Effect of coenzyme Q10 supplementation on mitochondrial function after myocardial ischemia reperfusion.

BACKGROUND: Coenzyme Q10 (CoQ10) protects myocardium from ischemia-reperfusion (IR) injury as evidenced by improved recovery of mechanical function, ATP, and phosphocreatine during reperfusion. This protection may result from CoQ10's bioenergetic effects on the mitochondria, from its antioxidant properties, or both. The purpose of this study was to elucidate the effects of CoQ10 supplementation on mitochondrial function during myocardial ischemia-reperfusion using an isolated mitochondrial preparation. METHODS: Isolated hearts (n = 6/group) from rats pretreated with liposomal CoQ10 (10 mg/kg iv, CoQ10), vehicle (liposomal only, Vehicle), or saline (Saline) 30 min before the experiments were subjected to 15 min of equilibration (EQ), 25 min of ischemia (I), and 40 min of reperfusion (RP). Left ventricular-developed pressure (DP) was measured. Mitochondria were isolated at end-equilibration (end-EQ), at end-ischemia (end-I), and at end-reperfusion (end-RP). Mitochondrial respiratory function (State 2, 3, and 4, respiratory control index (RCI, ratio of State 3 to 4), and ADP:O ratio) was measured by polarography using NADH (alpha-ketoglutarate, alpha-KG)- or FADH (succinate, SA)-dependent substrates. RESULTS: CoQ10 improved recovery of DP at end-RP (67 +/- 11% in CoQ10 vs 47 +/- 5% in Vehicle and 50 +/- 11% in Saline, P < 0.05 vs Vehicle and Saline). CoQ10 did not change preischemic mitochondrial function. IR decreased State 3 and RCI in all groups using either substrate. CoQ10 had no effect in the mitochondrial oxidation of alpha-KG at end-I. CoQ10 improved State 3 at end-I when SA was used (167 +/- 21 in CoQ10 vs 120 +/- 10 in Saline and 111 +/- 10 ng-atoms O/min/mg protein in Vehicle, P < 0.05). Using alpha-KG as a substrate, CoQ10 improved RCI at end-RP (4.2 +/- 0.2 in CoQ10 vs 3.2 +/- 0.2 in Saline and 3.0 +/- 0.3 in Vehicle, P < 0.05). Using SA, CoQ10 improved State 3 (181 +/- 10 in CoQ10 vs 142 +/- 9 in Saline and 140 +/- 12 ng-atoms O/min/mg protein in Vehicle, P < 0.05) and RCI (2.21 +/- 0.06 in CoQ10 vs 1.85 +/- 0.11 in Saline and 1.72 +/- 0.08 in Vehicle, P < 0.05) at end-RP. CONCLUSIONS: The cardioprotective effects of CoQ10 can be attributed to the preservation of mitochondrial function during reperfusion as evidenced by improved FADH-dependent oxidation.     

Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men

INTRODUCTION: Fibroblast growth factor (FGF-23) is a novel phosphaturic factor. Current data suggest that serum phosphate, dietary phosphate and 1,25 dihydroxyvitamin D regulate circulating FGF-23 levels in vivo. We examined if hypogonadism-induced increases in serum phosphate are associated with increases in circulating FGF-23 in healthy men in the absence of dietary manipulation. MATERIALS AND METHODS: 25 healthy men were administered goserelin acetate (GnRH analog) 3.6 mg subcutaneously every 4 weeks for 12 weeks to induce acute testosterone and estrogen deficiency. Subjects consumed an ad libitum diet. Morning fasting blood and urine samples were collected to measure serum phosphate, serum intact FGF-23, PTH, and the maximum tubular reabsorption of phosphate (T(m)P/GFR) at baseline, weeks 4 and 12. The changes in serum FGF-23 and phosphate at weeks 4 and 12 were compared to baseline using paired t-tests. RESULTS: Goserelin therapy decreased mean serum testosterone levels from 543+/-160 ng/dL to 33+/-15 ng/dL at week 4 (p<0.001), and to 20+/-10 ng/dL at week 12 (p<0.001). Serum phosphate increased significantly from 3.4+/-0.6 mg/dL to 3.9+/-0.4 mg/dL at week 4 (p=0.002), and to 4.3+/-0.4 mg/dL at week 12 (p<0.001). T(m)P/GFR increased significantly from 3.2+/-0.6 mg/dL to 3.6+/-0.5 mg/dL at week 4 (p<0.004), and to 4.1+/-0.6 mg/dL at week 12 (p<0.001). FGF-23 levels, however, did not change during the 12-week study. CONCLUSIONS: Gonadal steroid deprivation increased serum phosphate levels in men but did not affect serum FGF-23 concentrations. The absence of any change in circulating FGF-23 suggests that supraphysiologic levels of serum phosphate may be required to stimulate circulating FGF-23 or that FGF-23 production is primarily sensitive to changes in dietary phosphate or 1,25 dihydroxyvitamin D within this physiologic serum phosphate range.     

Chondroitin‐6‐sulfate incorporation and mechanical stimulation increase MSC‐collagen sponge construct stiffness

Using functional tissue engineering principles, our laboratory has produced tendon repair tissue which matches the normal patellar tendon force‐displacement curve up to 32% of failure. This repair tissue will need to withstand more strenuous activities, which can reach or even exceed 40% of failure force. To improve the linear stiffness of our tissue engineered constructs (TECs) and tissue engineered repairs, our lab is incorporating the glycosaminoglycan chondroitin‐6‐sulfate (C6S) into a type I collagen scaffold. In this study, we examined the effect of C6S incorporation and mechanical stimulation cycle number on linear stiffness and mRNA expression (collagen types I and III, decorin and fibronectin) for mesenchymal stem cell (MSC)‐collagen sponge TECs. The TECs were fabricated by inoculating MSCs at a density of 0.14 × 10⁶ cells/construct onto pre‐cut scaffolds. Primarily type I collagen scaffold materials, with or without C6S, were cultured using mechanical stimulation with three different cycle numbers (0, 100, or 3,000 cycles/day). After 2 weeks in culture, TECs were evaluated for linear stiffness and mRNA expression. C6S incorporation and cycle number each played an important role in gene expression, but only the interaction of C6S incorporation and cycle number produced a benefit for TEC linear stiffness. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1092–1099, 2010     

Prospective evaluation of combined upper and lower extremity DVT

The clinical importance of upper extremity deep venous thrombosis (UEDVT) has been increasingly demonstrated in recent literature. Not only has the risk of pulmonary embolism from isolated upper extremity DVT been demonstrated, but a significant associated mortality has been encountered. Examination of this group of patients has demonstrated the existence of combined upper and lower extremity deep venous thrombosis (DVT) in some patients who exhibit an even higher associated mortality. As a result of this information, it has become the standard practice at this institution to search for lower extremity DVTs in patients found to have acute thrombosis of upper extremity veins. Since January 1999, there have been a total of 227 patients diagnosed with acute UEDVT. Within this group, 211 (93%) patients had lower extremity studies; 45 of these 211 (21%) had acute lower extremity DVTs by duplex examination in addition to the upper extremity DVTs. Overall, there were 145 women, 66 men, and the average age was 70 +/-1.2 (SEM); 22 of these patients had bilateral lower extremity thrombosis (LEDVT), and 8 patients were found to have chronic thrombosis of lower extremity veins. Of the patients with bilateral upper extremity DVTs, there were 3 with bilateral LE acute DVTs. Finally, 8 of the remaining 166 patients (5%) with originally negative lower extremity studies were found to develop a thrombosis at a later date. These data serve to confirm previous studies, on a larger scale, that there should be a high index of suspicion in patients with UEDVT of a coexistent LEDVT.     

A new SNP in a negative regulatory region of the CYP19A1 gene is associated with lumbar spine BMD in postmenopausal women

Osteoporosis is a common disease of bone possessing a strong genetic component. Cytochrome P450 aromatase, which is encoded by the CYP19A1 gene, converts androgens to estradiol. Considerable evidence suggests that extragonadal estrogens play an important role in determining bone mineral density (BMD) in postmenopausal women, and, among them, those synthesized in bone cells may also be important for the determination of bone phenotype. Therefore, CYP19A1 is an excellent candidate gene for osteoporosis. Since a region upstream of exon I.3, including exon I.6, was identified as containing repressor elements of promoter pII, we conducted a search for SNPs in this region of CYP19A1. Two SNPs [Aro1(rs4775936) and Aro2] located in exon I.6 and promoter I.6, respectively, were identified and their association with BMD analyzed in a cohort of 256 Spanish postmenopausal women. Aro1(rs4775936), but not Aro2, was associated with lumbar spine BMD (P = 0.029). Homozygotes AA (16% of the women) exhibited significantly higher lumbar spine BMD, compared with GG or GA individuals. Therefore, this study describes the Aro1 polymorphism which lies within a regulatory region and which may be a functional polymorphism, partially responsible for the bone phenotype it is associated with.     

Tooth and periodontal clinical attachment loss are associated with hyperglycemia in patients with diabetes

Background: Periodontal disease has been associated with diabetes, but there is still controversy on the relationship between periodontal clinical parameters and glycemic control. The purpose of this study is to assess the relationship between blood glucose levels and clinical parameters of periodontal disease in individuals with diabetes. Methods: A total of 65 individuals with diabetes and 81 individuals without diabetes were included in the study. A full-mouth periodontal examination and preprandial fasting glycemia values were recorded for each individual. Glycosylated hemoglobin was only measured in patients with diabetes. A comparative analysis between groups (Mann-Whitney U test) and a correlation analysis between glycemia and periodontal parameters were performed (Spearman test). Results: Patients without diabetes presented more teeth than individuals with diabetes (P <0.05). Patients with diabetes with periodontitis displayed loss of periodontal clinical attachment compared to patients without diabetes, but the highest value was observed in patients with periodontitis that reported a smoking habit. Furthermore, patients with diabetes with periodontitis presented higher glycemia and glycated hemoglobin values in contrast to patients with gingivitis. Patients with diabetes with hyperglycemia had a higher risk to develop periodontitis (odds ratio = 2.24; 95% confidence interval = 1.02 to 4.93). A positive correlation was observed between glycemia and clinical attachment loss (AL), whereas a negative correlation between glycemia and the number of teeth present was found (P <0.05). Conclusions: Tooth and periodontal AL were increased by hyperglycemia in individuals with diabetes. This study contributes additional evidence that diabetes could aggravate periodontal disease and affect the systemic health of individuals.