency and inner membrane integrity were found. These results show that contrary to what was expected, liver mitochondria felt to adjust their oxidative phosphorylation efficiency in response to the decrease in the mitochondrial oxidative activity induced by CLP. This loss of mitochondrial bioenergetics plasticity might be related to mitochondrial oxidative stress and liver cytokines production.

Effects of a breakfast spread out over time on the food intake at lunch and the hormonal responses in obese men.

The effects of frequent eating on health and particularly on appetite and metabolism are unclear. We have previously shown that frequent eating decreased appetite and energy intake at the subsequent meal in lean men. In the present study, we tested the same pattern in obese subjects. Seventeen obese men participated in: (i) two sessions consisting of a breakfast consumed in one eating episode at T0 (F1), or in four isocaloric eating episodes at T0, T60, T120, and T180min (F4), followed by an ad libitum buffet (T240) in an experimental restaurant. Subjects rated their appetite throughout the sessions. (ii) two sessions consisting of the same breakfasts F1 and F4 in a Clinical Centre, followed by a standardized meal. Blood sampling was performed to study ghrelin, glucagon-like peptide-1 (GLP-1), and metabolic kinetics. Indirect calorimetry measurements were performed. After F4, at T240min, ghrelin concentration (P=0.03) and hunger ratings (P<0.001) were lower while GLP-1 concentration (P=0.006) and satiety ratings (P=0.02) were higher. In F4, subjects consumed at the buffet, less food in grams (P=0.04) and less energy from low energy dense foods (P=0.01), but total energy intakes were not different between conditions. In F4, the area under the curve was lower for insulin (P=0.02) and non-esterified fatty acids (NEFA) (P=0.03). Diet induced thermogenesis was reduced in F4 (P=0.03) between T0 and T240. Even if subjective and physiological data suggest a beneficial effect of frequent eating on appetite in obese men, no effect was demonstrated on energy intake. Moreover, the decrease in diet induced thermogenesis and lipolysis, reflected by NEFA profiles, could be deleterious on energy balance in the long run.

Higher serum osteocalcin is associated with lower abdominal aortic calcification progression and longer 10-year survival in elderly men of the MINOS cohort.

CONTEXT: Abdominal aortic calcification (AAC) is an indicator of cardiovascular risk, especially in the diseases characterized by insulin resistance such as type 2 diabetes. Osteocalcin is a bone-secreted hormone that favors insulin sensitivity and insulin secretion. OBJECTIVES: We investigated whether total serum osteocalcin level at baseline is associated with AAC progression and 10-year all-cause mortality in elderly men. DESIGN AND PARTICIPANTS: We assessed 774 men aged 51-85 years from the MINOS cohort who had osteocalcin measurement and lumbar spine radiographs at baseline. They were followed-up prospectively for 10 years. Among them, 615 patients had a follow-up radiograph at 3.5 or 7 years. MAIN OUTCOME MEASURES: Serum total osteocalcin was measured with an immunoradiometric assay on morning fasting serum collected at baseline. Kauppila's AAC score was assessed from lumbar spine radiographs. AAC progression rate was calculated as the difference between AAC on the last available radiograph and AAC at baseline divided by the follow-up time. Death status was collected over 10 years. RESULTS: In multivariate analysis, higher baseline total osteocalcin was associated with lower AAC progression rate (odds ratio = 0.74 [0.57-0.97] per 10 ng/mL variation; P = 0.029). At the 10-year follow-up, there were 599 men alive (77%), 181 dead (23%), and 2 lost to follow-up. Higher osteocalcin was associated with lower 10-year all-cause mortality (hazard ratio = 0.62 [0.44-0.86] per 10 ng/mL variation; P = 0.005). CONCLUSION: Higher baseline total osteocalcin concentrations were associated with lower AAC progression rate and lower mortality. These data suggest that osteocalcin level might be an independent indicator of cardiovascular risk and global health in elderly Caucasian men.

An isocaloric increase of eating episodes in the morning contributes to decrease energy intake at lunch in lean men.

The effects of increasing eating frequency on human health are unclear. This study used an integrated approach to assess the short-term consequences on appetite and metabolism. Twenty normal-weight men participated in: (i) two sessions consisting of a breakfast consumed in one eating episode at T0 (F1), or in four isocaloric eating episodes at T0, T60, T120, and T180 min (F4), and followed by an ecological ad libitum buffet meal (T240) designed in an experimental restaurant. Intakes were assessed for the whole buffet meal and for each temporal quarter of the meal. (ii) two sessions consisting of the same two breakfasts F1 and F4 in a Clinical Investigation Centre. Blood sampling was performed to study the kinetics of ghrelin, glucagon-like peptide-1 (GLP-1), glucose, insulin, triglycerides and non-esterified fatty acids (NEFA). Substrate oxidation was measured by indirect calorimetry. During each of the 4 sessions, participants rated their appetite throughout the experiment. After F4, at T240 min, GLP-1 concentration was higher (P=0.006) while ghrelin concentration and hunger ratings were lower (P<0.001). We showed a trend for subjects to consume less energy (-88±61 kcal, P=0.08) at the buffet after F4, explained by a decrease in lipid intake (P=0.04). Marked differences in consumption were observed during the last temporal quarter of the meal for total energy and lipid intake (P=0.03). Mixed models highlighted differences between F1 and F4 for the kinetics of glucose, insulin and NEFA (P<0.001). The area under the curve was lower for insulin (P<0.001) and NEFA in F4 (P=0.03). Diet induced thermogenesis was reduced in F4 (P<0.05). This study demonstrated the beneficial short-term effect of increasing eating frequency on appetite in lean men considering subjective, physiological and behavioral data. However, the loss of the inter-prandial fast was associated with an inhibition of lipolysis, reflected by NEFA profiles, and a decrease in energy expenditure.

Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients.

OBJECTIVE: To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk. RESEARCH DESIGN AND METHODS: Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR. RESULTS: In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid-reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs. CONCLUSIONS: A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.

Small-volume hypertonic saline/pentastarch improves ileal mucosal microcirculation in experimental peritonitis.

We compared the effects of hypertonic saline 7.2%/6% hydroxyethyl starch (HSS-HES) and isotonic saline 0.9%/6% hydroxyethyl starch (ISS-HES) on ileal microcirculatory blood flow (MBF) at the initial phase of septic shock. Pigs were anesthetized and mechanically ventilated. Catheters were inserted into right atrium, pulmonary artery, carotid artery, and portal vein for hemodynamic measurements and for blood sampling. Ileal mucosal and muscularis MBF was continuously measured by laser Doppler flowmetry (LDF). Septic shock was obtained 240 min after induction of fecal peritonitis; then animals were randomized to receive 10 mL.kg(-1) during 10 min of either HSS-HES or ISS-HES. Systemic and microcirculatory blood flow as well as systemic metabolism were assessed. Fecal peritonitis promoted a hypodynamic septic shock, with significant reduction of mean arterial pressure (MAP) and cardiac index (CI). Ileal mucosal MBF (-34%) and ileal muscularis MBF (-54%) significantly diminished from baseline. Contrary to ISS-HES group, mucosal MBF significantly augmented after HSS-HES (+192% at min 150 post-shock) despite low blood pressure. There was weak correlation with CI (r(2)= 0.2, P=0.01) . Muscularis MBF didn't change. HSS-HES-treated animals had a significantly higher osmolarity and sodium concentration than ISS-HES group. Other variables did not change. Small-volume resuscitation with HSS-HES, but not ISS-HES, improved ileal microcirculatory impairment in experimental peritonitis model of septic shock even when MAP was low. This beneficial microcirculatory effect could be valuable in the management of early severe sepsis.

Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study.

AIMS: Resuscitated cardiac arrest (CA), leading to harmful cardiovascular dysfunction and multiple organ failure, includes a whole-body hypoxia-reoxygenation phenomenon. Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in ischaemia-reperfusion injury. We hypothesized that pharmacological inhibition of mPTP opening may prevent the post-CA syndrome. METHODS AND RESULTS: Anaesthetized New Zealand White rabbits underwent a 15 min primary asphyxial CA and 120 min of reperfusion following resuscitation. At reflow, animals received an intravenous bolus of either cyclosporine A (CsA, 5 mg/kg) or NIM 811 (2.5 mg/kg), two potent inhibitors of mPTP opening, or the CsA vehicle (control). Short-term survival, haemodynamics, regional (sonomicrometry), and global cardiac function (dP/dt and aortic flow) were assessed. We measured markers of cellular injuries and/or organ failure, including troponin Ic release, lacticodehydrogenase, lactate, creatinine, and alanine aminotransferase. Cyclosporine A and NIM 811 significantly improved short-term survival, post-resuscitation cardiac function, as well as liver and kidney failure (P < 0.05). CsA and NIM 811 both attenuated in vitro mPTP opening (calcium retention capacity by spectrofluorimetry) and restored oxidative phosphorylation when compared with controls (P < 0.05). CONCLUSION: These data suggest that pharmacological inhibition of mPTP opening, added to basic life support, attenuates the post-CA syndrome and improves short-term outcomes in the rabbit model.

Men with metabolic syndrome have lower bone mineral density but lower fracture risk--the MINOS study.

Data on the association of the metabolic syndrome (MetS) with bone mineral density (BMD) and fracture risk in men are inconsistent. We studied the association between MetS and bone status in 762 older men followed up for 10 years. After adjustment for age, body mass index, height, physical activity, smoking, alcohol intake, and serum 25-hydroxycholecalciferol D and 17beta-estradiol levels, men with MetS had lower BMD at the hip, whole body, and distal forearm (2.2% to 3.2%, 0.24 to 0.27 SD, p < .05 to .005). This difference was related to abdominal obesity (assessed by waist circumference, waist-hip ratio, or central fat mass) but not other MetS components. Men with MetS had lower bone mineral content (3.1% to 4.5%, 0.22 to 0.29 SD, p < .05 to 0.001), whereas differences in bone size were milder. Men with MetS had a lower incidence of vertebral and peripheral fractures (6.7% versus 12.0%, p < .05). After adjustment for confounders, MetS was associated with a lower fracture incidence [odds ratio (OR) = 0.33, 95% confidence interval (CI) 0.15-0.76, p < .01]. Among the MetS components, hypertriglyceridemia was most predictive of the lower fracture risk (OR = 0.25, 95%CI 0.10-0.62, p < .005). Lower fracture risk in men with MetS cannot be explained by differences in bone size, rate of bone turnover rate and bone loss, or history of falls or fractures. Thus older men with MetS have a lower BMD related to the abdominal obesity and a lower risk of fracture related to hypertriglyceridemia. MetS probably is not a meaningful concept in the context of bone metabolism. Analysis of its association with bone-related variables may obscure the pathophysiologic links of its components with bone status.