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.

Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition.

The opening of the mitochondrial permeability transition pore (PTP), which is regulated by the matrix protein cyclophilin D (CypD), plays a key role in the pathophysiology of post-cardiac arrest (CA) syndrome. We hypothesized that therapeutic hypothermia could prevent post-CA syndrome through a CypD-mediated PTP inhibition in both heart and brain. In addition, we investigated whether specific pharmacological PTP inhibition would confer additive protection to cooling. Adult male New Zealand White rabbits underwent 15 min of CA followed by 120 min of reperfusion. Five groups (n = 10-15/group) were studied: control group (CA only), hypothermia group (HT, hypothermia at 32-34 °C induced by external cooling at reperfusion), NIM group (injection at reperfusion of 2.5 mg/kg NIM811, a specific CypD inhibitor), HT + NIM, and sham group. The following measurements were taken: hemodynamics, echocardiography, and cellular damage markers (including S100ß protein and troponin Ic). Oxidative phosphorylation and PTP opening were assessed on mitochondria isolated from both brain and heart. Acetylation of CypD was measured by immunoprecipitation in both the cerebral cortex and myocardium. Hypothermia and NIM811 significantly prevented cardiovascular dysfunction, pupillary areflexia, and early tissue damage. Hypothermia and NIM811 preserved oxidative phosphorylation, limited PTP opening in both brain and heart mitochondria and prevented increase in CypD acetylation in brain. There were no additive beneficial effects in the combination of NIM811 and therapeutic hypothermia. In conclusion, therapeutic hypothermia limited post-CA syndrome by preventing mitochondrial permeability transition mainly through a CypD-dependent mechanism.

GFR estimation in adolescents and young adults.

The performance of creatinine-based equations to obtain the estimated GFR in adolescents and young adults is poorly understood. We assessed creatinine-based GFR estimating equations in a cross-section of 751 adolescents and young adults (1054 measurements), using inulin clearance (measured GFR [mGFR]) as the reference method. We evaluated the following: Cockcroft-Gault, four-variable Modified Diet in Renal Disease, and the Chronic Kidney Disease Epidemiology Collaboration equations for adult participants, as well as the Schwartz 2009 and Schwartz-Lyon equations for pediatric age groups. Participants ranged in age from 10 to 26 years (mean 16.8 years); we divided the population into four groups according to age (10-12 years, 13-17 years, 18-21 years, and 21-25 years). Evaluation of the agreement between these formulas and mGFR (e.g., correlation, Bland-Altman plots, bias, and accuracy) showed that there was a good correlation between mGFR and both pediatric formulas in all age groups, whereas the adult formulas substantially overestimated mGFR. In conclusion, we recommend the use of pediatric equations to estimate GFR from childhood to early adulthood.

Dose and timing of injections for effective cyclosporine A pretreatment before renal ischemia reperfusion in mice.

BACKGROUND: There is experimental evidence that lethal ischemia-reperfusion injury (IRI) is largely due to mitochondrial permeability transition pore (mPTP) opening, which can be prevented by cyclosporine A (CsA). The aim of our study is to show that a higher dose of CsA (10 mg/kg) injected just before ischemia or a lower dose of CsA (3 mg/kg) injected further in advance of ischemia (1 h) protects the kidneys and improves mitochondrial function. METHODS: All mice underwent a right unilateral nephrectomy followed by 30 min clamping of the left renal artery. Mice in the control group did not receive any pharmacological treatment. Mice in the three groups treated by CsA were injected at different times and with different doses, namely 3 mg/kg 1 h or 10 min before ischemia or 10 mg/kg 10 min before ischemia. After 24 h of reperfusion, the plasma creatinine level were measured, the histological score was assessed and mitochondria were isolated to calculate the calcium retention capacity (CRC) and level of oxidative phosphorylation. RESULTS: Mortality and renal function was significantly higher in the CsA 10 mg/kg-10 min and CsA 3mg/kg-1 h groups than in the CsA 3mg/kg-10 min group. Likewise, the CRC was significantly higher in the former two groups than in the latter, suggesting that the improved renal function was due to a longer delay in the opening of the mPTP. Oxidative phosphorylation levels were also higher 24 h after reperfusion in the protected groups. CONCLUSIONS: Our results suggest that the protection afforded by CsA is likely limited by its availability. The dose and timing of the injections are therefore crucial to ensure that the treatment is effective, but these findings may prove challenging to apply in practice.

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.

Postconditioning with cyclosporine a reduces early renal dysfunction by inhibiting mitochondrial permeability transition.

BACKGROUND: Ischemia-reperfusion (IR) injury leads to mitochondrial permeability transition pore opening, which contributes to cell death. The aim of this study is to determine whether ischemic or pharmacological postconditioning with cyclosporine A (CsA) might protect the kidney from lethal reperfusion injury. METHODS: Male mice underwent a unilateral (right) nephrectomy followed by 30 minutes of contralateral (left) clamping of the renal artery. We studied 4 groups at 20 minutes and 24 hours of reperfusion: a sham group (n = 4), an ischemic group (n = 6), CsA-postconditioned group (postcond-CsA, injection of 3 mg/kg of CsA 5 minutes before the end of ischemia, (n = 6), and an ischemic postconditioning (IPC) group (n = 6), consisting of 3 cycles of 30 seconds of renal ischemia with 30 seconds intervening reperfusion. After 24 hours of reperfusion, we measured plasma creatinine, urea, and histological kidney injury. The kidney mitochondria were isolated to assess the mitochondria calcium retention capacity and oxidative phosphorylation. RESULTS: At 24 hours after reperfusion, serum creatinine decreased in postcond-CsA and IPC compared to ischemic group. The histological score was also significantly improved with postcond-CsA and IPC. At 20 minutes and 24 hours of reperfusion, calcium retention capacity was decreased significantly in the ischemic group. The mitochondrial respiration stay decreased in the ischemic group at 24 hours of reperfusion, whereas the respiration was improved significantly in the postcond-CsA and IPC group. Bax and cleaved caspase 3 decreased in PostCsA and IPC group. CONCLUSIONS: Our results suggest that IPC and CsA, administered immediately before reperfusion, protect the kidney from lethal injury.

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.

Ubiquitous protective effects of cyclosporine A in preventing cardiac arrest-induced multiple organ failure.

Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in myocardial ischemia-reperfusion (I/R) injury. Resuscitated cardiac arrest (CA) leads to the post-CA syndrome that encompasses, not only myocardial dysfunction, but also brain injury, failure of other organs (kidney, liver, or lung), and systemic response to I/R. We aimed to determine whether cyclosporine A (CsA) might prevent multiple organ failure following CA through a ubiquitous mPTP inhibition in each distant vital organ. Anesthetized New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion. At the onset of resuscitation, the rabbits received CsA, its non-immunosuppressive derivative NIM811, or vehicle (controls). Survival, hemodynamics, brain damage, organ injuries, and systemic I/R response were analyzed. Fresh mitochondria were isolated from the brain, heart, kidney, liver, and lung to assess both oxidative phosphorylation and permeability transition. CsA analogs significantly improved short-term survival and prevented multiple organ failure, including brain damage and myocardial dysfunction (P < 0.05 vs. controls). Susceptibility of mPTP opening was significantly increased in heart, brain, kidney, and liver mitochondria isolated from controls, while mitochondrial respiration was impaired (P < 0.05 vs. sham). CsA analogs prevented these mitochondrial dysfunctions (P < 0.05 vs. controls). These results suggest that CsA and NIM811 can prevent the post-CA syndrome through a ubiquitous mitochondrial protective effect at the level of each major distant organ.

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.

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.