In vivo and in vitro studies on multidirectional mechanism of anti-allergic activity of budesonide.

Most studies on the effects of glucocorticosteroid therapy in rhinitis relate to their inhibitory effect on activation and the number of inflowing cells that are involved in the development and maintenance of inflammation. It is also very important to determine the range of effect of budesonide on residing cells (epithelial cells). The purpose of this study was to evaluate the effect of local budesonide therapy on the cytological image of the nasal mucosa, with attention paid to columnar cells in patients with rhinitis. The in vivo results obtained were analyzed in correlation with changes in normal CHO-K1 cells exposed to budesonide at concentrations falling within the pharmacological dose range. Fifty patients diagnosed with rhinitis with suspected allergic background without nasal polyps were included in clinical trials. The control group were 10 healthy people without clinical signs of rhinitis. Only in patients with homogeneous cytological picture, exfoliative cytology was performed before treatment and after 4 weeks of therapy with budesonide used in aerosol form. Papanicolaou and Pappenheim - stained smears were evaluated qualitatively and quantitatively for changes in nasal mucosal cells. The nasal mucosal image of the patients before treatment clearly indicated the pathological state confirmed by the presence of numerous neutrophils, eosinophils, abundant bacterial flora and goblet or epithelial cells prevalence. In contrast, in smears of patients post-treatment budesonide observed a clear improvement in their nasal mucosa by reducing inflammation. There was a significant increase in the number of columnar cells and the appearance of very numerous epithelial cells with increased cytoplasmic vacuolization and visible leucophagocytosis. In vitro studies were performed on normal CHO-K1 cells that were treated with budesonide at concentrations of 0.5 µM - 45 µM. After 48 hours of incubation with the test agent, the samples were prepared for optical microscopy using the H&E method and transmission electron microscopy. Comparison of cells exposed to budesonide with control cells (without addition of test agent) revealed vacuolization changes with autophagy. Apoptotic changes have also been demonstrated, which occured to a lesser extent than vacuolization. The changes observed after budesonide treatment in the cytological picture of patients with allergic rhinitis indicate the therapeutic effect of this drug. On the other hand, the changes observed in the cytoplasm of epithelial cells, such as autophagy (clearly promoted in CHO-K1 cells) and leucophagocytosis, may indicate an additional mechanism of action for budesonide.

Cement salvage of instrumentation-associated vertebral fractures.

BACKGROUND AND PURPOSE: Spinal instrumentation plays a key role in the treatment of spinal instability in patients with metastatic tumors. Poor bone quality, radiation, and diffuse osseous tumor involvement present significant challenges to spinal stabilization with instrumentation and occasionally result in postinstrumentation compression fractures. Vertebral cement augmentation has been effective in the treatment of painful tumor-related compression fractures. Our objective was to describe cement augmentation options in the treatment of vertebral compression fractures associated with spinal instrumentation in patients with metastatic tumors. MATERIALS AND METHODS: Patients who underwent percutaneous vertebral cement augmentation in the treatment of instrumentation-associated vertebral compression fractures between 2005 and 2011 were included in the analysis. Only fractures that occurred within the construct or at an adjacent level were included. The change in Visual Analog Scale and need for further surgery were analyzed. RESULTS: Eleven patients met the inclusion criteria, with 8 tumors located in the thoracic spine and 3 tumors in the lumbar spine. The median time between instrumented surgery and vertebral augmentation was 5 months (1-48 months) and the median follow-up after cement augmentation was 24 months (4-59 months). A total of 22 vertebrae that were either within or immediately adjacent to the surgical instrumentation underwent vertebral augmentation. All patients reported a decrease in their pain scores (mean decrease: 6 Visual Analog Scale points; P < .003). One patient required reoperation after cement augmentation. None of the patients experienced vertebral cement augmentation-related complications. CONCLUSIONS: Vertebral cement augmentation represents a safe and effective treatment option in patients with recurrent or progressive back pain and instrumentation-associated vertebral compression fractures.

A large family characterised by nocturnal sudden death.

BACKGROUND: We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family. METHODS: From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically. RESULTS: Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced INa amplitude, a positive shift of voltage-dependence of activation and a substantial negative shift of voltage-dependence of inactivation of INa. From 1978 onwards, a pacemaker for anti-brady pacing was implanted for prevention of sudden death. In patients in whom a prophylactic pacemaker was implanted no unexplained sudden death occurred, whereas 5 sudden deaths occurred in the group of patients who did not receive a pacemaker. CONCLUSION: We have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT3, Brugada syndrome and familial conduction system disease. Anti-brady pacing was successful in preventing sudden death. The mode of death is possibly bradycardic.

Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome.

INTRODUCTION: We recently identified a novel mutation of SCN5A (1795insD) in a large family with features of both long QT syndrome type 3 and the Brugada syndrome. The purpose of this study was to detail the clinical features and efficacy of pacemaker therapy in preventing sudden death in this family. METHODS AND RESULTS: The study group consisted of 116 adult family members: 60 carriers (29 males) and 56 noncarriers (28 males) of the mutant gene. Investigations included 24-hour Holter monitoring, ergometry, and electrophysiologic studies. Mean, lowest, and highest heart rate were lower in the carriers, but heart rate variability was comparable. In carriers, disproportional QT prolongation was present during bradycardia. No complex ventricular ectopy was recorded, and there were fewer isolated premature beats (both ventricular and atrial) in carriers. All patients were asymptomatic, except for two individuals who experienced syncope; in one of these patients, asystolic episodes (up to 9 sec) were repeatedly recorded. Prolonged HV intervals were present in 5 of 6 patients. Thirty carriers received a prophylactic backup pacemaker. During median follow-up of 4.5 years (range 0.0 to 22.6), their survival rate was 100%. There were five sudden deaths among the remaining 30 carriers without a pacemaker (P = 0.019). CONCLUSION: This family with a high incidence of nocturnal sudden death is characterized by bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, and generalized conduction abnormalities. There is a striking absence of complex ventricular ectopy, and pacemaker implantation was effective in preventing sudden death. These findings raise the possibility of a bradycardic rather than tachycardic mode of death.

Metabolic responses to moderate exercise in lambs with aortopulmonary shunts.

In a previous study we found, after an overnight fast of 18 hours, a lower arterial glucose concentration and a depressed glycogenolysis in lambs with aortopulmonary left-to-right shunts. During exercise, glucose and free fatty acids (FFA) concentrations normally increase. The aim of this study was to investigate whether the shunt lambs could compensate for a depressed glycogenolysis by increasing gluconeogenesis and by increasing levels of blood substrates such as FFA and glycerol during exercise. Therefore, we investigated glucose kinetics, with [U-(13)C]glucose, in five 7-week-old shunt and 7 control lambs of a similar age, at rest and during moderate exercise (treadmill; 50% of VO(2) peak). The glucose production rate and the rate of disappearance of glucose were lower in shunt than in control lambs, both at rest and during exercise. We found no difference in metabolic clearance rate of glucose, glucose recycling, or gluconeogenesis between both groups of lambs. Glycogenolysis was at rest lower in shunt than in control lambs and tended to be lower during exercise. The arterial concentrations of pyruvate, lactate, FFA, and total and free glycerol increased during exercise in both groups of lambs. In conclusion, shunt lambs have lower arterial glucose concentrations than control lambs, both at rest and during moderate exercise. This was due to a lower glucose production rate, in particular a lower glycogenolysis. In addition, the reduced glycogenolysis rate was not offset by an increase in gluconeogenesis nor by an increase in other substrates that can be utilized by working muscles.

A sodium-channel mutation causes isolated cardiac conduction disease.

Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening; however, a chief function of the Na+ channel is to initiate cardiac impulse conduction. Here we provide the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent 'gating' behaviour that can be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.

Cross-stimulation during lead impedance monitoring.

At the age of 4 years, a total cavopulmonary connection was performed in a boy with a complex congenital heart defect. On addition, a DDDR pacemaker was implanted for sick sinus syndrome. Atrial and ventricular leads were epicardially placed at the left atrium and left ventricle. At the age of 10 years, a new epicardial ventricular lead was placed because of malfunction of the existing lead. At the same operation the pulse generator was replaced by a Medtronic Kappa DR 731. After replacement, the boy experienced episodes of phrenic nerve stimulation associated with feelings of discomfort. Holter recordings revealed ventricular stimulation from the atrial stimulus for 2 consecutive beats. This phenomenon repeated exactly every 3 hours and was caused by the automatic lead impedance measurement that used a 5-V, 1-ms stimulus output.

An integrated functional magnetic resonance imaging procedure for preoperative mapping of cortical areas associated with tactile, motor, language, and visual functions.

OBJECTIVE: To evaluate an integrated battery of preoperative functional magnetic resonance imaging (fMRI) tasks developed to identify cortical areas associated with tactile, motor, language, and visual functions. METHODS: Sensitivity of each task was determined by the probability that a targeted region was activated for both healthy volunteers (n = 63) and surgical patients with lesions in these critical areas (n = 125). Accuracy of each task was determined by the correspondence between the fMRI maps and intraoperative electrophysiological measurements, including somatosensory evoked potentials (n = 16), direct cortical stimulation (n = 9), and language mapping (n = 5), and by preoperative Wada tests (n = 13) and visual field examinations (n = 6). RESULTS: For healthy volunteers, the overall sensitivity was 100% for identification of the central sulcus, visual cortex, and putative Wernicke's area, and 93% for the putative Broca's area (dominant hemisphere). For patients with tumors affecting these regions of interest, task sensitivity was 97% for identification of the central sulcus, 100% for the visual cortex, 91% for the putative Wernicke's area, and 77% for the putative Broca's area. These sensitivities were enhanced by the use of multiple tasks to target related functions. Concordance of the fMRI maps and intraoperative electrophysiological measurements was observed whenever both techniques yielded maps and Wada and visual field examinations were consistent with fMRI results. CONCLUSION: This integrated fMRI task battery offers standardized and noninvasive preoperative maps of multiple critical functions to facilitate assessment of surgical risk, planning of surgical routes, and direction of conventional, intraoperative electrophysiological procedures. Thus, a greater range of structural and functional relationships is brought to bear in the service of optimal outcomes for neurosurgery.

Perinatal changes in myocardial metabolism in lambs.

BACKGROUND: Lactate accounts for a third of myocardial oxygen consumption before and in the first 2 weeks after birth. It is unknown how the remainder of myocardial oxygen is consumed. Glucose is thought to be important before birth, whereas long-chain fatty acids (LC-FA) are the prime substrate for the adult. However, the ability of the myocardium of the newborn to use LC-FA has been doubted. METHODS AND RESULTS: We measured the myocardial metabolism of glucose and LC-FA with [U-(13)C]glucose and [1-(13)C]palmitate in chronically instrumented fetal and newborn lambs. In fetal lambs, myocardial oxidation of glucose was high and that of LC-FA was low. Glucose and LC-FA accounted for 48+/-4% and 2+/-2% of myocardial oxygen consumption, respectively. In newborn lambs, oxidation of glucose decreased, whereas oxidation of LC-FA increased. Glucose and LC-FA accounted for 12+/-3% and 83+/-19% of myocardial oxygen consumption. To test whether near-term fetal lambs could use LC-FA, we increased the supply of LC-FA with a fat infusion. In fetal lambs during fat infusion, the oxidation of LC-FA increased 15-fold. Although the oxidation of LC-FA was still lower than in newborn lambs, the contribution to myocardial oxygen consumption (70+/-13%) was the same as in newborn lambs. CONCLUSIONS: These data show that glucose and lactate account for the majority of myocardial oxygen consumption in fetal lambs, whereas in newborn lambs, LC-FA and lactate account for the majority of myocardial oxygen consumption. Moreover, we showed that the fetal myocardium can use LC-FA as an energy substrate.

Development, validation and application of assays to quantify metrifonate and 2,2-dichlorovinyl dimethylphosphate in human body fluids.

Gas chromatographic procedures [GC with electron-capture detection (ECD) and GC-MS] for the quantitative analysis of metrifonate and its active metabolite 2,2-dichlorovinyl dimethylphosphate (DDVP) in human blood and urine were developed, validated, and applied to the analysis of clinical study samples. Analysis of metrifonate involved extraction of acidified blood with ethyl acetate followed by solid-phase clean-up of the organic extract. Acidified urine was extracted with dichloromethane and the residue of evaporated organic phase was reconstituted in toluene. ECD and diethyl analogue of metrifonate internal standard (I.S.) were used for quantitation of metrifonate. The metrifonate lower limit of quantitation (LOQ) was 10.0 microg/l. The DDVP metabolite was chromatographed separately after cyclohexane extraction of acidified blood and urine using d6-DDVP I.S. and MS detection. The LOQ of DDVP was 1 microg/l. Stability studies have confirmed that the matrix should be acidified prior to storage at -20 degrees C or -80 degrees C to inhibit chemical and enzymatic degradation of the analytes and to avoid overestimation of DDVP concentrations. Metrifonate was found to be stable in acidified human blood after 20 months of storage at -20 degrees C and after 23 months of storage at -80 degrees C. Under these conditions DDVP was found to be stable after 12 months of storage. Both assay procedures were cross-validated by different world-wide laboratories and found to be accurate and robust during analyses of clinical study samples.

Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone.

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C(max)) and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) were 3. 4 mg/liter and 30.2 mg. h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg. h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C(max)/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C(max)/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

Lower arterial glucose concentrations in lambs with aortopulmonary shunts after an 18-hour fast.

Spontaneously occurring hypoglycemia has been described in children with severe acute congestive heart failure. Hypoglycemia may be the result of an increase in glucose utilization in tissues, a decrease in glucose production, or a decrease in the dietary intake of nutrients. To determine whether hypoglycemia may also occur in congenital heart disease with volume overloading, we investigated glucose metabolism during and after an 18-hour fast in nine lambs with an aortopulmonary left-to-right shunt and nine control lambs. Plasma levels of hormones involved in the endocrine control of glucose metabolism were determined. The glucose production rate (rate of appearance [Ra]) was studied using [U-13C]glucose. Gluconeogenesis through the Cori cycle was estimated by measuring glucose 13C recycling. The arterial glucose concentration (3,409 +/- 104 v 4,338 +/- 172 micromol/L, P < .001) and Ra of glucose (16.97 +/- 0.89 v 25.49 +/- 4.28 micromol x min(-1) x kg(-1), P < .05) were lower in shunt versus control lambs. There were no differences in hormone levels between control and shunt lambs. Fractional glucose 13C recycling via the Cori cycle (6.9% +/- 2.8% v 7.1% +/- 2.5%) and gluconeogenesis from pyruvate and lactate (1.24 +/- 0.58 v 1.95 +/- 0.67 micromol x min(-1) x kg(-1)) were similar in both groups of lambs. The sum of glycogenolysis and gluconeogenesis from precursors other than pyruvate and lactate was lower in shunt versus control lambs (15.73 +/- 1.07 v 23.54 +/- 4.27 micromol x min(-1) x kg(-1), P < .05). In conclusion, after an 18-hour fast, the arterial glucose concentration is lower in lambs with aortopulmonary shunts. This lower glucose concentration is associated with a decreased glucose production rate. In shunt lambs, glycogenolysis is decreased, while there is no difference in gluconeogenesis or hormonal control.

Brain mapping in sedated infants and young children with passive-functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) in pediatric patients presents a unique set of problems due to the need for patient compliance, the frequent need for sedation and an early developmental status. A new method for using fMRI in sedated infants and young children is presented using passive stimuli focused on visual, sensorimotor and language functions. All of these stimuli are presented such that no patient interaction is required. Eight sedated children undergoing diagnostic MRI scans of the brain participated in these passive fMRI procedures. Cortical regions were identified using standard techniques applied to the blood-oxygen-level-dependent signal which is the basis for fMRI. The results support the feasibility of brain mapping in sedated children with passive fMRI techniques.

Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.

Myocardial lactate metabolism in fetal and newborn lambs.

BACKGROUND: Around birth, myocardial substrate supply changes from carbohydrates before birth to primarily fatty acids after birth. Parallel to these changes, the myocardium is expected to switch from the use of primarily lactate before birth to fatty acids thereafter. However, myocardial lactate uptake and oxidation around birth has not been measured in vivo. METHODS AND RESULTS: We measured myocardial lactate uptake, oxidation, and release with infusion of [1-13C]lactate and myocardial flux of fatty acids and glucose in chronically instrumented fetal and newborn (1 to 15 days) lambs. Myocardial lactate oxidation was the same in newborn (81.7+/-14.7 micromol. min-1. 100 g-1, n=11) as in fetal lambs (60.7+/-26.7 micromol. min-1. 100 g-1, n=7). Lactate uptake was also the same in newborn as in fetal lambs. Lactate uptake was higher than lactate flux, indicating lactate release simultaneously with uptake. In the newborn lambs, lactate uptake declined with age. Lactate uptake was strongly related to lactate supply, whereas lactate oxidation was not. The supply of fatty acids or glucose did not interfere with lactate uptake, but the flux of fatty acids was inversely related to lactate oxidation. CONCLUSIONS: We show that lactate is an important energy source for the myocardium before birth as well as in the first 2 weeks after birth in lambs. We also show that there is release of lactate by the myocardium simultaneously with uptake of lactate. Furthermore, we show that lactate oxidation may be attenuated by fatty acids but not by glucose, probably at the level of pyruvate dehydrogenase.

Lactate kinetics at rest and during exercise in lambs with aortopulmonary shunts.

In a previous study [G. C. M. Beaufort-Krol, J. Takens, M. C. Molenkamp, G. B. Smid, J. J. Meuzelaar, W. G. Zijlstra, and J. R. G. Kuipers. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H1503-H1512, 1998], a lower systemic O2 supply was found in lambs with aortopulmonary left-to-right shunts. To determine whether the lower systemic O2 supply results in increased anaerobic metabolism, we used [1-13C]lactate to investigate lactate kinetics in eight 7-wk-old lambs with shunts and eight control lambs, at rest and during moderate exercise [treadmill; 50% of peak O2 consumption (VO2)]. The mean left-to-right shunt fraction in the shunt lambs was 55 +/- 3% of pulmonary blood flow. Arterial lactate concentrations and the rate of appearance (Ra) and disappearance (Rd) of lactate were similar in shunt and control lambs, both at rest (lactate: 1, 201 +/- 76 vs. 1,214 +/- 151 micromol/l; Ra = Rd: 12.97 +/- 1.71 vs. 12.55 +/- 1.25 micromol. min-1. kg-1) and during a similar relative workload. We found a positive correlation between Ra and systemic blood flow, O2 supply, and VO2 in both groups of lambs. In conclusion, shunt lambs have similar lactate kinetics as do control lambs, both at rest and during moderate exercise at a similar fraction of their peak VO2, despite a lower systemic O2 supply.

Comparison of longevity, pacing, and sensing characteristics of steroid-eluting epicardial versus conventional endocardial pacing leads in children.

OBJECTIVE: Because of either cardiac anatomy or small size, pacing in children often occurs by means of epicardial leads. The disadvantage of epicardial leads is the shorter longevity of these leads compared with endocardial leads. During short-term follow-up, improved stimulation thresholds were found for the newer steroid-eluting epicardial leads. The longevity of these leads may be better than that of conventional epicardial leads. An improved longevity of epicardial leads may influence the choice to either epicardial or endocardial pacing in children. METHODS: We studied the longevity and the pacing and sensing characteristics of 33 steroid-eluting epicardial pacing leads (group I, 15 atrial, 18 ventricular) implanted between November 1991 and October 1996 in 20 children with a mean age of 7.6 +/- 6.5 years (mean +/- SD), and 29 endocardial pacing leads (group II, 15 atrial, 14 ventricular) implanted during the same period in 21 children with a mean age of 11.7 +/- 4.7 years. RESULTS: The mean follow-up in group I was 2.9 +/- 1.6 years and in group II 3.1 +/- 1.7 years (P =.61). The 2-year survival of the leads in group I was 91% +/- 5% and in group II 86% +/- 7% (P =.97). Lead failure occurred in both groups in 4 leads (P =.85). Chronic stimulation and sensing thresholds were similar. CONCLUSIONS: Steroid-eluting epicardial leads have the same longevity as the conventional endocardial leads. Pacing and sensing thresholds were similar and did not change during follow-up. Therefore steroid-eluting epicardial pacing leads are a good alternative for endocardial leads in small children and in children with congenital heart disease.

Increased myocardial lactate oxidation in lambs with aortopulmonary shunts at rest and during exercise.

Free fatty acids are the major fuels for the myocardium, but during a higher load carbohydrates are preferred. Previously, we demonstrated that myocardial net lactate uptake was higher in lambs with aortopulmonary shunts than in control lambs. To determine whether this was caused by an increased lactate uptake and oxidation or by a decreased lactate release, we studied myocardial lactate and glucose metabolism with 13C-labeled substrates in 36 lambs in a fasting, conscious state. The lambs were assigned to two groups: a resting group consisting of 8 shunt and 9 control lambs, and an exercise group (50% of peak O2 consumption) consisting of 9 shunt and 10 control lambs. Myocardial lactate oxidation was higher in shunt than in control lambs (mean +/- SE, rest: 10.33 +/- 2.61 vs. 0. 17 +/- 0.82, exercise: 38.05 +/- 8.87 vs. 16.89 +/- 4.78 micromol. min-1. 100 g-1; P < 0.05). There was no difference in myocardial lactate release between shunt and control lambs. Oxidation of exogenous glucose, which was approximately zero at rest, increased during exercise in shunt and control lambs. The contribution of glucose and lactate to myocardial oxidative metabolism increased during exercise compared with at rest in both shunt and control lambs. We conclude that myocardial lactate oxidation is higher in shunt than in control lambs, both at rest and during exercise, and that the contribution of carbohydrates in myocardial oxidative metabolism in shunt lambs is higher than in control lambs. Thus it appears that this higher contribution of carbohydrates occurs not only in the case of pressure-overloaded hearts but also in myocardial hypertrophy due to volume overloading.

Quantitative analysis of HBY 097 and its metabolites in human serum and urine by HPLC.

Two HPLC methods were developed: one for the quantitation of HBY 097 reverse transcriptase inhibitor and its metabolites M2 and M3 in human serum, and one for the quantitation of metabolite M5 in urine. The HPLC procedure for the quantitation of HBY 097 and its metabolites M2 and M3 in human serum involved protein precipitation with acetonitrile followed by automated on-line trace enrichment. The HPLC procedure for the analysis of metabolite M5 in urine involved enzymatic hydrolysis of urine with beta-glucuronidase to convert metabolite M5 (glucuronide of M3) to M3. Reverse phase chromatographic separation with gradient elution. UV detection at 335 nm, and internal standard were used to quantitate analytes in both procedures. The lower quantitation limits were 25 ng ml-1 for HBY 097 and metabolites M2 and M3 in serum, and 0.5 microgram ml-1 for the metabolite M5 in urine measured as metabolite M3 after hydrolysis. The HBY 097 and metabolite M3 concentrations were specific but metabolite M2 was semi-specific because the two diastereomers of M2 were not resolved by the present chromatographic procedure. Both procedures were applied to the quantitation of HBY 097 and its metabolites in serum and urine of HIV positive patients who were enrolled in a clinical study of drug safety and pharmacokinetics.