bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Chronic Aminophylline on the Anticonvulsant Efficacy of Phenobarbital and Valproate in Mice
Authors: Wlaż Piotr , Rolinski Zbigniew , Kleinrok Zdzislaw , Czuczwar Stanistaw J.
Published: October 2005

Summary: The protective efficacy of phenobarbital (PB, 120 min before testing) and valproate (VPA, 30 min before testing) alone or combined with aminophylline (a single dose of 50 mg/kg, 3‐day or 14‐day administration twice daily 50 mg/kg at 8.00 a.m. and 8.00 p.m.) was evaluated against maximal electroshock‐induced seizures (MES) in male mice. All drugs were given intraperitoneally (i.p.), and the protection provided by PB and VPA was evaluated as the respective ED50 value (in mg/kg). Aminophylline in a single dose of 50 mg/kg (30 min before electro‐convulsions) distinctly reduced the protective efficacy of both PB and VPA, reflected by the increase in the respective ED50 values from 22 to 31 mg/kg (p < 0.001) for PB and from 247 to 281 mg/kg (p < 0.001) for VPA. After administration of aminophylline for 3 days (electroshock was performed 30 min after the last aminophylline injection), the respective ED50 values for PB and VPA were 29.5 (p < 0.01) and 269 mg/kg (p < 0.01 vs. saline‐treated animals). Chronic treatment with aminophylline (14 days) resulted in further impairment of the protective activity of PB and VPA. Specifically, the ED50 value of PB was 39 mg/kg (p < 0.05 vs. PB + single injection of aminophylline) and that of VPA was 318 mg/kg (p < 0.01 vs VPA + single injection of aminophylline). Plasma levels of both PB and VPA were not affected by chronic aminophylline; moreover, the plasma level of theophylline was even lower after chronic aminophylline as compared with single aminophylline administration. The results of the present study provide evidence that no tolerance exists to aminophylline‐induced impairment of antiepileptic drug efficacy; moreover, this phenomenon may even be increased with chronic aminophylline administration.
Validity of Family History Data on Seizure Disorders
Authors: Ottman Ruth , Mauser W. Allen , Susser Mervyn
Published: October 2005

Summary: Accurate family histories of seizure disorders are important for both clinical practice and genetic research. This study evaluated validity of seizure histories of parents and siblings, obtained by interviewing 1,957 adults with epilepsy (probands). Probands were asked two questions to screen for occurrence of seizures in each relative; the first asked about epilepsy specifically, the second asked about “other seizures.” For each relative who screened positive for seizures, a detailed clinical description was obtained. The final diagnosis was based on a review of all assembled information. Whenever possible, the proband's mother was interviewed independently about the family history, as were eligible relatives reported to have had seizures. Sensitivity, or the proportion of affected relatives who screened positive for seizures, was higher for epilepsy than for other seizures (87% vs. 32% assuming the mother's report to be correct, and 93% vs. 18% assuming self‐report to be correct). For epilepsy, estimates of risk in siblings based on the final diagnoses were similar to previously reported findings in Rochester, Minnesota. For both isolated unprovoked seizures and acute symptomatic seizures, however, risk estimates were lower than in Rochester. These findings suggest that adults with epilepsy can report reasonably accurately about epilepsy in their parents and siblings, but isolated unprovoked seizures and acute symptomatic seizures are underreported.
Identical Morphology of the Rolandic Spike‐and‐Wave Complex in Different Clinical Entities
Authors: van der Meij W. , Wieneke G. H. , van Huffelen A. C. , Schenk‐Rootlieb A. J. F. , Willemse J.
Published: October 2005

Summary: The morphology of the rolandic spike, the trough between the rolandic spike and the following slow wave, and of the slow wave itself was quantitatively studied in 43 children, classified into five clinical groups: (a) functional with epilepsy benign focal epilepsy of childhood with centrotemporal spikes (BECT) with oropharyngeal seizures or (b) BECT with unilateral or generalized seizures or (c) functional without epilepsy, and (d) organic with or (e) without epilepsy. The morphologic features of the rolandic spike‐and‐wave complex were identical in the five clinical categories. Thus, a quantitative description of the rolandic spike‐and‐wave complex can be given that is valid for the 43 children of the present study, although they represent a heterogeneity of associated clinical syndromes. The rolandic spike appeared to be not a spike but a sharp wave with a mean duration of 88 ms. In contrast to the opinion of several investigators, the morphology of the rolandic spike does not provide a clue to its “epileptogenicity” or to the presence or absence of an organic cerebral lesion in the individual child. In clinical practice, additional information (background activity of the EEG, computed tomography (CT) scan, or magnetic resonance imaging (MRI) of the brain) is needed to determine the significance of rolandic spikes occurring in the EEG of a child with respect to the probability of a cerebral lesion and the prognosis in relation to epileptic seizures.
Anterior, Total, and Two‐Stage Corpus Callosum Section: Differential and Incremental Seizure Responses
Authors: Spencer Susan S. , Spencer Dennis D. , Sass Kimberlee , Westerveld Michael , Katz Amiram , Mattson Richard
Published: October 2005

Summary: Published reports suggest that control of generalized seizures is improved by callosotomy but do not necessarily indicate that completion of failed anterior callosotomy is beneficial. We studied 42 patients after anterior callosotomy and 22 after total callosotomy, of whom 14 underwent a two‐stage procedure. Cure or marked diminution of seizures was most dramatic for atonic and tonic‐clonic seizures after anterior callosotomy (100 and 83%), and for tonic‐clonic and tonic seizures after total callosotomy (68 and 57%). For the 14 patients who failed to improve after anterior section and then underwent total section, incremental responses were noted for all seizure types, with cure or marked diminution of partial seizures in 2 of 14 patients, of tonic‐clonic seizures in 6 of 10, of tonic seizures in 2 of 4, of atonic seizures in 2 of 5, and of myoclonic seizures in 1 of 1. More than two seizure types, verbal IQ <80, and diffuse ictal EEG patterns were significantly more common in the anterior callosotomy failures. Total callosotomy can be of benefit when anterior callosotomy fails, especially for persistent tonic‐ clonic and tonic seizures, and will most often be necessary in patients with diffuse cerebral abnormalities.
Correlations Between Night Sleep Duration and Seizure Frequency in Temporal Lobe Epilepsy
Authors: Rajna P. , Veres J.
Published: October 2005

Summary: Correlations between occurrence of complex partial seizures and altered sleep duration were analyzed in a small but strongly homogeneous population of temporal lobe epilepsy patients. Sleep deprivation and oversleep were determined individually; 682 epileptic seizures occurring on 4,995 days were related to occasional alterations of night sleep duration. The seizure‐inducing effect of an actual relative sleep deprivation was 67‐100% in four cases and 49‐64% in four cases. Oversleep had no consistent seizure‐provoking effect. Relative sleep deprivation may have a seizure‐provoking effect, especially in temporal lobe epilepsy. This information may be used to instruct epileptic patients concerning sleep hygiene which might improve the efficacy of antiepileptic drug (AED) treatment, even if no change is made in medication.
Electrophysiology of Bimanual‐Bipedal Automatisms
Authors: Swartz B. E.
Published: October 2005

Summary: To determine the localizing value and electrophysiology of bimanual‐bipedal automatisms (BBAs), we studied these behaviors in 54 seizures of 8 patients with temporal or frontal lobe seizure onset. BBAs occurred with a frequency of 27% in frontal lobe epilepsy (FLE) and of 7% in temporal lobe epilepsy (TLE). The distribution of electrode sites showing ictal activity during these automatisms was significantly different in the two patient groups (0.0001 Chi‐square). Mesioand/or laterotemporal plus orbital frontal areas were involved areas when the behaviors appeared in patients with TLE; dorsolateral and mesiofrontal regions were the most commonly involved when the behaviors occurred during the course of frontal lobe seizures. We concluded that BBAs represent activation of frontal lobe circuitry but are not unique to seizures of frontal lobe origin. Eyelid flutter and repetitive body movements in either the axial or sagittal plane were significantly associated with the frontal lobe group whereas oral‐alimentary automatisms were associated with the temporal lobe group. Thus, these associated behaviors may help indicate whether a frontal or temporal lobe seizure onset has occurred when BBAs are observed. A new concept of ictal expression is proposed to conform with the results as well as with other apparently disparate ictal behaviors that may have localizing value.
Focal Electroencephalographic Abnormalities in Juvenile Myoclonic Epilepsy
Authors: Aliberti V. , Grünewald R. A. , Panayiotopoulos C. P. , Chroni E.
Published: October 2005

Summary: A detailed study of EEGs of patients with an unequivocal diagnosis of juvenile myoclonic epilepsy (JME) showed a high prevalence of focal EEG abnormalities. Focal slow waves, spikes, and sharp waves and focal onset of the generalized discharge were present in 36.7% of EEGs in our patients with JME. In more than half of the patients, at least one EEG showed focal abnormalities. These features should not be misconstrued as indicative of partial epilepsy.
Topiramate: Preclinical Evaluation of a Structurally Novel Anticonvulsant
Authors: Shank Richard P. , Gardocki Joseph F. , Vaught Jeffry L. , Davis Coralie B. , Schupsky James J. , Raffa Robert B. , Dodgson Susanna J. , Nortey Samuel O. , Maryanoff Bruce E.
Published: October 2005

Summary: Topiramate [TPM, 2,3:4,5‐his‐O‐(1‐methyl‐ethylidene)‐β‐D‐fructopyranose sulfamate] (RWJ‐17021‐000, formerly McN‐4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident 0.5. h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)‐induced clonic seizures at high doses in mice (ED50= 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF‐525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.
Predictive Factors for Success in Surgical Treatment for Partial Epilepsy: A Multivariate Analysis
Authors: Guldvog B. , Løyning Y. , Hauglie‐Hanssen E. , Flood S. , Bjønæs H.
Published: October 2005

Summary: We conducted a longitudinal self‐controlled study of 131 patients aged 4–60 treated with resectivesurgery for medically uncontrolled partial epilepsy from 1949 to 1988. Using multivariate logistic regression, weshowed that pre‐ and perioperative variables can be usedto predict “success” or “failure” of surgical resectivetreatment in ∼79% of cases. If the predicted probability is >0.75 or < 0.25, the model predicts a correct result in 87% of cases. Eight predictive factors emerged with abackward multivariate logistic regression model with the likelihood‐ratio (LR) test to exclude variables from theequation: (a) the influence of the surgical team and surgical procedure, (b) the presence of paresis preoperatively, (c) duration of disease, (d) age at treatment, (e) positive neuroradiologic findings in preoperative investigations, (f) preoperative complex partial seizures (CPS), (g) nonepileptic EEG abnormalities, and (h) generalizedspike activity in EEG preoperatively. Sex, age at firstseizure, area of resection, presence of simple or generalized seizures preoperatively, preoperative seizure frequency, tissue pathology, use of computed tomography/nuclear magnetic resonance (CTINMR) in preoperativeinvestigations, degree of preoperative neurologic deficit, perioperative electrocorticographic results, and bilateralEEG spikes did not have predictive value in the model.
Childhood Epilepsy and Asthma: Comparison of Quality of Life
Authors: Austin Joan K. , Smith M. Shelton , Risinger Michael W. , McNelis Angela M.
Published: October 2005

Summary: We report results from the first data collection on an ongoing longitudinal study aimed at describing thenatural history of adaptation to childhood epilepsy andasthma in children and their families. We studied 136 children with epilepsy and 134 children with asthma aged 8–12 years. Data were collected from the children, theirmothers, and their school teachers through interviews, school records, and questionnaires. The two sampleswere compared on four domains of quality of life: physical, psychological, social, and school. Data were analyzed by a 2 × 2 between‐subjects multivariate analysis ofcovariance with type of illness (epilepsy or asthma) as theindependent variable and length of time since onset ofillness as a covariate. A significant main effect was notedfor illness [multivariate F (15, 236) = 11.36, p < 0.001].Our major finding was that children with epilepsy had arelatively more compromised quality of life in the psychological, social, and school domains. In contrast, children with asthma had a more compromised quality of lifein the physical domain. Our findings suggest that attention simply to seizure control in the clinical setting willnot address the full range of quality‐of‐life problems ofchildren with epilepsy.
Depressive Symptomatology in a General Hospital Sample of Outpatients with Temporal Lobe Epilepsy: A Controlled Study
Authors: Robertson Mary M. , Channon Shelley , Baker Jane
Published: October 2005

Summary: We compared temporal lobe epilepsy (TLE) outpatients attending a general hospital with depressed psychiatric patients and normal control subjects to investigate depressive symptomatology. Both clinicianrated measures and self‐report questionnaires were used. Rates of depressive and anxious symptomatology in TLE subjects were higher than those in a normal control sample, but TLE subjects did not differ significantly from controls on anxiety measures. The depressed psychiatric group scored higher than the TLE and control groups on both depression and anxiety measures. Rates of depressive symptomatology in the TLE group were lower than those reported in previous studies for persons attending specialist epilepsy clinics, but similar to the findings of one community study.
Ictal Patterns of Cerebral Glucose Utilization in Children with Epilepsy
Authors: Chugani Harry T. , Rintahaka Pertti J. , Shewmon D. Alan
Published: October 2005

Summary: To determine seizure propagation patterns, we analyzed ictal positron emission tomography (PET) studies of regional cerebral glucose utilization in 18 children (11 male and 7 female aged weeks to 16 years) with epilepsy (excluding infantile spasms IS). Three major metabolic patterns were determined based on degree and type of subcortical involvement: Nine children had type I; asymmetric glucose metabolism of striatum and thalamus. Of these, the 7 oldest children showed unilateral cortical hypermetabolism (always including frontal cortex) and crossed cerebellar hypermetabolism. Two infants (aged <1 year) had a similar ictal PET pattern but no cerebellar asymmetry, presumably owing to immaturity of corticopontocerebellar projections. Five children had type II, symmetric metabolic abnormalities of striatum and thalamus; this pattern was accompanied by hippocampal or insular cortex hypermetabolism, diffuse neocortical hypometabolism, and absence of any cerebellar abnormality. Four children had type III, hypermetabolism restricted to cerebral cortex. This classification can accommodate ictal PET and single photon emission computed tomography (SPECT) patterns described by other investigators. Future studies should be directed at the clinical relevance of this classification, particularly with regard to epilepsy surgery.
Pattern Sensitivity and Photosensitivity in Epileptic Children with Visually Induced Seizures
Authors: Brinciotti M. , Matricardi M. , Pelliccia A. , Trasatti G.
Published: October 2005

Summary: We evaluated photosensitivity and pattern sensitivity in 74 epileptic children (38 males, 36 females aged 4 4–19 years; mean age 11.9 years) with reflex seizures induced by environmental visual stimuli and analyzed clinical and EEG characteristics of patients according to type of sensitivity. Standard procedures of visual stimulation were used in all cases. Seven children were excluded because of poor cooperation (3) or no activation (4).Fifty‐one percent of the remaining 67 patients showed sensitivity to both light and pattern, whereas 33% showed photosensitivity and 16% showed pattern sensitivity. Generalized abnormalities were more frequently elicited by intermittent light stimulation than by pattern (73 vs. 36%, p < 0.001). Significant differences in clinical and EEG findings were noted among patients according to their sensitivity to light or/and pattern. In particular, pattern‐sensitivity patients without photosensitivity had a higher occurrence of localization‐related symptomatic epilepsies, neurologic abnormalities, and epileptiform EEG abnormalities, mainly focal, at rest.
Markedly Increased Mesiotemporal Lobe Metabolism in a Case with PLEDs: Further Evidence that PLEDs are a Manifestation of Partial Status Epilepticus
Authors: Handforth Adrian , Cheng Jung Tung , Mandelkern Mark A. , Treiman David M.
Published: October 2005

Summary: The pathophysiologic and clinical significance of periodic lateralized epileptiform discharges (PLEDs) is unclear; whether PLEDs represent an ictal condition that should be treated remains uncertain. We performed FDG‐positron emission computed tomography (FDG‐ET) in a patient with PLEDs at 3 days, 18 days, and 10 weeks after onset. During left temporal PLEds, the initial scan showed intense hypermetabolism of the left mesiotemporal region. The second scan, performed when PLEDs were resolving, displayed reduced hypermetabolism. The follow‐up scan, when PLEDs had resolved, showed left temporal hypometabolism. These findings, together with clinical evidence from the literature, are compatible with the interpretation that PLEDs represent partial status epilepticus (SE); whether vigorous therapy is required to prevent neuronal damage from this focal seizure activity remains uncertain.
Voltage‐Sensitive Calcium Channel Development in Epileptic DBA/2J Mice Suggests Altered Presynaptic Function
Authors: Esplin M. S. , Abbott J. R. , Smart M. L. , Burroughs A. F. , Frandsen T. C. , Litzinger Marcia J.
Published: October 2005

Summary: Aberrant synapse formation has been implicated in development and propagation of epileptic potential. Litzinger et al. (1993a) showed that ω‐GVIA conotoxin may be used as a marker for synapse formation in nonepileptic mice. We conducted ω‐GVIA binding in synaptosomal preparations from epileptic DBA/2J mice at different developmental ages. Binding in DBA/2J mice was compared with ω‐GVIA binding in synaptosomal preparations from nonepileptic C57/B1, Swiss Webster, and AJ mice. Striking differences between these strains of mice are evident in the developmental sequence and pattern of N‐type voltage‐sensitive calcium channels (VSCC). In contrast to nonepileptic mice, the DBA/2J mice show a slow increase in ω‐GVIA binding between postnatal days 2 and 8. This increase corresponds to onset of susceptibility to seizure in this strain. In addition to the difference in developmental sequence, DBA/2J mice have fewer binding sites for ω‐GVIA throughout development, suggesting changes in channel structure or number. These data show that in DBAI2J mice development of the VSCC in brain is different from that in nonepileptic mice. This difference in development in presynaptic membranes responsible for neurotransmitter release may represent a change in synaptic activity that plays a role in epileptogenesis.
Absence Seizures and Carbamazepine in Adults
Authors: Liporace Joyce D. , Sperling Michael R. , Dichter Marc A.
Published: October 2005

Summary: Carbamazepine (CBZ) therapy was associated with development of absence seizures in 4 adults with generalized epilepsy. Two patients had new appearance of absence seizures and 2 patients had recrudesence of remote absence seizures. The seizures abated after discontinuation of CBZ therapy or addition of ethosuximide (ESM) in 1 patient intolerant of valproate (VPA).
Plasma Trace Element, Plasma Glutathione Peroxidase, and Superoxide Dismutase Levels in Epileptic Children Receiving Antiepileptic Drug Therapy
Authors: Kürekçi A. Emin , Alpay Faruk , Tanindi Şakir , Gokçay Erdal , Ozcan Okan , Akin Ridvan , Işimer Aşkin , Sayal Ahmet
Published: October 2005

Summary: Some antiepileptic drugs (AEDs) may altertrace element metabolism and free radical scavenging enzyme activities in humans and experimental animals. We investigated the effect of longterm AED therapy on copper (Cu), zinc (Zn), manganese (Mn), selenium (Se), magnesium (Mg), glutathione peroxidase (GSH‐PX), and superoxide dismutase (SOD) in the plasma in children with epilepsy. During treatment with valproate (VPA) or carbamazepine (CBZ) monotherapy plasma Cu, Zn, Mn, Se, and Mg concentrations of patients were not statistically different from those of control subjects. The level of seoxidation may be causally involved in some forms of epilepsies, and the decreased free radical scavenging enzyme activity is believed to cause the increased risk of anidiosyncratic drug reaction encountered in the manage‐ment of epilepsy. Because GSH‐PX and SOD are themost important members of antioxidant defense mechanisms, we quantitated the activities of these enzymes inplasma of children with epilepsy receiving VPA or CBZ. Only plasma GSH‐PX activities in VPA group werehigher than those of the control group, and the differencewas statistically significant.
Estimating Cardiorespiratory Fitness in Well‐Functioning Older Adults: Treadmill Validation of the Long Distance Corridor Walk
Authors: Simonsick Eleanor M. , Fan Ellen , Fleg Jerome L.
Published: October 2005

Objectives: To determine criterion validity of the 400‐m walk component of the Long Distance Corridor Walk (LDCW) and develop equations for estimating peak oxygen consumption (VO2) from 400‐m time and factors intrinsic to test performance (e.g., heart rate (HR) and systolic blood pressure (SBP) response) in older adults.

Design: Cross‐sectional validation study.

Setting: Gerontology Research Center, National Institute on Aging, Baltimore, Maryland.

Participants: Healthy volunteers (56 men and 46 women) aged 60 to 91 participating in the Baltimore Longitudinal Study of Aging between August 1999 and July 2000.

Measurements: The LDCW, consisting of a 2‐minute walk followed immediately by a 400‐m walk “done as quickly as possible” over a 20‐m course was administered the day after maximal treadmill testing. HR and SBP were measured before testing and at the end of the 400‐m walk. Weight, height, activity level, perceived effort, and stride length were also acquired.

Results: Peak VO2 ranged from 12.2 to 31.1 mL oxygen/kg per minute, and 400‐m time ranged from 2 minutes 52 seconds to 6 minutes 18 seconds. Correlation between 400‐m time and peak VO2 was −0.79. The estimating equation from linear regression included 400‐m time (partial coefficient of determination (R2)=0.625), long versus short stride (partial R2=0.090), ending SBP (partial R2=0.019), and a correction factor for fast 400‐m time (<240 seconds; partial R2=0.020) and explained 75.5% of the variance in peak VO2 (correlation coefficient=0.87).

Conclusion: A 400‐m walk performed as part of the LDCW provides a valid estimate of peak VO2 in older adults. Incorporating low‐cost, safe assessments of fitness in clinical and research settings can identify early evidence of physical decline and individuals who may benefit from therapeutic interventions.
Evidence That Activation Following Failed Defibrillation Is Not Caused by Triggered Activity
Authors: ZHENG XIANGSHENG , WALCOTT GREGORY P. , SMITH WILLIAM M. , IDEKER RAYMOND E.
Published: October 2005

Background: Earliest postshock activation following failed defibrillation shocks slightly lower than the defibrillation threshold (DFT) in large animals appears to arise from a focus. We tested the hypothesis that these foci are caused by early or delayed afterdepolarizations (EADs or DADs) by performing epicardial electrical mapping and giving the EAD inhibitor pinacidil or the DAD inhibitor flunarizine to see if the foci were extinguished or altered in timing or location.

Methods and Results: A sock containing 504 electrodes was placed over the entire ventricular epicardium of 12 open‐chested pigs. After the DFT was determined and additional shocks given, pinacidil was administered to 6 pigs and flunarizine to 6 pigs. Then, the DFT was again determined and additional shocks were given. Pinacidil significantly shortened the effective refractory period (ERP) (162 ± 16 vs 130 ± 28 msec) and action potential duration (APD90) (179 ± 6 vs 149 ± 19 msec) and significantly increased the peak frequency of the power spectrum of a left ventricle (LV) electrode during ventricular fibrillation (VF) (9.3 ± 0.6 vs 10.5 ± 1.0 Hz), while flunarizine did not significantly alter the ERP (162 ± 8 vs 167 ± 18 msec) or APD90 (187 ± 12 vs 191 ± 20) but significantly reduced the peak frequency (9.2 ± 0.5 vs 7.5 ± 1.0 Hz). These findings suggest the drugs had their expected electrophysiological effects. However, the DFT was not significantly changed by either drug. Following the same strength shock 10% below the predrug DFT, earliest postshock activation arose in a focal epicardial pattern from the anterior‐apical LV both before and after the drugs. The time from the shock until the appearance of this activation was not significantly different before and after either drug.

Conclusion: The lack of change in DFT as well as the lack of change in the incidence, location, and timing of the postshock focus with sub‐DFT strength shocks before and after pinacidil and flunarizine provide evidence that these foci are not caused by triggered activity.
Left Mitral Isthmus Ablation Associated with PV Isolation: Long‐Term Results of a Prospective Randomized Study
Authors: FASSINI GAETANO , RIVA STEFANIA , CHIODELLI ROBERTA , TREVISI NICOLA , BERTI MARCO , CARBUCICCHIO CORRADO , MACCABELLI GIUSEPPE , GIRALDI FRANCESCO , BELLA PAOLO DELLA
Published: October 2005

Background: The deployment of an ablation line connecting the left inferior PV to the mitral annulus (mitral isthmus line [MIL]) enhances the efficacy of pulmonary vein disconnection (PVD) in preventing atrial fibrillation (AF) recurrences.

Objectives: To investigate the long‐term effect of the additional linear lesion in a prospective randomized study.

Methods: One hundred and eighty‐seven patients (37 females, mean age: 55 ± 11 years) with paroxysmal (126) or persistent (61 patients) AF, were prospectively randomized into two groups: PVD (group A, 92 patients) or PVD combined with MIL (group B, 95 patients), performed by means of an irrigated‐tip ablation catheter.

Results: Successful disconnection of all PVs was achieved in all patients. A bidirectional block (BB) along the left atrial isthmus was obtained in 72 of 95 (76%) patients in group B, most of whom required additional RF pulses from within the distal CS. A transient ischemic attack occurred in 1 patient of group A, and a cardiac tamponade occurred in 1 patient of group B. At 1 year, 53 ± 5% (group A) and 71 ± 5% (group B) remained arrhythmia free (P = 0.01); subgroup analysis highlights a higher improvement among patients with persistent AF (74 ± 9% vs 36 ± 9%; P < 0.01) than what was observed in paroxysmal AF (76 ± 6% vs 62 ± 6%; P < 0.05); antiarrhythmic drugs were continued in 56% and 50%, respectively, in groups A and B (P = ns).

Conclusions: The addition of mitral isthmus line to the PV disconnection allows a significant improvement of sinus rhythm maintenance rate, particularly in patients with persistent AF, without the risk for major complications.
Response Surface Designs for Experiments in Bioprocessing
Authors: Gilmour Steven G.
Published: October 2005

SummaryMany processes in the biological industries are studied using response surface methodology. The use of biological materials, however, means that run‐to‐run variation is typically much greater than that in many experiments in mechanical or chemical engineering and so the designs used require greater replication. The data analysis which is performed may involve some variable selection, as well as fitting polynomial response surface models. This implies that designs should allow the parameters of the model to be estimated nearly orthogonally. A class of three‐level response surface designs is introduced which allows all except the quadratic parameters to be estimated orthogonally, as well as having a number of other useful properties. Thesesubset designsare obtained by using two‐level factorial designs in subsets of the factors, with the other factors being held at their middle level. This allows their properties to be easily explored. Replacing some of the two‐level designs with fractional replicates broadens the class of useful designs, especially with five or more factors, and sometimes incomplete subsets can be used. It is very simple to include a few two‐ and four‐level factors in these designs by excluding subsets with these factors at the middle level. Subset designs can be easily modified to include factors with five or more levels by allowing a different pair of levels to be used in different subsets.
Hierarchical Bayesian Methods for Estimation of Parameters in a Longitudinal HIV Dynamic System
Authors: Huang Yangxin , Liu Dacheng , Wu Hulin
Published: October 2005

SummaryHIV dynamics studies have significantly contributed to the understanding of HIV infection and antiviral treatment strategies. But most studies are limited to short‐term viral dynamics due to the difficulty of establishing a relationship of antiviral response with multiple treatment factors such as drug exposure and drug susceptibility during long‐term treatment. In this article, a mechanism‐based dynamic model is proposed for characterizing long‐term viral dynamics with antiretroviral therapy, described by a set of nonlinear differential equations without closed‐form solutions. In this model we directly incorporate drug concentration, adherence, and drug susceptibility into a function of treatment efficacy, defined as an inhibition rate of virus replication. We investigate a Bayesian approach under the framework of hierarchical Bayesian (mixed‐effects) models for estimating unknown dynamic parameters. In particular, interest focuses on estimating individual dynamic parameters. The proposed methods not only help to alleviate the difficulty in parameter identifiability, but also flexibly deal with sparse and unbalanced longitudinal data from individual subjects. For illustration purposes, we present one simulation example to implement the proposed approach and apply the methodology to a data set from an AIDS clinical trial. The basic concept of the longitudinal HIV dynamic systems and the proposed methodologies are generally applicable to any other biomedical dynamic systems.
Noninvasive Risk Stratification of Subjects with a Brugada‐Type Electrocardiogram and No History of Cardiac Arrest
Authors: Ikeda Takanori , Takami Mitsuaki , Sugi Kaoru , Mizusawa Yuka , Sakurada Harumizu , Yoshino Hideaki
Published: October 2005

Background: Recent studies suggest that the Brugada‐type electrocardiogram (ECG) is much more prevalent than the manifest Brugada syndrome. Although invasive electrophysiologic investigations have been proposed as a risk stratifier, their value is controversial, and alternative noninvasive techniques may be preferred. We sought a noninvasive strategy to detect a high‐risk group in a long‐term follow‐up study of subjects with a Brugada‐type ECG, and no history of cardiac arrest.

Methods: This study enrolled 124 consecutive subjects with a Brugada‐type ECG. Prognostic indices included: age, sex, a family history of sudden death, syncopal episodes, a spontaneous coved‐type ST‐segment elevation, maximal magnitude of ST‐segment elevation, a spontaneous change in ST segment, a mean QRS duration, maximal QT interval, QT dispersion, late potentials (LP) by signal‐averaged ECG, and microvolt T‐wave alternans.

Results: Of the 124 subjects, 20 consenting subjects had an implantable defibrillator before follow‐up. During a 40 ± 19‐month follow‐up, 12 subjects (9.7%) reached one of the endpoints (sudden death or ventricular tachyarrhythmia). Of the 12 risk indices, a family history of sudden death, syncopal episodes, a spontaneous coved‐type ST‐segment elevation, a spontaneous change in ST segment, and LP had significant values. In multivariate analysis, a spontaneous change in ST segment had the most significance (a relative hazard, 9.2; P = 0.036). Combined assessment of this index and other significant indices obtained higher positive predictive values (43–71%).

Conclusions: A spontaneous change in ST segment is associated with the highest risk for subsequent events in subjects with a Brugada‐type ECG. The presence of syncopal episodes, a history of familial sudden death, and/or LP may increase its value.
Effects of Mobile Telephones on the Function of Implantable Cardioverter Defibrillators
Authors: Tandogan Izzet , Ozin Bulent , Bozbas Huseyin , Turhan Sibel , Ozdemir Ramazan , Yetkin Ertan , Topal Ergun
Published: October 2005

Objective: We investigated whether mobile telephones affect the function of implantable cardioverter defibrillators (ICDs).

Background: It is well known that electromagnetic fields can affect medical devices.

Methods: The study included 43 patients with ventricular tachycardia and/or fibrillation treated with transvenous pectoral ICDs. Testing was done under continuous electrocardiograph monitoring under supervision of an ICD programmer. Initially, each patient was tested during spontaneous rhythm. Then the ICD was programmed to a pace rhythm higher than the patient's heart rate, and the tests were repeated at paced rhythm. In 7 patients, tests were performed during the implantation procedure as well. In 3 of the patients, only a single defibrillation zone was active. The other 40 patients had one or more active ventricular tachycardia zones. Two mobile phones (both GSM 900 MHz) were positioned 50 cm away from the implanted device in opposite directions and switched on. Communication was established between these phones, two investigators had a 20‐second conversation, and then the phones were switched off. The same procedure was repeated at 30, 20, and 10 cm away from the implantation site, respectively. Finally, the procedure was performed with the antennae of both phones touching the device pocket. In the above‐mentioned 7 cases where testing was done during implantation of the ICD, a call was made from one phone to the other, ringing occurred for 5 seconds, and then two investigators conversed while the device was implanted.

Results: There was no change in the function of the ICDs during any of the phone testing procedures. In 5 cases, artifacts were noted on the surface electrocardiographic (ECG) screen of the programmer during the tests, but no such changes were observed on the simultaneous intracardiac ECGs.

Conclusion: The results of the study suggest that mobile phones have no effects on ICD function.
Differences in Outcomes Between Patients Treated with Single‐ versus Dual‐Chamber Implantable Cardioverter Defibrillators: A Substudy of the Multicenter Automatic Defibrillator Implantation Trial II
Authors: Berenbom Loren D. , Weiford Brian C. , Vacek James L. , Emert Martin P. , Hall W. Jackson , Andrews Mark L. , McNitt Scott , Zareba Wojciech , Moss Arthur J. ,   for the MADIT‐II Investigators
Published: October 2005

Objectives:We sought to evaluate the influence of single‐ versus dual‐chamber implantable cardioverter defibrillators (ICDs) on the occurrence of heart failure and mortality as well as appropriate and inappropriate ICD therapy in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT‐II).

Background:In MADIT‐II, ICD therapy in patients with a prior myocardial infarction and ejection fraction ≤0.30 was associated with a 31% reduction in risk of mortality when compared to conventionally treated patients. An unexpected finding was an increased occurrence of hospitalization for heart failure in the ICD group.

Methods:Data from 717 patients randomized to ICD therapy with single‐ or dual‐chamber pacing devices in MADIT‐II were retrospectively analyzed. Endpoints selected for analysis included death from any cause, new or worsening heart failure requiring hospitalization, death or heart failure, appropriate therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), and inappropriate ICD therapy for atrial fibrillation or supraventricular tachycardia.

Results:A total of 404 single‐chamber ICDs (S‐ICDs) and 313 dual‐chamber ICDs (D‐ICDs) were implanted. Patients receiving D‐ICDs were at a higher risk at baseline than those receiving S‐ICDs, with older age, higher NYHA class, more frequent prior CABG, wider QRS complex, more LBBB, higher BUN level, a history of more atrial arrhythmias requiring treatment, and a longer time interval from their index myocardial infarction to enrollment. While there was a trend toward an increase in adverse outcomes in the D‐ICD group, no statistically significant differences in heart failure or mortality were observed between S‐ICD versus D‐ICD groups.

Conclusions:Patients with D‐ICDs had a nonsignificant trend toward higher mortality and heart failure rates than patients with S‐ICDs.
Vagal Afferent Stimulation as a Cardioprotective Strategy? Introducing the Concept
Authors: Fallen Ernest L.
Published: October 2005

The effect of vagal afferent signaling on cardioinhibition has been well known for over 130 years. Both experimental and clinical studies have demonstrated not only the potential adverse effect of unrestrained sympathoexcitation in high risk patients with ischemic heart disease but the potential for cardioprotection by programmed vagal activity. The vasodepressor and negative chronotropic effects of efferent vagal stimulation has been a cause for concern. However it is becoming clear that favorable shifts towards increased cardiac vagal modulation can be achieved by vagal afferent nerve stimulation. This phasic effect appears to operate though central medullary pathways. Thus by engaging vagal afferent fibers in humans there is the possibility that one can exploit the benefits of central cardioinhibition without adversely affecting heart rate, respiration or hemodynamics. This commentary explores the background and rationale for considering vagal afferent stimulation as a plausible cardioprotective strategy.
Our Search for the Porcine Mother Rotor
Authors: Ideker Raymond E. , Huang Jian
Published: October 2005

A single stationary mother rotor, located in the fastest activating region and giving rise to activation fronts that propagate throughout the remainder of the myocardium, has been hypothesized to be responsible for the maintenance of ventricular fibrillation (VF). Others have reported a mother rotor in guinea pigs and rabbits. We wanted to see if a mother rotor exists in a larger heart, that is, pigs. Epicardial mapping studies have demonstrated that VF wavefronts in pigs tend to propagate from the posterior basal LV to the anterior LV and on to the anterior RV, raising the possibility of a mother rotor in the posterior LV. However, no sustained reentry consistent with a mother rotor was found on the posterior LV epicardium, even though an intramural mapping study showed that the fastest activating transmural layer was near the epicardium. Many wavefronts in the posterior LV entered the mapped region from the posterior boundary of the mapping array, adjacent to the posterior descending coronary artery, raising the possibility that a mother rotor is located in the right ventricle or septum. Since a previous study has shown that the RV activates more slowly than the LV during VF, the more likely site for a mother rotor was the septum. However, we then performed a study in which we recorded from the right side of the septum and found that reentry was uncommon there also and that the activation rate was slower than the posterobasal LV. Many of the VF wavefronts in the septum passed from the posterior septum toward the anterior septum. This fact coupled with the fact that many wavefronts passed from the posterior LV free wall toward the anterior LV free wall point to the region where the posterior free wall intersects with the septum, the region where the posterior papillary muscle is located, as the possible site of a mother rotor. Indeed, a recent abstract by others reports that, after propranolol, a stable reentrant circuit is present on the endocardium at the insertion of the posterior papillary muscle into the LV free wall in pigs.
Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT‐CRT): Design and Clinical Protocol
Authors: Moss Arthur J. , Brown Mary W. , Cannom David S. , Daubert James P. , Estes Mark , Foster Elyse , Greenberg Henry M. , Hall W. Jackson , Higgins Steven L. , Klein Helmut , Pfeffer Mark , Wilber David , Zareba Wojciech
Published: October 2005

The planned MADIT‐CRT trial is designed to determine if CRT‐D will reduce the risk of mortality and HF events by approximately 25% in subjects with ischemic (NYHA class I‐II) and non‐ischemic (NYHA class II) cardiomyopathy, left ventricular dysfunction (EF ≤ 0.30), and prolonged intraventricular conduction (QRS duration ≥ 130 ms).
Safety and Efficacy of Flecainide in Subjects with Long QT‐3 Syndrome (ΔKPQ Mutation): A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial
Authors: Moss Arthur J. , Windle John R. , Hall W. Jackson , Zareba Wojciech , Robinson Jennifer L , McNitt Scott , Severski Patricia , Rosero Spencer , Daubert James P. , Qi Ming , Cieciorka Michael , Manalan Allan S.
Published: October 2005

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT‐3 patients with the ΔKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the ΔKPQ deletion.

Methods:A randomized, double‐blind, placebo‐controlled clinical trial was conducted with flecainide and placebo in six male LQT‐3 subjects with the ΔKPQ deletion.

Results:The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open‐label, dose‐ranging investigation using one‐fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6‐month alternating periods of flecainide and placebo therapy based on the open‐label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of −27.1 ms (95% confidence interval: −36.8 ms to −17.4 ms; P < 0.001) at a mean flecainide blood level of 0.11 ±0.05 μg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects.

Conclusions:Chronic low‐dose flecainide significantly shortens the QTc interval in LQT‐3 subjects with the ΔKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation.
Molecular analysis of PDGFRα/β genes in core binding factor leukemia with eosinophilia
Authors: Monma Fumihiko , Nishii Kazuhiro , Lorenzo Felipe , Usui Eiji , Ueda Yuichiro , Watanabe Yasuyuki , Kawakami Keiki , Oka Koji , Mitani Hidetsugu , Sekine Takao , Tamaki Shigehisa , Mizutani Minoru , Yagasaki Fumiharu , Doki Noriko , Miyawaki Syuichi , Katayama Naoyuki , Shiku Hiroshi
Published: October 2005

Abstract:  Eosinophilia sometimes occurs in acute myeloid leukemia (AML), especially in core binding factor (CBF) leukemia. However, the pathogenesis of the differentiation from leukemic progenitors to eosinophils is not well understood in this type of leukemia. Recent reports showed that a novel fusion tyrosine kinase, Fip1‐like1 (FIP1L1) platelet‐derived growth factor receptor alpha (PDGFRα), is found in idiopathic hypereosinophilic syndrome. The involvement of another chimeric gene, PDGFRβ, was also reported in myeloproliferative disorder with eosinophilia. These chimeric genes cause constitutive activation of PDGFR tyrosine kinases. On the other hand, a two‐hit model for the pathogenesis of AML, which seems to be caused by inactivating mutations in transcription factors and genetic lesions in tyrosine kinase resulting in constitutive activation, has been proposed. On the basis of these findings, we screened for the expression of the FIP1L1‐PDGFRα fusion gene and for mutations in the juxtamembrane and tyrosine kinase domains of PDGFRα/β genes in 22 cases of CBF leukemia with eosinophilia. Among these cases, no FIP1L1‐PDGFRα fusion gene was found. Although cDNA sequencing also detected three types of single‐nucleotide alterations at kinase domains in PDGFRα/β genes, all of them were silent changes and polymorphisms. Therefore, PDGFRα/β genes do not appear to play a significant pathogenetic role in eosinophilia or leukemogenesis of CBF leukemia.