Influence of circulating levels of fibrinogen and perioperative coagulation parameters on predicting postoperative blood loss in cardiac surgery: a prospective observational study.

BACKGROUND: Fibrinogen, the major clotting protein in blood plasma, plays key roles in blood coagulation and thrombosis. In this prospective cohort study, we measured patient's fibrinogen levels and common coagulation parameters before and after cardiopulmonary bypass (CPB) and examined their relationships with postoperative blood loss. STUDY DESIGN: Patients undergoing cardiac surgery with CPB who did not have pre-existing coagulopathy were eligible. Standard blood and coagulation testing were performed before and after CPB. The association of these variables with postoperative blood loss (estimated blood loss from CPB) was assessed with Spearman's ranked correlation and multivariable linear regression models. RESULTS: Two hundred and fifty patients were enrolled in the study. The median blood loss was 780 mL (range 320-2340 mL). Variables independently associated with increasing blood loss were lower post-CPB platelet counts (p<0.001), lower postoperative fibrinogen levels (p<0.001), and larger percent decrease in fibrinogen levels (p<0.05). There was no correlation between preoperative fibrinogen levels and preoperative coagulation tests with postoperative bleeding. The only significant independent predictors of transfusion in a logistic regression model were postoperative fibrinogen concentration. CONCLUSION: Postoperative fibrinogen, the larger percent decrease in fibrinogen, and postoperative platelet levels are markers of bleeding and blood transfusion requirements after CPB than preoperative standard screening tests. Postoperative fibrinogen had the best predictive value of all tests of postoperative blood loss.

Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease.

BACKGROUND: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. METHODS AND RESULTS: Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. CONCLUSIONS: Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states.

Local suture annuloplasty for posterior mitral valve repair: 18-year experience.

We retrospectively reviewed 128 consecutive patients who underwent quadrangular resection of a prolapsed posterior mitral leaflet and local suture annuloplasty. The median age was 68.1 ± 10.0 years (range, 30-84 years) and 63.3% were male. Mean left ventricular ejection fraction was 63.8% ± 10.2% (range, 25%-80%). The etiology of mitral regurgitation was fibroelastic degeneration in 94 (73.4%) patients, myxomatous degeneration in 26 (20.3%), myxomatous infective endocarditis in 7 (5.5%), and post-infarction papillary rupture in one. There was 1 (0.8%) hospital death. The median follow-up was 4.7 ± 4.7 years (range, 0.01-18.29 years). The freedom from reoperation was 98%, 94%, 87%, and 79% at 1, 5, 10, and 15 years, respectively, improving for the most recent 107 patients, subsequent to technical modification, to: 100%, 96%, 94%, and 90% at 1, 5, 10, and 14 years, respectively. Ten- and 15-year freedom from severe mitral regurgitation was 91%, and 88%, respectively. The overall actuarial 1-, 5-, 10-, and 15-year survival rates were 98%, 90%, 70%, and 52%, respectively, similar to that of the age- and sex-matched United Kingdom population. The long-term results of this technique in selected patients with prolapsed posterior leaflet were considered acceptable.

Myocardial transfection of hypoxia inducible factor-1alpha via an adenoviral vector during coronary artery bypass grafting. - A multicenter phase I and safety study -.

BACKGROUND: Increasing numbers of patients with advanced coronary artery disease have limited options for percutaneous and/or surgical revascularization. A prospective, randomized, phase I clinical multicenter trial was performed to assess the feasibility and safety of delivering a pro-angiogenic transcription factor termed "hypoxia inducible factor-1alpha", delivered to ischemic cardiac muscle via a type 2 adenoviral (Ad2HIF) vector. METHODS AND RESULTS: The 13 patients were included under the following criteria: 1 hypoperfused area of viable ventricular muscle without options for revascularization and left ventricular ejection fraction > or =30%. After coronary artery bypass grafting was completed, 10 injections of the study drug (n=10), in 3 escalating doses up to 1 x 10(11) viral particles or saline (n=3) as a placebo control, were injected intramyocardially. After completion of the 1-year follow-up, all patients had uncomplicated postoperative courses, are alive and feeling well; 1 patient had a self-limited run of tachycardia postoperatively and at 6 months, 1 patient developed recurrent angina. Positron emission tomography perfusion analysis revealed improvement in the Ad2HIF injected areas in selected patients. CONCLUSIONS: These data support the feasibility and preliminary safety of adenoviral transfection with Ad2HIF in regions of viable myocardium. Additional studies will be required to determine the efficacy and safety of Ad2HIF.

3f prosthesis aortic cusp replacement: implantation technique and early results.

Stentless aortic bioprostheses have been successfully used for over a decade. The 3f bioprosthesis is a new equine pericardial stentless valve, unique in its tubular design, preserving the native aortic sinuses post-implant. Forty-six consecutive aortic valve replacements with the 3f bioprosthesis were performed between June 2003 and January 2005. The patients were prospectively assessed and echocardiography was performed at 6 months, 12 months, and annually thereafter. The median follow-up was 2.1 + or - 0.9 years. There was one early and 4 late deaths; none were valve-related. The 2-year mean transvalvular gradient was 8.8 + or - 3.8 mm Hg, the mean echocardiographic aortic regurgitation grade was 0.4 + or - 0.7 (grade 1 being trivial). Echocardiographic sizing of the aortic annulus before surgery accurately predicted prosthesis size. The 3f bioprosthesis is easy to implant. Early clinical results are favorable, with hemodynamic profiles consistent with those of other stentless prostheses. Longer follow-up is required to confirm its durability.

Advantages of sutureless aortic valve in a patient with unsuspected pheochromocytoma.

We describe a 60-year-old man who underwent elective aortic valve replacement and concurrent single graft coronary artery bypass surgery with acute intraoperative hypertension. The early suspicion of a pheochromocytoma and immediate aggressive pharmacologic intervention are discussed. Expeditious surgery contributed to the good outcome. It is possible that the short implant time of the sutureless valve may have been beneficial, but this is speculative. The management of an undiagnosed pheochromocytoma presenting during general anesthesia is reviewed.

Multiple sternotomies for repeated aortic root replacement--optimising the surgical approach.

A 44-year-old patient with fungal endocarditis required a total of five sternotomies over ten years. We present the course of his treatment, details of the surgical techniques employed as well as other interesting points encountered in the management of this patient.

MTHFR 677 C>T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis.

BACKGROUND: The role of circulating homocysteine as an atherosclerosis risk factor has recently been questioned. However, 5-methyl-tetrahydrofolate (5-MTHF), the circulating metabolite of folic acid participating in homocysteine metabolism, has direct effects on vascular function. We sought to distinguish the effects of plasma versus vascular tissue 5-MTHF and homocysteine on vascular redox and endothelial nitric oxide bioavailability in human vessels. METHODS AND RESULTS: We used the methyl tetrahydrofolate reductase (MTHFR) gene polymorphism 677C>T as a model of chronic exposure of the vascular wall to varying 5-MTHF levels in 218 patients undergoing coronary artery bypass graft surgery. Vascular superoxide, vascular 5-MTHF, and total homocysteine were determined in saphenous veins and internal mammary arteries obtained during surgery. Nitric oxide bioavailability was evaluated by organ bath studies on saphenous vein rings. MTHFR genotype was a determinant of vascular 5-MTHF (not vascular homocysteine). Both MTHFR genotype and vascular 5-MTHF were associated with vascular nitric oxide bioavailability and superoxide generated by uncoupled endothelial nitric oxide synthase. In contrast, vascular homocysteine was associated only with NADPH-stimulated superoxide. CONCLUSIONS: Genetic polymorphism 677 C>T on MTHFR affects vascular 5-MTHF (but not homocysteine) and can be used as a model to distinguish the chronic effects of vascular 5-MTHF from homocysteine on vascular wall. Vascular 5-MTHF, rather than plasma or vascular homocysteine, is a key regulator of endothelial nitric oxide synthase coupling and nitric oxide bioavailability in human vessels, suggesting that plasma homocysteine is an indirect marker of 5-MTHF rather than a primary regulator of endothelial function.

Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis.

BACKGROUND: Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered to be a risk factor for atherosclerosis. However, the mechanisms relating ADMA with vascular function have been evaluated in vitro and in animal models, but its effect in human vasculature is unclear. AIMS: We examined the impact of serum ADMA on endothelial nitric oxide (NO) bioavailability and vascular superoxide radical (O2-) production in patients with advanced atherosclerosis. METHODS AND RESULTS: Paired samples of saphenous veins (SVs) and internal mammary arteries (IMAs) were collected from 201 patients undergoing coronary bypass surgery, and serum ADMA was measured pre-operatively. The vasomotor responses of SV segments to acetylcholine (ACh) and bradykinin (Bk) were evaluated ex vivo. Vascular O2- was measured in paired SV and IMA by lucigenin-enhanced chemiluminescence. The l-NAME-inhibitable as well as the NADPH-stimulated vascular O2- generation was also determined by chemiluminescence. High serum ADMA levels were associated with decreased vasorelaxation of SV to ACh (P < 0.05) and Bk (P < 0.05). Similarly, high serum ADMA was associated with higher total O2- production in both SVs and IMAs (P < 0.05) and greater L-NAME-inhibitable vascular O2- (P < 0.05). However, serum ADMA was not associated with NADPH-stimulated vascular O2-. In multivariable linear regression, serum ADMA was independently associated with vascular O2- in both SVs [beta (SE): 0.987 (0.412), P = 0.019] and IMAs [beta (SE): 1.905 (0.541), P = 0.001]. Asymmetrical dimethylarginine was also independently associated with maximum vasorelaxation in response to both ACh [beta (SE): 14.252 (3.976), P = 0.001] and Bk [beta (SE): 9.564 (3.762), P = 0.013]. CONCLUSION: This is the first study that demonstrates an association between ADMA and important measures of vascular function, such as vascular O2- production and NO bioavailability directly in human vessels. Although serum ADMA has no effect on NADPH-stimulated superoxide in intact vessels, it is associated with greater eNOS uncoupling in the human vascular endothelium of patients with coronary artery disease.

Production and in vitro characterization of solid dosage form incorporating drug nanoparticles.

The objective of this study was to develop a tablet formulation of ketoconazole incorporating drug nanoparticles to enhance saturation solubility and dissolution velocity for enhancing bioavailability and reducing variability in systemic exposure. The bioavailability of ketoconazole is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of ketoconazole was developed. Ketoconazole nanoparticles were prepared using a media-milling technique. The nanosuspension was layered onto water-soluble carriers using a fluid bed processor. The nanosuspensions were characterized for particle size before and after layering onto water-soluble carriers. The saturation solubility and dissolution characteristics were investigated and compared with commercial ketoconazole formulation to ascertain the impact of particle size on drug dissolution. The drug nanoparticles were evaluated for solid-state transitions before and after milling using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). This study demonstrated that tablet formulation incorporating ketoconazole nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared with commercially available tablet formulation. There was no affect on solid-state properties of ketoconazole following milling. The manufacturing process used is relatively simple and scalable indicating general applicability to enhance dissolution and bioavailability of many sparingly soluble compounds.

Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial.

OBJECTIVE: Renal dysfunction following cardiac surgery is more apparent in high-risk patients with pre-existing renal dysfunction, diabetes and impaired left-ventricular function, and following complicated procedures involving prolonged cardiopulmonary bypass (CPB). The aim of this prospectively randomised double-blinded placebo-controlled study was to evaluate reno-protective effect of low-dose furosemide infusion in this high-risk group. METHODS: Patients with preoperative serum creatinine >130 micromol/l (1.4 mg/dl), left-ventricular ejection fraction <50%, congestive heart failure, diabetes, or procedures involving prolonged CPB were randomised to receive either saline at 2 ml/h (n=21), or furosemide at 4 mg/h (n=21). Infusion was commenced after induction of anaesthesia and continued for 12h postoperatively. Renal dysfunction was defined as >50% increase in serum creatinine postoperatively, or >130 micromol/l (1.4 mg/dl), or requirement for haemodialysis, or all of these. In patients with preoperative serum creatinine >130 micromol/l, >50% increase over preoperative levels was used to define postoperative renal dysfunction. RESULTS: Following cardiac surgery, patients receiving furosemide had a higher urine output (3.4+/-1.2 ml/kg/h in furosemide group and 1.2+/-0.5 ml/kg/h in placebo group; p<0.001), higher postoperative fluid requirement (4631+/-1359 ml in furosemide group and 3714+/-807 ml in placebo group, p=0.011), and lower urinary-creatinine (2+/-1.3 micromol/l in furosemide group and 5.9+/-2.5 micromol/l in placebo group p<0.001). Both groups had significant increase in retinol binding protein/creatinine ratio (7.2+/-6 to 3152+/-1411 in furosemide group; 4.9+/-2.1 to 2809+/-1125 in placebo group; p<0.001) and peak serum creatinine (98+/-33 to 177+/-123 micromol/l in furosemide group; 96+/-20 to 143+/-87 micromol/l in placebo group; p<0.001), and a significant decrease in peak creatinine-clearance (64.3+/-29.4 to 39.1+/-16.6 ml/min in furosemide group; 65.5+/-38.6 to 41.8+/-17.8 ml/min in placebo group; p<0.001) following cardiac surgery, implying significant renal injury following cardiac surgery. Peak creatinine levels (177+/-123 micromol/l in furosemide group and 143+/-87 micromol/l in placebo group; p=0.35) and peak creatinine-clearance (39.1+/-16.6 ml/min in furosemide group and 41.8+/-17.8 ml/min in placebo group; p=0.61) were similar in the two groups. Importantly, there was no difference in incidence of renal dysfunction between the furosemide group (9/21) and the control group (8/21) (relative risk 1.1, 95% confidence interval 0.6-2.2; p=0.99). CONCLUSIONS: Our randomised trial did not demonstrate any benefit of furosemide-infusion postoperatively in high-risk cardiac surgical patients. Although urinary output increased with furosemide, there was no decrease in renal injury, and no decrease in incidence of renal dysfunction.

Association of atrial nicotinamide adenine dinucleotide phosphate oxidase activity with the development of atrial fibrillation after cardiac surgery.

OBJECTIVES: Our goal was to evaluate the role of myocardial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and plasma markers of oxidative stress in the pathogenesis of post-operative atrial fibrillation (AF). BACKGROUND: Atrial fibrillation is a common complication of cardiac surgery, leading to increased morbidity and prolonged hospitalization. Experimental evidence suggests that oxidative stress may be involved in the pathogenesis of AF; however, the relevance of this putative mechanism in patients undergoing cardiac surgery is unclear. METHODS: We measured basal and NADPH-stimulated superoxide production in right atrial appendage samples from 170 consecutive patients undergoing conventional coronary artery bypass surgery. Plasma markers of lipid and protein oxidation (thiorbabituric acid-reactive substances, 8-isoprostane, and protein carbonyls) were also measured in blood samples drawn from a central line before surgery and after reperfusion. RESULTS: Patients who developed AF after surgery (42%) were older and had a significantly increased atrial NADPH oxidase activity than patients who remained in sinus rhythm (SR) (in relative light units/s/mug protein: 4.78 +/- 1.44 vs. 3.53 +/- 1.04 in SR patients, p < 0.0001). Plasma markers of lipid and protein oxidation increased significantly after reperfusion; however, neither pre-operative nor post-operative measurements differed between patients who developed AF and those who remained in SR after surgery. Multivariate analysis identified atrial NADPH oxidase activity as the strongest independent predictor of post-operative AF (odds ratio 2.41; 95% confidence interval 1.71 to 3.40, p < 0.0001). CONCLUSIONS: Atrial NADPH oxidase activity is independently associated with an increased risk of post-operative AF, suggesting that this oxidase system may be a key mediator of atrial oxidative stress leading to the development of AF after cardiac surgery.

Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation.

BACKGROUND: Tetrahydrobiopterin (BH4) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH4 levels are altered in human atherosclerosis and the importance of BH4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH4 levels affect endothelial function, eNOS coupling, and vascular superoxide production. METHODS AND RESULTS: Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor N(G)-nitro-L-arginine methyl ester. High vascular BH4 was associated with greater vasorelaxations to acetylcholine (P<0.05), whereas high plasma BH4 was associated with lower vasorelaxations in response to acetylcholine (P<0.05). Furthermore, an inverse association was observed between plasma and vascular biopterins (P<0.05 for both saphenous veins and internal mammary arteries). High vascular (but not plasma) BH4 was associated with reduced total and N(G)-nitro-L-arginine methyl ester-inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels (P<0.001). CONCLUSIONS: An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.

Comparison of hospital episode statistics and central cardiac audit database in public reporting of congenital heart surgery mortality.

OBJECTIVE: To verify or refute the value of hospital episode statistics (HES) in determining 30 day mortality after open congenital cardiac surgery in infants nationally in comparison with central cardiac audit database (CCAD) information. DESIGN: External review of paediatric cardiac surgical outcomes in England (HES) and all UK units (CCAD), as derived from each database. SETTING: Congenital heart surgery centres in the United Kingdom. DATA SOURCES: HES for congenital heart surgery and corresponding information from CCAD for the period 1 April 2000 to 31 March 2002. HES was restricted to the 11 English centres; CCAD covered all 13 UK centres. MAIN OUTCOME MEASURE: Mortality within 30 days of open heart surgery in infants aged under 12 months. RESULTS: In a direct comparison for the years when data from the 11 English centres were available from both databases, HES omitted between 5% and 38% of infants operated on in each centre. A median 40% (range 0-73%) shortfall occurred in identification of deaths by HES. As a result, mean 30 day mortality was underestimated at 4% by HES as compared with 8% for CCAD. In CCAD, between 1% and 23% of outcomes were missing in nine of 11 English centres used in the comparison (predominantly those for overseas patients). Accordingly, CCAD mortality could also be underestimated. Oxford provided the most complete dataset to HES, including all deaths recorded by CCAD. From three years of CCAD, Oxford's infant mortality from open cardiac surgery (10%) was not statistically different from the mean for all 13 UK centres (8%), in marked contrast to the conclusions drawn from HES for two of those years. CONCLUSIONS: Hospital episode statistics are unsatisfactory for the assessment of activity and outcomes in congenital heart surgery. The central cardiac audit database is more accurate and complete, but further work is needed to achieve fully comprehensive risk stratified mortality data. Given unresolved limitations in data quality, commercial organisations should reconsider placing centre specific or surgeon specific mortality data in the public domain.

Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease.

BACKGROUND: Although dietary folate fortification lowers plasma homocysteine and may reduce cardiovascular risk, high-dose folic acid therapy appears to not alter clinical outcome. Folic acid and its principal circulating metabolite, 5-methyltetrahydrofolate, improve vascular function, but mechanisms relating folate dose to vascular function remain unclear. We compared the effects of folic acid on human vessels using pharmacological high-dose versus low-dose treatment, equivalent to dietary folate fortification. METHODS AND RESULTS: Fifty-six non-folate-fortified patients with coronary artery disease were randomized to receive low-dose (400 microg/d) or high-dose (5 mg/d) folic acid or placebo for 7 weeks before coronary artery bypass grafting. Vascular function was quantified by magnetic resonance imaging before and after treatment. Vascular superoxide and nitric oxide bioavailability were determined in segments of saphenous vein and internal mammary artery. Low-dose folic acid increased nitric oxide-mediated endothelium-dependent vasomotor responses, reduced vascular superoxide production, and improved enzymatic coupling of endothelial nitric oxide synthase through availability of the cofactor tetrahydrobiopterin. No further improvement in these parameters occurred with high-dose compared with low-dose treatment. Whereas plasma 5-methyltetrahydrofolate increased proportionately with treatment dose of folic acid, vascular tissue 5-methyltetrahydrofolate showed no further increment with high-dose compared with low-dose folic acid. CONCLUSIONS: Low-dose folic acid treatment, comparable to daily intake and dietary fortification, improves vascular function through effects on endothelial nitric oxide synthase and vascular oxidative stress. High-dose folic acid treatment provides no additional benefit. These direct vascular effects are related to vascular tissue levels of 5-methyltetrahydrofolate rather than plasma levels. High-dose folic acid treatment likely confers no further benefit in subjects already receiving folate supplementation.

MRI-based modeling for evaluation of in vivo contact mechanics in the human wrist during active light grasp.

Investigations of in vivo joint mechanics are important for understanding the joint function under functional loading and the mechanisms of pathology. In this study we used magnetic resonance imaging (MRI) based joint contact modeling to evaluate in vivo joint contact mechanics in the human wrist. MRI scans were performed on the wrists of four subjects while they maintained light grasp of a cylinder, and with the same wrist relaxed. 3D models of the radius, scaphoid and lunate, including cartilage surface data, were constructed from the relaxed image data. These models were transformed into the loaded configuration, as determined from the grasp image data, and contact mechanics were evaluated. The resulting contact pressures, areas and forces were then analyzed for each articulation and for each subject. Contact areas were measured directly from grasp MRI images for comparison to the model predictions. The first-ever estimates for in vivo radioscaphoid and radiolunate contact pressure agreed reasonably well with previous cadaveric studies. This investigation also produced novel in vivo scapholunate contact results that were similar to radiolunate data. The specimen-specific contact area comparison generally showed substantial variability between the models and the direct measurements from MRI. On average, the models were within about 10% of the direct MRI measurements for radioscaphoid and scapholunate contact areas, but radiolunate contact areas from the model were only within 55% of the direct measurements. Overall, the results of the study suggest that MRI-based modeling has substantial potential for evaluation of in vivo joint contact mechanics, especially as technology and methodology improve.

5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling.

BACKGROUND: The circulating form of folic acid, 5-methyltetrahydrofolate (5-MTHF), may have beneficial effects on endothelial function; however, its mechanisms of action remain uncertain. Decreased nitric oxide (NO) bioavailability and increased vascular superoxide production in vascular disease states are due in part to endothelial NO synthase (eNOS) uncoupling related to deficiency of the eNOS cofactor tetrahydrobiopterin (BH4), but whether this mechanism is important in human atherosclerosis and represents a rational therapeutic target remains unclear. We hypothesized that 5-MTHF would improve endothelial function by decreasing superoxide and peroxynitrite production and by improving eNOS coupling, mediated by BH4 availability. METHODS AND RESULTS: Vascular superoxide/peroxynitrite production and vasomotor responses to acetylcholine and bradykinin were determined in saphenous veins and internal mammary arteries from 117 patients undergoing CABG. The effects of 5-MTHF were examined ex vivo (n = 61) by incubating vessels with 5-MTHF (1 to 100 micromol/L) and in vivo by intravenous infusion of 5-MTHF or placebo before vessel harvest (n = 56). 5-MTHF improved NO-mediated endothelium-dependent vasomotor responses and reduced vascular superoxide, both ex vivo and in vivo. These changes were not explained by direct superoxide scavenging by 5-MTHF in vitro or by changes in plasma total homocysteine in vivo. Rather, 5-MTHF was a strong peroxynitrite scavenger and increased vascular BH4 and the BH4/total biopterin ratio. Furthermore, 5-MTHF reversed eNOS uncoupling, as assessed by NG-nitro-l-arginine methyl ester-inhibitable superoxide production, increased the eNOS dimer:monomer ratio, and enhanced eNOS activity. CONCLUSIONS: 5-MTHF has beneficial effects on endothelial function and vascular superoxide production in human atherosclerosis, by preventing peroxynitrite-mediated BH4 oxidation and improving eNOS coupling.

Transsternal thymectomy for myasthenia gravis: surgical outcome.

BACKGROUND: Transsternal thymectomy is well established in the treatment of myasthenia gravis. Surgical strategy and patient selection, however, remain controversial. This paper reports the experience of a supraregional center looking into the influence of different preoperative risk factors on surgical outcome. METHODS: Between 1987 and 1998, 85 consecutive patients (65 female; mean age, 30.5 years) were enrolled. The mean preoperative Myasthenia Gravis Foundation of America stage was 2.3. The preoperative, early, and late follow-up data were analyzed retrospectively. RESULTS: Mean follow-up was 4.5 years (range, 1 to 14; 376 follow-up years). Mean duration of disease before surgery was 31 months. There were no operative or late deaths. Eight patients had major complications. Seventy-two patients were free from any early or late morbidity. Immunosupression therapy patients were more prone to have complications. At their last visit, 15 patients (17%) were in complete remission; 67 reported clinical improvement. Sixty-three were asymptomatic or in stage I on no or minimal treatment. Remission and clinical improvement were not predicted by patient's age, sex, duration of disease prior to surgery, thymic pathology, or antiacetylcholine receptor antibodies titer. Greater severity of symptoms before surgery was associated with greater subsequent improvement. Remission at 1 year predicted remission at the end of follow-up. CONCLUSIONS: Transsternal thymectomy for myasthenia gravis is safe and effective. It benefits most patients, especially those with severe symptoms. The long interval from diagnosis to surgery demonstrates it is never too late for thymectomy.

A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation.

Human atrial fibrillation (AF) has been associated with increased atrial oxidative stress. In animal models, inhibition of reactive oxygen species prevents atrial remodeling induced by rapid pacing, suggesting that oxidative stress may play an important role in the pathophysiology of AF. NAD(P)H oxidase is a major source of superoxide in the cardiovascular system; however, whether this enzyme contributes to atrial oxidative stress in AF remains to be elucidated. We investigated the sources of superoxide production (using inhibitors and substrates of a range of oxidases, RT-PCR, immunofluorescence, and immunoblotting) in tissue homogenates and isolated atrial myocytes from the right atrial appendage (RAA) of patients undergoing cardiac surgery (n=54 in sinus rhythm [SR] and 15 in AF). A membrane-bound gp91phox containing NAD(P)H oxidase in atrial myocytes was the main source of atrial superoxide production in SR and in AF. NADPH-stimulated superoxide release from RAA homogenates was significantly increased in patients with AF in the absence of changes in mRNA expression of the p22phox and gp91phox subunits of the NAD(P)H oxidase. In contrast with findings in SR patients, NO synthases (NOSs) contributed significantly to atrial superoxide production in fibrillating atria, suggesting that increased oxidative stress in AF may lead to NOS "uncoupling." These findings indicate that a myocardial NAD(P)H oxidase and, to a lesser extent, dysfunctional NOS contribute significantly to superoxide production in the fibrillating human atrial myocardium and may play an important role in the atrial oxidative injury and electrophysiological remodeling observed in patients with AF.