Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart.
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The majority of clinically used inotropes act by increasing cytosolic calcium levels, which may hypothetically worsen reperfusion stunning and provoke arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan (levo) given during ischemia alone or ischemia and reperfusion would improve reperfusion function without promoting arrhythmias. The Langendorff-perfused guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used. Left ventricular developed pressure (LVDP) was used as an index of mechanical function. The effect of levo (300 nM) or dobutamine (0.1 microM) on the incidence of ischemia/reperfusion arrhythmias was also investigated. Control hearts (vehicle-perfused) had LVDPs of 69.4 +/- 2.1 mm Hg whereas hearts treated with levo during ischemia and reperfusion (300 nM) had LVDPs of 104.5 +/- 2.7 mm Hg (p <.05). Hearts treated with levo during ischemia alone (10 nM) had reperfusion LVDPs of 95.8 +/- 4.2 mm Hg (p <.05) after 30-min reperfusion. Hearts treated with both levo and 10 microM glibenclamide (K(ATP) channel blocker) during ischemia had reperfusion LVDPs of 73.4 +/- 4.3 mm Hg after 30-min reperfusion. Of control hearts, 25% developed reperfusion ventricular tachycardia but not ventricular fibrillation. Levo-treated hearts had no ischemia/reperfusion arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts developed ventricular tachycardia and 33% (p <.05 versus levo) developed reperfusion ventricular fibrillation. Levo improved reperfusion function without promoting arrhythmias in this model. This was possibly achieved by opening the K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus instead of elevating cytosolic calcium levels in reperfused hearts. (+info)
Outcomes of irradiated polyglactin 910 Vicryl Rapide fast-absorbing suture in oral and scalp wounds.
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BACKGROUND: This study evaluated the outcome of wounds closed with irradiated polyglactin 910 (IRPG) Vicryl Rapide (Ethicon, Somerville, N.J.). METHOD: Seventy-one patients with 80 oral wounds and 42 patients with 42 scalp wounds closed with IRPG were evaluated on the day of surgery, then one, seven, 14, 28 and 90 days following surgery. The incidence of inflammation, suppuration and hypertrophic scarring was recorded, along with the timing of spontaneous suture disappearance. This suture material was compared with polytetrafluoroethylene (PTFE) sutures used in dental implant patients, traditional polyglycolic acid (PGLA) sutures used in osteotomy patients and skin staples used in patients with scalp wounds. RESULTS: In the group with intraoral wounds, there were two cases of suppuration with no inflammatory reactions or hypertrophic scarring when IRPG sutures were used, compared to three cases of suppuration with the traditional PGLA sutures. In the group with scalp wounds, there was no suppuration or hypertrophic scarring with IRPG sutures and one inflammatory reaction with skin staples. IRPG sutures never required removal, while all staples, PGLA and PTFE sutures eventually required separate removal. CONCLUSION: Irradiated polyglactin 910 Vicryl Rapide is a useful suture material with both intra- and extraoral applications in the pediatric and adult populations. (+info)
Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes.
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Observations on lactate transport in brain cells and cardiac myocytes indicate the presence of a high-affinity monocarboxylate transporter. The rat monocarboxylate transporter isoform MCT2 was analysed by expression in Xenopus laevis oocytes and the results were compared with the known characteristics of lactate transport in heart and brain. Monocarboxylate transport via MCT2 was driven by the H(+) gradient over the plasma membrane. Uptake of lactate strongly increased with decreasing pH, showing half-maximal stimulation at pH 7.2. A wide variety of monocarboxylates and ketone bodies, including lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, 2-oxoisovalerate and 2-oxoisohexanoate, were substrates of MCT2. All substrates had a high affinity for MCT2. For lactate a K(m) value of 0.74+/-0.07 mM was determined at pH 7.0. For the other substrates, K(i) values between 100 microM and 1 mM were measured for inhibition of lactate transport, which is about one-tenth of the corresponding values for the ubiquitously expressed monocarboxylate transporter isoform MCT1. Monocarboxylate transport via MCT2 could be inhibited by alpha-cyano-4-hydroxycinnamate, anion-channel inhibitors and flavonoids. It is suggested that cells which express MCT2 preferentially use lactate and ketone bodies as energy sources. (+info)
Effect of the lactic acid bacterium Streptococcus thermophilus on ceramide levels in human keratinocytes in vitro and stratum corneum in vivo.
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The effects of Streptococcus thermophilus on ceramide levels either in vitro on cultured human keratinocytes or in vivo on stratum corneum, have been investigated. In vitro, Streptococcus thermophilus enhanced the levels of ceramides in keratinocytes in a time-dependent way. The presence of high levels of neutral, glutathione-sensitive, sphingomyelinase in Streptococcus thermophilus could be responsible for the observed ceramide increase. The application of a base cream containing sonicated Streptococcus thermophilus in the forearm skin of 17 healthy volunteers for 7 d also led to a significant and relevant increase of skin ceramide amounts, which could be due to the sphingomyelin hydrolysis through bacterial neutral sphingomyelinase. Indeed, similar results were obtained with a base cream containing purified bacterial neutral sphingomyelinase. In addition, the inhibition of bacterial neutral sphingomyelinase activity through glutathione blocked the skin ceramide increase observed after the treatment. The topical application of a sonicated Streptococcus thermophilus preparation, leading to increased stratum corneum ceramide levels, could thus result in the improvement of lipid barrier and a more effective resistance against xerosis. (+info)
Role of protons in activation of cardiac sympathetic C-fibre afferents during ischaemia in cats.
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1. Chest pain caused by myocardial ischaemia is mediated by cardiac sympathetic afferents. The mechanisms of activation of cardiac afferents during ischaemia remain poorly understood. Increased lactic acid production is associated closely with myocardial ischaemia. The present study examined the role of protons generated during ischaemia in activation of cardiac sympathetic C-fibre afferents. 2. Single-unit activity of cardiac afferents innervating both ventricles was recorded from the left sympathetic chain in anaesthetized cats. Epicardial tissue pH was measured within 1-1.5 mm of the surface by a pH-sensitive needle electrode. Responses of cardiac afferents to myocardial ischaemia, lactic acid, sodium lactate, acidic phosphate buffer and hypercapnia were determined. 3. Occlusion of the coronary artery for 5 min decreased epicardial tissue pH from 7.35 +/- 0.21 to 6.98 +/- 0.22 (P < 0.05). Epicardial placement of isotonic neutral phosphate buffer, but not saline, prevented the ischaemia-induced decrease in epicardial pH. This manoeuvre significantly attenuated the response of 16 afferents to 5 min of ischaemia (1.56 +/- 0.23 pre-treatment vs. 0.67 +/- 0.18 impulses s-1). Topical application of 10-100 microg ml-1 of lactic acid, but not sodium lactate, concentration-dependently stimulated 18 cardiac afferents. Inhalation with high-CO2 gas failed to activate 12 separate cardiac afferents. Furthermore, lactic acid stimulated cardiac afferents to a greater extent than acidic phosphate buffer solution, applied at a similar pH to the same afferents. 4. Collectively, this study provides important in vivo evidence that protons contribute to activation/sensitization of cardiac sympathetic C-fibre afferents during myocardial ischaemia. (+info)
Measurement of the urinary lactate:creatinine ratio for the early identification of newborn infants at risk for hypoxic-ischemic encephalopathy.
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BACKGROUND: Newborn infants with perinatal asphyxia are prone to the development of hypoxic-ischemic encephalopathy. There are no reliable methods for identifying infants at risk for this disorder. METHODS: We measured the ratio of lactate to creatinine in urine by proton nuclear magnetic resonance spectroscopy within 6 hours and again 48 to 72 hours after birth in 58 normal infants and 40 infants with asphyxia. The results were correlated with the subsequent presence or absence of hypoxic-ischemic encephalopathy. RESULTS: Hypoxic-ischemic encephalopathy did not develop in any of the normal newborns but did develop in 16 of the 40 newborns with asphyxia. Within six hours after birth, the mean (+/-SD) ratio of urinary lactate to creatinine was 16.75+/-27.38 in the infants who subsequently had hypoxic-ischemic encephalopathy, as compared with 0.09+/-0.02 in the normal infants (P<0.001) and 0.19+/-0.12 in the infants with asphyxia in whom hypoxic-ischemic encephalopathy did not develop (P<0.001). A ratio of 0.64 or higher within six hours after birth had a sensitivity of 94 percent and a specificity of 100 percent for predicting the development of hypoxic-ischemic encephalopathy. The sensitivity and specificity of measurements obtained 48 to 72 hours after birth were much lower. The mean ratio of urinary lactate to creatinine was significantly higher in the infants who had adverse outcomes at one year (25.36+/-32.02) than in the infants with favorable outcomes (0.63+/-1.50) (P<0.001). CONCLUSIONS: Measurement of the urinary lactate: creatinine ratio soon after birth may help identify infants at high risk for hypoxic-ischemic encephalopathy. (+info)
The roles of two amino acid residues in the active site of L-lactate monooxygenase. Mutation of arginine 187 to methionine and histidine 240 to glutamine.
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Lactate monooxygenase (LMO) catalyzes the conversion of L-lactate to acetate, CO(2), and water with the incorporation of molecular oxygen. Arginine 187 of LMO is highly conserved within the family of L-alpha-hydroxyacid oxidizing enzymes (Le, K. H. D., and Lederer, F. (1991) J. Biol. Chem. 266, 20877-20881). By comparison with the equivalent residue in flavocytochrome b(2) from Saccharomyces cerevisiae (Pike, A. D., Chapman, S. K, Manson, F. D. C,. Reid, G. A. , Gondry, M., and Lederer, F. (1996) in Flavins and Flavoproteins (Stevenson, K. J., Massey, V., and Williams, C. H., Jr., eds) pp. 571-574, University of Calgary Press, Calgary, AB, Canada), arginine 187 might be expected to have an important role in catalytic efficiency and substrate binding in LMO. Histidine 240 is predicted to be close to the substrate binding site of LMO, although it is not conserved within the enzyme family. Arginine 187 has been replaced with methionine (R187M), and histidine 240 has been replaced with glutamine (H240Q). L-Lactate oxidation by R187M is very slow. The binding of L-lactate to the mutant enzyme appears to be very weak, as is the binding of oxalate, a transition state analogue. The binding of pyruvate to the reduced enzyme is also very weak, resulting in complete uncoupling of enzyme turnover, with H(2)O(2) and pyruvate as the final products. In addition, anionic forms of the flavin are unstable. The K(d) for sulfite is increased nearly 400-fold by this mutation. The semiquinone form of R187M is also thermodynamically unstable, although the overall midpoint potential for the two-electron reduction of R187M is only 34 mV lower than for the wild-type enzyme. H240Q more closely resembles the wild-type enzyme. The steady-state activity of H240Q is completely coupled. The k(cat) is similar to that for the wild-type enzyme. (+info)
Female-related skeletal muscle phenotype in patients with moderate chronic heart failure before and after dynamic exercise training.
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This study hypothesized that female patients with chronic heart failure (CHF), similarly as previously reported for male patients, have a decreased proportion of type I (slow twitch) muscle fibers combined with fiber atrophy, and respond to exercise training with an increased muscular fiber area and performance, and with an unaltered fiber type distribution. METHODS: Sixteen women [age 62 +/- 10 years (mean +/- SD)] with stable, moderate CHF (left ventricular ejection fraction 28 +/- 8%) underwent percutaneous needle biopsies of the lateral vastus muscle, and assessments of isokinetic muscle strength and exercise tests with respiratory gas and blood lactate analyses, before and after 8 weeks of intensive knee extensor endurance training. RESULTS: When compared to healthy age-matched women, the women with CHF unexpectedly had a normal proportion of type I fibers (51 +/- 15%), but a decreased cross-sectional area in both type I and II fibers. Exercise training increased the cross-sectional area of muscle fibers up to the reference range (21%, p < 0.04), while the relative number of type I fibers decreased (12%, p < 0.03). Training also increased muscle strength (16%, p < 0.0001) and peak oxygen uptake (20%, p < 0.0001). The increase in peak oxygen uptake was directly related to the training-induced increase in fiber areas (r = 0.63; p < 0.03), and decrease in lactate accumulation was inversely related to the training-induced decrease in the relative number of type I fibers (r = -0.62; p < 0.02). CONCLUSIONS: As for men with CHF, a skeletal muscle atrophy was found in women, but contrary to the hypothesis, the proportion of type I muscle fibers was normal. Exercise training counteracted the atrophy suggesting skeletal muscle trainability in female CHF patients. (+info)