BEta versus Gamma Utrecht Trial-Cypher (BEGUT-CYPHER): Is intracoronary brachytherapy still superior to drug-eluting stents?

DESIGN: Prospective, randomised single-centre pilot study comparing a beta with a gamma source and a sirolimus-eluting stent in patients with an estimated high risk of restenosis (40 to 50%). PURPOSE: Although the majority of patients referred for revascularisation are now being treated with percutaneous coronary intervention (PCI) combined with stenting, a small number still suffer from recurrent restenosis which can be invalidating for the patient and frustrating for the cardiologist due to repeated PCIs. In this prospective single-centre pilot study we will test the hypothesis of three different treatment strategies to use in this special patient subset, to determine if we can find a positive 'trend' in one arm, in order to either make a selection for one of the treatment strategies, or to provide a base to expand the study into a larger multicentre randomised study. TIME COURSE AND ENROLLMENT: A total of 120 patients will be included, 40 in each treatment arm. All patients with either in-stent and/or native restenosis and/or diabetics and/or type C lesions (ACC/AHA) are eligible. The usual exclusion criteria for intracoronary brachytherapy and prolonged antiplatelet therapy are applied. All lesions <44 mm in length and with a vessel diameter 2.4>4.0 mm are suitable. Angiographic, intravascular ultrasound imaging and clinical follow-up at one year will become available in the first quarter of 2005.

Long term course of childhood epilepsy following relapse after antiepileptic drug withdrawal.

OBJECTIVE: To explore the course of epilepsy following relapse after antiepileptic drug (AED) withdrawal. METHODS: Forty two patients were identified with onset of epilepsy in childhood in whom AEDs had been withdrawn after at least 2 years of seizure freedom, and in whom a relapse had occurred. Two patients were lost to follow up. RESULTS: Median follow up after AED withdrawal was 5.9 years (range 1.6-13.2 years). Relapse occurred in more than half of the patients within 6 months of AED withdrawal. At the end of follow up, 12 patients (30%) were seizure free for at least 1 year (mean 10.4 years) without medication; 16 (40%) were seizure free for at least 1 year (mean 5.3 years) with ongoing medication; and 12 patients (30%) were seizure free for less than 1 year with medication. No status epilepticus occurred in any patient after withdrawal. Age at onset, if over the age of 5, combined with normal intelligence were predictive of an excellent outcome; presence of a neurological disorder, and hence symptomatic aetiology, was predictive of poor outcome after a relapse. CONCLUSIONS: Fears that premature withdrawal of AEDs might result in uncontrollable seizures were unsubstantiated in this study. The current practice of withdrawing AEDs in children who have been seizure free for 2 years can be beneficial to most of these patients.

COL5A1 exon 14 splice acceptor mutation causes a functional null allele, haploinsufficiency of alpha 1(V) and abnormal heterotypic interstitial fibrils in Ehlers-Danlos syndrome II.

We studied four affected individuals from a family of three generations with Ehlers-Danlos Syndrome II. Type V collagen transcripts of affected individuals were screened by reverse transcriptase-polymerase chain reaction. Amplification of the exon 9-28 region of alpha1(V) yielded normal and larger products from the proband. Sequencing of cDNA revealed a 100-base pair insertion from the 3'-end of intron 13 between exons 13 and 14 in one allele. The genomic defect was identified as an A(-2)--> G substitution at the exon 14 splice acceptor site. A cryptic acceptor site -100 nucleotide within intron 13 is used instead of the mutant splice site. The insertion shifts the reading frame +1 and results in a stop codon within exon 17. The mutant transcript was much less abundant than normal allele product in untreated cultured fibroblasts but was approximately equimolar in cycloheximide-treated cells, suggesting that the mutation causes nonsense-mediated decay of mRNA. By RNase protection experiments, the level of mutant transcript was determined to be 8% that of the normal transcript in untreated proband fibroblasts. Relative to type I collagen, proband fibroblasts secreted only 65% of the amount of type V collagen secreted by normal controls. Selective salt precipitation of proband secreted collagen provided supportive evidence that the alpha chain composition of type V collagen remains alpha1(V)(2)alpha2(V) even in the context of alpha1(V) haploinsufficiency. Type V collagen incorporates into type I collagen fibrils in the extracellular matrix and is thought to regulate fibril diameter. Transmission electron micrographs of type I collagen fibrils in a proband dermal biopsy showed greater heterogeneity in fibril diameter than in a matched control. The proband had a greater proportion of both larger and smaller fibrils and occasional fibrils with a cauliflower configuration. Unlike the genotype/phenotype relationship seen for type I collagen defects and osteogenesis imperfecta, the null allele in this family appears to cause clinical features similar to those seen in cases with structural alterations in type V collagen.

The course of benign partial epilepsy of childhood with centrotemporal spikes: a meta-analysis.

We performed a meta-analysis of studies on benign epilepsy of childhood with centrotemporal spikes (BECT) to ascertain whether clinical characteristics and outcome can be stated unequivocally. Using the Index Medicus and Medline CD+, we identified 525 publications. After applying the criteria of the International League against Epilepsy (ILAE) for BECT, 32 publications on 2,561 patients remained. After correction for inclusion bias and multiple publications on the same patient groups, 13 cohorts, comprising a total of 794 patients, were included. The aggregate proportional remission was 0.977; hence, no factors influencing outcome could be identified. Age at onset ranged from 3 months to 14 years, age at last seizure ranged from 3 to 18 years. A Kurtzke survival analysis of proportions of children in remission by age was performed; at an older age, the proportion of patients in remission was 0.9997. Publications had highly heterogeneous methodologies and population characteristics; we conclude that current knowledge on BECT has been determined mainly by retrospective studies of biased cohorts, and that the uniformity per se of BECT as an epileptic syndrome may be, at least in part, a result of selection bias. We conclude that early prediction of seizure outcome in a new patient with BECT can not be given with certainty. Prospective, population-based studies are needed to delineate the clinical and EEG characteristics of this syndrome.

The outcome of absence epilepsy: a meta-analysis.

We performed a meta-analysis of studies on absence epilepsy (AE) to ascertain whether the outcome of this well-defined type of epilepsy can be stated unequivocally. Using the Index Medicus and Medline CD+, we identified 1,619 publications. After applying the criteria of the International League against Epilepsy (ILAE) for AE, 26 publications on 23 study cohorts with a total of 2,303 patients were included. Remission rates ranged from 0.21 to 0.89; they differed substantially due to heterogeneity between the studies in inclusion criteria, methods, follow-up length, and outcome definitions. One half of the patients developed generalized tonic-clonic seizures (TCS) in the course of the disease. The proportion seizure free was 0.78 for patients with absence seizures (AS) only, and 0.35 for those who developed TCS. The outcome of AE may be worse than previously stated due to the considerable proportion of patients developing TCS in the course of their disease. Early prediction of outcome in patients who present with AS cannot be provided with certainty.

Vasomotor tone affects diastolic coronary flow and flow impediment by cardiac contraction similarly.

We studied the effect of cardiac contraction on coronary arterial flow with vasomotor tone (control) and during maximal vasodilation with adenosine in the isolated blood-perfused rat heart at constant perfusion pressure (105 mmHg) with a left ventricular balloon (n = 6). Ventricular pressure was changed by volume changes and contractility via postextrasystolic potentiation. Contractility was expressed as the slope of the end-systolic pressure-volume ratio, elastance. Constant vasomotor tone was judged from stable diastolic flow. Coronary flow reduction (diastolic minus systolic flow, delta CBF, ml.min-1.g-1) due to contraction was related to developed ventricular pressure (devPLV) and developed elastance (devELV, systolic minus diastolic elastance) by multiple regression: delta CBF = SP.devPLV+SE.devELV+I, where SP and SE represent changes in coronary blood flow due to changes in devPLV and devELV, respectively, and I is intercept. In control, delta CBF = (0.016 +/- 0.008).devPLV + (0.0022 +/- 0.0009).devELV + (0.29 +/- 0.77); during vasodilation, delta CBF = (0.046 +/- 0.011).devPLV + (0.009 +/- 0.0053).devELV + (2.50 +/- 2.56). Diastolic flow increased by a factor of 4.06 +/- 1.57 (SD) during vasodilation. The increases in diastolic flow, SP, and SE were not different. We conclude that vasodilation has similar effects on diastolic flow and flow amplitude without affecting the relative contributions of ventricular pressure and contractility.

Coronary arterial inflow impediment during systole is little affected by capacitive effects.

During cardiac contraction coronary arterial inflow is impeded, whereas venous flow is augmented. These effects are assumed to be caused by diameter reductions of intramyocardial blood vessels. The reduction in vascular diameter (and thus vascular volume) during contraction increases coronary resistance and/or decreases back pressure so that flow decreases and the rate of change of volume results in a capacitive flow. The aim of this study was to estimate the contribution of capacitive flow to total coronary inflow impediment. Isolated blood-perfused (100 mmHg and constant), maximally vasodilated, ryanodine-pretreated rat hearts (n = 8) with intraventricular balloons were used. The coronary inflow impediment during isovolumic beats at a heart rate of 2-3 Hz (dynamic contractions) and during prolonged systoles obtained by fast pacing (static contractions, no capacitive flow impediment) were compared. Changing left ventricular balloon volume enabled us to vary left ventricular pressure and to relate systolic flow to systolic left ventricular pressure. We found that for the same contractility (expressed in terms of systolic pressure-volume relationship and maximal elastance) and same left ventricular pressure, the ratio of coronary inflow impediment in dynamic and static contractions is not significantly different from unity (P < 0.005). This implies that under our experimental conditions coronary inflow impediment in dynamic contractions is little affected by capacitive effects.

Rational diagnosis and treatment in unclassified arthritis: how clinical data may guide requests for Lyme serology and antibiotic treatment.

To improve the appropriateness and efficiency of diagnostic serological tests and subsequent antibiotic treatment, clinical data from 102 patients with unclassified arthritis were analysed to investigate whether the presence of positive IgG antibodies to Borrelia burgdorferi could be predicted. The clinical data were blindly ranked from 1 to 4 (1, Lyme arthritis unlikely; 4, Lyme arthritis very likely). Antibodies to B burgdorferi were positive in nine of 102 patients (9%). Six of 15 (40%) patients with rank numbers 3 and 4 were positive for antibodies to B burgdorferi, in contrast with only three of 87 (3%) patients with rank numbers 1 and 2. The likelihood ratio of positive Lyme serology for patients ranked 3 and 4 was 12.0, for patients ranked 2 to 4, 4.5, and for patients with arthritis of the knee, 3.0. These likelihood ratios were associated with a post-test probability of 55, 30, and 20% respectively. The clinical history in patients with unclassified arthritis can largely predict the presence of antibodies to B burgdorferi. The absolute value of a likelihood ratio can be a contributing factor in deciding to request tests for antibodies to B burgdorferi in patients with unclassified arthritis.

Nitric oxide is an important determinant of coronary flow in the isolated blood perfused rat heart.

Many vasoactive substances are involved in the regulation of vasomotor tone and some of them, like nitric oxide (NO), are derived from the endothelium. Nitric oxide is able to relax preconstricted coronary resistance vessels almost completely. However, it is not clear what the contribution of NO is to vasomotor tone in the intact blood perfused heart. The aim of the present study was to evaluate the contribution of NO to coronary pressure-flow relations. We used isovolumically beating, donor supported, blood perfused isolated rat hearts. We measured pressure-flow relations under control conditions, after blocking endothelial NO production with NG-nitro-L-Arginine (LNNA) and after administration of L-Arginine (L-Arg) in order to overrule the blocking effect. Administration of LNNA at a perfusion pressure of 105 mm Hg resulted, after about 40 min, in a significant (Wilcoxon's signed-rank test, (n = 8) p < 0.05) reduction of coronary flow to 47 +/- 5% (mean +/- SEM) of control and a reduction of developed isovolumic left-ventricular pressure to 62 +/- 4% of control. L-Arg returned flow to 60 +/- 7% of control which is a significant increase with respect to LNNA (p < 0.05). L-Arg did not increase the left-ventricular pressure. The entire perfusion pressure-flow relation (pressure range 65-125 mm Hg) was significantly shifted downwards after LNNA with respect to control. Pressure-flow relations after L-Arg were in between those during control and after block of NO production. L-Arg alone was found to have no effect on flow and left-ventricular pressure (n = 2) and both LNNA and L-Arg were found to have no effect on contractility of isolated trabeculae (n = 6), thus, coronary blood flow reduction after LNNA administration is mainly the result of inhibition of endothelial NO production. At a perfusion pressure of 105 mm Hg reactive hyperemia is still present after LNNA and subsequent L-Arg administration, indicating that endothelial NO is not the only factor involved in flow regulation. We conclude that endothelium-derived NO is involved in the control of coronary flow in the blood perfused rat heart.

Lyme borreliosis presenting as acrodermatitis chronica atrophicans.

A patient is described who developed acrodermatitis chronica atrophicans, arthralgias and polyneuropathy as manifestations of Lyme borreliosis. The clinical diagnosis was confirmed by histological and serological examinations. Despite a long delay before the diagnosis was established, the patient responded very well to treatment with doxycycline.

Determining the prognosis of childhood epilepsies by establishing immune abnormalities.

When seizures develop in a child, an accurate prediction on outcome of the disorder can hardly be given. Literature indicating an association between seizure disorders and Immunoglobulin (Ig) abnormalities, HLA typing and the occurrence of anti-brain antibodies is shortly reviewed. It is argued that by determining such anti-brain antibodies, early ascertainment of prognosis in seizure disorders may be possible.

Coronary resistance increase by nondefatted albumin in saline-perfused rabbit hearts.

In isolated hearts perfused with salt solutions, albumin is often added in low concentrations for preservation of endothelial function. Albumin in low concentrations is also sometimes used as an intravascular indicator in such preparations. We perfused isolated rabbit hearts according to Langendorff with a constant flow of Tyrode solution. Despite maximal vasodilation with 10 microM adenosine, coronary vascular resistance increased by 14% after 0.3 g/100 ml nondefatted bovine serum albumin (Sigma A-9647) was added to the perfusate compared with the control resistance with no albumin present. The 50% response time for the vasoconstrictive response to the step change in albumin concentration was 20 +/- 13 s (mean +/- SD). When 0.3 g/100 ml of defatted albumin (Sigma A-6003) was added, the resistance increase was only 1.4% and is explained by increased viscosity. Vasoconstrictive effects of certain nondefatted albumin preparations must be taken into account by investigators who perfuse organs with albumin-containing solutions.

Oxygen uptake in saline-perfused rabbit heart is decreased to a similar extent during reductions in flow and in arterial oxygen concentration.

In experiments reported in the literature, oxygen uptake in saline-perfused heart decreased after small reductions in arterial O2 concentration (CaO2) at constant perfusion flow. This may have resulted from the decrease in O2 supply, but may also have been due to decreased O2 demand caused by reduced perfusion pressure following hypoxic vasodilation (garden hose effect). We tested both possibilities in 8 isolated rabbit hearts, perfused with Tyrode solution at 37 degrees C, perfusion pressure 94 +/- 4 mm Hg (mean +/- SD). Vasodilation with 10 microM adenosine in the perfusate prevented changes in perfusion pressure during hypoxia. Oxygen uptake decreased significantly by 5.8 +/- 2.1% for a 10% decrease in CaO2 at constant flow, and by 4.4 +/- 1.8% per 10% decrease in flow at constant CaO2. In both cases a 10% reduction in oxygen supply was applied and the decrease in oxygen uptake was not significantly different. The decrease in perfusion pressure during flow reduction did therefore not cause a detectable decrease in oxygen consumption via the garden hose effect in addition to the decrease caused by reduced oxygen supply. The data show that oxygen uptake in saline-perfused rabbit heart, at 37 degrees C, is limited by O2 supply.

Discontinuation of antiepileptic therapy: a prospective study in children.

Anticonvulsant medication was stopped in a prospective study in 116 children with epilepsy who had had no seizures for a period of 2 years. A remission rate of 80.5% was found 5 years after withdrawal. The population studied was unselected, and based on children directly referred by general practitioners to the outpatient department. Among the many variables examined, such as type of epilepsy or seizure, presence of concomitant neurological or intellectual deficit, and epileptiform activity on the EEG, only the age of onset of seizures was significantly and positively correlated with the probability of recurrence after discontinuation of medication. In contrast to other recent studies, it was concluded that there are no reliable predictive factors for withholding from any individual "epileptic" child the benefit of attempts to stop medication after 2 years of seizure freedom.

Spelling errors made by children with mild epilepsy: writing-to-dictation.

Errors and corrections made by 64 mildly epileptic children of at least average intelligence who were attending ordinary elementary schools when writing in response to dictation (writing-to-dictation) were assigned to one of 28 descriptive error categories. Numbers and types of errors were compared with those obtained in 630 form-matched, healthy control subjects (Wilcoxon's two-sample test, less than or equal to 0.01). Epileptic children made significantly more errors than control subjects. Separate error categories had no diagnostic power. The groups could not be distinguished on the basis of skill-related errors. However, performance errors (erroneous deviations from the intended product), were found to be made more frequently by epileptic children. Epileptic children made more corrections and also left more errors uncorrected than control children. No relationship could be established with illness variables. Deficient problem-solving strategies, probably resulting from emotional concomitants of epilepsy, may explain the results.

Liquid-chromatographic determination of 4-aminopyridine in serum, saliva, and urine.

We have developed "high-performance" liquid-chromatographic methods for determining 4-aminopyridine, an acetylcholine-releasing drug, in serum, saliva, and urine. As little as 1 microgram/L can be detected by extracting the alkalinized sample plus the internal standard (3,4-diaminopyridine) into dichloromethane, mixing the organic phase with 1-pentanol, evaporating the dichloromethane, and injecting the residue onto a reversed-phase column, where it is eluted with acetonitrile/methanol/aqueous ammonium carbonate, with detection at 245 nm. Analytical recoveries from serum averaged 86.7%. The CV at 50 micrograms/L was 2.9% (n = 8). For urine samples containing very high concentrations of 4-aminopyridine, we mixed urine and potassium carbonate in an automatic injector vial, extracted the drug into dichloromethane, centrifuged, and injected an aliquot of the extract into the chromatograph. Analytical recoveries averaged 92%, and the CV was about 2% for drug concentrations of 0.1-8 mg/L of urine.