Multigenerational hybridisation and its consequences for maternal effects in Atlantic salmon.

Outbreeding between segregating populations can be important from an evolutionary, conservation and economical-agricultural perspective. Whether and how outbreeding influences maternal effects in wild populations has rarely been studied, despite both the prominent maternal influence on early offspring survival and the known presence of fitness effects resulting from outbreeding in many taxa. We studied several traits during the yolk-feeding stage in multigenerational crosses between a wild and a domesticated Atlantic salmon (Salmo salar) population up to their third-generation hybrid in a common laboratory environment. Using cross-means analysis, we inferred that maternal additive outbreeding effects underlie most offspring traits but that yolk mass also underlies maternal dominant effects. As a consequence of the interplay between additive and dominant maternally controlled traits, offspring from first-generation hybrid mothers expressed an excessive proportion of residual yolk mass, relative to total mass, at the time of first feeding. Their residual yolk mass was 23-97% greater than those of other crosses and 31% more than that predicted by a purely additive model. Offspring additive, epistatic and epistatic offspring-by-maternal outbreeding effects appeared to further modify this largely maternally controlled cross-means pattern, resulting in an increase in offspring size with the percentage of domesticated alleles. Fitness implications remain elusive because of unknown phenotype-by-environment interactions. However, these results suggest how mechanistically co-adapted genetic maternal control on early offspring development can be disrupted by the effects of combining alleles from divergent populations. Complex outbreeding effects at both the maternal and offspring levels make the prediction of hybrid phenotypes difficult.

Bufotenine: toward an understanding of possible psychoactive mechanisms.

A review of the neuropharmacology of the alleged hallucinogen bufotenine is presented, including recent experimental results showing activity similar to LSD and other known hallucinogens (psilocin and 5-MeO-DMT) at the purported hallucinogenic serotonin (5-HT) receptors, 5-HT2A and 5-HT2C. In addition, current reports of computer modeling of the receptors and ligand binding sites give evidence of bufotenine's ability to bind and activate these receptors. While binding and activation of the purported hallucinogenic receptors are not the full extent of the hallucinogenic signature, this evidence shows support for the rationale that the reported lack of the drug's classic hallucinogenic response in human experiments is due to poor ability to cross the blood brain barrier (BBB), not lack of activation of the appropriate brain receptors. Further evidence is reviewed that in some physiological states, some drugs with characteristics similar to bufotenine which do not normally cross the BBB, cross it and enter the brain. While direct human experimental evidence of bufotenine's hallucinogenic activity seems lacking, the above combined factors are considered, and possible explanations of bufotenine's reported psychoactivity are suggested. Additionally, updated experimental models testing the possible nature of bufotenine's hallucinogenic potential are proposed.

Electrographic seizures in neonates correlate with poor neurodevelopmental outcome.

OBJECTIVE: To quantify the number, duration, and intensity of electrographic seizures (ESz) in neonates and to compare the outcome of neonates with ESz with those who were at risk but did not have ESz recorded. METHODS: The EEG and outcome data were reviewed from 68 infants who met at-risk criteria for neonatal seizures and underwent prolonged continuous EEG monitoring. Forty infants had ESz. The control group contained 28 infants monitored for at least 18 hours and found not to have ESz. Outcomes for both groups were evaluated using hospital and follow-up clinic records and a standardized telephone interview. RESULTS: The etiology of ESz included asphyxia (n = 23), stroke (n = 7), and other (n = 10, intraparenchymal, subdural, and subarachnoid bleeding; meningitis; sepsis; hyponatremia; and unknown). The cumulative recorded ESz duration was 8 minutes to 30 hours. Forty-three percent of infants with ESz spent 38 minutes to 32 hours in electrographic status. Despite doses of 40 mg/kg of phenobarbital and 20 mg/kg of phenytoin, 30% of infants continued to have ESz. Ten infants with ESz and one without died from causes related to neurologic instability. The occurrence of ESz was correlated with microcephaly (p = 0.04), severe cerebral palsy (CP) (p = 0.03), and failure to thrive (p = 0. 03). In the subgroup of infants with asphyxia, those with ESz were more likely to die of neurologic causes (p = 0.02) and have microcephaly (p = 0.05) or severe CP (p = 0.04). Additionally, those with the greatest number of ESz were more likely to have these severe outcomes. CONCLUSION: The authors' data indicate an association between the amount of electrographic seizure activity and subsequent mortality and morbidity in at-risk infants in general and in infants with perinatal asphyxia. Only with more effective treatment of neonatal electrographic seizures can their potential contribution to poor neurodevelopmental outcome, independent of degree of insult, be ascertained.

EEG background as predictor of electrographic seizures in high-risk neonates.

PURPOSE: Experience with continuous EEG monitoring in 29 consecutive infants at risk of neonatal seizures demonstrated that background abnormalities on the initial EEG were strongly associated with electrographic seizures in the subsequent 18-24 h. To test this association prospectively, we examined the relationship between EEG background and the presence of electrographic seizures in the next 22 at-risk infants monitored for seizures. METHODS: A standard EEG was recorded for each infant at risk for seizures. Based on specific criteria, the background was graded as normal; immature for age; or mildly, moderately, or severely abnormal. The EEG was then monitored continuously until no electrographic seizures were recorded for 18-24 h. RESULTS: Findings in the retrospective group of 29 infants and the prospective group of 22 infants did not differ. For the combined 51 infants, a normal or immature initial EEG background predicted the absence of seizures in the subsequent 18-24 h with a sensitivity of 96% [confidence interval (CI) 0.88, 1.0] and specificity of 81% (CI 0.67, 0.96). Administration of antiepileptic drugs (AEDs) before the start of the EEG recording did not affect this association. CONCLUSIONS: In 51 consecutively monitored infants at risk for neonatal seizures, a normal or immature EEG background strongly predicted the absence of electrographic seizures in the subsequent 18-24 h; background abnormalities strongly predicted the occurrence of electrographic seizures concomitantly or in the subsequent 18-24 h of recording. Screening infants at risk for neonatal seizures with a routine EEG allows identification of infants at highest risk for seizures, thus conserving resources required for continuous EEG monitoring and facilitating early intervention for seizures.

Failure of standard magnetic resonance imaging in patients with refractory temporal lobe epilepsy.

OBJECTIVE: To compare the sensitivity of standard magnetic resonance imaging (MRI) scans done outside an epilepsy center with that of special protocol MRI scans done at an epilepsy center in delineating relevant lesions of the temporal lobe. SUBJECTS: Eighty-four consecutive patients who had temporal lobe resections for refractory temporal lobe epilepsy between January 1, 1993, and February 1, 1996. DESIGN: The reports of findings on standard MRI scans done outside an epilepsy center were compared with the findings of special protocol MRI scans done with 1.5-mm T1-weighted coronal and 3-mm T2-weighted coronal images (no gaps) on a 1.5-T system. Both sets of MRI findings were compared with findings on histologic examination of the resected tissue. RESULTS: Of the 84 patients, 51 had standard MRI scans done outside an epilepsy center; of these, there were 34 patients with normal results, 10 with tumors, 2 with vascular malformations, 2 with hippocampal atrophy, 2 with unclassified abnormalities, and 1 with cortical malformation. In 32 of the 34 patients with normal results of an MRI scan done outside an epilepsy center, abnormalities were found on our special protocol MRI scans. These included hippocampal atrophy in 27 patients, tumors in 2, and cortical malformations in 1. Additionally, all 17 of the abnormalities detected on the standard MRI scans done outside the epilepsy center were identified on our special protocol MRI scans. Important pathologic abnormalities of the temporal lobe were identified in 16 (35%) of the 46 patients with standard MRI scans done outside an epilepsy center and in 44 (96%) with our special protocol MRI scans. In the 29 patients for whom adequate surgical specimens were available and results of standard MRI scans were normal, our special protocol MRI scans showed the abnormality in 27 (93%). CONCLUSIONS: Conventional neuroimaging studies are inadequate for diagnosing hippocampal sclerosis although they fairly readily detect low-grade tumors and vascular malformations. Magnetic resonance imaging scans for the evaluation of patients with refractory temporal lobe epilepsy should be done with a special temporal lobe protocol and read by physicians experienced with the findings in hippocampal sclerosis. Health care dollars are wasted on neuroimaging done for refractory temporal lobe epilepsy outside epilepsy centers.

Electrocorticography and stimulation.

Although acute electrocorticography (ECoG) is routinely used during epilepsy surgery there is little agreement as to its value nor criteria for its interpretation. Specific issues are reviewed on the basis of the literature and personal studies: does failure to resect the entire irritative zone prejudice seizure control, and are residual discharges predictive of failure; does activation of the ECoG by intravenous barbiturates provide information of clinical value; does intraoperative electrical stimulation help to improve localisation or avoid postoperative deficits; is the ECoG of value for monitoring functional procedures; can the value of ECoG be increased by new interpretive approaches? It is suggested that resection of the entire area of interictal discharge is not essential for satisfactory surgical outcome, but a distinction may need to be made between those discharging regions that function as pacemakers and those in which ECoG spikes appear secondarily. There is also evidence that, apart from any consideration of determining the area resected, the topography of epileptiform discharge may be predictive of pathology and surgical outcome. It is concluded that more detailed topographic and quantitative analysis of the ECoG is required before its value in planning surgery can be determined or objective interpretive criteria established.

Predictive value of intraoperative electrocorticograms in resective epilepsy surgery.

The preresection and postresection intraoperative electrocorticograms of 76 consecutive patients undergoing resective surgery for intractable epilepsy were analyzed to see if location, configuration, and discharge rate of epileptiform activity correlated with type and location of pathology of the resected specimens and outcome in regard to seizure control. The location of the predominant spike focus did not correlate with either type of location of pathology or with seizure outcome from temporal lobe surgery (n = 58). The presence of spontaneous or activated spikes outside the resected area did not correlate with outcome from any surgery type. Positive spikes recorded from the amygdala and anterior hippocampus (n = 37) were not associated with type or location of pathology, but bursts of fast repetitive spikes on these needle recordings tended to associate with mesiotemporal pathology (p = less than 0.02) and with mesial temporal sclerosis (p = less than 0.04). A preresection spike discharge rate of 1 per 4 minutes or less was associated with a poor outcome in 5 of 6 patients (p = 0.03), whereas a rate of 18 or more per minute was associated with a good outcome in 15 of 18 patients (p less than 0.06). Persistence of 50% or more of the preresection epileptiform activity in the postresection electrocorticogram after temporal lobectomy correlated with poor outcome in 80% (p = less than 0.03), although the absolute amount of epileptiform activity remaining in the postresection electrocorticogram did not correlate with outcome. Further studies are needed to define the role of intraoperative electrocorticograms in resective epilepsy surgery.

Effects of methylphenidate on processing negativities in patients with attention-deficit hyperactivity disorder.

This study compared the impact of methylphenidate on patients with Attention-deficit Hyperactivity Disorder (ADHD) with and without aggressive/noncompliant features in an oddball test consisting of a randomly ordered series of loud (frequent) tones, soft (rare) tones, bright (frequent) lights, and dim (rare) lights. In alternate conditions, subjects were required to respond to either the rare tones or the rare lights. These tasks were administered in a drug-free baseline session and after a counterbalanced treatment of 14 days each of methylphenidate (0.3 mg/Kg b.i.d.) and placebo (lactose b.i.d.). In comparison with placebo, methylphenidate resulted in greater accuracy and speed of reactions to targets of both modalities. The amplitude of N1 to auditory nontargets was larger when the target was a rare tone as opposed to a rare light, and this attention-related effect was increased by methylphenidate. The same differential amplitude enhancement by stimulant treatment was found for an early area measure of difference ERPs. In contrast, for N1 to visual nontargets the effect of selective attention (larger amplitude when the target was a rare light vs. a rare tone) was not significant and was not affected by stimulant medication. All these findings were comparable for the three ADHD subgroups, a result attesting to the generality of stimulant effects on information processing.

Lorazepam versus diazepam for the treatment of status epilepticus.

A retrospective study was performed to compare intravenous lorazepam and intravenous diazepam in the treatment of status epilepticus. Forty-five episodes of status epilepticus in children between the ages of 2 weeks and 18 years were reviewed. Lorazepam and diazepam proved similar in efficacy of seizure control and incidence of adverse effects. The dose of lorazepam required to control status epilepticus ranged from 0.03 to 0.22 mg/kg with a mean of 0.11 mg/kg (S.D. = 0.05 mg/kg). Among children treated with lorazepam, only children younger than 2 years of age had respiratory depression which required intubation.

An individual double-blind crossover trial for assessing methylphenidate response in children with attention deficit disorder.

To obtain more objective data on response to therapy and to overcome parents', teachers', psychologists', and physicians' concerns about potential overuse, I instituted individual double-blind crossover trials of methylphenidate for children with attention deficit disorder (ADD). Each child is given 0.3 mg/kg/dose twice daily for 2 weeks and placebo for 2 weeks in random order and in double-blind fashion. Parents and teachers record observations of behavior and academic performance. Analysis of 70 trials and follow-up clinical data demonstrated that (1) 51 children showed improvement in one of the 2-week periods and that period corresponded with methylphenidate therapy in 48 (69%); (2) 6 of the 22 who did not respond to methylphenidate experienced worsening of function while taking the drug; (3) history and physical findings were not helpful in predicting methylphenidate response; (4) there were no serious side effects during the trial; and (5) all but three of the responders took methylphenidate for at least 1 year with sustained improvement in behavioral function, academic function, or both. Individual double-blind crossover trials can be used in an office setting to identify objectively which children with ADD respond to treatment with methylphenidate. Because the trial demonstrates to parents, teachers, psychologists, and physicians that methylphenidate is or is not beneficial to a particular child, this clinical tool is associated with a high level of confidence that the drug is being appropriately prescribed.

Tourette's syndrome in Monroe County school children.

We examined children from Monroe County, New York, to establish the prevalence of Gilles de la Tourette's syndrome (TS) in the county's schools. Patients were recruited for free evaluations from physicians, other health professionals, school personnel, and through extensive coverage in the local news media. Forty-one TS patients were detected among the 142,636 pupils enrolled in the county's public and private schools at the time of the study (estimated prevalence, 28.7 per 100,000). Twenty patients had obsessive-compulsive symptoms, but only three had an impairing, diagnosable disorder. Fifty-six percent had a positive family history for TS or tics. Eighteen needed pharmacotherapy, although, for most, TS was a mild disorder requiring no drug treatment.

Sucking disorders in neurologically impaired infants: assessment and facilitation of breastfeeding.

Neurologically impaired infants have immature, damaged, or abnormally developed nervous systems that may cause abnormalities of sucking and swallowing, among other problems. Sucking abnormalities usually present as absence of the sucking response, weakness or incoordination of sucking and swallowing, or some combination of these problems. More investigation of the responses of these infants to various stimuli and training techniques is greatly needed. Although training neurologically impaired infants to breastfeed may present a challenge to even the most experienced neonatal nurse, physician, or therapist, most infants improve and can learn to suckle at the breast. If a mother has intended to nurse her infant, she should be encouraged to do so, even when the infant has abnormalities of sucking, except in the rare and most severely affected infants who remain dependent on gavage or gastrostomy feedings. Various techniques of stimulating, positioning, and progressive weaning to the breast can be helpful in teaching mother and infant to breastfeed. Encouraging support should be provided by all professionals involved with the mother and infant, as well as by a team experienced in helping with such problems. Most importantly, mother and staff must be patient, because the rewards for both the infant and mother are worth the effort.

Long-term behavioral effects of phenobarbital in suckling rats.

Long-term effects of phenobarbital on behavior and learning, persisting after drug withdrawal, have not been defined. To look for such effects on the developing nervous system, we treated albino rat pups with phenobarbital for 30 days and then tested them at intervals starting 10 days after the cessation of drug therapy. Beginning at age 6 days, 12 pups were given Ph subcutaneously, gradually increasing the dose to 30 mg/kg/dose b.i.d. by 11 days and continued until 36 days. Twelve control pups were injected with saline. Serum phenobarbital concentrations at 16 days were 54 to 32 micrograms/ml and at 31 days 36 to 4 micrograms/ml. From 46 to 55 days, all animals were tested in a water T maze. The experimental animals completed the four daily runs faster than controls (P = 0.003), made fewer errors (P = 0.003), and spent less time on error-free runs (P = 0.04). When the same animals were retested in the maze at 129 to 136 days, the trend toward faster times was not significant. There were no differences in brain weights of experimental and control rats at 157 days. Twelve pups treated similarly with phenobarbital at 20 mg/kg/dose b.i.d. spent less time on error-free runs than 12 controls when tested at 48 to 57 days of age (P = 0.05) but no differences were found when 12 similarly treated pups were tested at 79 to 85 days. There were no differences in brain weights of the treated and control rats at 78 days of age. Thus it was shown that phenobarbital administration in suckling rats had an effect on behavior that was present 10 to 20 days after the drug was cleared from their serum.

Absence of behavioral effects of intrauterine phenobarbital exposure in rats.

Phenobarbital (Ph) exposure in experimental animals has been associated with impaired brain growth and maturation. In order to look for behavioral correlates of these structural changes, rat pups were tested after intrauterine exposure to Ph. Five Sprague-Dawley rat dams were fed powdered chow containing Ph (0.75 mg/g of chow) from day 8 through the remainder of pregnancy, resulting in serum Ph levels of 19 to 36 micrograms/ml. Control (C) dams were fed plain chow. All pups were cross-fostered to control dams at birth. During their first 3 weeks of age, the acquisition of signs of physical maturation and neurologic development (such as incisor eruption, free-fall righting, rope climbing and descending, etc.) and the development of exploratory behavior in an open chamber were assessed. On days 39 to 48, 24 pups were tested in a water-T maze. Litter size and pup size were smaller in Ph-exposed dams than in controls, but acquisition of all signs of development except eye opening, activity in the exploratory chamber, and time and error scores on water-T maze testing did not differ between the two groups. The reasons that behavioral effects were not found in this study compared with previous studies may include the young age of the animals tested, the differences among behavioral parameters examined, the fact that controls were matched by weight with the experimental animals in this study, and different susceptibility to teratogenic effects among different species.

Pathogenesis of four-layered microgyric cortex in man.

Microgyria (polygria, polymicrogyria) has stimulated continued interest since its first description by Meschede [28]. Based on analysis of case material, available staining techniques, and known principles of human cortical development, subsequent investigators have proposed numerous theories to explain its pathogenesis. We have studied a case which cannot be fully explained by these previously proposed theories. In this case, four-layered microgyria is present bilaterally in middle cerebral artery distribution, but in one hemisphere, in the center of the malformed area, the deep acellular and cellular layers are replaced by radially aligned neurons extending ectopically into prospective white matter. Analysis of the findings in this case provide evidence that the recently described pathogenetic mechanism observed in a rat model of this malformation [15,16] is applicable to its formation in man.

Complex partial status epilepticus in young children.

Complex partial status epilepticus (CPSE) has rarely been described in children. We have recently studied four girls, aged 1 to 4 years, who presented with CPSE. Their seizures were characterized by decreased level of consciousness, lack of response to familiar persons, diminished response to pain, starting, slow visual tracking, eye deviation, picking at nearby objects, and lip smacking. Three patients developed focal clonic activity during their seizures and one progressed to a generalized motor seizure after 4 hours of CPSE. Two patients had ictal electroencephalograms demonstrating temporooccipital polyspikes and slow waves.