Adenosine A3 pretreatment before cardioplegic arrest attenuates postischemic cardiac dysfunction.

Background. The cardioprotective effects of the adenosine A₃ receptor in a cardioplegia model have not been described. We tested the hypothesis that infusion of the A₃ receptor agonist, Cl-IB-MECA (100 nM), as a pretreatment (PTx) and/or as a cardioplegic (CP) additive reduces postischemic myocardial injury.

Methods. Isolated perfused rat hearts underwent 30 minutes of normothermic ischemia, 60 minutes of intermittent hypothermic cardioplegia (10°C), followed by 2 hours of reperfusion. Hearts were divided into four groups: (1) no pretreatment (PTx) and unsupplemented cardioplegia (CP) (control), (2) Cl-IB-MECA PTx and unsupplemented CP (A₃-PTx), (3) no PTx and Cl-IB-MECA CP (A₃-CP), or (4) Cl-IB-MECA PTx and Cl-IB-MECA CP (A₃-[PTx+CP]).

Results. Coronary flow was not increased after A₃ pretreatment when compared to baseline values. After 2 hours of reperfusion, left ventricular developed pressure in control and A₃-CP groups was depressed to 43% ± 3% and 47% ± 2% of baseline; while A₃-PTx and A₃-[PTx+CP] significantly increased left ventricular developed pressure (65% ± 3% and 61% ± 5%) from baseline relative to control and A₃-CP. Effluent creatine kinase activity was significantly decreased by A₃-PTx (1520 ± 32 IU/L), A₃-[PTx+CP] (1481 ± 41 IU/L) from control (1734 ± 54 IU/L) and A₃-CP (1750 ± 43 IU/L). Myocardial edema (% tissue water) was significantly less in A₃-PTx (78 ± 0.6%) and A₃-[PTx+CP] (76% ± 2%) compared with control (85% ± 0.4%) and A₃-CP (83% ± 2%).

Conclusions. Adenosine A₃ receptor stimulation as a pretreatment attenuates postischemic cardiodynamic dysfunction and creatine kinase release but has no cardioprotection as an adjunct to cold cardioplegia.     

Epoxyeicosatrienoic acids (EET11,12) may partially restore endothelium-derived hyperpolarizing factor–mediated function in coronary microarteries

Background. Endothelial cells derive nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The cytochrome P-450–monooxygenase metabolites of arachidonic acid (epoxyeicosatrienoic acids [EETs]) have been suggested to be EDHF. This study was designed to examine the effect of EET_11,12 with regard to the possibility of restoring EDHF function when added into hyperkalemic cardioplegic solution.Methods. Porcine coronary microartery rings were studied in a myograph. In groups 1 and 2, paired arteries were incubated in either hyperkalemic solution (K⁺ 20 mmol/L) or Krebs’ solution (control). In group 3, the paired arteries were incubated in hyperkalemia plus EET_11,12 (1 × 10^−6.5 mol/L) or hyperkalemia alone (control) at 37°C for 1 hour, followed by Krebs’ washout and then precontracted with 1 × 10^−8.5 mol/L U46619. The EDHF-mediated relaxation to EET_11,12 (group 1) or bradykinin (groups 2 and 3) was studied in the presence of N^G-nitro-l-arginine, indomethacin, and oxyhemoglobin.Results. After exposure to hyperkalemia, the EDHF-mediated maximal relaxation by bradykinin (72.5% ± 7.8% versus 41.6% ± 10.6%; p < 0.05), but not by EET_11,12 (18.4% ± 3.3% versus 25.1% ± 4.9%; p > 0.05) was significantly reduced. Incubation with EET_11,12 partially restored EDHF function (33.3% ± 9.5% versus 62.0% ± 8.5%; p < 0.05).Conclusions. In coronary microarteries, hyperkalemia impairs EDHF-mediated relaxation, and EET_11,12 may partially mimic the EDHF function. Addition of EET_11,12 into cardioplegic solution may partially restore EDHF-mediated function reduced by exposure to hyperkalemia.     

Double Blind Randomized Control Study of Intramuscular Vitamin D3 Supplementation in Tropical Calcific Pancreatitis

Vitamin D deficiency is prevalent in chronic pancreatitis (CP), but the optimal route and dose of vitamin D supplementation are unknown. We evaluated the relative efficacy of two different doses of intramuscular (i.m.) vitamin D₃ in patients with CP and vitamin D insufficiency. In a double-blind randomized study, 40 patients with tropical calcific pancreatitis with serum 25-hydroxyvitamin D (25OHD) <75 nmol/L (mean 27.0 ± 14.5 nmol/L, <50 nmol/L in 90 %) were divided into three groups. Groups 1 and 2 received 600,000 IU (15,000 μg) and 300,000 IU (7,500 μg) i.m. cholecalciferol, respectively, while group 3 received i.m. saline. All groups received 1 g calcium and 500 IU (12.5 μg) vitamin D₃ orally daily and were studied for 9 months. The primary outcome was the proportion of patients with vitamin D sufficiency (25OHD >75 nmol/L) at 6 months. Vitamin D sufficiency was significantly different in the three groups (85, 29, and 0 % in groups 1, 2, and 3, respectively; p < 0.001). Mean 25OHD remained >75 nmol/L in months 1–6 in group 1 but reached a lower level (50–75 nmol/L) at these time points in group 2. At 6 months, serum alkaline phosphatase decreased significantly only in group 1 (230 ± 73 vs 165 ± 39 IU/L, p = 0.004). No patient in any group developed hypervitaminosis D or hypercalcemia. In conclusion, in patients with CP, a single i.m. injection of 600,000 IU was more effective at achieving vitamin D sufficiency over 6 months compared with 300,000 IU vitamin D₃. (Clinical Trials.gov number NCT00956839)     

Adenosine and the Stunned Heart

Abstract Adenosine is one agent under investigation as a therapeutic intervention of myocardial stunning. Adenosine caused numerous effects on the cardiovascular system through its interaction with A₁ and A₂ receptors. We investigated adenosine A₁ receptor mediated mechanisms of cardiac protection in the stunned rat myocardium. Previous studies showed that both adenosine and R-phenylisopropyladenosine (PIA), an A₁ receptor agonist, prolonged the time to onset of ischemic contracture in ischemic isolated rat hearts. Phenylaminoadenosine, an A₂ receptor agonist, did not have any effect, while receptor antagonists blocked adenosine and PIA action. Direct attenuation of the effects of myocardial stunning was observed by altering levels of interstitial fluid adenosine. Our laboratory has shown that administration of erthro-9(2-hydroxy-3-nonyl) adenine (EHNA; an adenosine deaminase inhibitor) to dogs subjected to left anterior descending coronary artery (LAD) occlusion followed by reperfusion results in dramatic increases in ischemic levels of interstitial fluid adenosine and postischemic myocardial function. Using a similar model in dogs, we have shown that exogenous intracoronary adenosine (50 μg/kg per min) augmented postischemic recovery of function, as assessed by significant enhancement (p < 0.01) of systolic wall thickness (7.0 ± 3.0 pretreatment vs ?5.7 ± 1.7 controls). These data support the role for an adenosine A₁ receptor mediated mechanism for protection against myocardial stunning.     

Transurethral needle ablation (TUNA) of the prostate: a clinical and urodynamic evaluation

Objectives. This prospective study evaluated the clinical and urodynamic changes in patients with obstruction due to benign prostatic hyperplasia (BPH) treated with transurethral needle ablation (TUNA)Methods. One hundred twenty patients with obstructive uropathy due to BPH were treated with the TUNA procedure between January 1994 and December 1995. All patients were selected according to the criteria established by the guidelines proposed by the International Consensus Committee (World Health Organization, Paris, 1993). The TUNA procedure was performed in an outpatient setting using topical intraurethral anesthesia (2% lidocaine gel).Results. Patients showed a decrease in irritative symptoms as measured by the International Prostate Symptom Score (IPSS) and postprocedure urodynamic parameters. The mean (± SD) pretreatment IPSS was 20.8 ± 4.5. At 3 months, the IPSS decreased to 9.7 ± 3.0 (108 patients) (P <0.001). At 6 months it decreased to 6.8 ± 3.1 (86 patients) and remained at 6.2 ± 2.9 (72 patients) and 6.7 ± 3.8 (42 patients) at 12 and 18 months, respectively (P <0.001). At 1 year after treatment, the peak flow rate (Qmax) increased from 8.2 ± 3.4 mL/s to 15.9 ± 2.1 mL/s and was 14.1 ± 2.5 mL/s at 18 months of follow-up (P <0.01). Urodynamic re-evaluation performed in 72 patients 12 months after TUNA demonstrated the absence of obstruction in 30 (41.7%). An additional 30 patients (41.7%) had equivocal results, whereas the remaining 12 (16.6%) still had obstruction, according to the Abrams-Griffith nomogram. Mean detrusor pressure at Qmax decreased from 85.3 ± 18.5 cm H₂O to 63.7 ± 24.9 cm H₂O at 12 months of follow-up.Conclusions. Our results confirm that the TUNA procedure is safe and effective when performed as an outpatient procedure. In addition, TUNA produced better results in patients presenting with moderate to severe irritative symptoms and minimal obstruction as determined by pressure/flow studies.     

Hepatitis C Virus Sensitivity to Combined Antiviral Therapy in Liver Transplant Versus Immunocompetent Patients

Recurrent hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) frequently causes allograft failure, because viral aggressiveness has been shown to be increased among immunosuppressed patients. Several studies have reported lower efficacy of antiviral therapy after OLT associated with worse tolerability. The aim of this study was to compare the logarithmic falls in viral loads at 4 and 12 weeks of treatment with pegylated interferon alpha and ribavirin among OLT versus immunocompetent patients. OLT patients (group 1) were recruited from 3 Spanish centers. Two age- and sex-matched controls (group 2) were randomly assigned to each case. We excluded coinfection with human immunodeficiency virus or hepatitis B or cholestatic hepatitis. Among group 1 (n = 66) were 72.7% men with an overall mean age of 52.7 ± 10.1 years; 90.9% were genotype 1. The mean baseline viral load was 6.0 ± 0.6 log10 IU/mL, and 19% of patients had cirrhosis. Among group 2 (n = 132) were 72.7% men with an overall mean age of 50.1 ± 10.1 years; 92.4% were genotype 1. The mean baseline viral load was 5.9 ± 0.5 log10 IU/mL, and 17% of patients had cirrhosis. There were no significant differences in patient characteristics between the 2 groups. The logarithmic falls in viral loads at 4 weeks of treatment were similar in groups 1 and 2: 2.3 ± 2.1 vs 2.4 ± 1.9 log10 IU/mL (P = .49); they were also similar at 12 weeks of treatment: 3.9 ± 1.9 vs 3.7 ± 2.4 log10 IU/mL (P = .66). In conclusion, in our study HCV sensitivity to combined antiviral therapy was the same among transplant versus immunocompetent patients.     

Vitamin D supplementation during pregnancy: Double‐blind,randomized clinical trial of safety and effectiveness

The need, safety, and effectiveness of vitamin D supplementation during pregnancy remain controversial. In this randomized, controlled trial, women with a singleton pregnancy at 12 to 16 weeks' gestation received 400, 2000, or 4000 IU of vitamin D₃ per day until delivery. The primary outcome was maternal/neonatal circulating 25‐hydroxyvitamin D [25(OH)D] concentration at delivery, with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] production. Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different (p < 0.0001), and the percent who achieved sufficiency was significantly different by group, greatest in 4000‐IU group (p < 0.0001). The relative risk (RR) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000‐ and the 400‐IU groups (RR = 1.52, 95% CI 1.24–1.86), the 4000‐ and the 400‐IU groups (RR = 1.60, 95% CI 1.32–1.95) but not between the 4000‐ and. 2000‐IU groups (RR = 1.06, 95% CI 0.93–1.19). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)₂D₃ concentrations throughout pregnancy (p < 0.0001), with maximal production of 1,25(OH)₂D₃ in all strata in the 4000‐IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels. It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race, whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations, especially in African Americans. © 2011 American Society for Bone and Mineral Research     

The dependency of solute diffusion on molecular weight and shape in intact bone

Solute transport through the bone lacunar–canalicular system (LCS) is essential for osteocyte survival and function, but quantitative data on the diffusivity of various biological molecules in the LCS are scarce. Using our recently developed approach based on fluorescence recovery after photobleaching (FRAP), diffusion coefficients of five exogenous fluorescent tracers (sodium fluorescein, dextran-3k, dextran-10k, parvalbumin, and ovalbumin) were measured in murine tibiae in situ. These tracers were chosen to test the dependency of solute diffusion on molecular weight (376–43,000 Da) and shape (linear vs. globular). Among the five tracers, no fluorescence recovery (and thus mobility) was detected for dextran-10k and the diffusion coefficients (D_LCS) of the other four tracers were 295 ± 46, 128 ± 32, 157 ± 88, 65 ± 21 μm² s^− 1 in the LCS, respectively. Overall, the rate of solute diffusion in the bone LCS showed strong dependency on molecular size and shape. Diffusivity decreased with increasing molecular weight for both linear and globular molecules, with the linear molecules decreasing at a faster rate. Compared with free diffusion (D_free) in aqueous solutions, the relative diffusivities (D_LCS / D_free) of the four tracers were not significantly different for sodium fluorescein, dextran-3k, parvalbumin, and ovalbumin (55.0 ± 8.6%, 68.1 ± 17.0%, 79.7 ± 44.7%, 61.0 ± 19.6%, respectively). This result did not agree with the homogenous molecular sieve model proposed for the osteocytic pericellular matrix structure. Instead, a heterogeneous porous model of the pericellular matrix may account for the observed solute transport in the LCS. In summary, the present study provides quantitative data on diffusion of various nutrients and signaling molecules in the LCS that are important for bone metabolism and mechanotransduction.     

Prevention of postischemic reperfusion injury: The improvement of myocardial tissue blood flow after ischemia by terminal Nicorandil-Mg cardioplegia

We evaluated the preventive effect of postischemic reperfusion injury by Nicorandil-Mg cardioplegia given just prior to reperfusion as terminal cardioplegia. Twenty seven dogs were placed on cardiopulmonary bypass and the aorta was cross-clamped for 90 min under hypothermic (17–19°C) cardioplegic arrest. The canine hearts were divided into three groups: in group A (n=10) the hearts were reperfused without any treatment; in group B (n=9) the hearts received coronary perfusion with Nicorandil-Mg solution (Nic, 8 mg/l; Mg, 20 mEq/l; glucose, 50 g/l) for 2 min just prior to reperfusion; and in group C (n=8) the hearts received coronary perfusion with Nicorandil-Mg free solution (glucose, 50g/l). During and after ischemia, the myocardial tissue PCO₂ (t-PCO₂) was continuously monitored by an ion-sensitive field effective transistor (ISFET) sensor. In addition, the myocardial tissue blood flow (TBF), oxygen consumption, and lactate flux were then calculated at 5, 10, 20, and 40 min of reperfusion. In the initial reperfusion period, Group B showed an improved TBF compared to group A and C (at 5 min, group B was 42.7±11.9; group A was 29.4±11.2, P<0.025; and group C was 33.9±9.2% of the preischemic control level, P<0.05). T-PCO₂ in group B was significantly decreased at 5 min of reperfusion (group B, 127.5±22.5 42.5±9.7; group A, 117.5±23.0 85.2±17.4, P<0.001; group C, 122.3 mmHg 68.2±18.7 mmHg, P<0.01), and group B had a better metabolic recovery. These results suggest that terminal Nicorandil-Mg cardioplegia might reduce the rate of postischemic reperfusion injury.     

Preoperative Transcatheter Arterial Chemoembolization and Prognosis of Patients with Hepatocellular Carcinomas: Retrospective Analysis of 120 Cases

1 (n= 24) and B₁ (n= 57), and those with tumors > 8 cm were assigned to groups A₂ (n= 20) and B₂ (n= 19), respectively. Although no significant differences in survival between groups A₁ and B₁ were found, group A₂ presented superior 1-, 2-, and 3-year tumor-free survival rates of 80%, 55%, and 32% and 1-, 3-, and 5-year cumulative survival rates of 90%, 53%, and 42%. These figures are in comparison with the tumor-free survival rates of 50%, 22%, and 11% (p= 0.06), and the cumulative survival rates of 72%, 33%, and 11% (p= 0.01) during the same periods for group B₂, respectively. The Cox regression model revealed that for patients with tumors > 8 cm, the relative risk of preoperative TAE for overall survival was 0.38 (p= 0.017), indicating that preoperative TAE might benefit patients with tumors > 8 cm but not those with tumors 2 to 8 cm.     

Effect of Preconditioning With Triiodothyronine on Renal Ischemia/Reperfusion Injury and Poly(ADP-Ribose) Polymerase Expression in Rats

The ischemia/reperfusion (I/R) model in rats allows pharmacological investigation of protective renal effects of certain agents to thereby diminish the incidence of delayed graft function (DGF). The aim of this study was to determine the effects of preconditioning with triiodothyronine (T₃) on renal function and oxidative status in renal I/R injury. Forty male Wistar rats were preconditioned with T₃ (100 μg/kg) or control (normal saline) at 24 hours prior to 45 minutes of renal ischemia, followed by a 4-hour (groups C-4h and T₃-4h) or 24-hour (groups C-24h and T₃-24h) reperfusion period. We determined renal function parameters (urea, creatinine, and proteinuria), oxidative stress biomarkers in plasma (malondialdehyde [MDA], glutathione [GSH], and superoxide dismutase [SOD]), urine (hydrogen peroxide [H₂O₂]), and renal tissue (GSH and MDA), and poly(ADP-ribose) polymerase (PARP-1) expression. Proteinuria was significantly lower in the T₃-treated group (4.63 ± 1.9 vs 9.27 ± 0.72 mg/mL/100 g body weight). Pretreated rats showed lower levels of plasma and tissue MDA and urine H₂O₂ (50.57 ± 1.17 vs 71.16 ± 1.14 μmol/100 g body weight). The T₃ treatment was associated with lower postischemia GSH concentrations (3.82 ± 1.16 vs 4.89 ± 0.68 nmol/mg protein) and higher SOD levels at 24 hours (11.27 ± 0.86 vs 9.92 ± 1.77 nmol/mg protein). Preconditioning with the hormone also reduced PARP-1 tissue expression by 18% (P ≤ .05). These findings suggested that preconditioning with T₃ reduced proteinuria, improved lipid peroxidation biomarkers, and increased antioxidant enzyme levels in renal I/R injury.     

Effect of Vitamins D<Subscript>2</Subscript> and D<Subscript>3</Subscript> Supplement Use on Serum 25OHD Concentration in Elderly Women in Summer and Winter

Vitamin D₂ and D₃ are generally considered equipotent in humans. A few studies have reported that serum 25OHD levels are higher in vitamin D₃- compared with vitamin D₂-supplemented subjects. As both vitamin D₂ and D₃ supplements are commonly used by elderly in United States, in the present study we determined the effect of self-reported vitamin D₂ and vitamin D₃ supplement use on serum total 25OHD levels according to season in elderly women aged 65–77 years. Serum total 25OHD levels were determined in winter and summer in unsupplemented women (N = 307) and in women who reported taking vitamin D₂ (N = 56) and vitamin D₃ (N = 55) supplements by competitive protein binding assay. In vitamin D₂-supplemented women, the contribution of vitamin D₂ and D₃ to the mean serum total 25OHD level was assessed by HPLC. In summer, there were no significant differences in the mean total serum 25OHD levels (ng/ml) among the vitamin D₂ (32 ± 2.1), vitamin D₃ (36.7 ± 1.95), and unsupplemented (32.2 ± 0.95) groups. In winter, the mean serum total 25OHD levels were higher in women on vitamin D₂ (33.6 ± 2.34, P < 0.05) and vitamin D₃ (29.7 ± 1.76, NS) supplements compared with unsupplemented women (27.3 ± 0.72). In vitamin D₂-supplemented women, about 25% of the mean serum total 25OHD was 25OHD₂, in both summer and winter. Twelve percent of unsupplemented women and 3.6% of vitamin D-supplemented women had a mean serum total 25OHD level below 15 ng/ml in winter. In elderly subjects, both vitamin D₂ and Vitamin D₃ supplements may contribute equally to circulating 25OHD levels, with the role of vitamin D supplement use being more predominant during winter. This work was presented in part as an abstract at Second Joint Meeting of the American Society for Bone and Mineral Research and The International Bone and Mineral Society, San Francisco, CA, 1–6 December 1998.     

Blood cardioplegia supplementation with the sodium-hydrogen ion exchange inhibitor cariporide to attenuate infarct size and coronary artery endothelial dysfunction after severe regional ischemia in a canine model

BACKGROUND: Activation of the sodium-hydrogen ion exchange mechanism results in accumulation of intracellular calcium through the sodium-calcium ion antiport mechanism. Administration of a sodium-hydrogen ion exchange inhibitor before or during ischemia attenuates myocardial ischemia and reperfusion injury. However, the cardioprotection exerted by sodium-hydrogen ion exchange inhibitors as adjuncts to cardioplegia without perioperative administration has not been tested in a model of surgical reperfusion of acute coronary occlusion with cardiopulmonary bypass. This study tested the hypothesis that sodium-hydrogen ion exchange inhibitor-supplemented blood cardioplegia would reduce postcardioplegia injury after severe regional ischemia. METHODS: In anesthetized open-chest dogs, the left anterior descending coronary artery was occluded for 75 minutes, after which total cardiopulmonary bypass was initiated. After crossclamping, cold (4 degrees C) antegrade blood cardioplegia was delivered every 20 minutes for a total of 60 minutes of cardioplegic arrest. In 8 dogs, the blood cardioplegic solution was unsupplemented (vehicle group), whereas in 8 others the solution was supplemented with the sodium-hydrogen ion exchange inhibitor cariporide (10 micro mol/L, cariporide group). RESULTS: In the in vitro studies, the direct effects of cariporide on neutrophil function were determined. Isolated canine neutrophils were stimulated by platelet activating factor. Cariporide attenuated superoxide anion production in a concentration-dependent manner, with no appreciable effect at 10 micro mol/L (the concentration used in blood cardioplegia) and a peak effect at 100 micro mol/L. In the in vivo cardiopulmonary bypass model, infarct size was significantly (P <.05) smaller in the cariporide group than in the vehicle group (22.4% +/- 3.5% vs 40.1% +/- 5.1% of area at risk), although there were no group differences in postischemic regional wall motion after 2 hours of reperfusion (0.1% +/- 0.9% vs -0.2% +/- 0.3% systolic shortening). Transmural myocardial edema in the area at risk was significantly decreased in the cariporide group (80.6% +/- 0.5%) relative to the vehicle group (83.1% +/- 0.6%). Myeloperoxidase activity in the area at risk, an index of neutrophil accumulation, was significantly lower in the cariporide group than in the vehicle group (4.7 +/- 0.9 absorbence units/[min. g tissue] vs 10.3 +/- 2.3 absorbence units/[min. g tissue]). In isolated postischemic left anterior descending coronary artery rings, maximum relaxation in response to the endothelium-dependent vasodilator acetylcholine was significantly greater in the cariporide group than in the vehicle group (77.5% +/- 7.4% vs 51.4% +/- 8.0%), whereas smooth muscle relaxation in response to nitroprusside was comparable between groups. CONCLUSION: In this canine model, supplementation of blood cardioplegia with cariporide, a sodium-hydrogen ion exchange inhibitor, reduced infarct size, attenuated neutrophil accumulation in the area at risk, and reduced postischemic coronary artery endothelial dysfunction without directly inhibiting neutrophil activity. Cariporide as an adjunct to blood cardioplegia without perioperative administration attenuated surgical ischemia-reperfusion injury in jeopardized myocardium.     

Conduction block by clonidine is not mediated by α2-adrenergic receptors in rat sciatic nerve fibers

Background and Objectives: Clonidine, an α₂-adrenergic agonist, has been shown to prolong local anesthesia. It appears that clonidine by itself produces conduction block by acting on peripheral nerves. However, whether clonidine-induced conduction block is mediated through α₂-adrenergic receptors remains unclear. The purpose of this study was to see if clonidine's nerve-blocking action was through α₂-adrenergic receptors by examining clonidine's action in the presence of α₂-adrenergic antagonists. Methods: The compound action potentials (CAPs) evoked by electrical stimuli were recorded from the isolated rat sciatic nerve in a recording chamber. Conduction block was examined by analyzing CAPs with regard to peak amplitude and time-to-peak in the presence of clonidine alone or clonidine plus α₂-adrenergic antagonist yohimbine or idazoxan. Results: Both clonidine and yohimbine produced concentration-dependent, reversible, conduction block. Based on concentration-response relationships, the 50% of effective concentration (EC₅₀) were estimated to be 1.61 ± 0.51 mmol/L (mean ± SD) for clonidine and 51.4 ± 27.2 μmol/L for yohimbine. A mixture of equal volumes of 2.07 mmol/L clonidine and 55.6 μmol/L yohimbine produced conduction block to a level close to the mean value between conduction blocks induced by 2.07 mmol/L clonidine alone and 55.6 μmol/L yohimbine alone. Addition of idazoxan, a more specific α₂-adrenergic antagonist than yohimbine, to clonidine was without effect on clonidine-induced conduction block. Conclusions: The results indicated that the mixture of clonidine and yohimbine, in which either drug inhibited impulse conduction, produced conduction block in an additive manner, and that clonidine-induced conduction block was not reversed by coapplication with a specific α₂-adrenergic antagonist idazoxan. These data suggest that clonidine's effects likely depend on mechanisms not mediated by α₂-adrenergic receptors. Reg Anesth Pain Med 2000;25:620-625.     

Is Reperfusion Injury from Multiple Aortic Cross-Clamping a Current Myth of Cardiac Surgery?

Four hundred eighty adult patients undergoing cardiac operations had systemic and topical hypothermic anoxic arrest supplemented with potassium chloride pharmacological cardioplegia in a prospective randomized study. Group 1 (217 patients) had continuous aortic cross-clamping and one single anoxic arrest period during the cardiac portion of the operation which resulted in a transmural myocardial infarction rate of 8.3%, myocardial “injury” incidence of 12.4%, 4.6% cardiac-related deaths, 11.5% and 24.8% severe and malignant ventricular arrhythmias, 21.7% rate of severe vasopressor usage, a mean group serum glutamic oxaloacetic transaminase (SGOT) of 140 ± 39 IU, and a mean group lactic dehydrogenase (LDH) of 636 ± 78.2 IU. Group 2 (263 patients) had intermittent aortic cross-clamping with multiple reperfusion intervals, which resulted in a significantly lower incidence of transmural myocardial infarction at 1.9% (p < 0.01), rate of myocardial injury at 5.66% (p < 0.02), number of cardiac deaths at 0.76% (p < 0.02), 8.7% and 16.0% severe and malignant ventricular arrhythmias (p < 0.01), severe vasopressor utilization rate of 14.3% (p < 0.05), mean group SGOT at 72.0 ± 3.1 IU (p < 0.01), and mean group LDH at 471.0 ± 12.3 IU (p < 0.05) than Group 1. These results do not support the contention that intermittent aortic cross-clamping in conjunction with hypothermia and pharmacological cardioplegia leads to increased clinical cardiac damage compared with continuous aortic cross-clamping. The converse is implied, in that the anoxic heart may benefit from the physiological effects of briefly reperfused oxygenated blood.     

Estrogen improves endothelial function

Purpose: To determine the effect of estrogen on endothelium-dependent relaxation in the cutaneous microcirculation of women. Methods: Three groups of women participated in the study. Group 1 (n = 20) was premenopausal and had a mean age of 39 years (range 24-50 years). Group 2 (n = 9) was postmenopausal and had a mean age of 58 years (range 53-65 years). Group 3 (n = 11) was postmenopausal and taking estrogen replacement therapy; the mean age was 53 years (range 43-58 years). Eleven women in group 1 underwent testing twice, once during menstruation (mean serum estradiol level 73 ± 30 pg/ml) and once during midcycle (mean serum estradiol level 268 ± 193 pg/ml; p = 0.003). Single-point laser Doppler ultrasound and laser Doppler imaging with a scanner were used to measure vasodilatation in the forearm skin in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium-independent smooth muscle relaxant). Results: All three groups were matched for body mass index and fasting glucose, total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglyceride levels. All women had normal blood pressure, and none smoked. Mean serum estradiol levels were 196 ± 170 pg/ml (group 1), 35 ± 12 pg/ml (group 2), and 107 ± 78 pg/ml (group 3) (p = 0.004). Maximum microvascular vasodilatation (percentage increase over baseline) in response to acetylcholine was reduced in group 2 (93% ± 43%) compared with group 1 (187% ± 63%) and group 3 (142% ± 56%) (p = 0.001). The response to sodium nitroprusside also was diminished in group 2 (73% ± 27%) compared with group 1 (126% ± 45%) and group 3 (100% ± 32%) (p = 0.02). Within group 1 the acetylcholine response was higher during the midcycle phase (186% ± 31%) compared with the menstrual phase (147% ± 57%) (p < 0.05). The sodium nitroprusside response also was higher during the midcycle phase (144% ± 31%) compared with the menstrual phase (94% ± 41%) (p < 0.05) Conclusion: The results indicate that estrogens might enhance endothelium-dependent and endothelium-independent vasodilatation in the microcirculation of women.(J Vasc Surg 1998;27:1141-7.)     

Short- and Long-Term Changes in Bone Mineral Density of the Lumbar Spine After Parathyroidectomy in Patients with Primary Hyperparathyroidism

The aims of this study were (1) to analyze whether correlations exist between lumbar spine (LS) bone mineral density (BMD) and the main preoperative biochemical parameters in a large population of patients with primary hyperparathyroidism (HPT); and (2) to evaluate the LS-BMD changes after parathyroidectomy (PTx) at long-term follow-up. Sixty-two patients (median age 57 years, range 23–82 years) with confirmed primary HPT underwent LS osteodensitometry by dual-energy X-ray absorptiometry with BMD measurements at the L2–L4 region before surgery and at 1 year and 2 years after successful PTx. Three groups of patients were considered: Group A (men, n = 14, 22.6%), Group B (premenopausal women, n = 12, 19.3%), and Group C (postmenopausal women, n = 36, 58.1%). There were no linear correlations (P = NS) among the main biochemical parameters, the age of the patients, and their baseline LS-BMD values that were significantly (P < 0.01) lower in Group C patients. At 2-year follow-up the LS-BMD improved by 13.0%, 11.5%, and 11.7% in Groups A, B, and C, respectively (P = NS). In order to compare groups with the same linear relationship between age and LS-BMD, a subgroup of postmenopausal patients aged 60 years (Group C2) was considered. ANOVA showed that the improvement of the LS-BMD at l- and 2-year follow-up was higher (P = 0.002) in Group B than in Group C2 patients. The result was confirmed by using the Mann-Whitney U-test (P = 0.0078). Improvement of LS-BMD after successful PTx was significantly (P < 0.01) higher in premenopausal women, suggesting a possible role of estrogen hormone in complete bone remodeling. This study was presented at the XXVII European Symposium on Calcified Tissue, Tampere, Finland, 6–19 May, 2000     

Continuous perfusion of donor hearts with oxygenated blood cardioplegia improves graft function

Donor hearts cannot be preserved beyond 6 h using cold storage (CS). Improving preservation methods may permit prolonged storage of donor heart. We compared graft function in large animal model after prolonged preservation (8 h) using continuous perfusion (CP) and CS method. Twenty‐four miniature pigs were used as donors and recipients. Donor hearts were either stored in University of Wisconsin solution (UW solution) for 8 h at 0–4 °C (CS group, n = 6) or were continuously perfused with oxygenated blood cardioplegia at 26 °C for 8 h (CP group, n = 6). After preservation, hearts were transplanted into recipients and reperfused for 3 h. Left ventricular (LV) function, cardiac output (CO), malondialdehyde (MDA) and adenosine triphosphate (ATP) levels, and water content were measured. Although water content of CP hearts was higher than that of CS, LV contractility and diastolic function of CP hearts were superior to those of CS. In addition, CP hearts performed better than CS hearts on CO in working heart state. ATP was better preserved and MDA levels were lower in CP hearts compared with those of CS (P < 0.0001). Donor hearts can be preserved longer using continuous perfusion with oxygenated blood cardioplegia and this method prevents time‐dependent ischemic injury.     

Influence of internal mammary artery grafting and completeness of revascularization on long-term outcome in octogenarians

Background. It has been well established that complete revascularization with internal mammary artery (IMA) grafting is important in young patients undergoing coronary artery bypass grafting (CABG). Applying these principles to octogenarians remains controversial.Methods. From 1986 to 1999, 358 consecutive patients aged 80 to 94 years underwent CABG. Revascularization was complete in 291 (81%) and incomplete in 67 (19%). The IMA was used in 231 (65%) cases.Results. Operative mortality was 7% ± 1%, but was not statistically different with or without IMA grafting (IMA 5% ± 2% versus no IMA 10% ± 3%, p = 0.11) or complete revascularization (p > 0.41). Midterm survival improved with IMA grafting (70% ± 3% versus 56% ± 5% at 4 years, p < 0.03; 36% ± 4% versus 29% ± 5% at 8 years, p < 0.08), but was not significant beyond 8 years. Among 138 survivors, those with IMA grafts were more likely to be angina free (82% versus 53%, p < 0.001) and in New York Heart Association class I (60% versus 36%, p < 0.03). Survival, recurrent angina, and functional class were independent of completeness of revascularization (p > 0.21).Conclusions. IMA grafting improved survival, angina, and functional class of octogenarians, but complete revascularization did not have a similar impact.     

Effects of retroviral-mediated tissue plasminogen activator gene transfer and expression on adherence and proliferation of canine endothelial cells seeded onto expanded polytetrafluoroethylene

Purpose: Seeding prosthetic arterial grafts with genetically modified endothelial cells (ECs) has the potential to substantially improve graft function. However, preliminary applications suggest that grafts seeded with retrovirally transduced ECs yield a significantly lower percent surface coverage than those seeded with nontransduced ECs. The objective of this study was to test the hypothesis that canine ECs transduced with the human tissue plasminogen activator (tPA) gene would have a lower rate of adherence to pretreated expanded polytetrafluoroethylene (ePTFE) both in vitro and in vivo and that they would proliferate at a slower rate on pretreated ePTFE in vitro.Methods: Early passage ECs derived from canine external jugular vein were transduced with the retroviral MFG vector containing the gene for human tPA. ECs exposed to media alone served as controls. Iodine 125 – labeled ECs were seeded in vitro onto ePTFE graft segments pretreated with canine whole blood, fibronectin (50 μg/ml), or media alone, and the percent of ECs adherent at 1 hour were determined (n = 3). Additional tPA-transduced and –nontransduced ECs were grown for 10 days on either fibronectin (50 μg/ml) – pretreated ePTFE wafers or tissue culture plastic pretreated with gelatin (1%) or fibronectin (50 μg/ml), and the EC proliferation rates were determined (n = 3). Furthermore, ¹²⁵I-labeled ECs were seeded onto fibronectin (50 μg/ml) – pretreated ePTFE graft segments implanted as carotid and femoral artery interposition grafts (n = 3). The grafts were harvested after 1 hour, and the percent of ECs adherent was determined.Results: Human tPA was detected by immunohistochemical staining in 61% ± 5% of the transduced ECs and was expressed at 35.4 ± 12.9 ng/hr/10⁶ cells. Fibronectin and whole blood pretreatment of the ePTFE grafts led to greater EC adherence in vitro than did media alone (90.9% ± 5.3% vs 77.8% ± 5.8% vs 4.7% ± 1.1%, p ≤ 0.05). No significant difference in the rates of adherence or proliferation was seen in vitro between the transduced and nontransduced ECs. No significant difference in proliferation was found for the transduced ECs on the three matrices tested in vitro. In contrast, adherence of the transduced ECs in vivo was significantly lower than that of nontransduced ECs (64.7% ± 2.1% vs 73.7% ± 4.1%, p ≤0.05) 1 hour after implantation.Conclusions: Lower rates of surface endothelialization by genetically modified ECs in vivo do not appear to be due to an impaired capacity to initially adhere or proliferate on the synthetic graft but may result from decreased adherence after exposure to in vivo hemodynamic forces. (J VASC SURG 1995;22:795-803.)